Pediatric Surgery: 2-Volume Set (Grosfeld, Pediatric Surgery) 6th ed

Molecular Clinical Genetics and Gene Therapy Alan W. Flake

The topics of this chapter are broad in scope and outside the realm of a classic core education in pediatric surgery. However, both molecular genetics and gene therapy will be of increasing clinical importance in all medical specialties, including pediatric surgery, in the near future. A few conservative predictions include improvements in the diagnostic accuracy and prediction of phenotype, the development of new therapeutic options for many disorders, and the optimization of pharmacotherapy based on patient genotype, but there are many other possible uses. The goal here is to provide an overview of recent developments that are relevant or potentially relevant to pediatric surgery.

MOLECULAR CLINICAL GENETICS Although hereditary disease has been recognized for centuries, only relatively recently has heredity become the prevailing explanation for numerous human diseases. Before the 1970s, physicians considered genetic diseases to be relatively rare and irrelevant to clinical care. With the advent of rapid advances in molecular genetics, we currently recognize that genes are critical factors in virtually all human diseases. Although an incomplete indicator, McKusick's Mendelian Inheritance in Man has grown from about 1500 entries in 1965 to 10,000 in 2000, documenting the acceleration of knowledge in human genetics. 44 Even disorders that were once considered to be purely acquired, such as infectious diseases, are now recognized to be influenced by genetic mechanisms of inherent vulnerability and genetically driven immune system responses. Despite this phenomenal increase in genetic information and the associated insight into human disease, there remains a wide gap between the identification of genotypic abnormalities that are linked to phenotypic manifestations in humans and any practical application to patient treatment. With the notable exceptions of genetic counseling and prenatal diagnosis, molecular genetics presently has little impact on the daily practice

of medicine or, more specifically, on the practice of pediatric surgery. The promise of molecular genetics cannot be denied, however. IdentifYing the fundamental basis of human disorders and of individual responses to environmental, pharmacologic, and disease-induced perturbations is the first step toward understanding the downstream pathways that may have a profound impact on clinical therapy. The ultimate application of genetics would be the correction of germline defects for affected individuals and their progeny. Although germline correction remains a future fantasy fraught with ethical controversy,56 there is no question that molecular genetics will begin to impact clinical practice in myriad ways within the next decade. A comprehensive discussion of the field of molecular genetics is beyond the scope of this chapter, and there are many sources of information on the clinical genetics of pediatric surgical disorders.

Human Molecular Genetics and Pediatric Surgical Disease The rapid identification of genes associated with human disease has revolutionized the field of medical genetics, providing more accurate diagnostic, prognostic, and potentially therapeutic tools. However, increased knowledge is always associated with increased complexity. Whereas the classic model assumed that the spread of certain traits in families is associated with the transmission of a single molecular defect-with individual alleles segregating into families according to Mendel's lawstoday's model recognizes that very few phenotypes can be satisfactorily explained by a mutation at a single gene locus. The phenotypic diversity recognized in disorders that were once considered monogenic has led to a reconceptualization of genetic disease. Although mendelian models are useful for identifying the primary cause of familial disorders, they appear to be incomplete as models of the true physiologic and cellular nature of defects. 15 .66 ,71 Numerous disorders that were initially

Ability to predict phenotype from genotype • Higher •

Multifactorial

<

.

~

Polygenic

Lower

m ::l

::l

3

CD ::l

[ Oligogenic

a

cCD

::l

"oCD ::l

"C

:::r

CD ::l

~

"C

Number of genetic loci influencing phenotype

CD

WlIIii#§1 Conceptual continuum of modern molecular genetics. The genetic characterization of a disorder depends on (1) whether a major locus makes a dominant contribution to the phenotype, (2) the number of loci that influence the phenotype, and (3) the presence and extent of environmental influence on phenotype. The farther toward the right a disorder lies, the greater the complexity of the genetic analysis and the less predictive genotype is of phenotype.

characterized as monogenic are proving to be either caused or modulated by the action of a small number of loci. These disorders are described as oligogenic disorders, an evolving concept that encompasses a large spectrum of phenotypes that are neither monogenic nor polygenic. In contrast to polygenic or complex traits-which are thought to result from poorly understood interactions between many genes and the environment-oligogenic disorders are primarily genetic in etiology but require the synergistic action of mutant alleles at a small number of loci. One can look at modern molecular genetics as a conceptual continuum between classic mendelian and complex traits (Fig. 2-1). The position of any given disorder along this continuum depends on three main variables: (1) whether a major locus makes a dominant contribution to the phenotype, (2) the number of loci that influence the phenotype, and (3) the presence and extent of environmental influence on phenotype.

cohorts indicated that this assumption was an oversimplification of the true genetic nature of this phenotype, particularly with respect to the substantial phenotypic variability observed in some CF patients. For instance, although CFTR mutations show a degree of correlation with the severity of pancreatic disease, the severity of the pulmonary phenotype-which is the main cause of mortality-is difficult to predict. 1,16,45 Realization of the limitations of a pure monogenic model prompted an evaluation of more complex inheritance schemes. This led to the mapping of a modifier locus for the intestinal component ofCF in both human and mouse. 63 ,73 Further phenotypic analysis led to the discovery of several other loci linked to phenotype, including (1) the association of low-expressing mannose-binding lectin (MBL; also known as MBL2) alleles, human leukocyte antigen (HLA) class II polymorphisms, and variants in tumor necrosis factor-a (TNFa) and transforming growth factor-I3-1 (TGF{3I) with pulmonary aspects of the disease5,6,21,30; (2) the correlation of intronic nitric oxide synthase 1 (NOSI) polymorphisms with variability in the frequency and severity of microbial infections 22 ; and (3) the contribution of mucin 1 (Muc1) to the gastrointestinal aspects of the CF phenotype in mice (Fig. 2-2).55 Recently, further layers of complexity have been discovered for both CFTR and its associated phenotype. First, heterozygous CF mutations have been associated with susceptibility to rhinosinusitis, an established polygenic trait.69 Second, and perhaps more surprising, a recent study reported that some patients with a milder CF phenotype do not have any mutations in CfTR. This indicates that the hypothesis that CFlR gene dysfunction is requisite for the development of CF might not be true. 23

TNFa TGF~1

MBL2

~I

ICFTR . . . .

Disease-Specific Examples of Changing Concepts in Molecular Genetics Monogenic Disorders Cystic fibrosis (CF) is an example of a disorder close to the monogenic end of the continuum, but it also illustrates the complexity of the genetics of some disorders, even when a mutation of a major locus is the primary determinant of phenotype. On the basis of the observed autosomal recessive inheritance in families, the gene CFTR (cystic fibrosis transmembrane conductance regulator) was first mapped in humans to chromosome 7q31.2. 68 Once the CfTR gene was cloned,62 it was widely anticipated that mutation analyses might be sufficient to predict the clinical outcome of patients. However, analyses of CFTR mutations in large and ethnically diverse

Severity of pulmonary phenotype

HLAII

Cystic Fibrosis

~

Microbial infections

I

~1'

Pancrealic/GI phenotype

1

CFMl

I Meconium ileus I

WlII"#§J Complexity in monogenic diseases. Mutations in the cystic fibrosis transmembrane conductance regulator (CFIR) almost always cause the cystic fibrosis (CF) phenotype. Owing to modification effects by other genetic factors, the presence and nature of mutations at the CFrR locus cannot predict the phenotypic manifestation of the disease. Therefore, although CF is considered a mendelian recessive disease, the phenotype in each patient depends on a discrete number of alleles at different loci. aMI, cystic fibrosis modifier 1; GI, gastrointestinal; HLAII, major histocompatibility complex class II antigen; MBL2, mannose-binding lectin (protein C) 2; Mucl, mucin 1; NOSI, nitric oxide synthase 1; TGF{3I, transforming growth factor-~-I; TNFa, tumor necrosis factor-a encoding gene.

Oligogenic Disorders Recent developments in defining the molecular genetics of Hirschsprung's disease (HD) exemplifY a relatively new concept in genetics-the oligogenic disorder. Although mathematical analyses of oligogenicity are beyond the scope of this discussion,18,47 it is important to recognize that modifications of traditional linkage approaches are useful tools for the study of oligogenic diseases, especially if a major locus that contributes greatly to the phenotype is known. In the case ofHD, two main phenotypic groups can be distinguished on the basis of the extent of aganglionosis: short-segment HD (S-HD) and the more severe long-segment HD (L-HD). Autosomal dominant inheritance with incomplete penetrance has been proposed for L-HD, whereas complex inheritance that involves an autosomal recessive trait has been observed in S-HD. Oligogenicity has been established in both HD variants by virtue of several factors: a recurrence risk that varies from 3% to 25%, depending on the length of aganglionosis and the sex of the patient; heritability values close to 100%, which indicates an exclusively genetic basis; significant clinical variability and reduced penetrance; and nonrandom association of hypomorphic changes in the endothelin receptor type B (EDNRB), with rearranged during transfection (RET) polymorphisms and HD.54,57 So far, a combination of linkage, positional cloning studies, and functional candidate gene analyses has identified eight HD genes (Table 2-1), 2 of which the proto-oncogene RET is thought to be the main predisposing locus,4.39 particularly in families with a high incidence ofL-HD.2o The nonmendelian transmission of HD has hindered the identification of predisposing modifier loci by

conventional linkage approaches. When these approaches (parametric and nonparametric linkage studies) were carried out on a group of 12 L-HD families, very weak linkage was observed on 9q31. However, based on the hypothesis that only milder RET mutations could be associated with another locus, families were categorized according to the RET mutational data. Significant linkage on 9q31 was detected when families with potentially weak RET mutations were analyzed independently,39 indicating that mild RET alleles, in conjunction with alleles at an unknown gene on chromosome 9, might be required for pathogenesis. The mode of inheritance in S-HD has proved to be more complex than in L-HD, requiring further adjustments to the linkage strategies. Recently, the application of model-free linkage, without assumptions about the number and inheritance mode of segregating factors, showed that a three-locus segregation was both necessary and sufficient to manifest S-HD, with RET being the main locus, and that the transmission of susceptibility alleles was additive. 2o The inheritance patterns observed in disorders such as HD illustrate the power of both expanded models of disease inheritance that account for reduced penetrance and phenotypic variability and the ability of these models to genetically map loci involved in oligogenic diseases-a first step toward identifYing their underlying genes. More important, the establishment of nonmendelian models caused a change of perception in human genetics, which in turn accelerated the discovery of oligogenic traits.

Polygenic or Complex Disorders Polygenic or complex disorders are thought to result from poorly understood interactions between many genes and the environment. An example of a polygenic

~ TABLE 2-1 Genes Associated with Hirschsprung's Disease and Relationship to Associated Anomalies Population

Associated Anomalies

Incidence in

CCHS MEN2A MEN2B

1.8-1.9 2.5-5.0 Unknown

AD

17-38 (S-HD) 70-80 (L-HD) 50 (familial) 15-35 (sporadic) <1*

CCHS

1.8-1.9

AD

<1*

Unknown

Unknown AD/AR

3-7

Ligand for EDNRB

AD/AR

5

EDN3 processing gene Transcription factor

AD AD

<1 <1

Gene

Gene Locus

Gene Product

Inheritance

RET

10ql1.2

Coreceptor for GDNF

AD

GDNF

5p12-13.1

NTN

19p13.3

GFRa-l EDNRB

10q26 13q22

Ligand for RET and GFRa-l Ligand for RET and GFRa-2 Coreceptor for GDNF Receptor for EDN3

EDN3

20q13.2-13.3

ECE-l

lp36.1 22q13.1

SOX10

Unknown Waardenburg's syndrome CCHS Waardenburg's syndrome Unknown Waardenburg's syndrome type 4

HD

Unknown 1.8-1.9 Unknown

Unknown

*Limited data available. No mutations detected thus far in humans, but associated with HD in mice. AD, autosomal dominant; AR, autosomal recessive; CCHS, congenital central hypoventilation syndrome (Ondine's curse); ECE-l, endothelin-converting enzyme-l; EDNRB, endothelin receptor B; EDN3, endothelin-3; GDNF, glial cellline-derived neurotrophic factor; GFRa-l, GDNF family receptor a-l; HD, Hirschsprung's disease; L-HD, long-segment HD; MEN, multiple endocrine neoplasia; NTN, neurturin; RET, rearranged during transfection; S-HD, short-segment HD; SOX, Sry-Iike HMG bOX. t

disorder relevant to pediatric surgery is hypertrophic pyloric stenosis (HPS). The genetic cause of HPS has long been recognized, with frequent familial aggregation, a concordance rate of 25% to 40% in monogenetic twins, a recurrence rate of 10% for males and 2% for females born after an affected child, and a ratio of risk of IS for first-degree relatives compared with the general population. 46 However, this risk is considerably less than would be predicted based on mendelian patterns of inheritance.1O In addition, HPS has been reported as an associated feature in multiple defined genetic syndromes,9,35,36,59,67 chromosomal abnormalities, 12,27,29,60,70 and anecdotally with many other defects,24,31,37,42,72 suggesting a polygenic basis, Although the molecular genetic basis of HPS remains poorly defined, a likely common final pathway causing the disorder is altered expression of neural nitric oxide synthase (nNOS) within the pyloric muscle,51 A detailed analysis of the molecular mechanisms of this alteration has been published, describing a reduction of messenger RNA (mRNA) expression ofnNOS exon lc, with a compensatory up-regulation of nNOS exon If variant mRNA in HPS.5! DNA samples of 16 HPS patients and SI controls were analyzed for nNOS exon lc promoter mutations and single nucleotide polymorphism (SNP). Sequencing of the 5'-flanking region of exon lc revealed mutations in 3 of 16 HPS tissues, whereas SI controls showed the wild-type sequence exclusively. Carriers of the A allele of a previously uncharacterized nNOS exon lc promoter SNP (-S4G/ A SNP) had an increased risk of developing HPS (odds ratio, S.O; 95% confidence interval, 2.5 to 25.6), which could indicate that the -S4G/ A promoter SNP alters expression of nNOS exon lc or is in linkage dysequilibrium with a functionally important sequence variant elsewhere in the nNOS transcription unit and therefore may serve as an informative marker for a functionally important genetic alteration. The observed correlation of the -S4G/ A SNP with an increased risk for the development of HPS is consistent with a report showing a strong correlation of a microsatellite polymorphism in the nNOS gene with a familial form of HPS,13 However, the -S4G/ A SNP does not account for all HPS cases; therefore, other components of the nitric oxide-dependent signal transduction pathway or additional mechanisms and genes may be involved in the pathogenesis of HPS. This is in accordance with other observations suggesting a multifactorial cause of HPS,46 In summary, genetic alterations in the nNOS exon lc regulatory region influence expression of the nNOS gene and may contribute to the pathogenesis of HPS, but there are likely numerous other genes that contribute to the development of HPS as well as predispose to environmental influences in this disorder. These examples provide insight into the complexity of current models of molecular genetics and illustrate the inadequacy of current methods of analysis to fully define genetic causes of disease, particularly polygenic disorders. The majority of pediatric surgical disorders currently fall into the category of undefined multifactorial inheritance, which is even less well understood than the genetic categories described. In these disorders, no causative, predisposing, or influencing gene loci have been identified. Isolated regional malformations are presumed

to result from interactions between the environment and the actions of multiple genes. Multifactorial inheritance is characterized by the presence of a greater number of risk genes within a family. The presumption of a genetic basis of the anomalies is based on recurrence risk. The recurrence risks in multifactorial inheritance disorders, although generally low, are higher than in the general population; they are increased further if more than one family member is affected, if there are more severe malformations in the proband, or if the parents are closely related, Beyond these generalizations, genetics can provide little specific information about this category of disorder,

Utility of Molecular Genetics in Clinical Pediatric Surgery Genetic Counseling and Prenatal Diagnosis As mentioned earlier, there is still a gap between genotypic understanding of a disorder and direct application to clinical treatment. The exceptions are in the areas of genetic counseling and prenatal diagnosis. Pediatric surgeons are likely to require some knowledge of molecular genetics as their role in prenatal counseling of parents continues to increase. Molecular genetics can supply specific information about an affected fetus by providing genotypic confirmation of a phenotypic abnormality, a phenotypic correlate for a confirmed genotype, and, in many instances, the recurrence risk for subsequent pregnancies and the need for concern (or lack thereof) about other family members. Once again, HD is an example of how molecular genetics can be valuable in genetic counseling. 8 ,64 The generalized risk to siblings is 4% and increases as the length of involved segment increases. In HD associated with known syndromes, genetic counseling may focus more on prognosis related to the syndrome than on recurrence risk. In isolated HD, a more precise risk table can be created. Risk of recurrence of the disease is greater in relatives of an affected female than of an affected male. Risk of recurrence is also greater in relatives of an individual with longsegment compared with short-segment disease. For example, the recurrence risk in a sibling of a female with aganglionosis beginning proximal to the splenic flexure is approximately 23% for a male and IS% for a female, whereas the recurrence risk in a sibling of a male with aganglionosis beginning proximal to the splenic flexure is approximately 11 % for a male and S% for a female. These risks fall to 6% and lower for siblings of an individual with short-segment disease. Prenatal diagnosis is possible if the mutation within the family is known. However, because the penetrance of single gene mutations is low (except for SOXIO mutations in Waardenburg's syndrome), the clinical usefulness of prenatal diagnosis is limited. More commonly, a general knowledge of genetics can allow accurate counseling of recurrence risk and reassurance for parents of an affected fetus diagnosed with a multifactorial inheritance defect, the most common circumstance involving prenatal consultation with a

pediatric surgeon. Pediatric surgeons should also be aware of the value of genetic evaluation of abortus tissue in cases of multiple anomalies when, after counseling, the parents choose to terminate the pregnancy. It is a disservice to the family not to send the fetus to an appropriate center for a detailed gross examination and a state-of-the-art molecular genetic assessment when appropriate. As molecular genetics increasingly characterizes the genes responsible for specific disorders, their predisposing and modifier loci, and other genetic interactions, a better ability to predict the presence and severity of specific phenotypes will inevitably follow. This will allow prenatal counseling to be tailored to the specific fetus and lead to improved prognostic accuracy, giving parents the opportunity to make more informed prenatal choices.

Postnatal Treatment In the future, molecular genetics will allow specific therapies to be optimized for individual patients. This may range from specific pharmacologic treatments for individual patients based on genotype and predicted pharmacologic response to anticipation of propensities for specific postoperative complications, such as infection or postoperative stress response. Of course, the ultimate treatment for an affected individual and their progeny would be to correct the germline genetic alteration responsible for a specific phenotype. Although there are many scientific and ethical obstacles to overcome before considering such therapy, it is conceivable that a combination of molecular genetics and gene transfer technologies could correct a germline mutation, replacing an abnormal gene by the integration of a normal gene and providing the ultimate preventive therapy. Although the state of gene transfer technology is far from this level of sophistication, progress in the past 3 decades can only be described as astounding. The next section provides an overview of the current state of gene transfer and its potential application for therapy.

GENE THERAPY Gene therapy continues to be embroiled in controversy, its seemingly unlimited potential obscured by repeated disappointments and, more recently, adverse events. The year 2000 brought the first clinical gene therapy success-treatment of X-linked severe combined immune deficiency (XSCID) II-only to have this dramatic achievement undermined by the occurrence ofleukemia in two patients. This and other adverse events threaten to overshadow the substantial progress made in gene transfer technology in recent years. Slowly but surely, methods for gene transfer are being developed that will have greater safety, specificity, and efficacy than ever before. Although complex issues remain to be solved, it is likely that successful gene therapy strategies will be developed and proved within the next few years. The technology of gene transfer can be divided into viral vector-based gene transfer and nonviral gene transfer. Because of the

limited scope of this chapter and the limited efficiency of nonviral-based gene transfer thus far, only the current state of viral-based gene transfer is reviewed.

Viral Vectors for Gene Transfer Viruses are highly evolved biologic machines that efficiently penetrate hostile host cells and exploit the host's cellular machinery to facilitate their replication. Ideally, viral vectors harness the viral infection pathway but avoid the subsequent replicative expression of viral genes that causes toxicity. This is traditionally achieved by deleting some or all of the coding regions from the viral genome but leaving intact those sequences that are needed for the vector function, such as elements required for the packaging of viral DNA into virus capsid or the integration of vector DNA into host chromatin. The chosen expression cassette is then cloned into the viral backbone in place of those sequences that were deleted. The deleted genes encoding proteins involved in replication or capsid or envelope proteins are included in a separate packaging construct. The vector genome and packaging construct are then cotransfected into packaging cells to produce recombinant vector particles (Fig. 2-3). Given the diversity of therapeutic strategies and disease targets involving gene transfer, it is not surprising that a large number of vector systems have been devised. Although there is no single vector suitable for all applications, certain characteristics are desirable for all vectors if they are to be clinically useful: (l) the ability to be reproducibly and stably propagated, (2) the ability to be purified to high titers, (3) the ability to mediate targeted delivery (i.e., to avoid widespread vector dissemination), and (4) the ability to achieve gene delivery and expression without harmful side effects. There are presently five main classes of vectors that, at least under specific circumstances, satisfY these requirements: oncoretroviruses, lentiviruses, adeno-associated viruses (AAVs) , adenoviruses, and herpesviruses. Table 2-2 compares the general characteristics of these vectors. Oncoretroviruses and lentiviruses are "integrating," that is, they insert their genomes into the host cellular chromatin. Thus, they share the advantage of persistent gene expression. Nonintegrating viruses can achieve persistent gene expression in nondividing cells, but integrating vectors are the tools of choice if stable genetic alteration needs to be maintained in dividing cells. It is important to note, however, that stable transcription is not guaranteed by integration and that transgene expression from integrated viral genomes can be silenced over time. 53 Oncoretroviruses and lentiviruses differ in their ability to penetrate an intact nuclear membrane. Whereas retroviruses can transduce only dividing cells, lentiviruses can naturally penetrate nuclear membranes and can transduce nondividing cells, making them particularly useful for stem cell targeting applications. 19 ,74 Because of this difference, lentivirus vectors are superseding retrovirus vectors for most applications. Both types of vector, because of their ability to integrate, share the potential hazard of alteration of the host cell genome.

Parental virus

Inverted repeats Structural protein genes

I I I

Genes required for DNA replication

I]

Poly (A)

Pathogenicity genes

Genes encoding envelope proteins

Promoter

A

Transgene

Vector genome

C B

Packaging construct

Viral vector

Structural proteins

mllh••'

Requirements for the creation of a generic viral vector. A. The basic machinery of a chosen parental virus is used, including genes encoding specific structural protein genes, envelope proteins, and proteins required for DNA replication, but not genes encoding proteins conferring pathogenicity. B, The vector is assembled in a packaging cell. A packaging (helper) construct, containing genes derived from the parental virus, can be delivered as a plasmid or helper virus or stably integrated into the chromatin of the packaging cell. Pathogenicity functions and sequences required for encapsidation are eliminated from the helper construct so that it cannot be packaged into a viral particle. In contrast, the vector genome contains the transgenic expression cassette flanked by inverted terminal repeats and cis-acting sequences that are required for genome encapsidation. Viral structural proteins and proteins required for replication of the vector DNA are expressed from the packaging construct, and the replicated vector genomes are packaged into the virus particles. C, The viral vector particles are released from the packaging cell and contain only the vector genome. (See color plate.)

This could lead to the undesirable complications of human germ line alteration or insertional mutagenesis, particularly important considerations for pediatric or fetal gene therapy.56 Nevertheless, these vectors have proved most efficient for long-term gene transfer into cells in rapidly proliferative tissues and for stem cell-directed gene transfer. Nonintegrating vectors include adenovirus, AAV, and herpesvirus vectors. Adenovirus vectors have the advantages of broad tropism, moderate packaging capacity, and high efficiency, but they carry the usually undesirable properties of high immunogenicity and consequent short duration of gene expression. Modifications of adenovirus vectors to reduce immunogenicity and further increase the transgene capacity have consisted primarily of deletion of "early" (EI-E4) viral genes that encode immunogenic viral proteins responsible for the cytotoxic immune response. 3 ,38 The most important advance,

however, has been the development of helper-dependent adenoviruses (HD-Ads) that are deleted of all viral genes, thus eliminating the immune response to adenoviralassociated proteins. 48 These vectors may ultimately be most valuable for long-term gene transfer in tissues with very low rates of cell division, such as muscle or brain. AAV is a helper-dependent parvovirus that, in the presence of adenovirus or herpesvirus infection, undergoes a productive replication cycle. AAV vectors are single-strand DNA vectors and represent one of the most promising vector systems for safe long-term gene transfer and expression in nonproliferating tissues. AAV is the only vector system for which the wild-type virus has no known human pathogenicity, adding to its safety profile. In addition, the small size and simplicity of the vector particle make systemic administration of high doses of vector possible without eliciting an acute inflammatory response or other toxicity. Although the majority of the

~

TABLE 2-2 Five Main Viral Vector Groups

Vector Type

Coding Material

Retrovirus

RNA

Lentivirus

RNA

HSV-l

dsDNA

AAV

ssDNA

Adenovirus

dsDNA

Tissue Tropism

Vector Genome

8

Only dividing cells

Integrated

8

Broad, including stem cells

Integrated

40

Neural

Episomal

<5

Broad

8

Broad

Episomal (90%) Integrated (<10%) Episomal

Packaging Capacity (kb)

30*

Advantages

Disadvantages

Persistent gene transfer in dividing cells Integrates into nondividing cells; perSistent gene transfer Inflammatory response; limited tropism Noninflammatory; nonpathogenic Extremely efficient gene transfer in most tissues

Requires cell division; may induce oncogenesis Potentia I for oncogenesis

Large packaging capacity; strong tropism for neurons Small packaging capacity Capsid-mediated potent immune response; transient expression in dividing cells

• Helper dependent. AAV, adeno-associated vector; ds, double-strand; HSV-l; herpes simplex virus-l; ss, single-strand.

AAV vector genome after transduction remains episomal, an approximately 10% rate of integration has been observed. 50 There are two primary limitations of AAV vectors. The first is the need to convert a single-strand DNA genome into a double strand, limiting the efficiency of transduction. Recently this obstacle has been overcome by the development of double-strand vectors that exploit a hairpin intermediate of the AAV replication cycle. 43 Although these vectors can mediate a 10- to 100-fold increase in transgene expression in vitro and in vivo, they can package only 2.4 kb of double-strand DNA, limiting their therapeutic usefulness. This relates to the second primary limitation of AAV vectors, which is limited packaging capacity (4.8 kb of single-strand DNA). One approach to address this limitation is to split the expression cassette across two vectors, exploiting the in vivo concatemerization of rAAV genomes. This results in reconstitution of a functional cassette after concatemerization in the cell nucleus. 17 ,49 Finally, an approach that has become common for enhancing or redirecting the tissue tropism of AAV vectors is to pseudo type the vectors with capsid proteins from alternative serotypes of AAy'58 Although most rAAV vectors have been derived from AAV2, eight distinct AAV serotypes have been identified thus far, all of which differ in efficiency for transduction of specific cell types. AAV vectors have proved particularly useful for muscle, liver, and central nervous system directed gene transfer. Herpes simplex virus (HSV-l) vectors are the largest and most complex of all currently used vector systems. Their primary advantages are a very large packaging capacity (up to 40 kb) and their strong neurotropism, allowing lifelong expression in sensory neurons. This has made neuropathologic disorders a primary target for HSV-1-mediated gene transfer.

Clinically Relevant Challenges in Gene Transfer Recent adverse events demonstrate the potential for disaster when using vector-based gene transfer. Major initiatives must be undertaken to delineate the potential complications of gene transfer with specific vectors to convince physicians and the public of their safety for future clinical trials. Nevertheless, because of the potential benefit, continued efforts to develop safe and efficacious strategies for clinical gene transfer are warranted. One of the primary obstacles to successful gene therapy continues to be the host immune response. The intact immune system is highly capable of activation against viral vectors using the same defense systems that combat wild-type infections. Viral products or new transgene encoded proteins are recognized as foreign and are capable of activating an immune response of variable intensity. Adenovirus vectors are the most immunogenic of all the viral vector types and induce multiple components of the immune response, including cytotoxic T-Iymphocyte responses, humoral virus-neutralizing responses, and potent cytokine-mediated inflammatory responses. 7 Great progress has been made in reducing T-cell responses against adenoviral antigens by the development of HD-Ad vectors that are deleted of all adenoviral genes. These vectors have demonstrated reduced immunogenicity with long-term phenotypic correction of mouse models and negligible toxicity.14.34 However, even HD-Ad vectors or less immunogenic vector systems such as AAV or lentivirus vectors can induce an immunologic response to capsid proteins or to novel transgene encoded proteins, a potentially limiting problem in a large number of human protein deficiency disorders caused by a null mutation. Thus, the application of gene transfer technology to many human disorders may

require the development of effective and nontoxic strategies for tolerance induction. Another major area of interest that may improve the safety profile of future viral vector-based gene transfer is specific targeting to affected tissues or organs. Whereas wild-type virus infections are generally restricted to those tissues that are accessible through the route of transmission, recombinant vectors are not subject to the same physical limitations. The promiscuity of viral vectors is a significant liability, because systemic or even local administration of a vector may lead to unwanted vector uptake by many different cell types in multiple organs. For instance, lack of adenovirus vector specificity was directly linked to the induction of a massive systemic immune response that resulted in a gene therapy-related death in 1999. 7 Because many of the toxic effects of viral vectorbased gene transfer are directly related to dose, increasing the efficiency with which viral vectors infect specific cell populations should reduce viral load and improve safety. There are a variety of promising methods to achieve the targeting of viral vectors for specific organs or cell types. Perhaps the simplest approach is vector pseudotyping, which has been performed for retrovirus, lentivirus, and AAV vectors. By changing the capsid envelope proteins to alternative viral types or serotypes, a portfolio of vectors with different tropisms can be generated. 40 Another approach is the conjugation of capsid proteins to molecular adapters such as bispecific antibodies with specific receptor binding properties. 33 ,61 A third approach is to genetically engineer the capsid proteins themselves to alter their receptor binding (i.e., to abolish their normal receptor binding) or to encode a small peptide ligand for an alternative receptor. 28 These and other approaches, when combined with the appropriate use of tissue-specific promoters, may significantly reduce the likelihood of toxicity from viral-based gene therapy. Another important obstacle to human gene therapyparticularly fetal gene therapy-is the potential for insertional mutagenesis when using integrating vectors. Until recently, this risk was considered extremely low to negligible, based on the assumption that oncogenesis requires multiple genetic lesions and the fact that induced cancer had not been observed in any of the hundreds of patients treated with retrovirus vectors in the many gene therapy trials. However, recently 2 of 11 patients treated in an otherwise successful trial ll ,25 of retroviral gene therapy for XSCID developed a leukemia disorder.26 Evidence suggests that this was caused by retroviral genome insertion in or near the oncogene LM02. These concerns have been further heightened by evidence that retroviral genes are not randomly inserted, as previously believed; rather, they preferentially integrate into transcriptionally active genes. 65 Although such events may be more likely to occur under the unique selective influences of XSCID, it is clear that the risk of insertional mutagenesis can no longer be ignored. Approaches designed to neutralize cells expressing transgene if and when an adverse event occurs, such as engineering suicide genes into the vector, are one option, but this would also neutralize any therapeutic effect. More exciting approaches are based on site-specific integration-for

instance, taking advantage of site-integration machinery of bacteriophage <j>X3l.5 2 This is undoubtedly only one of many approaches that will use site-specific integration in the future and should, if successful, negate the risk of insertional mutagenesis. Finally, a critical issue for in vivo gene transfer with integrating vectors in individuals of reproductive age is the potential for germline transmission, with alteration of the human genome. The risk of this event is poorly defined at present and is most likely extremely low, although in some circumstances (e.g., fetal gene transfer), it could be increased. 56 Although still not technically possible, the intentional site-specific correction of defects in the germline would be the ultimate in gene therapy. However, even if the technology becomes available, the intentional alteration of the human genome raises profound ethical and societal questions that will need to be thoroughly addressed before its application. The considerations are similar to those for insertional mutagenesis, so many of the approaches mentioned earlier for gene targeting and reduction of the potential for insertional mutagenesis are applicable here as well.

Overview of the Current Status of Gene Transfer At present it is clear that viral vectors are the best available vehicle for efficient gene transfer into most tissues. Several gene therapy applications have shown promise in early-phase clinical trials. Although the adverse events noted in the XSCID trial have dampened enthusiasm, this still represents the first successful treatment of a disease by gene therapy. The treatment of hemophilia B using rAAV is also promising. 32 ,41 The next few years are likely to bring advances in the treatment of certain types of cancer using conditionally replicating oncolytic viruses and in the treatment of vascular and coronary artery disease using viral vectors that express angiogenic factors. In the future, new disease targets are likely to become approachable through the fusion of viral vectormediated gene transfer with other technologies such as RNA interference, a powerful tool to achieve gene silencing, Such vectors could be useful in developing therapy for a range of diseases, such as dominantly inherited genetic disorders, infectious diseases, and cancer, Advances in the understanding of viral vector technology and DNA entry into cells and nuclei will likely lead to the development of more efficient nonviral vector systems that may rival viral vectors in efficiency and have superior safety, Gene vector systems of the future may be very different from those in use today and will ultimately provide efficient delivery of target-specific, regulated, transgene expression for an appropriate length of time.

REFERENCES 1. Acton JD, Wilmott RW: Phenotype of CF and the effects of possible modifier genes. Paediatr Respir Rev 2001;2: 332-339. 2, Arnie! J, Lyonnet S: Hirschsprung disease, associated syndromes, and genetics: A review,J Med Genet 2001;38:729-739,

Ethical Considerations Donna A. Caniano and Carolyn Ells

In his classic text The Surgeon and the Child, Potts noted that "the satisfaction of correcting a deformity in a newborn infant lies in the fact that all his life lies before him. Parents hope for miracles, but are grateful for the best that can be given by a mere human being."lg This profound statement underscores the essence of pediatric surgery, whether repairing a major congenital anomaly, treating a devastating traumatic injury, or resecting a malignancy. Each endeavor offers the pediatric surgeon the joy of providing a child with relief of suffering and the potential for a full and productive life. The ethical challenges faced by pediatric surgeons encompass the basic moral principles of medical practice, issues that are distinctive to the profession of surgery, and other factors that are unique to the care of infants and children. In this chapter we review some of the basic ethical concepts and responsibilities pertinent to pediatric surgical ethics. We also address some new areas of ethical and surgical controversy, including the operative management of children with morbid obesity and sex assignment surgery in infants with intersex conditions.

PEDIATRIC SURGICAL mHICS What is distinctive about surgical ethics flows first from what is distinctive about the relationship between surgeons and their patients. Little" has identified five pillars that mark the moral domain of the surgeon-patient relationship: rescue, proximity, ordeal, aftermath, and presence. These factors may be present in other therapeutic relationships as well, but they have a special intensity in surgery. The term rescueacknowledges the elements of surrender and dependency that patients and their families experience when surgery is pursued. To be rescued from a serious threat, patients open themselves up to invasive and traumatic surgcal remedies over which they have little control. Surgeons and patients and their families (parents in most pediatric surgical encounters) need to work together to confront and negotiate the patient's surrender and dependency within the context of the surgeon's power. Proximity refers to surgeons' acknowledgment of the close, intimate interactions they have with their patients. Remarkably, surgeons explore the inner bodies of their

patients, an aspect of the encounter that differs from other medical interactions. Surgeons see and touch, and incise and suture, parts of patients that the patients themselves can barely imagine. Proximity privileges surgeons with knowledge and an understanding of suffering that patients cannot reciprocate. Patients cannot know their surgeons in this intimate way, nor can they know themselves in the way that their surgeons come to know them. Surgeons must realize that surgery is an ordeal for patients; it is an extreme experience that must be endured. Little" has emphasized that surgical patients forgo their autonomy, acknowledge dependency, place trust, face risk, confront embodiment and mortality, lose control over time and space, and experience alienation, pain, fear, discomfort, suffering, and boredom. Depending on the surgical procedure, the patient's sense of personal identity may be irrevocably challenged or changed. In the aftmath of surgery, surgeons must recognize that some patients may have difficulties long after their immediate recovery. Physical and emotional scars, discomfort, risks, and other types of suffering can be reminders of a past illness or injury and signs of vulnerability to future illness or injury. Understanding the aftermath of surgery can help surgeons understand threats to their patients' existential experiences, as well as to their own. In pediatric surgery, aftermath takes on a unique aspect in its dual nature, affecting the child-patient and the parents, both of whom experience the consequences of the surgical encounter. Presence is both a virtue and a duty for surgeons. They must be a visible and engaged presence throughout the entire surgical experience. In pediatric surgery, this professional obligation extends to the long-term follow-up of their patients, often into young adulthood. For example, pediatric surgeons may be the only specialistswho understand the potential long-term complications and functional difficulties that may arise from major neonatal reconstructive operations in the gastrointestinal and hepatobiliary systems. Meeting this duty requires a patient-centered approach to care in which each patient, and his or her particular situation and experience, guides the surgeon in nurturing the surgical relationship and promoting the patient's interests.

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Surgeons bring to the surgical relationship the values and ethical principles of their profession, which give priority to the interests and well-being of their patients. 111 Surg-icnl ethic^, McCullough et a1.'2 present patients' rights related to the surgical encounter, each of which implies a key professional value. They remind us that patients have the right "not to be killed intentionally or negligently by the surgeon, not to be harmed by intent or negligence of the surgeon ... not to be deceived by the surgeon ... to be adequately informed about the risks and benefits of surgery, to be treated by a knowledgeable, competent practitio~ler,to have his or her health and well-being more highly valued than the surgeon's ow11econornic inierest, and to decide whether to accept treatlneilt under the conditions described."" In pediatric surgery, the professional commitment to fi~llyirlform patients, to enable them to choose treatment or nontreatrnent, and to not deceive them typically requires third parties (in most cases, their parents) to speak, understand, and consent on behalf of infants, children, arid adolescents. Although parents are usually the surrogate decision makers for their children, courtappointed guardians or other spokespersons may fulfill this role, depending on relevant laws. In somejurisdictions, and in certain specific circumstances, adolescent patients may be granted authority to make their own decisions about the health care they receive. This situation is particularly applicable to adolescents with chronic illnesses, such as sickle cell disease, cystic fibrosis, and advanced malignancies. However, when an adolescent's consent to or refusal of surgery is in direct opposition to parental wishes, the assistance of social services and legal counsel may be required. Including the family or surrogate decision makers in the surgical relationship is necessary notjust to authorize (or refuse) surgery on behalf of patients. Providing patient-centered care requires an understanding that the patient lives in a family context, which defines, in part, who he or she is as an individual. It also requires acknowledging the greater vulnerability of minor patients who have less of a voice-or often no voice-in treatment decisions and little or no understanding of the surgical process. These patients must be provided with the support they need to optimize their care and the protection they need in light of their vulnerability. Extending the surgical relationship to others helps the surgeon understand the patient and make recommendations that are in the patient's best interests, and it allows others to share in providing the support that these young patients require. One ethical challenge routinely faced by pediatric surgeons (and surrogate decision makers) is determining the interests of patients whose moral characters and values are not yet substantially (much less fully) formed. The character traits, goals, values, and preferences of minor patients should be factored into plans for their care, but judgment is needed to determine what weight to give them. Pediatric surgeons should have in their armamentarium various approaches to ethical decision making and problem solving. Baylis and Canianol advocate a team approach to difficult ethical problems encountered in the surgical treatment of infants and children. This approach acknowledges that contemporary health care in tertiary pediatric

hospitals relies on several teams: the patient-parent unit, the nursing and allied health care members, and the surgical-medical professionals. The health care team for any given patient must unite around a common moral language and an understanding of the ethical issues relative to the particular situation. For example, the caregivers and decision makers for an extremely premature neonate with multiple congenital anomalies must have practical and cognitive knowledge about the pertinent ethical issues. The team or team leaders must have the capacity to elucidate the values and goals that are important to the parents and other involved family mernbers. The values of the parents and Family assume particular relevance when their cultural or religious background differs from that of the health care team in substantive ways. For instance, certain cultural practices may dictate that the authority for medical decision making resides with individuals other than the parents, such as grandparents or community elders. Finally, the team must decide on a specific decision-making method. Several maxims apply to difficult ethical problems in pediatric surgery: (1) good ethics begin with good facts; (2) rational people may hold opposing and irreconcilable views; (3) generally, the best decisions are those developed by consensus; (4) most decisions do not need to be made in haste; and (5) in cases of severe neonatal and pediatric illness, most decisions are painful, and many do not have happy solutions. Most ethical dilemmas arise when there is a dispute or disagreement between the surgical-medical professionals and the patient-parents. These disagreements usually center on what constitutes the best interests of the patient (e.g., continued life with the burdens of severe disability) and what describes an acceptable quality of life for the patient. Glover and %aniano7have outlined a process for ethical decision making that involves several components, including identifying the decision makers, gathering all the medical-surgical facts with the best available prognostic indications, clarifying the relevant values from the "stakeholders" (usually the parents or close family members, in the case of infants), defining all available treatment and nontreatment options, evaluating all options and making recommendations (usually the responsibility of the pediatric surgeon), and achieving a consensus resolution (an ethics consultant or mediator may be useful in cases of significant dispute). Some of these approaches are addressed later in this chapter, when we discuss some of the newer ethical challenges faced by pediatric surgeons.

INNOVATION AND RESEARCH Most citizens of progressive societies place great value on innovation in all areas, including medicine. To achieve advances and technical improvements in pediatric surgery, the profession has relied on the individual and collective innovation of its members. Society expects surgeons to pursue innovation and to develop new therapies and treatment techniques. Patients gravitate toward new operations that offer a presumed benefit, as witnessed by the rapid conversion from open to laparoscopic

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cholecystectomy 2 decades ago. Patients also give great latitude to their surgeons in allowing, or even expecting, them to modify or refine traditional surgical techniques as necessary to complete an operation. McKneallyls observed that individual surgeons are usually acknowledged for their original thinking and technical accomplishments by having operations named in their honor. Numerous operations in pediatric surgery carry the names of those surgeons who first described them, including Ladd's procedure for midgut volvulus and the Duhamel pullthrough for Hirschsprung's disease. In contrast to other areas of medicine, in which randomized clinical trials precede the introduction of new drugs and treatments, the field of surgery has been free to develop new operations without stringent legal and professional regulations.Ulthough some notable procedures, such as pneumatic reduction of intussusception and the Swenson pull-through for Hirschsprung's disease, were tested in animal models, most operations in pediatric surgery are piloted and perfected on patients. New operations are typically introduced by means of a presentation at a professional meeting of pediatric surgeons and subsequent publication in a peer-reviewed journal. The pediatric surgeon who developed the operation usually reports on his or her experience, in terms of complications and outcomes, in patients treated at a single institution with a variable period of follow-up. Reasons given for adopting operations in humans without rigorous scrutiny include the following: (1) suitable animal models may be lacking for the particular anatomic condition; (2) the new operation represents an extension of standard, accepted techniques applied in a novel manner; (3) the new operation is meant to benefit an individual patient rather than to learn something; (4) professional standards are lacking for the introduction of new operations; (5) it is often unclear when an operation should undergo clinical trials; and (6) the current system has worked reasonably well for patients in terms of safety and presumed benefit. In fact, numerous operations have been abandoned either because they did not achieve the desired outcome (e.g., sympathectomy for Hirschsprung's disease) or because they had unacceptably high morbidity and mortality rates (e.g.,jejunoileal bypass for morbid obesity). Research is considered to be a systematic investigation designed to develop or contribute generalizable knowledge. In pediatric surgery, an operation may be performed in a novel way to treat a single patient; thus, in a strict sense, such an operation is not research. But, as is often the case, subsequent operations are performed on additional patients, data are collected, and the novel procedure is presented and published. What began as a treatment for a single patient has crossed over into clinical research, making it subject to the ethical standards for human investigation. In 1966 Beecher published a seminal article in the Nnu England Journal of Mdicine detailing several examples of medical and surgical treatments that had been published in respected journals yet violated the ethical norms of informed consent and safety.* Although the Nuremberg trials following World War I1 had unveiled the horrors of unethical human experimentation,

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mainstream medical research in the United States was largely unregulated, and examples of unethical research practices were problematic. Beecher's report galvanized the public to demand, and the federal government to reqiire, institutional review to ensure the-ethical acceptability of all research (medical, behavioral, and surgical) on human subjects. Through the National Research Act of 197'4, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research convened a group of respected clinical scientists, physicians, and experts in ethics, religion, and law to review the basic principles that should characterize the conduct of research involving human subjects and to develop guidelines to ensure the conduct of ethical research. The commission issued its summary statement, the Belmont Report," in 1979. The report identified the principles of respect for persons (which it divided into respect for autonomy and protection of the vulnerable), beneficence, and.justice as particularly relevant to research ethics. These principles have subsequently become important in clinical practice as well, although their application differs. Within the Belmont Report were two features of critical importance to pediatric surgeons: the role of informed consent for research subjects, and the protection that must be accorded when research is performed on vulnerable subjects, such as children. Parents and society expect that pediatric surgeons will be conservative guardians in surgical innovation, relying on a long tradition of generally safe operations and of progress in ameliorating the effects of congenital anomalies. Levinel0 has described some newly introduced procedures as nonvalidated, a term that acknowledges the ethical and medical hazards of novel o~erations.which may be obscured by the terminology of innovation. For both pediatric surgeons and parents, the concept of a nonvalidated operation is more transparent and honest; it embodies the fact that the proposed operation has not been subjected to rigorous clinical investigation. The presumption that a given novel operation is superior to its traditional counterpart is, in reality, a presumption only if it lacks an empirical basis. Clinical trials of a nonvalidated operation may reveal that it is superior to, equal to, or worse than conventional procedures. For example, the recent National 1nstit;tes of Healthfunded clinical trial of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia was stopped after the enrollment of 24 patients because survival was unexpectedly higher for the infants who received standard care (planned delivery and postnatal care at a tertiary center) compared with those undergoing the fetal intervention." Lacking rigorous scrutiny, the current system of surgical innovation may hinder the determination of an optimal surgical therapy for a given condition. A compelling argument can be made that pediatric surgeons have an ethical obligation to participate in well-designed prospective, multi-institutional clinical trials that seek to establish the best operations or treatments for their patients.Vatients and their families have a right to expect pediatric surgeons to practice competent surgical care that includes the best proven surgical treatments

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and operations. When pediatric surgeons perform nonvalidated operations on their patients, no matter how well intentioned, they may be providing treatments that are not optimal, because they have not been rigorously tested.

BARlATRlC SURGERY Obesity among children and adolescents is recognized as a major public health concern in many developed countries. In the United States, obesity affects about 16% of children, one third of whom are considered morbidly obese. Although the causes of this trend are not fully apparent, the decline in physical activity and the high-calorie diets of American children are likely contributing factors. Obesity in children and adolescents has significant ramifications for the individual and for public health. Because obesity is associated with serious conditions such as hyperlipidemia, hypertension, and type 2 diabetes, the financial and social costs are high. The adverse psychological factors associated with obesity in children and adolescents have not been well studied, but these may have considerable social and financial costs as well. Health care professionals and the broader social community share concerns about the effects of obesity on children and adolescents, in part because of the serious ramifications for their physical and mental health and long-term well-being. Treatment for morbid obesity includes medical and surgical approaches. The range of success with these approaches varies, and research is needed to better assess them, particularly in a pediatric population. Medical therapy that includes a comprehensive program of exercise and diet has not been successful in adults over the long term. Few children's hospitals have developed comprehensive medical obesity programs; thus, there is scant evidence in the pediatric literature about the outcomes of such programs. For adults with morbid obesity, surgical therapy is quite popular because it has been successful in achieving weight reduction with acceptable morbidity and mortality rates. Based on the good results in the adult population, it is not surprising that pediatric surgeons are being asked by the public-in particular, eager patients and their parents-to provide bariatric surgery for children and adolescents with morbid obesity (see Chapter 78). Roux-en-Y gastric bypass and gastric banding, both performed laparoscopically, are the two bariatric operations performed most frequently in adults in North America and Europe. Although both achieve weight loss, gastric banding does not alter the anatomy and is reversible; gastric bypass alters the anatomy in an essentially irreversible manner. Gastric bypass is very effective in achieving weight loss not only because it reduces the size of the stomach but also because it causes malabsorption. Long-term studies in adults indicate that gastric banding is somewhat less effective in achieving major weight loss but is successful in reducing the comorbid conditions of hypertension and diabetes.

There are some ethical concerns about bariatric surgery that pediatric surgeons should consider.9 Both operations are currently nonvalidated therapies for pediatric patients, and neither safety nor efficacy has been proved by multi-institutional clinical trials in this population. Patients and their surrogate decision makers should understand the nonvalidated nature of these operations before they make an informed choice to have a bariatric operation. Moreover, pediatric surgeons performing these operations should participate, whenever possible, in well-designed clinical studies that seek to define the safety, efficacy, and long-term outcomes of these surgeries in pediatric patients with morbid obesity. As with other nonvalidated treatments, research evaluating the safety and efficacy of bariatric procedures should be designed in a way that does not interfere with the therapeutic objectives of patients. Because of insufficient research and the relatively recent history of bariatric surgery (isolated case reports in adolescents), the risks and potential benefits of these operations are difficult to assess. Although early results have shown these operations to be safe for adolescents, the long-term outcomes are unknown. The gastric bypass operation raises concerns about chronic nutritional issues, such as vitamin deficiencies, and possible adverse effects over a lifetime. An additional concern is that patients must comply with prescribed dietary restrictions and undergo medical surveillance indefinitely. It is generally well recognized that patients tend to forgo regular checkups over the long term, particularly if they have no physical complaints. Because the long-term risks of these operations for adolescents are unknown, subtle aberrations in physiology that would be detected by close medical supervision might go unnoticed and undiagnosed until they cause serious consequences. Risks alone do not render a therapy unethical. The ethical assessment of risks involves taking into account the gravity of the risks, the probability that they will occur, and the potential benefits that patients may experience. The potential benefits should be assessed in light of the available evidence and the particular patient's situation. Where there are gaps in research, pediatric surgeons should draw on evidence from the adult population and extrapolate to adolescent patients, as their experience and expertise deem appropriate. In the informed choice process, pediatric surgeons should be honest with patients and their surrogate decision makers about what is known, what is unknown, and the reasoning behind their recommendations regarding a bariatric operation for a particular patient. For children or adolescents with morbid obesity, bariatric surgery may be viewed as a quick and easy "fix" compared with nonsurgical means of achieving weight loss. Quick and easy solutions are certainly desirable, but if nonsurgical means or less invasive procedures are (or prove to be) safer or more effective, or if they protect important options for children and adolescents (e.g., the ability to make important decisions about their health, bodies, and lives in the future), pediatric surgeons should be wary about agreeing to perform bariatric surgery. Pediatric surgeons, in their role as child advocates, have

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a professional responsibility to encourage a more balanced reflection and assessment of the therapeutic options for morbid obesity. In general, surgeons should be hesitant to operate on patients who are not capable of making their own informed decisions when the surgery can be safely delayed until they are capable of making such decisions. This is especially true when the surgery has irreversible effects and the safety and efficacy of the surgery are unknown. Pediatric surgeons must consider not only whether bariatric surgery is a potential therapeutic option for a particular patient but also whether it is the best option for a particular patient. Although the choice to have or forgo surgery is ultimately up to the patient and his or her surrogate decision makers, the surgeon's recommendations are usually an important factor. For some patients, this may mean recommending a less effective but reversible surgical technique or delaying a decision about surgery until the patient is older and pursuing medical therapy in the meantime.

SEX ASSIGNMENT SURGERY A variety of conditions in infancy, including ambiguous genitalia, cloacal exstrophy, and penile agenesis: may lead pediatric surgeons to consider sex assignment surgery. During the past decade, the traditional medical and surgical management of newborns with genital ambiguity has become controversial, with individuals who were "reconstructed" in infancy challenging the appropriateness of their treatment and questioning the success of their outcomes. Through advocacy organizations such as the Intersex Society of North America and the Androgen Insensitivity Support Group, adults with intersexuality (most of whom had sex assignment surgery in infancy and childhood) have publicly voiced their extreme dissatisfaction with several aspects of their medical and surgical care. Intersex is the term now used bv medical wrofessionals and the public to refer to congenital conditions that result in nonstandard male or female genital anatomy. A primary assumption underlying sex assignment surgery is that having nonstandard genitalia will cause psychological harm and that this harm can be avoided or reduced by performing surgery to normalize the appearance of the genitals, so that the child can be raised in the gender tha
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behavior and maternal feelings, but that the postnatal environment is the primary determinant of gender identity. In essence, Money's theory implied that for humans, behaviors that are denoted male or female are sociocultural constructs rather than biologic imperatives. For infants with intersexuality, Money's theories had significant implications for decisions about the sex of rearing. First, because the postnatal environment would be critical in determining the infant's gender identity, successful treatment would involve giving unequivocal and clear messages about that gender identity. Second, because gender identity does not depend on the cause of the genital ambiguity, sex and gender assignment should be based on anatomic considerations (and the potential for surgical reconstruction), reproductive potential, and capacity for intercourse. Thus, the individual was assigned a sex and a gender that were medically determined and, in most cases, reinforced by surgical reconstruction in infancy. Advocates from the intersex organizations, social scientists, and others cite several concerns about early sex assignment surgery. They have identified a paucity of objective, long-term, multi-institutional data on outcome in terms of sexual function, sexual pleasure, and psychosexual identity.14 Single-institution series involving small numbers of patients who had feminizing surgery in infancy have reported acceptable anatomic, functional, and psychosexual outcomes.18Other more recent reports (in which the evaluators were not part of the original pediatric surgical team) indicate that the long-term results of feminizing surgery are not optimal, with funcW study of tional problems and poor c o ~ m e s i s . ~ Jrecent 14 genetic males with cloacal exstrophy who had female sex assignment surgery in the newborn period found discordant sexual identity in 8 individuals, who reassigned themselves as male.*()Because there are so few reports on comprehensive outcomes for the various intersex conditions, it is not clear whether the dissatisfaction voiced by those opposed to early sex assignment surgery represents a vocal minority of patients or is reflective of less than optimal results in the majority of patients. A major ethical concern about the traditional approach involves the paternalistic decision making of medical and surgical professionals. Parents were frequently not given the entire truth about the diagnosis, and if they were, they were told to withhold certain aspects of the condition from the child to lessen gender identity conflicts. Thus, for most individuals with intersexuality, their diagnosis was not revealed to them by their parents or physicians. As adults or adolescents, if they experienced gender identity problems or sexual difficulties and eventually discovered the truth, they expressed tremendous anger and resentment about their treatment as infants and children. In addition to causing disrespect and distrust toward parents and physicians, lying to patients about their intersexuality and withholding their medical histories denies them the opportunity to come to terms with who they are and what has happened to them, to receive psychological counseling, and to seek support from others who have had the same or similar experiences. The ethical duty of informed consent

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requires that parents of infants with intersexuality be given all relevant information about the diagnosis, treatment options (including no early sex assignment surgery), expected outcomes (including the paucity of comprehensive data on long-term results), and the availability of advocacy organizations and counseling. In most cases, early sex assignment surgery is not necessary for the infant's physical health. In fact, advocates from the intersex organizations argue that it is not necessary for the child's psychological health either and that it sometimes causes harm. Daaboul and Fraders argue that a "middle way" approach should be adopted when making decisions about infants with severely intersexed genitalia and complete discordance with the assigned gender.Vhey note that delaying surgical reconstruction in these infants may cause considerable psychosocial difficulty in the school-age and adolescent years. Further, there are no reliable data on the outcomes of intersex children in developed countries whose genitalia are significantly discordant with their assigned gender. Parents of these severely affected infants should be allowed to make decisions regarding early sex assignment surgery, as long as they have been given full disclosure of the current state of knowledge (or lack thereof) about functional and sexual outcomes. Adherence to the ethical obligation of full and honest disclosure to the parents of infants with intersexuality should include a willingness by pediatric endocrinologists and pediatric surgeons to honor parental choices, including the rejection of early sex assignment surgery. As long as deferral of surgery carries no risk of physical harm (infection, malignancy in dysgenetic gonads), parents of these infants should be accorded the same authority for decision making that they are given in all other areas of medical treatment. REFERENCES 1. Baylis F, CanianoDA. Medical ethics and the pediatric surgeon. In Oldham KT, Colombani PM, Foglia RP (eds): Surgery of Infants and Children: Scientific Principles and Practice. I'hiladelphia, Lippincott-Raven, 1997, p 382. 2. Beecher H: Ethics and clinical research. N Engl J Med 1966;274:1354. 3. Caniano DA: Ethical issues in the management of neonatal surgical anonlalies. Semin Perinatol 2004;28:240.

4. Creighton SM, Minto CL, Steele SJ: Objective cosmetic and anatomical outcomes at adolescence of feminizing surgery for ambiguous genitalia done in childhood. Lancet 2001; 358:124. 5. Daaboul J, Frader J : Ethics and the management of the patient with intersex: A middle way. J Pediatr Endocrinol Metab 2001;14:1575. 6. Frader.1, Caniano DA: Research and innovation in surgery. In McCullough LB, Jones JW, Brody BA (eds): Surgical Ethics. New York, Oxford University Press, 1998. 7. GloverJ, Caniano DA: Ethical considerations in newborn surgery. In Puri P (ed): Newborn Surgery. Oxford, Butterworth-Heinemann, 2003. 8. Harrison MR, Keller R1, Hawgood SB, et al: A randomized trial of fetal endoscopic occlusion for severe fetal congenital diaphragmatic hernia. N Engl .J Med 2003;349: 1916. 9. Inge TH, Krebs NF, Garcia VF, et al: Bariatric surgery for severely overweight adolescents: Conccrns and recommendations. Pediatrics 2003;114:217. 10. Levine RJ: Ethics and Regulation of Clinical Research, 2nd ed. New Haven, Corm, Yale University Press, 1988. 11. Little M: Invited commentary: Is there a distinctively surgical ethics? Surgery 2001;129:668. 12. McCullough LB, Jones JW, Brody BA: Principles and practice of surgical ethics. In McCullough I,B, .Jones JW, Brody BA (eds): Surgical Ethics. New York, Oxford University Press, 1998. 13. McKneally MF: Ethical problems in surgery: Innovation leading to unforeseen complications. World J Surg 1999;23:786. 14. Meyer-Bahlburg HF: Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metab 1999;84:3455. 15. Minto CL, Liao LM, Woodhouse CRJ, et al: The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: A crosssectional study. Lancet 2003;361: 1252. 16. Money.1: Gender: History, theory and usage of the term in sexology and its relationship to nature/nurture. .J Sex Marital Ther 1985;11:71. 17. National Commission for the Protection of' Human Subjects of Biomedical and Behavioral Research: The Belmont Report. OPPR Reports. Washington, DC, US Government Printing Office, 1979. 18. Newman K, Randolph J, Parson S: Functional results in young women having clitoral reconstruction as infants. J Pediatr Surg 1992;27:180. 19. Potts WJ: The Surgeon and the Child. Philadelphia, WB Saunders, 1959, p 3. 20. Reiner WG, Gearhart JP: Discordant sexual identity in some genetic males with cloaca1 exstrophy assigned to female sex at birth. N Engl J Med 2004;350:333.

Accident Victims and Their Emergencv Management Jeffrey R. Lukish and Martin R. Eichelberger

EPIDEMIOLOGY OF CHILDHOOD INJURY Preventable injuries take an enormous financial and emotional toll on injured children and their families, but also on society as a whole. Unintentional injury is the leading cause of death among children aged 14 and younger in the United States, claiming more than 5600 lives annually or, an average, 15 children each day.2 In addition, there were nearlv 11.8 million medical visits for unintentional injury among American children aged 14 and younger in 2000, or one injury visit for every five children. More than 16% of all hospitalizations for unintentional injuries among children result in permanent di~ability.~ The death rate from unintentional injuries among children aged 14 and younger declined 39% from 198'7 to 2000; it declined 42% for children between 1 and 14 years. Nevertheless, unintentional injury continues to be the leading cause of death among children in this age group in the United States. In 2000 the leading cause of fatal unintentional injury among children was motor vehicle occupant injury (28%), followed by drowning (16%) and airway obstruction injury (14%). Falls were the leading cause (36%) of nonfatal injuries seen in hospital emergency rooms in 2001.2O Leading causes of unintentional injury-related death vary according to child's age and are dependent on the child's developmental abilities and exposure to potential hazards, in addition to parental perceptions of their child's abilities and injury risk. The smallest decline in the injury death rate occurred among infants younger than 1 year; the decline in that age group was only 1096, compared with 42% in those aged 1 to 4 years, 42% in those 5 to 9 years, and 40% in those 10 to 14 years. Children younger than 1 year have the highest rate of unintentional injury-related death-more than twice that of all children. Airway obstruction is the leading killer in this age group. In children aged 1 to 4 years, drowning accounts for 27% of unintentional injury deaths and is the leading cause of injury-related death. The lowest rate of unintentional death is in the 5- to 9-year age group; the most common cause of death in

this age group and in those aged 10 to 14 years is motor vehicle occupant injury (Fig. 15-1).2" In all age groups, male children are at higher risk for unintentional injury than are females. This may be due to greater exposure to activities that result in injury, risk taking, and rough play in male children. Race and ethnicity are also important risk factors for unintentional injury in children. American Indian and Alaskan native children have the highest unintentional injury death rate, and African American children have the second highest. These racial and ethnic disparities likely have more to do with living in impoverished communities, a primary predictor of injury, than with biologic differences.17.2" Intentional injury and death may result from homicide, child abuse, or suicide. Recognition of this intent requires referral to child protective services for assessment. The resuscitation of these children is frequently a challenge because abuse may be chronic, which results in a child with a limited physiologic reserve (refer to Chapter 24 on child abuse).

RESUSCITATION AND IMPACT ON OUTCOME Resuscitation of an injured child includes the actions necessary to reverse and control the sudden alterations in physiologic homeostasis that occur as a result of injury. Children are remarkably resilient; however, the initial period of stability has been shown to be significantly shorter as age decreases.lq Therefore, resuscitation is not complete until injuries have been definitively treated and the child displays physiologic stability without continued intervention. Differences between children and adults with respect to patterns of injury, physiologic presentation, and management are important, particularly in children younger than 2 years. Physicians who treat injured children must recognize and understand these important distinctions so that the resuscitation process addresses the special needs of the child. The principle of a trimodal pattern of trauma-related mortality and morbidity in adults must be modified

266

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Leading Causes of Fatal Unintentional Injury Children 14 and under, 2000

.

Leading Causes of Nonfatal Unintentional Injury Children 14 and under, 2001

C I I I ; I ~ C01'

fitt:~l ; I I I ~ ~i l li e( ~s I I ~ I c I I . ~ I I

agc3c1 1 4 ).(.;IIS : ~ n t ly o u n g c l i l l t l l c l ' i i i t c . t l SI:IICS, 2 0 0 0 - 2 0 0 1 . ( F Y O ~ I I N i l ~ i o n ; ~( l; ~ I I I C Y f i ) ~ l. l c : d t 1 1 S t ; ~ t i s t i c . s ,( : ~ I I I ~ I 101. . S I)isc;~sc ( : O I I I I ~ O I: I I I ( ~ I ' I ~ ( ~ V C I I I ~ O N;iiio11;11 II: F.lc(~t~~o~~ic I I + I I . ~ S I I I Y ( ~ ~ I I ; I I I S( ~~CS I CAI lIl I111j11i.y

Motor vehicle Occupant Bicycle 4% 4%

Other

I'CIX

I I O I I ~ ~ I I ;I II~I I ~ I I I ~ I I I ~ i~ ~I !I ~j ~I ~~

2%

Falls

36% owning

Firearm 2%

Against

1%

for children. In the trirnodal model, the first mortality peak ;\inong i11j1u.ed children occurs within seconds or minutes afier injury, due to damage to the central or peripheral nervous system and the central vasculature. Survival call be improved in this group only through pi-evention efforts. The second mortality peak occurs minutes to houi-s aftel- injury and is due to mass lesions in the central Iler\rotrs system (CNS), usually subdural and cpid111.;11 hernatoril;~s;solid organ injury; or collections oi' fluid in the pleural and pericardial spaces. These inj~lriesrequire r;ipid identification and treatment because resuscitation is shorter in chilthe time limit f i ~effective dren than in adults by as much as 50%; the Advanced Tra~umalA'r S11ppo1-tprotocol focuses on such injuries. Although initial physiologic compensation may have been sufficie~~t to achieve some temporary accommodation, progi-cssive dysfi~nctionand exhausted reserves bring about a cl-itical impairment of oxygen delivery and the child's eve~itualdemise. Advances in the aggressive and systci~~;~tic delivci~yof' emergency medical services f i x children h;~vchad a salutary effect on preventable death in children. The third mortality peak occurs days to weeks fie^- the initial injury and is the result of complications of' i i j u ~ ysuch as sepsis and systemic inflarnrnato~yresponse syndrome, leading to multiple organ failiu-e syndrome.lVhis late peak in traumarelated mortality is less frequent in younger children.

PRINCIPLES OF RESUSCITATION

Dog bite 2%

twice that of adults in thc out-of~hosl>ital ~)hascoi'~.c.s~iscitation. Similarly, tllc s~~rvival rate f0r ()lit-of-hospital cardiac arrest in children is only half' that of' adlllts.1' Although part of this discrepancy results fi-on1 the diilkl-ent causes of cardiac arrest in children and adults, ~mfamiliarity and inadequate training with childr-en also (,ontributes to poor outcome. The fhi1ur.e rate fiw resl~scitationinterventions in the field is twice as high in cllildrcn as in adults; the failure rate {Or prehospit;il cndolr;~c.llcal intubation in children is close to 5O'%.li Unt:nrnili;~rity with pediatric resuscitation skills is undcrstandahlc; although trauma is the most common indication fiw pediatric ambulance transport, it accounts fi)r lcss than 10'%1of'total paramedic patient volume in most metropolitan areas. The most important objectives for emergency pcrsonnel in the field are:

1. Recognition and treatment of' immediate lift-threatening dysfu~lction. 2. Assessment of the mechanism of trauma and extent of injuries. 3. Documentation of pertinent medical d;~t;i. 4. Triage to an appropriate-level pediatric trii1111l;ifi~cility. Added to these are the challenges of comfi)rting a tei-rified and hurt child as well as the distraught pa~.cnts. Thus, the paramedic's task can be forniidahle. Consequently, prehospital personnel fi~nctionbest by adopting strict protocols to treat in-jured children. The priorities and techniques associated with pediatric field resuscitation are similar to those for emergency department care described later.

Prehospital Care Systematic management is essential to an injured child's sulvi11al. The resuscitation process begins when emergency transport personnel first encounter the child in the field. The fate of any child can turn o n the decisions and interventions that ti-anspil-e during these first crucial moments. The inj~u-y-acijusteddeath rate for children is

Primary Survey and Treatment of Life-Threatening Injuries When an injured child encounters medical personnel, whether in the field o r in the emergency room, events should transpire in a rapid sequence designed to

CHAPTER

15

recognize and treat acute injuries. This systematic approach allows the standardization of diagnostic and treatment decisions so that individual variations in patterns of injury do not prevent caregivers from recognizing and treating subtle injuries that can have a profound impact on outcome. This systematic framework comprises a primary survey, a resuscitation phase, and a definitive secondary survey. The primary survey is the initial process of identifying and temporizing injuries that are potentially life threatening and follows the ABCDE sequence: airway, breathing, circulation, disability, and exposure. The system relies on simple observations to assess physiologic derangement and immediate intervention to prevent death.

Airway and Cervical Spine Control Provision of airway control is perhaps the least controversial of all priorities in pediatric trauma management. The inability to establish and maintain a child's airway, leading to hypoxia and inadequate ventilation, continues to be a common cause of cardiorespiratory arrest and death. Significant clinical hypoxia is suspected when oxygen saturation is less than 95%. Assessment of the airway includes inspection of the oral cavity; manual removal of debris, loose teeth, and soft tissue fragments; and aspiration of blood and secretions with mechanical suction. If a child is neurologically intact, phonates normally, and is ventilating without stridor or distress, invasive airway management is unnecessary. Airway patency can be improved in a spontaneouslybreathing child by the use ofjaw-thrust or chin-lift maneuvers. An airway that is unsecured because of coma, combativeness, shock, or direct airway trauma requires endotracheal intubation. A nasopharyngeal or oropharyngeal airway can improve management during bag-mask ventilation, but this is a temporizing measure until definitive control is established. In most cases, orotracheal intubation with in-line cervical spine stabilization is the preferred approach to airway control. Although nasotracheal intubation is recommended in nonapneic adults with potential cervical spine injuries, this approach is not indicated and is poorly tolerated in children. Pediatric ainvay anatomy is unique and affects management technique. The child's larynx is anatonlically higher and more anterior than in the adult, necessitating an upward angulation of the laryngoscope to place the endotracheal tube properly. Removing the anterior half of the rigid cervical collar allows access to the neck for gentle cricoid pressure. The pediatric epiglottis is shorter, less flexible, and tilted posteriorly over the glottic inlet. Because of this, direct control of the epiglottis with a straight blade is usually necessary for proper visualization of the vocal cords. The vocal cords themselves are fragile and easily damaged. The narrowest point in the pediatric ainvay is the subglottic trachea at the cricoid ring, as opposed to the glottis in adult patients. Therefore, passage of the endotracheal tube through the vocal cords does not guarantee safe advancement into the trachea or avoidance of subglottic injury. Appropriate endotracheal tube selection is an important part of pediatric resuscitation. The internal diameter can range from 3.0 to 3.5 mm in newborns to 4.5 mm at 1 to 2 years of age. After 2 years of age, the internal diameter can

Accident Victims a n d T h e i r Emergency Management

267

be estimated by the following formula: Internal diameter = Age/4 + 4. Approximating the diameter of the patient's little finger is also useful. Because of the narrow subglottic trachea, an uncuffed endotracheal tube is indicated in children 8 years of age or younger (Fig. 15-2).1 1-13 The technique of intubation depends on the urgency of establishing an airway. In a hypotensive, hypoxemic, comatose child, orotracheal intubation is accomplished without delay as an integral part of the resuscitation. In a more elective situation, more attention is given to adequate preoxygenation by bag-mask ventilation with 100% oxygen and premedication. Thoracic trauma can preclude intubation or make attainment of adequate oxygen saturation impossible. Inducing hypocarbia (carbon dioxide partial pressure [Pac:02]30 to 35 mm Hg) by hyperventilation is advantageous. Following preoxygenation using mask ventilation, children should receive atropine sulfate (0.01 to 0.02 mg/kg) to ensure that the heart rate remains high during intubation. It is important to maintain an adequate heart rate because this is directly proportional to cardiac output; stroke volume does not change much in children. Also, children should be premedicated with intravenous sedatives and muscle relaxants. Appropriate sedatives include short-acting barbiturates such as thiopental sodium (5.0 mg/kg) if volume status is normal or a benzodiazepine such as midazolam (0.1 mg/kg) if hypovolemia is suspected. Muscle relaxation is achieved with short-acting nondepolarizing agents (vecuronium bromide 0.1 mg/kg) or shorter-acting depolarizing agents (succinylcholine chloride 1.0 mg/kg) . The presence of burns and devitalized tissue precludes the use of succinylcholine because of the risk of hyperkalemia. Continuous monitoring of an intubated child with end-tidal Co, and pulse oximetry is essential. In the rare case when tracheal intubation is not possible as a consequence of oral or maxillof'acial trauma or congenital anomaly, a surgical airway is indicated. A surgical cricothyrotomy is the preferred approach in children older than 10 years. The cricothyroid membrane is easily exposed through a transverse skin incision to accommodate placement of a small, uncuffed endotracheal tube. Morbidity is lower than with an emergency tracheostonly because of the superficial location of the cricothyroid membrane. The cricothyrotomy should be converted to a formal tracheostomy when the child is stabilized, to avoid subglottic stenosis. In small children, the cricoid cartilage is a delicate structure and provides the rnajority of support to the trachea. Injury of this membrane during emergency cricothyrotomy can lead to significant morbidity and lifelong laryngotracheomalacia. To avoid this complication, children younger than 10 years should undergo needle cricothyrotomy andjet insu!Tlation of the trachea. A 16- to 18gauge intraverious catheter is used to access the tracheal lumen through the cricothyroid ine~nbraneand is connected to a 100% oxygen source at a high flow rate of 10 to 12 L,/miiiute. Needle-jet ventilation is limited ill children by the hypercarbia that occurs ill approximately 30 minutes; therefore, this method is effective fi)r only a short time. Following stabilization of' the child, endotracheal intubation or formal tracheostorny is necessary.1"

268

PART

I1

TRAUMA

. .. .,.y -

i

.

F -

End

nx and supraglottic space are anterior and angled cephalad compared with the

position in adults. A posterior neck roll optimizes visualization of the vocal cords in children. B, The tongue is large relative to the space in a child's oral cavity. The tongue should be moved to one side of the oral cavity to facilitate exposure of the posterior pharynx and supraglottic area. C,The laryngoscope blade is inserted from the right side of the mouth and slides back along the vallecula. 0, With the blade in the proper position and the child's neck slightly extended in the sniffing position, lifting the handle (positions 1, 2, 3) raises the epiglottis and brings the vocal cords into direct vision. E, In all except newborns, the straight blade should be placed over the epiglottis to lift it, along with the base of the tongue, to expose the larynx. A stylet with the tip curved within the endotracheal tube facilitates successful intubation. The endotracheal tube is held in place while the laryngoscope is removed and secured after verification of bilateral breath sounds. (From Eichelberger MR: Pediatric Trauma, Prevention, Acute Care, Rehabilitation. St. Louis, Mosby, 1993.)

Breathing Compromised breathing and ventilation in an injured child are usually the result of either head injury (impaired spontaneous ventilatory drive) or thoracic injury (impaired lung expansion). Recognition of a head injury is usually obvious, but recognition of a thoracic

injury that impairs lung expansion requires a detailed survey. The potential seriousness of these injuries is underscored by the fact that mortality rates for thoracic trauma in children approach 25%.14 Following thoracic trauma, air, fluid, or viscera can compromise the pleural space. Compression of the pulmonary parenchyma can result in impaired gas exchange sufficient

CHAPTER

15

to produce respiratory distress. In the case of traumatic rupture of the diaphragm, loss of muscular integrity also has a direct effect on lung expansion. The child's mediastinum is extremely mobile; as pressure increases in the pleural space, the mediastinum is displaced to the opposite side, causing compression of the contralatera1 lung. The distortion of mediastinal vascular structures, along with elevated intrathoracic pressure, can result in a critical reduction in venous return. Loss of chest wall integrity from flail chest impairs ventilation and oxygenation. Consequently, paradoxical chest wall movement occurs during inspiration, preventing complete lung expansion; assisted positive-pressure breathing is the best treatment. Because of the flexible nature of a child's chest, the force required to fracture multiple ribs is enormous and is transmitted to the underlying lung parenchyma, resulting in a pulmonary contusion. Regions of parenchymal hemorrhage and edema impair ventilationperfusion matching, and the decrease in pulmonary compliance can dramatically increase the work of breathing; both can precipitate ventilatory failure. Recognition of ventilatory compromise is usually not difficult, especially with a high index of suspicion. The sound of air movement at the mouth and nares is assessed, as are the rate, depth, and effort of respirations. On inspection, asymmetrical excursion of the chest wall suggests a ventilatory abnormality. Percussion elicits dullness or hyperresonance, depending on the presence of fluid or air in the pleural space, and breath sounds are decreased. With tension hemopneumothorax, mediastinal shift can be detected by tracheal deviation, displacement of the point of maximal cardiac impulse, and distended neck veins caused by impaired venous return. Mechanical ventilatory failure is life threatening and requires immediate treatment during the primary survey. All children require supplemental oxygen by nasal cannula, mask, or endotracheal tube. Endotracheal intubation and assisted ventilation are sufficient to treat hypoventilation due to head injury, pain from rib fractures, flail chest, and pulmonary contusions. Simple hemopneumothorax may be well tolerated with supplemental oxygen until tube thoracostomy can be performed after the primary survey (Fig. 15-3). In cases of hemopneumothorax that results in compromised ventilation or hypotension, tube thoracostomy is required, often combined with endotracheal intubation and intravenous access for rapid fluid infusion. If tension is present, the hemodynamic derangements can be minimized by needle thoracostomy in the second intercostal space at the midclavicular line, followed by thoracostomy tube placement. A chest tube of adequate caliber to evacuate blood and air should be inserted into the pleural cavity. The narrow intercostal space of a small child usually limits the size of the tube, but the largest-caliber tube that can be placed should be used. The tube is placed in the midaxillary line at the nipple level (fourth or fifth intercostal space) to avoid intra-abdominal placement through an elevated diaphragm. The tube is directed posterior and cephalad, to evacuate both blood and air, and is connected to a Pleurovac closed-suction drainage system set at -15 cm H 2 0 (see Fig. 15-3).Persistent hemorrhage

Accident Victims and Their Emergency Management

269

from a thoracostomy tube is uncommon in children; however, drainage of 1 to 2 mL/kg per hour is a sign of significant ongoing bleeding from a vascular or mediastinal injury that may require thoracotomy to identify and control the source. When endotracheal intubation has been performed, the child's fraction of oxygen in inspired air should be loo%, with a tidal volume of 10 to 12 cc/kg at a rate of 15 to 20 cycles/minute. Oxygenation and ventilation should be manipulated to maintain an arterial oxygen ~ tension (PO?) greater than 80 mm Hg and a P C Oof 30 to 35 mm Hg, with a positive end-expiratory pressure not to exceed 5 cm H 2 0 . The goal is to prevent secondary brain injury by optimizing oxygenation and cerebral perfusion by minimizing intracranial pressure (ICP). Children with head trauma are best managed by moderate hyperventilation and hypocarbia (Pco, 30 to 35 mm Hg) to reduce ICP.6,13,18

Circulation and Vascular Access The third priority in the primary survey is the rapid assessment of circulation and the establishment of venous access. Seriously injured children often have normal vital signs, even with significantly decreased circulating volume; their cardiovascular reserve delays the early hemodynamic signs of hypovolemia until relatively late in the resuscitation phase. A high index of suspicion based on the mechanism of injury and continuous careful scrutiny of physiologic parameters and clinical signs are necessary to minimize morbidity. A reliable sign of adequate perfusion is normal mental status. As the child is resuscitated, clinical signs of the efficacy of resuscitation should be monitored. Improvement in the following parameters is consistent with hemodynamic stability and success of resuscitation:

1. 2. 3. 4. 5.

Slowing of the heart rate (20 mm Hg). Return of normal skin color and peripheral perfusion. Increased warmth of extremities. Clearing of the sensorium (improving Glasgow Coma Scale score). 6. Increased systolic blood pressure (>80 mm Hg). 7. Urinary output of 1 to 2 mL/kg per hour in infants and 1 mL/kg per hour in adolescents.

After establishment of an adequate airway, provision of venous access in a hypovolemic child is often a challenge. Two functioning catheters are best in all cases of significant injury. Optimally, venous access should be achieved above and below the diaphragm, given the potential for extravasation of resuscitation fluids from occult intra-abdominal venous injuries. Nevertheless, in children, any peripheral venous access is useful. Two attempts should be made to place large-bore peripheral lines in the upper extremities. If percutaneous placement is unsuccessful, insertion of an intraosseous line is useful in a child younger than 6 years (see later). In children older than 6 years, a venous cutdown performed at the ankle is best. The greater saphenous vein is easily exposed through short transverse incisions 0.5 to 1 cm proximal and anterior to the medial malleolus.

270

PART

I1

TRAUMA

, Thoracostomy tube insertion. A, An incision is made in the midaxillary line just below the nipple in a male or inframammary fold in a female (fourth intercostal space). B, The dissection is carried out in a cephalad direction subcutaneously over two ribs. A long subcutaneous track is preferable in a child to minimize air leak around the tube. C, The fourth intercostal space is the ideal place for thoracostomy tube placement. 17, The entrance into the pleural space should be made just over and superior to the rib to avoid injury to intercostal vessels. E, Lateral view of the technique. (From Eichelberger MR: Pediatric Trauma, Prevention, Acute Care, Rehabilitation. St. lmuis, Mosby, 1993.)

T h e exposed vein is suspended over a silk ligature, and t h e largest appropriate i~ltravenouscatheter is introduced r vision. Transection o r i n t o t h e vessel lume11 ~ u l d e direct ligation o f t h e vein is n o t necessary (Fig. 15-4). Central vexlous catheterization can result i n significant complications, s u c h as laceration o f t h e subclavian o r femoral artery, rnakirlg it a less useful technique. T h e femoral r o u t e is preferred because o f ease o f access. I f subclavian v e n o u s access is necessary, t h e child should b e placed i n t h e T r e n d e l e n b u r g position with t h e head maintained i n a neutral position without t h e placement o f a posterior shoulder roll. T h i s positio~i provides

optimal cross-sectional area o f t h e subclavian vein i n b o t h children a n d adults.12 An intraosseous line is a simple, reliable, and safe route for t h e administration o f fluids, blood products, a n d medications. T h e t e c h n i q u e is applicable i n children 6 years o f age and younger because t h e marrow is well perfused i n early childhood. T h e preferred site for intraosseous i n s e r t i o n is t h r o u g h t h e flat a n t e r o m e dial surface o f t h e tibia, about 2 t o 3 c m below t h e tibia1 plateau. T h e needle is angled 60 degrees f r o m horizontal a n d pointed toward t h e foot. T h e cortex is penetrated, and t h e marrow cavity is detected b y aspirating

CHArTeu

15

blood arid particulate material. Alternative sites include the midline distal femur, 3 cm above the condyles directed cephalad i r i sinall children, arid the distal tibia above the 111edi;llrnalleolus or the proximal humerus in adolescents, although the need for an intraosseous line is I :ti e in this age group. Specially designed intraosseous needles shot~ldhe available in the pediatric resuscitation roo111to facilitate this maneuver; however, a 1 4 to lcgauge needle can be used. The coinplication rate is low, but potential coniplications include osteomyelitis, cellulitis, fi-actwe,growth plate injury, fat embolism, and compartment syndrome. As soon as vascnlar access is established, fluid resuscitation with ;I bolus of fluid is begun. Generally, isotonic cryst;~lloidsolution, such as lactated Ringer's solution, is ;~dniinistei-cd in 20 mI,/kg increments. If evidence of

Accident Victims arid T h e i r Emergency M a ~ ~ a g e ~ l ~ r ~271 lt

hypovolemia persists after 40 mI,/kg has been given, tl-ansfi~sionof ABO-matched packed red blood cells is initiated in a bolt~sof' 10 1n1Jkg. Packed red blood cells have the advantages of raising colloid oncotic pressure and effecting a AOI-crapid and sustained intravascula~expansion than ciystalloid. In addition, the red blood cell provides hemoglobin to increase oxygcn carrying capacity. All fluids (crystalloid, colloid, and blood) should be warmed during iiifi~sion.This is accolnl)lishcd by microwaving crystalloid solutions oi- using a warrning device. It is important to reassess the child's I-csponsct o I-csnscitation contirlually. to characterile the nati11-cand extent of the injuries, and to avoid the coniplic;jtions of cxccssive fluid resuscitation. As pel-fi~sionis restored, the rate of fluid infusion is gradually reduced to avoid unnecessary fluid administra6on. Puliiionary c d e ~ n ararely occurs i n

a

-

(;rc;~tcrs;lplw~io~isv\'c.i~i c.;~nnulatiotl

A, <:011sistentemergency \.enous ;tc.crss is ;~chicvc*d

Medial malleolus

at the ankle, atltcrior to the 111rdi;d~ t i i ~ l l e ovia l ~ ~illc s saphrno~tsvein. R, A i~.ansvc~-sc incisio~iis tilade anterioi- to thc 1nedi;ll m;rlleol~~s ( 1 ( I I I ; I I I ~ ~ I . ;111d ~ ~ I 1 cm cephalad). Perl,ct~dicula~d i s s r c t i o ~in~ tlic. incision exposes the sal~licnousveiii. (,', TIic vcin is disscctcd cii.curntcrc~~ii;lIly. I), A S I I ~ I Ilig;~tui.c I-c is passed around the vessel. I(;ltid 1; (;c1111ct ~ ; l c t i o ~ ~ o n thc sut~u-c ficilit;%lcs c n i l ~ c t c ~ ~ . i l ; ~ofi i ot11c ~i (From Eic11elhe1-gct-MU: I'rdi;~ti.icl't.;~u~na. Prevention, Ac~tte(:arc, Reli;lhilit;~tion.St. I.ouis, Mosby, 1993.)

272

PART

I1

TRAUMA

normal lungs, but considerable morbidity results from fluid sequestration in a region of pulmonary or cerebral contusion. If hemodynamic stabilization does not occur with crystalloid and blood resuscitation, hemorrhage is likely from an intra-abdominal or pelvic source, cardiac dysfunction due to tamponade or contusion, tension hemopneumothorax, cerebrospinal injury such as atlantooccipital dissociation, or profound h y p ~ t h e r m i a . ~ , ~ "

Disability A rapid neurologic evaluation is included in the primary survey to identifjiserious injuries that may have immediate consequences for airway management. A rapid method for describing gross cerebral function is the AWU mnemonic: alert, voice responsive, pain responsive, or unresponsive. An assessment of pupillary responsiveness and symmetry is also useful. Transtentorial herniation secondary to an expanding intracranial hematoma causes ipsilateral pupillary dilation and loss of light reflex. Direct trauma to the eye is an equally common cause of unilateral anisocoria, but this is usually obvious. Characterization of extremity posturing as decorticate or decerebrate indicates the loss of cortical or global brain function, respectively. In a comatose child with a unilateral fixed and dilated pupil, measures to reduce ICP are imperative. These include early controlled endotracheal intubation to keep the Pco,, regulated (30 to 35 mm Hg) with moderate hyperventilation, which causes cerebral vasoconstriction and decreases cerebral blood flow. This lowers brain volume and ICP, with a resulting increase in cerebral perfusion pressure (CPP). The reverse Trendelenburg position, in which the head is elevated 30 degrees, can also reduce intracranial hypertension but should be used only in children with normal cardiac function.

Exposure Complete exposure of the child is essential to facilitate a thorough examination and identification of injury. A conscious child does not understand the need for such action, so exposure must be done carefully. A thorough primary survey on a stable child with a normal Glasgow Coma Scale score can be performed without removing all items of clothing simultaneously. Children are particularly apprehensive about pain when exposing an injury that was previously covered, so attention to these special sensitivitiesfrequently results in a more efficient evaluation. In a child, hypothermia affects physiologic parameters, such as cognitive function, cardiac activity, and coagulation. It is important to maintain core temperature above 35°C to 36OC. A warm resuscitation room preserves core body temperature and minimizes heat loss. Similarly, resuscitation fluid and inhaled gases should be warmed and humidified. Overhead and bed warmers are essential, but a radiant warmer is best for an injured infant.

Resuscitation Phase The cornerstone of resuscitation is continuous reappraisal of the child's response to therapeutic intervention. Deterioration at any point requires repetition of the

primary survey. After the ABCDEs are complete and life-threatening injuries are stable, a gastric tube and urinary catheter should be placed, followed by the drawing of blood for analysis and placement of a cardiac monitor. In children, acute gastric dilatation can cause both respiratory compromise and vagus-mediated bradycardia. Gastric decompression to evacuate the stomach and reduce the risk of vomiting and aspiration is important in all injured children, especially those with a decreased level of consciousness. Assessment for a stable midface and for the presence of cerebrospinal fluid rhinorrhea is important before the placement of a nasogastric tube for decompression. If the assessment is abnormal, oral gastric tube placement is in order. A urinary catheter is also placed following a thorough perineal assessment, including a rectal examination. In instances of a high-riding prostate, meatal bleeding, perineal or scrota1 ecchymosis, or unstable anterior pelvic fracture, a retrograde urethrogram is indicated before insertion of the catheter. An electrocardiogram is essential to monitor cardiac rhythm, which is rarely abnormal. Secondary abnormalities are occasionally seen and include sinus bradycardia due to advanced shock; electromechanical dissociation from hypovolemia, tension pneumothorax, or pericardial tamponade; and ventricular fibrillation due to hypothermia or acidosis. Ventricular ectopy, low voltages, and signs of ischemia can accompany myocardial contusion. Beyond evaluating the actual rhythm, diffuse low voltage may be the first indication of hemopericardium. After vascular access is obtained, blood and urine are obtained for laboratory analyses, including complete blood count and metabolic studies, urinalysis, and arterial blood gas analysis. Blood alcohol level and a toxicology screen are not routine in children but reasonable in adolescents. Blood should also be drawn for type and cro~smatch.~,~

Neuroresuscitation Brain injury is the most common cause of acquired disability and mortality during childhood. It is estimated that each year, 1 in 500 children in the United States sustains a brain injury, 7000 children die from head injuries, and 28,000 children become permanently disabled.IJ0Largely as a result of prevention strategies and regional trauma systems, the overall mortality from severe traumatic brain injury has decreased from approximately 50% in the 1970s to 36% today. In children, the current overall mortality from injury is 3%; the primary cause of death in 70% of cases is central nervous system injury. Overall, the outcome for children older than 3 years is better than for adults with comparable injuries; however, outcome in children younger than 3 years is often p ~ o r . ~ , l " l ~ Traumatic brain injury can be defined as either primary or secondary. Primary brain injury is the structural derangement of cerebral architecture that occurs from direct mechanical impact, resulting in cellular and vascular disruption, infarction, or tissue loss. The child's brain is susceptible to injury of the deep white matter, shear, punctate hemorrhage, brain swelling, and linear nondepressed skull fracture, rather than mass lesions such as subdural

CHAPTER

15

and intracerebral hematomas and depressed skull fractures, which are more frequently encountered in adults. Children, however, have a higher incidence of epidural hematoma, perhaps because the thinner, less rigid skull is more apt to fracture and lacerate the meningeal artery. The proportionately larger size of the cranium in children, along with a less muscular and more flexible ligamentous cervical spine, may account for the increased incidence of diffuse axonal injury in injured children. Primary brain injury responds only to preventive efforts, whereas secondary brain injury is the target of clinical neuroresuscitation. Secondary brain injury occurs as a result of decreased cerebral perfusion following the traumatic event. Both diffuse and regional brain swelling impairs oxygen and substrate delivery largely as a result of increasing ICP and its effect on CPP. CPP, ICP, and mean arterial pressure (MAP) are related by the following equation: CPP = MAP - ICP. Resuscitation should optimize CPP by controlling ICP and maintaining MAP. When ICP exceeds venous outflow pressure (as a result of brain swelling), it acts as a Starling resistor and determines the pressure gradient for cerebral blood flow. Normal CPP values and the ideal range of ICP in children with severe brain injury are not clear.*Favorable outcomes in children are possible by maintaining the ICP less than 20 mm Hg in all ages and a CPP greater than 45 mm Hg in children younger than 8 years and 70 to 80 mm Hg in older ~ h i l d e n . ~ Efforts to reduce secondary brain injury focus on maintaining a therapeutic ICP and CPP and normalizing the MAP. The most expeditious method is intubation and controlled hyperventilation, initially reducing PCO? to 30 to 35 mm Hg, Po2 to greater than 100 mm Hg, and pH to 7.40 + 0.05. Hypocarbia and alkalosis promote cerebral vasoconstriction, limiting cerebral blood volume and lowering ICP. The effect is rapid but can be limited in duration by re-equilibration of cerebrospinal fluid pH balance. The maximal duration of the effect is unknown but may range from several hours to several days. Current therapy maintains PCO*in the 30 to 35 mm Hg range. This regimen avoids excessive hyperventilation, which may be deleterious in patients with severe brain injury by converting borderline regions of cerebral . ~ ventriculostomy is usually ischemia into i n f a r c t i ~ nA placed, allowing cerebrospinal fluid to drain to further optimize CPP. A repeat head computed tomography scan is indicated 24 to 48 hours after injury to assess the extent of brain edema, identify new infarcts, or demonstrate the development of a new hematoma or large contusion that may require evacuation. The status of ventilation and fluid hydration should be reassessed and optimized frequently in the first 48 hours. If these measures fail to control ICP, osmotherapy is undertaken with a rapid bolus intravenous infusion of 20% mannitol at a dose of 0.25 to 0.5 g/kg - every 4 to 6 hours. Mannitol is withheld if the serum sodium concentration is greater than 145 mEq/L, serum osmolarity is greater than 310 mOsm, urine output is less than 0.5 mL/kg per hour, or blood pressure is low. Mannitol exerts a therapeutic effect by creating a hyperosmolar environment in the cerebral microcirculation; this improves brain oxygen delivery by exerting a diuresis of free water from the cerebral interstitium, which improves blood flow.*

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273

The induction of mild to moderate hypertension may reverse abnormal ICP and raise CPP by improving brainstem microvascular perfusion.16 Therapy is begun with an intravenous infusion of dopamine at a dose of 5 to 20 pg/kg per minute. Hyperthermia and seizures are common after traumatic brain injury and can adversely affect efforts to normalize ICP and CPP. Both fever and seizures promote further secondary brain injury by increasing the metabolic demands of the already compromised brain. Therefore, core temperature should be maintained in the normal range (35" C to 36' C) with acetaminophen 10 mg/kg every 4 to 6 hours. Cooling blankets may be necessary for recalcitrant fever. A single seizure in a child following head injury and a subsequent normal neurologic assessment does not require treatment. Seizures that occur within 1 week after injury are treated with phenobarbital in children younger than l year and with phenytoin in those older than 1 year. Either drug is administered in a one-time intravenous dose of 10 to 20 mg/kg, followed by daily dosage of 5 mg/kg. Treatment is discontinued after 7 days. Children who develop late seizures require long-term anticonvulsant medication. Whether a comatose child who has not demonstrated seizure activity requires anticonvulsant prophylaxis during the resuscitation process is controversial.

Coagulopathy Dysfunctional coagulation related to injury occurs in several circumstances: extreme hypothermia, massive transfusion, and severe brain injury. Hypothermia causes excessive bleeding by reducing the efficiency of enzymatic processes that promote coagulation. Massive transfusion, defined as the acute administration of blood products equal to or greater than one blood volume (65 to 80 mL/kg), also causes coagulopathy. Another mechanism results from the storage of blood in anticoagulants containing ethylenediaminetetraacetic acid or citrate (citrate-phosphate-dextrose), both of which chelate calcium and inhibit the calcium-dependent steps of the coagulation cascade. Acute hypocalcemia is another consequence of massive transfusion. The most common mechanism by which massive transfusion causes coagulopathy is dilutional thrombocytopenia. Coagulopathy due to dilution of other clotting factors is much less common because of a much greater functional reserve of these components. As continued hemorrhage depletes circulating platelets and blood is replaced with red blood cells, a progressive reduction in the platelet count ensues. With acute injury, a reduction in the platelet count to 50,000 can produce surgical bleeding. Platelet levels below 100,000 signify impending coagulopathy, and levels of 50,000 or less require platelet transfusion. Administration of ABO-matched platelets at an initial dose of 0.1 U of concentrate/kg or 4 U/m2 of body surface area raises the platelet level by about 40,000. Severe head injury is also associated with coagulopathy unrelated to platelet dilution. Presumably, large amounts of procoagulant tissue thromboplastin are released from injured areas of the brain, initiating disseminated intravascular coagulation and a consumptive coagulopathy

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in which all clotting factors and fibrinogen are depleted, as well as platelets. <:oagulopathy after head illjury is a grim prognostic sign. Treatment requires administration of matched ti-esh frozen plasma at a dose of 15 to 30 mL/kg. amounts of fibrinogen, (:ryoprecipitate c o n t a i ~ ~large s factoi- VIII, factor XIII, and von Willebrand's factor and can be given at a dose of 0.1 U/kg in addition to fresh fi-oxcn pl;isma. Admi~~istration of fresh frozen plasma, cryoprccipikltc, o r both may also he required in the setcoag~ilopathiessuch as hemophilia, ting of' ~m~existiiig von M'illcl,r;lnd's disease, alitl advanced liver disease.'"

PAIN MANAGEMENT The primary goals of acute pain management are to rcd~icethe sti-css on the injured child and to improve ontcoine. Acute pain s r ~ - \ ~as c s a i~oxiousstimulus that Ic;lds to activation of'the physiologic stress response. The 1.cs11ltis ;lcti\.a~ionof'thc ne~~rocndocrine response, which has a 1~1-ofi)undiind deleterious rffect o n metabolism, thermoi-cgt~latioi~, wound healing, and immunity. T h r fi~llowingare critical elements in the management of' pa it^ in inj~u-cdchildren: 1. An cxprrienced ii1terdisciplina1-yteam, led by a clinician devoted to pail1 management. 2. A cori~niitrncntto ensure the least possible pain. 3. Recognition that rffective pain managcrnent requires const;tnt adjustri~cnt. 4. Recognition that anxiety needs to he considered and ti-ciitcd bec;it~seit may altei- the effectiveness of pail1 trcatlnellt. 5. ?'he ability ;1nd knowledge to effectively use all pain thcrapy in I-eal-tirne coordination with the rest of the child's supportive care and treatment plan. A team-oriented, protocol-based algorithm that attempt? to control pain i11 this environment will enhance the overall success of' the emergency management of these children."

CONCLUSION A systematic approach to injured children can save lives. Nevertheless, prevention of injury is essential. T h c unintentional injury death rate among children has declined nearly 40% during the past 16 years."' The most notable progress in prevention has beer1 a 72% decline in childhood deaths from unintentional firearm i~lj~lrics and a 60% decline in deaths from bicycle-related i~ljtuies.The death rate from fire and burn injuries declined 56%, while that from pedestrian injuries dropped 51 %. Unfortunately, the motor vehicle occupant death rate, particularly among children aged 5 to 9, has been slow to decline, and the death rate from airway obstn~ctioninjury among infants remains unchanged. Many Factors have contributed to the overall dramatic decline in the unintentional childhood injury death rate. It is clear that the highest priority should be on injury prevention, with a particular emphasis on minimizing the injury risk to minorities, younger children, and inotor vehicle occupants. Once injury occurs, however, proper resuscitation can save lives.

REFERENCES 1. Centers for Disease Co11tr-ol:(:l~iltlhood iniuries in the United States. Am.] l)is i:hild 1990;144:(i'L7-(i4(i. 2. Centers f < ~Disease r (:oritrol and 1'rc.vcntion: Wcl1-hascd Injury Statistics Qnery and Reporting Systc>ni(W'ISQAKS). Fatal Injury Reports 1999-2000. National (:cntcr fi)l-Irljul~ Prevention and Control, (:cntc3rsfix I)isc;~sc(:ontrol and Prevention. Available at www.cdc.go\~/nci~,c/wisqa~~s. 3. Chambers IR, Trr,adwell I., Mrndclow AI): I)ctcr~nination of threshold levels of cerebral pcrfi~sion pressure and intracranial pressure in ~e\~c.rcIicad injr11.y 1,y using receiver-operating characteristic cit~.vcs:An o1,servational study in 291 patients.J Nc~~rostlrg 2001 ;!14:4 12-4l (i. 4. <:l-iildren's Safety Nctwork, Economics and Insr~rance Resonrce Center: Special run: Hoslti talizc,d 11ninten tional injury among children 15 and r~ndcr.1;eh 2003. 5. Chn UB, Clevenger FW, Ilnani ER, ct ;+I:'l'hc in11);lc.tof' selective laboratory evaluation o n ~~tilization of' laboratory resollrces and patient call in :I Icvcl 1 tralllrla ccntcr. Aln J Surg 1996;172:558-562. 6. <:ornmittee on Quality Inlprovc~ncnt,Amc~.ic.anAcademy of Pediatrics, and Commission o n i:linici~lI'olicies and Research, American Academy o f ' Family 1'hysici;ins: The management of niinor closed head it!jltt.y i l l chiltlren. Pediatrics 1999;104:1407-1415. 7. <:ommittee on Trauma of the Alnc~.ican <;allege of St~rgeons:Advanced Trauma I.ili. Su\)l)ort instructor Manual. Chicago, American (:ollcgc 01 S~~r.geons, 1997. 8. Faillace WJ: Management of cliiltlllood ncl11.otlatllna. Su1.g Clin North Am 2002;82:349-363. 9. Golianu B, Krane EJ, Galloway KS, Yastcr M: Acute pain in children: Pediatric acute pain managclncllt. I'cdiatr i:lin North Am 2000;47:1-24. 10. I(ra11s.JRRoltk A, Heniyaris P: Brain illjury among infants, Aln ,j Dis i:hild children, adolescents, and young ad~~lts. 1990;144:684691. 11. 1,osek JD, Bonadio WA, Walsh-Kelly <:,ct al: I'rehospital pediatric endotracheal intubation pcrfit~.mance review. Pediatr Emerg Care 1989;5:1. 12. 1,nkish J , Valladares E, Bulas 11, et al: i:lassic;tI positioning decreases subclavian vein cross sectional area i l l children. J Tr-anma 2002;53:272-275. 13. Magnnson DK, Eichelberger MR: Apprt~achto the pediatric trauma patient. In Surgery of Infants and i:hiltlren. Philadelphia, 1,ippincott-Raven, 1997, pp 391-414. 14. I'eclet MH, Ncwman KD, Eichelberger MR, ct al: Thoracic traltna in children: An indicator of increaseti ~nortality. J Pediatr Surg 1990;2.5:961. 15. RarnenoE5ky MI,, 1,uterman A, Q~~intilen E, et al: Maximum survival in pediatric trauma: The ideal system. J Trauma 1984;24:818. 16. Rosner MJ: Pathophysiology and management of increased intracranial pressllre. In Andrcws BT (ed): Nelrros~~rgical Intensive <:are. New York, MrGraw-Iiill, 1993, pp 57-1 12. 17. Scheidt PC, et al: The epidemiology of nonfatal irljr~ries among US children and youth. Am J Public Health 199.5; 85:932-938. 18. Stafford PW, Blineman TA, Nance MI,: Practical points in evaluation and resuscitation of the injured child. Surg Clin North Am 2002;82:273-302. 19. Taylor GA, Ei~helherg~r MR: Abdominal <:T in children with neurological impairment following blunt trauma. Ann Surg 1989;210:229-233. 20. Wallace AI,, Cody BE, Mickalide AD: Report to the Nation: Trends in Unintentional i:hildhood 1nj11ry Mortality, 1987-2000.Washington, D(:, National Safe Kids Campaign, May 2003.

Thoracic Injuries --

David E. Wesson

EPIDEMIOLOGY AND PREVENTION

The most common thoracic injuries are lung contusion, pneumothorax, hemothorax, and fracture of the ribs, Injuries to the chest wall, diaphragm, lungs, and medisternum, or scapula. Injuries to the heart, aorta, trachea, astinal structures occur in about 25% of children treated bronchi, and diaphragm are much less common but in level I pediatric trauma centers, usually after highenergy potentially more dangerous. The most common immediately blunt or penetrating trauma. Low-energy mechanisms, life-threatening injuries to the chest are airway obstrucsuch as simple falls from playground equipment, seldom tion, tension pneumothorax, massive hemothorax, and cause chest injury. Thoracic injuries range in severity cardiac tamponade. Open pneumothorax and massive from minor to rapidly fatal, but virtually all chest injuries flail chest are rare. The most common potentially lifecan be treated successfully if they are promptly diagnosed. threatening injuries of the chest are myocardial contusion, Although chest injuries are less common than injuries to aortic disruption, ruptured diaphragm, tracheobronchial the abdomen, soft tissues, and extra-axial skeleton, they disruption, and esophageal rupture. are more lethal. Because of the impact required to cause The relative incidence of blunt and penetrating thoracic such injuries, patients have a significant risk of mortality. trauma varies widely, depending on the amount of violence In fact, thoracic injuries account for a high proportion of in the community. Peterson et a1." reported a large series all trauma deaths not caused by central nervous system (CNS) injury. As with most types of pediatric trauma, the male-tofemale ratio is between 2:l and 3:l. Thoracic injuries can be classified by anatomic site (e.g., rib fracture, pulmonary contusion, bronchial laceration), mechanism (blunt or penetrating), or threat to life (immediate or potential). Although most serious blunt injuries to the chest are Blunt Penetrating Total (%) *motor vehicle related in all age groups, the proportion of children injured as pedestrians is much higher than Pneumothorax/hemothorax in adults. The causes of penetrating thoracic injuries in Pneumothorax teenagers mimic those in adults-mostly knife and gunHemopneumothorax Hemothorax shot wounds. BBs or pellets fired from air guns, although Lung often considered relatively innocuous, may also cause Contusion life-threatening injury." The causes of penetrating Laceration injuries in preadolescent children include a number of Heart other unusual mechanisms, such as impalement by shards Contusion of broken glass or metal rods.64 Laceration The most common thoracic injuries seen clinically Diaphragm are listed in Table 16-1." Autopsy series, which include Rib fractures prehospital and emergency department deaths, reveal Aorta a higher proportion of rapidly fatal major vascular and Bronchus Esophagus In adults, rib fractures are by far the cardiac inj~ries.:~ most common type of blunt trauma to the chest. In chil~ dren, pulmonary contusions are the most f r e q ~ e n t . ~ 2 , . ~ *Percentage of the total cases with each type of injury. Overall, 83% of injuries were Tracheobronchial lacerations are more common in chilblunt, 15%were penetrating, and 2% were caused by other mechanisms. dren than in adults, whereas the opposite is true for From Cooper A, Barlow B, DiScala C, String D: Mortality and truncal injury: The pediatric perspective.J Pediatr Surg 1994;29:33. traumatic rupture of the aorta.*l

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of adults and children with thoracic trauma. Blunt injuries constituted 81% of thoracic injuries in children 12 years of age or younger; penetrating injuries accounted for 58% of chest injuries in adolescents. In Nakayama and Ramenofsky's series,j8 97% of thoracic injuries in children up to 17 years of age were blunt. Meller et al.sQeported a series in which nearly all wounded teenagers had penetrating injuries. The National Pediatric Trauma Registry (NPTR) reflects the combined experience of many pediatric trauma centers across North America. From 1985 to 1991, more than 25,000 cases were reported to the NPTR, including 1553 cases of thoracic injury.l2 Eighty-six percent of injuries were blunt (mostly motor vehicle related). The remaining 14% were penetrating (mostly stab or gunshot wounds). The overall mortality rates for blunt and penetrating cases were almost identical, at 15% and 1496, respectively.l2 Mortality increases with the number of associated injuries. Most of the deaths in the group that had blunt trauma were caused by associated head injuries, whereas most of the deaths in the group with peneirating injuries resulted from the chest injuries themselves. Overall, thoracic injuries were second only to CNS injuries as the cause of death in the NPTR. Most deaths from chest injuries occur at the scene of the accident or in transit to the hospital and result from fatal injuries to vital organs. Patients with thoracic injuries who reach the hospital alive are potentially salvageable. Although the ratio of blunt to penetrating injuries varies in adults and children, the spectrum of chest injuries and the basic principles of diagnosis and treatment are the same for all ages. The most common injuries-pulmonary contusion, rib fracture, pneumothorax, and hemothorax-can be treated with simple measures such as tube thoracostomy, oxygen, and analgesia. Approximately 20% of patients with these injuries also require endotracheal intubation and mechanical ventilation, often for the management of associated head iniuries. ., Several thoracic injuries virtually always require operation: major airway lacerations, aortic injuries, structural cardiac and pericardial injuries, and esophageal perforations. One of the greatest challenges in thoracic trauma is to recognize as soon as possible the rare cases that need surgery. In Nakayama's series,58 2 of 3 patients with penetrating injuries and only 3 of 83 patients with blunt injuries had chest operations. In Peterson's report,64 15% of the children with blunt injuries required thoracotomy (about the same as in adult series), and 40% of those with penetrating injuries required surgery (much higher than in adult series). Although clinicians are naturally concerned about the treatment of patients, no discussion of chest injuries in children woild be complete without mentioning prevention. Motor vehicle accidents and gunshot wounds cause the vast majority of severe pediatric thoracic injuries. These injuries are all preventable. Increasing the use of seat belts and child restraints would substantially reduce the risk of injury to motor vehicle occupants. Reducing the illegal use of firearms would also have major benefits, especially for teenagers. Chest protectors may be effective in reducing the incidence of chest injuries, including commotio cordis, in young a t h l e t e ~ . " , ~ V ncombination, these measures would L,

substantially reduce the incidence and severity of pediatric thoracic trauma and the death and disability that result from it.

CLINICAL PRESENTATION The pathophysiology of thoracic trauma and the anatomy and physiology on which management strategies are based differ significantly between children and adults. The most important anatomic factors in children are the relatively narrow airway, which is prone to obstruction; the anterior and superior of the glottis, which makes nasotracheal intubation difficult and therefore inappropriate in an emergency; and the short trachea. which increases the risk of endobronchial intubation. The increased oxygen consumption and low functional residual capacity of children predispose them to hypoxia. Because young children rely largely on the diaphragm to breathe, any increase in intra-abdominal pressure compounds the problem by restricting diaphragmatic excursion. Children with significant thoracic injuries may present with minimal signs and symptoms. A large adult series from the Maryland Institute of Emergency Medical Services Systems (MIEMSS) found that two thirds of patients with thoracic injuries arrived with stable vital signs.79 This same finding was reported in ~hildren.~%bout 25% of the patients with significant intrathoracic injuries in the MIEMSS series did not have a rib fracture. These "occult" injuries included pneumothorax, hemothorax, myocardial contusion, cardiac rupture, tracheobronchial injury, pulmonary laceration, ruptured diaphragm, and ruptured aorta. The ribs of a child are more liable than those of an adult. Consequently, rib fractures are much less common in children. However, it is important to note that because of the elasticity of the chest wall in childhood. severe thoracic injuries may occur without external signs of injury. In Nakayama's series,s8less than half the children with significant thoracic injuries had rib fractures. The flexibility and compressibility of the chest wall may also explain why traumatic asphyxia is almost unique to children and why major airway trauma is so much more common in children-than in adults. The mediastinal structures are more mobile in children than in adults. Therefore, tension pneumothorax is more likely to shift the mediastinum, compromising ventilation of the contralateral lung and impairing return of venous blood to the heart.

DIAGNOSIS AND INITIAL RESUSCITATION Diagnosis and initial treatment of patients with traumatic chest injury must occur simulta~eously.Although the manifestations of thoracic injury may be immediate or delayed by hours or days, the initial goal is to rule out injuries that are immediately life threatening, such as airway obstruction, tension vneumothorax~ massive hemothorax, and cardiac tamponade. All injury victims should be managed according to the principles of the Advanced Trauma Life Support (ATLS)

CHAPTER

program of the American College of Surgeons.' The overall plan is as follows:

1. 2. 3. 4.

Primary survey. Resuscitation of vital functions. Detailed secondary survey. Definitive care.

All children with thoracic trauma must have supplemental oxygen, two large-bore intravenous lines, and a nasogastric tube to prevent gastric distention. A nasogastric tube may also reveal an abnormal position of the esophagus or stomach, indicating aortic injury or a ruptured diaphragm. Children with thoracic trauma should be observed closely. Vital signs and oxygen saturation in arterial blood (Sao,) should be contiriuously monitored. If the child is intubated, end-tidal carbon dioxide should be monitored continuously or checked frequently. Blood should be available for transfusion. The equipment and skilled personnel needed to address breathing problems and to manage the airway with suction, oral airways, endotracheal tubes, laryngoscopes, and a bag-valve-mask apparatus must always be on hand, especially during transport and diagnostic procedures. Life-threatening injuries should be identified and treated during the initial resuscitation phase of the ATLS protocol. The first priority is to clear and secure the airway. Endotracheal intubation may be required. After intubation, the position of the endotracheal tube must be checked by observing chest excursion, listening for bilateral air entry, monitoring end-tidal carbon dioxide, and obtaining a chest radiograph. A colorimetric carbon dioxide detector may be used to verify endotracheal tube position, especially in the prehospital setting." The second priority is to ensure adequate ventilation. Tension pneumothorax, if present, should be treated before a radiograph is obtained. Occasionally, open pneumothorax or massive flail chest requires intubation and assisted ventilation during the initial resuscitation. Persistent shock despite adequate fluid administration usually indicates ongoing blood loss (most likely abdominal). However, if no obvious cause of hypovolemia can be found, the possibility of acute pericardial tamponade should be considered; this condition can be relieved, at least temporarily, by pericardiocentesis. The indications for urgent thoracotomy may become obvious at any stage (Table 16-2). The most common indications are massive bleeding, massive air leak, and

Penetrating wound of the heart or great vessels Massive or continuous intrathoracic bleeding Open pneumothorax with major chest wall defect Aortogram indicating injury to the aorta or major branch Massive or continuing air leak, indicating injury to a major airway Cardiac tamponade Esophageal perforation Diaphragmatic rupture Impalpable pulse with sardiac massage

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cardiac tamponade. Emergency room (ER) or resuscitative thoracotomy is a controversial technique that does not seem to have clear indications or contraindications. In the report from MIEMSS,79 none of 39 adult patients who presented without vital signs in the ER survived after emergency thoracotomy. However, emergency thoracotomy may be lifesaving in children, especially those with penetrating cardiac injuries. Powell et a1.W reported a 26% survival rate in a series of children and adolescents who had ER thoracotomy. These authors recommend thoracotomy in the ER for post-traumatic arrest, or near arrest, in three situations:

1. All cases of penetrating thoracic trauma. 2. Blunt trauma with acute deterioration but signs of life in the ER. 3. Blunt trauma with signs of life at the scene when the scene is in proximity to the hospital. The incision for emergency thoracotomy should be on the left anterolateral chest wall in the fifth interspace. A rib spreader should be used. If evidence of pericardial tamponade exists, the pericardium should be opened longitudinally, anterior to the phrenic nerve. Cardiac wounds should be controlled by direct pressure and simple suture unless coronary artery damage has occurred, in which case repair may be required. If cardiac tamponade is not present, the aorta should be cross-clamped. If the patient has massive lung injury, the hilum should be clamped or twisted off (see Treatment). Patients who respond to these measures should then have definitive repair performed in the operating room. In most cases of thoracic trauma, the child is physiologically stable. After initial resuscitation, the next step is the detailed secondary survey. To avoid missing a significant injury, a complete and careful assessment is essential. In nearly all cases, a history that suggests significant impact to the chest can be elicited. Therefore, it is crucial to obtain as much information as possible regarding the details of the accident. Children involved in motor vehicle accidents, occupants and pedestrians alike, require an especially careful assessment. A history of difficulty breathing also indicates significant thoracic injury. A systematic physical examination of the chest by inspection, percussion, palpation, and auscultation is the next step of the secondary survey. Tachypnea and tenderness and abrasions of the chest wall are predictive of e look for cyanosis, intrathoracic i n j ~ r y . ~ , 2 W nshould dyspnea, noisy breathing, tracheal deviation, hoarseness or stridor, subcutaneous emphysema, open or sucking chest wounds, reduced or absent breath sounds, venous engorgement, pulsus paradoxus, and hypotension. Dyspnea and cyanosis suggest inadequate oxygenation. Noisy breathing may result from an injury to the airway or the presence of foreign material, such as blood, mucus, or vomitus. Tracheal deviation implies tension pneumothorax or massive hemothorax. Hoarseness, stridor, or other difficulty with phonation suggests direct laryngeal or tracheal injury. Surgical emphysema suggests a tracheal or bronchial laceration or, on rare occasions, an esophageal perforation. Jugular venous engorgement, hypotension, and pulsus paradoxus greater than 10 mm Hg imply cardiac tamponade. The patient should also be checked for signs of acute aortic

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coarctation, which can be caused by injury to the thoracic aorta. The most sensitive sign of a significant cardiac injury is hypotension or a large fluid requirement that is not explained by bleeding. A cardiac injury may also cause a loud systolic murmur. Acute congestive heart failure may result from valvular injury or a traumatic ventricular septa1 defect. Holmes et a1.v developed a set of clinical predictors for the presence of chest injuries in a group of children younger than 16 years with blunt torso trauma. The strongest predictors were hypotension, increased respiratory rate, abnormal physical examination of the thorax, associated femur fracture, and a Glasgow Coma Scale score less than 15. Ninety-eight percent of proven cases had at least one of these predictors. Inspection and palpation were the most sensitive, but abnormalities detected on auscultation had the highest positive predictive value. This confirms the importance of clinical assessment in children with blunt trauma. The most common injuries were lung contusion, pneumothorax, and rib fracture, in that order. In recent years, bedside surgeon-performed ultrasonography (US) has proved helpful in assessing abdominal trauma, and US is now a routine part of the clinical S has a role assessment of all major trauma c a ~ e s . ~ Walso in chest trauma. It is sufficiently accurate to be clinically useful in diagnosing pneumothorax, hemothorax, and . ~ ~ recent ," report documents pericardial e f f u ~ i o n . ~ ~One that surgeon-performed US in the ER is an accurate screening test for the presence of a p n e u m ~ t h o r a x . ~ ~ Because it lacks sensitivity and specificity, clinical assessment is routinely supplemented by diagnostic imaging, which is usually the key step in identifying those children who need an operation.Z7 Plain chest radiographs are routine, although some authors suggest that they are not necessary in blunt trauma cases when the chest physical examination is completely norma1.7.47 A standard posteroanterior and lateral examination is best, but a supine anteroposterior film will suffice. The chest radiograph should be repeated on arrival at the trauma center, even if the patient has been transferred from another hospital. The inlportant signs of chest injury on plain chest radiographs include subcutaneous emphysema, fi-actures of the rib or other bony structures, hemothorax, n other parenchymal lesion pneumothorax, c o n t ~ ~ s i oor (e.g., aspiration pneumonia), mediastinal shift or widening, and diaphragmatic rupture. Computed tomography (CT) provides greater detail than plain radiographs and is more sensitive in the diagnosis of pneuinothorax, rib fracture, and pulmonary contusion. It may also help i11 the diagnosis of ruptured diaphragm. Because chest films are not 100% sensitive, some groups recommend that CT be used to screen all patients suspected of having a chest injury. The most common injuries identified by CT are pulmonary contuMany pneumothoraces revealed sions and laceratio~ls.~~) by <:T are either not evident or underestimated on plain films. Mansol1 et al.?" concluded that plain radiographs, especially those obtained in the trauma resuscitation roonl, are only "a gross screening examination" for thoracic injury and recorrln~endeddynamically enhanced CT in all cases of significant thoracic trauma diagnosed

clinically or by plain radiograph. In such cases, CT provides better definition of the injuries already recognized and may reveal occult injuries not visible on plain radiographs. Exadaktylos et al.'O support this view. In their experience, CT revealed potentially life-threatening aortic injuries even when the plain chest radiographs were normal. They recommend routine chest CT in all patients with major chest trauma. Renton et al.70 studied the question of whether CT should replace routine chest radiographs as the initial diagnostic imaging test and concluded that it should not, mainly because the increased cost was not justified by the relatively few changes in management that resulted from the use of CT scans. They estimated that 200 CT scans would have to be done for each clinically significant change in management. In summary, CT should be used liberally in cases of suspected chest injury. Occasionally, other diagnostic tests, including US, transthoracic or transesophageal echocardiography, bronchoscopy, radionuclide bone scan, angiography, and even video-assisted thoracic surgery are helpful. US is more sensitive than supine anteroposterior chest radiographs and equally sensitive as CT in the diagnosis of traumatic pneumothorax.72 Recent case reports document the use of video-assisted thoracic surgery to diagnose pericardial rupture and herniation of the heart.65 In cases of suspected child abuse, a radionuclide bone scan helps detect recent and long-standing rib fractures. Although impractical in most emergencies, magnetic resonance imaging is helpful in defining injuries to the thoracic spine, especially when spinal cord involvement is suspected. It may also help identify diaphragmatic injuries in equivocal ca~es.5~ For many years, angiography has been the gold standard for the diagnosis of injuries to the aorta and its main branches. However, there is a clear trend to use helical CT as the initial test for suspected aortic injury, reserving aortography for proven cases to guide the repair or, in some cases, eliminating aortography entirely. Transthoracic echocardiography is a useful way to diagnose all types of structural heart injury and ventricular dysfunction caused by contusion. It may reveal intracardiac injuries or pericardial tamponade. Transesophageal echocardiography (TEE) is a useful screening test for traumatic rupture of the aorta. It can identify the cause of mediastinal hematomas seen on plain radiographs or CT scans.46 Pericardiocentesis may be used for diagnosis when cardiac tamponade is suspected and echocardiography is unavailable. All patients with thoracic trauma shoi~ldhave continuous electrocardiographic monitoring during assessment in the ER. A full 12-lead electrocardiograin should be obtained in cases of suspected cardiac contusion to rule out an arrhythmia. Bronchoscopy should be done in the operating room under general anesthesia in cases of suspected major airway traun~a.

TREATMENT The treatment of thoracic injuries varies fro111supportive (oxygen, analgesia) to simple intel-ve~ltions(entiotrxheal intubation, ventilation, tube thoracostorny) to operation

of' rib fi-actures inclndes rest and analgesia. Oral or (niinimally invasive, open thoracotomy with 01-without intravenous narcotics are usually sufficient for pain cardiopnl~nona~y bypass), depending on the specific st111ccontl-01. Intercostal nerve blocks may also be helpful. t~u-esinjtu-cd and the scverity of the injuries. However; (:hiidsen rarely expel ience l)ulmonary atelectasis most patients d o not I-cqnirc an operation and can be from splinting of the chcst wall. Kib fi.;ictnrcs usually managed with supportive measures, with or without tube heal spontaneously witllin (5 weeks. The overall morthoracostonly. '2 tality rate for children with rib fi-actul-cs in the NPTK When ;III operation is indicated, the ideal location was 10%.'2 for the incision varies, depending on the preoperative Rib fi-actures in infants a n d toddlers younger than diagnosis. An ;interolatcral incision in the fifth interspace, 3 years old al-e ofien c;tuscd I)y child a l ) t ~ s c . ~ "The l . ~likewhich can Ilc cxtcndcd across the midline, is best in an emergency. A trapdoor incision may be best for vascl~lar liiood of nonaccidcntal injul'y in children with one or more sib f~.actnl-esdecreases with increasing age.*' injlu-ies in the t~l)pcr rncdiastinum. For esophageal In cases of' t hild abuse, the typical site of fi-actwe is injul-ics,a right postcl-olatcral thoracotomy gives adeqnate exposure, except for tlic most distal thol-acic csophag~~s, the neck of'thc rib near the costotransvcrse process al-ticnlation. Kleininan ct al.4" described f'ractures of'the head \vliich is best viewed fi-om thc Icfi. Median stcrnotonly is of' the rib in allused infants; these ir1jt11-icsare nst~ally best for cardiac i~ljnries.<:a~-diopnlmonasy bypass is only undetectable on radiographs l)ecar~sctile l ~ e ; ~isd c.artiI-arely needed e~nergentlyfor injuries such as coronary laginous. Cystic lesions of' the I-ills that arc located artery laceration and I;~ccration of' the thoracic aorta. uoste~io~-lv are another inclic ation of cl~ilda l ) ~ s e ,as' ~are 11itracardi;ic injul-ics to thc atrioventricl~la~valves or the ~nultiplerib f r a c t ~ ~ r at e svarying st;~gesof'11e;tliilg. scptac do require bypass, but they atrial or ventric~~lar can 1)e repail-ed sc~nielec.ti\~ely. The conccpt of' damage control, which is now well Flail Chest established fhr intra-abdominal trauma, can also bc Flail chest is relatively uncommon in children. It occ111-s ;ipplied in selected c;tscs of' intrathol-acic injury. when a segment of the chest wall is desta1)ilized by Nonanatomic resection of' the lung to control bleeding the fracture of sevel-a1 acijacent ribs. The injured chest and massive air leak, pulmona~ytractotomy with a (;IA wall moves paradoxically-in dlu-ing inspiration and stapler for throt1gh-a1ld-tl11-o11g11 wotlnds of the l l ~ n gen , out during expisation. Ventilation is inefficient l)ecat~se masse pneumonectomy, and hil;ir twistxxmay he lifesa\ing. The last has been reported in cases of uncont~-ollable of the pal-adoxical movement. Flail (,hest is usually assobleeding or air leak from the lung. The infClior p ~ ~ l m o n a ~ yciated kith a lung contusion. <:hest wall splinting and ineffective coughing of'tcn compound the 111i m a ~ yinjury. ligament is divided, and the lower lobe is twisted antel-iThis leads to consolidation and collapse of the affected orly over the upper lobe. This controls the situation lung, which in turn s c s ~ ~ lin t s \.entilation-l,e~.fi~sio~~ rnisso that the patient can be taken back to the intensive match and hypoxia. care unit (IGU) for stabilization and returned to the Initial treatment of flail chest i n t l ~ ~ d s~~pplemental es operating room later for definitive control, usually by oxygen, pain relief (intercostal nerve I~locks,or-al or pneurnonectomy. intravenous narcotics, or an epidural blockade given as a continuous infusion), and physiotherapy. Fluid therapy must bc carefully monitored to avoid pt~l~nonary Blunt Injuries edema, and ICU monitoring is advisable. (:hiidsen with isolated flail chest and no othel- significant injuries seldom Chest Wall require ventilation. If respiratory fai1tu-c develops, endotracheal intubation and positive-pressm-c ventilation Soft Tissue with positive end-expiratoly may be I-equired for several days. Tracheotomy is rarely nccessar-y. In the Although seldom clinically important, injuries to the soft NPTR, the overall mortality rate fhr patients with flail tissue of the chest wall suggest the possibility of more chest was 40%.12 serious intrathoracic injuries. Soft tissue injuries to the chest wall should be managed according to accepted principles of wound care. Sternal Fracture <,

pressure

Rib Fracture In childhood, the ribs are strong and pliable. Therefore, rib fractures are less common in children than in adults, and flail chest is quite rare. Because rib fractures require a great deal of force, they are an indication of severe injury. FI-actl~rc of' the first rib suggests the possibility of a major vascular injury, especially to the subclavian artery.2g First rib fractures may also be complicated by Horner's syndrome and thoracic outlet syndrome. The goal of treatment is to prevent atelectasis and pneumonia while optimizing patient comfort. The treatment

Sternal fractures are less common in young children than in adults because the sternum is cartilaginous.

Pleural Space

Pneumothorax Pneumothorax can result from an injury to the chest wall, lung parenchyma, tracheobronchial trcc, or esophagus. High energy is required to produce a pneumothorax, so it must be considered a marker for other occult injuries.

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Open Pneumothorax: Open pneumothorax is rare in children. In cases of open pneumothorax, the intrapleural pressure is equal to that of the atmosphere. As a result, the lung collapses and alveolar ventilation decreases. Sucking wounds should be recognized clinically. They can be treated by inserting a Heimlich valve or applying an occlusive dressing to the wound-taping the dressing on only three sides so that it can act as a flutter valveand inserting a chest tube in the usual location.

Simple Pneumothorax: Simple pneumothorax may cause chest pain, respiratory distress, tachypnea, decreased air entry on the affected side, and oxygen desaturation. Careful examination may reveal an abrasion of the chest wall, crepitus, or tracheal shift. However, many patients show no clinical signs or symptoms. This underscores the importance of routine chest radiographs for all trauma cases. The radiographic signs include unilateral or asymmetrical lucency, a sharp outline of the mediastinum, mediastinal shift, and a visible visceral pleural border away from the chest wall. The diagnosis of simple pneumothorax should be confirmed by chest radiograph before treatment. Simple pneumothoraces should be treated by intercostal chest tube drainage (Fig. 16-1). The best location for chest tube insertion is the fourth or fifth intercostal space (nipple level) in the anterior axillary line. The recommended chest tube sizes are as follows: newborns, 12 to 16 French; infants, 16 to 18 French; school-age children, 18 to 24 French; and adolescents, 28 to 32 French. The chest tube should be connected to an underwater seal on gentle suction and removed when the air leak stops. For most cases, this is the only treatment necessary. A continued or massive air leak suggests injury to the tracheobronchial tree. A small, asymptomatic pneumothorax may be observed in carefully selected cases. If the patient is to be transferred to another hospital or intubated and ventilated for any reason, or if the pneumothorax exceeds 15%,it should be drained. When in doubt, a chest tube should be inserted.

A

Tension Pneumothorax: Tension pneumothorax may develop when a one-way valve effect occurs, allowing air to enter the pleural space but not to escape (Fig. 16-2). The underlying cause is usually a pulmonary laceration or injury to the trachea or a large bronchus. The intrapleural air pressure exceeds that of the atmosphere, collapses the ipsilateral lung, pushes the mediastinum to the opposite side, flattens the diaphragm, impairs ventilation of the opposite lung, and reduces the return of venous blood to the heart. The pulse and respiratory rate increase, and the patient develops severe distress. The trachea is usually deviated away from the involved side, and the neck veins may become engorged. The ipsilateral side of the chest is hyperresonant to percussion, with diminished breath sounds. Frank cyanosis is a late sign. The most important differential diagnosis is pericardial tamponade. However, this disorder can be distinguished from tension pneumothorax because the trachea is not displaced and the chest is normal to percussion. Tension pneumothorax should be considered when an injured patient, especially one on a

B

A, Left hemopneumothorax; note the nasogastric tube in situ. B, The same patient after insertion of an intercostal drain; no other treatment was required. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1994;3:&3.)

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of blood loss. It is wise to establish two large-bore intravenous catheters; begin treatment for shock, if present; and obtain blood for transfusion before draining a massive hemothorax, because it may precipitate further bleeding. However, drainage and re-expansion of the lung usually stop the bleeding. In most cases, intercostal drainage is the only treatment needed. However, thoracotomy may be indicated for the following reasons:

1. Initial drainage exceeds 20% to 25% of estimated blood volume. 2. Continued bleeding exceeds 2 to 4 mL/kg per hour. 3. Bleeding is increasing. 4. The pleural space cannot be drained of blood and clots. Hoth et a1.35 reported an increased likelihood of nontherapeutic exploration when thoracotomy is performed for increased chest tube output in cases of blunt trauma. Autotransfusion may be helpful during surgery for massive intrathoracic bleeding.

Lung Left tension pneumothorax. This photograph demonstrates the classic findings with tension pneumothorax, including mediastinal shift, depression and inversion of the diaphragm, and widening of the interspaces on the involved side. This child had hypotension in addition to respiratory distress because of caval torsion, which was relieved following tube thoracostomy drainage.

mechanical ventilator, suddenly deteriorates for no h gaskc dilatation and right apparent reason. ~ 0 t acute mainstem intubation may result in diminished breath sounds on the left and should not be confused with a tension pneumothorax. The treatment for tension pneumothorax is immediate needle catheter drainage (without waiting for chest radiographs) through either the second intercostal space in the midclavicular line or the fourth or fifth interspace in the axilla, followed by insertion of a chest tube.

Hemothorax When enough blood is lost into the thorax to cause shock, the term massive hemothorax is used. Massive hemothorax is more common after penetrating than blunt trauma. Hemothorax may result from laceration of an intercostal or internal mammary artery, a lung, or a mediastinal blood vessel. Free bleeding into the pleural space from a major vessel, such as the aorta or one of the pulmonary hilar vessels, is usually rapidly fatal. Most bleeding from the lung stops spontaneously because of the low pressure in the pulmonary circulation. Bleeding from a systemic vessel, such as an intercostal artery, is more likely to cause massive hemothorax, producing signs of hypovolemia, mediastinal shift, diminished breath sounds, and dullness to percussion on the affected side. Hemothorax is often associated with pneumothorax (see Fig. 16-1). The treatment is intercostal drainage to prevent a clotted hemothorax and to monitor the rate and total volume

Hematoma and Contusion Pulmonary contusion is the most common type of blunt injury to the chest in children. Direct force to the lung causes disruption of the parenchyma, bleeding, and edema in a nonanatomic distribution, often without obvious injury to the chest wall. Specific clinical signs or symptoms are seldom evident at presentation, although rib fractures and abrasions over the chest may be present. Because of the lack of specific physical features, routine chest radiographs are the key to the diagnosis of hematoma and contusion. Pulmonary contusions are usually obvious on plain radiographs taken at admission (Fig. 16-3) and are even more striking on CT, which has shown that they usually lie posteriorly or po~teromedially.~~ However, there is no need for CT when a contusion is obvious on plain films. Pulmonary contusions may be progressive, especially when compounded by edema and atelectasis. Children with pulmonary contusions seldom require mechanical ventilation and almost never develop adult respiratory distress syndrome. The differential diagnosis includes aspiration pneumonia, which can result from aspiration at the scene, during transportation, during intubation, or with vomiting after admission. It affects the right lower lobe most frequently. Patients with extensive lung hematomas or contusions should be monitored carefully with continuous Sao, measurements, preferably in an ICU. The treatment for these disorders is supportive, with analgesia, physiotherapy, supplemental oxygen, and fluid restriction. Endotracheal intubation and mechanical ventilation are less likely to be needed for children than for adults. Deterioration after admission is unusua1.H It is important to guard against overhydration and aspiration of gastric contents. The most common complication is infection of the lung. Most pulmonary hematomas and contusions clear within 10 days unless the lung becomes infected.

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Pulmonary contusion. A, Crush injury with pulmonary contusion; note the multiple rib fractures. B, The same patient 2 days later; note the progression of the lesion. C, Gunshot wound with pulmonary contusion and subcutanet011s emphysema. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1993;3:423.)

Pulmonary contusions may be complicated by pneumothorax, hemothorax, or pleural effusion, all of which may require intercostal drainage. These secondary phenomena are much more common in the presence of concomitant fractures of the bones of the chest wall and may be delayed as long as 48 hours. Therefore, serial chest radiographs should be obtained in cases of pulmonary contusion (see Fig. 16-3). Occasionally, a post-traumatic pneumatocele forms when the injured lung cavitates during healing. Because pneumatoceles usually resolve spontaneously in a few months, treatment is seldom necessary.

Laceration Pulmonary lacerations are most often seen after penetrating injuries and usually result in a pneumothorax or hemothorax. They may also be caused by rib fractures. Air embolus is the most serious complication of pulmonary laceration. This diagnosis should be

suspected in all children with thoracic trauma who suddenly deteriorate, especially while receiving positive-pressure ventilation in the absence of a pneumothorax. Air embolus may cause focal neurologic deficits. Frothy blood aspirated from an arterial cannula is a telltale sign. Emergency thoracotomy, clamping of the pulmonary hilum, and aspiration of air from the heart or right ventricular outflow tract may be l i f e s a ~ i n g . ~ ~

Trachea and Bronchi Injuries to the major airways are uncommon in children. Nearly all are caused by blunt trauma.12 The most common specific lesions are partial or complete transections of one of the main bronchi and tears of the membranous trachea. Airway injuries usually occur within 2 to 3 cm of the carina and may be rapidly fatal if not recognized and treated promptly. Injuries to distal lobar bronchi are also common.

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Some patients with major airway injuries die from respiratory failure before reaching the hospital or shortly thereafter. Most present with dyspnea, which is often caused by tension pneumothorax. Other characteristics of patients with major airway injuries are voice disturbance, cyanosis, hemoptysis, massive subcutaneous and mediastinal emphysema, and failure of the lung to expand or continuing large-volume air leak despite properly functioning chest tubes. A lung that fails to expand or a continuous massive air leak after intercostal drainage strongly suggests a major airway injury (Fig. 16-4). Although not common, "dropped lung," in which the lung actually falls to the lower half of the pleural cavity below the level of the injured bronchus, is virtually diagnostic of a major airway injury. Finally, some patients present late with chronic collapse and infection of the involved lung from bronchial obstruction. Initial management in the trauma room depends on the clinical situation. The initial treatment of airway injuries is to control the airway and breathing according to the ATLS protocol. This may require endotracheal intubation and intercostal drainage. If the patient has a good airway and is well oxygenated, it is prudent not to manipulate the airway by attempting intubation before taking the patient to the operating room. Flexible bronchoscopy may facilitate endotracheal intubation beyond the site of the injury or selective intubation of the uninjured bronchus. High-frequency ventilation with low mean airway pressure may be more effective than conventional

methods in the presence of a massive air leak and may help stabilize the patient for surgical repair.69 Helical CT may be a good initial test in stable patients with suspected major airway injuries, but bronchoscopy is more reliable. Bronchoscopy is indicated whenever the lung fails to expand or a massive air leak continues after intercostal drainage. It should be performed in the operating room under general anesthesia using a rigid, ventilating bronchoscope. If possible, the patient should be allowed to breathe spontaneously during induction of anesthesia and passage of the bronchoscope. Staff and equipment for thoracotomy must be at hand. In unstable patients or those with possible or confirmed cervical spine injuries, flexible bronchoscopy with the patient awake or through an endotracheal tube may also demonstrate the lesion. At bronchoscopy, a defect in the wall of the airway may be visible. Other bronchoscopic signs of injury include mucosal disruption or exposed cartilage. Bronchography may be needed for distal bronchial injury. Spontaneous healing is the rule for small lacerations in the membranous trachea and some partial bronchial tears involving up to one third of the circumference. These may be treated nonoperatively. For larger lacerations of the trachea or bronchi, primary surgical repair through a posterolateral thoracotomy is the best way to ensure good long-term results. Distal injuries to a lobar or segmental bronchus may be sealed with fibrin glue or treated by lung resection rather than direct repair. The right side of the chest allows the best exposure of the trachea, carina, and right main bronchus; the left side gives better exposure for injuries to the distal left main bronchus. In the presence of a massive air leak, it may be necessary to clamp the hilum before attempting to repair the airway. Advancing the endotracheal tube or passing a sterile tube across the surgical field into the distal airway may also be helpful during the repair. Simple, interrupted sutures after debridement of the margins work best. Although lobectomy or pulmonary segmentectomy may be necessary, pulmonary resection is done only as a last resort in unstable patients or when the lung is extensively damaged. The late functional results of pulmonary resection or bronchial repair are usually excellent.59 Bronchial injuries that are missed initially may seal spontaneously, but there is a risk of stenosis. After months or years, children with spontaneously sealed bronchial injuries may have persistent atelectasis, often with pneumonia or frank bronchiectasis in the involved lung, caused by a bronchial stricture. The diagnosis can be confirmed by bronchography or bronchoscopy. This type of stricture can be dilated in some cases, but open repair or even resection of the involved lung is usually necessary. One report illustrates that late repair of a completely transected mainstem bronchus with preservation of the lung is possible.78

This patient had a sustained air leak associated with blunt thoracic injury despite adequate chest tube drainage. Blood was noted in the right upper lobe bronchus, and contrast injection demot~stratedthe location and extent of the leak, whic was contl.ollcd by the injection of fihrin glue and chest tube drainage. Opvrative closure or resection is sometimes required.

Esophagus The most common causes of esophageal injury are ingestion of caustic liquids and penetrating trauma, which includes iatrogenic instrumentation. Forceful vomiting and retching rarely cause esophageal tears in childhood.

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with other severe injuries. They may be asymptomatic or cause abdominal, thoracic, or ipsilateral shoulder tip pain. Physical examination is rarely helpful in the diagnosis of diaphragmatic injuries. The diagnosis is usually based on the plain chest radiograph, which is the most important diagnostic test (Fig. 16-5). Table 16-3 summarizes the radiographic signs of diaphragmatic injury. Basically, any abnormality of the diaphragm or near the diaphragm on plain chest radiographs should arouse suspicion. Chest radiographs are initially normal in 30% to 50% of cases.Vherefore, repeat radiographs should be obtained if a diaphragmatic injury is suspected. Because other injuries often dominate the clinical picture, delayed diagnosis of a diaphragmatic injury is common. At first, herniation of abdominal viscera into the chest may not have occurred, especially in patients receiving mechanical ventilation. However, the negative intrathoracic pressure of normal breathing may gradually draw the stomach and bowel up into the chest. This can be recognized on plain radiographs, especially if the stomach herniates with a nasogastric tube in place. In the absence of a nasogastric tube, acute dilatation of the herniated stomach may develop, leading to severe respiratory distress. The diagnosis can be confirmed, if necessary, by upper or lower intestinal radiographic contrast studies. However, these studies may not be possible in patients with multiple acute injuries. Here, CT with multiplanar reconstruction may be helpful. The signs of diaphragmatic injury on CT include discontinuity of the diaphragm, herniation

External blunt trauma rarely causes esophageal injury. The mechanism of esophageal injury from blunt trauma is believed to be a sudden increase in intraesophageal pressure caused by expulsion of gas from the stomach through the gastroesophageal junction. Esophageal perforations cause fever, chest pain, and tachycardia. Occasionally, subcutaneous emphysema develops in the neck. Mediastinal or intrapleural air may be visible on routine chest radiographs or CT. If esophageal injury is suspected, a water-soluble contrast swallow, endoscopy, or both should be done. When diagnosed within the first 12 hours, esophageal injuries are best treated by primary closure and drainage. When diagnosed later, they may require salivary diversion by means of a cervical esophagostomy and gastrostomy, in addition to thoracic drainage.

Diaphragm Although rare in children, diaphragmatic injuries can be caused by a forceful impact to the abdomen or by a penetrating missile. It is important to recognize these injuries, because the stomach and bowel may herniate through the defect and strangulate. Ninety percent of diaphragmatic injuries occur on the left side. In blunt trauma, tears are usually in or near the central tendon and oriented radially. Diaphragmatic injuries are easily missed at initial presentation, especially because they are often associated

A

B Ruptured diaphragm. A, Plain chest radiograph. B, Herniated bowel on gastrointestinal contrast study.

CHAPTER

Obscured hemidiaphragm Elevated hemidiaphragm Herniated viscera causing abnormal gas pattern above the diaphragm Tip of nasogastric tube curled up into the chest Atypical pneumothorax Platelike atelectasis adjacent to the diaphragm

of intra-abdominal viscera into the chest, and constriction of the stomach as it passes through the defect.89 In stable patients, magnetic resonance imaging may also help establish the diagnosis. Some patients present with obstruction or strangulation of the herniated gut late in the course of the disorder. This causes severe abdominal or chest pain (or both), nausea, and vomiting. Primary repair through an abdominal incision is indicated. The usual repair is via open laparotomy, but several recent reports of laparoscopic repair demonstrate the feasibility of this approach.52.67 Thoracotomy may be required for patients presenting late, because of adhesions in the chest.

Heart and Pericardium Blunt trauma to the heart can produce several types of injury: concussion, contusion, or frank rupture of myocardium, valve, or septum.57Although rare, disruption or thrombosis of a coronary artery may also occur. A tear of the pericardium may allow herniation of the heart into the pleural space, thereby impairing cardiac function and causing a low output state. Occasionally, blunt trauma to the chest produces occult structural cardiac injuries without gross impairment of cardiac function, bleeding, or cardiac tamponade.18 These injuries include atrial or ventricular septal defects, mitral or tricuspid insufficiency, and ventricular aneurysm formation. Often, the only sign is a new murmur or a change in the electrocardiogram. The diagnosis can be confirmed by echocardiographyor cardiac catheterization.These injuries may be repaired electively once the patient is stable.18 Follow-up echocardiography should be arranged in all cases of known or suspected injury to the heart. Several case reports have appeared documenting sudden cardiac arrest in children after a direct blow to the chest. The term commotio cordis has been applied to this entity.51,8Wommotio cordis occurs most often during organized sporting events such as baseball. No contusion or other sign of injury can be found at autopsy, and death is usually attributed to ventricular fibrillation. When performing emergency surgery for cardiac trauma, the surgeon should bear in mind a few simple rules:

1. Prepare and drape the entire chest.

2. Place the incision in the left fourth or fifth interspace in an anterolateral direction (except for stable patients undergoing elective repair of known cardiac injuries, which should be repaired through a median sternotomy).

3. 4. 5. 6.

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Avoid the phrenic nerve when opening the pericardium. Apply direct pressure to control the bleeding. Suture the heart using pledgets as required. Leave the pericardium open.

Some authors have reported the use of skin staples to control cardiac wounds, but direct suture is preferable. A Foley catheter may be introduced through the defect to control the bleeding during repair. Although most cardiac injuries can be repaired without cardiopulmonary bypass, this option should be available. During the operation, the surgeon should always check for a thrill, which might indicate a ruptured valve or traumatic ventricular septal defect. It is also important to check for intracardiac lesions by listening for new murmurs and performing echocardiography in the postoperative period. Follow-up echocardiography should also be done after discharge.

Myocardial Contusion Myocardial contusion is the most common type of blunt cardiac injury. It produces focal damage to the heart that can be identified histologically. It can cause lifethreatening arrhythmias and cardiac failure. Treatment is aimed primarily at these complications. Contusion can be distinguished from concussion and commotio cordis because the latter does not produce any structural change, even at the microscopic level. Contusions are usually, but not always, associated with an injury to the chest wall. Myocardial contusions may be completely silent or cause an arrhythmia (supraventricular tachycardia or ventricular fibrillation) or hypotension secondary to reduced cardiac output. Unfortunately, although many tests have been proposed, including electrocardiography, echocardiography, myocardial enzyme determinations (CKMB, cardiac troponin I and troponin T ) , and radionuclide scans, there is no definitive diagnostic test for cardiac c o n t u s i ~ n . ~ ~ ~ This makes it difficult to define the indications for any of the currently available diagnostic tests and even more difficult to decide on treatment. Tellez et al.84concluded that a "comprehensive diagnostic evaluation of the heart in all children sustaining multiple injuries from blunt trauma cannot be justified." The simplest test is a 12-leadelectrocardiogram, which may reveal reversible changes to ST segments and T waves. Echocardiography may show reduced ejection fraction, localized systolic wall motion abnormality, or an area of increased enddiastolic wall thickness and echogenicity. Swaanenburg et a1.80 found that cardiac troponin I and T levels were more accurate and reliable than any of the other diagnostic tests in selecting patients for ICU monitoring. They also recommended a repeat analysis after admission for patients suspected of having myocardial contusion but with normal values at admission. A prospective study of 41 children with blunt thoracic trauma using a battery of tests, including serum enzyme levels, electrocardiography, echocardiography, and pyrophosphate myocardial scanning, revealed a high incidence of abnormal tests. However, there was little correlation between any of the test results and the

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clinical course."? The authors concluded that myocardial contusion is rarely clinically significant in pediatric thoracic trauma. For practical purposes, significant myocardial contusion can be ruled out when findings on the 12-lead electrocardiogram and echocardiography are normal. Treatment of myocardial contusion includes inotropic support as indicated, with electrocardiographic monitoring for 12 to 24 hours and frequent blood pressure determinations. Complications tend to occur early in the disorder or not at all.'Vellez et a1." recommended cardiac monitoring in the ER and ICU to identify arrhythmias and, in patients with arrhythmias and obvious thoracic injuries, serial electrocardiograms and cardiac enzyme tests.

Myocardial Rupture Rupture of the heart is usually rapidly fatal. In fact, myocardial rupture is the most common cause of death from thoracic injury. In a population-based autopsy series, Bergman et al.Vound that two thirds of these patients died at the scene of the accident and one third died in the emergency room. Most cases of cardiac rupture result from high-energy impacts, such as those sustained in motor vehicle accidents or falls from great heights. The atria tend to rupture when impact occurs during late systole; ventricles rupture from impact during late diastole. The right ventricle is the most commonly ruptured site. Children with myocardial rupture usually present with pericardial tamponade (see later). Myocardial necrosis, aneurysm formation, and delayed rupture may also occur.54 Those with a traumatic atrial septal defect or ventricular septal defect may present with a new murmur without obvious cardiac failure. All patients with chest trauma should be checked carefully for a new murmur before discharge. Any new murmur is an indication for echocardiography. Occasionally, with early diagnosis and repair, patients can survive myocardial rupture.

Valve lnjury Valve injuries are rare but well recognized after blunt tra~~ma.~.~Qtrioventricular valves are most commonly injured, causing incompetence by damage to the annulus or rupture of the chordae tendinae or papillary muscle (Fig. 16-6). This is one type of blunt cardiac injury that can be repaired semielectively.

Pericardial Tamponade Pericardial tamponade can result from an accumulation of blood in the pericardial sac after blunt trauma. The full spectrum of pericardial tamponade-pulsus paradoxus and Beck's triad (elevated jugular venous pressure, systemic hypotension, and muffled heart sounds)-rarely develops in patients with acute trauma. Pericardial tamponade is usually associated with tachycardia, peripheral vasoconstriction, jugular venous distention, and persistent hypotension despite aggressive fluid resuscitation.

Cardiomegaly and pulmonary edema 2 days after blunt chest trauma; note the Swan-Ganz catheter. A tom mitral valve annulus and chordae tendinae were successfully repaired. (From Wesson DE: Trauma of the chest in children. (:hcst Clin North Am 1995;3:423.)

In fact, pericardial tamponade should be suspected in all cases of unexplained hypotension, especially when it is associated with elevated jugular venous pressure. The best way to confirm the diagnosis is by transthoracic echocardiography, which can be performed by the surgeon at the bedside in conjunction with the focused abdominal sonography for trauma (FAST) -examination. 10.62 Treatment of suspected pericardial tamponade begins with control of the airway and breathing plus restoration and expansion of the circulating blood volume. The diagnosis should be confirmed b y echocardiography, which is the single best diagnostic tool. However, if the patient is in severe shock, needle catheter drainage of the pericardial space may be lifesaving (Fig. 16-7). Therefore, in emergency situations or when echocardiography is not available, immediate pericardiocentesis is indicated. The needle should be inserted by the subxiphoid approach at a 45-degree angle upward and toward the left shoulder. A successful tap is confirmed by aspiration of nonclotting blood. A catheter should be inserted and left for repeated aspirations, if necessary, pending definitive treatment. Pericardiocentesis may be complicated by bleeding or damage to the left anterior descending coronary artery. If pericardiocentesis does not stabilize the patient, immediate thoracotomy should be performed to relieve the tamponade a n d control the bleeding.

Pericardial Laceration The pericardium may be torn by blunt trauma. The most common site is on the left, anterior to the phrenic nerve. The heart may herniate through the defect and undergo

CHAPTER

A

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287

B

Pericardial tanlponade from blunt chest trauma. The patient was a backseat passenger in a high-speed frontal collision. There was a seat-belt nark over the lower sternum. Shock was unresponsive to fluid, and pericardial effusion was demonstrated on transihoracic echorardiography. A, Normal heart on plain chest radiograph, with evidence of pulmonary contusion. B, Chest radiograph after catheter drainage of bloody pericardial effusion. No further treatment was required. (From Wesson DE: Trauma of the chest in children. Chest Clin North Am 1993;3:423.)

torsion, impairing its function and reducing cardiac output. This type of injury may be recognized on CT or by video-assisted thoracic s ~ r g e r y . ~ ~ , ~ ~ , ~ ~

Aorta Traumatic rupture of the aorta and its major branches is uncommon in children.' Eddy et al.17 reported that aortic injuries caused 2.1% of all traumatic deaths in children in King County, Washington. Traumatic rupture of the aorta causes a higher proportion of traumatic deaths in adults (approximately 10%) than in children, probably because adult aortas are more brittle and easily torn. Predictors of aortic injury include hypotension, head injury, unrestrained motor vehicle occupant, pelvic fracture, extremity fracture, and other chest injury. However, it is not clear whether mechanism is a reliable predictor. Dyer et al.lVound it to be "imperfect" and "subjective." Horton et al." found that velocity of 20 miles per hour or greater and near-side passenger compartment intrusion of 15 inches or greater correlated strongly with aortic injury. Traumatic rupture of the aorta occurs with rapid deceleration, which applies shear stress to the wall of the aorta. The most common sites of injury are near the ligamentum arteriosum, the root of the aorta, or one of the other main branch points, such as the takeoff of the innominate, vertebral, or carotid artery. Tears of the distal arch are usually located on the anteromedial aspect of the aorta and oriented horizontally. Children with Marfan's syndrome are at risk for aortic dissection following blunt trauma to the torso. Although it is usually rapidly fatal, in some cases, the adventitia and pleura contain the blood and

prevent exsanguination. The natural history of patients who do not exsanguinate immediately is unknown, but imminent rupture in these patients is unlikely. Therefore. it is unhecessarv to rush them to the o ~ e r a t ing room before stabi~izatibn,a full diagnostic wdrkup, and treatment of other injuries. This may require laparotomy, craniotomy, or both before repair of the aorta. he management of aortic injuriks in children is ~ ~ , ~ ~ is difficult essentially the same as in a d ~ l t s .Diagnosis because there may be no clinical evidence of thoracic injury. Acute coarctation syndrome-upper limb hypertension, a difference in blood pressure between the upper and lower limbs, and a loud murmur over the precordium or back-is rare. DelRossi et al.I3 reported series of 27 cases of aortic injury without a singie case of coarctation syndrome. The diagnosis is most often suggested by plain chest radiographs, which are sensitive (false-negative 2% to 7%) but not specific (false-positive 80%). The radiographic signs of traumatic rupture of the aorta are the same as described for adults (Table 16-4, Fig. 16-8).

a

Widened mediastinum (mediastinum-chest ratio >0.25) Loss or abnormal contour of aortic knob Depression of left main bronchus (>40 degrees below horizontal) Deviation of trachea (left margin to right of T4 spinous process) Deviation of esophagus (nasogastric tube to right of T4 spinous process) Left pleural cap Left hemothorax

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D Traumatic rupture of the aorta and branches. A, Widened mediastinum with deviation of the endotracheal and nasogastric tube the right. B, In the same patient as in A, aortic injury is confirmed by aortogram. C, Widened mediastinum in a different patient who sustainc Int trauma to the chest. D,In the same patient as in C, there is an innominate artery laceration at its origin (amow). (From Wesson DE: Traum the chest in children. Chest Clin North Am 1993;3:423.)

Nearly all reported cases demonstrate widening of the mediastinum (mediastinurn-chest ratio >0.25) and an abnormal aortic contour. Until recently, most authors considered aortography the gold standard diagnostic test. Many now believe that contrast-enhanced multislice helical CT, which is equally sensitive to aortography, is the definitive test for diagnosing aortic injury (Fig. 16-9).l6,2554,61

If the helical CT scan is normal, an aortogram is unnecessary. This has substantially reduced the number of negative aortograms done for patients with blunt chest trauma and suspicious plain radiographs. The techniques of helical CT and CT-angiography have been reviewed by Melton e t a1." and Rubin.73 Timing of the contrast injection, as well as the volume and rate of infusion, must be carefully controlled to

CHAPTER

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Thoracic Injuries

B Helical computed tomography scan reconstruction showing traumatic rupture of the aorta in a 14year-old boy. A, Transaxial view. Note the periaortic hematoma at the isthmus. B, Three-dimensional reconstruction. Note the interruption of flow at the isthmus.

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yield optimal results. Helical CT costs about half as much as a o r t ~ g r a p h y . ~ ~ There is still a role for aortography in equivocal cases or to provide more anatomic detail before repair in proven cases. However, many authorities now argue that helical CT alone is sufficient for the management of aortic injuries.54 Transesophageal echocardiography also has a role in the diagnosis of injuries to the descending thoracic aorta, especially for unstable patients in the ICU who are unable to go to the radiology department. It is not useful for injuries of the ascending aorta or its branches. Unfortunately, TEE is operator dependent and not universally available. Le Bret et al.46noted three signs on TEE that are sensitive enough to screen patients for aortic injury: increased distance (>3 mm) between the probe and the aorta, double contour of the aortic wall, and US signal between the aorta and the visceral pleura. The sensitivity for diagnosing traumatic rupture of the aorta by TEE was 100% in this report; the specificity was 75%. The authors proposed that TEE be done in all cases of severe chest trauma. TEE is also useful in cases with equivocal findings on CT or aortography to avoid an unnecessary thora~otomy.~~ Once the diagnosis is proved, treatment options include open repair, endovascular stent-graft, or even nonoperative observation in some cases. Aortic surgery carries a significant risk of complications, including intracranial hypertension, which may exacerbate bleeding; left ventricular strain; renal failure; and spinal cord ischemia. Heparin may increase the likelihood of bleeding at remote sites of injury. A small intimal flap may heal spontaneously, but surgical repair through a left posterolateral thoracotomy is the treatment of choice, after the patient has been stabilized (the bleeding at other locations should be repaired first). Surgery can be safely delayed pending repair or control of associated severe injuries to the CNS, extensive burns, septic or contaminated wounds, solid organ injuries likely to bleed with heparinization, and respiratory failure." In such cases, beta blockade to control mean arterial blood pressure and ICU monitoring are essential until repair can be safely accomplished. Esmolol is the preferred beta blocker. Cardiopulmonary bypass (usually left heart bypass) should always be available during repair in case the injury extends to the aortic root. The left lung should be collapsed and retracted. Care is required when dissecting the aorta for cross-clamping to avoid injury to the branches that supply the spinal cord and injury to the vagus nerve and its recurrent branch. Some partial tears can be repaired primarily; however, repair usually requires placement of a woven Dacron graft, especially when the tear is circumferential. There are three basic ways to perform the operation: 1. Clamp and sew. 2. Intraoperative shunt. 3. Mechanical circulatory support. The simplest is to clamp and sew without a shunt or cardiopulmonary bypass. This is the fastest method

and requires the shortest cross-clamp time; it is adequate if the injury is not too extensive. Razzouk et a1.68 reported that the clamp-and-sew technique is feasible in the majority of patients without increased mortality or spinal cord injury. Kwon et a1.43concur that the clamp technique does not increase mortality or morbidity. However, others strongly disagree. Hochheiser et al." reported a lower incidence of postoperative paraplegia after repair with mechanical circulatory support. Another option is intraoperative shunting with a heparin-bonded shunt. This may reduce the risk of ischemic damage to the spinal cord without the risks of systemic heparinization; however, there are no controlled studies to prove this. The third method is to use mechanical circulatory support during the repair. The most common choice is cardiopulmonary bypass from the left superior pulmonary vein or left atrium to the femoral artery.56 Femoralfemoral bypass with direct perfusion of the distal descending thoracic aorta has also been used. Some authorities believe that cardiopulmonary bypass reduces the risk of paraplegia, but it requires systemic heparinization, which can increase the incidence of intracranial hemorrhage.44 The rate of paraplegia after repair of traumatic rupture of the aorta is about 5% to 10%. Individual variations in spinal cord blood supply, crossclamp time, and intraoperative hypotension are important determinants of spinal cord injury. There have been several recent reports of transfemoral stent insertion (endovascular stent-grafts) for injuries to the thoracic aorta in adults. Early results indicate that the outcome may be better than with standard open repair. Three case series have had remarkably low incidences Endovascular stent-grafts have been of paraplegia.15,39,60 reported in a small series of children, but there are no reports of long-term results.38 Only 1 of 13 patients in Eddy's report,17a populationbased study that included prehospital deaths, survived traumatic rupture of the aorta. In contrast, DelRossi et al.13 reported a '75% survival rate in a clinical series. Three of the 21 survivors in DelRossi's series were paraplegic after repair, but two later recovered. DelRossi found no evidence to support one technique of repair over the others. However, Fabian et a1.Z1 reported that the clamp-andsew technique is more likely than repair with bypass to result in paraplegia, especially if the cross-clamp time is longer than 30 minutes. As is true for many types of injury, outcome also depends on associated injuries.44 Hormuth et a1.33reported excellent overall results in a series of 11 children with thoracic aortic injuries. They repaired isthmus injuries with left heart bypass and direct perfusion of the distal thoracic aorta, and arch injuries were repaired with hypothermic arrest.

Chylothorax Injury to the thoracic duct, though rare, causes chylothorax. Most cases resolve spontaneously with nutritional support (total parenteral nutrition or elemental diet with medium-chain triglycerides). Occasionally, ligation of the thoracic duct is necessary.

CHAPTER

Traumatic Asphyxia Traumatic asphyxia, a clinical syndrome that is unique to children, occurs with sudden compression of the abdomen or chest (or both) against a closed glottis.76 This event causes a rapid rise in intrathoracic pressure, which is transmitted to all the veins that drain into the valveless superior vena cava. Extravasation of blood occurs into the skin of the upper half of the body, the sclerae, and possibly the brain. The brain may also be damaged by hypoxia during and after the injury. The clinical features of this disorder include seizures, disorientation, petechiae in the upper half of the body and conjunctivae, and respiratory failure (Fig. 16-10). Treatment is supportive, and most patients recover uneventfully.

Penetrating Injuries The initial management of penetrating injuries is the same as for blunt trauma: clear the airway, give oxygen and intravenous fluids, carefully assess the patient, and obtain a plain chest radiograph in every case. An attempt should be made to determine the path of the injury by marking the entry and exit wounds on the plain films. Endotracheal intubation and chest tube insertion should be done as needed during the initial resuscitation. It is important to consider the possibility of a concomitant abdominal injury with any wound below the nipple line. Bronchoscopy is indicated for suspected injury to the major airways; esophagoscopy and water-soluble contrast studies are indicated for suspected

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esophageal wounds. Echocardiography can be used in stable patients to diagnose suspected heart injuries. Treatment is also the same as described for blunt trauma. Most patients do not require thoracotomy. The most common indications for surgery are massive bleeding, massive air leak, and pericardial tamponade. Penetrating injuries are more likely to involve the heart, especially with anterior wounds medial to the midclavicular line. These injuries may cause pericardial tamwonade or, if the wericardium has a defect. exsanguinating hemorrhage into the chest. Shock is a clear indication for urgent thoracotomy in cases of penetrat, management of ing wounds to the chest. ~ o w e v e i the patients with wounds near the heart who present with normal physiologic parameters is problematic. The most conservative and safest approach is to take all such patients to the operating room for a subxiphoid pericardial window, followed by thoracotomy through a median sternotomy, if necessary. Recent reports suggest that early echocardiography may be a sensitive test for occult cardiac injuries and that this technique can be used to select patients who require a pericardial window, thereby In minimizing unnecessary invasive proced~res.~0.~7,62 one report, only patients with pericardial effusions on echocardiography underwent subxiphoid pericardial window; if blood was found, a median sternotomy followed. Patients with normal echocardiographs were observed clinically. Harris et a1.Z8 reported a large experience with penetrating cardiac injuries and recommended cardiac US to diagnose these injuries in stable patients. When an operation is required for a penetrating cardiac injury, a Foley catheter through the defect may control the bleeding temporarily to facilitate suture of the defect. Median sternotomy is best for known cardiac injuries.

COMPLICATIONS There is little information in the literature on the morbidity of chest injuries or the complications after surgical management of thoracic injuries in children. The two most common postoperative complications are pulmonary atelectasis and pneumonia. The most serious is paraplegia, which occurs in 5% to 10% of cases of injury to the thoracic aorta.

OUTCOME

Traumatic asphyxia. This child, injured in an auto accident, was restrained but still suffered a severe compression injury of the chest. In addition to petechial hemorrhages over his upper torso, he had 48 hours of mental confusion, indicating that his brain suffered hemorrhage as w l l .

The risk for death from thoracic injury varies with the type of injury and the number and severity of associated injuries, particularly to the CNS. Roux and Fisher71 reported a series of 100 consecutive children with motor vehicle-related chest trauma in South Africa. Ninety-one pedestrians constituted the largest subgroup. The eight patients who died had a mean injury severity score of 34, compared with a score of 25 among the survivors. Seven of the eight children who died had fatal head injuries. Thus, in children with blunt injuries to the chest, the severity of injury and the presence of concomitant head injuries are the main determinants

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of survival. In children, death from thoracic injury tends to occur in the first few days after the injury, usually from other injuries and not from respiratory failure or sepsis, as is the case in adults. The overall mortality for chest injuries was 15% in the NPTR-virtually identical to most adult series.l2 Mortality increases with each individual chest injury: 30% for a ruptured diaphragm, 40% for cardiac injury; and 50% for injury to a major vessel. The morbidity among survivors is remarkably low. DiScala'4 reported that 90% of survivors in the NPTR had no impairment at the time of discharge.

12. 13. 14. 15. 16.

SUMMARY The following points summarize the management of thoracic injuries in children:

1. Most thoracic injuries can be diagnosed by a combination of clinical assessment and plain chest radiographs. 2. Most heal with supportive treatment and tube thoracostomy drainage. 3. Life-threatening thoracic injuries are relatively uncommon. 4. A few thoracic injuries require surgery, but even the most severe can be managed successfully if they are recognized and treated expeditiously.

REFERENCES

17. 18. 19. 20.

21.

22. 23.

1. American College of Surgeons: Advanced Trauma Life Support Program for Physicians. Chicago, American College of Surgeons, 1993. 2. Banks E, Chun J, Weaver F: Chronic innominate artery dissection after blunt thoracic trauma: Case report. J Trauma 1995;38:975. 3. Bergman K, Spence L, Wesson D, et al: Thoracic vascular injuries: A post mortem study. J Trauma 1990;30:604. 4. Bertrand S, Laquay N, El Rassi I, et al: Tricuspid insufficiency after blunt chest trauma in a nine-year-old child. Eur J Cardiothorac Surg 1999;16:587. 5. Bhende MS, Thompson AE: Evaluation of an end-tidal COP detector during pediatric cardiopulmonary resuscitation. Pediatrics 1995;95:395. 6. Blackmore CC, Zweibel A, Mann FA: Determining risk of traumatic aortic injury: How to optimize imaging strategy. AJR Am J Roentgen01 2000;174:343. 7. Bokhari F, Brakenridge S, Nagy K, et al: Prospective evaluation of the sensitivity of physical examination in chest trauma. J Trauma 2003;54:1255. 8. Bonadio WA, Hellmich T, Wisconsin M: Post-traumatic pulmonary contusion in children. Ann Emerg Med 1989;8:1050. 9. Brandt M, Luks FI, Spigland NA, et al: Diaphragmatic injury in children. J Trauma 1992;32:298. 10. Carillo EH, Guin BJ, Ali AT, et al: Transthoracic ultrasonography is an alternative to subxiphoid ultrasonography for the diagnosis of hemopericardium in penetrating precordial trauma. Am J Surg 2000;179:34. 11. Chen MY, Miller PR, McLaughlin CA, et al: The trend of using computed tomography in the detection of acute

24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

thoracic aortic and branch vessel injury after blunt thoracic trauma: A single-center experience over 13 years. J Trauma 2004;56:783. Cooper A, Barlow B, DiScala C, String D: Mortaliw and truncal injury: The pediatric ' J ~ e d i a t rSurg 1994:29:33. DelRossi AJ, Cernaianu AC, Madden LD, et al: Traumatic disruptions of the thoracic aorta: Treatment and outcome. Surgery 1990;108:864. DiScala C: Biannual Report. National Pediatric Trauma Registry, 1995. Dunham MB, Zygun D, Petrasek P, et al: Endovascular stent grafts for acute blunt aortic injury. J Trauma 2004; 56:1173. Dyer DS, Moore EE, Ilke DN, et al: Thoracic aortic injury: How predictive is mechanism and is chest computed tomography a reliable screening tool? A prospective study of 1561 patients. J Trauma 2000;48:682. Eddy AC, Rusch VW, Fligner CL, et al: The epidemiology of traumatic rupture of the thoracic aorta in children: A 13-year review. J Trauma 1990;30:989. End A, Rodler S, Oturanlar D, et al: Elective surgery for blunt cardiac trauma. J Trauma 1994;37:798. Eren S, Balci AE, Ulku R, et al: Thoracic firearm injuries in children: Management and analysis of prognostic factors. Eur J Cardiothorac Surg 2003;23:888. Exadaktylos AK, Sclabas G, Schmid SW, et al: Do we really need routine computed tomography scanning in the primary evaluation of blunt chest trauma in patients with "normal" chest radiograph? J Trauma 2001;51:1173. Fabian TC, Richardson JD, Croce MA, et al: Prospective study of blunt aortic injury: Multi-center trial of the American Association for the Surgery of Trauma. J Trauma 1997;42:374. Fernandez L, Radhakrishna J, Gordon RT, et al: Thoracic BB injuries in pediatric patients. J Trauma 1995;38:384. Frame SB, Thompson TC: Blunt cardiac injuries. Adv Trauma Crit Care 1995;10:15. GarciaV, Gottschall CS, Eichelberger MR, et al: Rib fractures in children: A marker of severe trauma. J Trauma 1990;30:695. Gavant ML, Menke PG, Fabian T, et al: Blunt traumatic aortic rupture: Detection with helical CT of the chest. Radiology 1995;197:125. Gittleman MA, Gonzalea-del-ReyJ, Brody AS, et al: Clinical predictors for the selective use of chest radiographs in pediatric blunt trauma evaluations. J Trauma 2003;55:670. Hall A, Johnson K: The imaging of paediatric thoracic trauma. Paediatr Respir Rev 2002;3:241. Harris DG, Bleeker CP, Pretorius J, et al: Penetrating cardiac injuries-current evaluation and management of the stable patient. S Afr J Surg 2001;39:90. Harris GJ, Soper RT: Pediatric first rib fractures. J Trauma 1990;30:343. Hirsch R, Landt Y, Porter S, et al: Cardiac troponin I in pediatrics: Normal values and potential use in the assessment of cardiac injury. J Pediatr 1997;130:853. Hochheiser GM, Clark DE, Morton JR: Operative technique, paraplegia, and mortality after blunt traumatic aortic injury. Arch Surg 2002;137:434. Holmes JF, Sokolove PE, Brant WE, et al: A clinical decision rule for identifying children with thoracic injuries after blunt torso trauma. Ann Emerg Med 2002;39:492. Hormuth D, Cefali D, Rouse T, et al: Traumatic disruption of the thoracic aorta in children. Arch Surg 1999; 134:759. Horton TG, Cohn SM, Heid MP, et al: Identification of trauma patients at risk of thoracic aortic tear by mechanism of injury. J Trauma 2000;48:1008.

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35. HothJ, Scott MJ, Bullock TK, et al: Thoracotomy for blunt trauma: Traditional indications may not apply. Am Surg 2003;69:1108. 36. Hu J, Wall MJ Jr, Estrera AL, et al: Surgical management of traumatic pulmonary injury. Am J Surg 2003; 186:620. 37. Janson JT, Harris DG, Pretorius J, et al: Pericardial rupture and cardiac herniation after blunt chest trauma. Ann Thorac Surg 2003;75:754. 38. Karmay-Jones R, Hoffer E, Meissner M, et al: Management of traumatic rupture of the thoracic aorta in pediatric patients. Ann Thorac Surg 2003;75:1513. 39. Kasirajan K, Heffernan D, Langsfield M: Acute thoracic aortic trauma: A comparison of endoluminal stent grafts with open repair and nonoperative management. Ann Vasc Surg 2003;17:589. 40. Kleinman P, Mark SE, Spevak MR, et al: Fractures of the rib head in abused infants. Radiology 1992;185:119. 41. Knudtson JL, Dort JM, Helmer SD, et al: Surgeon-performed ultrasound for pneumothorax in the trauma suite. J Trauma 2004;56:527. 42. Kulshrestha P, Munshi I, Wait R: Profile of chest trauma in a level I trauma center. J Trauma 2004;57:576. 43. Kwon CC, Gill IS, Fallon WF, et al: Delayed operative intervention in the management of traumatic descending thoracic aortic rupture. Ann Thorac Surg 2002;74:1888. 44. Langanay T, Verhoye JP, Corbineau H, et al: Surgical treatment of acute traumatic rupture of the thoracic aorta-timing reappraisal? Eur J Cardiothorac Surg 2002;21:282. 45. Langer JC, Winthrop AL, Wesson DE, et al: Diagnosis and incidence of cardiac injury in children with blunt thoracic trauma. J Pediatr Surg 1989;24:1091. 46. Le Bret F, Rue1 P, Rosier H, et al: Diagnosis of traumatic mediastinal hematoma with transesophageal echocardiography. Chest 1994;105:373. 47. Lomoschitz FM, Eisenhuber E, Linnau KF, et al: Imaging of chest trauma: Radiological patterns of injury and diagnostic algorithms. Eur J Radiol 2003;48:61. 48. Magid N, Glass T: A "hole in a r i b as a sign of child abuse. Pediatr Radiol 1990;20:334. 49. Mandavia DP, Joseph A: Bedside echocardiography in chest trauma. Emerg Med Clin North Am 2004;22:601. 50. Manson D, Babyn PS, Palder S, et al: CT of blunt chest trauma in children. Pediatr Radiol 1995;23:1. 51. Maron BJ, Gohman TE, Kyle SB, et al: Clinical profile and spectrum of commotio cordis. JAMA 2002;287:1142. 52. Matthews BD, Bui H, Harold KL, et al: Laparoscopic repair of traumatic diaphragmatic injuries. Surg Endosc 2003; 17:254. 53. Meller JL, Little AG, Shermeta DW: Thoracic trauma in children. Pediatrics 1984;74:813. 54. Melton SM, Kerby JD, McGiffin D, et al: The evolution of chest computed tomography for the definitive diagnosis of blunt aortic injury: A single-center experience. J Trauma 2004;56:243. 55. Mirvis SE, Shanmuganathan K: MR imaging of thoracic trauma. Magn Reson Imaging Clin N Am 2000;8:91. 56. Moore EE, Burch JM, Moore JB: Repair of the torn descending thoracic aorta using the centrifugal pump for partial left heart by-pass. Ann Surg 2004;240:38. 57. Nagy K, Lohmann C, Kim DO, et al: Role of echocardiography in the diagnosis of occult penetrating cardiac injury. J Trauma 1995;38:859. 58. Nakayama DK, Ramenofsky ML: Chest injuries in childhood. Ann Surg 1989;210:770. 59. Nakayama DK, Rowe MI: Intrathoracic tracheobronchial injuries in childhood. Int Anesthesiol Clin 1988;26:42.

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60. Ott MC, Stewart TC, Lawlor DK, et al: Management of blunt thoracic aortic injuries: Endovascular stent versus open repair. J Trauma 2004;56:565. 61. Parker MS, Matheson TL, Rao AV, et al: Making the transition: The role of helical CT in the evaluation of potentially acute thoracic injuries. AJR Am J Roentgen01 2001;176:1267. 62. Patel AN, Brennig C, CotnerJ, et al: Successful diagnosis of penetrating cardiac injury using surgeon performed ultrasonography. Ann Thorac Surg 2003;76:2046. 63. Patel HN, Hahn D, Comess KA: Blunt chest trauma: Role of intravascular and transesophageal echocardiography in cases of abnormal thoracic aortogram. J Trauma 2003;55:330. 64. Peterson RJ, TepasJ 3rd, Edwards FH, et al: Pediatric and adult thoracic trauma: Age-related impact on presentation and outcome. Ann Thorac Surg 1994;58:14. 65. Place RJ, Cavanaugh DG: Computed tomography to diagnose pericardial rupture. J Trauma 1995;38:882. 66. Powell RW, Gill EA, Jurkovich GJ, et al: Resuscitative thoracotomy in children and adolescents. Am Surg 1988;54:188. 67. Pross M, Manger T, Mirow L, et al: Laparoscopic management of late-diagnosed major diaphragmatic rupture. J Laparoendosc Adv Surg Tech A 2003;10:111. 68. Razzouk AJ, Gundry SR, Wang N, et al: Repair of traumatic aortic rupture: A 25-year experience. Arch Surg 2000; 135:913. 69. Reinoso-Barbero F, Sanabria P, Bueno J, et al: Highfrequency ventilation for a child with traumatic bronchial rupture. Anesth Analg 1995;81:183. 70. Renton J, Kincaid S, Ehrlich PF: Should helical CT scanning of the thoracic cavity replace the conventional chest x-ray as a primary assessment tool in pediatric trauma? An efficacy and cost analysis. J Pediatr Surg 2003;38:793. 71. Roux P, Fisher RM: Chest injuries in children: An analysis of 100 cases of blunt chest trauma from motor vehicle accidents. J Pediatr Surg 1992;27:551. 72. Rowan KR, Kirkpatrick AW, Liu D, et al: Traumatic pneumothorax detection with thoracic US: Correlation with chest radiography and CT-initial experience. Radiology 2002;227:305. 73. Rubin GD: CT angiography of the thoracic aorta. Semin Roentgen01 2003;38:115. 74. RuDusky BM: Myocardial contusion culminating in a ruptured pseudoaneurysm of the left ventricle-a case report. Angiology 2003;54:359. 75. Salehian 0,Mulji A: Tricuspid valve disruption and ventricular septa1 defect secondary to blunt chest trauma. Can J Cardiol 2004;20:231. 76. Sarihan H, Abes M, Akyazici R, et al: Traumatic asphyxia in children. J Cardiovasc Surg (Torino) 1997;38:93. 77. Scorpio RS, Wesson DE, Smith CR, et al: Blunt cardiac injuries in children: A postmortem study. J Trauma 1996; 41:306. 78. Shabb BR, Taha M, Nabbout G, et al: Successful delayed repair of a complete transection of the right mainstem bronchus in a five-year-old girl: Case report. J Trauma Injury Infect Crit Care 1995;38:964. 79. Shorr R, Crittenden M, Indeck M, et al: Blunt thoracic trauma: analysis of 515 patients. Ann Surg 1987;206:200. 80. SwaanenburgJC, KlaaseJM, DeJongste MJ, et al: Troponin I, troponin T, CKMB-activity and CKMB-mass as markers for the detection of myocardial contusion in patients who experienced blunt trauma. Clin Chim Acta 1998; 272: 171. 81. Sybrandy KC, Cramer MJ, Burgersdijk C: Diagnosing cardiac contusion: Old wisdom and new insights. Heart 2002;89:485.

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82. Taskinen SO, Salo,JA, Halttunen PE, et al: Tracheobronchial rupture due to blunt chest trauma: A follow-up study. Ann Thorac Surg 1989;48:846. 83. Tatou E, Steinmetz E, Jazayeri S, et al: Surgical outcome of traumatic rupture of the thoracic aorta. Ann Thorac Surg 2000;69:70. 84. Tellez DW, Hardin WD Jr, Takahashi M, et al: Blunt cardiac injury in children. J Pediatr Surg 1987;22:1123. 85. Thomas P, Saux P, Lonjon T, et al: Diagnosis by video-assisted thoracoscopy of traumatic pericardial rupture with delayed luxation of the heart: Case report. J Trauma 1995;38:967.

86. Wang JN, Tsai YC, Chen SL, et al: Dangerous impactcommotio cordis. Cardiology 2000;93:124. 87. Williams RL, Connolloy PT: In children undergoing chest radiography what is the specificity of rib fractures for non-accidental injury? Arch Dis Child 2004;89:490. 88. Wilson A, Wall MJ Jr, Maxson R, et al: The pulmonary hilum twist as a thoracic damage control procedure. Am J Surg 2003;186:49. 89. Worthy S, Kang EY, Hartman TE, et al: Diaphragmatic rupture: CT &dings in 11 patients. ~adidlogy-1995; 194:885.

Abdominal Trauma Steven Stylianos and Richard H. Pearl

Who could have imagned the influence of Simpson's 1968 publication on the successful nonoperative treatment of select children presumed to have splenic injury?142Initially suggested in the early 1950s by Warnsborough, then chief of general surgery at the Hospital for Sick Children in Toronto, the era of nonoperative management of splenic injury began with the report of 12 children treated between 1956 and 1965. The diagnosis of splenic injury in this select group was made by clinical findings, along with routine laboratory and plain radiographic findings. Keep in mind that this report predated ultrasonography (US), computed tomography (CT), or isotope imaging. Subsequent confirmation of splenic injury was made in one child who required laparotomy years later for an unrelated condition, when it was found that the spleen had healed in two separate pieces. Nearly 4 decades later, the standard treatment of hemodynamically stable children with splenic injury is nonoperative, and this concept has been successfully applied to most blunt injuries of the liver, kidney, and pancreas as well. Surgical restraint is now the norm. based on an increased awareness of the anatomic patterns and physiologic responses of injured children. Our colleagues in adult trauma care have slowly acknowledged this success and are applying many of the principles learned in pediatric trauma to their patients.7g A recent review of the National Pediatric Trauma Registry (NPTR) indicates that 8% to 12% of children suffering blunt trauma have an abdominal injury.z8 Fortunately, more than 90% of them survive. Although abdominal injuries are 30% more common than thoracic injuries, they are 40% less likely to be fatal. The infrequent need for laparotomy in children with blunt abdominal injury has created a debate regarding the role of pediatric trauma surgeons in their treatment. Recent analyses of the NPTR and the National Trauma Data ~ a n emphasize k the overall "surgical" nature of pediatric trauma patients, with more than 25% of injured children requiring operative intervention.l.141 Clearly, a qualified pediatric trauma surgeon would be the ideal coordinator bf such care. Few surgeons have extensive experience with massive abdominal solid organ injuries requiring immediate surgery. It is imperative that surgeons familiarize themselves with current treatment algorithms for life-threatening

abdominal trauma. Important contributions have been made in the diagnosis and treatment of children with abdominal injury by radiologists and endoscopists. The resolution and speed of CT, the screening capabilities of focused abdominal sonography for trauma (FAST), and the percutaneous, angiographic, and endoscopic interventions of nonsurgeon members of the pediatric trauma team have all enhanced patient care and improved outcomes. This chapter focuses on the more common blunt injuries and unique aspects of care in children. Renal and genitourinary injuries are covered separately in Chapter 18.

DIAGNOSTIC MODALITIES The initial evaluation of an acutely injured child is similar to that of an adult. Plain radiographs of the cervical spine, chest, and pelvis are obtained after the initial survey and evaluation of the ABCs (airway, breathing, and circulation). Other plain abdominal films add little to the acute evaluation of pediatric trauma patients. As imaging modalities have improved, treatment algorithms have changed significantly in children with suspected intra-abdominal injuries. Prompt identification of potentially life-threatening injuries is now possible in the vast majority of children.

Computed Tomography CT has become the imaging study of choice for the evaluation of injured children owing to several advantages. CT is now readily accessible in most health care facilities; it is a noninvasive, accurate method of identifying and qualifying the extent of abdominal injury; and it has reduced the incidence of nontherapeutic exploratory laparotomy. Use of intravenous contrast is essential, and "dynamic" methods of scanning have optimized vascular and parenchymal enhancement. The importance of a contrast "blush" in children with blunt spleen and liver injury continues to be debated and is discussed later (Fig. 17-1).3Wead CT, if indicated, should be performed first without contrast, to avoid concealing a hemorrhagic

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A ,

B

A, Abdominal computed tomography scan demonstrating a significant injury to the right hepatic lobe with intravenous contrast "blush." This patient had successful angiographic embolization and avoided operation. B, Abdominal computed tomography scan demonstrating a significant injury to the spleen with intravenous contrast "blush" (arrow). The patient remained hemodynamically stable and avoided operation.

brain injury. Enteral contrast for enhancement of the gastrointestinal (GI) tract is generally not required in the acute trauma setting and can lead to aspiration. Not all children with potential abdominal injuries are candidates for CT evaluation. Obvious penetrating injury often necessitates immediate operative intervention. A hemodynamically unstable child should not be taken out of an appropriate resuscitation room for the performance of CT. These children may benefit from an alternative diagnostic study, such as peritoneal lavage or FAST, or urgent operative intervention. The greatest limitation of abdominal CT in trauma is the inability to reliably identify intestinal rupture.flJ5 Findings suggestive but not diagnostic of intestinal perforation are pneumoperitoneum, bowel wall thickening, free intraperitoneal fluid, bowel wall enhancement, and dilated A high index of suspicion should exist for the presence of bowel injury in a child with intraperitoneal fluid and no identifiable solid organ injury on CT.lZ7The diagnosis and treatment of bowel injury are reviewed in detail later.

Focused Abdominal Sonography for Trauma Clinician-performed sonography for the early evaluation of an injured child is currently being evaluated to determine its optimal use. Examination of Morrison's pouch; the pouch of Douglas; the left flank, including the perisplenic anatomy; and a subxiphoid view to visualize the pericardium is the standard four-view FAST examination (Fig. 17-2). This bedside examination may be a good rapid screening study, particularly in patients too unstable to undergo an abdominal CT scan. Early reports have found FAST to be a helpful screening tool in children, with a high specificity (95%)but low sensitivity (33%) in

.

Schematic of a focused abdominal sonography for trauma (FAST) examination, with emphasis on views of the subxiphoid, right upper quadrant and Morrison's pouch, left upper quadrant and left paracolic region, and pelvic region and pouch of Douglas. (Original illustration by Mark Mazziotti, MD.)

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identifying intestinal injury,lObnda lack of identifiable free fluid does not exclude a significant injury. FAST may be useful in decreasing the number of CT scans performed for "low-likelihood" injuries. Repetition of the study may be necessary, depending on clinical correlation, and the finding of free fluid in itself is not an indication for surgical intervention. Recently, a simple scoring system for quantifylng the amount of hernoperitoneum has been shown to be predictive of the need for laparotomy in a small series of children after blunt abdominal trauma.lo1Prospective validation of such a FAST score is necessary.

Diagnostic Peritoneal Lavage and Laparoscopy Diagnostic peritoneal lavage (DPL) has been a mainstay in trauma evaluation for more than 3 decades. However, its utility in pediatric trauma is limited. Because up to 90% of solid organ injuries do not require surgical intervention, the finding of free blood in the abdomen by DPL has limited clinical significance. Hemodynamic instability and the need for ongoing blood replacement are the determinants for operation in patients with solid organ injury in the absence of blood in the abdominal cavity. Additionally, the speed and accuracy of CT have further decreased the'indications for DPL in pediatric trauma. The sensitivity of CT in diagnosing solid organ injuries and more subtle injuries to the duodenum, pancreas, and intestines continues to improve. This has relegated DPL to the evaluation of patients with clinical findings suggestive of bowel injury and no definitive diagnosis on CT. In this setting, the presence of bile, food particles, or other evidence of GI tract perforation is diagnostic. Recent literature has suggested that laparoscopy can both diagnose and, in some cases, allow definitive surgical management without laparotomy, further limiting the usefulness of DPL. In a study from Dundee, Scotland, comparing DPL and laparoscopy, both tests were highly sensitive (loo%), but laparoscopy had a higher specificity (94% versus 83%).Z9 Large prospective trials using laparoscopy in adults have demonstrated increased diagnostic accuracy, decreased nontherapeutic laparotomy rates, and a significant decrease in hospital length of stay, with an attendant reduction in costs. For example, in a report from the University of Tennessee, 55% of patients with abdominal trauma avoided laparotomy after laparoscopic e~aluation.3~ Similar work from Jacobi Medical Center in New York City revealed a direct relationship between a reduction in negative laparotomies and increased use of laparoscopy for diagnosis and rnanagement.l26 Multiple adult studies have shown the utility of laparoscopy not only in trauma evaluation but also in the definitive management of related injuries. Repairs of gastric and intestinal perforation, bladder rupture, liver laceration, diaphragmatic injury, and splenic injury have all been reported.21J28J40The extent of feasible operations is directly related to the surgeon's skill with advanced laparoscopic techniques and the patient's overall stability. At the Children's Hospital of Illinois, our two most recent handlebar injuries causing bowel perforation were successfully treated laparoscopically.As with elective abdominal surgery, the role of laparoscopy in trauma will increase substantially as trauma centers redirect their training of

17

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297

residents to this modalitv and as more ~ediatriccenters report outcome studies for laparoscopic trauma management in ~hildren.2O>~~,Q

SOLID ORGAN INJURIES Spleen and Liver The spleen and liver are the organs most commonly injured in blunt abdominal trauma, with each accounting for one third of the injuries. Nonoperative treatment of isolated splenic and hepatic injuries in stable children has been universally successful and is now standard practice. However, there is great variation in the management algorithms used by individual pediatric surgeons. Review of the NPTR and recent surveys of the American Pediatric Surgical Association (APsA) membership confirm the wide disparity in practice.",'" Controversy also exists regarding the utility of CT grading and the finding of contrast blush as a predictor of outcome in liver and spleen injury.49,82,89,106Several recent studies reported contrast blush in 7% to 12% of children with blunt spleen injury (see Fig. 17-1).2"76,wThe rate of operation in the "blush" group approached or exceeded 20%. The authors emphasized that CT blush was worrisome but that most patients could still be managed successfully without operation. The role of angiographic embolization in pediatric spleen injury has yet to be determined. Recently the APSA Trauma Committee analyzed a contemporary multi-institution database of 832 children treated nonoperatively at 32 centers in North America from 1995 to 1997 (Table 17-1). 135 Consensus guidelines

Grade I

Grade II

Grade Ill Grade lV

(n = 116) (n = 341) (n = 275) (n =ZOO) Admitted to ICU (%) No. hospital days (mean) No. hospital days (range) Transfused (%) Laparotomy (%) Follow-up imaging (%) Activity.restriction (mean wk) Activity restriction (range wk)

55.0

54.3

72.3

85.4

4.3

5.3

7.1

7.6

1-7

2-9

3-9

410

1.8 0 34.4

5.2 1.0 46.3

10.1* 2.77 54.1

26.6* 12.67 51.8

5.1

6.2

7.5

9.2

2-6

2-8

4-12

6-12

*Grade Ill vs grade IV, p < 0.014. tGrade Ill vs grade IV, p < 0.0001. CT, computed tomography; ICU, intensive care unit. From Stylianos S, APSATrauma Committee: Evidence-based guidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg 2000;35:164-169.

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Grade l Grade I1 Grade Ill Grade lV ICU days Hospital stay (days) Predischarge imaging Postdischarge imaging Activity restriction (wk)*

0 2 None None 3

0 3 None None 4

0 4 None None 5

1 5 None None

6

CT, computed tomography; ICU, intensive care unit. *Return to full-contact, competitive sports (e.g., football, wrestling, hockey, lacrosse, mountain climbing) should be at the discretion of the individual pediatric trauma surgeon. The proposed guidelines for return to unrestricted activity include "normal" age-appropriateactivities. From Stylianos S, APSA Trauma Committee: Evidence-basedguidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg2000; 35: 164-169.

on intensive care unit (ICU) stay, length of hospital stay, use of follow-up imaging, and physicai activity restriction for clinically stable children with isolated spleen or liver injuries (CT grades I to IV) were defined based on this analysis (Table 17-2). The guidelines were then applied prospectively in 312 children with liver or spleen injuries treated nonoperatively at 16 centers from 1998 to 2000.l36 Patients with other minor injuries such as nondisplaced, were noncomminuted fractures or soft tissue injuries ., included as long as the associated injuries did not influence the variables in the study. The patients were grouped by severity of injury defined by CT grade. Compliance with the proposed -guidelines was analyzed for -age, organ injured, and injury grade. All patients were followed for 4 months after injury. It is imperative to emphasize that these proposed bidelines askme hemodynakic stability. The extremely low rates of transfusion and operation document the stability of the study patients. Specific guideline compliance was 81% for ICU stay, 82% for length of hospital stay, 87% for follow-up imaging, and 78% for activity restriction. There was a significant improvement in compliance from year 1 to year 2 for ICU stay (77% versus 88%, P < 0.02) and activity restriction (73% versus 87%, P < 0.01). There were no differences in compliance by age, gender, or organ injured. Deviation from the guidelines was the surgeon's choice in 90% of cases and patient-related in 10%. Six patients (1.9%) were readmitted, although none required operation. Compared with the previously studied 832 patients, the 312 patients managed prospectively by the proposed guidelines had a significant reduction in ICU stay (P< 0.0001), hospital stay (P < 0.0006), follow-up imaging ( P < 0.0001), and interval of physical activity restriction ( P < 0.04) within each grade of injury. From these data it was concluded that prospective application of specific treatment guidelines based on injury severity resulted in conformity in patient management, improved utilization of resources, and validation of guideline safety. Significant reductions in ICU stay,

hospital stay, follow-up imaging, and activity restriction were achieved without adverse sequelae when compared with the retrospective database. The attending surgeon's decision to operate for spleen or liver injury is best based on evidence of continued blood loss, such as low blood pressure, tachycardia, decreased urine output, and falling hematocrit unresponsive to crystalloid and blood transfusion. The rates of successful nonoperative treatment of isolated blunt splenic and hepatic injury now exceed 90% in most pediatric trauma centers and in adult trauma centers with a strong pediatric commitment (H. N. Loworn, personal communication) .87,135.'3" A study of more than 100 patients from the NPTR indicated that nonoperative treatment of spleen or liver injury is indicated even in the presence of associated head injury if the patient is hemodynamically stable.63 Rates of operative intervention for blunt spleen or liver injury were similar with and without an associated closed head injury. Not surprisingly, adult trauma services have reported excellent survival rates for pediatric trauma patients; however, an analysis of treatment for spleen and liver injuries reveals alarmingly high rates of operative treatThis discrepancy in operative rates ment.42,64,87,113 emphasizes the importance of disseminating effective guidelines, because the majority of seriously injured children are treated outside of dedicated pediatric trauma centers. Mooney and Forbess8reviewed the New England Pediatric Trauma Database in the 1990s and identified 2500 children with spleen injuries. Two thirds were treated by nonpediatric trauma surgeons, and two thirds were treated in nontrauma centers. After allowing for multiple patient- and hospital-related variables, the authors found that the risk of operation was reduced by half when a surgeon with pediatric training provided care to children with spleen injuries. In a similar review using the KIDS 2000 administrative data set, Rothstein et al.lI4 found that despite adjustment for hospital- and patient-specific variables, children treated at an adult general hospital had a 2.8 greater chance ( P < 0.003), and those treated at a general hospital with a pediatric unit had a 2.6 greater chance ( P < 0.013), of undergoing splenectomy than those cared for at a freestanding pediatric hospital. Adult trauma surgeons caring for injured children must consider the anatomic, immunologic, and physiologic differences between pediatric and adult trauma patients and incorporate these differences into their treatment protocols. The major concerns are related to the potential risks of increased transfusion requirements, missed associated injuries, and increased length of hospital stay. Each of these concerns has been shown to be without merit.78,86,90,95,104,118,133

Associated Abdominal Injuries Advocates of surgical intervention for splenic trauma cite their concern about missing associated abdominal injuries if no operation is performed. Morse and Garciago reported successful nonoperative treatment in 110 of 120 children (91%) with blunt splenic trauma, of whom 22 (18%) had associated abdominal injuries. Only 3 of

CHAPTER

A

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B

A, Splenic pseudoaneurysm after (arrows) nonoperative treatment of blunt splenic injury. B, Successful angiographic embolization (arrozus show occlusion of ruptured vessels). a

these 120 patients (2.5%) had GI injuries, and each was discovered at early celiotomy done for a specific indication. There was no morbidity from missed injuries or delayed surgery. Similarly, a review of the NPTR from 1988 to 1998 revealed 2977 patients with solid abdominal visceral injuries; only 96 (3.2%) had an associated hollow visceral injury.95 Higher rates of hollow visceral injury were observed in assaulted patients and in those with multiple solid visceral injuries or pancreatic injuries. Differences in mechanism of injury may account for the much lower incidence of associated abdominal injuries in children with splenic trauma. There is no justification for an exploratory celiotomy solely to avoid missing potential associated injuries in children.

Complications of Nonoperative Treatment

liver injury.l3,40 These rare occurrences lead to caution when determining a minimum safe interval before the resumption of unrestricted activities. Routine follow-up imaging studies have identified pseudocysts and pseudoaneurysms following splenic injury (H. N. Loworn, personal c o m m u n i ~ a t i o n ) .Splenic ~~~~~ pseudoaneurysms often cause no symptoms and appear to resolve with time. The true incidence of self-limited, posttraumatic splenic pseudoaneurysms is unknown because routine follow-up imaging after successful nonoperative treatment has been largely abandoned. Once identified, the actual risk of s ~ l e n Gdseudoaneurvsm nmture is also unclear. Angiographic embolization techniques can successfully treat these lesions, obviating the need for open surgery and loss of splenic parenchyma (Fig. 17-3).Splenic pse~d6cystscan achieve enormous size, leading to and GI disturbance (Fig. 17-4). Simple percutaneous aspiration leads to a high recurrence rate. Laparoscopic excision and marsupialization are highly effective (Fig. 17-5).

Nonoperative treatment protocols have been the standard for most children with blunt liver and spleen injuries for the past 2 decades. This cumulative experience has allowed us ;o evaluate both the benefits and the risks of the non-operative approach. Fundamental to the success of a nonoperative strategy is the early, spontaneous cessation of hemorrhage. Transfusion rates for children with isolated spleen or liver injuries have fallen below lo%, confirming the lack of continued blood loss in the majority of patients.7".8'.87.13".'"6 Despite many favorable observations, isolated reports of significant delayed hemorrhage with adverse outcomes continue to appear.13,40,46J23 Shilyansky et a1.lz3 reported two children with delayed hemorrhage 10 days after blunt liver injury. Both children had persistent right upper quadrant and right shoulder pain despite normal vital signs and stable hematocrits. The authors recommended continued inhouse observation until symptoms resolve. Other reports a Computed tomography scan of post-traumatic have described patients with significant bleeding 38days after grade I1 spleen injury and 24 days after grade IV splenic pseudocyst.

CHAPTER

A

.

17

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299

B

-

A, Splenic pseudoaneurysm after ( a m s )nonoperative treatment of blunt splenic injury. B, Successful angiographic embolization (arrou~s show occlusion of ruptured vessels).

these 120 patients (2.5%) had GI injuries, and each was discovered at early celiotomy done for a specific indication. There was no morbidity from missed injuries or delayed surgery. Similarly, a review of the NPTR from 1988 to 1998 revealed 2977 patients with solid abdominal visceral injuries; only 96 (3.2%) had an associated hollow visceral injury.95 Higher rates of hollow visceral injury were observed in assaulted patients and in those with multiple solid visceral injuries or pancreatic injuries. Differences in mechanism of injury may account for the much lower incidence of associated abdominal injuries in children with splenic trauma. There is no justification for an exploratory celiotomy solely to avoid missing potential associated injuries in children.

Complications of Nonoperative Treatment

liver injury.lS4O These rare occurrences lead to caution when determining a minimum safe interval before the resumption of unrestricted activities. Routine follow-up imaging studies have identified pseudocysts and pseudoaneurysms following splenic injury (H. N. Loworn, personal communication).41.g* Splenic pseudoaneurysms often cause no symptoms and appear to resolve with time. The true incidence of self-limited, posttraumatic splenic pseudoaneurysms is unknown because routine follow-up imaging after successful nonoperative treatment has been largely abandoned. Once identified, the actual risk of splenic pseudoaneurysm rupture is also unclear. Angiographic embolization techniques can successfully treat these lesions, obviating the need for open surgery and loss of splenic parenchyma (Fig. 17-3).Splenic pseudocysts can achieve enormous size, leading to pain and GI disturbance (Fig. 174). Simple percutaneous aspiration leads to a high recurrence rate. Laparoscopic excision and marsupialization are highly effective (Fig. 17-5).

Nonoperative treatment protocols have been the standard for most children with blunt liver and spleen injuries for the past 2 decades. This cumulative experience has allowed us io evaluate both the benefits and the risks of the non-operative approach. Fundamental to the success of a nonoperative strategy is the early, spontaneous cessation of hemorrhage. Transfusion rates for children with isolated spleen or liver injuries have fallen below lo%, confirming the lack of continued blood loss in the majority of patient~.7"."2.87.~35,~36 Deswite many favorable observations, isolated reports of significant delayed hemorrhage with adverse outcomes continue to appear.13,40,46,123 Shilyansky et al.123 reported two children with delayed hemorrhage 10 days after blunt liver injury. Both children had persistent right upper quadrant and right shoulder pain despite normal vital signs and stable hematocrits. The authors recommended continued inhouse observation until symptoms resolve. Other reports Computed tomography scan of post-traumatic have described patients with significant bleeding 38days after grade I1 spleen injury and 24 days after grade IV splenic pseudocyst.

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A , -

B

A, Laparoscopic view of splenic pseudocyst capsule. B, Appearance of cyst wall after laparoscopic aspiration and before marsupialization.

Sequelae of Damage-Control Strategies Even the most severe solid organ injuries can be treated without surgery if there is a prompt response to resuscitation.lo8 In contrast, emergency laparotomy, embolization, or both are indicated in patients who are hemodynamically unstable despite fluid and red blood cell transfusion. Most spleen and liver injuries requiring operation are amenable to simple methods of hemostasis using a combination of manual compression, direct suture, topical In young chilhemostatic agents, and mesh ~rapping.l~2~2 dren with significant hepatic injury, the sternum can be divided rapidly to expose the suprahepatic or intrapericardial inferior vena cava, allowing for total hepatic vascular isolation (Fig. 17-6).150 Children can tolerate periods of vascular isolation for 30 minutes or longer as long as their blood volume is replenished. With this exposure, the liver and major perihepatic veins can be isolated and the bleeding controlled, permitting direct suture repair or ligation of the offending vessel. Although the cumbersome and dangerous technique of atriocaval shunting has been largely abandoned, newer endovascular balloon catheters can be useful for temporary vascular occlusion to allow access to the juxtahepatic vena ~ a v a . ~ The early morbidity and mortality of severe hepatic injuries are related to the effects of massive blood loss and replacement with large volumes of cold blood products. The consequences of prolonged operations with massive blood product replacement include hypothermia, coagulopathy, and acidosis. Although the surgical team may keep pace with blood loss, life-threatening physiologic and metabolic consequences are inevitable, and many of these critically ill patients are unlikely to survive once their physiologic reserves have been exhausted. A multiinstitutional review identified exsanguination as the cause of intraoperative death in 82% of 537 patients at eight academic trauma centers.57 The mean pH was 7.18 and the mean core temperature was 32°C before death.

Moulton et al.Y3reported survival in only 5 of 12 (42%) consecutive operative cases of retrohepatic vascular or severe parenchymal liver injury in children. Maintenance of physiologic stability during the struggle for surgical control of severe bleeding is a formidable challenge even for the most experienced surgical team, particularly when hypothermia, coagulopathy, and acidosis occur. This triad creates a vicious circle in which each derangement exacerbates the others, and the

.

Total hepatic vascular isolation with occlusion of the porta-, supra-, and infrahepatic inferior vena cava and supraceliac aorta (optional). (Original illustration by Mark Mazziotti, MD.)

CHAPTER

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Abdominal Trauma

301

physiologic and metabolic consequences often preclude completion of the procedure. Lethal coagulopathy from dilution, hypothermia, and acidosis can rapidly occur.145 Experimental studies have defined the alterations in proPhase 1 Abbreviated laparotomy for exploration and anticoagulant enzyme processes, platelet activation, Control of hemorrhage and contamination and platelet adhesion defects with varying degrees of Packing and temporary abdominal wall closure hypothermia.14' The infusion of activated recombinant Aggressive ICU resuscitation Phase 2 Core rewarming factor VII in patients with massive hemorrhage has been Optlmizatlon of volume and oxygen delivery promising in several case reports.68 Correction of coagulopathy Increased emphasis on physiologic and metabolic Planned reoperation(s) for packing change Phase 3 stability in emergency abdominal operations has led to Definitive repair of injuries the development of staged, multidisciplinary treatment Abdominal wall closure plans, including abbreviated laparotomy, perihepatic packing, temporary abdominal closure, angiographic embolization, and endoscopic biliary stenting.5,32a45.69J4g ICU, intensive care unit. Asensio et aL6 reported on 103 patients with mostly penetrating grade IV or V hepatic injuries treated between have been proposed beyond the conventional vital signs 1991 and 1999. Mean blood loss was estimated at 9.4 L, and urine output, including serum lactate, base deficit, and mean volume infusion in the operating room was mixed venous oxygen saturation, and gastric mucosal 15 L. Packing of the hepatic injuries was used in 50% of pH. Once a patient is rewarmed, coagulation factors are patients at the first operation. Forty percent of patients Eeplaced, and oxygen delivery is optimized, he or she can who survived the initial operative control of hemorrhage be returned to the operating room for pack removal and had postoperative angiographic embolization (Fig. 17-7). definitive repair of injuries. A review of nearly 700 adult Survival was 63% in grade IV patients and 24% in grade V patients, emphasizing the lethality of such injuries patients treated by abdominal packing from several instidespite a well-choreographed, staged, multidisciplinary tutions demonstrated hemostasis in 80%, survival of 32% to 73%, and abdominal abscess rates of 10% to 40%.26,53 approach. Trauma surgeons treating critically injured Although abdominal packing with planned reoperation children must familiarize themselves with these lifesaving has been used with increasing frequency in adults during techniaues. Abbreviated laparotomy with packing for hemostasis, the past 2 decades, there is little published experience in children.30,36,5"80~115,13'L~134.'38Nevertheless, we believe allowing resuscitation before planned reoperation, is an that this technique has a place in the management of chilalternative in unstable patients in whom further blood dren with massive intra-abdominal bleeding, especially loss would be untenable. This "damage-control" philosoafter blunt trauma. phy is a systematic, phased approach to the management The ~ J ~three 3 We reported a 3-year-old child who required abdomiof exsanguinating trauma p a t i e n t ~ . ~ , ~ phases of damage control are detailed in Table 17-3. nal packing for a severe liver injury, making closure of the &though controversial, several resuscitative end points abdomen impossible.138A Silastic "silo" was constructed

A

.

B

-

A, Hepatic artery angiogram in a patient with persistent hemorrhage after initial damage-control laparotomy. The bleeding vessel is identified (curved arrow). B, Successful embolization was performed.

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to accommodate the bowel until the packing could be removed. The patient made a complete recovery. The combined technique of packing and a silo allowed time for correction of the hypothermia, acidosis, and coagulopathy, without compromise of respiratory mechanics. One review reported 22 infants and children (age 6 days to 20 years) with refractory hemorrhage who were treated with abdominal packing.134The anatomic site of hemorrhage was the liver or hepatic veins in 14, retroperitoneum or pelvis in 7, and pancreatic bed in 1. Primary fascia1 closure was accomplished in 12 patients (55%), and temporary skin closure or prosthetic material was used in the other 10. Packing controlled hemorrhage in 21 of 22 patients (95%). Removal of the packing was possible within 72 hours in 18 patients (82%). No patient rebled after the packing was removed; however, 2 patients died with the packing in place. Seven patients (32%) developed an abdominal or pelvic abscess, and all were successfully drained by laparotomy (6 patients) or percutaneously (1 patient); 6 of the 7 patients with abdominal sepsis survived. Overall, 18 patients (82%) survived. Two deaths were due to multisystem organ failure, one to cardiac failure from complex cardiac anomalies, and one to exsanguination after blunt traumatic liver injury. There were no differences in the volume of intraoperative blood product transfusion, time to initiate packing, physiologic status, or type of abdominal closure between survivors and nonsurvivors. Although the success of abdominal packing is encouraging, it may contribute to significant morbidity, such as intra-abdominal sepsis, organ failure, and increased intra-abdominal pressure. Intra-abdominal packs are contaminated by skin and gut flora, but these organisms are not those implicated in subsequent patient sepsis.48 Adams et a1.2 evaluated fluid samples from 28 patients with abdominal packing and found peritoneal endotoxin and mediator accumulation even when cultures were sterile. The authors concluded that laparotomy pad fluid accumulating after damage-control laparotomy can contribute to neutrophil dysfunction by enhancing neutrophil respiratory burst and inhibiting neutrophil responses to specific chemotactic mediators needed to fight infection. Thus, the known propensity of such patients to both intraabdominal and systemic infection may be related to changes in neutrophil receptor status and effector function related to the accumulation of inflammatory mediators in the abdomen. Early washout, repetitive packing, and other efforts to minimize mediator accumulation deserve consideration. It is essential to emphasize that the success of the abbreviated laparotomy and planned reoperation depends on an early decision to employ this strategy before irreversible shock occurs. When employed as a desperate, lastditch resort after prolonged attempts at hemostasis have failed, abdominal packing has been uniformly unsuccessful. Physiologic and anatomic criteria have been identified as indications for abdominal packing. Most of these focus on intraoperative parameters, including pH (-7.2), core temperature (<35OC), and coagulation values (prothrombin time >16 seconds), in a patient with profuse hemorrhage requiring large volumes of blood product transfusion.

The optimal time for re-exploration is controversial, because neither the physiologic end points of resuscitation nor the increased risk of infection with prolonged packing are well defined. The obvious benefits of hemostasis provided by packing are also balanced against the potential deleterious effects of increased intra-abdominal pressure on ventilation, cardiac output, renal function, mesenteric circulation, and intracranial pressure. Timely alleviation of the secondary abdominal compartment syndrome may be a critical salvage maneuver for patients. Temporary abdominal wall closure at the time of packing can prevent the abdominal compartment syndrome. We recommend temporary abdominal wall expansion in all patients requiring packing until hemostasis is obtained and visceral edema subsides. A staged operative strategy for unstable trauma patients represents advanced surgical care and requires sound judgment and technical expertise. Intra-abdominal packing for control of exsanguinating hemorrhage is a lifesaving maneuver in highly selected patients in whom coagulopathy, hypothermia, and acidosis render further surgical procedures unduly hazardous. Early identification of patients likely to benefit from abbreviated laparotomy techniques is crucial for success.

Abdominal Compartment Syndrome The abdominal compartment syndrome is a term used to describe the deleterious effects of increased intra-abdominal pressure.l16 The syndrome includes respiratory insufficiency from worsening ventilation-perfusion mismatch, hemodynamic compromise from preload reduction due to inferior vena cava compression, impaired renal function from renal vein compression, decreased cardiac output, intracranial hypertension from increased ventilator pressures, splanchnic hypoperfusion, and abdominal wall overdistention. The causes of intra-abdominal hypertension in trauma patients include hernoperitoneum, retroperitoneal or bowel edema, and use of abdominal or pelvic packing. The combination of tissue injury and hemodynamic shock creates a cascade of events, including capillary leak, ischemia-reperfusion,and release of vasoactive mediators and free radicals, which combine to increase extracellular volume and tissue edema. Experimental evidence indicates that there are significant alterations in cytokine levels in the presence of sustained intra-abdominal pressure elevation.100J12 Once the combined effects of tissue edema and intra-abdominal fluid exceed a certain level, abdominal decompression must be considered. The adverse effects of abdominal compartment syndrome have been acknowledged for decades; however, abdominal compartment syndrome has only recently been recognized as a life-threatening but potentially treatable The incidence of this complication has increased markedly in recent years due to -high-volume resuscitation protocols. Measurement of intra-abdominal pressure can be useful in determining the contribution of abdominal compartment syndrome to altered physiologic Intra-abdominal presand metabolic parameter~.~g,fl.s4 sure can be determined by measuring bladder pressure. This involves instilling 1 mL/kg of saline into the Foley

CHAPTER

catheter and connecting it to a pressure transducer or manometer via a three-way stopcock. The symphysis pubis is used as the zero reference point, and the pressure is measured in centimeters of water or millimeters of mercury. Intra-abdominal pressures in the range of 20 to 35 cm H 2 0 or 15 to 25 mm Hg have been identified as an indication to decompress the abdomen. Many prefer to intervene according to alterations in other physiologic and metabolic parameters rather than a specific pressure measurement. Chang et al.19 reported 11 adult trauma patients with abdominal compartment syndrome in whom abdominal decompression using pulmonary artery catheters and gastric tonometry improved preload, pulmonary function, and visceral perfusion. Anecdotally, decompressive laparotomy has been used successfully to reduce refractory intracranial hypertension in patients with isolated brain injury without overt signs of abdominal compartment ~ y n d r o m e . ~ j Experience with abdominal decompression for abdominal compartment syndrome in children is limited.31,34,97,122.134,138 Nonspecific abdominal CT findings in children with abdominal compartment syndrome include narrowing of the inferior vena cava, direct renal compression or displacement, bowel wall thickening with enhancement, and a rounded appearance of the a b d ~ m e n .Neville ~~ et al?7 reported the use of patch abdominoplasty in 23 infants and children, only 3 of whom were trauma patients. These authors found that patch abdominoplasty for abdominal compartment syndrome effectively decreased airway pressures and oxygen requirements. Failure to respond with a decrease in airway pressures or fraction of inspired oxygen was an ominous sign in their series. Several authors have found that abdominal decompression resulted in decreased airway pressures, increased oxygen tension, and increased urine output in children with abdominal compartment syndrome.31,97J22 Many materials have been suggested for use in temporary patch abdominoplasty, including Silastic sheeting, Gore-Tex sheeting, intravenous bags, cystoscopy bags, ostomy appliances, and various mesh materials (Fig. 17-8). The vacuum-pack technique, used successfully in adults, seems pr0mising.~,~~J39

A I

17

Abdominal Trauma

303

Bile Duct Injury Nonoperative management of pediatric blunt liver injury is highly successful but is complicated by a 4% risk of persistent bile leakage.lOJ17 Radionuclide scanning is recommended when biliary tree injury is suspected.120 Delayed views may show a bile leak even if early views are normal. Several reports have highlighted the benefits of endoscopic retrograde cholangiopancreatography (ERCP) with placement of transampullary biliary stents for biliary duct injury following blunt hepatic trauma. Although ERCP is invasive and requires conscious sedation, it can pinpoint the site of injury and allow treatment of the injured ducts without open surgery (Fig. 17-9).Endoscopic transampullary biliary decompression is a recent addition to the treatment options for patients with persistent bile leakage. The addition of sphincterotomy during ERCP for persistent bile leakage following blunt liver injury has been advocated to decrease intrabiliary pressure and encourage internal decompre~sion.2',9"12~It is important to note that endoscopic biliary stents may migrate or become obstructed and require specific treatment.

INJURIES TO THE DUODENUM AND PANCREAS In contrast to the liver and spleen, injuries to the duodenum and pancreas are much less frequent, accounting for less than 10% of intra-abdominal injuries in children sustaining blunt trauma. Isolated duodenal and pancreatic injuries occur in approximately two thirds of cases, with combined injuries to both organs occurring in the remainder. The severity of the duodenal or pancreatic injury and associated injuries determines the necessity for operative versus nonoperative management. The "protected" retroperitoneum both limits the chance of injury and increases the difficulty of early diagnosis. Added to this diagnostic dilemma is the frequency of associated intra-abdominal or multisystem injuries, which can mask subtle physical and radiographic diagnostic signs of injury to the duodenum and pancreas.

B A, Abdominal wall expansion with Silastic sheeting. B, Abdominal wall expansion with a Gore-Tex patch.

304

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A

B

, A, Endoscopic retrograde cholangiopancreatography demonstrating several bile leaks after blunt liver injury. B, Endoscopic view of transarnpullary biliary stent.

Duodenum In a report on blunt duodenal rupture, Ballard et reviewed a &year statewide (Pennsylvania) experience. Of 103,864 patients registered from 28 trauma centers, blunt injury to the duodenum occurred in 206 (0.2%),of whom only 30 (14%) had full-thickness rupture. The mechanism of iniury was car crash in 70%, which included both adults

number were interpreted as ndrma~.~ o r t a l i 6was <3% and was not affected by a delay in diagnosis or treatment. This study emphasizes the difficulty of analyzing this injury owing to the low numbers reported by individual centers (and surgeons). Additionally, the investigators reviewed the range of repairs performed-from duodenal closure to the Whipple procedure-but commented that no definitive recommendations could be made because of the small number of patients and the many centers reporting. In contrast, a group from Toronto reported a singlecenter experience in a series of 27 children (mean age, 7 years) sustaining blunt duodenal injuries and treated over a 10-year period (1986 to 1996).124 Thirteen children had duodenal perforations (mean age, 9 years), and 14 sustained duodenal hematomas (mean age, 5 years). Associated injuries were seen in 19 patients (10 pancreas, 5 spleen, 4 liver, 2 long bone fracture, 1 central nervous system, 1 renal contusion, 1jejunal perforation, and 1 gastric rupture). Seventeen patients were transferred from other facilities, with a 4hour median time to transfer. The median interval from injury to surgery in those sustaining perforation was 6 hours. A comparison of the clinical

presentation, laboratory evaluation, and radiographic findings in those with duodenal hematoma versus perforation is presented in Table 174. Most patients had abdominal CT scans performed with oral and intravenous contrast (Figs. 17-10 and 17-11). A comparison of CT findings in these patient groups is presented in Table 17-5. These data

I

1

Patient Characteristic -- - ..--

--

Duodenal - --Hematoma -

Duodenal Perforation -

1

Number Age (YO ISS score Seat belt worn: no. (%) Presentation Pain or tenderness: no. (%) Bruising: no. (%) GCS score Associated injuries Pancreatic: no. (%) Lumbar spine: no. (%) Total: no. (%) Laboratory evaluation Hgb: mg %/Hct Amylase: units (%)

*Statistically significant difference. GCS, Glasgow Coma Scale; Hct, hematocrit; Hgb, hemoglobin; ISS, Injury Severity Scale. From Shilyansky J, Pearl RH, Kroutouro M, et al: Diagnosis and management of duodenal injuries in children.J Pediatr Surg 1997:32:880-886.

CHAPTER

24 days after her injury.

A

B

portions of the duodenum was

A

B

17

Abdominal Trauma

305

306

PART

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TRAUMA

Finding

Duodenal Hematoma ( n = 10) No. (%)

Duodenal Perforation ( n = 9) No. (%)

Free air Free fluid Retroperitoneal fluid Bowel wall and peritoneal enhancement Duodenal caliber change Thickened duodenum Mural hematoma Retroperitoneal air Retroperitoneal contrast7 Retroperitoneal air or contrast

*The child had an associatedjejunal perforation. tEnteral contrast was not administered in two children. From Shilyansky J, Pearl RH, Kroutouro M, et al: Diagnosis and management of duodenal injuries in children. J Pediatr Surg 1997:32:880-886.

demonstrate that the clinical presentation is strikingly similar in both groups, with only age and injury severity score achieving statistical significance (but of little clinical relevance in individual patients). However, extravasation of air or enteral contrast into the retroperitoneal, periduodenal, or prerenal space was found in every child with a duodenal perforation (9 of 9) but in none ofthe 10who had duodenal hematoma. The authors noted that few previous reports in the literature described these specific CT findings with duodenal injuries in general, and in particular, no previous series of pediatric patients had been reported. This experience and a 1986report from the same center146summarize a total of 24 patients with duodenal hematoma, all treated nonoperatively. The CT scans (or upper GI contrast studies in equivocal cases) showing duodenal narrowing, corkscrewing, or obstruction without extravasation were diagnostic in all cases. In the current series of 14 patients treated nonoperatively, the duration of nasogastric decompression was 12 days (mean),and the length of total parenteral nutrition administration was 18 days (mean). Symptoms resolved in 13 of 14 patients an average of 16 days after injury. The remaining child developed a chronic fibrous stricture requiring operative duodenoplasty 49 days after injury. This child also had a pancreatic contusion. Desai et a1.33 from St. Louis Children's Hospital reviewed their experience with 24 duodenal injuries from blunt abdominal trauma.33 There were 19 duodenal hematomas (15 diagnosed by CT, and 4 by upper GI studies), 17 of which were treated nonoperatively. In those with perforation, 4 of 5 were amenable to simple suture repair. The experiences from Salt Lake City and Pittsburgh emphasize an alarming finding that a common cause of duodenal trauma is child abuse, especially in younger patient~.'~,~"herefore, isolated duodenal injures should

raise suspicion if the history or mechanism of injury described is inconsistent with the actual injury. In all these series, patients sustaining duodenal perforation were treated operatively in a variety of ways, depending on the injury severity and the surgeon's preference. We recommend primary closure of a duodenal perforation (whenever possible). Primary closure can be combined with duodenal drainage and either pyloric exclusion with gastrojejunostomy (Fig. 17-12) or gastric drainage with feedingjejunostomy. These surgical options decrease the incidence of duodenal fistula, reduce the time to GI tract alimentation, and shorten hospital stay. When faced with complicated duodenal trauma, an effective combination is the three-tube technique: duodenal closure (primary repair, serosal patch, or anastomosis) with duodenal drainage tube for decompression (tube 1), pyloric exclusion with an absorbable suture via gastrotomy and gastric tube placement (tube 2), and feeding jejunostomy (tube 3). Several closed suction drains are placed adjacent to the repair. When the duodenum is excluded (via an absorbable suture for temporary closure of the pylorus), complete healing of the injury routinely occurs before the spontaneous reopening of the pyloric channel (Fig. 17-13). However, no matter what repair the surgeon selects, a summary of the literature demonstrates that protecting the duodenal closure

-

Lateral duodenal injury treated by primary duodenal

repair and pyloric exclusion consisting of closing the pylorus with an absorbable suture and gastrojejunostomy. Closed suction drainage of the repair is not depicted. (Original illustration by Mark Mazziotti, MD.)

CHAPTER

, -

17

Abdominal Trauma

307

Upper gastroin-

testinal study of a 7-year-old girl with duodenal perforation resulting from a motor vehicle accident. Primary repair, pyloric exclusion, retrograde tube duodenostomy, gastrojejunostomy, and feeding gastrostomy were performed. The child tolerated jejunal feeds 6 days after the injury and oral feeds 12 days after the injury. A, Six weeks postinjury, an upper gastrointestinal study demonstrated spontaneous closure of the gastre jejunostomy (arrow).B, A patent pyloms is evident (arrow).

A

(drain and exclusion) and a route for enteral feeding (gastrojejunostomy or feeding jejunostomy) reduces morbidity and hospital length of stay.39,70 The surgical options are listed in Table 17-6 and illustrated in Figures 17-12 and 17-14. Of note, pancreatic o d ~ o d e n e c t o(the ~ ~ Whipple procedure)-is rarely required. Although occasionally reported in the literature, pancreaticoduodenectomy should be reserved for the host severe iniuries to the duodenum and Dancreas in ,. which the common blood supply is destroyed and reconstruction is impossible.

B

The mechanism of injury was car or bike crashes. Sixteen of the 18 patients had CT scans on admission. Of these, 11 suggested injury; in 5, the injury was missed. Distal pancreatectomy was performed in 8 patients (44%).In 5 of 6 patients with either proximal duct injuries or injuries missed on the initial CT scan, pseudocysts developed;

Pancreas Injuries to the pancreas are slightly more frequent than duodenal injuries, with estimated ranges from 3% to 12% in children sustaining blunt abdominal trauma.'l As with duodenal injuries, individual centers frequently have small patient numbers and thus are unable to evaluate their results critically. Recently, two centers (Toronto and San Diego) reported their experience with divergent methods of managing blunt traumatic pancreatic Here, we cominjuries in a series of report~.16,17,61,75,125~~~* pare these papers and excerpt other authors' experience to make management recommendations. Canty and Weinman (San Diego)l7 reported 18 patients with major pancreatic injuries over a 14year period.

Repair of the duodenum Diversion of the gastrointestinal tract (pyloric exclusion or duodenal diverticularization) Gastric decompression (gastric tube insertion or gastrojejunostomy) Gastrointestinal tract access for feeding (jejunostomy tube or gastrojejunal anastomosis) Decompression of the duodenum (duodenostomy tube) Biliary tube drainage Wide drainage of the repaired area (lateral duodenal drains)

, -

Duodenal diverticularization for combined proxi-

mal duodenal and pancreatic injury. Resection and closure of the duodenal stump, tube duodenostomy, tube cholecystostomy, gastrojejunostomy, and multiple closed suction drains are depicted. A feeding jejunostomy should be strongly considered (not depicted). (Original illustration by Mark Mazziotti, MD.)

308

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pseudocysts also occurred in 2 other children who had minimal initial symptoms and no admission CT scans. Of these 7 pseudocysts, 2 resolved and 5 were treated TWO patients, treated more recently, by cystogast~ostomy. received ERCP with duct stenting and experienced resolution of symptoms and complete healing. The authors concluded that distal injuries should be treated with distal pancreatectomy, proximal injuries with observation, and pseudocysts with observation or cystogastrostomy. They also concluded that acute ERCP management with stent placement is safe and effective, and that CT is suggestive but not always diagnostic for the type and location of pancreatic i n j u r i e ~ . l 6 , l ~ ~ ~ ~ The experience summarized in three reports from The extensive CT Toronto is markedly different.i5,125J44 findings suggestive of pancreatic injury are detailed in Table 17-7. In the first brief report, 2 patients with documented duct disruption (by ERCP or catheter-gram) had complete duct healing without operative intervention.75 This was followed by a summary report of 35 consecutive children treated over 10 years (1987 to 1996).l2"wentythree had early diagnosis. (<24 hours), whereas diagnosis was delayed (2 to 14 days) in 12 patients. Twenty-eight children were treated nonoperatively, and the other 7 had operations for other injuries. In the 28 cases treated nonoperatively, CT was diagnostic, revealing five patterns of injury: contusion, stellate fragmentation, partial fracture, complete transection, and pseudocyst (Fig. 17-15). The patients were placed in three clinical groups based on

1 Associated Finding

No. of Children

lntraperitoneal fluid Lesser sac fluid Focal peripancreatic fluid Retroperitoneal fluid Right anterior pararenal fluid Left anterior pararenal fluid Thickened Gerota's fascia (right and left) Mesenteric fluid or hematoma Left posterior pararenal fluid Fluid separating SV and pancreas Fluid surrounding SMV and PV Fluid separating pancreas and duodenum CT, computed tomography; PV, portal vein; SMV, superior mesenteric vein; SV, splenic vein. Data from references 75, 125, 144.

CT grade (Table 17-8). In these 28 patients, pseudocysts occurred in 10 (2 of 14 in group 1 , 5 of 11 in group 2, and 3 of 3 in group 3). No patients in group 1 required drainage, whereas 4 in group 2 and all 3 in group 3 required intervention. These drainage procedures occurred 10 to 14 days after injury. Average time for the

CHAPTER

Group (Clinical) 1 2 3

17

Abdominal Trauma

309

No. of Children

Grade (CT)

Pancreatic Injury

Description

I II Ill IV V

Contusion Stellate fragmentation Partial fracture Complete transection Pseudocyst

Diffuse or focal swelling of the pancreas Fluid or blood dissecting within pancreatic parenchyma Incomplete separation of two portions of the pancreas Complete separation of two portions of the pancreas Persistent peripancreatic fluid collection

14 2 1 8 3

I

I

Data from references 75, 125, 144.

San Diego (OR = 40%)17

initiation of oral feeding was 15 days (11 days for group 1, 15 days for group 2, and 23 days for group 3). Mean hospital stay for all patients treated nonoperatively was 21 days. A comparison of the San Diego and Toronto protocols is depicted in Figure 17-16. The striking differences in these series are the 100% diagnostic sensitivity of CT in Toronto versus 69% in San Diego and the 44% operative rate in San Diego versus 0% in Toronto. A subsequent study from Toronto reviewed the follow-up on 10 patients Four of these children (40%) with duct tran~ecti0ns.l~~ developed pseudocysts, three of which were drained percutaneously (Fig. 17-17). The mean hospital stay was 24 days, and all recovered. Follow-up CT in eight of nine patients revealed atrophy of the distal pancreas in six and completely normal glands in two. There was no exocrine or endocrine dysfunction in a mean of 47 months of follow-up. The authors concluded that following nonoperative management of pancreatic blunt trauma, atrophy (distal) or recanalization occurs in all cases with no longterm morbidity. Reports from Dallas and Seattle favor early distal pancreatictomy for transection to the left of t'he spine to shorten hospital stay.81p83However, long-term seq;elae of adhesive intestinal obstruction and endocrine and exocrine dysfunction were not assessed. Other reports document the efficacy of magnetic resonance pancreatography as a diagnostic tool, early ERCP intervention for diagnosis and treatment with ductal stenting, and the use of somatostatin to decrease pancreatic secretions and proOf note, a large singlecenter mote healing.12,51~65~111,130 series from Japan reported nonoperative management in 19 of 20 children with documented pancreatic injury (9 contusions, 6 lacerations, and 5 main duct disruptions).67 In all cases, recovery was complete witho;t surgery. That center's experience with pseudocyst formation and treatment and overall outcome virtually mirrors that of the Toronto report. These reports from major pediatric trauma centers are clearly in conflict. Some favor and document the efficacy and safety of observational care for virtually all pancreatic injuries, including duct disruption; others advocate aggressive surgical management with debridement or resection. Because proponents supply compelling data for each of these treatments, algorithms reflecting individual hospital or surgeon preference will probably determine which treatment plan is selected. However, it is clear that with simple transection of the pancreas at or to the left of the spine, spleen-sparing distal pancreatectomy

N=18*

-1

CT scan

Positive = 11 : Negative = 5

I

J.

ERCP with stent = 2

Distal pancreatectomy = 8

Pseudocyst = 7

Cystogastrostomy = 5

Resolved = 2

A

* 1 death. unrelated Toronto (OR = 0%)126

Contusion= 14

Transection = 11

Pseudocyst = 3

4

Pseudocyst = 10

B

$.

Resolved = 4

$.

Drained = 5; Aspiration = 1

a Comparison of protocols in the management of blunt pancreas injury in children. A, San Diego. B, Toronto. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; OR, operating room. (A, from Canty TG Sr, Weinman D: Management of major pancreatic duct injuries in children.J Trauma 2001;50:1001-1007.B, from ShilyanskyJ, Sen LM, Kreller M, et al: Nonoperative management of pancreatic injuries in children. J Pediatr Surg 1998;33:343-345.)

310

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INJURIES OFTHE STOMACH, SMALL INTESTINE, AND COLON

, -

Contrast study through a percutaneous drain

placed into a pancreatic pseudocyst (arrowhead) after blunt trauma in a child. Communication with the main pancreatic duct (arrow) is demonstrated. The pseudocyst resolved without fistula formation or operative intervention.

can provide definitive care for this isolated injury, with short hospitalization and acceptable morbidity (Fig. 17-18). With this controversy in mind, we favor conservative therapy whenever possible, including the following:

1. Early spiral CT with oral and intravenous contrast in all patients who, by history, physical examination, or mechanism of injury, may have blunt trauma to the pancreas. 2. Documentation of injuries and early ERCP to provide duct stenting in selected cases. 3. Nonoperative management with total parenteral nutrition. 4. Expectant management of pseudocyst formation. 5. Percutaneous drainage for symptomatic, infected, or enlarging pseudocyst.

.

-

Spleen-sparing distal pancreatectomy. (Original

illustration by Mark Mazziotti, MD.)

Injuries to the stomach, small intestine, and colon are easier to diagnose and manage than those previously discussed. In blunt trauma there are three different mechanisms that cause distinct patterns of injury to these organs. First is a crush injury that occurs as the stomach, jejunum, ileum, or transverse colon is compressed violently against the spine. Hematomas, lacerations, or partial or complete transections can occur, with instantaneous or delayed perforation or obstruction. Second, burst injury occurs when rapid compressive forces are applied to a filled and distended hollow viscus, without direct mechanical compression. Shoulder- and seat-belt injuries to the GI tract can occur in this fashion. Third is shear injury caused by rapid acceleration-deceleration of an organ that is tethered at one end, such as the ligament of Treitz, ileocecal region, or rectosigmoidjunction. With deceleration, the injury is caused by the tearing of tissue at the point of fixation. Regardless of the mechanism of injury, a perforated viscus causes rapid contamination of the abdominal cavity. On the initial trauma assessment, virtually all neurologically intact patients have some symptoms (pain) and physical findings (tenderness, guarding, rebound). In fact, many reports have documented that the initial and serial physical examinations have a higher degree of diagIn nostic specificity than US or CT for these injuries.2"~O~gl a series from New Mexico reporting 48 patients with small bowel injury, all conscious patients had abnormal physical findings either on presentation or after serial physical examinations.91 Other diagnostic tests (US, CT, DPL, lab tests) were of comparatively less value. These findings were confirmed by a similar series from North Carolina involving 32 children with intestinal injury confirmed at laparotomy; 94% had physical findings suggestive of intestinal injury on admission, with 84% having diffuse abdominal tenderness (peritoneal signs) .60 Prompt diagnosis of these injuries is possible when free air and GI contrast extravasates into the abdominal cavity at the time of the initial injury. However, when partial-thickness lacerations, hematomas, or avulsed mesenteric blood vessels occur, progression to full-thickness defects with leakage can be delayed over hours to days (Fig. 17-19). A high index of suspicion is indicated, along with the liberal use of serial physical examinations. Injuries to the stomach and small intestine are straightforward to repair. A full stomach usually ruptures at the greater curvature with a blowout or stellate configuration. Debridement with direct repair is virtually always sufficient. Small intestinal injuries run the gamut from simple laceration to transection to complete avulsion with larger segments of compromised bowel. However, unless the contamination is massive (or other injuries require extensive repair), debridement or resection with anastomosis is usually sufficient. In colon injures, particularly if there is a delay in diagnosis and significant fecal contamination, colostomy with a defunctionalized distal mucous fistula or Hartmann's pouch is in order. If isolated colon injuries occur and are repaired

CHAPTER

.

-

Small bowel mesentery avulsion with ischemic bowel.

early, on-table bowel irrigation, bowel anastomosis, and perioperative antibiotic coverage are safe and effective and avoid the complications caused by stomas and reoperation. The critical factors with injuries to the intraperitoneal GI tract are early recognition of the injury; prompt resuscitation; expeditious surgery, with complete removal of contaminated and devitalized tissue; reconstruction or diversion of the GI tract, as clinically indicated; and broad-spectrum antibiotics, with the duration of therapy dependent on the degree of contamination and postoperative clinical course (e.g., normalization of white blood cell count, absence of fever, return of GI tract function).

17

Abdominal Trauma

31 1

Multiple studies have documented increased abdominal injuries to both solid and hollow organs with this finding.18,131,148 An interesting triad of injuries has been noted: abdominal wall contusions or herniation, Chance fractures of the lumbar spine, and isolated jejunal or ileal perforations. One report reviewed 95 patients admitted with abdominal trauma, all of whom were wearing seat belts at the time of injury; in 60 of 95 there was a seat-belt sign.148Nine of the 60 patients with the seat-belt sign had intestinal injuries, compared with none of the 35 without the seat-belt sign. The more common injuries described earlier can distract both the patient and the trauma team, causing delay in the diagnosis of serious vascular injuries involving the aorta and iliac vessels.94J07 In recent reports from Philadelphia, a database created by the State Farm Insurance Company was used to review 147,985 children who were passengers in motor ~ , ~series, ~ 1967 children (1.33%) vehicle c r a ~ h e s .In~ that had abdominal bruising from seat-belt restraints. Although abdominal wall bruising was infrequent, those with this finding were 232 times more likely to have a significant intra-abdominal injury than were those without a bruise. These data further revealed that 1 of 9 children with an abdominal seat-belt sign had a significant intraabdominal injury. Therefore, although the seat-belt sign is rare, CT scanning (admission and serial) is mandated when it is present. Optimal (n = 881) and suboptimal (n = 1086) use of seat-belt restraints was noted. After adjusting for age and seating position, optimally restrained children were more than three times less likely (odds ratio 3.51) than suboptimally restrained children to suffer an abdominal injury.

Imaging for Gastrointestinal Injury Seat-Belt Sign Frequent physical examinations and vigilance are required for the subset of injuries caused by lap-belt restraints when children are passengers in high-speed automobile crashes.2Vhese children present with visible seat-belt signs on physical examination of the abdomen (Fig. 17-20).

.

Seat-belt sign across the lower abdomen

Imaging of the GI tract has evolved over the past decade, with spiral CT or FAST examinations done by surgeons in the emergency department directly impacting diagnostic accuracy and decision making. Some of the strengths and weaknesses of CT diagnosis have already been discussed. However, the ability to diagnose and treat blunt abdominal trauma in children has clearly been enhanced by this modality. Two studies from Toronto examined these issues. The first, in 1992, reviewed 12 patients with blunt abdominal trauma evaluated by CT." It found that bowel wall enhancement was a sign of either global GI tract ischemia associated with fatal central nervous system injury or, when seen with bowel wall thickening and free peritoneal fluid, bowel perforation. A follow-up study in 1996 reviewed 43 patients evaluated over 10 years with surgically confirmed GI tract perforaair was seen in 47%, with one t i ~ n Extraluminal . ~ ~ false-positive. Five CT findings were found to be suggestive but not diagnostic of GI tract perforation: extraluminal air, free intraperitoneal fluid, bowel wall thickening, bowel wall enhancement, and bowel dilatation. In every patient who had all five of these findings, bowel perforation was confirmed. However, this occurred in only 18% of the study population. All patients had at least one of these five specific CT findings. There were no false-negative studies.

312

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As mentioned previously, although CT scanning is a reliConversely, injuries sustained by sexual abuse are comable modality for assessing GI tract perforations, it monly rectal or vaginal penetrations from violent, should not replace and does not improve on diligent nonconsensual acts or the purposeful insertion of serial clinical evaluations. A similar study from Calgary objects into these orifices. Therefore, when examining a reviewed 145 children with blunt abdominal t r a ~ m a . ~ 7 child with injuries to the perineum, isolated rectal or CT scans were interpreted as positive for GI tract injury vaginal trauma should always be considered child abuse in 20 and negative in 152 (several children had more until proved otherwise; conversely, polytrauma to the than one study). The sensitivity of abdominal CT scan perineum with genital, perineal, and anal involvement is was determined to be 0.93 for mesenteric or intestinal typically accidenta1.62JlO Diagnosis of the extent of perineal injury frequently injuries requiring surgery, with a negative predictive requires examination under anesthesia by means of procvalue of 0.99 in this study population. Therefore, CT toscopy, sigmoidoscopy, and retrograde urethrogram. rarely misses significant mesenteric or intestinal injuries. The significance of isolated free intraperitoneal fluid After assessing the degree of injury, surgical strategies include repair of urethral injuries (directly or via stentin the absence of solid organ injury has frequently been heralded as a sign of intestinal trauma. Hulka et al.58 ing), urinary diversion with a suprapubic cystostomy, reported a series of 259 CT scans (all with oral and intrarepair of rectal tears, rectal irrigation, placement of drains venous contrast) and found only 24 patients (9%) with when required, and, in more complex injuries, fecal isolated free intraperitoneal fluid. Among the 16 patients diversion by colostomy. After recovery, detailed radiologic with only a "small amount" of isolated fluid, only 2 confirmation of complete healing (e.g., by intravenous pyelogram, cystogram, urethrogram, contrast enemas) required laparotomy. However, 4 of 8 patients (50%) with fluid in more than one location had a bowel injury must be performed before reconstruction of fecal contirequiring exploration. These authors also noted that nuity or removal of urinary stents or urinary undiversion. enteral contrast is rarely present to aid in the diagnosis of Although rare, pediatric fatalities have been reported bowel injury. Similar findings were reported by Holmes with rectal impalement from abuse.102 Neonatal rectoet a1.,55 with small quantities of intraperitoneal fluid vaginal injuries have also been reported as an infrequent having little clinical significance. In their report, only but life-threatening complication of traumatic delivery.74 However, more commonly, rectal insertion of thermome8% of abdominal CT scans were positive for isolated ters, Hegar dilators, or enema tubes can cause significant intraperitoneal fluid, and in only 17% of these cases was there an identifiable injury. This represented only 7 of rectal injuries in newborns, requiring surgical repair. the 542 children (1.3%) studied. We recently treated a 3-day-old infant with perforation of Finally, FAST was found to be useful as a screening the rectosigmoidjunction from frequent enemas required tool, with high specificity (95%) but low sensitivity (33%) for the treatment of obstipation from cystic fibrosis; in evaluating intestinal injury.lO3 In that study of 89 FASTlaparotomy and colostomy were required. Therefore, in negative children, only 20 went on to have CT scans newborns, apparently innocuous rectal manipulation can performed, all at the surgeon's request. Without this cause severe injuries requiring surgical evaluation and finding, they all might have had abdominal CT scans. intervention. Clearly, FAST can decrease the number of unnecessary CT scans performed, but it cannot detect the specific abdominal organs injured. FAST is therefore of limited DIAPHRAGMATIC INJURIES value in assessing these injuries. Finally, to come full Traumatic injury to the diaphragm is infrequently circle, in a large study from Pittsburgh, 350 children with observed, even at the largest pediatric trauma centers. abdominal trauma were reviewed, with 30 requiring At Children's Hospital of Illinois, only two traumatic laparotomy (8.5%).3There were five false-negative CT diaphragmatic injuries were treated from 1998 to 2002 scans (26%) in 19 patients who underwent delayed laparotomy (3.5 hours or longer after injury). Those out of more than 800 admissions requiring level I pediatric trauma evaluation. At the Hospital for Sick authors concluded that serial physical examination, not CT scanning, is the gold standard for diagnosing GI tract Children in Toronto, only 15 children with this injury perforations in children. We concur. were seen from 1977 to 1998.66J09In a similar report covering 1992 to 2002 at Denver Children's Hospital, 1397 children were admitted and observed for blunt abdominal trauma, 387 had intra-abdominal injuries, but there INJURIES TO THE PERINEUM, ANUS, were only 6 diaphragmatic ruptures (0.5%).9The injury AND GENITALIA is caused by massive compressive forces to the abdominal Children present with injuries to the perineum, anus, cavity, creating acceleration of abdominal contents cephaand external genitalia primarily from two mechanisms: lad, rupturing the diaphragmatic muscle. Occasionally, accidental falls and sexual abuse. Accidental injuries are penetrating trauma causes this injury; however, in these sustained by falling onto blunt or sharp objects in a stradcases, the injury is often found incidentally at explodled fashion. These injuries are characterized by bruising, ration for other injuries. In the series reported from contusion, laceration, or penetration, depending on the Toronto, 13 of 15 patients had diaphragmatic rupture object struck and the height of the fall. Accidental from blunt trauma; the mean age was 7.5 years, with the injuries frequently involve the external genitalia, urethra, right and left diaphragm equally involved.lO9 The diagnoperineal body, and anus but rarely involve the rectum. sis was made with only a chest radiograph in more than

CHAPTER

half the patients. T h r e e injuries were missed a t t h e initial evaluation. Owing to t h e force required t o cause this injury, multiple associated injuries should b e expected. In this report, 81% of patients h a d multiple injuries, including liver laceration (47%),pelvic fracture (47%), major vascular injury (40%),bowel perfusion (33%),long bone fracture (20%),renal laceration (20%),splenic laceration (13%),a n d closed head injury (13%).As expected, ive a n d a mean there were many ~ o m ~ l i c a t i o n s ~ fdeaths, hospital stay of 20 days. Emergent surgery i n children with this constellation of associated injuries should include palpation of both diaphragms as routine part of the abdominal exploration. Direct suture repair is usually possible after debridement of any devitalized tissue. Pledgeted sutures can b e used to buttress the repair a n d prevent tearing of t h e muscle, making the closure m o r e secure. If sufficient diaphragm tissue is destroyed, a tension-free closure with a 2-mm Gore-Tex patch can b e used, similar to t h e repair of congenital diaphragmatic hernias i n newborns. Reports of laparoscopic o r thoracoscopic repair of this injury include delayed repairs on stable patients without associated i n j u r i e ~ . ~Delayed ~J~~ diagnosis of this injury in infants has b e e n reported; as has renal avulsion into t h e chest through a traumatically ruptured diaphragm.27,129,137Owing to the infrequent presentation of this injury, o n e must have a high index of suspicion when the mechanism of injury a n d t h e degree a n d location of o t h e r injuries support t h e possibility of diaphragmatic injury.

a

SUMMARY Recent advances i n the treatment of trauma a n d the provision of critical care i n children have resulted i n improved outcomes following major injuries. It is imperative that pediatric surgeons familiarize themselves with c u r r e n t t r e a t m e n t algorithms f o r life-threatening abdominal trauma. Important contributions have been made in the diagnosis a n d treatment of children with abdominal injury by radiologists a n d endoscopists. Clinical experience a n d published reports addressing specific concerns about t h e nonoperative treatment of children with solid organ injuries a n d recent radiologic a n d endoscovic contributions have m a d e vediatric trauma care increasingly nonoperative. Although the trend is i n this direction, t h e pediatric surgeon should remain the physician of record i n the m u l ~ d i ~ c i ~ l i n a r y care of critically injured children. T h e decision n o t t o operate is always a surgical decision.

REFERENCES 1. Acierno SP, Jurkovich GJ, Nathens AB: Is pediatric trauma still a surgical disease? Patterns of emergent operative intervention in the injured child. J Trauma 2004;56: 960-966. 2. Adams JM, Hauser CJ, Livingston DH, et al: The immunomodulatory effects of damage control abdominal packing on local and systemic neutrophil activity. J Trauma 2001;50:792-800.

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Albanese CT, Meza MP, Gardner MJ, et al: Is computed tomography a useful adjunct to the clinical examination for the diagnosis of pediatric gastrointestinal perforation from blunt abdominal trauma in children? J Trauma 1996;40:417-421. Angeles AP, Agarwal N, Lynd C: Repair of a juxtahepatic inferior vena cava injury using a simple endovascular technique. J Trauma 2004;56:918-921. Asensio JA, Demetriades D, Chahwan S: Approach to the management of complex hepatic injuries. J Trauma 2000;48:66-69. Asensio JA, Roldan G, Petrone P, et al: Operative management and outcomes in 103 AAST-OIS grades IV and V complex hepatic injuries: Trauma surgeons still need to operate, but angioembolization helps. J Trauma 2003; 54647-654. Ballard RB, Badellino MM, Enyon CA, et al: Blunt duodenal rupture: A 6 year statewide review. J Trauma 1997;43:729-733. Barker DE, Kaufman HJ, Smith LA, et al: Vacuum pack technique of temporary abdominal closure: A 7-year experience with 112 patients. J Trauma 2000;48:201-207. Barsness KA, Bensard DD, Ciesla D, et al: Blunt diaphragmatic rupture in children. J Trauma 2004;56:80-82. Bass BL, Eichelberger MR, Schisgall R: Hazards of nonoperative therapy of hepatic trauma in children. J Trauma 1984;24:978-982. Bensard DD, Beaver BL, Besner GE, et al: Small bowel injury in children after blunt abdominal trauma: Is diagnostic delay important?J Trauma 1996;41:476483. Boman-VermeerenJM, Vermeeren-Walters G, Broos P, et al: Somatostatin in the treatment of a pancreatic pseudocyst in a child. J Pediatr Gastroenterol Nutr 1996;23:422-425. Brown RL, Irish MS, McCabe AJ, et al: Observation of splenic trauma: When is a little too much? J Pediatr Surg 1999;34:1124-1126. Brunet C, Sielezneff I, Thomas P, et al: Treatment of hepatic trauma with perihepatic mesh. J Trauma 1994;37:200-204. Bulas DI, Taylor GA, Eichelberger MR: The value of CT in detecting bowel perforation in children after blunt abdominal trauma. AJR Am J Roentgen01 1989;153:561-564. Canty TG Sr, Weinman D: Treatment of pancreatic duct disruption in children by an endoscopically placed stent. J Pediatr Surg 2001;36:345-348. Canty TG Sr, Weinman D: Management of major pancreatic duct injuries in children. J Trauma 2001;50:1001-1007. Chandler CF, Lane JS, Waxman KS: Seatbelt sign following blunt trauma is associated with increased incidence of abdominal injury. Am Surg 1997;63:885-888. Chang MC, Miller PR, D'Agostino R, et al: Effects of abdominal decompression on cardiopulmonary function and visceral perfusion in patients with intra-abdominal hypertension. J Trauma 1998;44:440-445. Chen MK, Schropp KP, Lobe TE: The use of minimal access surgery in pediatric trauma: A preliminary report. J Laparoendosc Surg 1995;5:295-301. Chen RJ, Fang JF, Lin BC, et al: Selective application of laparoscopy and fibrin glue in the failure of nonoperative management of blunt hepatic trauma. J Trauma 1998;44:691-695. Church NG, May G, Sigalet DL: A minimally invasive approach to bile duct injury after blunt liver trauma in pediatric patients. J Pediatr Surg 2002;37:773-775. Ciftci AO, Tanyel FC, Salman AB, et al: Gastrointestinal tract perforation due to blunt abdominal trauma. Pediatr Surg Int 1998;13:259-264. Clendenon JN, Meyers RL, Nance ML, et al: Management of duodenal injuries in children. J Pediatr Surg 2004; 39:964-968.

314

PART

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TRAUMA

25. Cloutier DR, Baird TB, Gormley P, et al: Pediatric splenic injuries with a contrast blush: Successful nonoperative management without angiography and embolization. J Pediatr Surg 2004;39:969-971. 26. Cogbill TH, Moore EE, Jurkovich GJ: Severe hepatic trauma: A multicenter experience with 1335 liver injuries. J Trauma 1988;28:1433-1438. 27. Cohen Z, Gabriel A, Izrachi S, et al: Traumatic avulsion of kidney into the chest through a ruptured diaphragm in a boy. Pediatr Emerg Care 2000;3:180-181. 28. Cooper A, Barlow B, DiScala C, et al: Mortality and truncal injury: The pediatric perspective. J ~ e d i a t rSurg 1994; 29:33-38. 29. Cuschieri A, Hennessy TP, Stephens RB, et al: Diagnosis of si~nificant abdominal trauma after road traffic accidents: " Preliminary results of a multicentre clinical trial comparing mini-laparoscopy with peritoneal lavage. Ann R Coll Surg Engl 1988;70:153-155. 30. Davies MRQ: Iatrogenic hepatic rupture in the newborn and its management by pack tamponade. J Pediatr Surg 1997;32:14141419. 31. DeCou JM, Abrams RS, Miller RS, et al: Abdominal compartment syndrome in children: Experience with three cases. J Pediatr Surg 2000;35:840-842. 32. Denton .JR, Moore EE, Codwell DM: Multimodality treatment for grade V hepatic injuries: Perihepatic packing, arterial embolization, and venous stenting. J Trauma 1997;42:964968. 33. Desai KM, Dorward IG, Minkes RK, et al: Blunt duodenal injuries in children. J Trauma 2003;54:640-646. 34. Epelman M, Soudack M, Engel A, et al: Abdominal compartment syndrome in children: CT findings. Pediatr Radio1 2002;32:319-322. 35. Eubanks JW, Meier DE, Hicks BA, et al: Significance of "blush" on computed tomography scan in children with liver injury. J Pediatr Surg 2003;38:363-366. 36. Evans S, Jackson RJ, Smith SD: Successful repair of major retrohepatic vascular injuries without the use of shunt or sternotomy. J Pediatr Surg 1993;28:317-320. 37. Fabian TC, Croce MA, Stewart RM, et al: A prospective analysis of diagnostic laparoscopy in trauma.- Ann Surg 1993;217:557-565. 38. Fallat ME, Casale AJ: Practice patterns of pediatric surgeons caring for stable patients with traumatic solid organ injury. J Trauma 1997;43:820-824. 39. Fang JF, Chen RJ, Ling BC: Controlled reopen suture technique for pyloric exclusion. J Trauma 1998;45:593-596. 40. Fisher JC, Moulton SL: Nonoperative management and delayed hemorrhage following pediatric liver injury. J Pediatr Surg 2004;39:619-622. 41. Frumiento C, Sartorelli K, Vane DW: Complications of splenic injuries: Expansion of the nonoperative theorem. J Pediatr Surg 2000;35:788-791. 42. Frumiento C, Vane DW: Changing patterns of treatment for blunt splenic injuries: An 11-year experience in a rural state. J Pediatr Surg 2000;35:985-989. 43. Gaines BA, Shultz BS, Morrison K, et al: Duodenal injuries in children: Beware of child abuse. J Pediatr Surg 2004;39:600-602. 44. Gandhi RR, Stringel G: Laparoscopy in pediatric abdominal trauma. JSLS 1997;1:349-351. 45. Ginzburg E, Klein Y, Sutherland M, et al: Prolonged clamping of the liver parenchyma: A salvage maneuver in exsanguinating liver injury. J Trauma 2004;56: 922-923. 46. Goettler CE, Stallion A, Grisoni ER, et al: Delayed hemorrhage after blunt hepatic trauma. J Trauma 2002;52: 556-559.

47. Graham JS, Wong AL: A review of computed tomography in the diagnosis of intestinal and mesenteric injury in pediatric blunt abdominal trauma. J. Pediatr Surg 1996;31:754756. 48. Granchi TS, Abikhaled JA, Hirshberg A, et al: Patterns of microbiology in intra-abdominal packing for trauma. J Trauma 2004;56:45-51. 49. Hackam DJ, Potoka D, Meza M, et al: Utility of radiographic hepatic injury grade in predicting outcome for children after blunt abdominal trauma. J Pediatr Surg 2002;237:386-389. 50. Hara H, Babyn PS, Bourgeois D: Significance of bowel wall enhancement on CT following blunt abdominal trauma in childhood. J Comput Assist Tomogr 1992;16:9498. 51. Harrell DJ, Vitale GC, Larson GM: Selective role for endoscopic retrograde cholangiopancreatography in abdominal trauma. Surg Endosc 1998;12:400-404. 52. Hawegawa T, Miki Y, YoshiokaY, et al: Laparoscopic diagnosis of blunt abdominal trauma in children. Pediatr Surg Int 1997;12:132-136. 53. Hirshberg A, Mattox KL: Planned re-operation for severe trauma. Ann Surg 1995;222:3-8. 54. Hobson KG, Young KM, Ciraulo A, et al: Release of abdominal compartment syndrome improves survival in patients with burn injury. J Trauma 2002;53:1129-1134. 55. Holmes JF, London KL, Brant WE, et al: Isolated intraperitoneal fluid on abdominal computed tomography in children with blunt trauma. Acad Emerg Med 2000;7: 335-341. 56. Horwitz JR, Black T, Lally KP: Venovenous bypass as an adjunct for the management of a retrohepatic venous injury in a child. J Trauma 1995;39:584585. 57. Hoyt DB, Bulger EM, Knudson MM: Death in the operating room: An analysis of a multi-center experience. J Trauma 1994;37:426-432. 58. Hulka F, Mullins RJ, Leonardo V, et al: Significance of peritoneal fluid as an isolated finding on abdominal computed tomographic scans in pediatric trauma patients. J Trauma 1998;44:1069-1072. 59. Jamieson DH, Babyn PS, Pearl R: Imaging gastrointestinal perforation in pediatric blunt abdominal trauma. Pediatr Radiol 1996;26:188-194. 60. Jerby BL, Attorri RJ, Morton D Jr: Blunt intestinal injury in children: The role of the physical examination. J Pediatr Surg 1997;32:580-584. 61. Jobst MA, Canty TG Sr, Lynch FP: Management of pancreatic injury in pediatric blunt abdominal trauma. J Pediatr Surg 1999;34:818-824. 62. Kadish HA, Schunk JE, Britton H: Pediatric male rectal and genital trauma: Accidental and nonaccidental injuries. Pediatr Emerg Care 1998;14:95-98. 63. Keller MS, Sartorelli KH, Vane DW: Associated head injury should not prevent nonoperative management of spleen or liver injury in children. J Trauma 1996;41:471-475. 64. Keller MS, Vane DW: Management of pediatric blunt splenic injury: Comparison of pediatric and adult trauma surgeons. J Pediatr Surg 1995;30:221-225. 65. Kim HS, Lee DK, Kim IW, et al: The role of retrograde pancreatography in the treatment of traumatic pancreatic duct injury. Gastrointest Endosc 2001;54:45-55. 66. Koplewitz BZ, Ramos C, Manson DE, et al: Traumatic diaphragmatic injuries in infants and children: Imaging findings. Pediatr Radiol 2000;30:471-479. 67. Kouchi K, Tanabe M, Yoshida H, et al: Nonoperative management of blunt pancreatic injury in children. J Pediatr Surg 1999;34:1736-1738. 68. Kularni R, Daneshmand A, Guertin S, et al: Successful use of activated recombinant factor VII in traumatic liver injuries in children. J Trauma 2004;56:1348-1352.

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69. Kushimoto S, Arai M, Aiboshi J, et al: The role of interventional radiology in patients requiring damage control laparotomy. J Trauma 2003;54:171-176. 70. Ladd AP, West KW, Rouse TM, et al: Surgical management of duodenal injuries in children. Surgery 2002;132:748-753. 71. Lane MJ, Mindelzun RE, Jeffery RB: Diagnosis of pancreatic injury after blunt abdominal trauma. Semin Ultrasound CT MR 1996;17:177-182. 72. Lange DA, Zaret P, Merlotti GJ, et al: The use of absorbable mesh in splenic trauma. J Trauma 1988;28:269-275. 73. Lenwand MJ, Atkinson CC, Mooney DP: Application of the APSA evidence-based guidelines for isolated liver or spleen injuries: A single institution experience. J Pediatr Surg 2004;39:487-490. 74. Lickstein DA, Moriary KP, Feins NR: Neonatal rectovaginal tear during cesarean section. J Pediatr Surg 1998;33: 1315-1316. 75. Lucaya J, Vasques E, Caballerro F, et al: Nonoperative management of traumatic pancreatic pseudocysts associated with pancreatic duct laceration in children. Pediatr Radio1 1998;28:5-8. 76. Lutz N, Mahboubi S, Nance ML, et al: The significance of contrast blush on computed tomography in children with splenic injuries. J Pediatr Surg 2004;39:491-494. 77. Lutz N, Nance ML, Kallan MJ, et al: Incidence and clinical significance of abdominal wall bruising in restrained children involved in motor vehicle crashes. J Pediatr Surg 2004;39:972-975. 78. Lynch JM, Ford H, Gardner MJ: Is early discharge following isolated splenic injury in the hemodynamically stable child possible? J Pediatr Surg 1993;28:1403-1407. 79. Malhotra AK, Fabian TC, Croce MA, et al: Blunt hepatic injury: A paradigm shift from operative to nonoperative management in the 1990s. Ann Surg 2000;231:804813. 80. Markley MA, Mantor PC, Letton RW, et al: Pediatric vacuum packing wound closure for damage-control laparotomy. J Pediatr Surg 2002;37:512-514. 81. McGahren ED, Magnuson D, Schauer RT, et al: Management of transection of the pancreas in children. Aust N Z J Surg 1995;65:242-246. 82. Mehall JR, Ennis JS, Saltzman DA, et al: Prospective results of a standardized algorithm based on hemodynamic status for managing pediatric solid organ injury. J Am Coll Surg 2001;193:347-353. 83. Meier DR, Coln CD, Hicks BA, et al: Early operation in patients with pancreas transection. J Pediatr Surg 2001; 36:341-344. 84. Meyer G, Huttl TP, Hatz RA, et al: Laparoscopic repair of traumatic diaphragmatic hernias. Surg Endosc 2000; 14:lOlO-1014. 85. Miglietta MA, Salzano LJ, Chiu WC, et al: Decompressive laparotomy: A novel approach in the management of severe intracranial hypertension. J Trauma 2003;55:551-555. 86. Miller K, Kou D, Stallion A, et al: Pediatric hepatic trauma: Does clinical course support intensive care unit stay?J Pediatr Surg 1998;33:1459-1462. 87. Mooney DP, Birkmeyer NJO, Udell JV: Variation in the management of pediatric splenic injuries in New Hampshire. J Pediatr Surg 1998;33:1076-1080. 88. Mooney DP, Forbes PW: Variation in the management of pediatric splenic injuries in New England. J Trauma 2004;56:328-333. 89. Moore EE, Cogbill TH, Jurkovich GJ: Organ injury scaling: Spleen and liver (1994 revision). J Trauma 1995;38: 323-324. 90. Morse MA, Garcia VF: Selective nonoperative management of pediatric blunt splenic trauma: Risk for missed associated injuries. J Pediatr Surg 1994;29:23-27.

17

Abdominal Trauma

315

91. Moss RL, Musemeche CA: Clinical judgment is superior to diagnostic tests in the management of pediatric small bowel injury. J Pediatr Surg 1996;8:1178-1181. 92. Moulton SL, Downey EC, Anderson DS: Blunt bile duct injuries in children. J Pediatr Surg 1993;28:795-797. 93. Moulton SL, Lynch FP, Canty TG: Hepatic vein and retrohepatic vena caval injuries in children: Sternotomy first? Arch Surg 1991;126:1262-1266. 94. Muniz AE, Haynes JH: Delayed abdominal aortic rupture in a child with a seat-belt sign. J Trauma 2004;56:194197. 95. Nance ML, Keller MS, Stafford PW: Predicting hollow visceral injury in the pediatric blunt trauma patient with solid visceral injury. J Pediatr Surg 2000;35:1300-1303. 96. Nance ML, Lutz N, Arbogast KB, et al: Optimal restraint reduces the risk of abdominal injury in children involved in motor vehicle crashes. Ann Surg 2004;239:127-131. 97. Neville HL, Lally KP, Cox CS: Emergent abdominal decompression with patch abdominoplasty in the pediatric patient. J Pediatr Surg 2000;35:705-708. 98. Norotsky MC, Rogers FB, Shackford SR: Delayed presentation of splenic artery pseudoaneurysms following blunt abdominal trauma: Case reports. J Trauma 1995;38:444-447. 99. Nwomeh BC, Nadler EP, Meza MP, et al: Contrast extravasation predicts the need for operative intervention in children with blunt splenic trauma. J Trauma 2004; 56:537-541. 100. Oda J, Ivatury RR,Blocher CR, et al: Amplified cytokine response and lung injury by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory model of ischemia-reperfusion. J Trauma 2002; 52:625-632. 101. Ong AW, McKenney MG, McKenney KA, et al: Predicting the need for laparotomy in pediatric trauma patients on the basis of the ultrasound score. J Trauma 2003;54: 503-508. 102. Orr CJ, Clark MA, Hawley DA, et al: Fatal anorectal injuries: A series of four cases. J Forensic Sci 1995; 40:219-221. 103. Patel JC, Tepas JJ: The efficacy of focused abdominal sonography for trauma (FAST) as a screening tool in the assessment of injured children. J Pediatr Surg 1999; 34:4447, 52-54. 104. Pearl RH, Wesson DE, Spence LJ: Splenic injury: A five year update with improved results and changing criteria for conservative management. J Pediatr Surg 1989;24:428-431. 105. Pitcher G. Fiber-endoscopic thoracoscopy for diaphragmatic injury in children. Semin Pediatr Surg 2001;10:17-19. 106. Potoka DA, Schall LC, Ford HR: Risk factors for splenectomy in children with blunt splenic trauma. J Pediatr Surg 2002;37:294299. 107. Prince JS, LoSasso BE, Senac MO: Unusual seat-belt injuries in children. J Trauma 2004;56:420-427. 108. Pryor JP, Stafford PW, Nance ML: Severe blunt hepatic trauma in children. J Pediatr Surg 2001;36:974979. 109. Ramos CT, Koplewitz BZ, Babyn PS, et al: What have we learned about traumatic diaphragmatic hernias in children?J Pediatr Surg 2000;35:601-604. 110. Reinberg 0 , Yazbeck S: Major perineal trauma in children. J Pediatr Surg 1989;24:982-984. 111. Rescorla FJ, Plumley DA, Sherman S, et al: The efficacy of early ERCP in pediatric pancreatic trauma. J Pediatr Surg 1995;30:336-340. 112. Rezende-Neto JB, Moore EE, de Andrade MVM, et al: Systemic inflammatory response syndrome secondary to abdominal compartment syndrome: Stage for multiple organ failure. J Trauma 2002;53:1121-1128. 113. Rhodes M, Smith S, Boorse D: Pediatric trauma patients in an "adult" trauma center. J Trauma 1993;35:384393.

316

PART

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114. Mooney DP, Rothstein DH, Forbes PW: Variation in the management of pediatric splenic injuries in the United States. J Trauma Surg (in press). 115. Rotondo MF, Schwab CW, McGonigal MD: Damage control: An approach for improved survival in exsanguinating penetrating abdominal injury. J Trauma 1993;35:375-383. 116. Saggi BH, Sugerman HJ, Ivatury RR, et al: Abdominal compartment syndrome. J Trauma 1998;45:597-609. 117. Scioscia PJ, Dillon PW, Cilley RE: Endoscopic sphincterotomy in the management of posttraumatic biliary fistula. J Pediatr Surg 1994;29:36. 118. Shafi S, Gilbert JC, Carden S: Risk of hemorrhage and appropriate use of blood transfusions in pediatric blunt splenic injuries. J Trauma 1997;42:1029-1032. 119. Shapiro MB, Jenkins DH, Schwab CW, et al: Damage control: Collective review.J Trauma 2000;49:969-978. 120. Sharif K, Pimpalwar AP, John P, et al: Benefits of early diagnosis and preemptive treatment of biliary tract complications after major blunt liver trauma in children. J Pediatr Surg 2002;37:1287-1292. 121. Sharpe RP, Nance ML, Stafford PW: Nonoperative management of blunt extrahepatic biliary duct transection in the pediatric patient. J Pediatr Surg 2002;37:1612-1616. 122. Sharpe RP, Pryor JP, Gandhi RR,et al: Abdominal compartment syndrome in the pediatric blunt trauma patient treated with paracentesis: Report of two cases. J Trauma 2002;53:380-382. 123. ShilyanskyJ, Navarro 0 , Superina RA, et al: Delayed hemorrhage after nonoperative management of blunt hepatic trauma in children: A rare but significant event. J Pediatr Surg 1999;34:60-64. 124. ShilyanskyJ , Pearl RH, Kroutouro M, et al: Diagnosis and management of duodenal injuries in children. J Pediatr Surg 1997;32:880-886. 125. ShilyanskyJ, Sen LM, Kreller M, et al: Nonoperative management of pancreatic injuries in children. J Pediatr Surg 1998;33:343-345. 126. Simon RJ, Rabin J , Kuhls D: Impact of increased use of laparoscopy on negative laparotomy rates after penetrating trauma. J Trauma 2002;53:297-302. 127. Sivit CJ, Taylor GA, Bulas DI, et al: Blunt trauma in children: Significance of peritoneal fluid. Radiology 1991; 178:185-188. 128. Smith RS, Fry WR, Morabito DJ, et al: Therapeutic laparoscopy in trauma. Am J Surg 1995;170:632-637. 129. Sola JE, Mattei P, Pegoli W Jr, et al: Rupture of the right diaphragm following blunt trauma in an infant: Case report. J Trauma 1994;36:417420. 130. Soto JA, Alvarez 0 , Munera F, et al: Traumatic disruption of the pancreatic duct: Diagnosis with MR pancreatography. AJR Am J Roentgen01 2001;176:175-178. 131. Stassen NA, Lukan JK, Carrillo EH, et al: Abdominal seat belt marks in the era of focused abdominal sonography for trauma. Arch Surg 2002;137:718-723. 132. Strear CM, Graf JL, Albanese CT, et al: Successful treatment of liver hemorrhage in the premature infant. J Pediatr Surg 1998;33:849-851.

133. Stylianos S: Controversies in abdominal trauma. Semin Pediatr Surg 1995;4:116119. 134. Stylianos S: Abdominal packing for severe hemorrhage. J Pediatr Surg 1998;33:339-342. 135. Stylianos S, APSA Trauma Committee: Evidence-based guidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg 2000;35:164169. 136. Stylianos S, APSA Trauma Study Group: Prospective validation of evidence-based guidelines for resource utilization in children with isolated spleen or liver injury. J Pediatr Surg 2002;37:453-456. 137. Stylianos S, Bergman KS, Harris BH: Traumatic renal avulsion into the chest: Case report. J Trauma 1991; 31:301-302. 138. Stylianos S, Jacir NN, Hoffman MA, et al: Pediatric blunt liver injury and coagulopathy managed with packs and silo. J Trauma 1990;30:1409-1410. 139. Suliburk JW, Ware DN, Balogh Z, et al: Vacuum-assisted wound closure achieves early fascia1 closure of open abdomens after severe trauma. J Trauma 2003;55: 1155-1160. 140. Taner AS, Topgul K, Kucukel F, et al: Diagnostic laparoscopy decreases the rate of unnecessary laparotomies and reduces hospital costs in trauma patients. J Laparoendosc Adv Surg Tech A 2001;11:207-211. 141. TepasJJ, Frykberg ER, Schinco MA, et al: Pediatric trauma is very much a surgical disease. Ann Surg 2003;237:775-781. 142. Upadhyaya P, Simpson JS: Splenic trauma in children. Surg Gynecol Obstet 1968;126:781-790. 143. Vargo D, Sorenson J, Barton R: Repair of grade VI hepatic injury: Case report and literature review. J Trauma 2002;53:823-824. 144. Wales PW, Shuckett B, Kim PC: Long term outcome of non-operative management of complete traumatic pancreatic transection in children. J Pediatr Surg 2001;36:823-827. 145. Watts DD, Trask A, Soeken K, et al: Hypothermic coagulopathy in trauma: Effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma 1998;44:846854. 146. Winthrop AL, Wesson DE, Filler RM: Traumatic duodenal hematoma in the pediatric patient. J Pediatr Surg 1986;21:757-760. 147. Wolberg AS, Meng ZH, Monroe DM, et al: A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 2004;56:1221-1228. 148. Wotherspoon S, Chu K, Brown AF: Abdominal surgery and the seat-belt sign. Emerg Med 2001;13:61-65. 149. Yang EY, Marder SR, Hastings G, et al: The abdominal compartment syndrome complicating nonoperative management of major blunt liver injuries: Recognition and treatment using multimodality therapy. J Trauma 2002;52:982-986. 150. Yellin AE, Chaffee CB, Donovan AJ: Vascular isolation in treatment of juxtahepatic venous injuries. Arch Surg 1971;102:566573.

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Genitourinary Tract Trauma Rebeccah L. Brown and Victor F. Garcia

EPIDEMIOLOGY Injury is the leading cause of death in children and young adults in the United States, with injury to the kidney from either blunt or penetrating trauma being the most common genitourinary tract injury.2l,l22Almost 50% of genitourinary tract injuries involve the kidney.lZ1 Blunt abdominal trauma is responsible for 90% of pediatric genitourinary tract injuries," with the kidney being injured in 10% to 20% of all blunt trauma cases.121J22 The kidney is the most commonly injured solid organ, injured more frequently than the liver, spleen, Serious renal injuries are most often or pan~reas.2~8~3J30 associated with injuries to other organs, with multiple organ involvement occurring in 80% of those with penetrating trauma and 75% of those sustaining blunt trauma.'% The majority of associated injuries are closedhead injuries a n d extremity fractures.7~43J45Associated abdominal injuries occur in 42% to 74% of patients, primarily involving the spleen and liver in blunt trauma The and the bowel in penetrating trauma.102,104,122,179,182 majority of isolated renal injuries can be classified as relatively minor injuries.40 Mortality is rare due to isolated renal trauma and is more often attributed to the combined effects of major multisystem trauma.

however, violent deceleration with severe flexion-extension as seen with seatbelts is a well-recognized mechanism of renal injury associated with a higher risk of renal pedicle avulsion and ureteropelvic junction (UPJ) injury. Interestingly, bicycle crashes are the most common sports-related cause of renal injury in children and are associated with a significant risk of high-grade renal injury.75Although there is a perception among pediatric surgeons and urologists that contact sports such as football, hockey, and martial arts incur the greatest risk for renal injury in children,l75 a review by McAleer and c0lleaguesl2~ demonstrated that bicycle crashes accounted for 24% of injuries compared with only 5% for contact sports. This may have some impact on the type of counseling that should be provided regarding activity for children after severe renal injury and for those with solitary kidneys. Penetrating genitourinary tract injuries are becoming more common and should be suspected with any penetrating injuries to the chest, ~~ abdomen, flank, and lumbar r e g i 0 n s . 2 ~Iatrogenic injuries are uncommon and generally readily diagnosed. A significant risk of trauma occurs with needle puncture of the kidney for biopsy or endourologic access; endoscopic access of the urethra, bladder, or ureter; and procedures done on viscera adjacent to the genitourinary system. The most common iatrogenic injury is to the ureter during gynecologic and oncologic procedures.

MECHANISMS OF INJURY Most blunt renal injuries are due to sudden deceleration forces. Confined within Gerota's fascia, the kidney may be crushed against the ribs or the vertebral column, resulting in laceration or contusion. Direct injury to the renal parenchyma and collecting system may also occur from penetration of sharp, bony fragments of adjacent fractured ribs. Rawid deceleration mav cause arterial or venous injury from stretching of the fixed renal vascular pedicle.Z1 Because the intima of the renal artery is less elastic than that of the media and adventitia, it is predisposed to laceration, which may lead to subintimal dissection and arterial thrombosis.69 Mechanisms of blunt renal injury include pedestrian/motor vehicle crashes (60%),falls (22.5%),sports injuries (lo%),assault (3.5%), and other causes (4%).17jMost children who sustain renal injury in motor "chicle accidents are unrestrained122;

ANATOMIC CONSIDERATIONS Children are considered to be at increased risk for genitourinary tract trauma owing to unique anatomic differences between children and In children, the kidneys are larger relative to the size of the child's body and positioned lower in the abdomen, making them more exposed and vulnerable to injury. They are also less protected because of decreased perirenal fat, weaker abdominal wall musculature, and a poorly ossified thoracic rib cage. Because many pediatric kidneys retain their fetal lobulations, the risk for renal parenchymal disruption and lower pole amputation is increased. Furthermore, the renal capsule and Gerota's fascia are less developed than in adults, creating a greater potential for laceration, nonconfined bleeding,

r

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and urinary extravasation. Because of the relative mobility of a child's kidney, rapid deceleration is more likely to result in renal pedicle injury and UPJ disruption. In a comparative series of children and adults who sustained blunt renal trauma, Brown and colleagues21 concluded that although the likelihood of major renal injury was significantly higher in the pediatric population, the severity of trauma was significantly lower. For similar reasons, preexisting renal disease or congenital renal anomalies may predispose children to an increased risk of genitourinary tract injury from blunt trauma. The reported incidence of preexisting renal disease or congenital genitourinary anomalies in children sustaining renal trauma varies from 1% to 23%.19,"345,67,1*1,122,1352146 Underlying congenital anomalies associated with hydronephrosis (UPJ obstruction), abnormal kidney position (horseshoe kidneys, crossed fused renal ectopia), or abnormal kidney consistency (polycystic kidney disease, urinary reflux) may predispose the kidney to significant injury despite relatively minor f o r c e ~ . ~ W r o shematuria s associated with an ostensibly minor trauma should alert the physician to the possibility of an underlying pathologic lesion of the urinary tract and should prompt further radiologic imaging. Although underlying congenital genitourinary anomalies may have an increased risk of injury in children, they do not appear to be associated with any increased morbidity or long-term disability.lZ3

and disruption of the UPJ have both been described in the absence of hematuria. 14.3"38.43,131 ,I 58,166,'79 Whereas fractures of the lower ribs and lumbar spine mav be associated with renal trauma. fractures of the may be associated with bladder and urethral injuries. Eight percent of patients with a pelvic fracture have associated lower urinary tract injuries. The comparative incidence of lower urinary tract injury with various types of pelvic fractures is 27% in patients with symphysiolysis, 17% in patients with pelvic fracture, and 2% in uatients with a fracture of the uubis.196 In a study by Aihara and associate^,^ certain types of pelvic fractures were found to be associated with increased risk for rectal, bladder, or urethral injuries. Rectal injury was associated with widening of the symphysis p6bis. Bladder injuries were most commonly associated with widening of the sacroiliacjoint, symphysis pubis, and fractures of the sacrum, with widening of the symphysis pubis being the strongest predictor of bladder injury. Urethral injuries were most commonly associated with widening of the symphysis pubis and fractures of the inferior pubic ramus. Fractures involving these locations should heighten suspicion of associated rectal and lower urinary tract injuries and prompt directed diagnostic studies. Gross hematuria in the presence of a pelvic fracture strongly suggests a bladde; perforation. kny degree of hematuria in the presence of a pelvic fracture is an indication for cystography. Ninety-five percent of patients with bladder injuries have gross hematuria, and the remaining patients have microscopic hematuria.

CLINICAL FEATURES The evaluation of possible injury to the genitourinary tract is a part of the systematic and expeditious assessment required in all seriously injured patients. The mechanism of injury is important to know in order to assess the risk of injury. Direct blows to the abdomen or flank and significant deceleration forces as may occur in motor vehicle accidents and falls should alert the physician to the possibility of renal injury. Penetrating injuries to the abdomen, flank, back, chest, and pelvis should also raise suspicion for injury to the genitourinary tract. Although the presence of abdominal or flank tenderness and flank ecchymosis or mass suggests renal injury, up to 25% of patients with severe renal injury have unremarkable abdominal examinations. Indeed, only 55% of children with significant renal injuries present with tenderness over the injured kidney. Conversely, only about half of children with renal tenderness on examination have a condition more serious than minor renal trauma.lG7 Perineal ecchymosis, swelling, laceration, and bleeding are highly suggestive of genitourinary trauma. The presence of blood at the urinary meatus or a boggy mass or upward displacement of the prostate on digital rectal examination in boys requires formal urethrography to evaluate for possible injury to the urethra before any attempts at urethral catheterization. Gross hematuria is indicative of genitourinary trauma and mandates further radiologic imaging. Conversely, the absence of hematuria, either gross or microscopic, does not exclude the possibility of significant genitourinary trauma. In fact, complete avulsion of the renal vascular pedicle

DIAGNOSTIC EVALUATION A urine sample should be obtained in all trauma patients to assess for potential injury to the genitourinary tract. Gross hematuria is highly indicative of trauma to the genitourinary tract, a1t.hough it does not necessarily correlate with severity of injury. In the absence of gross hematuria, the urine dipstick is a safe and reliable method to screen for the presence of hematuria. The false-positive rate is 4.3%.58Dipstick results that are negative for hematuria do not need the added expense of microscopic analysis. However, if hematuria is revealed by dipstick evaluation, the suecimen should be examined microscopically for more accurate quantification.44.58It should be noted that microscopic hematuria can be associated with such procedures as atraumatic passage of a urethral catheter. However, in this instance, the degree of hematuria is minimal, and more than 5 red blood cells (RBCs) per high-powered field (HPF) should be considered abn0rmal.~~J78 A critical issue in the management of suspected genitourinary tract injury is the need for and extent of radiographic evaluation. Although most would agree that gross hematuria is an indication for formal diagnostic evaluation, much controversy exists as to whether microscopic hematuria as an isolated finding on urinalysis in pediatric trauma patients warrants further radiologic imaging." It remains unclear what degree of microscopic hematuria, if any, warrants radiographic evaluation in children. *See references 7,8,22,30,71,90,91, 102,112,114,121,133,140, 145, 167,170, 174, 182, and 183.

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18

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319

CT has replaced the intravenous pyelogram (IVP) Several studies have a t t e m ~ t e dto answer the cluestion as in the hemodynamically stable patient. However, a oneto whether the adult criteria for imaging of renal trauma, shot IVP still remains useful in the hemodynamically including findings of gross hematuria, shock, major unstable patient before emergent surgical exploration associated injuries, and significant deceleration injury, to determine the presence of two functional kidneys, can be applied to children. &though degrees of microhematuria ranging from any degree of rnicrohematurial12Js3 the presence and extent of urinary extravasation, and to 20 RBCs per HPFS1 to 50 RBCs per HPF14j have been the presence of renal pedicle injury. In children, 2 to reported assignificant in the literature, a careful analy3 mL/kg of nonionic contrast is injected intravenously, sis of published reports on 382 children with renal followed by an abdominal radiograph immediately injuries reveals that the application of adult criteria for and 10 minutes later.133It should be recognized that the IVP provides only very basic information and is not imaging would have identified 98% to 100% of all renal ini~ries.l7~ useful in staging of renal injuries. In fact, some studies ., It is generally accepted that abdominal trauma assohave shown that as many as 20% of patients with significant renal injuries will have a normal IW.Likewise, ciated with shock warrants radiographic evaluation of nonvisualization of the kidney on IVP does not necessarily the genitourinary system. several- a;thors have found correlate with arterial occlusion or injury. Other factors, that young adults with a history of blunt trauma and microscopic hematuria without shock, associated major including renal contusion with vascular spasm, overhydraintra-abdominal injuries, or a history of rapid deceleration tion, and hypotension or hypoperfusion, may produce similar findings in up to half of patients.48 can be managed safely without renal imaging.29,128,138,152 However, up to 25% of patients with any degree of Arteriography has been largely supplanted by CT hematuria and shock have significant renal and CT angiography for the diagnosis and staging of One of the pitfalls in applying adult criteria for the renal injury. More invasive than CT, arteriography imaging of renal trauma to children, especially with requires the expertise of an experienced interventional regard to the presence or absence of shock, is that chilradiologist and may be associated with a formidable dren are unique in their ability to maintain normal risk for arterial injury in small children whose vessels blood pressure in the face of significant hypovolemia may be prohibitively small, fragile, and difficult to access and blood loss. In fact, only 5% of children with major or cannulate. The current role of arteriography is in Therefore, renal injury have clinical signs of sho~k.lOl,l6~ the diagnosis of delayed or ongoing renal hemorrhage, hypotension itself is not a reliable indicator of the renovascular injury, or delayed arteriovenous fistula or seierity of renal injury in the pediatric p ~ p u l a t i o n . l ~ ~ ,pseudoaneurysm l~~ formation where interventional techor niques such as selective embolization61,64,93,116,137,184 Tachycardia typically precedes hypotension as an early endovascular stenting23J1IJ" may be therapeutic. indicator of shock in children and may be a worrisome Ultrasound, although utilized extensively in Europe sign. Accordingly, the decision on imaging in children, for the assessment of acute renal trauma, has not found as in adults, should be based not on isolated findincs u but rather on the whole clinical picture, including widespread acceptance in the United States. In the mechanism of injury (direct blow, major deceleration, United States, ultrasonography in the trauma patient or flexion-extension injury), vital signs (tachycardia or is mostly limited to the Focused Assessment with Sonography for Trauma (FAST) examination, which is hypotension), physical examination findings (abdominal/ performed primarily to detect the presence of free flank tenderness or contusion), urinalysis (microhemaintraperitoneal fluid. The FAST examination has not turia or gross hematuria), and associated injuries. In most cases, microhematuria is not an isolatedVfinding. Most been particularly useful in children except perhaps in children with microhematuria will have some other paramthe hemodynamically unstable patient with an associated eter, such as mechanism of injury, physical findings, or closed-head injury to rapidly exclude the presence of intraabdominal hemorrhage. In the hemodynamically stable other associated injuries, that would warrant further imagchild, CT provides more useful information. Ultrasound ing, therefore decreasing the likelihood of missed injury. Abdominal computed tomography (CT) is the stanis not particularly sensitive for detecting parenchymal dard for radiographic evaluation of abdominal trauma in injuries, except in the most experienced hands, and only with close color and pulsed Doppler interrogation can a children and is the most accurate imaging and staging CT is modality for evaluation of renal inj~ry.ls,l02,~2~,20~ vascular injury be diagnosed. Therefore, its utility in the highly sensitive and specific for detection of parenchymal acute setting at present remains quite limited. contusions/lacerations, perinephric/retroperitoneal It is critical to remember that CT and IVP are not hematoma, urinary extravasation, and segmental or major sensitive for bladder laceration unless the bladder is arterial injuries; delineation of nonviable, nonperfused fully distended. Haas and coworkerss6 compared the accuracy of routine helical CT versus conventional tissue or segmental infarction; and demonstration of cystography in 15 patients with suspected bladder injury. other associated intra-abdominal injuries. With the advent Cystography accurately diagnosed and classified the of the newer, faster helical CT scanners, it is essential injury in all 15 patients, whereas CT was only about to obtain delayed images during the nephrogram 60% accurate. Consequently, cystography is the imaging phase (>80 seconds) to detect renal parenchymal and venous injury as well as during the excretory phase modality of choice when bladder injury is suspected. (2 to 10 minutes) to avoid missing urine or blood For conventional cystography, after a scout film is extravasation. Extravasated urine accumulates, whereas obtained, a small amount of contrast medium is infused, extravasated arterial contrast dilutes out after the bolus followed by a second radiograph to check for gross of contrast agent is stopped.l"J76 extravasation. If gross extravasation is seen, a Foley

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catheter is inserted and placed to drainage. If extravasation is not seen, then the remainder of the contrast medium is instilled and radiographs are obtained in the anteroposterior, oblique, and lateral projections. It is essential for the bladder to be fully distended to avoid missing small-to-moderate tears of the bladder wall. The bladder of adolescents should be filled with 300 to 400 mL of contrast medium. The bladder of smaller children should be filled by gravity infusion until the patient becomes uncomfortable or the bladder capacity is reached. In children younger than 2 years of age, the bladder capacity is 7 mL x weight (kg). In children 2 to 11 years of age, the bladder capacity is age in years plus 2 x 30 mL.68,106 As part of the cystogram, all the contrast medium is drained from the bladder and a wostevacuation radiograph is taken. Up to 15% of extraperitoneal bladder ruptures are identified only on the radiograph taken after evacuation. The extent of extravasation seen with extra~eritoneal bladder rupture may be limited to the pelvic area or be quite dramatic, extending into a pelvic hematoma or coursing along the lateral pelvic wall. Extravasation from an intraperitoneal bladder rupture flows into the peritoneum, outlining the bowel with contrast agent. More recently, CT cystography has been found to be faster and equally accurate for defining and staging bladder injuries provided that the basic principles for conventional cystography, including complete distention of the bladder and imaging both before and after evacuation, are followed. ~ i k p i yclamping a Foley catheter after intravenous contrast agent administration for CT is not adequate and will result in an unacceptably high rate of missed inj~ries.fl3J5~ Retrograde pyelography plays a role in the assessment of ureteral and renal pelvic integrity when UPJ injury is suspected. Failure of opacification of the distal ureter on CT should raise suspicion for a ureteral injury187; and if insufficient detail is provided by CT, then retrograde pyelography is indicated. Retrograde urethography is indicated when urethral injury is suspected. A Foley catheter with a minimally inflated balloon is inserted into the fossa navicularis of the distal urethra, and approximately 30 mL of vision. contrast medium is instilled under fluorosco~ic I A normal retrograde urethrogram should demonstrate complete filling of the intact urethra with passage of contrast medium into the bladder. The presence of filling defects or extravasation of the contrast agent indicates urethral disruption. In the presence of hematuria, a cystogram should follow the retrograde urethrogram, even if the retrograde urethrogram is normal, because 10% to 15% of watients with urethral disruption from a pelvic fracture will have a concomitant bladder injury.48

INJURY GRADING AND SCORING SYSTEMS FOR GENITOURINARY INJURIES In 1989, the American Association for the Surgery of Trauma (AAST) Injury Scaling Committee devised and published a classification or grading system for

genitourinary tract injuries (Table 18-1) to standardize injury descriptions for research and data collection purposes. Figure 18-1 is an illustrative depiction of this grading system. Injuries are graded on scale from I to V ranging from the most minor injury (grade I) to the most complex (grade V). For the kidney, this grading system has proved highly applicable, and a study by Santucci and associates173 of 2467 renal trauma patients validated its usefulness as a measure of the seriousness of renal injury and as a predictor of the need for surgery. For example, patients with a grade I injury require observation only, whereas those with a grade V injury are more likely to require nephrectomy. Those with intermediate injuries (grades I1 to IV) require individualized therapy, with a trend toward more invasive therapy as injury grade increases. It should be noted, however, that this study was composed primarily of adult patients. Thus, extrapolation of results from this series may not be entirely applicable to children. Furthermore, the AAST system has been criticized for grouping complex parenchymal injury with major renovascular injury in the grade IV and V categories, because management may be quite different for the same grades of injury. Modifications addressing this issue have been proposed for future iterations of the scaling system. The AAST scaling systems for ureteral, bladder, and urethral injury (see Table 18-1) have not gained as widespread acceptance and have been used less consistently.

MANAGEMENT OF SPECIFIC INJURIES Kidney Blunt Injuries As with traumatic injuries to the spleen and liver, the majority of blunt renal trauma in children can be safely managed nonoperatively.' Almost 85% of pediatric renal injuries are considered relatively minor, with grade I and I1 contusions and minor parenchymal lacerations predominating. These lower grade renal injuries will invariably heal without further sequelae. Major parenchymal injuries occur in 10% to 15%, whereas major disruption of the renal pedicle occurs in the remaining 5% of ~hildren.~8J79 Children with microscopic hematuria and a minor renal injury diagnosed and graded by CT may require brief hospitalization for observation or may be discharged home with clear follow-up instructions. Children with higher-grade renal injury by CT and/or gross hematuria are hospitalized and placed at bed rest with close monitoring of vital signs and serial physical examinations and blood cell counts. Traditionally, ambulation is begun once the patient is fully resusci;ated and hemodynimically stable, blood cell counts have stabilized, and gross hematuria has resolved. It is not unusual for patients with gross hematuria to occlude their bladder outlet or ~olefcatheterwith clot. Decreased urine output, bladder distention, or bladder spasms should alert the clinician *See references 2, 7, 8, 43, 88, 109, 112, 118, 120, 168, 171, 179, and 197

CHAPTER

18

Genitourinary Tract Trauma

Grade*

lnjury Description?

Renal lnjury Scale l Contusion Hematoma II Hematoma Laceration Ill Laceration IV Laceration Vascular V Laceration Vascular

Microscopic or gross hematuria; urologic studies normal Subcapsular, nonexpanding without parenchymal laceration Nonexpanding perirenal hematoma confined to the renal retroperitoneum <1 cm parenchymal depth of renal cortex without urinary extravasation >1 cm parenchymal depth of renal cortex without collection system rupture or urinary extravasation Parenchymal laceration extending through the renal cortex, medulla, and collecting system Main renal artery or vein injury with contained hemorrhage Completely shattered kidney Avulsion of renal hilum that devascularizes kidney

Ureter lnjury Scale l Hematoma II Laceration Ill Laceration IV Laceration V Laceration

Contusion of hematoma without devascularization 150% transection >50% transection Complete transection with 2 cm devascularization Avulsion of renal hilum that devascularizes kidney

Bladder lnjury Scale I Hematoma Laceration II Laceration Ill Laceration IV Laceration V Laceration

Contusion, intramural hematoma Partial thickness Extraperitoneal bladder wall laceration 1 2 cm Extraperitoneal (>2 cm) or intraperitoneal (12 cm) bladder wall lacerations lntraperitoneal bladder wall laceration >2 cm Intra- or extraperitoneal bladder wall laceration extending into the bladder neck or ureteral orifice (trigone)

Urethral lnjury Scale l Contusion II Stretch injury Ill Partial disruption IV Complete disruption V Complete disruption

321

Blood at urethral meatus; urethrography normal Elongation of urethra without extravasation on urethrography Extravasation of urethrographic contrast medium at injury site, with contrast visualized in the bladder Extravasation of urethrographic contrast medium at injury site without visualization in the bladder; <2 cm of urethral separation Complete transection with >2 cm urethral separation, or extension into the prostate or vagina

--

*Advance one grade for multiple injuriesto the same organ. tBased on most accurate assessment at autopsy, laparotomy, or radiologic study. From Moore EE, Shackford SR, Pachter HL, et al: Organ injury scaling: Spleen, liver, and kidney. J Trauma 1989;29:1664

Grade

.

- Artist's rendition of the American Association for the Surgery of Trauma grading system for genitourinary tract trauma. (Reproduced with permission from Coburn M: Genitourinary trauma. In Moore E, Feliciano DV, Mattox KL [eds]: Trauma, 5th ed. New York, McGraw-Hill, 2004.)

to this possibility. Placement of a Foley catheter or irrigation or replacement of an existing Foley catheter should remediate the problem. Although it is generally suggested that patients maintain a decreased level of activity until the microscopic or gross hematuria resolves, there are no evidence-based guidelines in the literature addressing appropriate length or type of activity restrictions for renal trauma. The period of time at which healing is adequate to allow return to full activity without risk has not yet been defined. Prospective studies are warranted. Although there is little controversy regarding management of the lower grade, less complex renal injuries in hemodynamically stable patients or the management of high grade, complex renal injuries in hemodynamically unstable patients, the management of those with intermediate injuries remains less well defined. Although the AAST grading scale appears to have some predictive value on the need for surgery, indications for surgery are based more on hemodynamic stability of the patient and associated injuries, rather than on grade of renal injury based on imaging criteria. The only absolute indication for surgery is hemodynamic instability with ongoing bleeding and transfusion requirements. Radiographic signs of

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ongoing renal bleeding include an expanding or unconwith major renal lacerations with a devitalized fragment tained retroperitoneal hematoma or complete avulsion after blunt abdominal trauma, Husmann and associof the mai; renal artery or vein with extravasation as ate@ found that renal exploration and surgical repair significantly improves the prognosis only in those demonstrated by CT or arteriography.g4 Although significant renal injury with urinary patients with concomitant intraperitoneal injuries. extravasation has in the past been considered a relative, Therefore, operative exploration of the kidney should be considered in children-with major blunt renal injuries if not absolute. indication for renal exdoration, more with a devascularized segment in association with intesrecent studies would suggest that most of these types tinal perforation or complex pancreatic injury to reduce of injuries can be successfully managed nonoperatively in the hemodynamically stable patient.120~148,161~171the incidence of serious infectious com~lications. Nonoperative management of hemodynamically Matthews and associates120reported spontaneous resolution of urinary extravasation in 27 of 31 patients (87%), stable children with complex higher grade blunt renal injury has become the standard of care in most centers. while the remaining 4 patients required ureteral stents ~ o s t . ~ e d i a t rand i c adult series report successful nonopdue to ~ersistentextravasation. Similarly, ,. Russell and erative management of even the most complex injuries, coworkers171 reported management of 15 pediatric including shattered but perfused kidneys and complex patients with grade IV renal injuries with urinary lacerations with extensive verinewhric hematoma and extravasation-9 patients (60%) required observation urinary extravasation.6J71 Proponents of nonoperative only; 1 required emergent partial n&phrectomy due to management of these patients note that in the absence hypotension and ongoing bleeding; and 5 developed of prospective studies comparing immediate explourinomas, 2 of whom were treated with percutaneous ration versus expectant management, no reliable data drainage and 3 of whom required ureteral stents. are available to suggest that surgery done early in the ~ l t h o u g hcomplications can occur with nonoperative course of injury reduces the long- or short-term complimanagement, most complications associated with urinary cations. The risk for nephrectomy associated with extravasation are easily treated by percutaneous drainage171 immediate exploration is avoided, and delayed surgery or endoscopic stent pla~ement,120,161,1~~ thereby achieving higher rates of renal salvage. is only necessary in 0% to 13% of With recent advances in interventional radiology techPatients with major renal trauma associated with niques and equipment, the need for delayed open enteric or pancreatic injury may be at increased risk for surgery has diminished significantly.78 An algorithm serious infectious complications, such as perinephric for the management of renal injuries in children is abscess and infected urinoma. In a study comparing presented in Figure 18-2. nonoperative versus surgical management of patients

* PK-1

Kidney all grades injury

i"l

Observation

Exploration

Persistent gross hematuria Persistent transfusion requirement Expanding abdominallflank mass Persistent fever

I

Repeat CT scan I

;4 Nephrectomy

Enlarging urinoma

Enlarging hematoma

Angiography Selective emb~lizations~~ C4, 93,184

Percutaneous drainage171 Cysto~copy/stenting'20.~6~~ In Exploration if unresponsive to above

-

-

Algorithm for the management of renal injuries in children.

CHAPTER

Collective review of 10 retrospective pediatric series of blunt renal trauma published over the past 13 years (1991-2004)* consists of 668 patients with the following grades of injury: grade I (342); grade I1 (46); grade I11 (64); grade IV (85); grade V (24); grades IV and V (16); grades I and I1 (50); grades I to 111 (18); and grades I1 and 111 (23). Operative intervention for renal injury was required in 45 patients (6.7%),including 31 nephrectomies (4.6%), 11 partial nephrectomies (1.6%), 1 renorrhaphy, and 2 nephrostomies. All patients with grades I and I1 renal injuries were successfully managed nonoperatively. Only 2 patients with grade I11 renal injuries required operative intervention: 1with nephrectomy and 1 with a partial nephrectomy. Forty-one of 125 (33%) children with grade IV and V renal injuries required operative intervention, including 30 nephrectomies (13 grade IV, 15 grade V, 2 grades IV and V); 10 partial nephrectomies (8 grade lV, 1 grade V, and 1 grades IV and V), 1 renorrhaphy (grades IV and V), and 2 nephrostomies (grades IV and V). The indication for operative intervention in almost all cases was hemodynamic instability with ongoing bleeding, with most requiring emergent operations within 24 hours of admission. The percentage of patients requiring operative intervention for renal injury ranged from 1.7%"2 to 12.7%,118 with the vast majority being those with highgrade (IV to V) complex injuries. Nonoperative management was successful in 93% of all patients with blunt renal trauma, 97% of those with grade 111 renal injuries, 75% of those with grade IV renal injuries, and 33% of those with grade V renal injuries.

Penetrating Injuries Penetrating renal injuries are rare in children. Although most gunshot wounds to the abdomen will require abdominal exploration, retroperitoneal dissection and exploration isindicated only if preoperative or intraoperative assessment suggests a major renal injury with extravasation outside of Gerota's fascia, there is suspicion for significant nonurologic retroperitoneal injury -(great vessels, duodenum, pancreas, colon), and/or inspection reveals an expanding or pulsatile retroperitoneal hematoma.lgl McAninch and c0workersl2~ classified gunshot wounds involving the kidney into five categories: (1) contusions (18.4%), (2) minor lacerations (13.8%), (3) major lacerations (50.5%), (4) vascular injuries (6.9%), and (5) lacerations combined with vascular injury (10.3%). The majority of patients had multiple injuries, with 95% requiring associated procedures. The nephrectomy rate was 13.8%. Although many of the kidneys rembved were potentially salva&able, most were removed because of the patient's precarious hemodynamic status. For renal-proximity stab wounds, nonoperative treatment is appropriate in hemodynamically stable patients without associated injuries who have been staged approHowever, a high index priately by triple-contrast CT.68,198 of suspicion for missed ureteral and other associated injuries must be maintained if a nonoperative pathway is chosen. *See references 7,8, 21, 43, 112, 118, 158, 171, 174, and 179.

18

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323

In a retrospective review by McAninch and coworkers,l27 55% of renal stab wounds and 24% of renal gunshot wounds were successfully managed nonoperatively with an acceptable complication rate. In the hemodynamically unstable patient with penetrating trauma or those with a retroperitoneal hematoma at laparotomy, a oneshot IVP may be useful to identify renal injury and confirm the presence and function of two renal units to further guide management.

Renovascular Injuries

Major renovascular injuries are rare in children. Carroll and c0lleagues3~and Turner and associates1g0reported penetrating trauma as a cause of renovascular injiries in 64% and 68% of their patients, respectively. Conversely, Cass and coworkers39 identified blunt external trauma as the cause of renovascular injury in 76% of patients. Regardless of the mechanism, these patients tend to have high injury severity scores, large transfusion requirements, and associated life-threatening multisystem injury,31,39J79the management of which supersedes that of renal injury. Knudson and colleagues105 reported that factors associated with a poor outcome after renovascular injuries include blunt trauma, grade V injury, and attempted arterial repair. Grade V injuries are frequently associated with severe major parenchymal injuries, which contribute to poor function of the revascularized kidney. Patients with grade V injuries with severe parenchymal disruption may be better served by immediate nephrectomy, provided that a functional contralateral kidney is present. Bruce and associatesZ3 compared 12 patients with blunt renal artery injuries who underwent operative intervention (9 nephrectomies; 3 revascularizations) with 16 patients who were managed nonoperatively, 1 of whom underwent endovascular stent placement. They concluded that nonoperative management of unilateral blunt renal artery injuries is safe and often successful, with a 6% risk of developing post-traumatic renovascular hypertension. . The pathogenesis of renovascular injuries due to blunt trauma is thought to be caused by rapid deceleration, which results in stretching of the renal vasculature, disru~tionof the arterial intimar and arterial thr0mbosis.3~ Blunt arterial injury occurs more commonly on the left side than on the right side31,33,34,190because the right renal artery is longer than the left and may be better able to withstand the stretching " caused bv d e ~ e l e r a t i o n . ~ ~ Although hematuria may be absent or microscopic in 13% to 56% of patients with renovascular injuries,3l,39,65,128,179 most hatients have other symptoms or signs that raise suspicion for a major renal injury and prompt further diagnostic imaging.31J7g Renovascular injury is suggested on CT by (1) lack of renal enhancement or excretion, often in the Dresence of normal renal contour; (2) vein enhancement; (3) central hematoma; (4) abrupt cutoff of an enhanced renal artery; and (5) nonopacification of the pelvicaliceal ~vstem.31,~79 The approach to this type of injury depends on the time to diagnosis, the type and extent of the vascular injury, and the extent of the associated i n j ~ r i e s . ~ ~ J O ~ J ~ ~

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artery injury or solitary kidney~.~~,~6J60 Repair of the right renal vein may be difficult owing to its An algorithm for short length and proximity to the inferior vena cava. the management of renovascular injuries is presented in Nonetheless, injuries to the main renal vein can be Figure 18-3. r e ~ a i r e din mosi cases.31Laceration of the left renal vein at its origin can be managed by ligation because collatComplications eral circulation supplied by gonadal and adrenal veins Although most renal injuries in children can be managed usually allows for adequate venous drainage.31~83 Segmental arteries are difficult to repair and may best nonoperatively, nonoperative management is not withbe managed by ligation with accompanying partial out complications. If a nonoperative course is chosen, nephrectomy if the area of infarction encompasses more the patient must be carefully monitored. Falling blood than 15% of the kidney.g0However, others suggest that counts, ongoing transfusion requirements, and persistent nonoperative management should be considered in any gross hematuria may be indicative of ongoing bleeding. patient with segmental artery occlusion that is not associA repeat CT scan or arteriogram is warranted. An arteriogram may be especially useful since some injuries ated with uncontrolled retroperitoneal hemorrhage, with ongoing bleeding may be amenable to selective extensive urinary extravasation,o r other intra-abdominal embolization to control the bleeding. Indeed, the sucindications for $urgev. This management strategy has been associated with an acceptably low incidence of cess of nonoperative management may be enhanced by com~lications.~~3~ angiographic embolization in select patients.G4 However, Arterial repair is most appropriate and most sucprofuse bleeding not amenable to embolization requires cessful for renovascular injuries caused by penetrating emergent operative exploration. trauma. Notwithstanding occasional reports of successful Prolonged ileus, fevers, and expanding abdominal/ revascularization in patients 19 hours after injury,82the flank mass or discomfort may be indicative of persistent urinary extravasation or urinoma, which is the most success of the procedure greatly diminishes after 8 hours ~ ~ ~ , ~ ~and ~ coworkersg9 common complication after renal trauma. Russell and of renal i s ~ h e m i a . 3 1 , 6 9 , 8 2 ,Ivatury associates171reported that about two thirds of all urinoreviewed 40 penetrating renovascular injuries and mas in children will spontaneously resolve. Accordingly, concluded that salvage of a kidney with a renovascular small, noninfected, stable collections require no treatinjury is determined primarily by the nature and extent ment other than observation, whereas larger, expanding of associated injuries. Furthermore, they reported that collections may be managed by percutaneous drainage171 while attempts at renal artery repair are often futile, or endoscopic placement of ureteral ~tents.~20J61J~~ renal vein injuries are more amenable to repair and Broad-spectrum antibiotics are also administered intrahave a better prognosis. Nephrectomy, however, remains the procedure of choice in the hemodynamically unstavenously. Delayed renal bleeding is unusual and most commonly ble patient with multiple trauma. occurs within 2 weeks of injury. However, Teigen and Blunt injuries to the main renal artery are associated with ,l~~ reported two children who developed maslowest success rate for complete renal p r e ~ e r v a t i o n . 3 ~ J ~ ~coworkers184 Haas and associates85 reviewed the management of sive life-threatening hemorrhage several weeks after the initial injury diagnosed by arteriography and successfully 12 patients with complete renal artery occlusibn secondary to blunt trauma. Renal artery revascularization was treated by percutaneous transcatheter embolization. Perinephric abscesses may be associated with ileus, attempted in 5 patients with a median warm ischemia time of 5 hours (range: 4.5 to 36 hours). Although four high fevers, and sepsis. CT is diagnostic. Most of these of five revascularizationswere deemed technically successabscesses are successfully treated with intravenous broad-spectrum antibiotics and percutaneous drainage. ful at the time of operation, 3 patients demonstrated no function and 1 showed minimal function on postoperaMultiloculated abscesses not amenable to percutaneous tive renal function scans. Two patients required delayed drainage may require operative drainage. nephrectomy due to complications, and of the 7 patients Late complications may include hydronephrosis, who underwent nonoperative management, 3 patients arteriovenous fistula, pseudoaneurysm, pyelonephritis, developed significant hypertension requiring nephreccalculus formation, and delayed renal hypertension. Posttraumatic arteriovenous fistula and pseudoaneurysm may tomy for blood pressure control. Based on these results, be successfully managed by percutaneous endovascular the authors are unable to advocate emergency revascularization for unilateral renal artery occlusion in the embolization.ll6Jfl The incidence of renal hypertension Dresence of a normal functional conhalateral kidney after trauma is quite low, occurring in fewer than 5% of patient~.85,141~142~~9~ The incidence is thought to be even unless the patient is hemodynamically stable and warm lower in children. Although hypertension usually occurs ischemia time is less than 5 hours. Patients with unianywhere from 2 weeks to several months after lateral injury, complete arterial thrombosis, extensive i n j ~ r y , ~ ~long-term , ~ ~ 2 , ~follow-up ~~ is essential because associated injuries, and a prohibitively long period of onset may be delayed up to 10 to 15 years after injury.IG0 renal ischemia may be managed either by primary nephrectomy or expectant nonoperative management depending on the hemodynamic stability of the patient. Follow-UplOutcomes There are reports of successful endovascular stenting Evidence-based guidelines for follow-up of children for traumatic renal artery dissection and thrombosis after renal injury are conspicuously lacking in the literain both children134 and adults.23~flIAn attempt should be made to revascularize all patients with bilateral renal ture. In a retrospective study, Abdalati and associates1

I

CHAPTER

18

Fienovascular injury

I

Genitourinary Tract Trauma

325

4 Unstable

f5 Exploration

Observation Consider angiographyl endovascular stentZ4.I l l s 134

25 Nephrectomy

I

Kidney appears salvageable

Kidney appears unsalvageable

I

I

I

Attempt revascularization

-

25 Nephrectomy

.

Algorithm for the management of renovascular trauma in children.

correlated initial CT grading of renal injury with frequency of complications and time course of healing in 35 patients. From this study, they concluded that grades I and I1 injuries healed completely and required clinical but not radiologic follow-up. Grade I11 injuries were associated with the highest risk of complications (30%),with healing taking up to 4 months to complete. Thus, it was recommended that grade I11 injuries be followed by sequential imaging with CT, scintigraphy, and/or ultrasound for 3 to 4 months until complete healing was documented. Grade IV injuries were often associated with some degree of renal loss and required radiologic follow-up to assess complications and residual renal function. Although CT provides important information regarding healing and the presence of complications, quantitative dimercaptosuccinic acid (DMSA) scintigraphy is a more useful tool to assess residual renal function after injury.143A study by Keller and coworkers103evaluated the functional outcome of nonoperatively managed renal injuries in 17 children as measured by blood urea nitrogen (BUN), creatinine, blood pressure, and DMSA renal scan after radiographic evidence of complete healing. Similar to the findings of Abdalati and associates,l complete healing was documented radiographically within 3 months in all cases. They concluded that functional outcome correlates with injury grade, with grades I1 to IV injuries retaining near normal function and grade V injuries demonstrating significant loss of renal function due to scarring

and parenchymal volume loss. Despite diminished function on DMSA renal scans, all children were asymptomatic, normotensive, and had normal BUN and creatinine levels. Larger prospective clinical and radiologic outcome studies are warranted to further assess time to healing, incidence of complications, residual function, and longterm outcomes after renal trauma to provide the physician with a more evidence-based approach to appropriate follow-up and counseling for the injured child. At present, it is generally recommended that children with more severe renal injuries be followed with serial blood pressure monitoring and CT and DMSA at 3 to 6 months postinjury. Further imaging is also indicated for onset of any urologic symptoms or development of hypertension.

Operative Management of Renal Trauma Although most cases of renal trauma in children may be successfully managed nonoperatively, the surgeon should be familiar with techniques of operative management as well. As discussed previously, operative management of renal trauma is generally reserved for hemodynamically unstable patients or those patients with severe associated injuries. The patient is usually explored through a generous midline abdominal incision. Although traditionally it has been taught that the surgeon should first gain proximal control of the renal artery and vein before entering Gerota's fascia or the hematoma in order to reduce blood loss and decrease the nephrectomy rate,""

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this approach has recently been challenged. In both , ~ ~ a prospective, randomized retrospective s t ~ d i e s 4and clinical trials1 it was concluded that vascular control of the renal hilum before opening Gerota's fascia has no effect on the nephrectomy rate, transfusion requirements, or blood loss but does significantly prolong operative times by up to an hour or more. The nephrectomy rate appears to depend more on the degree of injury rather than on the type of renal vascular contr01.~ No matter what the approach, the kidney is exposed and vascular control is obtained at the hilum. With exsanguinating hemorrhage, rapid mobilization of the kidney with digital control of the hilum may be necessary. The left renal vein can be ligated because collateral drainage is provided by the left adrenal and gonadal veins. However, trauma to the right renal vein requires repair. Segmental arteries may be ligated and partial nephrectomy performed if the area of infarction encompasses more than 15% of the kidney.g0If the patient is hemodynamically stable, the kidney itself is salvageable, and the period of warm ischemia after injury is acceptable, renal artery repair and revascularization may be attempted. Otherwise, a nephrectomy should be performed. If it appears salvageable, the damaged kidney is debrided to viable tissue and intrarenal hematomas are evacuated. Hemostasis should be obtained with absorbable sutures placed in a figure-of-eight pattern. The open collecting system should be closed with fine, absorbable, monofilament sutures, because woven sutures may cut through renal tissue.1z6 Internal stents may be required if the ureter or renal pelvis has been injured. The renal capsule should be closed to approximate the renal margins. If the capsule is destroyed, the lacerated margins should be covered with omental pedicle grafts, retroperitoneal fat, or polyglycolic acid mesh.gOJ26 Approximation and covering of renal tissue aids in hemostasis and wound healing and prevents delayed bleeding and extravasation of urine.lZ6

Ureter Ureteral injury is uncommon and assumes secondary importance in children with potentially life-threatening injuries. Nonetheless, delays in diagnosis and treatment are associated with major morbidity and a significant risk for life-threatening urosepsis later during the course , 2 ~ , ~and ~ , ~colleague^^^ ~ reported the of i n j ~ r y . ~ ~Boone risk for urologic complications to be 13% when blunt UPJ disruption was diagnosed within 24 hours compared with 54% with delayed diagnosis. The risk for renal loss was 4.5% to 9% with early diagnosis compared with 32% to 33% with delayed diagnosis.'4,96 Ureteral trauma is classified by the anatomic location of the injury and by the extent of mural damage (see Blunt ureteral injuries are rare, occurring Table 18-1).144 in less than 1% of patients with blunt abdominal trauma. Direct injuries may result from crush injuries or severe hyperextension or flexion injuries. Direct compression against a transverse process or vertebral body has been described,'gg and an association with traumatic paraplegia has been noted.loOPatients with congenital ureteral

obstruction are also predisposed to injury of the collecting system.89 Surgical repair is unlikely to be successful if the underlying obstruction is not recognized and treated. Indirect mechanisms of ureteral injury in children include falls or rapid deceleration. As noted by Boone and colleagues,l4 the UPJ is particularly prone to disruption secondary to these mechanisms. Howerton and associates96 reviewed 54 cases of ureteral avulsion within 4 cm of the UPJ and found that this type of injury was three times more common in children than in adults. Similarly, the right kidney was injured three times more often than the left. Penetrating trauma involving the ureter occurs in approximately 4% of patients and is most often caused by a stab or gunshot wound. Although this type of injury is most commonly seen in adults, it occurs in a significant percentage of children as we11.l8I In the largest series to date, PerepBrayfield and coworkers1" reviewed 118 patients with gunshot wounds to the ureter managed by a variety of surgical procedures, depending on the location and severity of the defect. They reported a 20% incidence of comvlications and concluded that a high index of suspicion is necessary to avoid missing these injuries. Iatrogenic injuries to the ureter in children occur most cokmonlfduring ureteroscopic and percutaneous endourologic procedures. Open surgical procedures, such as those involving resection of an abdominal or pelvic tumor or colectomv. ,, mav, also be associated with ureteral trauma. Radiation injury is also occasionally encountered. The paucity of early signs and symptoms makes the nonoperative diagnosis of ureteral injuries difficult. Boone and colleagues14 encountered gross hematuria in 27% of patients with UPJ disruption, whereas an additional 26% of patients had microscopic hematuria with shock. Absence of hematuria was noted in about one third of patients. As reviewed by Brandes and coworkers,l6 23% to 37% of ureteral injuries reported in the literature have conspicuous absence of significant hematuria. Flank tenderness. ecchvmosis. and mass effect are encountered in only approximately 7% of patients with proximal ureteral injury.14 Patients occasionally present with anuria if the injury is bilateral or involves a solitarv kidnev. Imaging modalities for diagnosis of ureteral trauma include CT and IVP. Up to 75% of ureteral injuries are missed by IVP.'69'65 Ureteral injuries may be difficult to diagnose by CT as well. With the faster helical CT scanners currently in use, it is critical to obtain delayed images during the excretory phase (2 to 10 minutes) so that ureteral extravasation is not missed. Failure of opacification of the ureter should also raise suspicion for ureteral injury.187 Retrograde pyelography is quite sensitive and should be performed in hemodynamically stable patients suspected to have a ureteral injury. Delayed diagnosis of ureteral injury occurs in approximately half of patients owing to the subtle nature of the clinical findings, frequent absence of hematuria, lack of sensitivity of radiolbgic imaging techniques, and high incidence of multisystem injury with concomitant patient instability.14J6Wreteralinjuries may be heralded

CHAPTER

by sepsis, vascular collapse, or drainage of urine from surgical wounds. Periureteral fibrosis, phlegmon, and abscess are common. Other complications include obstruction from stenosis and renal failure. In contrast to management of renal injuries, nonoperative management has limited application for ureteral injuries. Minor ureteral injuries with limited extravasation may be managed nonoperatively with a retrograde stent. However, most patients with ureteral injuries fare better with early operative repair. If the diagnosis is delayed significantly, temporary stenting or percutaneous nephrostomy diversion followed by interval operative reconstruction may be indicated, owing to the increased inflammation, friability, and complications associated with attempts at repair more than 3 to 5 days after injury. The treatment of ureteral injuries is dictated primarily by the location and mechanism of injury, amount of tissue loss, and the condition of the local tissues. Ureteral injury associated with a severely damaged or shattered kidney is best managed by nephrectomy. In the absence of or with limited renal injury, attempts at primary ureteral repair should be attempted. Disruption of the UPJ is generally manageable by dismembered pyeloplasty. If damage to the renal pelvis is extensive, it should be surgically debrided and closed and ureteral continuity should be restored by ureterocalicostomy. Midureteral injuries are repaired by limited debridement to viable tissue and a spatulated end-to-end anastomosis using fine absorbable suture. Injuries to the pelvic ureter are often amenable to a simple ureteral reimplantation. Occasionally, a psoas hitch or Boari flap is required for ~ stents are used a tension-free a n a s t o m o ~ i s .Ureteral routinely. Patients with ureteral trauma from a bullet wound require that the ureter be debrided until the edges bleed freely. Intravenous fluorescein and a Wood's lamp are occasionally useful to predict viability. Peristalsis is not a reliable sign of viability. A spatulated end-to-end anastomosis is performed, and stenting is mandatory. Unstable patients with multiple injuries are best managed by exteriorization of the transected ureter as an intubated ureterostomy or by simple ureteral ligation with intraoperative or postoperative percutaneous nephrostomy. Simple ureteral ligation is also an excellent form of management for unstable patients in whom the length of the ureteral defect precludes primary repair. Definitive reconstruction of a long ureteral defect is done on an elective basis once the patient is stable.12J65J81 Options include renal mobilization (which can yield 3 to 5 cm) ,Is1 the Boari flap or psoas hitch,l5 and autotransplantation.12.193 Additionally, transureteroureterostomy and ileal interposition can be done.ls1 Delayed diagnosis associated with significant adjacent visceral injury (i.e., duodenal or pancreatic injury) may be particularly problematic. Such injuries are marginally amenable to reconstruction. Percutaneous antegrade ureteral stenting with later, elective surgical correction of stenosis or fistula, if encountered, is the preferred method of management.ls6 This may also be the best approach to management of ureteral injury associated with infected urinoma, abscess, delayed diagnosis, or ureteral contusions complicated by urinary extravasation.

18

Genitourinary Tract Trauma

327

Bladder Anatomy Although the bladder in children is located in the extraperitoneal space of Retzius, it is considered an the bony pelvis grows, the intra-abdominal organ.5" bladder assumes a pelvic position and is increasingly protected from injury. The anatomic attachments of the bladder influence the pattern of injury seen after some forms of trauma. The bladder is bound laterally by the internal obturator muscles and the umbilical ligaments.53At its base the bladder is attached to the urogenital diaphragm. Denonvillier's or the rectovesical fascia binds it posteriorly. Unlike the rest of the bladder, the dome is mobile and di~tensib1e.l~~

Causes

The bladder may be injured by blunt or penetrating trauma. Although penetrating injury to the bladder can be caused by any injury to the lower abdomen, the most common cause of unintentional injury is i a t r o g e n i ~ . ~ ~ ~ ~ 2 Migration or erosion of drains, ventriculoperitoneal shunts, intrauterine devices, and Foley catheters are rare causes of unintentional injury to the bladder.25,50,53,202 Intentional penetrating injuries are most commonly caused by gunshot wounds, which are usually associated with other intra-abdominal injuries. Blunt trauma accounts for 80% of injuries to the bladder. The susceptibility of the bladder to injury is somewhat dependent on the amount of urine contained at the time of injury.154 Motor vehicle crashes are the most common cause of blunt trauma to the bladder.53 Pelvic fractures with sharp bony fragments may lacerate the bladder (usually near the bladder neck), and shearing forces can tear the bladder at its mooring~.~3J~l A forceful, direct blow to the abdomen may rupture the dome of the bladder, even without an associated pelvic fracture.53JsO Because of its relatively protected position within the pelvis, considerable blunt force is required to cause bladder injury. Not surprisingly, serious injuries to other intra-abdominal organs are seen in almost half of patients with bladder injuries.70While 75% to 95% of bladder injuries are associated with pelvic fractures,27,70,151,180only 4% to 20% of patients with pelvic fractures have concomitant bladder i n j ~ r i e s . l ~ , 2 ~ , ~ 2 , l ~ ~

Classification and Definitions Bladder injuries due to blunt trauma may be further classified as contusions, and extraperitoneal and intraperitoneal ruptures. Extraperitoneal bladder ruptures occur in 60% to 65% of cases; intraperitoneal ruptures occur in 25% of cases; and a combination of the two occurs in 10% to 15% of cases.95 The AAST grading scale for bladder injuries is shown in Table 18-1. Contusions are disruptions in the bladder muscularis without loss of continuity of the bladder wall, whereas ruptures are complete disruptions of the bladder Contusions typically resolve without intervention.

328

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TRAUMA

Extraperitoneal bladder ruptures are usually assodeliberate evaluation of the patient. The weakest and Nineteen percent of ciated with pelvic fracture~.~2.~22~~ most mobile part of the bladder, the dome, is the most patients (mostly male) with extraperitoneal bladder common site of intraperitoneal rupture. This type of ruptures have a concomitant urethral injury, and 8% injury occurs more commonly in children."J2' have an associated intraperitoneal i n j ~ r y . ~ 3 , ~ ~ Intraperitoneal bladder ruptures are best managed by In contrast to extraperitoneal ruptures, intraperitoneal early operative repair. Protracted extravasation of urine ruptures are infrequently associated with pelvic fractures into the peritoneal cavity can lead to life-threatening (Fig. 18-4). These injuries are often caused by compresmetabolic, septic, and mechanical derangements.27.",92 Patients presenting more than 24 hours after intraperision (burst-type injury) from a suprapubic blow to a toneal rupture of the bladder may have elevated BUN, distended bladder or sudden, forceful de~eleration.~2~",l~~ creatinine, and potassium levels; a decreased serum Intraperitoneal ruptures most commonly occur at the sodium concentration; and a laboratory profile similar dome of the bladder, whereas extraperitoneal rupto that of patients with acute renal f a i l ~ r e . ~ z tures are usually caused by bony perforation or shearing f o r c e ~ . ~ ~infants ~ ~ V nand young children, the bladder The bladder should be approached through a lower midline abdominal incision to avoid lateral contained is an intraperitoneal organ, and if it is ruptured it will often cause intraperitoneal extravasation of urine.122 hematoma. If necessary, the rent in the dome of the Occasionally, bladder ruptures may result from an extenbladder can be widened to facilitate a thorough examsive hematoma of the bladder wall or, in neonates, ination of the inner aspect of the bladder. Associated from manipulation of an umbilical artery catheter.20Jj0 extraperitoneal tears can be closed from within by a single running layer of absorbable suture; however, the surgeon must ensure that the patency of the ureteral Management orifices is preserved. An intravenous injection of indigo carmine may help verify the location and Bladder Contusions integrity of the ureteral orifices. The dye should be seen effluxing from the ureteral orifices within 10 minutes. Most bladder contusions heal spontaneously without intervention. If the sacral innervation of the bladder is Lacerations extending into the bladder neck should be carefully repaired to reconstruct the sphincteric compointact, patients with bladder contusions have excellent nents and reduce the likelihood of later urinary outcomes. Patients with a large pelvic hematoma that causes considerable bladder distortion may have difficulty incontinence. Intraperitoneal bladder injuries are voiding and may benefit from Foley catheter drainage. repaired with absorbable suture in two layers. After the bladder is repaired, a closed-suction drain is placed and brought out through a separate stab incision. Intraperitoneal Rupture Although in the past most surgeons would insert a largeIntraperitoneal ruptures are frequently associated with bore suprapubic cystostomy tube instead of or in addition to a transurethral catheter for urinary drainage other significant injuries, necessitating a thorough and after repair of an intraperitoneal bladder rupture, more recent literature would suggest that transurethral catheter drainage is not only adequate, but preferable. For any degree of bladder injury, transurethral catheters are equally effective, are associated with fewer complications, and may be removed sooner than suprapubic catheters.Y5,18.i,192 Urinary drainage is generally maintained for 5 to 10 days. Most surgeons will obtain a cystogram before removal of the urinary drainage catheter to evaluate the integrity of the repair. If no extravasation is documented, then the urinary catheter and closed-suction drain can be removed.

Extraperitoneal Rupture

Voiding cystourethrography demonstrating intraperitoneal rupture of the bladder. The patient also had bilateral fractures of the superior ischial and inferior pubic rami.

The preferred management of extraperitoneal rupture is transurethral catheter drainage alone. This approach is safe and effective and obviates the need for bladder exploration, manipulation of the extraperitoneal hematoma, and converting a closed pelvic fracture into an open one. At times, the degree of extravasation of contrast medium may be alarming. However, because it is dependent not only on the size of the tear but also on the amount of contrast medium instilled,"g,55the degree of extravasation alone may not indicate the severity or extent of the tear in the bladder.'7.3"-"7," In most

CHAPTER

instances, the tear heals completely and transurethral catheter drainage is successful even with extensive Almost 90% of extraperiurinary extravasation.41~42~55 toneal bladder ruptures heal within 10 days and the remainder within 3 weeks.55 Operative intervention is rarely required.

Penetrating Injuries Because of the high likelihood of associated injuries, which often take priority in management, patients with penetrating injuries to the bladder generally require exploratory laparotomy. The peritoneal cavity is opened in the midline, and injuries to the intra-abdominal viscera and major vasculature are addressed first. Attention is then directed to the bladder, and the extent of injury is determined. All devitalized bladder tissue and debris from clothing or bony spicules are removed.27 The integrity of the ureters can be confirmed with intravenous injection of indigo carmine. A diligent search should be made for extravasation, and, if necessary, the ureters should be intubated. Bladder mobilization is unnecessary and invites precipitous bleeding. Large, nonexpanding hematomas should be left undisturbed. The bladder should be entered through the dome. Extraperitoneal defects should be closed intravesically with a single layer of running absorbable suture. A watertight closure is ideal but not essential. With adequate bladder drainage, even a tenuous closure can heal satisfactorily. Intraperitoneal defects should be closed in two layers with absorbable suture. Closed-suction drains are placed as previously described, and transurethral catheter drainage is maintained for 5 to 10 days.

Urethra Although urethral trauma is a secondary consideration in children with potential life-threatening trauma, such injuries account for a disproportionate degree of long-term morbidity. It remains unclear whether delayed or immediate repair is superior, and there are no prospective, randomized studies addressing the issue. The majority of the available data are based on retrospective series in adults. The only available pediatric series are limited by small numbers of patients. Data from adult studies may not be applicable to children owing to anatomic differences. For example, in contrast to adults, the posterior urethra is not protected by the prostate in children and may be injured at any level. Blunt trauma with disruption of the bony pelvis accounts for most posterior urethral injuries in children. About 5% of males with a fractured pelvis will also have an injury to the posterior urethra.153Of these cases, 10% to 20% will have an associated bladder rupture.55 Motor vehicle accidents account for 90% of urethral injuries, and the remaining 10% result from falls, crush injuries, or sporting injuries. A lateral pelvic force without pelvic fracture rarely results in urethral disruption. Penetrating injuries involving the posterior urethra including stab wounds, gunshot wounds, and iatrogenic causes are rare.

18

Genitourinary Tract Trauma

329

Anterior urethral injuries are often encountered after straddle injuries, such as a fall astride a fence, kicks, or bicycle injuries. Penetrating trauma to the anterior urethra is rare but may be seen with gunshot or stab wounds. Urethral instrumentation, penile surgery, and injuries from sexual intercourse and masturbation may also result in anterior urethral trauma. The diagnosis of urethral trauma is relatively straightforward. Symptoms of urethral injury may include the inability to void or the sensation of voiding without passing urine. Blood at the urinary meatus or gross hematuria after trauma strongly suggests urethral injury. Physical examination of the penis, scrotum, and perineum may reveal swelling and ecchymosis. The integrity of and boundaries of Buck's, Colles', and Scarpa's fascias indicate the region injured. Digital rectal examination may reveal upward displacement of the prostate or a boggy mass. This, however, may be difficult to assess in young children, so urethral imaging is required to confirm the diagnosis. If there is suspicion of a urethral injury, blind passage of a transurethral urinary catheter should not be attempted because there is a risk of creating a false passage with the catheter and converting a partial disruption into a complete one. Retrograde urethrography is the imaging modality of choice for diagnosis of urethral trauma. Findings of elongation, filling defect, or extravasation indicate urethral injury. If urethral integrity is demonstrated by retrograde urethrography, the catheter is then advanced and a cystogram is performed to exclude concomitant bladder injury. Table 18-1 outlines the classification of urethral injuries that includes contusions, stretch injuries, partial disruptions, and complete disruptions. A filling defect caused by contusion and hematoma or an elongated urethra without extravasation on retrograde urethrography indicates grade I or I1 injury. Urethral extravasation with bladder continuity indicates partial disruption (grade 111).Urethral extravasation with no admission of contrast agent into the proximal urethra or bladder suggests complete disruption (grade IV). Spasm of the periurethral musculature can mimic complete disruption. Figure 18-5 provides an example of injury to the bulbous urethra.

, - . Extravasation of contrast from the bulbous urethra due to penoscrotal urethral disruption. The posterior membranous and prostatic urethra is intact.

330

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The long-term sequelae of urethral trauma can be devastating and may include impotence, retrograde ejaculation, incontinence, and urethral strictures. Some of these complications may be a direct consequence of the trauma itself or may be related to surgical attempts at repair. ~ - d i a ~ n o sof i s anterior urethral injury is suggested if the retrograde urethrogram reveals only minimal extravasation with good urethral continuity and if the patient is able to void. Grade I or I1 injuries to the anterior urethra usually heal spontanedusly without insertion of any indwelling urinary catheters, as long as the patient is able to void. Intermediary grade anterior urethral injuries may be managed by an indwelling transurethral Foley catheter, whereas more complex injuries are best managed in the initial stages by placement of a suprapubic catheter. Delayed urethral strictures occur~commonly,and most are. amenable to urethroplasty. Penetrating injuries to the anterior urethra may be managed by exploration and primary repair or suprapubic urinary diversion. Husmann and colleaguesg7 reviewed management of 17 patients with partial transection of the anterior urethra due to low-velocity gunshot wounds and concluded that patients were best managed by aggressive wound debridement, corporeal repair, primary suture repair of the urethra, and placement of a suprapubic catheter. Strictures developed much less frequently with this approach (1 of 8) compared with suprapubic diversion and transurethral catheter stenting (7 of 9). In Ehildren, the majority of posterior urethral injuries may be managed nonoperatively. Grade I or I1 injuries, which may allow spontaneous voiding, are managed without surgery and without an indwelling urinary catheter. Patients who are unable to void are managed by insertion of a small, transurethral Foley catheter. Grade I11 injuries with minimal extravasation may also be managed by passing a small, transurethral Foley catheter under fluoroscopic guidance immediately after the retrograde urethrogram. If the catheter does not pass easily, however, a suprapubic tube should be placed. Options for repair of more complex posterior urethral injuries include primary surgical repair with anastomosis of the disrupted urethral ends, delayed primary surgical repair, primary surgical catheter realignment, primary endoscopic and radiologic realignment, or suprapubic cystostomy with delayed urethroplasty. Primary surgical repair involves evacuation of the pelvic hematoma, mobilization of the prostate and urethra, and direct end-to-end anastomosis between the prostatic and membranous urethra. Problems with this approach include increased risk of uncontrolled bleedin;" d u e to exploration of the injury site with release of the tamponade effect of the hematoma; increased risk of impotence due to dissection of the periprostatic and periurethral tissues; and increased risk of incontinence due to damage to the intrinsic urethral sphincter mechanism by dissection, mobilization, and debridement of torn urethral ends.51,53,56,57~108~1g5 TO minimize these complications, Mundy150 advocated delaying primary surgical repair

until 7 to 10 days after injury once the patient was more stable, the operative view was less obscured by bleeding, and before the onset of fibrosis. Primary surgical catheter realignment was first introduced by Ormond and Cothran in 1934 with multiple variations in technique over the ensuing y e a r ~ . ~ ~ ~ ~ ~ 7 " 1 0 7 Despite not requiring direct suturing of the disrupted urethral ends, this technique still requires an open procedure with entry into and evacuation of pelvic hematoma with all of the attendant risks of primary surgical repair. More recently, innovative combined transurethral and transvesical endoscovic and interventional radiologic techniques have been introduced to achieve primary alignment without the risk of explor,~~,~~~-~~2,~~ ing the disrupted ~ r e t h r a . ~ 7 , 4 9 , ~ ~Furthermore, because there is no manipulation of periprostatic tissues and no additional trauma to the cavernous nerves, there should be no additional risk of erectile dysfunction other than that caused by the injury itself. These minimally invasive techniques have produced encouraging results so far, but clinical experience is limited to small series. Postoperative outcomes of these small series indicate that 88% to 100% of patients are continent, 14% to 39% of patients have some degree of erectile dysfunction, and about half require subsequent internal urethrotomies. Concerns about the impact of primary open surgical repair or catheter realignment on potency and urinary continence led to the introduction of an alternative treatment approach, namely suprapubic cystostomy with delayed urethroplasty. First advocated by Johanson of Sweden in 1953, no attempt is made to explore the urethra but rather the urinary stream is simply diverted via a suprapubic cystostomy tube. A stricture is considered inevitable and is repaired several months later. This approach has gained widespread acceptance and is considered a standard approach to the management of complex posterior urethral disruptions. Advantages of this approach include avoiding entry into a fresh pelvic hematoma with risk of blood loss and infection, speed and simplicity of suprapubic tube insertion, and decreased incidence of i m ~ o t e n c eand incontinence due to avoidance of dissection of the prostate and urethra.73 Disadvantages include prolonged need for a suprapubic tube with risk of infection and stone formation as well as the nearly 100% risk for urethral strictures, which may be quite complex and difficult to repair even in the delayed setting.Io7 Tunc and colleagueslsg reviewed 77 cases of delayed repair of traumatic posterior urethral injuries and demonstrated adequate urethral continuity in 9596, postoperative incontinence in 9%, and postoperative erectile dysfunction in 16%. They concluded that delayed posterior urethroplasty is a successful treatment option with acceptable morbidity. After extensive literature review regarding different approaches to management of complex hosterGr urethral injuries, Holevar and associates" concluded that these injuries may be treated with either primary endoscopic realignment or suprapubic cystostomy with delayed urethroplasty with similar results. Urethral trauma in females is rare."J" The usual mechanism of injury involves pelvic fracture incurred

CHAPTER

during a motor vehicle accident. Straddle injury occasionally results in damage to the urethra. Female urethral injuries may be distal avulsion from the perineal attachment or proximal disruptions and lacerations. The latter type of injury is characteristically associated with other pelvic injuries, including vaginal and bladder neck lacerations. Perry and colleagues159 reviewed the evaluation of urethral injuries in females with pelvic fractures. Blood at the vaginal introitus mandates a meticulous vaginal examination. The urinary meatus must also be carefully examined and its patency confirmed by passage of a catheter. However, it is important to note that catheters can often be passed into the bladder even in the presence of a significant urethral injury. Development of vulva1 edema after removal of the catheter warrants prompt investigation. Because urethrography in young girls is difficult and unreliable, urethroscopy is the preferred diagnostic modality. Delays in diagnosis of urethral injury in girls occur frequently and have devastating consequences.159Such injury is misdiagnosed in about 50% of cases and can result in life-threatening sepsis and necrotizing fasciitis. Therefore, one should have a low threshold for performing urethroscopy when urethral injury is suspected in a young girl. Treatment is dictated by the extent and location of injury. Urethral injuries that extend into the bladder neck require meticulous repair with reapproximation of the bladder outlet and urethra. Such injuries are encountered about two thirds of the time.121,122,126,129 Associated vaginal injuries are repaired primarily. Urethral crush injuries that do not involve the bladder neck are managed by extended transurethral Foley catheterization (6 to 8 weeks) or, if necessary, suprapubic catheter drainage. Significant long-term complications associated with pediatric female urethral trauma are common and include urethral stenosis, urethrovaginal fistula, incontinence, and vaginal s t e n ~ s i s . ~ ~ Clearly every effort must be made to promptly detect and aggressively manage this uncommon injury.

External Genitalia Girls Blunt genital trauma in girls is fairly common. The presenting symptoms are usually the presence of blood in the underpants or on the perineum shortly after injury.l17 Blunt genital trauma most commonly results from straddle injury. The most common types of injury, in decreasing order of frequency, are lacerations or contusions of the perineal body, vagina, labia, urethra, and rectum. Due to the extreme difficulty of performing a thorough genitourinary examination in an awake, uncomfortable, anxious, and embarrassed child, the majority of patients are best evaluated in the operating room under general anesthesia. Indeed, as many as 76% of patients will have more extensive injuries than can be appreciated in the emergency department.l17 Management of female genital trauma is dictated by the type and extent of injury. Necrotic, contused tissue

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should be debrided. Lacerations are primarily repaired after hemostasis is achieved. Absorbable sutures are used to preclude the need for removal. Urethroscopy and proctoscopy may be necessary to more thoroughly evaluate the injury.

Boys The most common injury to the penis is iatrogenic injury during circumcision.80 Complications of circumcision include penile amputation, urethral fistulization, laceration of the glans penis, and inaccurate removal of the foreskin resulting in phimosis degloving injury. Most of these injuries are avoidable with use of proper technique. Penile injury resulting from blunt or penetrating trauma is rare in children. Urethral lacerations should be managed as described in the previous section. The findings of an expanding hematoma, palpable corporal defect, and excessive bleeding suggest cavernosal injuries. When possible, these injuries should be repaired primarily.17Urinary diversion with a suprapubic tube is occasionally necessary.79 The preferred method of management of gunshot wounds with a limited extent of injury is debridement of superficial wounds, repair of the cavernosal defects, and primary repair of the urethral injury.87 Penile erectile dysfunction (impotence) can occur after blunt pelvic and perineal trauma.149The dysfunction results from shearing of the penile blood vessels in the pelvis. Penile revascularization may restore potency.119 Priapism may also occur after blunt trauma. For this disorder, selective angiography is helpful to diagnose the injury and to embolize the arteriovenous fistula causing the priapism. Doppler ultrasonography is also useful to characterize and localize the lesion.lS8 Injury resulting from zipper entrapment of the penis can be addressed, in many cases, in the emergency department but may require a general anesthetic for release of the penis.20° Penile strangulation injuries due to constricting bands are managed by removal of the constricting band in as atraumatic a manner as possible. In children, hair tourniquets are common sources of constriction and may be quite difficult to remove. Severe strangulation injuries may result in necrosis of the distal penile skin, glans, cavernosum, or urethra. Conservative debridement and urinary diversion may be required.48 Scrota1 injuries may result from penetrating trauma, blunt trauma, or both. High-resolution ultrasonography is very useful in the evaluation of these injuries.1° Ultrasonography of penetrating injuries can identify testicular rupture and extratesticular soft tissue abnormalities as well as the presence and location of foreign bodies.110 This technique is also useful in distinguishing less serious injuries, such as scrota1 hematomas, hydroceles, and hematoceles, from surgical emergencies, such as testicular rupture and infarction. It should be noted that epididymal rupture is not as easily identified on ultrasonography.l55 Patients with hematoceles should be considered for exploration to evacuate the blood from the tunica vaginalis testis because this approach reduces morbidity and hastens recovery. Testicular disruption is managed by debridement and primary c l ~ s u r e . ~

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REFERENCES 1. Abdalati H, Bulas K, Sivit C, et al: Blunt renal trauma in children: Healing of renal injuries and recommendations for imaging follow-up. Pediatr Radiol 1994;24:573. 2. Ahmed S, Morris LL: Renal parenchymal injuries secondary to blunt abdominal trauma in childhood: A 10-year review. Br J Urol 1982;54:470. 3. Aihara R, Blansfield JS, Milham FH, et al: Fracture locations influence the likelihood of rectal and lower urinary tract injuries in patients sustaining pelvic fractures. J Trauma 2002;52:205. 4. Altala A, Miller FB, Richardson JD, et al: Preliminary vascular control for renal trauma. Surg Gynecol Obstet 1991; 173:386. 5. Altarac S: Management of 53 cases of testicular trauma. Eur Urol 1994;25:119. 6. Altman AL, Haas C, Dinchman KH, et al: Selective nonoperative management of blunt grade 5 renal injury.J Urol 2000;164:27-30. 7. Bass DH, Semple PL, Cywes S: Investigation and management of blunt renal injuries in children: A review of 11 years' experience. J Pediatr Surg 1991;26:196. 8. Baumann L, Greenfield, Aker J, et al: Nonoperative management of major blunt renal trauma in children: In-hospital morbidity and long-term followup. J Urol 1992;148:691. 9. Beaver BL, Colombani PM, Fa1 A, et al: The efficacy of computed tomography in evaluating abdominal injuries in children with major head trauma. J Pediatr Surg 1987; 22:1117. 10. Berman JM, Beidle TR, Kunberger LE, Letourneau JG: Sonographic evaluation of acute intrascrotal pathology. AJR Am J Roentgen01 1996;166:857. 11. Bertini JE Jr, Flechner SM, Miller P, et al: The natural history of trauma branch renal artery injury. J Urol 1986; 135:228. 12. Bodie B, Novick AC, Rose M, Strafton RA: Long-term results with renal autotransplantation for ureteral replacement. J Urol 1986;136:1187. 13. Bond SJ, Gotschall CS, Eichelberger MR: Predictors of abdominal injury in children with pelvic fracture.J Trauma 1991;31:1169. 14. Boone TB; Gilling PJ, Husmann DA: Ureteropelvic junction disruption following blunt abdominal trauma. J Urol 1993; 150:33. 15. Bracken RB, Sheldon CA: Psoas hitch, Boari flap and transureteroureterostomy. In Fowler JE Jr (ed): Mastery of Surgery: Urologic. Boston, Little, Brown, 1992. 16. Brandes SB, Chelsky MJ, Buckman RF,Hanno PM: Ureteral injuries from penetrating trauma. J Trauma 1994;36:766. 17. Brandes SB, Buckman RF, Chelsky MJ, Hanno PM: External genitalia gunshot wounds: A ten-year experience with 56 cases. J Trauma 1995;39:266. 18. Bretan APN Jr, McAninch JW, Federle MP, et al: Computerized tomographic staging of renal trauma: 85 consecutive cases.J Urol 1986;136:561. 19. Brower P, Paul J, Brosman SA: Urinary tract abnormalities presenting as a result of blunt abdominal trauma. J Trauma 1978;18:719. 20. Brown D, Maghill HL, Block DL: Delayed presentation of traumatic intraperitoneal bladder rupture. Pediatr Radiol 1986;16:253. 21. Brown SL, Elder JS, Spirnak JP: Are pediatric patients more susceptible to major renal injury from blunt trauma? A comparative study. J Urol 1998;160:138. 22. Brown SL, Haas C, Dinchman KH, et al: Radiologic evaluation of pediatric blunt renal trauma in patients with microscopic hematuria. World J Surg 2001;25:1557.

23. Bruce LM, Croce MA, Santaniello JM, et al: Blunt renal artery injury: Incidence, diagnosis, and management. Am Surg 2001;67:550. 24. Burgess AR, Eastridge BJ, Young JW, et al: Pelvic ring disruption: Effective classification systems and treatment protocols. J Trauma 1990;30:848. 25. Burnett DG: Near bladder perforation in urethra-catheter extrusion: An unusual complication of cerebrospinal fluidperitoneal shunting. J Urol 1982;127:543. 26. Campbell EW, Filderman PS, Jacobs SC: Ureteral injury due to blunt and penetrating trauma. Urology 1992;40:216. 27. Carroll PR, McAninchJW: Major bladder trauma: Mechanism of injury and a unified method of diagnosis and repair. J Urol 1984;132:254, 1984. 28. Carroll PR, McAninch JW: Operative indications in penetrating renal trauma. J Trauma 1985;25:587, 1985. 29. Carroll PR, McAninch JW: Current management of blunt renal trauma. Urol Ann 1987;l:171. 30. Carroll PR, McAninchJW: Staging renal trauma. Urol Clin North Am 1989;16:193. 31. Carroll PR, et al: Renovascular trauma: Risk assessment, surgical management, and outcome. J Trauma 1990;20:547. 32. Carter CT, Schafer N: Incidence of urethral disruption in females with traumatic pelvic fractures. A m J Emerg Med 1993;11:218. 33. Cass AS, SussetJ, Khan A, et al: Renal pedicle injury in the multiple injured patient. J Urol 1979;122:728. 34. Cass AS: Immediate radiological evaluation and early surgical management of genitourinary injuries from external trauma. J Urol 1979;122:772. 35. Cass AS: Immediate surgical management of severe renal injuries in multiple injured patients. Urology 1983;21:140. 36. Cass AS: Renal trauma in the multiple-injured child. Urology 1983;21:487. 37. Cass AS: Blunt renal pelvic and ureteral injury in multipleinjured patients. Urology 1983;22:268. 38. Cass AS: Blunt renal trauma in children. J Trauma 1983; 23:123. 39. Cass AS, Bubrick M, Luxenberg M, et al: Renal pedicle injury in patients with multiple injuries. J Trauma 1985; 23392. 40. Cass AS, Luxenberg M, Gleich P, et al: Clinical indications for radiographic evaluation of blunt renal trauma. J Urol 1986;136:370. 41. Cass AS, Luxenberg M: Features of 164 bladder ruptures. J Urol 1987;138:743. 42. Cass AS: Diagnostic studies and bladder rupture: Indications and techniques. Urol Clin North Am 1989;16:267. 43. Ceylan H, Gunsar C, Etensel B, et al: Blunt renal injuries in Turkish children: A review of 205 cases. Pediatr Surg Int 2003;19:710. 44. Chandhoke PJ, McAninch JW: Detection and significance of microscopic hematuria in patients with blunt renal trauma. J Urol 1988;140:16. 45. Chopra P, St-Vil D, Yazbeck S: Blunt renal trauma-blessing in disguise?J Pediatr Surg 2002;37:779. 46. Clark DE, Georgitis JW, Ray RS: Renal arterial injuries caused by blunt trauma. Surgery 1981;90:87. 47. Clark WR, Patterson DE, Williams HJ Jr: Primary radiologic realignment following posterior urethral disruption. Urology 1992;39:182. 48. Coburn M: Genitourinary trauma. In Moore E, Feliciano DV, Mattox KL (eds): Trauma, 5th ed. New York, McGrawHill, 2004. 49. Cohen J B Berg G, Carl GH, et al: Primary endoscopic realignment following posterior urethral disruption. J Urol 1991;146:1548. 50. Cohen MS, et al: Bladder perforation after orthopedic hip surgery. Urology 1977;9:291.

CHAPTER

51. Coffield KS, Weems WL: Experience with management of posterior urethral injury associated with pelvic fracture. J Urol 1977;117:722. 52. Corriere JN Jr, Sandler CM: Management of the ruptured bladder: Seven years experience with 111 cases. J Trauma 1986;26:830. 53. Corriere JN Jr: Trauma to the lower urinary tract. In Gillenwater JY, et a1 (eds): Adult and Pediatric Urology. Chicago, Year Book Medical, 1987. 54. Corriere JN Jr, Sandler CM: Mechanisms of injury patterns of extravasation and management of extraperitoneal bladder rupture due to blunt trauma. J Urol 1988;139:43. 55. Corriere JN Jr, Sandler CM: Management of extraperitoneal bladder rupture. Urol Clin North Am 1989;16:275. 56. Corriere JN Jr, McAndrew JD, Benson GS: Intraoperative decision making in renal trauma surgery. J Trauma 1991; 31:1390. 57. Crassweller PO, Farrow GA, Robson CJ, et al: Traumatic rupture of the supramembranous urethra. J Urol 1977; 118:770. 58. Daum GS, Krolikowski FJ, Reuter KL, et al: Dipstick evaluation of hematuria in abdominal trauma. Am J Clin Path01 1988;89:538. 59. DeWeerd JH: Immediate realignment of posterior urethral injury. Urol Clin North Am 1977;4:75. 60. Diamond DA, Ford C: Neonatal bladder rupture: A complication of umbilical artery catheterization. J Urol 1989; 142:1543. 61. Dinkel HP, Danuser H, Triller J: Blunt renal trauma: Minimally invasive management with microcatheter embolization experience in nine patients. Radiology 2002; 223:723. 62. Dmochowski R, Crondell SS, Corriere JN Jr: Bladder injury in uroascites from umbilical artery catheterization. Pediatrics 1986;77:421. 63. Dorai CDRT, Boucaut HAP, Dewan PA: Urethral injuries in girls with pelvic trauma. Eur Urol 1993;24:371. 64. Eastham JA, Wilson TG, Larsen DW, et al: Angiographic embolization of renal stab wounds. J Urol 1992;148:268. 65. Eastham JA, Wilson TG, Ahlering TE: Urological evaluation and management of renal-proximity stab wounds. J Urol 1993;150:1771. 66. Elliott DS, Barrett DM: Long-term follow-up and evaluation of primary realignment of posterior urethral disruptions. J Urol 1997;157:814. 67. Esho JO, Ireland GW, Cass AS: Renal trauma and preexisting lesions of kidney. Urology 1973;1:134. 68. Fairhurstg, Rubin CM, Hyde I, et al: Bladder capacity in infants. J Pediatr Surg 1991;26:55. 69. Fay R, Brosman S, Lindstrom R, Cohen A: Renal artery thrombosis: A successful revascularization by autotransplantation. J Urol 1974;111:572. 70. Flancbaum L, Morgan AS, Fleisher M, et al: Blunt bladder trauma: Manifestation of severe injury. Urology 1988;31:220. 71. Fleisher G: Prospective evaluation of selective criteria for imaging among children with suspected blunt renal trauma. Pediatr Emerg Care 1989;5:8. 72. Flint L, Babikan G, Anders M, et al: Definitive control of mortality from severe pelvic fracture. Ann Surg 1990; 211:703. 73. Follis HW, Koch MO, McDougal WS: Immediate management of prostatomembranous urethral disruptions. J Urol 1992;147:1259. 74. Gelbard MK, Heyman AM, Weintraub P: A technique for immediate realignment and catheterization of the disrupted prostatomembranous urethra. J Urol 1989;142:52. 75. Gerstenbluth RE, Spirnak JP, Elder JS: Sports participation and high grade renal injuries in children. J Urol 2002; 168:2575.

18

Genitourinary Tract Trauma

333

76. Ghali AM, El Malik EM, Ibrahim AI, et al: Ureteric injuries: Diagnosis, management, and outcome. J Trauma 1999; 46:150. 77. Gheiler EL, Frontera JR: Immediate primary realignment of prostatomembranous urethral disruptions using endourologic techniques. Urology 1997;49:596. 78. Gill B, Palmer L, Reda E, et al: Optimal renal preservation with timely percutaneous intervention: A changing concept in the management of blunt renal trauma in children in the 1990s. Br J Urol 1994;74:370. 79. Gomez RG, Castanheira AC, McAninch JW: Gunshot wounds to the male external genitalia. J Urol 1993;150:1147. 80. Gonzales ET Jr, Guerriero WG: Genitourinary trauma in children. In Kelalis PP, King LR, Bellman AB (eds): Clinical Pediatric Urology. Philadelphia, WB Saunders, 1985. 81. Gonzales RP, Falimirski M, Holevar MR, et al: Surgical management of renal trauma: Is vascular control necessary? J Trauma 1999;47:1039. 82. Guerriero WG, Carlton SE Jr, Scott RJr, et al: Renal pedicle injuries. J Trauma 1971;1:53. 83. Guerriero WG: Penetrating renal injuries in the management of renal pedicle injury. Urol Clin North Am 1977;4:3. 84. Guerriero WG: Ureteral injury. Urol Clin North Am 1989;16:237. 85. Haas CA, Dinchman KH, Nasrallah PF, et al: Traumatic renal artery occlusion: A 15 year review. J Trauma 1998; 45:557. 86. Haas CA, Brown SL, Spirnak JP: Limitations of routine spiral computerized tomography in the evaluation of bladder trauma. J Urol 1999;162:51. 87. Hall SJ, Wagner JR, Edelstein RA, et al: Management of gunshot wounds to the penis and anterior urethra. J Trauma 1995;38:439. 88. Haller JA Jr, Papa P, Drugas G, Colombani P: Nonoperative management of solid organ injuries in children. Is it safe? Ann Surg 1994;219:625. 89. Hardeman S, Husmann DA, Chinn HK, et al: Blunt urinary tract trauma: Identifying those patients who require radiological studies. J Urol 1989;141:1095. 90. Herschorn S, Kodona RT, Abara EO: Genitourinary trauma. In McMurtry R, McMillan GA (eds): Management of Blunt Trauma. Baltimore, Williams & Wilkins, 1990. 91. Herschorn S, Raadomski SB, Shoskes DA, et al: Evaluation and treatment of blunt renal trauma. J Urol 1991;146:274. 92. Heyns CF, Rimington PD: Intraperitoneal rupture of the bladder causing the biochemical features of renal failure. Br J Urol 1987;60:217. 93. Heyns CF, Van Vollenhoven P: Increasing role of angiography and segmental artery embolization in the management of renal stab wounds. J Urol 1992;147:1231. 94. Holcroft HW, Trunkey DD, Minagi H, et al: Renal trauma and retroperitoneal hematomas: Indications for exploration. J Trauma 1975;15:1045. 95. Holevar M, EbertJ, Luchette F, et al: Practice management guidelines for the management of genitourinary trauma. On Internet site for Eastern Association for the Surgery of Trauma, Copyright 2004. 96. Howerton RA: Proximal ureteral avulsion from blunt abdominal trauma. Milit Med 1991;156:311. 97. Husmann DA, Boone TB, Wilson WT. Management of low velocity gunshot wounds to the anterior urethra: The role of primary repair versus urinary diversion alone. J Urol 1993;150:70. 98. Husmann DA, Gilling PJ, Perry MO, et al: Major renal lacerations with a devitalized fragment following blunt abdominal trauma: A comparison between nonoperative (expectant) versus surgical management. J Urol 1993; 150:1774. 99. Ivatury RR, Zubowski R, Stahl WM: Penetrating renovascular trauma. J Trauma 1989;29:1620.

334

PART

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TRAUMA

100. Javadpour N, Guinan P, Bush IM: Renal trauma in children. Surg Gynecol Obstet 1973;136:237. 101. Jetvich MJ, Montero GG: Injuries to renal vessels by blunt trauma in children. J Urol 1969;102:493. 102. Karp MP, Jewett TC Jr, Kuhn JP, et al: The impact of computed tomography scanning on the child with renal trauma. J Pediatr Surg 1986;21:617. 103. Keller MS, Eric Coln C, GarzaJJ, et al: Functional outcome of nonoperatively managed renal injuries in children. J Trauma 2004;57:108-110. 104. Knudson MM, McAninchJW, Gomez R, et al: Hematuria as a predictor of abdominal injury after blunt trauma. Am J Surg 1992;164:482. 105. Knudson MM, Harrison PB, Hoyt DB, et al: Outcome after major renovascular injuries: A Western Trauma Association multicenter report. J Trauma 2000;49:1116. 106. Koff SA: Estimating bladder capacity in children. Urology 1983;21:248. 107. Koraitim MM: Pelvic fracture urethral injuries: Evaluation of various methods of management. J Urol1996;156:1288. 108. Koraitim MM: Pelvic fracture urethral injuries: The unresolved controversy.J Urol 1999;161:1433. 109. Kuszmarov IW, Morehouse DD, Gibson S: Blunt renal trauma in the pediatric population: A retrospective study. J Urol 1981;126:648. 110. Learch TJ, Hansch LP, Ralls PW: Sonography in patients with gunshot wounds of the scrotum: Imaging findings and their value. AJR Am J Roentgen01 1995;165:879. 111. Lee JT, White RA: Endovascular management of blunt traumatic renal artery dissection. J Endovasc Ther 2002; 9:354. 112. Levy JB, Baskin LS, Ewalt DH, et al: Nonoperative management of blunt pediatric major renal trauma. Urology 1993;42:418. 113. Lis LE, Cohen AJ: CT cystography in the evaluation of bladder trauma. J Comput Assist Tomogr 1990;14:386. 114. Livene PM, Gonzales ET: Genitourinary trauma in children. Urol Clin North Am 1985;12:53. 115. Londergan TA, Gundersen LH, Van Every MJ: Early fluoroscopic realignment for traumatic urethral injuries. Urology 1997;49:101. 116. Lupattelli T, Garaci FG, Manenti G, et al: Giant high-flow renal arteriovenous fistula treated by percutaneous embolization. Urology 2003;61:837. 117. Lynch JM, Gardner MJ, Albanese CT: Blunt urogenital trauma in prepubescent female patients: More than meets the eye. Pediatr Emerg Care 1995;11:372. 118. Margenthaler JA, Weber TR, Keller MS: Blunt renal trauma in children: Experience with conservative management at a pediatric trauma center. J Trauma 2002; 52:928. 119. Matthews LA, Herbener TE, Seftel AD: Impotence associated with blunt pelvic and perineal trauma: Penile revascularization as a treatment option. Semin Urol 1995; 13:66. 120. Matthews LA, Smith EM, Spirnak JP: Nonoperative treatment of major blunt renal lacerations with urinary extravasation. J Urol 1997;157:2056. 121. McAleer IM, Kaplan G, Sherz HC, et al: Genitourinary trauma in the pediatric patient. Urology 1993;42:563. 122. McAleer IM, Kaplan GW: Pediatric genitourinary trauma. Urol Clin North Am 1995;22:177. 123. McAleer IM, Kaplan GW, LoSasso BE: Congenital urinary tract anomalies in pediatric renal trauma patients. J Urol 2002;168:1808. 124. McAleer IM, Kaplan GW, LoSasso BE: Renal and testis injuries in team sports. J Urol 2002;168:1805.

125. McAninchJW, Carroll PR: Renal trauma: Kidney preservation through improved vascular control-A refined approach. J Trauma 1984;22:285. 126. McAninch JW: Genitourinary trauma. In Moore EE, Mattox KL, Feliciano DV (eds): Trauma. East Norwalk, CT, Appleton & Lange, 1991. 127. McAninchJW, Carroll P, Klosterman P, et al: Renal reconstruction after injury. J Urol 1991;145:932. 128. McAninch JW, Carroll PR, Armenkas NA, et al: Renal gunshot wounds: Methods of salvage and reconstruction. J Trauma 1993;35:279. 129. McAninchJW, Morey AF, BruceJE: Efficacy of radiographic imaging in pediatric blunt renal trauma. Proc Am Urol Assoc Suppl 1996;155:526A. 130. Medica J, Caldamone A: Pediatric renal trauma: Special considerations. Semin Urol 1995;13:73. 131. Mee SL, McAninchJW, Rovinson AL, et al: Radiographic assessment of renal trauma: A 10-year prospective study of patient selection. J Urol 1989;141:1095. 132. Melekos MD, Pantazakos A, Daouaher H, et al: Primary endourologic re-establishment of urethral continuity after disruption of the prostatomembranous urethra. Urology 1992;39:135. 133. Mercader VP, Gatenby RA, Curtis BR: Radiographic assessment of genitourinary trauma. Trauma 1996;13:129. 134. Merrott T, Portier F, Galinier P, et al: Trauma of the renal pedicle in children: Rewort of 2 cases of late revascularization with endovascular prosthesis. Prog Urol2000; 10:277. 135. Mertz JHO, Wishard WN JR, Nourse MH, et al: Injury to the kidney in children. JAMA 1963;183:830. 136. Miller SF, Chait PG, Burrows PE, et al: Post-traumatic arterial priapism in children: Management with embolization. Radiology 1995;196:59. 137. Miller DC, Forauer A, Faerber GJ: Successful angioembolization of renal artery pseudoaneurysms after blunt abdominal trauma. Urology 2002;59:444. 138. Miller KS, McAninchJW: Radiographic assessment of renal trauma: Our 15-year experience.J Urol 1995;154:352. 139. Monstrey SJ, vander Staak FH, vander Werken C, et al: Urinary tract injuries in children: Are they different from adults? Z Kinderchir 1988;43:31. 140. Monstrey SJ, vanderwerken C, Debruyne FM, et al: Rational guidelines in renal trauma assessment. Urology 1988;31:469. 141. Monstrey SJ, Beerthuizen GI, vander Werken C, et al: Renal trauma and hypertension. J Trauma 1989;29:65. 142. Montgomery RC, Richardson-ID, Harty TI: Post-traumatic renovascular hypertension after occilt renal injury. J Trauma 1998;45:106. 143. Moog R, Becmeur F, Dutson E: Functional evaluation by quantitative dimercaptosuccinic acid scintigraphy after kidney trauma in children. J Urol 2003;169:641. 144. Moore EE, Shackford SR, Pachter HL, et al: Organ injury scaling: Spleen, liver, and kidney. J Trauma 1989; 29: 1664. 145. Morey AF, Bruce JE, McAninch JW: Efficacy of radiographic imaging in pediatric blunt renal trauma. J Urol 1996;156:2014. 146. Morse TS, Smith JP, Howard WEIR, et al: Kidney injuries in children. J Urol 1967;98:539. 147. Morton JR, Crawford ES: Bilateral traumatic renal artery thrombosis. Ann Surg 1972;176:62. 148. Moudounie SM, Patard JJ, Manunta P, et al: A conservative approach to blunt renal lacerations with urinary extravasation and devitalized renal segments. Br J Urol 2001;87:290.

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149. Munarriz RM, Yan OR, Znehra A, et al: Blunt trauma: The pathophysiology of the hemodynamic injury. J Urol 1995;153:1831. 150. Mundy AR: The role of delayed primary repair in the acute management of pelvic fracture injuries of the urethra. Br J Urol 1991;68:273. 151. Murphy JP: Genitourinary trauma. In Ashcraft KW (ed): Pediatric Urology. Philadelphia, WB Saunders, 1990. 152. Nicolaisen GS, McAninch JW, Marshall GA, et al: Renal trauma: Re-evaluation of the indications for radiographic assessment.J Urol 1985;133:183. 153. Noe HN, Jerkins GR: Genitourinary trauma. In Kelalis PP, Kemp LR, Belman AB (eds): Clinical Pediatric Urology. Philadelphia, WB Saunders, 1992. 154. OliverJA, TaguchiY Rupture of the full bladder. BrJ Urol 1964;36:524. 155. Patil MG, Onuora VC: The value of ultrasound in the evaluation of patients with blunt scrota1 trauma. Injury 1994;25:177. 156. Peng MY, Parisky YR, Cornwell EE, et al: CT cystography versus conventional cystography in evaluation of bladder injury. AJR Am J Roentgenol 1999;173:1269. 157. Perez-Brayfield MR: Gunshot wounds to the ureter: A 40 year experience at Grady Memorial Hospital. J Urol 2001;166:119. 158. Perez-Brayfield MR, Gatti JM, Smith EA, et al: Blunt traumatic hematuria in children: Is a simplified algorithm justified? J Urol 2002;167:2543. 159. Perry MO, Husmann DA: Urethral injuries in female subjects following pelvic fractures. J Urol 1992;147:139. 160. Peterson NE: Review article: Traumatic bilateral renal infarction. J Trauma 1989;29:158. 161. Philpott JM, Nance ML, Carr MC, et al: Ureteral stenting in the management of urinoma after severe blunt renal trauma in children. J Pediatr Surg 2003;38:1096. 162. Pode D, Shapiro A: Traumatic avulsion of the female urethra: Case report. J Trauma 1990;30:235. 163. Poole GV, Ward EF, Griswold JA, et al: Complications of pelvic fractures from blunt trauma. Ann Surg 1992;58:225. 164. Porter JR, Takayama TK, Defalco AJ: Traumatic posterior urethral injury and early realignment using magnetic urethral catheters. J Urol 1997;158:425. 165. Presti JC, Carroll PR, McAninch JW: Ureteral and pelvic injuries from external trauma: Diagnosis and management. J Trauma 1989;29:370. 166. Pumberger W, Stoll E, Metz S: Ureteropelvic junction disruption following blunt abdominal trauma. Pediatr Emerg Care 2002;18:364. 167. Quinlan DM, Gearhart JP: Blunt renal trauma in childhood. Features indicating severe injury. Br J Urol 1990; 66:526. 168. Radmayr C, Oswald J, Muller E, et al: Blunt renal trauma in children: 26 years clinical experience in an alpine region. Eur Urol 2002;42:297. 169. Rehman J, Samadi D, Ricciardi R Jr, et al: Early endoscopic realignment as primary therapy for complete posterior urethral disruptions. J Endourol 1998;12:283. 170. Rober PE, Smith JB, Pierce JM: Gunshot injuries of the ureter. J Trauma 1990;30:83. 171. Russell TS, Gomelsky A, McMahon DR, et al: Management of grade IV renal injury in children. J Urol 2001;66:1049. 172. Sagalowsky AI, McConnell JD, Peters PC: Renal trauma requiring surgery: An analysis of 185 cases. J Trauma 23:128, 1983. 173. Santucci RA, McAninch JW, Safir M, et al: Validation of the American Association for the Surgery of Trauma

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organ injury severity scale for the kidney. J Trauma 2001; 50:195. 174. Santucci RA, Langenburg SE, Zachareas MJ: Traumatic hematuria in children can be evaluated as in adults. J Urol 2004;171:822. 175. Sharp DS, Ross JH, Kay R: Attitudes of pediatric urologists regarding sports participation in children with a solitary kidney. J Urol 2002;168:1811. 176. Shuman WP: CT of blunt abdominal trauma in adults. Radiology 1997;205:297. 177. Skinner D: Traumatic renal artery thrombosis: A successful thrombectomy and revascularization. Ann Surg 1973; 172:264. 178. Sklar DP, Diven B, Jones J: Incidence and magnitude of catheter-induced hematuria. Am J Emerg Med 1986; 4:14. 179. Smith EM, ElderJS, SpirnakJP: Major blunt renal trauma in the pediatric population: Is a nonoperative approach indicated? J Urol 1993;149:546. 180. Snyder H, Caldamone AA: Genitourinary injuries. In Welch KJ, Randolph JG, Ravitch MM (eds): Pediatric Surgery, 4th ed. Chicago, Mosby Year Book, 1986. 181. Spirnak JP, Persky L, Resnick MI: The management of civilian ureteral gunshot wounds: A review of 18 patients. J Urol 1985;134:733. 182. Stalker HP, Kaufman RA, Stedje K: The significance of hematuria in children after blunt abdominal trauma. AJR Am J Roentgenol 1990;154:569. 183. Stein JP, Kaji DM, Eastham J, et al: Blunt renal trauma in the pediatric population: Indications for radiographic evaluation. Urology 1994;44:406. 184. Teigen CL, Venbrux AC, Quinlan DM,Jeffs RD: Late massive hematuria as a complication of conservative management of blunt renal trauma in children. J Urol 1992;147:1333. 185. Thomae KR, Kilambi NK, Poole GV: Method of urinary diversion in nonurethral traumatic bladder injuries. Retrospective analysis of 70 cases. Am Surg 1998;64:77-80. 186. Toporoff B, Sclafani S, Scalea T, et al: Percutaneous antegrade ureteral stenting as an adjunct for treatment of complicated ureteral injuries. J Trauma 1992;32:534. 187. Townsend M, DeFalco AJ: Absence of ureteral opacification below ureteral disruption: A sentinel CT finding. AJR Am J Roentgenol 1995;164:253. 188. Tso EL, Beaver BL, Haller JJ Jr: Abdominal injuries in the restrained pediatric passenger. J Pediatr Surg 1993; 28:915. 189. Tunc HM, Tefekli AH, Kaplancan T, et al: Delayed repair of post-traumatic posterior urethral distraction injuries: Long-term results. Urology 2000;55:837. 190. Turner WW Jr, Snyder WH 111, Fry WJ: Mortality and renal salvage after renovascular trauma: A review of 94 patients treated in a 20 year period. Am J Surg 1983;146:848. 191. Velmahos GC, Degiannis E: The management of urinary tract injuries after gunshot wounds of the anterior and posterior abdomen. Injury 1997;28:535. 192. Volpe MA, Pachter EM, Scalea TM, et al: Is there a difference in outcome when treating traumatic intraperitoneal bladder rupture with or without a suprapubic tube?J Urol 1999;161:1103. 193. Wazzan W, Azoury B, Heinady K, et al: Missile injuries of the upper ureter treated by delayed renal autotransplantation and ureteropyelostomy. Urology 1993;42:725. 194. Weaver FA, Kuehne JP, Papanicolau G: A recent institutional experience with renovascular hypertension. Am Surg 1996;62:241. 195. Weems WL: Management of genitourinary injuries in patients with pelvic fractures. Ann Surg 1979;189:717.

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196. Werkman HA, Jansen C, Klein JP, e t al: Urinary tract injuries in multiply-injured patients: A rational guideline for the initial assessment. Injury 22:471, 1991. 197. Wessel LM, Scholz S,Jester I, et al: Management of kidney injuries in children with blunt abdominal trauma. J Pediatr Surg 2000;35:1326. 198. Wessells H, McAninchJW, Meyer A, et al: Criteria for nonoperative treatment of significant penetrating renal lacerations. J Urol 157:24, 1997.

199. Whitesides E, Kozlowdki DL: Ureteral injury from blunt abdominal trauma: Case report. J Trauma 1994;36:745. 200. Wyatt JB, Scobie WG: The management of penile zipper entrapment in children. Injury 1994;25:59. 201. Yale-Loehr AJ, Kramer SS, Quinlan DM, et al: CT of severe renal trauma in children: Evaluation and course of healing with conservative therapy. AJR Am J Roentgen01 1989; 152:109. 202. Zakin D: Perforation of the bladder by the intrauterine device. Obstet Gynecol Surv 1984;39:59.

Musculoskeletal Trauma Richard S. Davidson and Michelle S. Caird

Musculoskeletal trauma is the most common medical emergency in children. The number of cases continues to increase in association with the popularity of motor vehicles, all-terrain vehicles, and power lawn mowers. In a child with multiple injuries, optimal treatment requires a cooperating team of medical professionals with diverse specialties who understand the priorities of each team member. As in all other pediatric specialties, it is important to remember that children are not "little adults." Priority management need not compromise complete patient management. This chapter reviews the important differences between the musculoskeletal systems of children and adults, and it highlights the principles of evaluation and management in children with musculoskeletal injuries. The treatment of high-priority musculoskeletal injuries is specifically discussed, including open fractures, compartment syndrome, femoral neck fractures, mangled extremities, spine trauma, and suspected child abuse. For details on the management of specific musculoskeletal fractures and injuries of childhood, readers should refer to textbooks on children's f r a c t ~ r e s . l ~ , 2 ~ 2 ~

MUSCULOSKELETAL SYSTEMS OF CHILDREN AND ADULTS Differences in the musculoskeletal anatomy and biomechanics of children and adults determine the unique patterns of musculoskeletal injury seen in childhood. Injuries to growing bones are a double-edged sword: they can have a remarkable capacity for healing and remodeling, but they are also subject to the problems of overgrowth and growth disturbance, which can have lifelong consequences.

Anatomy The major anatomic distinctions of skeletally immature bones are the physis and the periosteum. Each long bone in a child contains the epiphysis, physis, metaphysis, and diaphysis (Fig. 19-1). The epiphysis is the area beyond the physis, or primary growth plate, which contains the

articular cartilage. The secondary center of ossification arises within the epiphysis and progressively enlarges as the cartilage ossifies during skeletal maturation. The physis provides longitudinal growth and converts the newly formed cartilage into bone in the metaphysis. The diaphysis, or shaft, is surrounded by periosteum, which generates new bone and provides circumferential bone growth. By adulthood, the growth plate closes, and there is limited potential for remodeling.

Biomechanics Skeletally immature bones are porous, less brittle, and better able to tolerate deformation than are mature bones. Pores stop the progression of a fracture line but weaken the bone under a compressive force. As a result, a greater variety of fractures is seen in children than in adults. A child's bone can bend without fracture (Fig. 19-2); it can buckle under compression;it can fracture like a "green stick," with an incomplete crack on the tension side and a bend on the compression side; and it can fracture completely. The thick periosteum that surrounds the diaphysis of the bone can minimize or prevent displacement of diaphyseal fractures. The periosteum tears on the tension side of a fracture but often remains intact on the compression side. The intact periosteum can then function as a hinge or a spring, increasing deformity. Depending on the injury, the periosteum may simplify or complicate reduction of a fracture (Fig. 19-3). In the complex of bone, ligaments, and cartilage in a child, the physis is the weakest part and therefore is the most likely site of failure. An angular force to a joint in a young child is most likely to cause a fracture along the growth plate, whereas in an adolescent or an adult, a ligamentous injury or dislocation would occur. Frankel and Nordin15 provide extensive information on the biomechanics of bone. In a fall on an outstretched hand, a young child is unlikely to sprain a wrist; more commonly, a child sustains a fracture with a displaced distal radius growth plate. Similarly, instead of spraining an ankle, a child is more likely to sustain a physeal fracture of the distal fibula. Under low-energy forces, these injuries are unlikely to lead to growth disturbance.

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. - .

Anatomy of the child's bone.

Articular cartilage Epiphysis Ossification center Growth plate

Physis

Primary and secondary spongiosa

Metaphysis

Cancellous bone Diaphysis Compact bone

The Salter-Harris classification system of fractures involving the physis can guide proper management (Fig. 194).28 Type 1 fractures extend along the entire physis. Type 2 fractures involve part of the growth plate and part of the metaphysis; these fractures are seldom associated with growth arrest except when they occur in the distal femur

i

d

........ ............ ...... ....... ....... ...............

Bend

Buckle

Greenstick

,

- -

Fracture types in children. (From Rang M: Children's

Fractures. Philadelphia, JB Lippincott, 1974.)

and proximal tibia. Type 3 fractures involve part of the physis and pass across the epiphysis into the joint. Because of the possibility of incongruity of the joint, type 3 fractures often require open reduction and fixation. Type 4 fractures occur longitudinally, crossing the physis from the metaphysis into the epiphysis. This type of fracture is commonly associated with subsequent formation of a bony bar across the physis, which causes partial growth arrest with subsequent angulation. Open reduction and internal fixation are usually required for type 4 fractures, because joint incongruity and fusion across the physis are common. Type 5 fractures are diagnosed retrospectively, when all or part of the physis fails to grow. It is hypothesized that injury to the physis results from direct compression or local vascular insult. Growth disturbance may result in loss of longitudinal growth or angular deformities. Damage to the physis in high-energy injuries can lead to asymmetrical growth in any of the fracture types.

The physiologic differences between the musculoskeletal systems of children and adults are found in healing and remodeling. Growing bones are also at risk for the unique problems of overgrowth and growth disturbance. Healing in children is rapid and age dependent. A newborn may achieve clinically stable union of a fracture in 1 week, whereas a similar fracture in an adolescent may take 6 weeks to heal. In children, the rapid healing process partially results from the thick periosteum, which may form its own bone bridge. Except for displaced

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= closed hinge

-

.

A, In children, the intact periosteum of a fracture prevents reduction by traction. B, By retracing the path of injury, the fracture can be reduced. C, Closing the hinge. D, A cast with three-point molding holds the hinge closed and keeps the fracture reduced. (From Rang M: Children's Fractures. Philadelphia, JB Lippincott, 1974.)

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intra-articular fractures or fractures with gross soft tissue interposition, nonunion of fractures is rare in children. The bones of children have great potential for remodeling, but the limitations must be understood. Remodeling potential is better in younger patients, in deformities closer to the physes, and where angulation is in the plane of motion of the nearestjoint. Remodeling does not effectively correct angulation perpendicular to joint motion or rotation. These deformities should be reduced before healing begins (Fig. 19-5). Growth stimulation may follow fractures of long bones. This can be especially apparent in the lower extremity. The inequality in leg length that results from such stimulation is less important in children younger than 2 years and in adolescents. For children of other ages, an average l c m increase can be expected in femur fractures.11,29,3* Although discrepancies in leg length are unpredictable, it is often possible to reduce the ultimate inequality by allowing the fracture to heal with a 1-cm overlap in an otherwise anatomic alignment. Most of the growth stimulation occurs within the first year after injury, so follow-up visits for 1 year are recommended, even after uneventful healing. Damage to the physis can produce severe shortening, angular deformity, or both. Although this may be caused by the initial trauma, it can also result from failure to obtain anatomic reduction of a physeal fracture or from repeated or overzealous attempts at reduction (Fig. 19-6). When major (>2 cm) limb length discrepancies in the lower extremities are evident, treatment depends on the amount of remaining skeletal growth and the projected difference in limb lengths. Treatment may involve timed ablation of the growth plate on the normal limb, shortening osteotomy of the normal limb, or lengthening of the short limb. Angular deformities can also be addressed, taking into consideration the patient's skeletal age and the severity of the deformity.

EVALUATION OF MUSCULOSKELETAL INJURIES Clinical Assessment The initial assessment of children with multiple injuries may be difficult. Details of the incident may be missing, and the patient's history may be incomplete. The Advanced Trauma Life Support (ATLS) system of assessment involves a primary evaluation to identify and immediately address life-threatening injuries, followed by a secondary

Salter-Harris classification of epiphyseal fractures. Type 1 involves the entire physis. Type 2 involves part of the growth plate and part of the metaphysis. Type 3 involves part of the physis and passes across the epiphysis into the joint. Type 4 is longitudinal, crossing the physis from the metaphysis into the epiphysis. Type 5 is diagnosed retrospectively when the physis fails to grow. See text for clinical implications of each fracture type.

7

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TRAUM Slwen2year m with eigh~degrees of re'moq :

a forearm fracture over a 9period. A to C, An teroplOStC plane. D t o E Late ral plane

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Anteroposterior radiograph of the knees in a 13-year-old boy shows growth disturbance of the left distal femoral growth plate after a fracture (on right in photo).

children, cannot provide a history,judicial use of special diagnostic studies can be critical.

evaluation to find and treat other significant injuries. The injuries identified in the secondary evaluation must also be treated in a timely manner to prevent devastating lifelong consequences. Postponing the management of serious musculoskeletal injury for an extended period can be associated with a poor prognosis for return to normal function. The musculoskeletal examination begins with observation of the patient for sites of deformity, swelling, contusions, abnormal color, and open fractures. If a fracture is suspected, confirmatory diagnostic studies may be integrated into the complete physical examination. If such studies cannot be done, it must be assumed that a fracture exists, and the suspected site must be splinted until the fracture is confirmed or ruled out. Splinting may also reduce discomfort and limit further damage to soft tissue. A complete neurovascular examination is essential in any case of suspected limb or spine injury. When an uncooperative patient will not allow an adequate physical examination or, in the case of comatose patients or preverbal

A

-

.

Radiographic Assessment Plain radiography is the first and most widely used test to identify skeletal injury in children, but it can also be a major source of misdiagnosis in this age group. Cartilage, which makes up a large percentage of the child's skeleton, is radiolucent but can fracture. Ossification centers appear at different ages in different locations. The timing of their appearance a i d their location vary greatly and can suggest fractures. Confusion most frequently occurs in the elbow, knee, and cervical spine. Comparison of the injured and uninjured limbs can be useful. Plain radiographic soft tissue signs, such as the posterior fat pad-sign in elbow injuries, are associated with a high likelihood of underlying fracture (Fig. 19-7).30

B

Lateral elbow radiographs of a 2-year-old boy with a mildly displaced supracondylar humerus fracture and posterior fat pad sign (A) and a normal age-matched elbow (B).

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A number of imaging studies are available for the assessment of pediatric musculoskeletal injuries and are injury and age specific. Radiographs may confirm fractures. Ultrasonography is a readily available, noninvasive imaging test that can be used to evaluate the unossified epiphysis, especially in injuries about the elbow.8 Magnetic resonance imaging (MRI) may also be helpful, especially in evaluating the injured spine, but it may require general anesthesia in a young or uncooperative patient. Computed tomography (CT) scanning is useful in periarticular fractures in children approaching skeletal maturity. For exarnple, ankle physeal fractures in children with partially closed physes are best delineated with CT scan.22 Arteriography may be required to assess vascular injury associated with a fracture. Rarely, proximal tibia1 physeal fractures and distal humerus fractures through the supracondylar region can be associated with disruption of the blood supply to the distal limb. These injuries require emergent treatment, and an intraoperative arteriogram may also be needed. Joint aspiration can identify blood and fat, which indicate an intra-articular fracture that would not be identified on radiographs. Finally, arthrography and arthroscopy may define intra-articular injury to the cartilage and ligaments.

MANAGEMENT OF MUSCULOSKELETAL INJURIES Immediate Treatment Priority treatment cannot interfere with complete treatment of an injured child. Proper timing and coordination of management with other disciplines are imperative. Traction or splinting often adequately stabilizes the musculoskeletal injury until other tests and treatments have been completed. Immobilization may also reduce the need for pain medications, which can mask the symptoms of other disorders, such as intra-abdominal injuries, and inhibit diagnosis. Although there are many types of splints, ranging from plaster to traction bows, the basic principles of fracture management remain the same. The injured part should be splinted as it is found, and the joints above and below the injury should be immobilized without compromising the circulation of the soft tissues. Portable traction splints or custom-molded, well-padded plaster or fiberglass splints can be used in the initial management of fractures. Failure to immobilize the fracture can cause further soft tissue damage from sharp bone ends, crushing of entrapped neurovascular elements, or reopening of clotted vessels.

The choice of fixation method depends on the child's age, the location of the fracture, the presence and extent of soft tissue injury, and the presence of multitrauma. Metaphyseal undisplaced or impacted fractures are likely to heal faster than diaphyseal or displaced fractures. Fractures with devitalized bone or soft tissues take longer to heal. Radiographic evaluation in conjunction with clinical judgment and experience is needed when determining the healing time of fractures in children. Fragments of bone must be held together until they are sufficiently strong to withstand the forces specific to the bone. A satisfactory position must be obtained, without harming adjacent tissue, before the fracture becomes fixed. Fractures in newborns and infants begin to heal within a few days, but fractures in adolescents can be moved freely for 10 to 14 days. Excessive cast padding, resolution of swelling, or a poorly applied cast may permit progressive malposition within the cast. Fractures should be followed with frequent radiographs until union is secure, to avoid displacement. Unstable fractures should be imaged before consolidation to evaluate for loss of alignment. This allows for easy repeat reduction. In children, the thick periosteum tears on the tension side of a fracture but often remains intact on the compression side. The intact periosteum can then function as a hinge, increasing the success of closed reduction of displaced fractures by three-point molding (see Fig. 19-3). Reduction must be performed gently. Forceful and repeated manipulation of physeal fractures can produce iatrogenic damage and growth disturbances. Entrapment of soft tissue occasionally prevents reduction of an otherwise stable fracture (Fig. 19-8) and requires open reduction and immobilization in a cast. In some cases, internal fixation with crossed pins, plates and screws, intramedullary nails, or external fixation with pins in metal outriggers or rods may be useful (Fig. 19-9). The benefits of each of these devices must be weighed against the future need for operative removal and the possible disturbance to the growth plate. Specific indications for internal and external fixation may include fractures with significant soft tissue injury, fractures in

Radial nerve

Definitive Fracture Management Adequate stabilization of fracture fragments prevents further soft tissue injury, frequently decreases pain, and facilitates wound care and patient mobilization. Techniques of definitive stabilization in children include splinting, casting, skeletal traction, external fixation, pinning, flexible intramedullary nailing, and plating.

, .

. - Supracondylar elbow fracture. Soft tissue may become

entrapped between bone fragments in these types of fractures.

CHAPTER

,

.

..

Anteroposterior radiographs of right femur

fractures fixed with a variety of fixation methods. A, SalterHarris type 2 fracture with crossed pins in a 9-year-old girl. B, Intertrochanteric fracture with screws and side plate in a 7-year-old boy. C,Transverse shaft fracture with elastic intramedullary nails in a 13-year-old boy. D, Subtrochanteric fracture with external fixator in an 8-year-old boy.

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children with closed head injury, those associated with neurovascular injury, and fractures that fail nonoperative treatment. Comminuted and oblique fractures and those with complete tears of the periosteum may be too unstable for cast immobilization. In cases of intra-articular fractures, such as Salter-Harris types 3 and 4, open reduction and internal fixation are frequently necessary to avoid incongruity of the joint or growth disturbances. Fractures associated with neurovascular injury requiring repair should be stabilized first.

HIGH-PRIORITY MUSCULOSKELETAL INJURIES Although many musculoskeletal injuries in children can be treated on an urgent rather than an emergent basis, the discussion of some high-priority musculoskeletal injuries in children is warranted. Even in nonurgent cases, it is important to remember that injuries to growing bones can have lifelong consequences.

Open Fractures and Traumatic Arthrotomies Open fractures are true orthopedic emergencies because a delay in treatment can lessen the chance of saving the limb. These injuries frequently result from high-energy trauma. The fractures communicate with the outside environment and are at increased risk for infection. The cornerstones of management include recognition, administration of appropriate antibiotics, stabilization of the fracture, and prompt irrigation and adequate debridement of wounds. Open fractures may require multiple surgical procedures to achieve adequate soft tissue coverage and fracture healing. When a laceration or abrasion is noted in proximity to a fracture, an open fracture must be suspected. Radiographic evidence of air shadows around the fracture may confirm the diagnosis. A sharp fragment of bone can tear through the skin, and the elastic properties of a child's bone can readily straighten the fracture fragments after the force is discontinued. The protruding point of bone can then draw back under the skin, taking debris and bacteria with it into the deep tissues. Minimal signs of injury do not necessarily mean a minimal chance of infection. Wounds should not be probed in the emergency department, where the risk of iatrogenic contamination is high and the likelihood of adequate debridement is low; if necessary, such procedures should be done in the operating room. The Gustilo system classifies open fractures according to the size and extent of soft tissue damage." Type I is an open fracture with a clean wound smaller than 1 cm. Type I1 is an open fracture with a laceration longer than 1 cm without extensive soft tissue damage, flaps, or avulsion~.Type I11 is an open fracture with extensive soft tissue injury and is further divided into three subtypes; type IIIA has adequate soft tissue coverage of a fractured bone despite extensive laceration of soft tissue, type IIIB involves extensive soft tissue injury with periosteal stripping that requires grafting or a flap for coverage, and type IIIC is an open fracture associated with arterial

injury that requires repair. The risk of infection is related to the severity of the injury: 2% in type I open fractures, 2% to 10% in type I1 open fractures, and up to 50% in type I11 open fractures.'7 Wounds should initially be dressed with sterile gauze soaked with antiseptic. Hemorrhage should be controlled by direct pressure. Patients should receive tetanus prophylaxis and antibiotics at recognition of the injury. Firstgeneration cephalosporins cover the gram-positive organisms found in type I and type I1 injuries. An aminoglycoside is added for type I11 injuries, and ampicillin or penicillin is added for farm injuries to fight potential anaerobic infection. Each wound must be adequately debrided and copiously irrigated with the patient under general anesthesia. Wounds may need to be re-evaluated after 2 or more days for additional debridement. Primary closure or delayed primary closure may be appropriate for some open fractures, whereas grafting or flap coverage is needed for larger soft tissue defects. The goal of debridement is removal of devitalized tissue to avoid the catastrophic consequences of an infection, which may include limb loss or chronic osteomyelitis. Adequate immobilization is necessary for soft tissue healing. For small lacerations, immobilization in a cast that has been windowed for wound inspection may suffice. For larger lacerations, external fixation is often necessary to provide stable fixation with access to the wound. Joint penetration by a foreign body can cause a diagnostic dilemma. Radiographs can be helpful if they reveal an "air arthrogram." Injection of sterile normal saline into the joint can also be diagnostic. If the liquid exits the wound or laceration, joint penetration has occurred and requires imgation and debridement in the operating room.

Compartment Syndrome Compartment syndrome occurs when pressure is elevated within a confined fascia1 space. This causes circulatory compromise and can progress to tissue necrosis. Closed fractures and crush injuries with associated edema may cause compartment syndrome. Forearm and leg compartments are most often involved. Ischemic injury starts when tissue pressure is 30 mm Hg below mean arterial pressure.Z0 The pressure within the compartments surrounding a fracture should be measured if compartment syndrome is suspected. Commercially available tissue pressure monitors or other measuring devices, including electronic arterial pressure monitoring devices, can be used. The diagnosis of compartment syndrome in children can be difficult. Adults with compartment syndrome verbalize extreme pain and demonstrate pain with passive stretch of the muscles within the affected compartments, whereas children often have difficulty communicating their discomfort. The classic signs of compartment syndrome are the five Ps-pain, pallor, paresthesia, paralysis, and pulselessness. These signs are rather unreliable in children and may manifest late in the process. An increasing analgesia requirement is an important sign of compartment syndrome in children.'

CHAPTER

With early recognition and timely management, full recovery can be achieved. All external compression is removed from the limb, compartment pressures are measured, and, if elevated, the compartments are surgically decompressed. In the forearm, volar and dorsal fasciotomies are required. In the leg, all four compartments (anterior, lateral, deep posterior, and superficial posterior) must be released. This can be accomplished with two incisions. Without prompt intervention, the result is irreversible damage to soft tissues with loss of function, subsequent contractures, and d e f ~ r r n i t y . ~ ~

Femoral Neck Fracture Although rare in children, fractures of the femoral neck and intertrochanteric regon require attention (Fig. 19-10). These fractures frequently result from high-energy impact, including traffic accidents and falls from a height,6 and are associated with a high complication rate from avascular necrosis, coxa vara, nonunion, delayed union, . ~ ~upper ~ end of the and premature physeal c l o s ~ r eThe femur lies within the joint capsule. After roughly 4 years of age, blood is supplied primarily by retinacular vessels that course from distal in the neck to proximal in the head. Delay in treatment of a fracture at the neck is associated with increased risk of avascular necrosis of the head and destruction of the joint and can cause lifelong disability. Early decompression of the hip joint, reduction of the fracture, and internal fixation can minimize the complication^.^

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neurovascular structures. Some limbs may be unsalvageable owing to extensive damage, some can be reconstructed with a resulting dysfunctional limb, and others can be salvaged with a good outcome. The Mangled Extremity Severity Score rates injuries based on objective criteria at initial presentation, including skeletal and soft tissue injury, limb ischemia, shock, and patient age. Although it originally developed in a primarily adult pop~lation,~s can be a useful adjunct to managing lower extremity trauma in children.12 Segmental bone loss is rare in children and does not necessitate amputation. If periosteum can be preserved, the potential to reform bone is extensive. P r o ~ e rtechniquis of debridement and stabilization, along k t h adequate time, may produce good results in children. External fixation techniques can allow for bone transport and osteogenesis to replace lost bone and axial deformity. Power lawn mower injuries are uncommon, preventable injuries that cause significant morbidity in children.lOJ3.23 Direct contact with the blade leads to laceration of tissue, amputation, or devitalizing shredding of the extremity. Such injury can result in damage to the vasculature and growth plate, joint stiffness, infection, or amputation. If salvage is undertaken, treatment follows that of open fractures. In the case of amputation, preservation of bony length and retention of all viable soft tissue are important for the ultimate functional outcome. Amputation through the diaphysis of a child's bone frequently results in overgrowth of the bony stump through the skin. This is especially true of the fibula, tibia, and humerus and can necessitate cutting back the bone every few years.

Mangled Extremities Severely traumatized or mangled extremities in children must be assessed and treated through a multidisciplinary approach on a case-bycase basis. They may involve extensive injury to or segmental loss of skin, muscle, bone, and

, - Anteroposterior pelvis radiograph of a l4year-old boy shows a left femoral neck fracture that required internal fixation.

Spine Trauma Injuries of the spine in children can be divided into those affecting the cervical spine and those in the thoracic and lumbar spine (see also Chapter 21).Just as in other parts

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A pediatric backboard should have a torso mattress or an occiput recess to accommodate the child's relatively large head and avoid potentially dangerous cervical spine flexion. of the body, patterns of injury to the spine in children differ from those in adults. Radiographic imaging can be challenging. Principles of immobilization are different for children as well. Cervical spine injuries in children differ from those in adults.' Children have greater ligamentous laxity and weaker neck musculature. In addition, they have large heads relative to body size; this effect is more pronounced in younger children. Cervical spine injuries in children tend to occur higher in the neck and can be primarily ligamentous or apophyseal without bony fracture.lg When immobilizing a child on a backboard, the relatively large head should be considered; a child's backboard splint should have a recess for the occiput or a mattress for the torso to maintain the alignment of the cervical spine, avoiding flexion of the neck (Fig. 19-11).zl Radiographic evaluation of the pediatric cervical spine can be challenging. Pseudosubluxation, or the apparent forward displacement of C2 on C3 and, less commonly, C3 on C4, is a welldescribed plain radiographic finding in normal children younger than 8 years.Wther sources

A

of difficulty in interpreting radiographs include incomplete ossification, epiphyseal variation, and elasticity of the disks and vertebral bodies relative to the neural structures, which allows extensive injury to the soft tissues without evidence of abnormality on plain radiographs or SCIWORA (spinal cord injury without radiographic abnormality). MRI is helpful in evaluating soft tissues in cases of possible cervical spine ligamentous injury in children.14 Injuries to the thoracic and lumbar spine are rare in children. The growth of vertebral bodies occurs through the apophyses or growth centers on the cranial and caudal ends of the bodies. With compression injury, adolescents are at risk for traumatic displacement of the vertebral apophysis and the attached disk into the spinal canal, especially in the lumbar region." Symptoms are similar to those seen in central disk herniation, including muscle weakness and absent reflexes. This injury requires recognition and emergent surgical decompression. Lap-belt injuries occur in children when they violently flex over the seat belt and the posterior spine is distracted." A fracture propagates from the posterior portions of the vertebra to the disks or vertebral body in the front (Fig. 19-12). In addition to the vertebral injury, children can sustain abdominal and aortic injuries. Such injuries should be suspected when an abdominal contusion, or the telltale seat-belt sign, is evident in a trauma patient. These injuries require immobilization and possible internal fixation if the injury is ligamentous.

B

Lap-belt injury of L4 in a 15-year-old girl without neurologic injury. A, Lateral lumbar spine radiograph shows fra L4 body and the I~osteriorspine. B, Sagittal magnetic resonance image of the 11umbar spine shows the extensive bony and soft tissue

both the

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Child Abuse The maltreatment of children is a complex medical and social problem, and its recognition is key to management (see also Chapter 24). Fractures before walking age in the absence of metabolic disease or child abuse are rare. Fractures are the second most common manifestation of child abuse after skin lesi0ns.2~Suspicion of abuse must be raised when there is a discrepancy between history and injury, when multiple fractures are present in different stages of healing, or when bruising, metaphyseal fractures, or long bone fractures appear in children younger than 1 year.3.26 No social stratum is free of this problem.

REFERENCES 1. Akbarnia B, Torg JS, Kirkpatrick J: Manifestations of the battered child syndrome. J Bone Joint Surg Am 1974; 56:1159. 2. Bae DS, Kadiyala RK, Waters PM: Acute compartment syndrome in children: Contemporary diagnosis, treatment, and outcome. J Pediatr Orthop 2001;21:680. 3. Blakemore LC, Loder RT, Hensinger RN: Role of intentional abuse in children 1 to 5 years old with isolated femoral shaft fractures. J Pediatr Orthop 1996;16:585. 4. Canale ST, Bourland WL: Fracture of the neck and intertrochanteric region of the femur in children. J Bone Joint Surg Am 197'7;59:431. 5. Cattell HS, Filtzer DL: Pseudosubluxation and other normal variations in the cervical spine in children. J Bone Joint Surg Am 1965;47:1295. 6. Cheng JCY, Tang N: Decompression and stable internal fixation of femoral neck fractures in children can affect the outcome. J Pediatr Orthop 1999;19:338. 7. Copley LA, Dormans JP: Cervical spine disorders in infants and children. J Am Acad Orthop Surg 1998;6:204. 8. Davidson RS, Markowitz RI, Dormans JP, et al: Ultrasonographic evaluation of the elbow in infants and young children after suspected trauma. J Bone Joint Surg Am 1994;76:1804. 9. Davison BL, Weinstein SL: Hip fractures in children: A long-term follow-up study. J Pediatr Orthop 1992;12:355. 10. Dormans JP, Azzoni M, Davidson RS, et al: Major lower extremity lawn mower injuries in children. J Pediatr Orthop 1995;15:78. 11. Edvardsen P, Syversen SM: Overgrowth of the femur after fracture of the shaft in childhood. J Bone Joint Surg Br 1976;58:339. 12. Fagelman MF, Epps HR, Rang M: Mangled extremity severity score in children. J Pediatr Orthop 2002;22:182. 13. Farley FA, Senunas L, Freenfield ML, et al: Lower extremity lawn-mower injuries in children. J Pediatr Orthop 1996;19:669. 14. Flynn JM, Closkey RF, Mahboubi S, et al: Role of magnetic resonance imaging in the assessment of pediatric cervical spine injuries. J Pediatr Orthop 2002;22:573.

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15. Frankel VH, Nordin M: Basic Biomechanics of the Skeletal System. Philadelphia, Lea & Febiger, 1980. 16. Green NE, Swiontkowski MF: Skeletal Trauma in Children, 3rd ed. Philadelphia, WB Saunders, 2003. 17. Gustilo RB, Anderson JT: Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones. J Bone Joint Surg Am 1976;58:453. 18. Helfet DL, Howey T, Sanders R, et al: Limb salvage versus amputation: Preliminary results of the mangled extremity severity score. Clin Orthop 1990;256:80. 19. Henrys P, Lyne ED, Lifton C, et al: Clinical review of cervical spine injuries in children. Clin Orthop 1977; 129:172. 20. Heppenstall RB, Sapega AA, Scott R, et al: The compartment syndrome: An experimental and clinical study of muscular energy metabolism using phosphorus nuclear magnetic resonance spectroscopy. Clin Orthop 1988; 226:138. 21. Herzenberg JE, Hensinger RN, Dedrick DK, et al: Emergency transport and positioning of young children who have an injury of the cervical spine: The standard backboard may be hazardous. J Bone Joint Surg Am 1989;71:15. 22. Karrholm J, Jansson LI, Laurin S: Computed tomography of intraarticular supination-eversion fractures of the ankle in adolescents. J Pediatr Orthop 1981;1:181. 23. Loder RT, Brown KL, Zaleske DJ, et al: Extremity lawnmower injuries in children: Report by the Research Committee of the Pediatric Orthopaedic Society of North America. J Pediatr Orthop 1997;17:360. 24. McMahon P, Grossman W, Gaffney M, et al: Soft tissue injury as an indication of child abuse. J Bone Joint Surg Am 1995;77:1179. 25. Ogden JA: Skeletal Injury in the Child, 3rd ed. New York, Springer, 2000. 26. Rex C, Kay PR: Features of femoral fractures in nonaccidental injury. J Pediatr Orthop 2000;20:411. 27. Rockwood CA Jr, Wilkins KD, Beaty JH, et al: Fractures in Children, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2001. 28. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 1963;45:587. 29. Shapiro F: Fractures of the femoral shaft in children: The overgrowth phenomenon. Acta Orthop Scand 1981; 52:649. 30. Skaggs DL, Mirzayan R: The posterior fat pad sign in association with occult fracture of the elbow in children. J Bone Joint Surg Am 1999;81:1429. 31. Smith WS, Kauffer H: Patterns and mechanisms of lumbar injuries associated with lap seat belts. J Bone Joint Surg Am 1969:51:239. 32. Stephens MM, Hsu LC, Leong JC: Leg length discrepancy after femoral shaft fractures in children: Review after skeletal maturity. J Bone Joint Surg Br 1989;71:615. 33. Techakapuch S: Rupture of the lumbar cartilage plate into the spinal canal in an adolescent: A case report. J Bone Joint Surg Am 1981;45:481. 34. Whitesides TE, Heckman MM: Acute compartment syndrome: Update on diagnosis and treatment. J Am Acad Orthop Surg 1996;4:209.

Hand, Soft Tissue, and knvenomation lnjuries Michael L. Bentz and Delora Mount

Evaluation of pediatric hand and soft tissue injuries requires a systematic approach that includes all relevant organ systems at the site of trauma.' A high index of suspicion is necessary to make an accurate diagnosis and exclude subtle problems, particularly in toddlers and infants who are unable to cooperate with a detailed examination. Injuries are triaged according to their threat to life. After such triage has taken place, the more peripheral and often more dramatic and distracting injuries can be better defined.Vhe history is important to define baseline function, previous injuries, right- or left-hand dominance, and the mechanism and timing of injury. The initial physical examination must define vascularity and perfusion because an ischemic or poorly perfused extremity necessitates emergent surgical intervention. Other findings can be handled in a less urgent fashion, after an orderly assessment is complete. The patient should be examined in a well-lighted area with the parents present to exert a calming influence over a frightened child and thus increase the reliability of findings. This chapter focuses on the acute evaluation and management of hand, soft tissue, and envenomation injuries to provide a foundation for the accurate triage of injured children.5.14

HAND AND SOFTTISSUE INJURIES Evaluation Vascularity The goal of the initial examination is to determine the presence or extent of vascular injury, hypoperfusion, or ischemia. Symptoms of ischemia include pallor, paresthesia, paralysis, pain, and lack of pulse. The digits should be pink and warm if the patient has not had hypothermic exposure or proximal tourniquet application. Normal capillary refill time is 3 seconds and is most accurately tested by compressing the lateral aspect of the distal phalanx adjacent to the nail plate. A delayed refill time indicates impaired arterial inflow, whereas a rapid refill

time suggests venous hypertension or insufficiency. The pulse should be palpated bilaterally at the radial, ulnar, and brachial arteries. Percutaneous Doppler ultrasonography can be used to qualitatively and quantitatively define inflow if the pulse cannot be detected or if it is asymmetrical. Allen's test is important to define the relative contributions of the radial and ulnar arteries to the palmar arches of the hand. The ulnar artery is the dominant source of inflow to the hand and continues into a patent palmar arch in 85% of uninjured hands.' Significant bleeding noted during the initial evaluation is managed by firm manual compression or, if the time until definitive intervention is expected to be prolonged, by proximal tourniquet application. A hemostat or clamp should not be placed blindly into the wound, because lack of blood flow may injure adjacent neural structures. Impaled or retained foreign objects should be left in situ until definitive management is possible because they may staunch the flow of blood from a vascular injury.

Peripheral Nerves Peripheral nerves should be evaluated after vascular inflow has been assessed. Isolated nerve injuries cause predictable neurologic deficits that manifest as abnormalities in sensation or motor function, depending on the location of injury.18 Vascular injuries can also cause neurologic deficits, particularly in subacute wounds; therefore, the evaluation of nerve and vascular injuries should generally occur in tandem. A clear concept of cross-sectional anatomy is helpful in visualizing potential at-risk structures. Evaluating the nerve function at the distal aspect of the hand can be used to screen for a more proximal nerve injury. The median nerve is responsible for sensation to the three and a half volar radial digits. The function of this nerve can be tested by a pinprick or, more objectively, by two-point tactile discrimination. Median nerve motor function can be tested by palpating the contraction of the abductor pollicis brevis and opponens pollicis muscles as the patient forms an "0"with the index finger

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The ability to form an "0'' with the index finger and thumb, Mnth palpable contraction of the thenar muscles , indicates an! intac median nerve.

and thumb (Fig. 20-1). The ulnar nerve supplies sensation to the one and a half ulnar digits. Motor function of this nerve is most accurately tested by palpating the contraction against the force of the first dorsal interosseous muscle while the fingers are spread (Fig. 20-2). There is no radial nerve motor innervation of the intrinsic hand muscles, so the motor function of the radial nerve is best screened by wrist and digit extension (Fig. 20-3). The radial nerves provide sensation to the three and a half dorsal radial digits of the hand to the level of the distal phalanges, although overlap is common. Serial examination can be quite helpful, and cooperation and a focused effort are essential for a reliable evaluation. Further, neurologic findings associated with compartment syndrome evolve over time and may not be obvious during the initial examination.l3

Digit spread with palp; traction of the first dorsal interosseous consistent with an intact ulnar nerve.

conscle is

Skeleton, Tendons, and Ligaments Although some skeletal injuries are obvious on routine examination, most require radiographic evaluation. Physical examination findings of fracture include deformity, crepitus, ecchymosis, pain, instability, and swelling. Anteroposterior, lateral, and oblique radiographs should be obtained for all but the most minor injuries to evaluate for fractures, dislocations, and foreign objects. Familiarity with the Salter-Harris classification of pediatric fractures is important because the specific fracture patterns offer prognostic information relevant to subsequent growth (see Chapter 19).'6,23 The presentation of frache tures has been well d o ~ u m e n t e d . ~ 2 . * Texamination and radiographic appearance are combined to accurately describe the fracture. Open fractures have an associated

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TRAUMA Digit and wrist extensiori demoInstrates radial nerve integrity because no muscles in the hand are innervated by radial nerves.

full-thickness soft tissue injury, whereas closed fractures do not. Simple fractures result in two bone fragments, whereas comminuted fractures involve several fragments. Greenstick fractures involve one cortex and are particularly relevant in children because of their malleable bones. The description of a fracture should also include information regarding length (shortened, elongated, normal), angulation (volar, dorsal, radial, ulnar), rotation (present or absent), and displacement as a percentage of normal alignment. Tendon injuries can be very difficult to diagnose, particularly in young or uncooperative children. In such cases, surgical exploration is necessary to definitely confirm certain injuries. The posture of the hand at rest gives information regarding tendon integrity. In a relaxed position, the hand should form a gentle cascade; this position results from passive tension of the tendons. With compression of the distal forearm, all digits should adopt flexion posturing as a result of the tenodesis effect. A digit that remains extended out of the cascade suggests

disruption of the flexor mechanism (Fig. 20-4). The flexor digitorum superficialis tendon to each of the four fingers is tested by holding the adjacent digits in a fixed position and allowing metacarpophalangealjoint flexion (Fig. 20-5). The flexor digitorum profundus and flexor pollicis longus tendons are evaluated by holding the middle phalanx and observing distal interphalangeal joint flexion. Ligament injuries can be difficult to diagnose, particularly in the presence of associated soft tissue or skeletal injuries.Z4 Abnormal joint stability is an indicator of disruption of the 1igaments.lZ If the opposite side is uninjured, joint stability should be compared with that side as an indicator of preinjury status. Plain and stress radiographs of an avulsion fracture at the site of ligament insertion can confirm clinical findings.

Soft Tissue A thorough determination of soft tissue injuries is important for a knowledgeable evaluation of wound healing,25 Forearm compression has failed to cause flexion of the index finger in this patient; this suggests flexor mechanism discontinuity to the index finger.

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Function of the flexor digitorum superficialis tendon is tested by demonstrating isolated metacarpophalangeal and proximal interphalangeal joint flexion. Flexor digitorum profundus tendon function is tested by holding the middle phalanx fixed and observing distal interphalangeal joint flexion.

but even more so for the evaluation of long-term function and outcome of primary or secondary reconstructive surgery. The amount of soft tissue present in the area of a wound determines the feasibility of primary repair of vascular, neural, and osteoligamentous injuries, and an adequate amount is required for proper healing. The size (measured objectively),shape, location, and general configuration of each wound is recorded, and the mechanism of injury and preinjury status of the patient are established. Obvious foreign objects are removed, although projectiles impaled through an extremity are left in situ until they can be managed definitively. Exposed vital structures as well as associated fractures and tendon injuries are noted.

Early Treatment Vascular Ischemia is one of the few surgical emergencies associated with upper limb trauma. Revascularization is a top priority after the correction of life-threatening injuries. Because irreversible changes start to occur after 4 hours of ischemia, expeditious surgical intervention is mandatory, especially if the ischemic tissue involves muscle. Primary vascular repair is the most effective procedure and is ideally accomplished by debridement, mobilization, and primary anastomosis of injured segments. Reversed vein grafts, which are frequently done with foot, forearm, saphenous, or cephalic veins, should be used liberally if tension or lack of tissue prevents easy approximation of adjacent segments. In general, all arteries and veins proximal to the elbow should be repaired. Repair of arterial injuries below the elbow should also be considered to prevent cold intolerance; however, only about half of these repairs remain patent.10 If necessary, the radial artery can be ligated primarily. Once repairs are complete, fasciotomy should be considered if ischemia has been prolonged,

soft tissue damage is significant, or adequate postoperative monitoring is not available.l~eria1examination should then be pursued in an effort to make an early diagnosis of recurrent ischemia or postsurgical thrombosis or bleeding. The role of anticoagulation therapy in this setting is controversial and is based on the surgeon's preference and experience.

Peripheral Nerves Injury to the peripheral nerves is not an emergency and can frequently be addressed when an adjacent vascular injury is being repaired. When a wound is clean, uninfected, and well vascularized, primary nerves should be repaired in an end-to-end fashion. Such repair can be facilitated through the mobilization of proximal and distal injured segments, which can reduce tension and augment blood flow. If mobilization of the injured segments cannot adequately repair the defect, interpositional nerve grafts can be used for definitive reconstruction. In such cases, early secondary repair in the first 10 days after injury is optimal. To ensure that the injured area remains intact, the involved limb should be splinted to minimize further proximal migration of the transected nerve before surgery and to relieve anastomotic tension.

Skeleton, Tendons, and Ligaments When injuries to the skeleton, tendons, or ligaments are diagnosed, restoration of normal or acceptable anatomy followed by appropriate immobilization is indicated. In children, an injury that is suspected but not objectively defined is particularly common. Hand fractures may not be evident on radiographs for several weeks. In this situation, presumptive treatment should be carried out, which usually involves immobilization of the potentially injured area, despite equivocal physical examination or radiographic findings. Immobilization is rarely contraindicated in children because it allows protection from further

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injury, improves pain control, and maintains local anatomy. Use of a splint (instead of a cast) is ideal because it allows swelling into a nonfixed space and limits the possibility of vascular compromise during the acute injury and postreduction periods. Anatomic reduction of fractures and dislocations can be done at the time of injury or in the following week, with good functional results.29 In the acute setting, excellent anesthesia can be obtained by performing a hematoma block. This is accomplished by injecting 2 to 3 mL of lidocaine 1% without epinephrine into the fracture site. Reduction in the subacute setting most commonly requires a traditional digital block. Particularly in smaller children, it must be kept in mind that the limiting dose of plain lidocaine is 4 mg/kg of body weight. A description of the reduction maneuvers for specific types of fractures is beyond the scope of this chapter, but in general, gentle manual traction or finger-trap distraction with simultaneous rotation or derotation allows improvement in many types of fractures and dislocation^.^ Postreduction radiographs should be obtained in most if not all patients before or after immobilization. The specific position of immobilization is less critical for children than adults because children are less prone to stiffening and tightening of the ligaments. The "position of safety" can always be used at least initially for splinting: the wrist is placed in 30 to 45 degrees of extension, the metacarpophalangeal joints are placed in 70 degrees of flexion, and the interphalangeal joints are left straight. Serial physical and radiographic examinations are tailored to the specific injury and clinical course.

Soft Tissue After soft tissue and associated vital structure injuries are documented, irrigation of all significant wounds should be performed with normal saline solution, after which foreign objects are removed and tissue that is clearly devitalized is debrided. These procedures may require a local anesthetic, which should be given only after a thorough neurologic examination has been completed. Simple lacerations and small surface-area avulsions can be closed primarily using the same layered closure method used for deep or gaping wounds under tension, Suture choice depends on the location, size, and cause of the wound, as well as the patient's age. A smaller child who requires sedation for the primary wound repair will be hypersensitive to suture removal, when sedation is usually not available. In such cases, absorbable sutures reinforced with Steri-strips and an adhesive are ideal. Permanent sutures should be used in older or cooperative patients to minimize the inflammatory response and avoid early scarring. The potential for scarring depends on the location of the wound and the mechanism of injury. Scarring can be minimized through judicious wound closure. Open wounds that cannot be closed primarily require more elaborate intervention. To bridge the gap between injury and wound closure, the wound must be managed and protected. Normal saline wet-to-wet dressings are a simple and effective way to provide limited debridement, allow the initiation of granulation, and prevent desiccation.

Povidone-iodine dressings should be reserved for shortterm use in infected wounds. Acetic acid solution (0.25%) is appropriate for wounds that have culture documentation of infection with Pseudomonas species. Quantitative wound biopsies should be reserved for nonthermal burns. If the skin defect is only partial thickness and no vital structures are exposed, split-thickness skin grafting or skin distraction is appropriate. Split-thickness skin grafts are used for larger wounds, less cosmetically significant wounds, or those in which the wound bed may not be optimal because of infection, inflammation, or ischemia. Full-thickness skin grafts contract less after revascularization and thus are ideal for cosmetically significant areas or those where wound contraction is undesirable. Local skin flaps can also be used in such settings, offering a cosmetically favorable replacement of like tissue. These skin flaps can be random if they have no specific blood supply or axial if the blood is supplied by a specific vessel." Regional muscle flaps can be used almost anywhere in the body, especially when highly vascularized tissue of significant bulk is required to cover exposed critical structures and fill dead space. Similar to axial pattern skin flaps, these muscle flaps are used on the basis of a known blood supply, which makes their dissection reliable and safe. Finally, when local tissue is not available or is inadequate to provide wound closure, microvascular free tissue transfer is indicated using specific donor "free flaps" to accomplish specific tasks.

Amputations Traumatic amputations in children should be considered for replantation by a qualified microsurgical team, given the excellent results obtained when compared with adult series.15 To optimize the chance of success, the amputated part should be wrapped in saline-moistened gauze, sealed in a plastic bag, and placed in a bag of ice and saline solution; the part must not contact the ice directly.

ENVENOMATION INJURIES Snakebites More than 2700 species of snakes exist; 115 of these species are indigenous to the United States, and only 19 of the 115 species are p o i ~ o n o u s .Pit ~ vipers, which are named for the pit located between their eyes and nostrils, account for most bites. Pit vipers include rattlesnakes, copperheads, and cottonmouth^.*^ Coral snakes represent the other poisonous family. Most bites occur during the summer months in the morning, late afternoon, or evening. Not all bites are associated with envenomation. Signs of envenomation include pain, edema, ecchymosis, nausea, vomiting, hypotension, disseminated intravascular coagulopathy, hemolysis, mental status changes, seizures, and death." The severity of signs is proportional to the degree of envenomation. Early intervention includes reassurance and support, immobilization, limb elevation, venous tourniquet application, and rapid transfer to the nearest medical facility. Cryotherapy and wound incision

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and suction are no longer recommended. Mild pit viper envenomations (characterized by mild pain, local edema, lack of systemic signs, and normal laboratory values) require up to 5 vials of antivenin; moderate envenomations (severe pain, extending edema, nausea, vomiting, neurologic signs, and abnormal laboratory values) require 10 to 15 initial vials of antivenin, with retreatment as necessary; and severe envenomations (rapid progression of local, systemic, and laboratory abnormalities) require an initial Antivenin is admindose of 15 to 20 vials of anti~enin.2~ istered intravenously only after a skin test has been done to rule out the possibility of an anaphylactic reaction. The initial dose for children is one and a half to two times that of adults because of the smaller circulating blood ~ . ~ ~ dosvolume and relative venom c o n ~ e n t r a t i o n .Initial ing should be followed by aggressive intravenous hydration. Fasciotomy should be considered but is seldom required.?"nitial management of bites from snakes from other countries is similar, although antivenin use requires adjustment, depending on the type of snake.2' In addition to its use for pit vipers from North America, antivenin is effective for bites from fer-de-lance, bushmaster, and cantil snakes, which are found in Central and South America. Australian species frequently known to cause envenomations include the common brown snake, mainland tiger snake, lowland copperhead, and red-bellied black snake.

Other Bite Injuries Gila monsters, which are found in the southwestern United States, and their relative the Mexican beaded lizard are active in late spring. These lizards inject venom as long as they cling to the victim. Wounds show edema, but tissue loss is less pronounced than that associated with envenomation by pit vipers; however, systemic signs can ultimately be similar. These injuries are managed by removing the animal from its victim, followed by local and systemic supportive care. Antivenin is not available. Radiographs should be obtained to exclude retained teeth." Black widow spiders are venomous New World spiders; the females are black with an hourglass-shaped red mark on the abdomen.%ocal signs of a bite can be limited, followed by systemic neuromuscular symptoms of diffuse rigidity and spasm that potentially lead to respiratory arrest approximately 1 hour later. Envenomations by black widow spiders are managed by local care, fluid and cardiovascular support, parenteral calcium gluconate, muscle relaxation, and antivenin.2,"11,z Scorpion stings in children have serious sequelae. Bark scorpions are the only toxic species in the United States; however, others are common in Mexico and equatorial countries. Local signs of envenomation are minimal, whereas systemic neuromuscular findings are present in the sympathetic and parasympathetic systems. Children are particularly susceptible to the severe cardiorespiratory and neuromuscular dysfunction associated with envenomation. Therapy of scorpion stings includes local wound care, topical ice, specific antivenin, and systemic support, including ventilation, control of

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tachyarrhythmias, and sedation. Treatment is similar to that for spider bites, although scorpion stings are generally less seri0us.2~ Finally, human bite wounds can pose some of the most challenging definitive management problems among .~ on the quantitative and all bite-induced i n j u r i e ~Based qualitative characteristics of oral flora, including the principal pathogen Eikenella corrodens, aggressive primary intervention is mandatory to achieve a satisfactory outcome in all these injuries. Thorough irrigation of penetrating bite wounds is mandatory, as well as broadspectrum antibiotic coverage, followed by frequent wound checks.

REFERENCES 1. Ablove RH, Moy OJ, Peimer CA: Pediatric hand disease: Diagnosis and treatment. Pediatr Clin North Am 1998;45: 1507-1524. 2. Allen C: Arachnid envenomations. Emerg Clin North Am 1992;10:269-298. 3. Banner W: Bites and stings in the pediatric patient. Curr Probl Pediatr 1988;18:1-69. 4. Bhende MS, Dandrea LA, Davis, HW: Hand injuries in children presenting to a pediatric emergency department. Ann Emerg Med 1993;22:1519-1523. 5. Binder LS: Acute arthropod envenomation: Incidence, clinical features and management. Med Toxic01 Adverse Drug Exp 1989;4:163-173. 6. Buncke GM, Buntic RF, Romeo 0: Pediatric mutilating hand injuries. Hand Clin 2003;19:121-131. 7. Coleman SS, Anson BJ: Arterial patterns in the hand based on a study of 650 specimens, Surg Gynecol Obstet 1961; 113:409424. 8. Eaton RG, LittlerJW: Joint injuries and their sequelae. Clin Plast Surg 1976;3:85-98. 9. Forks TP: Evaluation and treatment of poisonous snakebites. Am Fam Physician 1994;50:123-130. 10. Gelberman RH, et al: The results of radial and ulnar arterial repair in the forearm: Experience in three medical centers. J Bone Joint Surg Am 1982;64:383-387. 11. Hassen LB: Reptile and arthropod envenomations. Occup Med 1991;6:447-461. 12. Hastings H, Simmons BP: Hand fractures in children: A statistical analysis. Clin Orthop 1984;188:120-130. 13. Holden CEA: Compartmental syndromes following trauma. Clin Orthop 1975;113:95-102. 14. Innis PC: Office evaluation and treatment of finger and wrist injuries in children. Curr Opin Pediatr 1995; 7:83-87. 15. Jaeger SH, Tsai TM, Kleinert HE: Upper extremity replantation in children. Orthop Clin North Am 1981;12: 897-907. 16. Leclercq C, Korn W: Articular fractures of the finger in children. Hand Clin 2000;16:523-534. 17. McGregor IA, Morgan G: Axial and random pattern flaps. Br J Plast Surg 1973;16:202-213. 18. Moberg E: Evaluation of sensibility in the hand. Surg Clin North Am 1960;40:357-362. 19. Nofsinger CC, Wolfe SW: Common pediatric hand fractures. Curr Opin Pediatr 2002;14:42-45. 20. Rimsza ME, Zimmerman DR, Bergeson PS: Scorpion envenomation. Pediatrics 1980;66:298-302. 21. Rudolph R, et al: Snakebite treatment at a southeastern regional referral center. Am Surg 1995;61:767-772.

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22. Russell FE: Venomous arthropods. In Schacter LA, Hansen R (eds): Pediatric Dermatology. New York, Churchill Livingstone, 1988. 23. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 1963;45:587-622. 24. Simmons BP, Lovallo JL: Hand and wrist injuries in children. Clin Sports Med 1988;7:495-512. 25. Stewart GM, Quan L, Horton MA: Laceration management. Pediatr Emerg Care 1993;9:247-250. 26. Stewart RM, et al: Antivenin and fasciotomy/debridement in the treatment of the severe rattlesnake bite. Am J Surg 1989;158:543-547.

27. Tibballs J: Diagnosis and treatment of confirmed and suspected snake bite: Implications from an analysis of 46 paediatric cases. Med J Aust 1992;156:270-274. 28. Weber RA, White RR: Crotalidae envenomation in children. Ann Plast Surg 1993;31:141-145. 29. Wood VE: Fractures of the hand in children. Orthop Clin North Am 1976;7:527-542.

Central Nervous System Injuries Thomas G . Luerssen

Injuries to the brain and spinal cord continue to be the major cause of mortality and morbidity from childhood trauma. Despite 25 years of intensive clinical research, no specific medical therapy for any traumatic neurologic injury has yet been defined. Nevertheless, there has been a steady and substantial advance in our understanding of the natural history of brain and spinal cord injuries; moreover, there have been changes in management that have clearly resulted in improved outcomes. We have now entered the era of "evidence-based medicine" whereby recommendations for disease and injury management are supposed to be derived from critical analysis of available scientific research. In the past decade, management strategies for central nervous system (CNS) injuries have been subjected to this type of analysis. These efforts have resulted in the publication ~ ~ , ~ ~ of of practice management g u i d e l i n e ~ . 2 , 2 l ,Analysis the clinical evidence and development of these recommendations represent a substantial amount of work by many of the leading experts in the field. Unfortunately, these reviews also uncovered a remarkable lack of strong scientific evidence on which to develop recommendations, especially in the pediatric age group, so most of the available recommendations regarding the diagnosis and treatment of neurologic injuries can be supported only by the lowest degree of medical certainty. Nevertheless, these published practice parameters are useful summaries of the current understanding of the various treatments of brain and spinal cord injury. These publications are referenced frequently in this chapter, and interested readers are encouraged to review these practice parameters and the citations of the analyzed literature that serve as the basis for the recommendations.

BASIC STRATEGY FOR TREATMENT OF CENTRAL NERVOUS SYSTEM INJURY One of the most enduring concepts underlying the management of brain and spinal cord injury is that of primary and secondary injury.IZ4The primary neurologic injury involves the immediate disruption of neuronal, axonal, and supportive structures and vascular tissues.

The magnitude and location of the primary injury, along with the variety of irreversible cellular processes that immediately ensue, something that has been referred to as "delayed primary injury," are directly related to the mechanism of injury. These immediate tissue disruptions are also considered to be self-limited and are, by definition, essentially untreatable. Given all of this, one can easily see that the primary brain injury is the major determinant of injury outcome. Obviously, the primary injury can be devastating and, in many high-energy mechanisms, immediately lethal. In persons not immediately killed by an injury, the primary injury triggers a cascade of intracellular and extracellular biochemical changes, both in the region of the injury and systemically, many of which are deleterious and cause acceleration and augmentation of the initial injury. These reactive processes represent the onset of what has been termed the "secondary injury." These secondary reactive processes can begin at almost any time after the injury and can persist for some time. The secondary injury not only results in new damage, both in the region of the primary injury and in areas of previously uninjured brain or spinal cord, but also causes deleterious effects in other organs and body systems. Systemic reactions commonly seen after brain or spinal cord injury include hypotension and hypoxia. It has clearly been shown that even brief and mild episodes of either hypoxia or hypotension can have profoundly deleterious effects on the outcome of both brain and spinal cord injury.28,123,141 Although it is well known that spinally injured patients can be rendered hypotensive by an isolated injury, it is now also clear that isolated brain injury can cause systemic hypotension. Multiple injuries, occult organ injuries, or other causes of exsanguination that result in hypovolemia are not required for this hypotensive response to occur. Of the early systemic complications, it appears that hypotension is much more deleterious to an acutely injured brain than hypoxia is. This is probably also true for an acutely injured spinal cord. Finally, it is clear that these complications can occur very early, frequently, and in many cases so briefly that they are either undetected or unreported, even in modern intensive care ~ n i t s . I 2 , ~ ~

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There are also other common systemic responses, many of which occur shortly after an injury but can also cause further injury even days after the institution of therapy. Hyperthermia, either from fever or as a result of overly aggressive warming, is harmful to an injured brain.'" Hyperglycemia, which is commonly seen in the stress response and can be aggravated by fluid administration or attempted nutrition, is also believed to be deleterious to acutely injured neurons.18.*7J4Y Tissue disruptions, commonly referred to as cerebral or spinal cord contusions, cause reactive changes in the tissues immediately surrounding the area of injury. A variety of tissue factors are released, such as those in the kallikrein-kinin system, and these factors can cause disturbances in microcirculation and the blood-brain or blood-spinal cord barrier that ultimately result in the complex entity that has generally been referred to as post-traumatic edema.l13 There are hypermetabolic responses related to neural tissue injury that may outstrip the local or regional substrate supply.13 Excitotoxic amino acids such as glutamate and aspartate are released from injured neurons." Post-traumatic seizures, especially prolonged subclinical seizures, may contribute to this response in the injured brain.172 Along with the reactive biochemical changes, expanding local hemorrhages caused by direct vascular injury can lead to further compression of adjacent vessels and result in an ischemic penumbra around the acute injury. Although the systemic and biochemical processes of secondary injury are complex, it appears that the pathophysiologic end point of all of them is ischemic damage. Ischemic neuronal damage is almost universally seen in the neuropathologic examination of patients who have suffered traumatic brain and spinal cord injUry.70,164 Even though numerous biochemical cascades have been identified and physiologically characterized, and many have been the target of pharmaceutical intervention, no drug has yet been shown to be specifically effective for the treatment of CNS injury. Trials of high-dose steroids, calcium channel blockers, free radical scavengers, and glutamate antagonists have been generally negative, although small and specific subgroups of patients were identified in post hoc analyses that may have benefited from one or another of these therapies. More concerning is that some groups of patients were apparently harmed by the administration of some of these agents." Despite this lack of development of a specific therapy, 20 years of clinical trials involved in the assessment of these agents have shown steady improvement in neurologic outcomes, more so in the arena of brain injury than in spinal cord injury. This trend toward improved outcome is almost certainly due to the realization that many of the ischemic processes can be prevented by aggressive application of systemic manipulation, beginning with the resuscitation phase of the injury and continuing through the period of acute therapy. The essential therapeutic strategies for brain and spinal cord injury are based on preventing ischemic injury by the aggressive support of intravascular volume and blood pressure at all times. The historical idea of restricting fluids in head-injured patients is no

longer accepted. The early use of vasopressors is encouraged. Reduction of focal vascular compression by removal of mass lesions and aggressive prevention and management of reactive brain or cord swelling to protect perfusion are procedures that are aimed at minimizing local and general ischemic injury. These three relatively simplistic concepts--support of systemic blood pressure, reduction of intracranial pressure to ensure cerebral perfusion, and removal of compressive lesions plus prevention of deleterious complications-are now the mainstay of management of brain and spinal cord injuries.

IMMEDIATE ISSUES: RESUSCITATION AND TRANSPORT OF INJURED CHILDREN Effective supportive and preventive therapy should begin as quickly after the injury as possible. Goals of the initial resuscitation are twofold: prevention of as much secondary injury as possible and prevention of any new primary injury before undertaking neurodiagnostic studies. One can accomplish the first goal by ensuring oxygenated perfusion of the brain and spinal cord by restoring and maintaining age-appropriate normal blood pressure and volume as early as possible. This action, coupled with restoring and maintaining normal ventilation, is, at least at this time, more important than the administration of any drug. The exact means of accomplishing this goal, that is, the type of resuscitation fluid or the means of ensuring ventilation, is probably less important than accomplishing the goal itself. Most current studies indicate that isotonic or slightly hypertonic saline solution is an appropriate fluid for resuscitating and maintaining blood pressure in neurologically injured patients,2*,2gx181 although the use of colloids and more highly concentrated hypertonic solutions is also being investigated. Tissue oxygenation is important, and therefore adequate airway and ventilation support is required. Early intubation by experienced personnel with appropriate analgesia and sedation will certainly accomplish this goal. However, the role of intubation of injured children (and adults) in the field is still controversial.77 It appears that this maneuver is associated with a relatively high complication rate and may not be warranted in many s i t u a t i 0 n s . 2 ~ ~ ~ ~ 2 7 ~ 1 ~ ~ For patients with possible spinal injuries, prevention of further injury begins with stabilization of the spine. This maneuver involves much more than the application of a collar or securing a child to a rigid board. It is important that normal anatomic alignment be maintained. Very young children have proportionately larger heads and therefore have a tendency toward cervical flexion when lying supine." A cervical collar alone does not completely immobilize an injured spine in a child.83 Specific attention should be directed to immobilizing the spine in an anatomic position, including ensuring a normal relative position of the head to the body. Young children require some additional elevation of the body so that the head falls back to a truly neutral position. Once these parameters have been achieved, that is, stabilization of the spine in an anatomic position and establishment of systemic blood pressure and respiration

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support, an injured child may be transported for definitive diagnosis and treatment of the injury.

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focal or diffuse. Accepting the caveat that many traumatic injuries are "mixtures" of focal and diffuse injury, one can still base individual management strategies on the initial appearance of the type of brain injury.

TRAUMATIC BRAIN INJURY Focal or Diffuse Brain Injury?

Epidemiology Despite the frequency of head injury in children, epidemiologic data in this area are relatively limited. A study in the United Kingdom indicated that 40% of all patients seen in emergency departments for the treatment of head injuries were children." It is important, however, to distinguish between "head injury" and "brain injury" in discussing outcomes and therapy, although it is probably equally important to group these entities in discussing mechanisms and prevention. Accordingly, population-based studies indicate an average incidence of clinically important head injury in children of about 185 per 100,000, with the incidence generally dropping with increasing age.I9zg6Boys are injured at a rate approximately twice that of girls. Overall, 85% of the brain injuries sustained in childAlthough hood are mild and not life threatening.97,111 severe brain injuries are rare, they still constitute a major concern in pediatric trauma management. Reports from pediatric trauma centers have indicated that well over half of all deaths resulting from blunt trauma in children are caused by a brain injury.l*lJ71 The severity and mechanism of brain injury seem to be linked to outcomes. The mechanism of injury is also age dependent. The most common mechanism resulting in head injury in children is a fall, but the usual falls in childhood are not associated with severe injuries. The major cause of severe brain injury in young children seems to be abuse. In older children, severe brain injury is most commonly seen in relation to motor vehicle accidents. Many accidental brain injuries that occur in children are preventable. Proper use of occupant restraints in motor vehicles can prevent up to 90% of the serious injuries to young children.'47 The implementation of a mandatory child restraint law in Michigan reduced the number of motor vehicle-related injuries in children by 25%.llWearing helmets for bicycle riding, as well as for other recreational activities such as skateboarding, skating, skiing, and horseback riding, should decrease the risk for brain injury,l2"148,167 although educational programs regarding helmet use have had only limited success thus far." Many falls are preventable. Vigilance regarding open windows and stairways, including the use of gates or bars, substantially reduces the occurrence of these injuries.

The Spectrum of Traumatic Brain Injury There are many ways to undertake an overview of the major types of traumatic brain injury. The author has come to prefer one that includes a relationship of injury types, mechanism, and natural history. The simplest way to do this is by categorizing major injury types as either

Focal injuries include contusions, lacerations, traumatic hematomas, and localized damage caused by expanding masses and shifts and distortions of the brain. Diffuse injuries include the spectrum of diffuse axonal injury (DAI), which encompasses what is commonly called cerebral concussion, as well as other diffuse insults such as global ischemia, systemic hypoxia, diffuse brain swelling, and diffuse vascular injury. Focal injuries are usually immediately apparent on admitting computed tomography (CT) scans. Nonetheless, they may be clinically asymptomatic. In contrast, diffuse injuries may show much less striking changes on early neuroimaging studies, even though the patient may exhibit profound alterations in consciousness and neurologic function. Focal injuries are more likely to require therapeutic surgical procedures, whereas diffuse injuries may require extensive diagnostic studies to determine the type and magnitude of the injury. Diffuse injuries are also more likely to require prolonged monitoring of intracranial pressure (ICP) to guide therapy. It is useful to discuss the characteristics of these types of injuries individually, but it is important to remember that in many cases, especially with more severe injuries, both injury types may be present.

Focal Brain Injury Most focal brain injuries are associated with impactrelated mechanisms. Because short falls are the most common cause of accidental head injury in childhood, cranial impacts and their resulting focal injuries are also common. Furthermore, impact mechanisms are associated with skull fractures, which are also commonly seen in the pediatric age group. In fact, about 20% of head-injured children who are admitted to the hospital have skull fractures.105 Despite the frequency of skull fracture in childhood, the majority of children with this injury will not require any intervention or suffer any complication directly related to the fracture. Therefore, the clinical importance of most skull fractures is that the fracture serves as an indicator of both the mechanism and severity of the head injury. Most studies of the importance of skull fractures have determined that the finding of a skull fracture in a head-injured patient is statistically associated with a higher likelihood that an expanding intracranial hematoma or a significant brain injuly is also present.'"8',101~1~)5~166 Furthermore, complex skull fractures, or the occurrence of multiple fractures, is generally associated with higher-energy mechanisms and therefore more severe injuries to the brain. As indicated earlier, most focal brain injuries are immediately apparent on initial neuroimaging studies and, depending on the size and location, result in focal neurologic dysfunction. The most common focal injury resulting from nonpenetrating mechanisms is a cerebral contusion (Fig. 21-1). It is generally a surface lesion

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This cerebral contusion underlying a linear skull

fracture (not demonstrated) was the result of a cranial impact, as demonstrated by the overlying soft tissue swelling and hemorrhage. The patient had no neurologic deficit.

related to cranial impact or brain movement over irregular intracranial surfaces or along the edges of dura. The clinical manifestation of cerebral contusions depends mostly on the extent of the initial injury, the amount of associated hemorrhage resulting in a mass effect, and the location of the contusion in the brain. Even though cerebral contusions may result in localized swelling, isolated lesions are not generally life-threatening. Many cerebral contusions are neurologically silent, only to be discovered on the initial CT scan underlying a skull fracture or along the anterior cranial base. When these injuries are symptomatic, they usually cause a focal neurologic deficit or seizures. The latter are thought to occur commonly in adults with acute cerebral contusion^.^^ However, the incidence of seizures in children with cerebral contusions appears to be no greater than that in children with either normal CT scans or epidural he ma to ma^.'^ Traumatic intracerebral hematomas are unusual lesions in the pediatric age group. The pathogenesis of these hemorrhages is unclear, but it seems likely to be related to disruption of central arterial blood vessels. Accordingly, these lesions are associated with more severe mechanisms of injury and with more profound neurologic dysfunction. In many cases these lesions are part of a larger picture of DAI, which is discussed later. Traumatic intracerebral hematomas are distinguished from hemorrhagic contusions by their lack of contact with the surface of the brain.67 They can be quite large and, because of the location, can leave a child with a profound neurologic deficit. Surgical evacuation can be considered if ICP is high, but in the author's experience,

neurologic outcomes are not improved by evacuation of these hematomas. Children seem to be uniquely prone to nonmissile-associated penetrating injuries of the skull and brain. These injuries are usually the result of a fall onto or being struck by sharp objects such as nails, pencils, sharp sticks, or lawn toys (Fig. 21-2). One of the major dangers of these injuries is that unless the offending object remains embedded, the entry wound may be hidden or seem trivia1.22,44,'26 Anterior penetration of the skull base can be transorbital, via the orbital roof, or through the nose or mouth. Thus, direct evidence of cranial penetration may not be visible or may be masked by local swelling. Penetrating injuries can result in focal contusions, intracerebral hemorrhages, and cerebral lacerations, but these lesions are usually silent because of their locations and small size. Deeper penetrations are more likely to be symptomatic, not only because the tissue injury is more extensive but also because of the potential for injuring major vessels. Many penetrating injuries become symptomatic in delayed fashion because of expansion of intracerebral hemorrhage, recognition of a cerebrospinal fluid (CSF) fistula, or the development of symptoms indicating infection. Therefore, a very high index of suspicion is required, and careful radiologic studies are called for whenever there is a possibility of subtle cranial penetration. Wood, glass, and residual bits of debris may be difficult to detect on routine imaging studies, including CT.76 Cranial penetrating injury is also strongly associated with direct cerebrovascular injury." Magnetic resonance imaging (MRI) with the addition of magnetic resonance angiography (MRA) or the increasingly useful modality of CT angiography (CTA) should be considered whenever there is evidence of deep cranial penetration or if substantial subarachnoid or focal intracerebral hemorrhage is present.

Diffuse Brain Injuries The majority of brain injuries occurring in childhood are diffuse injuries. Diffuse brain injuries are characterized by general disturbances in neuronal function that begin immediately at the time of injury. Despite this, brain structure is generally preserved on admitting CT scans. Diffuse injuries occur as a direct result of energy dissipation within the substance of the brain or as a result of systemic insults. All these injuries exist on a continuum from extremely mild, and apparently completely reversible, to lethal. Frequently, the different types of diffuse brain injury occur together or in sequence and can act synergistically to affect neurologic status and the outcome. Diffuse primary brain injuries are generally the result of angular or translational acceleration (or deceleration), with the amount of tissue disruption being roughly proportional to the amount of energy dissipated in the brain substance.'j8 As the amount of neuronal disruption increases, the depth and duration of neurologic dysfunction increase and the neurologic outcome worsens. There is a strong association with the appearance of certain hemorrhages on CT scan, specifically, subarachnoid hemorrhage, small but widespread

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A

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B

The occult injury frequently seen with low-velocity cranial penetration in young children is demonstrated. The patient was struck in the left parietal region by a lawn dart, and loss of consciousness did not occur. The lawn dart fell out immediately. The injury was misinterpreted as a minor scalp laceration and was closed with butterfly bandages. Three days later, fever and headache developed. A, Appearance of the entry wound before surgical exploration. B, Computed tomography shows a compound fracture and intracerebral hematoma. During surgery, hair, dirt, and bone fragments were removed from the cerebral cortex. I

intracerebral hemorrhages, and intraventricular hemorrhage (Fig. 21-3).l Finally, although the occurrence of traumatic, surgically accessible masses is not characteristic of diffuse brain injury, subdural hematomas are seen commonly along with DAI, and some of these subdural hematomas are large enough that surgical evacuation may be a necessary component of initial therapy. However, these subdural hemorrhages are better viewed as another marker of the diffuse brain injury rather than as a mass that should be treated in isolation, such as an epidural hematoma or hemorrhagic contusion. Like all brain injuries, diffuse primary brain injuries occur within a spectrum of severity. At one end of the spectrum is a very mild, transient physiologic disturbance in neurologic function that includes the syndromes commonly associated with "cerebral concussion," whereas at the other end is the progressively more damaging and ultimately lethal entity that is now called "diffuse axonal injury." The modern view of cerebral concussion is based on the pioneering work of Ommaya and Gennarelli,130J31 which defines concussive brain injuries as a graded set of clinical syndromes showing increasing disturbances in the level and content of consciousness. This definition

allows the inclusion of specific post-traumatic disturbances that are commonly seen in children after so-called mild head injuries, including confusion without amnesia, confusion associated with amnesia of varying depth and duration, and the classic loss of consciousness with and without transient sensorimotor paralysis or disturbances in respiration or circulation. As the amount of energy in the injury mechanism increases, tissue disruption occurs and results in DAI. It is now clear that the most common cause of prolonged coma from mechanical brain injury is DAI. Patients who have suffered DAI are unconscious from the time of injury and remain so for a prolonged period.66 It is not uncommon to note pupillary changes, skewed gaze, and decerebration. This constellation of symptoms had been called "brainstem contusion" in the era before MRI, and although isolated brainstem contusion can certainly occur, it is extremely rare. Instead, most patients in coma who appear to have brainstem dysfunction after closed head injury have suffered DAI. The findings on initial CT scanning depend on the severity of the injury and the degree of associated hemorrhage. In some cases the initial CT scan may be normal. Subsequently, the characteristic lesions may be discovered

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The "classic" appearance of diffuse axonal injury on an admitting computed tomographic scan includes subarachnoid and intraventricular hemorrhage, brain swelling, and small petechial hemorrhages throughout the brain.

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on MRI and can vary from some transient signal changes in the deep white structures to widespread hemorrhagic and nonhemorrhagic shearing injury. The characteristic CT scan appearance of DAI is multiple petechial hemorrhages in the deep white matter and central structures. However, the finding of intraventricular hemorrhage or focal subarachnoid hemorrhage specifically located in the prepontine cistern is also strongly suggestive of DAI.

Gunshot Wounds Injuries from firearms are a major public health problem in children. Because of the way these injuries are reported, it is difficult to determine the overall incidence of this injury in children. However, recent reports indicate that 10% of all childhood injury deaths are related to firearms, a number exceeded only by deaths from motor From vehicle accidents, drowning, and house fi~-es."J~~ the standpoint of management and outcome, there is little to differentiate gunshot injuries in children from those in adults. Poor outcome is related to the depth of coma, bilateral or transventricular injury, elevated ICP, and large intracerebral hemorrhages.~3Vonetheless, most authorities recommend aggressive treatment of all patients except those with clearly nonsurvivable inj~ries,"~ although substantial neurologic and cognitive deficits can be e~pected:""l2~ Injuries caused by nonpowder firearms, such as BB and pellet guns, are three times more frequent than true gunshot wounds in children,176 with adolescent males having the highest risk for injury.122 These injuries are generally less severe and therefore associated with lower mortality rates. Surgical treatment is not usually required for BB gun injuries. Pellet rifle injuries, because they are higher-velocity and larger-caliber missile injuries, are more

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severe and are probably best treated as true gunshot wounds.

Crush Injuries Young children are susceptible to the unusual static loading-type crushing injury to the skull. These injuries occur as a result of a heavy object's falling on a child or being run over by a vehicle. Crush injuries are dramatic in both clinical and radiographic findings (Fig. 21-4), but neurologic outcomes can be quite g ~ o d . ~ W u l t i p l e skull fractures are typical and include complex basilar skull fractures and facial fractures. CSF leaks and cranial nerve palsies are commonly seen. The mechanism of injury and the clinical findings would suggest overwhelming injury and a poor outcome. However, despite the initial appearance of the injury, many times major cortical structures are preserved. Therefore, if the child has survived the initial injury, aggressive multidisciplinary management can result in satisfactory long-term functional outcomes.

Inflicted Injuries By far, the most common cause of severe and lifethreatening brain injury in infants is inflicted injury (also see Chapter 24). All physicians involved in the care of injured children should be familiar with the clinical manifestations and characteristic radiographic findings of inflicted injuries. This entity has recently been reviewed in detai1.37~47Infants with an alteration in consciousness, with or without a new onset of seizures, retinal hemorrhages, and acute intracranial hemorrhages on CT scan, are likely to have suffered nonaccidental injuries, especially if the history of the injury is unknown or reported

B

A -

<:rushing-type injury in an infant. This computed tomographic (CT) scan (A) and 3-D reconstruction (B) show a cranial "burst" injury. Despite intracranial hemorrhage and dural laceration, the structure of the brain is preserved and decompressed. The child required dural and cranial reconstruction but recovered with minimal deficits. e

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to be minor. The additional finding of new or healing skeletal fractures or other solid organ injuries is pathognomonic for this injury. Comprehensive multidisciplinary evaluation by physicians with expertise in child abuse is indicated for all infants who are suspected to have been abused.

Initial Assessment of Brain-Injured Children The purpose of the initial assessment of a brain-injured patient is twofold. First and most important, one establishes a working diagnosis of the type and severity of the injury in order to direct the selection of initial therapies, as well as the planning and coordination of other diagnostic studies and the management of any associated systemic injuries. Second, one establishes a baseline to measure the effects, both positive and deleterious, of the therapies or interventions. Historically, the main focus of the initial assessment of brain-injured patients was determining the severity of the injury by assessing the level of consciousness. The most widely used evaluation instrument for this purpose is the Glasgow Coma Scale.'" This score, as it was designed, correlates well with 0utcome.2~However, with the improvements in transport and field resuscitation of severely injured patients, which usually requires the prehospital administration of analgesics and sedation, neurologic assessment to determine the type and severity of brain injury becomes less useful.'" Furthermore, there is a small, but important group of brain-injured patients who have little or no impairment in consciousness but subsequently deteriorate because of mass lesions or brain welling.86,."5,114

Recently, it has become clear that certain findings on CT also correlate well with outcome after brain injury. This radiographic assessment can be obtained rapidly and is not affected by any ongoing therapies. Regardless of the apparent level of consciousness, the early radiographic identification of injury types and the institution of appropriate management or monitoring have substantially improved the overall outcome after traumatic brain injury. Furthermore, it is now clear that a head-injured patient with a completely normal CT scan has an exceedingly low risk for either deterioration or poor outcome. In the author's experience, the CT scan has become the most important element of the early diagnosis of brain injury, especially in young children. The important CT scan findings involve not only the detection of potentially surgically accessible mass lesions but also the search for and detection of the constellation of findings typically seen with diffuse brain injury: subarachnoid, intraventricular, or intraparenchymal hemorrhage and what may be very subtle early signs of brain swelling, including compression of the perimesencephalic cisterns or shift or compression of the ventricular system. Early identification of the presence of diffuse brain injury on the CT scan is more important than the clinical impression of injury severity. These findings should influence the expectations for outcome and the decisions for monitoring and therapy. The severity of diffuse brain injury can be graded by the appearance of the admitting CT scan. As shown in Figure 21-5, these specific findings correlate well with outcome," and therefore one can make immediate management decisions. Most current practice parameters regarding the evaluation of head-injured patients include recommendations

Poor outcome for diffuse injury by type

BTCDB RCH

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Injury type on CT scan

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Effect of the appearance of the admission computed tomographic scan on outcome after injury. The data for this graph were generated from information reported from the Traumatic Coma Data Bank (TCDB)'17 and from unpublished data on 1000 consecutive pediatric patients admitted for brain injury to the James Whitcomb Riley Hospital for Children, Indianapolis, IN (RCH). Poor outcome is defined as severely disabled, vegetative survival, or death according to the Glasgow Outcome Scale.139 Definitions: Difftlse injury I: No visible intracranial pathology seen on computed tomography. Diffuse injury 11: Cisterns are present with a midline shift of 0 to 5 mm or the presence of lesion densities (or both); no high- or mixed-density lesions larger than 25 cc. Diffuse injury 111: Cisterns compressed or absent with a midline shift of 0 to 5 mm; no high- or mixed-density lesion larger than 25 cc. Diffuse injury IV: Midline shift greater than 5 mm; no high- or mixed-density lesion larger than 25 cc.

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for an early diagnostic CT s ~ a n . ~ , Essentially, " ~ ~ ~ 2 ~all~ ~ ~necessary element of the initial evaluation of a headpotentially severely injured patients, that is, those with an injured patient. alteration in consciousness, should undergo CT scanning as soon as they are physiologically stable and can be safely transported and maintained in the scanner. For Early Management of Severe Brain Injury head-injured children with apparently minor trauma, current recommendations allow for clinical assessment As stated previously, the primary objective of resuscitation of a brain-injured patient is to preserve cerebral perfusion and a period of observation without undertaking any during transport and evaluation. The ongoing objective neuroimaging, so long there is a clear history of a lowof therapy for severe brain injury is to optimize the perfuenergy mechanism and, at most, only a brief loss of sion of injured and uninjured brain and create a milieu consciousness. One should add that these children should that minimizes the chance for additional secondary also be completely asymptomatic and neurologically injury and maximizes the amount of neuronal recovery. normal and have no complicating medical disorders. One must do this while avoiding or reversing deleterious On the other hand, any child with a history of more than processes that would result in further neuronal injury a few seconds of unconsciousness, a seizure, or clinical or the expansion of hemorrhagic masses, including signs of cranial impact, skull fracture, cranial penetration, systemic complications that directly affect an injured or CSF leak or any child with headache, persistent vomiting, brain such as sepsis, acute lung injury, hyperglycemia, lethargy, or irritability should undergo CT scanning as ~ ~ , ~ ~children ~ who have been and coagulopathy. soon as p o ~ s i b l e . Finally, injured via high-energy mechanisms that result in apparA variety of treatment strategies have been propounded ently isolated chest, abdominal, or skeletal injuries should for the treatment of traumatic brain injury. Most of these undergo a CT scan of the brain before the administration therapies involve systemic manipulations to achieve what is of an anesthetic or the institution of narcotic analgesia believed to be either a therapeutic or a protective or sedation that would preclude accurate ongoing response. All the "newer" therapies have theoretical attracneurologic examination. tions, and their proponents report outcomes that appear It should be clear from the previous discussion that to be better than those of historical controls. However, at plain skull radiography has only a limited and secondary least so far, when these therapies have been tested directly role in the initial evaluation of head injury. CT scanning against what could be termed "standard therapies," no benwill detect most clinically important skull fractures. efits have been demonstrated. Consequently, the treatment Conversely, skull radiographs provide only limited inforrecommendations currently in place are essentially mation about the type and location of any brain injury. descriptions of how to apply the historically "standard" MRI is more sensitive than CT scanning for detecting therapies of controlled ventilation, fluid management, most brain pathology and has supplanted CT as the study sedation, and control of blood pressure and ICP. of choice for many neurologic disorders. However, for To do this one must understand as much as possible acute traumatic brain injury, all necessary information for about the patient's intracranial dynamics and optimize making management decisions is still provided by CT cerebral perfusion by removing surgically accessible scanning. In most circumstances, CT scanning is still more masses and managing ICP by safely manipulating, as quickly and easily obtained and is less costly than MRI. much as possible, cerebral blood volume (arterial and Finally, while acknowledging the expanding primary venous), CSF volume, and brain For severely injured and some less severely injured patients, institution role of neuroimaging in the diagnosis and management of traumatic brain injury, a careful physical and neurologc and manipulation of therapies are guided by the placeexamination is still extremely important. The entire head ment of an ICP monitor. ICP monitoring provides the basis for making many of the important management should be inspected for indications of impact, scalp injury, cranial deformities, and cranial or orbital penetration. decisions for brain-injured patients.lo7J20 The application of individual medical therapies is Documentation of cranial nerve function, especially pupilbeyond the scope of this chapter. However, it is important lary size, shape, and reactivity, is necessary and will serve to realize that each of the current therapies for elevated as comparison for serial examinations. Evidence of ICP has both general and specific effects and that each anterior basilar skull fractures, manifested by periorbital has complications associated with its use. The historically ecchymoses, nasal hemorrhage, or CSF rhinorrhea, is a common administration of high-dose steroids to braincontraindication to the placement of nasogastric tubes injured patients is no longer considered to be beneficial until the integrity of the anterior cranial skull base can and may, in fact, be harmful. Accordingly, the current be determined. Retroauricular bruising, hemotympanum, guidelines do not recommend that any specific therapy, otorrhagia, and CSF otorrhea are indicative of temporal for instance, hyperventilation, osmotic diuretics, or other bone fractures that may not be immediately evident on medications, be administered "prophylactically" or unistandard screening CT and may result in the delayed versally for brain-injured patients. It is also suggested that appearance of cranial neuropathy. In the event of possible specific therapies be applied in a logical sequence and inflicted injury, dilated funduscopic examination by an ~ of guided by ICP monitoring and frequent reassessment of ophthalmologist is r e c ~ m r n e n d e d .Documentation the level of consciousness and any apparent motor or response to therapy. The basic level of therapy for severe traumatic brain sensory deficits, along with notation of the presence of confounders to the examination such as intubation, injury includes controlled ventilation with maintenance medications, swelling, splints, and other factors, is still a of normal oxygenation and P a m P concentrations.

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Intubated patients should have adequate sedation and analgesia at all times. Intravascular volume should be supported at all times with blood and fluids to maintain normal hematocrit and electrolyte concentrations. Fluid restriction is not recommended. Hypotonic fluids should be avoided to prevent any trend toward hyponatremia. The head of the bed may be elevated to reduce intracranial venous pressure, as long as normal central venous pressure is maintained by adequate volume replacement. For many severe diffuse brain injuries, this level of therapy may be all that is necessary. Escalated therapies include the use of CSF drainage, usually by way of a ventricular catheter, osmotic diuresis with mannitol, and mild hyperventilation. Whenever escalation of therapy is considered, one must also escalate the physiologic monitoring for treatment effect and complications. Table 21-1 summarizes the author's approach to escalating medical therapy for brain injury, based on current treatment guidelines. A small percentage of patients require even more intensive therapy for

Treatment Evaluation and Resuscitation Restoration of normal blood pressure lntubation and ventilation Basic-Level Therapy Elevation of head of bed Keep head in neutral position Sedation and muscular paralysis Mechanical ventilation to maintain Paco, at 3540 mm Hg Maintain normal to slightly increased intravascuiar volume Normal fluid and electrolyte status (no fluid restriction); avoid anemia, hyperglycemia Body temperature normal to slightly hypothermic Escalated Therapy Ventricular cerebrospinal fluid drainage Mannitol Moderate hyperventilation to maintain Paco, at 3@35 mm Hg

Monitoring Systemic blood pressure and oxygenation Neurologic examination End-tidal CO,

elevated ICP, including high-dose barbiturates, intensive osmotic therapy, or intensive hyperventilation. These therapies have a higher complication rate and should therefore be used only when absolutely necessary and by physicians with experience in neurologic critical care. Surgical decision making for severely injured patients is usually straightforward. Clearly, cranial penetrating injuries, including compound skull fractures, require urgent surgical attention. The removal of large, surgically accessible mass lesions may be the first step in the overall therapeutic management of a severe brain injury. Other than that, the initial surgical procedures may be limited to the placement of an ICP monitor, a ventricular catheter, or both. These procedures can be performed at the bedside if necessary. In many cases, such as closed depressed fractures, burst fractures, or comminuted cranial and craniofacial fractures, surgical correction can be performed when the patient is stable or improving from the neurologic injury. Typically, the major surgical therapy for brain injury involves the removal of traumatic intracranial hematomas. The overall incidence of surgically accessible hematomas in children is substantially lower than that in adults, and the distribution of hematoma types is different. Subdural hematomas are most common in infants, but are rarely of a size that requires surgical removal. As discussed at the outset of this chapter, acute subdural hematomas in older children are generally more indicative of a severe diffuse injury (Fig. 21-6). Extradural hematomas are the

Systemic blood pressure and oxygenation lntracranial pressure Arterial Po, Pco2, and pH Weight, urine output, pulse, and pulse pressure Hemogram, serum electrolytes, glucose, and blood urea nitrogen Monitor and aggressively treat for fever and sepsis Computed tomography

Ventricular catheter Central venous pressure Serum osmolality and electrolytes

Intensive Therapy for Refractory lntracranial Pressure High-dose barbiturate therapy Continuous or compressed spectral electroencephalography Lumbar cerebrospinal fluid Barbiturate levels drainage if indicated Profound hyperventilation Jugular venous oxygen saturation, monitors of cerebral blood flow

I . Acute subdural hematoma. The hemorrhage overlying the hemisphere (left side of the image) seems small. Note, however, the extensive shift of the brain and the hemispheric swelling, which are indicative of severe diffuse injury.

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are destined to recover completely, usually without any intervention whatsoever. However, within this large group there exists a small fraction of patients who are harboring an enlarging hematoma or who are in the early stages of brain swelling. These patients are at increased risk for delayed but rapid deterioration that will result in death or disability. The focus of the evaluation of an apparently minor brain injury is to identify patients who are at risk for neurologic deterioration or delayed complications and to prevent either from 0 ~ c u r r i n g . l ~ ~ In many ways, diagnosis and management of these patients are more challenging and important than managing severe injuries because successful intervention results almost universally in good outcome^.^"^^^ Recommendations about this issue have been p ~ b l i s h e d .As ~ ,with ~ ~ ~other types of brain injury, early CT scanning is the lynchpin to accurate diagnosis and recognition of brain-injured patients at risk for deterioration.42-82,1°6,128 Identification of cisternal compresAcute extradural hematoma. Note the thickness of the sion, hemorrhagic shear and contusion, or small trauhemorrhagic mass, but also note the lack of shift in comparison to what matic hematomas indicates that the patient is at risk for is demonstrated with a subdural hematoma in Figure 216. This lack of deterioration regardless of the level of consciousness. swelling and shift is an indication of an uninjured brain responding These patients are candidates for frequent reassessment, normally to the expanding mass. As long as this mass is removed before including repeat neuroimaging, ICP monitoring, and even the onset of coma, mortality and morbidity are essentially nil. the early application of therapies to control intracranial dynami~s.~lOJ~~ Attention to intravenous fluid management appears to be of major importance because many of the children with apparently trivial brain injuries seem more common surgically accessible masses in children, to deteriorate in the face of even mild hyp0natremia.8~J59 especially older children who have suffered a cranial Therefore, maintenance fluids for these patients, as for impact (Fig. 21-7). Small epidural hematomas over the most patients with brain injury, should be normal saline cerebral convexity are likely to resolve without surgical or its equivalent.lR1There should also be close attention removal. Those that occur in more limited "spaces," such to maintaining normal intravascular volume and serum as the temporal fossa or the posterior fossa, are more electrolyte status. concerning, and even small epidural hematomas in these Although the identification of patients at risk for deterilocations may need to be removed. Large hemorrhagic oration includes the appearance of certain abnormalities contusions or traumatic intracerebral hematomas are on CT scanning, an even more important finding from very rare in the pediatric age group."' the burgeoning literature about CT scanning and head Given this, the decision for removal of a traumatic injury is emerging. Specifically, the finding of a comintracranial hematoma should be part of an overall treatpletely normal CT scan in a mildly injured patient is ment strategy for the brain injury. Clearly, removal of a associated with essentially no risk for life-threatening large extradural hematoma may be the only therapy d e t e r i ~ r a t i o n . " J ~Given ~ that additional information needed. On the other hand, in the setting of diffuse from a normal CT scan, a child with a history of an brain injury, removal of what would otherwise be considaccidental minor head injury who does not have a skull ered a nonsurgical intracranial mass can result in substanfracture, does not have a history of seizures, and is tial improvement in the intracranial volume/pressure asymptomatic may be released to competent caretakers relationships that are essential to maintaining adequate and not be admitted for observation. cerebral perfusion. Expanding on this concept is the recent For adolescents who suffer cerebral concussion as rediscovery of "therapeutic decompressive craniectomy." a result of sporting activities, there are now published There is a growing, yet completely anecdotal literature guidelines describing the evaluation and management about the role of cranial decompressive surgery in the overall management of severe traumatic brain injury.2~~" of such individuals, along with recommendations about when athletes may return to sporting activities after a The procedure clearly increases available "volume" and COnCUSSion~4,2~,~2,~~5 lowers ICP. However, it is not clear whether decompressive craniectomy provides an additional or unique benefit over standard medical therapy. It is also not clear when in the course of injury management that this surgical Early Complications of Head Injury option should be undertaken. Acute complications of head injury include those related to skull fractures, infectious processes associated with craManagement of "Minor" Brain Injuries nial penetration and CSF fistulas, and acute neurologic complications such as post-traumatic epilepsy. As with The vast rnajority of children with head injury have trivial, most aspects of head injury management, recognition of minor, or minimal primary brain injuries. These children 0

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patients with injuries that put them at risk for these complications, followed by appropriate diagnostic studies, monitoring, and when possible, intervention, is key to optimizing outcome.

Complications of SkuN Fractures Simple nondepressed or minimally depressed skull fractures will heal spontaneously. Widely diastatic or cranial burst fractures45 in young children are indications of dural injury and are not likely to heal without surgical reconst~uction.With modern neuroimaging, early tification of these injuries allows early elective repair, thereby avoiding the complication usually referred to in the literature as a "
sen-

Basilar SkuN Fractures The major issue of acute clinical importance for patients with presumed basilar fractures is that these fractures are potentially compound and therefore place the patient at increased risk for infection. The obvious indication of CSF leaking from the nose or ear is present in only 10% to 20% of cases.31.89 Therefore, other signs of basilar fracture must be searched for because these fractures are easily missed on routine neuroimaging studies. Such signs include bilateral orbital ecchymoses or swelling, signs of midface or orbital fracture, hemotympanum, otorrhagia, and Battle's sign. These patients are at increased risk for the development of meningitis for several weeks after the injury. Given this and in view of the fact that compounding of basilar fractures probably occurs more often than not without any evidence of CSF fistulas, it is necessary that parents and caretakers of children who are thought to have sustained a basilar fracture be counseled not only about the importance of recognizing CSF rhinorrhea or otorrhea if it should occur at home but also about the urgent importance of seeking immediate medical attention for children who have signs or symptoms even remotely suggestive of bacterial meningitis up to several weeks after the injury. Despite the increased risk for bacterial meningitis, the administration of prophylactic antibiotics has not been shown to centers are administering be benefi~ial.~"94J~Wome pneumococcal vaccine to patients with presumed basilar skull fractures, although it is not yet clear that such vaccination reduces the occurrence of pneumococcal meningitis. Basilar skull fractures are also associated with cranial neuropathies. The olfactory nerve is the most commonly injured of all cranial nerves and is especially at risk in patients with anterior basilar fractures. Fractures that

occur more posteriorly along the skull base or that include the orbit and midface place the optic nerves at risk. Visual loss may be acute or delayed, and ophthalmologic evaluation and follow-up are warranted. Basilar fractures involving the petrous bone can result in auditory, vestibular, or facial nerve injury, or any combination of these injuries. These patients may need otologic evaluation and audiometric studies.108

Direct Cerebrovascular Injuries Although traumatic intracranial aneurysms are exceedingly rare after closed head injury, more than 20% of all post-traumatic aneurysms occur in the pediatric age gro~p.2 Penetrating ~ injuries, especially stab wounds and deep penetrations, have a high incidence of vascular injury associated with them. Suspicion is raised when a large amount of subarachnoid hemorrhage or a focal intracerebral hemorrhage is seen on the CT scan. CTA or MRA (or both) can screen for injury, but in some cases diagnostic angiography should be performed. If the studies are not conclusive, early repeat imaging is warranted.

Post-traumatic Seizures One of the most common complications of brain injury, even mild brain injury, is epilepsy. Most studies indicate that the incidence of post-traumatic seizures is subRisk ~~ stantially higher in children than in a d u l t s . 9 1 ~ factors associated with post-traumatic epilepsy include younger age and increasing injury severity.",73 However, it is not clear that infants with inflicted injuries, who would have a very high incidence of early epilepsy, were excluded from these studies."JYIf one removes this particular group from the analysis, the incidence of post-traumatic epilepsy in children appears to be relatively low. A distinction must be made between early and late posttraumatic seizures. Early seizures are generally defined as those that occur within the first week after iniurv. For pediatric patients, this definition would include the so-called impact-related seizure that occurs in up to 10% , ~ ~ Jseizures O~ are of mildly head-injured ~ h i l d r e n . ~ ~These usually self-limited and the CT scan is normal. Treatment is not recommended, and the long-term outcome is This particular syndrome is almost never seen in head-injured adults, in whom early epilepsy is strongly associated with structural brain injury or subdural hematoma. For severely head-injured children, that is, children in coma or with structural injury on the admitting CT scan, there is limited and conflicting information regarding the clinical significance and management of early and late post-traumatic Current recommendations indicate that all patients with severe injury who experience recurrent seizures should be treated with anticonvulsant medication. Phenytoin is the most widely recommended drug for this purpo~e.~,~"hereis some evidence that prophylactic administration of phenytoin to severely head-injured patients reduces the incidence of early post-traumatic seizures, although it is not clear J

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that outcomes after the injury are improved by this therapy.V1 On the other hand, there is strong evidence that routine administration of anticonvulsants to severely head-injured patients neither reduces the incidence of late epilepsy nor improves the outcome of the injury. Therefore, administration of anticonvulsants as seizure prophylaxis beyond the first week after the injury is not recomrnended."."~'~

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highest mortality and morbidity of childhood head injuries. The reported mortality approaches 40%.4"49 Morbidity is also high, especially if the infant shows evidence of cerebral infarction or hypoxic-ischemic injury.

Outcomes affer Mild Brain Injuries

A syndrome of neurologic dysfunction that seems to be unique to young children has been called the "pediatric concussion syndrome." Shortly after what would seem like a mild cranial impact injury the child exhibits the acute onset of pallor, diaphoresis, and impaired responsiveness. CT scans are normal and the syndrome appears to resolve as rapidly as it occurs. The underlying mechanism is unknown, although it has been suggested that it may be a variation of post-traumatic epilepsy.'j2 Other much more rarely occurring transient neurologic disturbances have been reported after mild head injury in children, including transient cortical blindness, speech arrest, ataxia, receptive dysphasia, and CT scans are, again, normal, prolonged di~orientation.~lJ~8 and the symptoms resolve spontaneously. The etiology is not clear.

Mild brain injury, that is, a brain injury with a limited effect on consciousness and with preservation of brain structure, is by far the most common CNS injury in the pediatric age group. Over three quarters of all childhood head injuries are classified as mild.lo0J Only recently has attention turned to the long-term outcomes after cerebral concussion in children.'" Although there is still variability in defining mild head injury and the spectrum of severity 0 J "general ~ ' ~ concepts appear within that t a ~ o n o m y , ~ ~ "~ to be emerging in the available literature. First, somatic complaints such as headache, visual disturbances, light and noise intolerance, and dizziness and emotional disturbances such as depression, anxiety or irritability, and cognitive impairment, including poor school performance, are common in mildly brain-injured children in the days and weeks immediately after the injury.57 Second, so long as the child did not suffer any cognitive or behavioral disturbances before the brain injury, all of the early postconcussion symptomsjust described appear to resolve completely in no more than a few months.169

Outcomes after Traumatic Brain Injury

SPINAL CORD INJURY

There is substantial variability in the reporting of outcomes after childhood head injury. With the exception of infants suffering inflicted head injuries, the overall mortality from head injury in children is roughly half that reported for head injury of similar severity in adults.21 In larger series of patients, mortality for head injury in children is generally less than 5% for all levels of injury severity and lower than 20% in children defined as having "severe" injuries based on either the Glasgow Coma Scale or other injury severity scoring systems.l02,fllJ70 Factors related to poor outcomes include high-energy mechanisms, structural injury, swelling and shift on admitting CT scans, persistent or resistant elevations in ICP, the presence of chest or abdominal injuries, and systemic complications. Traumatic brain injury is the leading cause of acquired disability in childhood.9Vor children who survive traumatic brain injury, neurologic and cognitive outcomes are related to the child's age, the severity of injury, and the amount of permanent structural injury to Children who have suffered severe the brain.8~14~m~10'~l19 brain injury are likely to have persistent adverse effects on intellectual function, memory, attention, language, and behavior.'03 It is likely that these deficits have ongoing and perhaps compounding effects on learning and socialization. Consequently, it is possible that the overall neurobehavioral outcomes for significant childhood head injury are worse for children than for similarly injured adults. Outcomes after inflicted brain injuries deserve separate discussion. This particular injury is associated with the

Spinal cord injuries in children are rare, but the consequences of such injuries can be devastating. As with traumatic brain injury, modern neuroimaging has contributed considerably to the diagnosis and management of traumatic myelopathy. As discussed at the beginning of this chapter, the major therapeutic efforts for spinal cord injury are the same as for brain injury and are aimed at preventing new primary injury and ameliorating the secondary injury. The first objective is accomplished by maintaining anatomic alignment of the vertebral column during the period of resuscitation and evaluation. , ~ begins The second objective is much more d i f f i c ~ l tbut with supporting blood pressure and oxygenation. In general, the diagnostic and therapeutic algorithms for children with spinal and spinal cord injury are similar to those used to manage adult patients. Guidelines for the management of spinal cord injury have been published recently and summarize current kn~wledge.~' However, there are important differences in clinical manifestations, anatomy, radiographic findings, and management of spinal injuries in children, especially very young children. This section concentrates on these issues.

Postconcussion Syndromes

Epidemiology Less than 10% of spinal cord injuries or approximately 1000 new spinal cord injuries occur each year in ~ h i l d r e n ? ~ Vertebral column injuries that do not involve the spinal cord are much more common. In a series of 122 children,

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only half the children with vertebral injuries had neurologic deficits.7' The mechanisms and pattern of injury are related to both age and gender. In very young children, the male-tofemale ratio is roughly equal. In older children, the more "adult" distribution appears, with a male-to-female ratio of about 4:l. Approximately half of pediatric spinal injuries are the result of motor vehicle accidents. A quarter of injuries are the result of diving accidents. Clearly, prevention efforts directed at these two mechanisms alone would dramatically reduce the rate of spinal injury in children. The remaining major mechanisms of injury are falls and sporting activities, each of which accounts for about 10% of reported injuries. Younger children are more likely to be injured as the result of a fall, whereas older children are more likely to be injured in diving accidents or ~ports.~Jss Younger children tend to have spinal column injuries in the cervical region, whereas older children tend to have a distribution of spinal injuries similar to adu1ts.ls1 Children are more like$ to experience spinal cord injury without apparent vertebral fractures or dislocations. These characteristics are generally thought to be related to the anatomic properties of the juvenile spine and are independent of the mechanism of injury. The pediatric spine has several properties that essentially allow significant, self-reducing displacement of the vertebral column. These properties include increased elasticity of the joint capsules and ligaments, shallow and horizontally oriented facet joints, anterior wedging of the vertebral bodies, and poorly developed uncinate processes."," Furthermore, young children have disproportionately larger heads and weaker cervical musculature. All of these elements permit a wider range of flexion and extension and rostrocaudal distraction. The fulcrum of motion is higher in the juvenile spine, which explains the greater incidence of rostral injuries in children. This tendency decreases and the incidence of more characteristic vertebral fracture and dislocation increases with increasing age.I0 Finally, it is important to remember that 10% to 15% of spinal injuries in children involve "skip" injuries with vertebral or cord injuries at multiple level^.^^^^ Therefore, depending on t h e mechanism bf injury, when a child is determined to have spinal cord injury or vertebral disruption, the entire spinal axis should be surveyed for othe; injuries. ~njuriesto the thoracic and lumbar spine are uncommon in children. Less than 20% of all spinal injuries in children occur below the cervical spine.143Major mechanisms involve falls from heights and high-energy motor vehicle accidents, including the characteristic spinal distraction injury resulting from automobile lap belts.71

The Clinical Spectrum of Spine and Spinal Cord Injury Because spinal cord injury is rare in children, it may be overlooked, especially in the very young and those with multiple injuries. As discussed in the next section, the presence of apparently normal plain radiographic studies will not completely rule out either vertebral

instability or spinal cord injury. Therefore, one must have an increased index of suspicion based on injury mechanism and the neurologic findings. High-energy mechanisms such as motor vehicle accidents and falls from heights are more likely to cause spinal or spinal cord injury. An unconscious patient of any age should be assumed to have a spinal cord injury until a complete assessment is possible. The clinical indicator of spinal injury in awake patients is pain and muscular spasm or guarding against movement. Any child complaining of neck or back pain or stiffness after an injury needs a complete assessment of the integrity and stability of the spine. Children can suffer torticollis as the result of atlantoaxial rotatory subluxation. Rotatory subluxation can occur as the result of apparently minor injury or even a coughing spell. Such children are usually neurologically normal. Plain radiographs can be deceiving, but CT scan of the spine in the axial plane is diagnostic.162 The cardinal sign of a spinal cord injury is neurologic dysfunction below an anatomic spinal motor or sensory level. Complete or severe incomplete cord injuries with motor dysfunction are readily detectable in conscious patients. A spinal cord injury is generally manifested as symmetrical flaccid paralysis with sensory loss at the same anatomic level. There are strong indirect indicators of spinal cord injury in a comatose patient or those with multiple injuries. Cervical spinal cord injuries can cause profound systemic hypotension, a syndrome known as "neurogenic shock" and caused by disruption of sympathetic pathways below the level of injury. Unlike the more common hypovolemic shock, neurogenic shock is suggested by the finding of bradycardia in the face of hypotension. These patients are also vasodilated despite being hypothermic. Hypovolemic shock results in hypotension, tachycardia, and vasoconstriction. Other systemic findings suggesting spinal cord injury include paradoxical respiration, priapism, Horner's syndrome, and an inability to sweat. Less severe injuries may result in transient neurologic dysfunction, dysesthesias, focal weakness, sensory loss, or dissociation of motor and sensory function such as in Brown-Sequard or other central cord syndromes. Any history of transient neurologic dysfunction involving the limbs or bladder, regardless of duration and apparent complete recovery, must be taken as strong evidence of spinal cord injury.

Spinal Cord Injury without Radiographic Abnormality Spinal cord injury without radiographic abnormality (SCIWORA) was defined by Pang and Wilberger in 1982 to describe patients who exhibit objective findings of traumatic myelopathy with no evidence of fracture or ligamentous instability on routine screening plain radiography or CT scanning.137 SCIWORA is essentially an injury of children, especially younger children, and is probably directly related to the biomechanical properties of the juvenile spine outlined earlier. As with vertebral injury, there is a tendency toward more rostral injury with younger age. Younger children suffering SCIWORA are

CHAPTER

more likely to have severe or complete cord injuries than older children are. Severe s ~ i n a lcord iniurv in older children is more typically associated with a vertebral injury than with SCIWORA.72,132,136 Diagnosis of this syndrome is complicated by the frequent %ccurrence of delayed neurologic deficits. Many children with this injury will demonstrate neurologic deficits hours to days after the reported injury and in the absence of any further injury.136The mechanism of this delayed deterioration is unknown, but Pang has speculated that there is repeated injury to an already mildly injured spinal cord, either because of the innate normal flexibility of the spine or because of subtle ligamentous injury with increased segmental movement at the injury site.13" This argument is supported by the observation that recurrent SCIWORA may occur in about 20% of children who are not immobilized and that immobilization of the cervical spine markedly reduces the incidence of this phenomenon.142 ina ally, this syndrome was initially described before the widespread use of MRI for the diagnosis of spinal disease. Although it is still true that these children do not have evidence of bony injury or overt instability on plain spine radiographs or CT scans, most (but not all) patients will have evidence of spinal cord or ligamentous or other soft tissue injury on MRI.s4,4"6Vherefore,it is essential that all physiciaks who provide early evaluations of injured children be aware of this disorder and continue to consider the possibility of spinal or spinal cord injury, even when the initial radiographic studies may be reported as normal. J

i

Initial Assessment of Spine or Spinal Cord Injury Detection of spinal injury in a child can be challenging. As with brain injury, the initial clinical findings will guide the decision for selecting diagnostic imaging. Unlike brain injury, plain spine radiography is still an important initial tool for assessment of a spinally injured patient. Any child who has neck pain, muscular guarding of spinal movement, or a neurologic deficit or who has multiple injuries from a high-energy mechanism, especially one that includes "distraction" of the spine, such as would occur with a seat-belted passenger in a motor vehicle collision, has a spinal injury until proved otherwise. Older children who are normally conscious can express appropriate clinical symptoms and signs that indicate spinal or neural injury. Current recommendations indicate that an older child who is awake and conversant and who has no neurologic deficit, or a history of one, or any pain or tenderness along the posterior spinal midline needs no further radiographic assessment or other diagnostic studies.8i Such is not the case for younger children, who are at higher risk for occult spinal and spinal cord injury simply because they are unable to express complaints of pain.g8 Therefore, a lower threshold for radiographic screening must apply to younger children. There are now fairly well proven "decision rules" for performing screening radiographic studies, specifically, anteroposterior, lateral, and open-mouth odontoid views in adult patient^.^^.^^ These studies indicate that there is extremely low probability of injury and low yield on

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radiographic studies if patients exhibit the following five criteria: no midline cervical tenderness, no focal neurologic deficit, normal alertness, no intoxication, and no painful distracting injury. The application of these decision rules to pediatric patients suggested similar findings, although the number of very young children in the study cohort was limited.Ii3 Accordingly, the caveats about young children also apply to this recommendation. Radiographic surveys of the spine in pediatric patients are complicated by the normal anatomic variations in the juvenile spine that are described in the preceding section. Growth centers and synchondroses can be mistaken for traumatic injuries. The increased normal flexibility of the spine coimonly appears as "pseudosubluxation."24J58 Most pseudosubluxation occurs between the second and third vertebral bodies, with allowable displacement of up to 4 mm in children younger than 8 years. This movement, along with the normal anterior movement between the atlas and the dens,'" can be mistaken for ligamentous injury. Therefore, spinal radiographic studies obtained in children must be interpreted with caution and with complete familiarity with developmental anatomy of the spine. Flexion-extension radiographs can be used to rule out ligamentous injury of the-cervical spine in awake and cooperative patients. However, most studies investigating the utility of dynamic radiographs have indicated that instability is not likely to be detected on these studies if routine static studies show normal alignment in the neutral p ~ s i t i o n . ~ ' J ~ ~ CT scanning of the spine is extremely helpful for detecting subtle fracture, soft tissue swelling, and rotatory subluxation, as well as for defining congenital abnormalities and developmentally normal variations that may mimic fractures on plain radiographs. Furthermore, CT is a rapid and accurate way to detect compromise of the spinal canal or nerve root foramina after traumatic injury. However, many spinal injuries are ligamentous and may be missed if CT scanning is the only study performed. Therefore, CT should be viewed as an adjunctive study to plain radiography, not a substitute. MRI is now the best study to image the injured spinal cord and to detect subtle ligamentous and other soft " tissue injuries. As discussed earlier, many, but not all patients with SCIWORA will show abnormalities on MRI that confirm the clinical diagnosis. Findings on MRI correlate with outcome afterspinal cord i;juv.s5-6gJ55 However, it is not clear that the management decisions required for spinal cord injury in children have been altered by any findings on MRL8'

Early Management of Spinal Cord Injury As with traumatic brain injury, aggressive support of systemic perfusion and oxygenation is of paramount importance. Because children will tend to have more rostra1 cervical cord injuries, impaired respiratory function is likely to be a concern. Furthermore, gastric dilatation commonly accompanies acute spinal injuries, and this can add a substantial mechanical barrier to effective respiration. Therefore, early nasogastric decompression of the stomach should be considered. For midlevel and

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higher cervical injuries, elective intubation may be needed to support respiration until a comprehensive assessment of the injury is completed. Endotracheal intubation of a spinally injured child is technically challenging and should be performed by an expert without manipulating the relative position of the head and neck. Restoration and support of systemic blood pressure will result in maintenance of perfusion of the injured spinal cord. Patients with severe cord injuries, especially in the cervical portion, are at most risk for systemic hypotension. Although the initial resuscitation can be undertaken with intravascular volume loading, neurogenic hypotension should be treated with vasopressors. Resuscitation and maintenance of normal blood pressure in a patient with a spinal cord injury are complicated and may be aided by invasive monitoring of central venous pressure. The pharmacotherapy of spinal cord injury has been the subject of active research and scientific controversy. After completion and reporting of the second National Spinal Cord Injury Study (NASCISII),lVt was recommended that all patients with acute spinal cord injuries be administered high-dose methylprednisolone. The recommendations did not officially extend to pediatric patients, but most centers applied these treatment recommendations to all age groups. Despite a subsequent studylQhat appeared to confirm the initial findings, the methodology and conclusions of these studies have been At this time, the administration seriously que~tioned."~,87 of highdose steroids to spinally injured patients, including children, is listed as a treatment option that should be undertaken only with the knowledge that evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit.87 Early surgical therapy is rarely needed. Most pediatric fractures and dislocations can be reduced and maintained in anatomic alignment with a variety of orthotic devices, including a halo brace. Early surgical reduction and fusion are considered only for cases in which clear neurologic deterioration is occurring in the face of irreducible subluxation or compression from bone fragments, extruded disk material, or an enlarging hematoma. These issues are unusual in young children. Adolescents suffer injury types similar to adults and can be treated according to the surgical recommendations available for adult patients." There is limited scientific information about the advisability and outcomes of operative management of spinal injury in young children, although recent reports indicate that surgical instrumentation is becoming more common.s4-aAnatomic reduction of deformity, stabilization of clearly unstable injuries, and decompression of neural elements are indications cited for surgical treatment of spinal injury in children. Most of these goals can be accomplished nonoperatively. Current recommendations indicate that most vertebral injuries in young children should initially be treated nonoperatively, with surgical management reserved for persistent or progressive deformity or ligamentous in~tability.~~

Complications Children are subject to all the complications associated with spinal injury, including skin breakdown, infections,

deep venous thrombosis, autonomic dysreflexia, contraccures, spasticity, neurogenic bladder and bowel, and progressive spinal deformity.180 However, the single major acute complication of spinal cord injury in children is respiratory compromise. The most common cause of death in the acute phase of injury is respiratory failure.40 Aggressive pulmonary care is essential, and ventilatory support may be necessary until the accessory muscles of respiration can strengthen. Many of the other complications can be avoided or minimized by the early intervention of physiatrists and other rehabilitation specialists. The incidence of venous thromboembolism in spinally injured children has been reported, probably incorrectly, to be roughly similar to that in adults.lX0 However, series involving only pediatric patients indicate that this complication is extremely rare.144 Therefore, specific recommendations for prophylaxis of this possible complication vary widely. For adults and, presumably, older children and adolescents, thromboprophylaxis consisting of low-molecular-weight or low-dose heparin in combination with rotating beds, pneumatic compression stockings, or electrical stimulation is recommended for up to 12 weeks after the inj~ry.~7-'~0

Outcomes

The mortality associated with spinal cord injury in children has been reported to be 28%, which is significantly higher than the mortality rate for this injury reported in ad~1t.s.~"~" The majority of these deaths appeared to occur at the scene and would not be affected by current management strategies. For survivors of spinal injury, outcomes are related to the level and severity of injury. Complete injuries remain complete, and although limited functional improvement may be seen over time, full recovChildren with incomplete ery is not expe~ted.~2,7~,l"J~6 spinal cord injuries have a good chance of showing significant functional improvement, even to complete recovery.72.74 The cost of long-term care for these injuries is staggering. The lifetime cost of care for a child with a spinal cord injury ranges in the millions of d o l l a r s . ~ ~ J ~ ~ J ~ ~ This cost must be added to the loss of productivity that accompanies these devastating injuries. The adult employment rate for individuals suffering childhood spinal cord injury is about 50%.180Factors associated with successful employment were younger age at injury, less severe neurologic impairment, better education, longer duration of living with the sequelae of the injury, and ability to drive independently.

REFERENCES 1. Adams JH: Brain damage in fatal non-missile head injury in man. In Braakman R (ed): The Handbook of Clinical Neurology, vol 13, Head Injury. New York, Elsevier, 1990, p 43. 2. Adelson PD, Bratton SL, Carney NA, et al: Guidelines for the acute medical management of severe traumatic brain injury in infants, children and adolescents. Crit Care Med 2003;31:S417.

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3. Amar AP, Levy ML: Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery 1999;44:1027. 4. American Academy of Neurology: Practice parameter: The management of concussion in sports (summary statement). Neurology 1997;48:581. 5. American Academy of Pediatrics: The management of minor closed head injury in children. Pediatrics 1999;104:1407. 6. American Academy of Pediatrics: Shaken baby syndrome: Rotational cranial injuries-technical report. Pediatrics 2001;108:206. 7. Anderson JM, Schutt AH: Spinal injury in children: A review of 156 cases seen from 1950 through 1978. Mayo Clin Proc 1980;55:499. 8. Anderson V, Catroppa C, Morse S, et al: Recovery of intellectual ability following traumatic brain injury in childhood: Impact of injury severity and age at injury. Pediatr Neurosurg 2000;32:282. 9. Annegers JF, Hauser WA, Coan SP, Rocca WA: A populationbased study of seizures after traumatic brain injuries. N Engl J Med 1998;338:20. 10. Apple JS, Kirks DR, Merten DF, Martinez S: Cervical spine fractures and dislocations in children. Pediatr Radio1 1987;17:45. 11. Bailey DK: The normal cervical spine in infants and children. Radiology 1952;59:712. 12. Bekar, A, Ipekoglu Z, Tureyen K, et al: Secondary insults during intrahospital transport of neurosurgical intensive care patients. Neurosurg Rev 1998;21:98. 13. Bergsneider M, Hovda DA, Shalmon E, et al: Cerebral hyperglycolysis following severe traumatic brain injury in humans: A positron emission tomography study.J Neurosurg 1997;86:241. 14. Berryhill P, Lilly MA, Levin HS, et al: Frontal lobe changes after severe diffuse closed head injury in children: A volumetric study of magnetic resonance imaging. Neurosurgery 1995;37:392. 15. Bracken MB, Shepard MJ, Collins WE et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury: Results of the second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405. 16. Bracken MB, Shepard MJ, Holford TR, et al: Administration of methylprednisolone for 24 or 48 hours or tirilizad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the third National Acute Spinal Cord Injury randomized controlled trial. National Acute Spinal Cord Injury Study. JAMA 1997;277:1597. 17. Brookes M, MacMillan R, Cully S, et al: Head injuries in accident and emergency departments. How different are children from adults? J Epidemiol Commun Health 1990;44:747. 18. Bruno A, Biller J, Adams HP, et al: Acute blood glucose levels and outcome from ischemic stroke: Trial of ORG 10172 in Acute Stroke Treatment (TOAST) investigators. Neurology 1999;59:280. 19. Bruns J, Hauser WA: The epidemiology of traumatic brain injury: A review. Epilepsia 2003;44:2. 20. Buckingham MJ, Crone KR, Ball WS, et al: Traumatic intracranial aneurysms in childhood: Two cases and a review of the literature. Neurosurgery 1988;22:398. 21. Bullock RM, Chesnut RM, Clifton GL, et al: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000;17:451. 22. Caldicott DG, Pearce A, Price R, et al: Not just another 'head lac' . .. low-velocity, penetrating intra-cranial injuries: A case report and review of the literature. Injury 2004;35:1044.

21

Central Nervous System Injuries

371

23. Cantu RC: Return to play guidelines after a head injury. Clin Sports Med 1998;17:45. 24. Cattell HS, Filtzer DL: Pseudosubluxation and other normal variations in the cervical spine in children. A study of one hundred and sixty children. J Bone Joint Surg Am 1965;47:1295. 25. Chan KH, Mann KS, Yue CP, et al: The significance of skull fracture in acute traumatic intracranial hematomas in adolescents: A prospective study. J Neurosurg 1990;72:189. 26. Chang BS, Lowenstein DH: Practice parameter: Antiepileptic drug prophylaxis in severe traumatic brain injury. Neurology 2003;60:10. 27. Cherian L, Goodman JC, Robertson CS: Hyperglycemia increases brain injury caused by secondary injury after cortical impact in rats. Crit Care Med 1997;25:1378. 28. Chesnut RM: Avoidance of hypotension: Conditio sine qua non of successful severe head injury management. J Trauma (Suppl) 1997;42:S4. 29. Chesnut RM: Management of brain and spine injuries. Crit Care Clin 2004;20:25. 30. Chiaretti A, De Benedictus R, Polidori G, et al: Early posttraumatic seizures in children with head injury. Childs Nerv Syst 2000;16:862. 31. Cooper PR: Cerebrospinal fluid fistulas and pneumocephalus. In Barrow DL (ed): Complications and Sequelae of Head Injury. Park Ridge, IL, American Association of Neurological Surgeons, 1992, p 1. 32. CRASH Trial Collaborators: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): Randomized placebo-controlled trial. Lancet 2004;364:1321. 33. Curran C, Dietrich AM, Bowman MJ, et al: Pediatric cervical spine immobilization: Achieving neutral position? J Trauma 1995;39:729. 34. Dare AO, Dias MS, Li V: Magnetic resonance imaging correlation in pediatric spinal cord injury without radiographic abnormality. J Neurosurg 2002;97(Suppl):33. 35. Davis PC, Reisner A, Hudgins PA, et al: Spinal injuries in children: Role of MR. AJNR Am J Neuroradiol 1993;14:607. 36. Davis RL, Mullen N, Makela M, et al: Cranial computed tomography scans in children after minimal head injury with loss of consciousness. Ann Emerg Med 1994;24:640. 37. Deputy S: Shaking-impact syndrome of infancy. Semin Pediatr Neurol 2003;10:112. 38. De Santis A, Cappricci E, Granata G: Early post traumatic seizures in adults: Study of 84 cases. J Neurosurg Sci 1979;23:207. 39. De Vivo MJ: Causes and cost of spinal cord injury in the United States. Spinal Cord 1997;35;809. 40. De Vivo MJ, Black KJ, Stover SL: Causes of death during the first 12 years after spinal cord injury. Arch Phys Med Rehabil 1993;74:248. 41. Dias MS, Carnevale F, Li V: Immediate posttraumatic seizures: Is routine hospitalization necessary? Pediatr Neurosurg 1999;30:232. 42. Dias MS, Lillis KA, Calvo C, et al: Management of accidental minor head injuries in children: A prospective outcomes study. J Neurosurg (Pediatrics) 2004;101:38. 43. Dickman CA, Zabramski JM, Hadley MN, et al: Pediatric spinal cord injury without radiographic abnormalities: Report of 26 cases and review of the literature. J Spinal Disord 1991;4:296. 44. DiRoio C,Jourdan C, Mottolese C, et al: Craniocerebral injury resulting from transorbital stick penetration in children. Childs Nerv Syst 2000;16:503. 45. Donahue DJ, Sanford RA, Muhlbauer MS, et al: Cranial burst fracture in infants: Acute recognition and management. Childs Nerv Syst 1995;11:692.

372

PART

I1

TRAUMA

Gildenberg, PL (eds): Head Injury: Basic and Clinical 46. Duhaime AC, Christian C, Moss E, et al: Long-term outcome Aspects. New York, Raven Press, 1982, p 129. in infants with shaking-impact syndrome. Pediatr Neurosurg 1996;24:292. 68. Gennarelli TA, Thibault LE: Biological models of head injury. In Becker DP, Povlishok JT (eds): Central Nervous 47. Duhaime AC, Christian CW, Roarke LB, Zimmerman RA: Nonaccidental head injury in infants-the "shaken-baby System Trauma Status Report 1985. Bethesda, MD, syndrome." N Engl J Med 1998;338:1822. NINCDS/NIH, 1985, p 391. 69. Grabb PA, Pang D: Magnetic resonance imaging in the 48. Duhaime AC, Eppley M, Margulies S, et al: Crush injuries to the head in children. Neurosurgery 1995;37:401. evaluation of spinal cord injury without radiographic abnormality in children. Neurosurgery 1994;35:406. 49. Duhaime AC, Gennarelli TA, Thibault LT, et al: The 70. Graham DI: The pathology of brain ischemia and possishaken baby syndrome: A clinical, pathological, and biobilities for therapeutical intervention. Br J Anaesth mechanical study. J Neurosurg 1987;66:409. 50. Duhaime AC, Sutton LN: Delayed sequelae of pediatric 1985;57:3. head injury. In Barrow DL (ed): Complications and 71. Greenwald TA, Mann DC: Pediatric seatbelt injuries: Sequelae of Head Injury. Park Ridge, IL, American Diagnosis and treatment of lumbar flexion-distraction Association of Neurological Surgeons, 1992, p 169. injuries. Paraplegia 1994;32:743. 51. du Trevou MD, van Dellen JR: Penetrating stab wounds to 72. Hadley MN, Zabramski JN, Browner CM, et al: Pediatric the brain: The timing of angiography in patients presenting spinal trauma: Review of 122 cases of spinal cord and with the weapon already removed. Neurosurgery 1992;31:905. vertebral column injuries. J Neurosurg 1988;68:18. 52. Dwek JR, Chung CB: Radiography of cervical spine injury 73. Hahn YS, Fuchs S, Flannery AM, et al: Factors influencin children: Are flexion-extension radiographs useful for ing posttraumatic seizures in children. Neurosurgery acute trauma? AJR Am J Roentgen01 2000;174:1617. 1988;22:864. 53. Einhorn A, Mizrahi EM: Basilar skull fractures in children. 74. Hamilton MG, Myles ST: Pediatric spinal injury: Review of The incidence of CNS infection and the use of antibiotics. 174 hospital admissions. J Neurosurg 1992;77:700. Am J Dis Child 1978;132:1121. 75. Hamilton MG, Myles ST: Pediatric spinal injury: Review of 61 deaths. J Neurosurg 1992;77:705. 54. Eleraky MA, Theodore N, Adams M, et al: Pediatric cervical spine injuries: Report of 102 cases and review of 76. Hansen JE, Gudeman SK, Holgate RC, Saunders RA: the literature. J Neurosurg 2000;92(Suppl):12. Penetrating intracranial wood wounds: Clinical limitations 55. Ewing-Cobbs L, Thompson NM, Miner ME, et al: Gunshot of computed tomography. J Neurosurg 1988;68:752. wounds to the brain in children and adolescents: Age and 77. Haydel MJ, Preston CA, Mills TJ, et al: Indications for neurobehavioral development. Neurosurgery 1994;35:225. computed tomography in patients with minor head injury. 56. Faden AI, Demediuk P, Panter SS, et al: The role of excitaN Engl J Med 2000;343:100. tory amino acids and NMDA receptors in traumatic brain 78. Haydel MJ, Shembekar AD: Prediction of intracranial injury. Science 1989;244:798. injury in children aged five years and older with loss of consciousness after minor head injury due to nontrivial 57. Farmer MY, Singer HS, Mellitus ED, et al: Neurobehavioral mechanisms. Ann Emerg Med 2003;42:507. sequelae of minor head injuries in children. Pediatr Neurosci 1987;13:304. 79. Hoffman JR, Mower WR, Wolfson AB, et al: Validity of a set of clinical criteria to rule out injury to the cervical spine in 58. Fesmire FM, Luten RC: The pediatric cervical spine: Developmental anatomy and clinical aspects. J ~ m e r c ~ e d patients with blunt trauma. N Engl J Med 2000;343:94. 1989;7:133. 80. Hoffman JR, Wolfson AB, Todd K, et al: Selective cervical spine radiography in blunt trauma: Methodology of the 59. Figaji AA, Fieggen AG, Peter JC: Early decompressive craniotomy in children with severe traumatic brain injury. National Emergency X-Radiography Utilization Study Childs Nerv Syst 2003;19:666. (NEXUS). Ann Emerg Med 1998;32:461. 60. Filley CM, Cranberg LD, Alexander MP, Hart EJ: 81. Holmes JF, Palchak MJ, Conklin MJ, Kuppermann N: Do Neurobehavioral outcome after closed head injury in childchildren require hospitalization after immediate posttraumatic seizures? Ann Emerg Med 2004;43:706. hood and adolescence. Arch Neurol 1987;44:194. 61. Finch GD, Barnes MJ: Major cervical spine injuries in 82. Hsiang JNK, Yeung T, Yu ALM, et al: High risk mild head children and adolescents. J Pediatr Orthop 1998;18:811. injury. J Neurosurg 1997;87:234. 62. Fingerhut LA, Kleinman JC, Godfrey E, et al: Firearm mor83. Huerta C, Griffith R, Joyce SM: Cervical spine stabilization tality among children, youth, and young adults 1-34 years in pediatric patients: Evaluation of current techniques. of age, trends and current status: United States, 1979-88. Ann Emerg Med 1987;16:1121. Monthly Vital Stat Rep 1991;39(Suppl):l. 84. Humphreys R, Hendrick EB, Hoffman H: The head63. Gabriel EJ, Ghajar J, Jagoda A, et al: Guidelines for prehosinjured child "who talks and dies." A preventable problem? pita1 management of traumatic brain injury. J Neurotrauma In Marlin A (ed): Concepts in Pediatric Neurosurgery X. 2002;19:113. Basel, Karger, 1990, p 196. 85. Hurlbert RJ: Methylprednisolone for acute spinal cord 64. Garton HJL, Luerssen TG: Head injuries. In Biller J, Bogousslavsky J (eds): Clinical Trials in Neurologic injury: An inappropriate standard of care. J. Neurosurg Practice. Boston, Butterworth Heinemann, 2001, p 77. 2000;93(Suppl):1. 65. Gausche M, Lewis RJ, Stratton SJ, et al: Effect of out-of86. Iverson GL, Love11 MR, Smith S, Franzen MD: Prevalence hospital pediatric endotracheal intubation on survival and of abnormal CT-scans following mild head injury. Brain Inj neurological outcome: A controlled clinical trial. JAMA 2000;14:1057. 87. Joint Section on Disorders of the Spine and Peripheral 2000;283:783. 66. Gennarelli TA, Adams JH, Graham DI: Diffuse axonal Nerves of the American Association of Neurological injury-a new conceptual approach to an old problem. Surgeons and the Congress of Neurological Surgeons: Guidelines for the management of acute cervical spine and In Baethmann A, Go KG, Unterberg A (eds): Mechanisms of Secondary Brain Damage. New York, Plenum Press, spinal cord injuries. Neurosurgery 2002;50(Suppl):S166. 1986, p 15. 88. Jones PA, Andrews PJD, Midgley S, et al: Measuring the 67. Gennarelli TA, Segawa H, Wald V, et al: Physiological resburden of secondary insults in head-injured patients ponse to angular acceleration of the head. In Grossman RG, during intensive care. J Neurosurg Anesthesiol 1994;6:4.

CHAPTER

89. Kadish HA, Schunk JE: Pediatric basilar skull fracture: Do children with normal neurologic findings and no intracranial injury require hospitalization? Ann Emerg Med 1995;26:37. 90. Kaufman HH: Treatment of civilian gunshot wound to the head. Neurosurg Clin N Am 1991;2:387. 91. Kaye EM, Herskowitz J: Transient post-traumatic cortical blindness: Brief v prolonged syndromes in childhood. J Child Neurol 1986;1:206. 92. Kelly JP, Nichols JS, Filley KO, et al: Concussion in sports: Guidelines for the prevention of catastrophic outcome. JAMA 1991;266:2867. 93. Kewalramani LS, KrausJF, Sterling HM: Acute spinal cord lesions in a pediatric population: Epidemiological and clinical features. Paraplegia 1980;18:206. 94. KlasterskyJ, Sadeghi M, BrihayeJ: Antimicrobial prophylaxis in patients with rhinorrhea or otorrhea. A double-blind study. Surg Neurol 1976;6:111. 95. Klauber MR, Marshall LF, Luerssen TG, et al: Determinants of head injury mortality: Importance of the low risk patient. Neurosurgery 1989;24:31. 96. Kraus JF: Epidemiological features of brain injury in children: Occurrence, children at risk, causes and manner of injury, severity and outcomes. In Broman SH, Michel ME (eds): Traumatic Head Injury in Children. New York, Oxford University Press, 1995, p 22. 97. Kraus JF, Rock A, Hemyari P: Brain injuries among infants, children, adolescents and young adults. Am J Dis Child 1990;144:684. 98. Laham JL, Cotcamp DH, Gibbons PA, et al: Isolated head injury versus multiple trauma in pediatric patients: Do the same indications apply? Pediatr Neurosurg 1994;122:431. 99. Lazar MF, Menaldino S: Cognitive outcome and behavioral adjustment in children following traumatic brain injury: A developmental perspective. J Head Trauma Rehabil 1995;10:55. 100. Lescohier I, DiScala C: Blunt trauma in children: Causes and outcomes of head versus intracranial injury. Pediatrics 1993;91:721. 101. Levi L, Guilburd JN, Linn S, Feinsod M: The association between skull fracture, intracranial pathology and outcome in pediatric head injury. BrJ Neurosurg 1991;5:617. 102. Levin HS, Aldrich EF, Saydjari C, et al: Severe head injury in children: Experience of the Traumatic Coma Data Bank. Neurosurgery 1992;31:435. 103. Levin HS, Ewing-Cobbs L, Eisenberg HM: Neurobehavioral outcome of pediatric closed head injury. In Michel ME, Broman SH (eds): Traumatic Head Injury in Children. New York, Oxford University Press, 1995, p 70. 104. Lewis RJ, Lee L, Inkelis SH, Gilmore D: Clinical predictors of post traumatic seizures in children with head trauma. Ann Emerg Med 1993;22:1114. 105. Lloyd DA, Carty H, Patterson M, et al: Predictive value of skull radiography for intracranial injury in children with blunt head injury. Lancet 1997;349:821. 106. Lobato R, Rivas J, Gomez P, et al: Head-injured patients who talk and deteriorate into coma: Analysis of 211 cases studied with computerized tomography. J Neurosurg 1991;75:256. 107. Luerssen TG: Intracranial pressure: Current status in monitoring and management. Semin Pediatr Neurol 1997;4:146. 108. Luerssen TG: Skull fractures after closed head injury. In Albright LA, Pollack IF, Adelson PD (eds): Principles and Practice of Pediatric Neurosurgery. New York, Thieme, 1999, p 813. 109. Luerssen TG, Huang JC, McLone DG, et al: Retinal hemorrhages, seizures and intracranial hemorrhages:

21

Central Nervous System Injuries

373

Relationships and outcomes in children suffering traumatic brain injury. In Marlin AE (ed): Concepts in Pediatric Neurosurgery XI. Basel, Karger, 1991, p 87. 110. Luerssen T, Hults K, Klauber M, et al: Improved outcome as a result of recognition of absent and compressed cisterns on initial CT scans. In Hoff J, Betz A (eds): Intracranial Pressure VII. Berlin, Springer-Verlag, 1989, p 598. 111. Luerssen TG, Klauber MR, Marshall LF: Outcome from head injury related to patient's age: A longitudinal prospective study of adult and pediatric head injury. J Neurosurg 1988;68:409. 112. Luerssen TG, Wolfla CE: Pathophysiology and management of increased intracranial pressure in children. In Andrews BT, Hammer GB (eds): Pediatric Neurosurgical Intensive Care. Park Ridge, IL, American Association of Neurological Surgeons, 1997, p 37. 113. Maier-Hauff K, Baethmann AJ, Lange M, et al: The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2-studies on kinin formation in focal and perifocal brain tissue. J Neurosurg 1984;61:97. 114. Mandera M, Wencel T, Bazowski P, Krauze J: How should we manage children after mild head injury? Childs Nerv Syst 2000;16:156. 115. Mansfield RT: Head injury in children and in adults. Crit Care Clin 1997;13:611. 116. Margolis LH, Wagenaar AC, Liu W: The effects of a mandatory child restraint law on injuries requiring hospitalization. Am J Dis Child 1988;142:1099. 117. Marshall LF, Marshall SB, Klauber LF, et al: A new classification of head injury based on computerized tomography. J Neurosurg 1991;75(Suppl)514. 118. Marshall LF, Toole BA, Bowers SB: The National Traumatic Coma Data Bank Part 2: Patients who talk and deteriorate: Implications for treatment. J Neurosurg 1983;59:285. 119. Mataro M, Poco MA, SahuquilloJ, et al: Neuropsychological outcome in relation to the Traumatic Coma Data Bank classification of computed tomography imaging.J Neurotrauma 2001;18:869. 120. Mayer SA, Chongp: Critical care management of increased intracranial pressure. J Intensive Care Med 2002;17:55. 121. Mayer T, Walker ML, Johnson D, et al: Causes of morbidity and mortality in severe pediatric trauma. JAMA 1981;245:719. 122. McNeill AM, Annest JL: The ongoing hazard of BB and pellet gun-related injuries in the United States. Ann Emerg Med 1995;26:187. 123. Megur K, Tator CH: Effect of multiple trauma on mortality and neurological recovery after spinal cord or cauda equina injury. Neurol Med Chir 1988;28:34. 124. Miller JD, Sweet RC, Narayan R, Becker DP: Early insults to the injured brain. JAMA 1978;240:439. 125. Miner ME, Ewing-Cobbs L, Kopaniky DR, et al: The results of treatment of gunshot wounds to the brain in children. Neurosurgery 1990;26:20. 126. Mono J, Hollenberg RD, Harvey JT: Occult transorbital intracranial penetrating injuries. Ann Emerg Med 1986;15:589. 127. Murray JA, Demetirades D, Berne TV, et al: Prehospital intubation in patients with severe head injury. J Trauma 2000;49:1065. 128. Nagy K, Joseph K, Krosner S, et al: The utility of head computed tomography after minimal head injury.J Trauma 1999;46:268. 129. Nelson DE, Bixby-Hammett D: Equestrian injuries in children and young adults. Am J Dis Child 1992;146:611. 130. Ommaya AK: Biomechanics of head injury: Experimental aspects. In Nahum AM, Melvin J (eds): The Biomechanics

374

PART

I1

TRAUMA

of Trauma. Norwalk, CN, Appleton-Century-Crofts, 1985, p 245. 131. Ommaya AK, Gennarelli TA: Cerebral concussion and traumatic unconsciousness: Correlation of experimental and clinical observations of blunt head injuries. Brain 1974;97:633. 132. Osenbach RK, Menezes AH: Spinal cord injury without radiographic abnormality in children. Pediatr Neurosci 1989;15:168. 133. Osenbach RK, Menezes AH: Pediatric spinal cord and vertebral column injury. Neurosurgery 1992;30:385. 134. Palchak MJ, Holmes JF, Vance CW, et al: A decision rule for identifying children at low risk for brain injuries after blunt head trauma. Ann Emerg Med 2003;42:492. 135. Pang D: Spinal cord injuries. In McLone DG (ed): Pediatric Neurosurgery, 4th ed. Philadelphia, WB Saunders, 2001, p 660. 136. Pang D, Pollack IF: Spinal cord injury without radiographic abnormality in children-the SCIWORA syndrome. J Trauma 1989;29:654. 137. Pang D, Wilberger JE: Spinal cord injury without radiographic abnormalities in children. J Neurosurg 1982;57:114. 138. Paret G, Barzilai A, Lahat E, et al: Gunshot wounds in brains of children: Prognostic variables in mortality, course, and outcome. J Neurotrauma 1998;15:967. 139. Pettigrew LEL, Wilson JTL, Teasdale G: Assessing disability after head injury: Improved use of the Glasgow Outcome Scale. J Neurosurg 1998;89:939. 140. Pezzotta S, Silvani V, Gaetani P, et al: Growing skull fractures in childhood. J Neurosurg Sci 1985;29:129. 141. Pigula FA, Wald SL, Shackford SR, Vane DW: The effect of hypotension and hypoxia on children with severe head injuries. J Pediatr Surg 1993;28:310. 142. Pollack IF, Pang D, Sclabassi R: Recurrent spinal cord injury without radiographic abnormalities in children. J Neurosurg 1988;69:177. 143. Proctor MR: Spinal cord injury. Crit Care Med 2002;30(Suppl)5489. 144. Radecki RT, Gaebler-Spira D: Deep vein thrombosis in the disabled pediatric population. Arch Phys Med Rehabil 1994;75:248. 145. Ralston ME, Chung K, Barnes PD, et al: Role of flexionextension radiographs in blunt pediatric cervical spine injury. Acad Emerg Med 2001;8:237. 146. Rathore MH: Do prophylactic antibiotics prevent meningitis after basilar skull fracture? Pediatr Infect Dis J 1991;10:87. 147. Rivara FP: Epidemiology and prevention of pediatric traumatic brain injury. Pediatr Ann 1994;23:12. 148. Rivara FP, Thompson DC, Thompson RS, et al: The Seattle Children's bicycle helmet campaign: Changes in helmet use and head injury admissions. Pediatrics 1994;93:567. 149. Rovlias A, Kotsou S: The influence of hyperglycemia on neurological outcome in patients with severe head injury. Neurosurgery 2000;46:335. 150. Ruff RM, Jurica P: In search of a unified definition for mild traumatic brain injury. Brain Inj 1999;13:943. 151. Ruge JR, Sinson GP, McLone DG: Pediatric spinal injury: The very young. J Neurosurg 1988;68:25. 152. Ryan CA, Edmonds J: Seizure activity mimicking brain stem herniation in children following head injuries. Crit Care Med 1988;16:812. 153. Sadowsky CL, Margherita A: The cost of spinal cord injury care. Spine 1999;13:593. 154. Satz P, Zaucha K, McCleary C, et al: Mild head injury in children and adolescents: A review of studies (1970-1995). Psycho1 Bull 1997;122:107.

155. Schaefer DM, Flanders AE, Olsterholm JL, et al: Prognostic significance of MRI in acute phase of spinal injury. J Neurosurg 1992;76:218. 156. Schutzman SA, Barnes P, Duhaime AC, et al: Evaluation and management of children younger than two years old with apparently minor head trauma: Proposed guidelines. Pediatrics 2001;107:983-993. 157. Servadei F, Teasdale G, Merry G, et al: Defining acute mild head injury in adults: A proposal based on prognostic factors, diagnosis, and management. J Neurotrauma 2001;18:657. 158. Shaw M, Burnett H, Wilson A, Chan 0 : Pseudosubluxation of C2 on C3 in polytraumatized children: Prevalence and significance. Clin Radio1 1999;54:377. 159. Snoek J, Minderhoud J, Wilmink J: Delayed deterioration following mild head injury in children. Brain 1984;107:15. 160. Stein SC, Ross SE: The value of computed tomographic scans in patients with low-risk head injuries. Neurosurgery 1990;26:638. 161. Stocchetti N, Pagan F, Calappi E, et al: Inaccurate early assessment of neurological severity in head injury. J Neurotrauma 2004;21:1131. 162. Suback BR, McLaughlin MR, Albright AL, Pollack IF: Current management of pediatric atlantoaxial rotatory subluxation. Spine 1998;23:2174. 163. Sullivan CR, Bruwer AJ, Harris LE: Hypermobility of the cervical spine in children. A pitfall in the diagnosis of cervical dislocation. Am J Surg 1958;95:636. 164. Tator CH, Koyanagi I: Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neu;osurg 1997;86:483. 165. ~ e a s d a l eG, Jennett B: Assessment of coma and impaired consciousness: A practical scale. Lancet 1974;2:81. 166. Teasdale GM, Murray G, Anderson E, et al: Risks of acute traumatic intracranial hematoma in children and adults: Implications for managing head injuries. BM J 1990;300:363. 167. Thompson DC, Rivara FP, Thompson R: Helmets for preventing head and facial injuries in bicyclists (Cochrane Review). In The Cochrane Library, Issue 2, 2002. Oxford, Update Software. 168. Thompson HJ, Tkacs NS, Saatman KE, et al: Hyperthermia following traumatic brain injury: A critical evaluation. Neurobiol Dis 2003;12:163. 169. Thompson MD, Irby JW: Recovery from mild head injury in pediatric populations. Semin Pediatr Neurol 2003; 10:130. 170. Tilford JM, Simpson PM, Yeh TS, et al: Variations in therapy and outcome for pediatric head trauma patients. Crit Care Med 2001;29:1056. 171. Vane DW, Keller MS, Sartorelli KH, Miceli AP: Pediatric trauma: Current concepts and treatments. J Intensive Care Med 2002;17:230. 172. Vespa PM, Nuwer MR, Nenov V, et al: Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J Neurosurg 1999;91:750. 173. Viccellio P, Simon H, Pressman BD, et al: A prospective multicenter study of cervical spine injury in children. Pediatrics 2001;108:E20. 174. Wang HE, Peitzman AB, Cassidy LD, et al: Out-of-hospital endotracheal intubation and outcorrie after traumatic brain injury. Ann Emerg Med 2004;44:439. 175. Warren WL, Bailes JE: On the field evaluation of athletic head injuries. Clin Sports Med 1998;17:13. 176. Wilson MH, Baker SP, Teret SP, et al: Saving Children: A Guide to Injury Prevention. New York, Oxford University Press, 1991, p 149.

CHAPTER

177. Winston K, Beatty RM, Fischer EG: Consequences of dural defects acquired in infancy. J Neurosurg 1983;59:839. 178. Yamamoto I,G, Bart RD: Transient blindness following mild head trauma. Clin Pediatr (Phila) 1988;27:479. 179. Young KD, Okada PJ, Sokolove PE, et al: A randomized, double-blinded, placebo controlled trial of phenytoin for

21

Central Nervous System Injuries

375

the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med 2004;43:435. 180. Zidek K, Srinivasan R: Rehabilitation of a child with a spinal cord injury. Semin Pediatr Neurol 2003;10:140. 181. Zornow MH, Prough DS: Fluid management in patients with traumatic brain injury. New Horizons 1995;3:488.

Vascular Injury Joseph J. Tepas I I I

the mechanism and mortality for 1368 children with at Principles of polysystem injury management have least one vascular injury recorded in the National undergone significant change during the past decade. Pediatric Trauma Registry (NPTR) between 1989 and The evolution of damage-control surgery; the progress 2001. Although this represents only 1.3% of registry cases, in understanding traumatic stress, especially as related the 13% crude mortality rate (compared with a 2.9% rate to the management of systemic inflammatory response for the entire registry) demonstrates the lethality of syndrome; and the emergence of increasingly sophistithese injuries and the variability of outcome based on cated imaging technology have all contributed to a body region affected (Table 22-2). more precise and effective system of care for the severely As in the adult population, vascular trauma can be injured. Included in this evolution has been continued divided into injuries that involve major truncal vessels refinement of the principles of evaluating and managing '~ of the predictive accuracy and extremity injuries that disrupt peripheral perfusion. vascular i n j ~ r i e s .Validation of clinical examination and better definition of indicaIn children, the latter are commonly associated with tions for arteriography have led to more timely operative skeletal fractures rather than penetrating injury. In fact, intervention based on effective resuscitation, accurate the incidence of vascular injury occurring in children assessment of associated injuries, and anticipation of with penetrating extremity trauma is remarkably low. reperfusion injury.'"17 With the emergence of endovasVictoroff et al.46reviewed their experience with 75 children sustaining 76 penetrating extremity injuries cular technology, acute management of some vascular (gunshot wounds) treated at National Children's injuries may well move from the operating room to the Medical Center from 1985 to 1989. There were no docuangiography suite. At the heart of managing vascular mented vascular injuries and only two nerve injuries injuries, however, is the technical repair of damaged caused by bullets or bullet fragments. The greater majority blood vessels and restoration of peripheral perfusion. of injuries were minor musculoskeletal disruption from Although the basic surgical skills required are similar for which recovery was quick and complete. Data from the patients of all ages, infants and children have unique char~ ~ , ~ listed ~ in Table 22-2 indicate a similarly low mortality acteristics that can present significant c h a l l e n g e ~ . " f l , ~ ~NPTR for extremity injuries, but with a significantly higher rate

EPIDEMIOLOGY In the adult population, most vascular injury is the result . ~ is not so for infants and of penetrating t r a ~ m a This ~hildren.2~).~() Blunt injury predominates in the pediatric population, with almost half of all vascular injuries in children resulting from this type of mechanism. Table 22-1 lists Region

1

Mechanism Penetrating Blunt Crush

Proportion (%) 52 47 1

Neck Chest Abdomen, pelvis Upper extremity Lower extremity

Mortality (%)

ICD9CM

Total No. No. No. Lived Died (%)

% Operated

900-901 901-902 902-903

249 161 374

196 98 248

53 (21) 63 (39) 126 (34)

41 70 50

903-904

497

494

3 (1)

21

904-905

326

318

8 (3)

36

I

ICD-9-CM,InternationalClassificationof Diseases, 9th ed, Clinical Modification.

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of vascular operative intervention, as indicated by International Classification of Diseases, 9th edition, Clinical Modification (ICD-9-CM) operative codes 35.00 through 39. Vascular injury in childhood has two distinct components. In addition to the inury resulting from external mechanical force, the increasing use of complex endovascular diagnostic and therapeutic procedures continues is associated with a low but consistent incidence of iatrogenic damage to vascular structure^.^^,^^^" With increasing refinement of technique and improved technology, however, this appears to be d e c r e a ~ i n g . ~ ~

EVALUATION General principles of assessment of acute vascular disruption are based on clinical evaluation. Regardless of cause, suspicion of vascular injury should stimulate a logical system of clinical assessment based first on the patient's history. During the initial clinical assessment, two immediate questions must be answered: (1) Is there evidence of disruption of the integrity of the circulatory system? (2) Is perfusion adequate? Despite the implied causal relationship of these two points, each can be deranged without immediate effect on the other. Prolonged postinjury spasm, a common characteristic of childhood vascular trauma, may cause peripheral ischemia in an otherwise anatomically intact vascular tree. Conversely, effective collateral circulation, enhanced by the absence of obliterative vascular disease, may sustain distal circulation despite deranged proximal flow. Thus, not every disruption of vascular flow produces immediate peripheral ischemia, and evidence of acute ischemia may not necessarily portend operative vascular injury. Regardless of circumstances, confirmation or restoration of cellular perfusion is the immediate priority in assessing any child with a vascular injury.32 Numerous investigators have validated the predictive accuracy of thorough clinical examination and, in the process, have refined the indications for arteriography.l"l6 The latter issue is especially important in pediatric patients because of the increased potential for additional iatrogenic injury. Frykberg et a1.16 demonstrated the predictive accuracy of "hard" signs of injury and recommended immediate operative intervention for any patient with active bleeding, expanding hematoma, pulse deficit, or bruit or thrill. Nonexpanding hematoma, hypotension, peripheral nerve deficit, or a history of bleeding from the wound were considered "soft" signs that required only clinical observation. Long-term follow-up of this population has confirmed the predictive accuracy of this approach and has validated the authors' initial recommendation that routine arteriography is not necessary for the management of proximity injury.S17For children, the issue of angiography is even more relevant because of the risk of iatrogenic injury to tiny vessels, contrast toxicity, and the increased frequency of persistent spasm as the major cause of ischemia. Reichard et a1.B analyzed the predictive accuracy of clinical signs in their review of 75 children with vascular injury treated on the pediatric trauma service

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at Cook County Hospital. Part of their report included a comparison to 12 children managed by an "adult" protocol that required arteriography. None of the studies performed for proximity alone was abnormal. All 10 children with vascular injury had hard signs. Four of 77 children with no vascular injury also manifested at least one hard sign, yielding a 100% sensitivity and 95% specificity of physical examination. Of note is that these data validate similar recommendations published by Meagher et a1." in 1979 and emphasize that arteriography for acute injury should be considered only if the risk of performance is outweighed by a risk of ischemia that cannot be defined by history and clinical signs.629.40 This is especially so when considering "one-shot" emergency department arteriography, despite recent reports of the safety and efficacy of this approach.'" For chronic injury, however, arteriography is considered essential for accurate planning of revascularization. Duplex Doppler, B-mode ultrasonography, multidetector computed tomography-angiography, and magnetic resonance angiography are newly established technologies in clinical imaging. The first two are reasonably portable and can define flow and flow velocity. Their role in the diagnosis of acute injury, however, has not been well established. The last two are the result of continued evolution of computer-enhanced imaging. They offer the capability of visualizing vascular anatomy and flow without direct invasion of the arterial tree.44Recent reports have demonstrated the value of these modalities in diagnosing suspected vascular injuries in children. Three-dimensional reconstructions can precisely define both the level of injury and the efficiency of collateral circulation (Fig. 22-1). Although noninvasive techniques avoid cannulation of the arterial tree, a higher volume of contrast material may be required. Patient selection must therefore consider the risk of arterial injury versus the potential toxicity of the contrast agent. Children usually do not suffer from atherosclerotic vascular disease. Because their vessels are elastic, they usually stretch and transiently deform, rather than rupture, in response to the application of force. The immediate effect of this is an increased potential for flow disruption secondary to intimal tears. The effect of such decreased flow may be acute ischemia or marginal insufficiency that stimulates increased collateralization. Whereas the former should be easily discernible on clinical examination, the latter can be very subtle and clinically silent. Therefore, functional and anatomic integrity of the circulation must be clinically confirmed and documented in every injured child. Of equal importance is the understanding that the unexplainable absence of palpable pulses, especially in the lower extremities, may be the result of preexisting rather than acute injury. If perfusion pressure is suddenly lowered because of other acute injuries, collateral circulation may become inadequate, and symptoms of progressive ischemia may emerge. In their analysis of the predictive accuracy of clinical findings of pediatric vascular injury, Reichard et al." extol the accuracy of the ankle-brachial index (ABI) as indicative of inadequate peripheral perfusion. Their data suggest that an ABI less than 0.99 indicates clinically critical vascular injury, reinforcing

378

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Computed tomographic angiogram from a 5-year-old

hit by a car. He underwent repair of transposition of the great vessels as an infant and was noted to have a pulseless right foot. Evaluation demonstrated a clinically silent femoral artery disruption.

intensive care nursery discharge data that suggest that the true incidence of vascular injury is higher than previously believed. In fact, findings reported by Seibert et a1.43 suggest that assessment of the peripheral pulses and measurement of the ABI should be part of the routine postdischarge assessment of any baby treated with an umbilical artery catheter.

TRAUMATIC INJURIES Traumatic injuries can be divided into those involving the trunk (neck and torso) and those involving the extremities (upper or lower). Each area presents unique challenges to accurate diagnosis and timely management.

Truncal Injuries Cervical vascular injuries appear to be rare in childhood. To test their proposed algorithm for the diagnosis of blunt cervical vascular injury, Rozycki et al.41reviewed injuries associated with a cervicothoracic seat-belt sign in 797 motor vehicle crash victims treated over 17 months by the Grady Memorial Hospital Trauma Service. The 3% of patients with carotid injury were all adults. No injuries were missed, and none were noted in children. With the gradual increase in compliance with childrestraint laws, the potential association between seat-belt marks and significant vascular injury will require continued

close follow-up. Cox's2 review of the operative management of 36 children with vascular injuries included 9 children with 11 carotid or jugular injuries. Eight of these were penetrating neck injuries. Mortality occurred in only two of the three hemodynamically unstable children. Torso vascular injuries are relatively rare in childhood. This is probably the result of the greater elasticity of young, healthy vessels. Although children are not immune to thoracic vascular disruption, most series that include pediatric patients demonstrate a low incidence compared with adults. Clinical reports of aortic injuries in children suggest that the natural history is no different from that of adults. Mortality is extremely high, especially for those children with a presenting systolic blood pressure below 90 mm Hg. Eddy et a1.8 reviewed the King County coroner's records over a 12-year period (1975 to 1987), and found 13 cases of aortic disruption in children. Only three of these children reached a hospital alive, and just one survived. Experience in the NPTR is somewhat more heartening, in that 26 of 54 children (48%) with aortic ruptures survived to hospital discharge. This representative sample from multiple contributing hospitals in North America is similar to that reported from a single institution by Cox et al.,' suggesting that the outcome from this catastrophic injury may be better than that consistently reported for adults. Major thoracic venous injuries are even less common and are usually associated with major pulmonary disruption. Because of the preponderance of blunt injury in the pediatric population, especially as a result of vehiclerelated mishaps, abdominal vascular injuries can and do occur.' Arterial disruption is far less common than venous disruption. Hypotension progressing to frank shock is the most common associated finding, making the decision to explore the abdomen relatively straightforward, expect when a solid viscus injury is the most likely cause. Fayiga et al.11 reviewed 18 years of experience in the operative management of pediatric blunt vascular injuries. Twenty-one major abdominal venous injuries were present in 17 patients and were lethal in 11 (65%). None of the abdominal venous injuries was recognized before laparotomy. As in numerous other series, survival was directly related to hemodynamic stability at presentation. Most complications were related to nonvascular injuries. The majority of vascular injuries were repaired directly, which parallels the experience from a similar series of 16 abdominal vascular injuries reported by Cox et al.,' wherein interposition grafts were required to repair only one aortic disruption and one superior mesenteric artery transection.

Extremity Injuries The vast majority of lower extremity vascular injuries are the result of blunt mechanisms, are arterial, and are commonly associated with skeletal f r a ~ t u r e . ~ J ~ . 2 * Popliteal injuries, in particular, are often the result of sports and cycling mishaps. Initial assessment must confirm the presence of palpable distal pulses and adequate capillary perfusion. Immediate reduction of

CHAPTER

displaced fracture fragments or subluxated joints often results in restoration of palpable distal pulses. If the duration of ischemia has been longer than 6 hours, the possibility of evolving compartment syndrome should prompt the consideration of fasciotomy.45 Interposition of reversed contralateral saphenous vein remains the treatment of choice for all disrupted segments. Synthetic material should be considered only as a last resort when autologous vessel cannot be harvested and fabricated into a patch or conduit.31Anastomoses are constructed using monofilament simple sutures.32 As the repair is being completed, the distal clamp is first released to confirm adequate backflow. The proximal clamp is then released to flush any residual air or clot before the final sutures are tied. Vasospasm, if significant, can usually be reduced by gentle mechanical dilation using coronary artery dilators. Veins should be repaired before arteries. Children who have undergone repair of venous injuries should be anticoagulated for 48 hours postoperatively. Some authors use heparin; others simply use dextran solutions for 2 to 3 days postoperatively. Reed et a1.3 reported their experience with seven children with popliteal artery injuries who underwent immediate operative repair. Four had blunt and three had penetrating injuries. Associated morbidity included three fractures, four severe soft tissue wounds, and one nerve injury. All patients underwent angiography. Three angiograms were intraoperative, so presumably the four preoperative studies were required to confirm the diagnosis. Treatment included two primary repairs and four vein graft bypasses. Anastomoses were spatulated and sutured in an interrupted fashion. One child required fasciotomy. There were no deaths, amputations, or reoperations. At the time of their report (1990), follow-up ranged between 10 and 42 months. All patients had normal Doppler pressures or distal pulses. These data illustrate the relationship between prompt, aggressive treatment and successful outcome. Other investigators report similar recommendations and emphasize that the high proclivity for prolonged vasospasm makes arterial anastomosis in childhood especially challenging.ll The vast majority of extremity vascular injuries in children are associated with axial skeletal disruption. In its most severe form, this combination of bone and soft tissue destruction can result in what has been called the "mangled extremity." It is usually characterized by major soft tissue avulsion that can be associated with significant tissue loss. Initial assessment must consider tissue viability, anticipated limb function, and the need for amputation of a potential source of massive tissue necrosis and sepsis. The Mangled Extremity Severity Score (MESS) has been proposed as an accurate system of evaluation and prediction of limb salvage (Table 22-3). Although originally devised for adults, Fagelman et al.1° demonstrated that the MESS had a predictive accuracy of 93% when retrospectively applied to 36 injured children. Vascular disruption associated with fractures must be addressed immediately so that subsequent axial skeletal repair will produce a viable extremity. Restoration of flow may be accomplished by temporary bypass until fracture fixation is achieved. When possible, venous repair should precede arterial repair.

22

Vascular Injury

1 Factor

379

score

1

Skeletal/soft tissue injury Low-energy (stab, simple fracture, pistol gunshot wound) Medium energy (open or multiple fractures, dislocation) High energy (high-speed crash, rifle gunshot wound) Very high energy (high-speed injury, gross contamination) Limb ischemia Reduced/absent pulse, normal perfusion Pulseless, paresthesias, poor capillary refill Cool, insensate, paralyzed, numb Shock Systolic blood pressure always >90 mm Hg Transient hypotension Persistent hypotension Age (yr) <30 30-50 >50 *Score doubled for ischemia >6 hr. MESS >7 = 100%prediction for amputation.

Devitalized tissue must be debrided, and fasciotomy should be considered. Nerve function must be evaluated and documented before debating amputation. Although . it is true that children recover amazing-lv well from what ", may initially appear to be devastating injuries, being permanently crippled by an insensate, immobile extremitv is a Door alternative to an active life with a functional and properly fitted prosthesis. The decision to amputate is therefore based on an assessment of limb viability and a prediction of limb functionality. The MESS serves as a Eeasonable guideline, but the ultimate decision rests with the surgeon, the child's parents, and, when possible, the child. Upper extremity vascular injury is usually associated with supracondylar fractures. Axillary stretch injuries, especially when associated with high-energy forces, such as vehicular ejection, may disrupt arterial or venous structures, producing a hematoma that is not as precisely definable as those seen with more distal injuries. In addition to signs of obvious blood loss, diffuse edema of the axilla or shoulder region and diminution of peripheral pulses should prompt angiographic confirkation of both the existence and the anatomic configuration of the injury. Supracondylar fractures may disrupt brachial arterial flow by direct injury or by compression, with or without prolonged spasm. As with the lower extremity, definitive management begins with an assessment of the adequacy of perfusion and confirmation of the vessel's integrity. Of interest is a recent report that describes use of the ipsilateral basilic vein as an ideal interposition graft for the reconstruction of vessels in which segmental loss has 0ccurred.2~Salvage from damage of upper extremity injuries is generally good, with return of functionality related to the nature of the associated musculoskeletal and neurologic disruption. The incidence of compartment syndrome as a result of prolonged ischemia in

380

PART

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the upper extremity is reported to be significantly lower than that for lower extremity injuries; however, careful follow-up for adequate perfusion and avoidance of postischemia muscle contracture must be part of longterm management.

IATROGENIC INJURY Despite the evolution of increasingly sophisticated methods of imaging for infants and children, the potential for damage to the vascular integrity of a small child or tiny infant remains ever present. There have been numerous reports over the past decade describing this ~ . ~ ~ have been case reports particular p r 0 b l e m . ' . l 2 , ~Many of complications from some usually innocuous maneuver of routine care. Demircin et al.,3 for example, reported an infant with brachial artery pseudoaneurysm resulting from inadvertent puncture during antecubital venipuncture. The lesion was repaired by direct suture under proximal compression. Gamba et al.19 reviewed their experience with iatrogenic vascular lesions in lowbirth-weight neonates. Of 335 infants encountered between 1987 and 1994, 9 (2.6%) were diagnosed with vascular injury. Mean birth weight was 880 g (range, 590 to 1450 g ) , although the mean weight at diagnosis was 1825 g (range, 1230 to 2730 g). Injuries were associated with venipuncture in seven of the nine cases and included six femoral arteriovenous fistulas, two of which were bilateral. One carotid lesion and five femoral arteriovenous fistulas were repaired using microvascular technique. Outcome as determined by follow-up clinical examination and D o ~ ~ l flow e r studies was excellent. leading the authors to emphasize the role of aggressive medical and microsurgical management of these injuries. In 1981 O'Neill et al."? reviewed their experience with the surgical management of 41 infants with-major thromboembolic problems associated with umbilical artery catheters. Although most complications were related to emboli distal to the femoral artery, eight infants required emergency operative intervention for acute aortic obstruction. Four infants underwent transverse aortic thrombectomies, three of whom recovered completely. As principles of umbilical artery catheter management have become better established, these problems appear to have become less frequent. The increasing use of extracorporeal membrane oxygenation has raised the question of the potential need to reconstruct cervical vessels, especially when the process of oxygenation support involves the use of both the carotid artery and the jugular vein. LaQuaglia et a1.2Vescribed their experience in nine children with iatrogenic arterial injuries repaired with microsurgery. An operating microscope was routinely used, and repair was performed using 9-0 to 11-0 nylon suture. Spasm was controlled with topical 2% lidocaine or papaverine. As microsurgical technique continues to evolve and better suture materials become available, this approach will become an increasingly valuable adjunc; ko the management of major injuries to tiny vessels. The femoral artery remains the most common site of iatrogenic injury. As noted earlier in the discussion of

.

L

traumatic injury, efficient collateralization of the pelvis and gluteal region may result in these lesions remaining clinically silent throughout most of childhood. Lin et a1.28 analyzed 1674 diagnostic or therapeutic catheterizations performed in 1431 infants between 1986 and 2001. Thirty-six procedures were required in 34 children. The authors stratified complications into nonischemic, acute femoral ischemia, and chronic femoral ischemia. Nonischemic lesions included pseudoaneurysms ( n = 4), arteriovenous fistulas ( n = 5), and groin hematomas ( n = 5 ) . All were repaired directly, using interrupted polydioxanone (PDS) or polypropylene (Prolene) sutures. Acute femoral ischemic lesions were the most common and required a variety of procedures from thrombectomy to patch repair. Chronic femoral ischemia was defined as evidence of flow disruption noted after 30 days post procedure. Seven children presented with clinical signs an average of 193 days (range, 31 to 842) after the index procedure. All seven were symptomatic with claudication, leg length discrepancy, or gait disturbance. Operative repair consisted of revascularization using reversed saphenous vein for ileofemoral bypass in five children and femorofemoral bypass in one child. Only one child required patch angioplasty. The authors' analysis of potential contributory factors identified a statistically significant predictive relationship for patient age younger than 3 years, more than three previous catheterizations, performance of a therapeutic versus simple diagnostic maneuver, and use of guiding catheters larger than 6 French. The value of this study lies both in the identification of potentially predictive factors and in the documentation of the relatively short time required for chronic ischemia to become symptomatic. Children at risk of vascular injury with any abnormal clinical finding must be followed for at least 5 years, and preferably through the start of adolescence. Limb length discrepancy as a result of disruption of a major vascular structure may not become manifest until years after the precipitating event.48 Recent reports have suggested that operative revascularization of iatrogenic injury before adolescence corrects some limb length discrepancy; however, these have been relatively small series and do not represent a consensus. As is the case with the management of traumatic injury, the high proclivity for spasm and the need to differentiate prolonged spasm from arterial disruption are challenging components of the initial assessment. Prolonged spasm is thought to be the result of intimal injury, which causes derangement of nitric oxide production and disrupts the control of arterial wall tensi0n.'~,~3 When endothelial-medial contact is lost, as can be caused by shearing friction from an oversized or overzealously placed catheter, underlying vascular smooth muscle is incapable of relaxation.2" Angiographic confirmation of spasm requires the additional risk of the very mechanism suspected of causing the problem. Computed tomography-angiography or magnetic resonance arteriography may be the solution to this clinical conundrum, although the dose and concentration of contrast must be carefully considered when comparing risk and benefit. The role of spasm in causing gangrene is controversial, despite case reports suggesting cause and effe~t.~2

CHAPTER

From a clinical perspective, once spasm has been confirmed to be the sole cause of diminished peripheral perfusion, management must focus on the confirmation of evidence of tissue viability and absence of signs of evolving compartment syndrome or peripheral ischemia. Assuming that the basic cause of acute spasm is at least partly related to intimal injury, the risk of thrombosis must be a primary consideration. Over the past few years, routine anticoagulation therapy has been supplemented by thrombolytic agents, especially urokinase.Z0 Recommended doses of urokinase vary and tend to be empirical. Up to 6000 U/kg per hour have been used in infants, with good success and no complications. Most recently, a report by Zenz et a1.49on the use of tissue plasminogen activator suggested that more rapid restoration of flow could be achieved with this drug.

Digital Ischemia Syndrome Intravenous catheter-related, ipsilateral digital ischemia may suddenly develop in infants or small children with an acute infectious disease, usually associated with dehydration and hypovolemia. In a review of 104 cases, Villavicencio et a1.47reported primary involvement of the hand in 68.2% of patients and of the foot in the remainder. The age of the patients ranged from 29 days to 36 months (mean age, 14 months). The infectious process was of respiratory origin in 27.8% of cases, localized to the gastrointestinal tract in 60.5%, and localized to other areas in 11.5%. The most frequently cultured microorganisms were Escherichia coli, Salmonella, Shigella, Streptococcus, Staphylococcus, Klebsiella, and Pseudomonas. Digital cyanosis usually occurs shortly after venous cannulation and is probably the result of venospasm provoked by the presence of an indwelling catheter. As described earlier, damaged endothelium may stimulate vasoconstriction. Immobilization causes constriction of the limbs and impairs the muscle action that is necessary to assist venous return. Persistence of these conditions increases extravascular pressure and gradually produces microcirculatory failure, leading to necrosis, which begins at the most distal areas of the digits. Treatment begins with the prompt recognition of persistent cyanosis, correction of the underlying systemic disorder, and immediate removal of the catheter. Anticoagulation should be initiated immediately. Lesions should be gently washed daily in warm water, and the involved limb should be actively and passively exercised through the full range of motion. Direct heating should be avoided because ischemic tissue burns at lower temperatures than normal. Small pieces of cotton should be placed between fingers or toes, and all lesions should be covered with sterile, dry dressings. Areas of dry gangrene do not require surgical removal. If some question of infection trapped under an eschar exists, the area can be gently elevated at its corners to allow adequate drainage. As is the case with arterial lesions, amputation should not be considered until clear demarcation has occurred.

22

Vascular Injury

381

SUMMARY Vascular injury in the pediatric population is considerably different from that encountered in adults. Traumatic injury presents a unique set of characteristics that reflect the epidemiology of pediatric trauma and, if carefully managed, can exploit the intrinsically healthy status of the child's vascular system. Iatrogenic injury is the price of miniaturization. It is a recognized trade-off for the dramatic advances that have made many lifesaving procedures possible. Attention to detail in those most at risk may not eliminate the problem but will at least reduce the incidence and raise awareness. Accurate diagnosis, timely revascularization, and aggressive management of reperfusion are essential for complete recovery and normal long-term growth. The key to success is a high index of suspicion, recognition of the unique characteristics discussed ealier, and aggressive operative intervention using the high level of precision that is the cornerstone of success in the surgical care of children.

REFERENCES 1. Chaikof EL, Dodson TF, Salam AA, et al: Acute arterial thrombosis in the very young. J Vasc Surg 1992;16: 428-435. 2. Cox CS Jr, Black CT, Duke JH, et al: Operative treatment of truncal vascular injuries in children and adolescents. J Pediatr Surg 1998;33:462-467. 3. Demircin M, Peker 0 , Tok M, et al: False aneurysm of the brachial artery in an infant following attempted venipuncture. Turk J Pediatr 1996;38:389-391. 4. Dennis JW, Frykberg ER, Crump JM, et al: New perspectives on the management of penetrating trauma in proximity to major limb arteries. J Vasc Surg 1990;11:8492. 5. Dennis JW, Frykberg ER, Veldenz HC, et al: Validation of nonoperative management of occult vascular injuries and accuracy of physical examination alone in penetrating extremity trauma: 5- to 10-year follow-up. J Trauma 1998; 44:242 (discussion). 6. Dennis JW, Jagger C, Butcher JL, et al: Reassessing the role of arteriogram in the management of posterior knee dislocations. J Trauma 1993;35:692-695. 7. de Virgilio C, Mercado PD, Arnell T, et al: Noniatrogenic pediatric vascular trauma: A ten-year experience at a level I trauma center. Am Surg 1997;63:781-784. 8. Eddy AC, Rusch VW, Marchioro T, et al: Treatment of traumatic rupture of the thoracic aorta: A 15-year experience. Arch Surg 1990;125:1351 (discussion 1355). 9. Eren N, Ozgen G, Ener BK, et al: Peripheral vascular injuries in children. J Pediatr Surg 1991;26:11641168. 10. Fagelman MF, Epps HR, Rang M: Mangled extremity severity score in children. J Pediatr Orthop 2002;22:182-184. 11. Fayiga YJ, Valentine RJ, Myers SI, et al: Blunt pediatric vascular trauma: Analysis of forty-one consecutive patients undergoing operative intervention. J Vasc Surg 1994; 20:419 (discussion 424). 12. Flanigan DP, Keifer TJ, Schuler JJ, et al: Experience with iatrogenic pediatric vascular injuries: Incidence, etiology, management, results. Ann Surg 1983;198:430-442. 13. Francis H, Thal ER, Weigelt JA, et al: Vascular proximity: Is it a valid indication for arteriography in asymptomatic patients? J Trauma 1991;31:512-514.

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14. Friedman RJ, Jupiter JB: Vascular injuries and closed extremity fractures in children. Clin Orthop 1984;188: 112-119. 15. Frykberg ER: Advances in diagnosis and treatment of extremity vascular trauma. Surg Clin North Am 1995; 75:207-223. 16. Frykberg ER, Crump JM, Dennis JW,et al: Nonoperative observation of clinically occult arterial injuries: A prospective evaluation. Surgery 1991;109:85-96. 17. Frykberg ER, DennisJW, Bishop K, et al: The reliability of physical examination in the evaluation of penetrating extremity trauma for vascular injury: Results at one year. J Trauma 1991;31:502-511. 18. Furchgott RF, ZawadzkiJV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376. 19. Gamba P, Tchaprassian Z, Verlato F, et al: Iatrogenic vascular lesions in extremely low birth weight and low birth weight neonates. Vasc Surg 1997;26:643-646. 20. Giacoia GP: High-dose urokinase therapy in newborn infants with major vessel thrombosis. Clin Pediatr 1993; 32:231-237. 21. Harris LM, Hordines J: Major vascular injuries in the pediatric population. Ann Vasc Surg 2003;17:266269. 22. Hoover JD, Almond PS: Isolated pediatric peripheral vascular injury caused by blunt trauma: A new occurrence. J Trauma 2004;56:198-200. 23. Itani KM, Rothenberg SS, Brandt ML, et al: Emergency center arteriography in the evaluation of suspected peripheral vascular injuries in children. J Pediatr Surg 1993;28:677-680. 24. Klein MD, Coran AG, Whitehouse WM Jr, e t al: Management of iatrogenic arterial injuries in infants and children. J Pediatr Surg 1982;17:933-939. 25. Kuo PC, Schroeder RA: The emerging multifaceted roles of nitric oxide. Ann Surg 1995;221:220-235. 26. LaQuaglia MP, Upton J, May JW Jr: Microvascular reconstruction of major arteries in neonates and small children. J Pediatr Surg 1991;26:1136-1140. 27. Lewis HG, Morrison CM, Kennedy PT, et al: Arterial reconstruction using the basilic vein from the zone of injury in pediatric supracondylar humeral fractures: A clinical and radiological series. Plast Reconstr Surg 2003;111:1159 (discussion 1 164). 28. Lin Ph, Dodson TF, Bush RL, et al: Surgical intervention for complications caused by femoral artery catheterization in pediatric patients. J Vasc Surg 2001;34:1071-1078. 29. McCorkell SJ, Harley JD, Morishima MS, et al: Indications for angiography in extremity trauma. AJR Am J Roentgenol 1985;145:1245-1247. 30. Meagher DP Jr, Defore WW, Mattox KL, et al: Vascular trauma in infants and children. J Trauma 1979;19:532-536. 31. Milas ZL, Dodson TF, Ricketts RR: Pediatric blunt trauma resulting in major arterial injuries. Am Surg 2004;70:443447.

32. Mills RP, Robbs JV: Paediatric arterial injury: Management options at the time of injury. J R Coll Surg Edinb 1991; 36:13-17. 33. Moncada S, Higgs A: The L-arginine:nitric oxide pathway. N Engl J Med 1993;329:2002-2012. 34. Nehler MR, Taylor LM Jr, Porter JM: Iatrogenic vascular trauma. Semin Vasc Surg 1998;11:283-293. 35. O'Neill JA, Neblett WW, Born ML: Management of major thromboembolic complications of umbilical artery catheters. J Pediatr Surg 1981;16:972-978. 36. Pigula FA, Buenaventura P, Ettedgui JA, et al: Management of retroperitoneal arterial injury after heart catheterization in children. Ann Thorac Surg 2000;69:1582-1584. 37. Reed MK, Lowry PA, Myers SI: Successful repair of pediatric politeal artery trauma. Am J Surg 1990;160:287-290. 38. Reichard KW, Hall JR, Meller JL, et al: Arteriography in the evaluation of penetrating pediatric extremity injuries. J Pediatr Surg 1994;29:19-22. 39. Reichard KW, Reyes HM: Vascular trauma and reconstructive approaches. Semin Pediatr Surg 1994;3:124132. 40. Reid.JD,WeigeltJA, Thal ER, et al: Assessment of proximity of a wound to major vascular structures as an indication for arteriography. Arch Surg 1998;123:942-946. 41. Rozycki GS, Tremhlay L, Feliciano DV, et al: A prospective study for the detection of vascular injury in adult and pediatric patients with cervicothoracic seat belt signs.J Trauma 2002;52:618 (discussion 623). 42. Russo VJ: Ti-aumatic arterial spasm resulting in gangrene. J Pediatr Orthop 1985;5:486488. 43. SeibertJ, Northington FJ, Miers JF, et al: Aortic thrombosis after umbilical artery catheterization in neonates: Prevalence of complications of long-term follow-up. AJRAm J Roentgenol 1991;156:567-569. 44. Soares G, Ibarra R, Ferral H: Abnominal aortic injury in a child: intravenous digital substraction angiogram (rVDSA) for the diagnosis of pediatric vascular trauma. Pediatr Radio1 2003;33:563-566. 45. Uslu MM, Altun NS, Gila E, at al: Relevance of mangled extremity severity score to compartment syndromes. Arch Orthop Trauma Surg 1995;114:229-232. 46. Victoroff BN, Robertson WW Jr, Eichelberger MR, et al: Extremity gunshot injuries treated in an urban children's hospital. Pediatr Emerg Care 1994;lO:l-5. 47. Villavicencio JL, Gonzalez-Carna JL: Acute vascular problems of children. Curr Probl Surg 1985;22:1-85. 48. Whitehouse WM, Coran AG, Stanley IC, et al: Pediatric vascular trauma: Manifestations, management, and sequelae of extremity arterial injury in patients undergoing surgical treatment. Arch Surg 1976;111:1269-1275. 49. Zenz W, Muntean W, Beitzke A, et al: Tissue plasminogen activator (Alteplase) treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. Br Heart J 1993;70:382-385.

Burns Dai H. Chung, Arthur I? Sanford, and David N. Herndon

In 1944 Lund and BrowderGg developed a diagram that allowed a quantifiable assessment of the percentage of total body surface area (TBSA) burned. While treating victims of the Coconut Grove fire in Boston in 1946, Cope and Moore18 were able to quantify the amount of fluid required to maintain the central electrolyte composition after "burn shock." In the 1960s the discovery of efficacious topical antimicrobial agents, such as 0.5% silver nitrate,75 mafenide acetate (Sulfamylon),68 and silver sulfadiazine ( S i l ~ a d e n e )had , ~ ~ a significant impact on reducing the incidence of burn wound sepsis. These and other advances in burn care during the past several decades have resulted in an overall i m ~ r & e d survival rate for major burn patients. In recent years, continued progress has been made in several areas of burn care. Early surgical excision of eschar and grafting have significantly minimized the incidence of burn wound sepsis and shortened the total length of hospital stay. Treatment with anabolic agents restores net positive nitrogen balance during the prolonged postburn hypermetabolic period. Acute recognition of inhalation injury and effective treatment have also improved the overall outcome for burn patients. These are but a few of the significant advances that have led to a further decline in burn-related deaths.Voday, the overall increased survival rate among major burn victims is most evident in the pediatric population, where the mortality rate is 50% in children 14 years and younger with 98% TBSA burns; in other age groups it is 50% for those with 75% TBSA burns."' Although the overall incidence of burn injuries has declined as a result of preventive measures and legislation, more than 1 million burn injuries still occur each year in the United States. Fortunately, most of these burn injuries are minor, but approximately 45,000 patients suffer moderate to severe burns that require hospitalization. Of these cases, 67% are young males, and 40% are children younger than 15 years3 As the second leading cause of accidental death in children younger than 5 years, burns resulted in 532 pediatric deaths in 2001. In 2002 an estimated 92,500 children younger than 14 years were treated in hospital emergency rooms for burn-related injuries (58,100 with thermal burns and 22,600 with scald burns)." Of the children aged 4

and younger who are hospitalized for burn-related injuries, 65% have scald burns, 20% have contact burns, and the remainder have flame burns. The majority of scald burns in infants and toddlers are from hot foods and liquids. Hot grease spills are notorious for causing deep burns to the involved areas. Hot tap-water burns, which can easily be prevented by installing special faucet valves so that water does not leave the tap at a temperature above 120°F (48.8"C), frequently result in large burned areas in children.' Children also suffer productrelated contact burns from curling irons, ovens, steam irons, and fireworks. Contact with the electrical current in wall outlets also causes a significant percentage of injuries, as does contact with electrical cords. Child abuse also represents a significant cause of burns in children (Fig. 23-1). Burns with bilateral symmetry or a stockingdistribution, particularly t; the dorsum of hands, along with a delay in seeking medical attention, should raise the suspicion of child abuse. In the adolescent age group, flame burns are more common, frequently occurring as a result of experimenting with fire and volatile agents.

, . Scald burn of lower extremities in an infant. Bilateral stocking distribution with well-demarcated margins is consistent with a burn injury resulting from child abuse.

383

384

PART

I1

TRAUMA

PATHOPHYSIOLOGY As the largest organ in the body, the skin maintains fluid and electrolyte homeostasis, guards against harmful environmental insults, and acts as a barrier to infection. Other important functions include thermoregulation, metabolism of vitamin D production, and processing of neurosensory inputs. The total surface area of skin ranges from 0.2 to 0.3 m2 in a typical newborn and 1.5 to 2.0 m2 in an adult, making up nearly 15% of total body weight. Anatomically, the epidermis is composed primarily of epithelial cells, specifically keratinocytes. The process of epidermal maturation from the basal layer of keratinocytes to desquamation generally takes about 2 to 4 weeks. The dermis is made up of fibroblasts, which produce collagen and elastin, and is subdivided into a superficial papillary dermis and a deep reticular dermis. The papillary dermis and reticular dermis are separated by a plexus of nerves and blood vessels. The reticular dermis and fatty layer contain skin appendages, such as hair follicles, sweat glands, and sebaceous glands. Therefore, burns involving the deep dermis are generally insensate to touch and painful stimuli. Thermal injury results in coagulation necrosis of the epidermis and varying degrees of injury to the underlying tissue. The extent of burn injury depends on the temperature, duration of exposure, skin thickness, ability of the skin to dissipate heat, and specific heat of the causative agent. For example, the specific heat of fat is higher than that of water; therefore, grease burns often result in much deeper burns than do scald burns from water with the same temperature and duration of exposure. Thermal energy is easily transferred from high-energy molecules to those of lower energy during contact, through the process of heat conduction. The skin generally provides a barrier to the transfer of energy to deeper tissues; therefore, much of the burn injury is confined to this layer. However, local tissue response to the zone of initial burn injury can lead to progressive destruction of surrounding tissue. The area of cutaneous burn injury is divided into three zones: coagulation, stasis, and hyperemia (Fig. 23-2). The zone of coagulation comprises the initial burn eschar, where cells become irreversibly damaged and necrotic at the time of injury. The area immediately surrounding the necrotic area is a zone of stasis, where most cells are initially viable but tissue perfusion becomes progressively

impaired from the local release of inflammatory mediators such as thromboxane A2,arachidonic acid, oxidants, and cytokines.95 Their influence on the microcirculation results in the formation of platelet thrombus, neutrophil adherence, fibrin deposition, and vasoconstriction, which lead to cell necrosis. However, adequate wound care and resuscitation may reverse this process and prevent extensive cell necrosis. Thromboxarie A2 inhibitors can significantly improve dermal blood flow to decrease the zone of stasis.19 Antioxidants as well as bradykinin antag~ ~ , ~ ~of onists also improve local blood f l o ~ . Inhibition neutrophil adherence to endothelium with anti-CD18 or anti-intercellular adhesion molecule monoclonal antibodies improves tissue perfusion in animal models.H,% Peripheral to the zone of stasis lies the zone of hyperemia, which is characterized by vasodilatation and increased blood flow as part of the inflammatory response. The burn-induced inflammatory response is not limited to the local wound in burns involving greater than 40% TBSA. A massive systemic release of thromboxane A2, along with other inflammatory mediators (bradykinin, leukotrienes, catecholamines, activated complement, vasoactive amines), imposes a major physiologic burden on the cardiopulmonary, renal, and gastrointestinal (GI) systems.97 Decreased plasma volume due to increased capillary permeability and subsequent plasma leak into the interstitial space can lead to depressed cardiac function. As a result of low cardiac output, renal blood flow can decrease, leading to a diminished glomerular filtration rate. Activation of other stress-induced hormones and mediators, such as angiotensin, aldosterone, and vasopressin, can further compromise renal blood flow, resulting in 0liguria.7~If not properly treated, this condition can progress to acute tubular necrosis and renal failure, which is associated with a poor outcome for burn patients.61 Atrophy of small bowel mucosa occurs as a result of increased epithelial apoptosis and decreased epithelial proliferation.l~l7JO0Intestinal permeability to macromolecules, which are normally repelled by an intact mucosal barrier, increases after a burn i n j ~ 1 r y . 1 ~ ~ ~ ~ ~ Transient mesenteric ischemia is thought to be an important contributing factor to increased intestinal permeability, which can result in a more frequent incidence of bacterial translocation and subsequent endotoxemia. Burn injury also causes a global depression of immune function. Macrophage production is decreased; neutrophils are impaired in terms of their functions such

.

-

Three zones of

burn injury: coagulation, stasis, and hyperemia.

Subcutaneous

Superficial 2" burn

Deep 2" burn

CHAPTER

23

Burns

385

as diapedesis, chemotaxis, and phagocytosis; cytotoxic ~ - 1 ~ m p h o c ~activity te is decreased: These impaired functions of neutrophils, macrophages, and T lymphocytes contribute to an increased risk for infectious complications after burns.j,6,"',7sfi4J01

First Aid A burn patient must immediately be removed from the source of burn injury, and potential life-threatening injuries must be quickly assessed and addressed independent of the cutaneous burns, as in the case of a multiple trauma victim. Burned clothing and metal jewelry are removed. Immediate cooling by pouring cold water onto the surface of burn wounds must be used with caution to avoid hypothermia. After the removal of clothing, the patient should be kept warm in blankets. With chemical burns, wounds should be irrigated with copious amounts of water, taking care not to spread the chemical to adjacent uninvolved areas. Attempts to neutralize chemicals are contraindicated, as this process may produce additional heat and increase the burn injury. As with any trauma patient, burn patients are quickly assessed through primary and secondary surveys. In the primary survey, airway, breathing, and circulation are assessed, and any potential life-threatening conditions are identified and treated quickly. Symptoms such as wheezing, tachypnea, and hoarseness indicate impending major airway problems; the airway must be rapidly secured with intubation and 100% oxygen support. Oxygen saturation is monitored using a pulse oximeter, and chest expansion is observed to ensure equal air movement. However, adequate oxygen saturation does not mean that the airway is protected, because children have the ability to compensate until just before catastrophic airway collapse occurs. Circumferential full-thickness burns to the chest can significantly impair respiratory function by constricting the trunk and preventing adequate chest expansion. If necessary, escharotomy should be performed to allow better chest expansion and subsequent ventilation. Blood pressure may be difficult to obtain in burned patients with charred extremities. Pulse rate can be used as an indirect measure of intravascular volume; the presence of tachycardia is an indication of the continued need for aggressive fluid resuscitation. Burn depth is categorized according to the involved layers of skin: epidermis, papillary dermis, reticular dermis, subcutaneous fat, and underlying structures (Fig. 23-3). First-degree burns are confined to the epidermis, which is intact, erythematous, and painful to touch. The application of topical ointment containing aloe Vera and the administration of oral nonsteroidal anti-inflammatory agents constitute standard treatment. First-degree burns (e.g., sunburn) heal spontaneously without scarring in 7 to 10 days. Second-degree burns are divided into superficial and deep, based on the depth of dermal involvement. Superficial second-degree burns are limited to the papillary dermis and are typically erythematous and painful with blisters. These burns spontaneously

Reticular

Deep

I

-2"-Burn - - -I

I I I I

Subcutaneous fat

3" Burn I ------I , Bum depth. Firstdegree burns are confined to the epidermis. Superficial seconddegree burns involve the papillary dermis, and deep seconddegree burns involve reticular dermis. Thirddegree burns are full-thickness injuries through the epidermis and dermis. (Adapted from Wolf S, Hemdon DN: Burns. In Townsend CM J r [ed]: Textbook of Surgery, 17th ed. Philadelphia, WB Saunders, 2004, p 571.)

re-epithelialize in 10 to 14 days from retained epidermal structures and may leave only slight skin discoloration. Deep second-degree burns extend into the reticular layer of the dermis. The deep epidermal appendages allow some of these wounds to heal slowly over several weeks, usually with significant scarring. Third-degree burns are full-thickness injuries resulting in complete destruction of the epidermis, dermis, and dermal appendages and are characterized by a dry, leathery eschar that is insensate to any stimuli. Without any residual epidermal or dermal appendages, such burn wounds heal by re-epithelialization from the edges. Fourthdegree burns, typically resulting from profound thermal or electrical injury, involve organs beneath the layers of the skin, such as muscle and bone. An accurate and rapid determination of burn depth is vital to the proper management of burn injuries. In particular, the distinction between superficial and deep dermal burns is critical, as this dictates whether the burn can be managed without surgical procedures. Unfortunately, the determination of whether an apparent deep dermal burn will heal in 3 weeks is only about 50% accurate, even when made by an experienced surgeon. Early excision and grafting provide better results than nonoperative therapy for such indeterminate burns. More precise, objective methods to determine burn depth include techniques such as laser Doppler flowmetry and fluorescein to determine blood flow; ultrasonography to detect denatured collagen; and light reflectance of the Ultimately, burn wound biopsy is the most precise diagnostic too1j3; however, it is not clinically useful because it is invasive and indicates only the static condition of the wound. It also requires an experienced pathologist to interpret histologic findings. Despite these modern technologies, clinical observation is still the most reliable method of determining burn depth.

386

PART

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TRAUMA

Full-thickness circumferential burns to the extremities produce a constricting eschar, which may result in vascular compromise to the distal tissues, including nerves. Accumulation of tissue edema beneath the nonelastic eschar impedes venous outflow, resulting in a compartment syndrome and eventually affecting arterial flow. When distal pulses are absent on palpation or Doppler examination, escharotomies of the extremities are performed to avoid vascular compromise of the limb tissues, after confirmation of the absence of a central circulation problem. Using either a scalpel or electrocautery, escharotomies are performed at the bedside along the lateral and medial aspects of the involved extremities (Fig. 23-4). When the hands are involved, incisions are carried down onto the thenar and hypothenar eminences and along the dorsolateral aspects of the digits, taking care to avoid injury to the neurovascular bundle. Because injuries requiring escharotomy are typically full thickness, minimal bleeding is encountered. If vascular compromise has been prolonged, reperfusion after an escharotomy may cause reactive hyperemia and further edema formation in the muscle compartments. Ischemia-reperfusion injury also releases free oxygen radicals, resulting in transient hypotension. If increased compartment pressures are noted, fasciotomy should be performed immediately to avoid permanent ischemic injuries to the nerves and soft tissues. Intravenous (IV) access should be established immediately to infuse lactated Ringer's solution according to resuscitation guidelines. Peripheral IV access is preferred, but femoral venous access is an ideal alternative in patients with massive burns. If the only IV access available is through burned tissue, this route should be chosen for immediate resuscitation and later changed to a more

appropriate site under sterile conditions. When vascular access is problematic in small children with burned extremities, the intraosseous route is an alternative in those younger than 6 years. A nasogastric tube is placed in all patients with major burns to combat the onset of gastric ileus. Almost immediate enteral nutrition can be initiated via a transpyloric feeding tube. A Foley catheter is placed to accurately monitor urine output as a measure of end-organ perfusion. Admission laboratory studies should include complete blood count, type and crossmatch for packed red blood cells, chemistry, urinalysis, coagulation profile, and chest radiograph. If inhalation injury is suspected, arterial blood gas with carboxyhemoglobin level should also be determined to guide respira
a

Fluid Resuscitation

.

-

Escharotomies. The incisions are made on the

medial and lateral aspects of the extremity. Hand escharotomies are performed on the medial and lateral digits and on the dorsum of the hand. (From Eichelberger MR [ed]: Pediatric Trauma: Prevention, Acute Care, Rehabilitation. St Louis, Mosby, 1993, p 569.)

Appropriate fluid resuscitation should begin promptly upon securing IV access. Peripheral IV access is sufficient in the majority of small to moderate burns. Saphenous vein cutdowns are useful in cases of difficult access; in children, however, percutaneous femoral central venous access may be easier and more reliable. There are many fluid resuscitation guidelines for delivering various concentrations of colloid and crystalloid solutions. The Parkland formula (4 mL of lactated Ringer's solution per kilogram of body weight per percentage of TBSA burned) is most widely used, but children's fluid resuscitation requirements should be based on body surface area rather than weight. Because children have' a greater body surface area in relation to weight, weight-based formulas can underresuscitate children with minor burns and may grossly overresuscitate those with extensive burns.36TBSA can be rapidly estimated from height and weight using standard nomograms (Fig. 23-6). The Galveston formula (Shriners Hospital for Children) uses 5000 mL/m%urned plus 2000 mL/m2 TBSA of lactated Ringer's solution given over the first 24 hours after the injury, with half the volume administered during the first 8 hours and the remaining half over the next 16 hours (Table 23-2).

CHAPTER

23

Burns

10

Adult (Rule of nines) a

-

Modified "rule of nines" for pediatric patients. (From Herndon DN [ed]: Total Burn Care, 2nd ed. Philadelphia, WB Saunders,

2002, p 429.)

albumin is added 12 hours after the injury. After the first 24 hours, 3'750 mL/m2 burned of lactated Ringer's solution is given to replace evaporative fluid loss, plus 1500 mL/m2 TBSA per 24 hours for maintenance. A dextrose-containing solution, such as 5% dextrose with one quarter to one half normal saline, is used as the primary solution. Children younger than 2 years are susceptible to hypoglycemia due to limited glycogen stores; therefore, lactated Ringer's solution with 5% dextrose is given during the first 24 hours after burns.

Regardless of which guidelines are used, the primary goal of fluid resuscitation is to achieve adequate organ tissue perfusion. Fluid administration should be titrated to maintain a urine output of greater than 1 mL/kg per hour. Approximately 50% of administered fluid is sequestered in nonburned tissues in 50% TBSA burns, owing to the increased capillary permeability that occurs, particularly in the first 6 to 8 hours after injury.z1 During this period, large molecules leak into the interstitial space to increase extravascular colloid osmotic pressure. Therefore, to maintain intravascular osmotic pressure,

Area Head Neck Anterior trunk Posterior trunk Buttock Genitalia Upper arm Lower arm Hand Thigh

<1Year 19 2 13 13 2.5 1 4 3 2.5 5.5 5 3.5

1-4 Years

17 2 13 13 2.5 1 4

3 2.5 6.5 5 3.5

5-9 Years

10-14 Years

13 2 13 13 2.5 1 4

3 2.5 8

5.5 3.5

I

Burn size estimates based on the area burned are more precise than the rule of nines for pediatric patients.

1 5 Years

Adult

11 2 13 13 2.5 1

9 2 13 13 2.5 1

7 2 13 13 2.5 1

4

4

4

3 2.5 8.5 6 3.5

3 2.5 9 6.5 3.5

3 2.5 9.5 7 3.5

388

PART

I1

~eibht

TRAUMA

For children of normal height for weight

-

, Standard nomogram for the determination of body surface area based on height and weight. A straight line drawn between the height and weight measurements determines the total body surface area in square meters.

- 1.30 80 7- 1.20 70--1.10 -

-

6 --0.20

4--0.15

-

Children often d o not exhibit clinical signs of hypovolemia until more than 25% of the circulating volume is depleted and complete cardiovascular collapse is imminent. Tachycardia reflects a compensatory response to hypovolemia, but caution is needed to avoid overinterpreting this finding, because reflex tachycardia

due to postinjury catecholamine response is common. A lethargic child with decreased capillary refill and cool, clammy extremities needs prompt attention. Measurement of arterial blood pH and base deficit values can also reflect the adequacy of fluid resuscitation. Hyponatremia is a frequent complication in pediatric burn patients

-

First 24 Hours

--

Parkland

Brooke

Galveston

-Thereafter

Lactated R~nger'ssolut~on4 mL/kg/% TBSA burned; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr Lactated Ringer's solution (with colloid 0.5 mL/kg/% TBSA burned) 2 mL/kg/% TBSA burned; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr Lactated Ringer's solution (12.5 g albumin/L added 1 2 hr after injury) 5000 mL/m2 burned + 2000 mL/m2 total; 50% total volume during first 8 hr after injury and remaining 50% over subsequent 1 6 hr

L

TBSA, total body surface area.

5% dextrose wlth Na+, K+, and album~nto ma~nta~n normal serum electrolytes and colloid oncotic pressure Titrate to maintain urine output 0.5-1.0 mL/kg/hr

3750 mL/m2 burned + 1500 mL/m2 total; substitute IV fluid volume with enteral formula

__1

CHAPTER

after aggressive fluid resuscitation. Frequent monitoring of serum chemistry with appropriate correction is required to avoid severe electrolyte imbalance. A serious complication such as central pontine myelinolysis can occur as a result of careless, rapid correction of hypernatremia.' Hypertonic saline resuscitation can be beneficial in treating bum-induced shock.74~96This process maintains intravascular volume more effectively by removing fluid from the interstitial space through osmosis, thus decreasing generalized tissue edema. However, it is not widely used because of the potential risk of hypernatremia, hyperosmolarity, renal failure, and alkalosis.""g7 Some favor the use of a modified hypertonic solution-adding an ampule of sodium bicarbonate to each liter of lactated Ringer's solution during the first 24 hours of re~uscitation.'~ After initial first aid and the start of appropriate fluid resuscitation, transferring the patient to a tertiary burn center should be considered. Burn units with experienced multidisciplinary teams are best prepared to treat patients with major burns. In addition to physicians and nurses, respiratory and rehabilitation therapists play a critical role in the management of acute burns. Any patient who sustains a "major burn injury," as defined by the American Burn Association (Table 23-3), should be transferred to a nearby burn center for further care.

Topical Antimicrobials Proper wound care is guided by an accurate assessment of burn depth and size. First-degree burns require no dressing, but the involved areas should be kept out of direct sunlight. They are generally treated with topical ointments for symptomatic pain relief. Superficial seconddegree burns are treated with daily dressing changes and topical antimicrobials. They can also be treated with simple application of petroleum gauze or synthetic dressings to allow rapid, spontaneous re-epithelialization.Deep second- and third-degree burns require excision of eschar and skin grafting.

Second- and third-degree burns > l o % TBSA in patients aged < I 0 or >50 yr Second- and third-degree burns >20% TBSA in other age groups Third-degree burns >5% TBSA in any age group Burns involving the face, hands, feet, genitalia, perineum, and skin overlying major joints Significant chemical burns Significant electrical burns, including lightning injury Inhalation injury Burns with significant concomitant trauma Burns with significant preexisting medical disorders Burns in patients requiring special social, emotional, and rehabilitative support (including suspected child abuse and neglect) TBSA, total body surface area.

23

Burns

389

Antimicrobial Agent

Characteristics

Silver sulfadiazine (Silvadene)

Broad-spectrum activity and painless; does not penetrate eschar; impairs epithelialization; leukopenia Broad-spectrum activity, including Pseudomonas; penetrates eschar; painful in second-degree burns; may cause metabolic acidosis (inhibits carbonic anhydrase inhibitor) and inhibition of epithelialization Broad-spectrum activity; does not penetrate eschar; discolors contacted areas; may cause hyponatremia, methemoglobinemia Painless, but limited antimicrobial activity Inhibits fungal growth; frequently used in combination with Silvadene Effective against Staphylococcus Broad-spectrum activity, but possible systemic absorption Effective against almost all microbes

Mafenide acetate (Sulfamylon; 10% cream or 5% soaks)

Silver nitrate (0.5%)

Bacitracin/Polysporin Nystatin Mupirocin (Bactroban) Povidone-iodine Dakin solution (0.025%)

Table 23-4 lists topical antimicrobial agents used for the management of burn wounds. None of these agents effectively prevents the colonization of organisms that are commonly harbored in the eschar, but they maintain the bacterial quantity at less than 10' to lo5 colonies per gram of tissue. Routine punch quantitative wound biopsy can indicate impending burn wound sepsis and possible failure of skin graft from infection. Silver sulfadiazine (Silvadene) is the most commonly used topical agent for burn wound dressings. Although it does not penetrate eschar, it has a broad spectrum of efficacy and soothes the pain associated with seconddegree burns. Silver sulfadiazine on fine mesh gauze can be used separately or in combination with other antimicrobial agents, such as nystatin. This combination, providing additional antifungal coverage, has significantly reduced the incidence of Candida infection in burned patients.z.24 The most common side effect is leukopenia; however, this is caused by margination of white blood cells and is only transient." When the leukocyte count falls below 3000 cells/mm" changing to another topical antimicrobial quickly resolves this complication. Mafenide acetate (Sulfamylon) is more effective in penetrating eschar and is therefore frequently used in third-degree burns. Fine mesh gauze impregnated with Sulfamylon (10%water-soluble cream) is applied directly to the burn wound. Compared with silver sulfadiazine, Sulfamylon has a much broader spectrum of efficacy, including coverage against Pseudomonas and Enterococcus. It is also available in a 5% solution to soak burn wounds, eliminating the need to perform frequent dressing changes. Sulfamylon is a potent carbonic anhydrase inhibitor, so it can cause metabolic acidosis. This side effect can usually be avoided by limiting its use to only 20% TBSA at any one time and rotating application sites

390

PART

I1

TRAUMA

every several hours with another topical agent, such as Silvadene. Additionally, it is painful when applied, limiting its use in an outpatient setting, especially with children. In addition to 5% Sulfamylon solution, 0.5% silver nitrate and 0.025% sodium hypochlorite (Dakin solution) are available. These solutions-are generally poured onto gauze dressings on the wound, avoiding the need for frequent dressing changes and the potential loss of grafts or healing cells. Silver nitrate is painless on application and has broad coverage, but its side effects include electrolyte imbalance (hyponatremia, hypochloremia) and dark gray or black stains. A new commercially available dressing containing biolog~callyactive silver ions' (Acticoat) retains the effectiveness of silver nitrate without the side effects. Dakin solution is effective against most microbes, including Pseudomonas. However, it requires frequent dosing because of the inactivation of hypochlorite when it comes in contact with protein; it can also retard healing - cells.38 Petroleum-based antimicrobial ointments such polymyxin B, bacitracin, and Polysporin are painless and transparent, allowing easier monitoring of burn wounds. These agents are generally effective only against gram-positive organisms, and their use is limited to facial burns, small areas of partial-thickness burns, and healing donor sites. Like Silvadene, these petroleumbased agents can be used in combination with nystatin to suppress skin Candida colonization.

Wound Dressings Superficial second-degree burns can be managed using various methods. Topical antimicrobial dressings using Silvadene are most commonly used, but synthetic dressings such as Biobrane and Opsite offer the unique advantage of eliminating frequent, painful dressing changes and tissue fluid loss. The general principle of these synthetic products is to provide sterile coverage of superficial second-degree burn wounds to allow rapid, spontaneous re-epithelialization of the involved areas. Biobrane is a thin, synthetic material composed of an inner layer of nylon coated with porcine collagen and an outer layer of rubberized silicone. It is pervious to air but not to fluids and is available in simple sheets or preshaped gloves (Fig. 23-7).@jAfter placement on clean, fresh, superficial second-degree burn wounds using Steri-strips and bandages, the Biobrane dressing dries up, becoming adherent to burn wounds within 24 to 48 hours. Once the dressing is adherent, the covered areas are kept open to air and examined closely for the first few days to detect any signs and symptoms of infection. As epithelialization occurs beneath the Biobrane, the sheet is easily peeled off the wound. If serous fluid accumulates beneath the Biobrane, sterile needle aspiration can preserve its use. However, if foul-smelling exudate is detected, the Biobrane should be removed and topical antimicrobial dressings applied. Alternatively, Opsite or Tegaderm can be used to cover superficial second-degree burn wounds. Commonly used as postoperative dressings in surgical patients, both are relatively inexpensive, are easy to apply, and provide

, Biobrane glove. Biobrane is an ideal synthetic wound coverage material for superficial second-degree burns. It promotes rapid re-epithelialization without painful dressing changes.

an impervious barrier to the environment. Their transparent nature allows easy monitoring of covered second-degree burn wounds. Despite lacking any special biologic factors (e.g., collagen and growth factors) to enhance wound healing, they promote a spontaneous re-epithelialization process. Biobrane and Opsite are preferred to topical antimicrobial dressings when dealing with small, superficial second-degree burn wounds, especially in outpatient settings, to avoid the pain associated with dressing changes. TransCyte, composed of human fibroblasts that are then cultured on the nylon mesh of Biobrane, is another option. Synthetic and biologic dressings are also available to provide coverage for full-thicknessburn wounds. Integra, which is made of a collagen matrix with an outer silicone sheet, is a synthetic dermal substitute for the treatment of full-thickness burn wounds. After the collagen matrix engrafts into the wound in approximately 2 weeks, the outer silicone layer is replaced with epidermal autografts. Epidermal donor sites heal rapidly without significant morbidity, and Integra-covered wounds scar less; however, they are susceptible to wound infection and must be monitored carefully. Alloderm is another dermal substitute with decellularized preserved cadaver dermis. These synthetic dermal substitutes have tremendous potential for minimizing scar contractures and improving cosmetic and functional outcome. Temporary wound coverage can be achieved using biologic dressings, such as xenografts from swine and allografts from cadaver donors. Particularly useful when dealing with large TBSA burns, biologic dressings can provide immunologic and barrier functions of normal skin. The areas of xenograft and allograft are eventually rejected by the immune system and sloughed off, leaving healthy recipient beds for subsequent autografts. Although extremely rare, the transmission of viral diseases from allograft is a potential concern.

Excision and Grafting Early excision with skin grafting has been shown to decrease operative blood loss and length of hospital stay

CHAPTER

and ultimately improve the overall survival of burn p a t i e n t ~ . ~ ' ~ ~ V y p i c a tangential lly, excision of a fullthickness burn wound is performed within 3 days of injury, after relative hemodynamic stability has been achieved. The accurate determination of burn depth is vital to proper management. In particular, distinguishing between superficial and deep thermal burns is critical, as this dictates whether the burn wound can be treated with dressing changes alone or requires surgical excision. Eschar is sequentially shaved using a powered dermatome (Zimmer) or knife blades (Watson, Weck) until a viable tissue plane is achieved. Early excision of eschar (usually <24 hours after burns) generally decreases operative blood loss, owing to the actions of vasoconstrictive substances such as thromboxane and catecholamines. Once the burn wound becomes hyperemic 48 hours after injury, bleeding during excision of the eschar can be excessive. Tourniquet and subcutaneous injections of epinephrine-containing solution can lessen-the blood loss, but these techniques may hinder the surgeon's ability to differentiate viable from nonviable tissue.'O A topical hemostatic agent such as thrombin can also be used, but it is expensive and not very effective against excessive bleeding from open wounds. In patients with deep full-thickness burns, electrocautery is used to rapidly excise eschar with minimal blood loss. More importantly, the earlier the excision, the less blood loss is anticipated in burns greater than 30% of TBSA.2Wowever, with scald burns it is more difficult to assess the burn depth initially; therefore, such burns require a more conservative approach, with delayed excision. Ideally, the excised burn wound is covered with autografts. Burns wounds less than 20% to 30% of TBSA can be closed at one operation with split-thickness autografts. Split-thickness autografts are harvested using dermatomes, and donor sites are dressed with petroleumbased gauze, such as Xeroform or Scarlet Red. Opsite can also be used to cover donor sites. Sheet autografts are preferred for a better long-term aesthetic outcome, but narrowly meshed autografts (1:l or 2:l) have the advantages &limiting the total surface area of donor harvest and allowing better drainage of fluid at the grafted sites. With massive burns, the closure of burn wounds is achieved by a combination of widely meshed autografts (4:1 to 6:l) with allograft (2:1) overlay (Fig. 23-8). Repeat grafting is required for large burns, with sequential harvesting of split-thicknessautograft from limited donor

23

Burns

391

sites until the entire burn wound is closed. As the meshed autografts heal, allografts slough off, but the formation of significant scar is a major disadvantage of this techniaue. Therefore, the use of widelv meshed graft is avoided in the face and functionally important hands. A full-thickness graft that includes both dermal and epidermal components provides the best outcome with diminished contracture and in wobnd coverage: " better pigment match. However, its use is generally limited to small areas, owing to the lack of abundant full-thickness donor skin. The limitation of donor sites in massively burned patients is partially addressed with the use of systemic recombinant human growth hormone. Administration of " growth hormone results in accelerated donor site healing, allowing more frequent donor site h a r ~ e s t . ~ ~ . ~ ~ In one study, growth hormone hastened donor site healing time'byan average of 2 days, which ultimately shortened the length of hospital stay from 0.8 to 0.54 day per percent of TBSA burned." These effects of growth hormone are thought to be due to stimulation of insulinlike growth factor-1 (IGF-1) release, along with the induction of IGF-1 receptors in the burn wound.44 Insulin given alone can also decrease donor site healing time from 6.5 to 4.7 days.8' Decreasing the time between each harvest by 1 day can significantly impact the total length of hospital stay in massively burned patients who require multiple grafting procedures. Administration of ~ r o w t hhormone in burned children was also associated " with a 23% reduction in total cost of hospital care for a typical 80% TBSA burn.39 Recently, the use of cultured keratinocytes from the patient's own skin has generated considerable interest as a potential solution for massively burned patients The concept of using with limited donor ~ites.~l,86,91 cultured skin to provide complete coverage is appealing but there are several problems to overcome before it can be widely used. Cultures of keratinocytes grow slowly and, once grafted, are very susceptible to mechanical trauma, resulting in only 50% to 70% graft take. Although a recent report showed that patients with greater than 80% TBSA burns receiving conventional treatment had shorter hospital stays than patients receiving cultured epithelial graft^,^ the latter technology is a potentially attractive concept to treat massively burned patients.

HYPERMmABOLIC RESPONSE

(//

.

l ~ x c i s e wound d

-

Wound coverage with 4:l meshed autograft and 2:l meshed allograft overlay. (From Eichelberger MR [ed]: Pediatric Trauma: Prevention, Acute Care, Rehabilitation. St Louis, Mosby, 1993, p 581.)

Burn patients demonstrate a dramatic increase in metabolic rate. Better understanding of the mechanisms involved in the hypermetabolic response in burn injuries is one of the factors responsible for decreased mortality from massive burns over the last 3 decades. The hypermetabolic response-which is generally greater with increasing burn size but reaches a plateau at 40% TBSA b u r n ~ ~ ~ - -characterized is by increased energy expenditure, oxygen consumption, proteolysis, lipolysis, and nitrogen losses. These physiologic changes are induced by the up-regulation of catabolic agents such cortisol, catecholamine, and glucagon, which act synergistically to increase the production of glucose, a principal fuel

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during acute i n f l a m m a t i ~ n Cortisol .~~ stimulates gluconeogenesis and proteolysis and sensitizes adipocytes to lipolytic hormones. Catecholamines stimulate the rate of glucose production through hepatic gluconeogenesis and glycogenolysis, as well as the promotion of lipolysis and peripheral insulin resistance, in which serum insulin levels are elevated but cells become resistant.j8 The increase in glucagon, which is stimulated by catecholamines, further promotes gluconeogenesis. A significant protein catabolism occurs in severe burns. Cortisol is catabolic and is partially responsible for the loss of tissue protein and the negative nitrogen balance. In addition, burn injury is associated with decreased levels of anabolic hormones, such as growth hormone and IGF-1, which contributes significantly to net protein loss. The synthesis of protein (which is essential for the production of collagen for wound healing), antibodies, and leukocytes to participate in the immune response requires a net positive nitrogen balance. Excess catecholamines in postburn patients also contribute to persistent tachycardia and-lipolysis. The consequences of these physiologic insults are cardiac failure and fatty infiltration of the liver. Growth hormone and IGF-1 levels are decreased after burn injury. Pharmacologic agents have been used to attenuate catabolism and stimulate growth despite a burn injury.77 Growth hormone, insulin, IGF-1, IGF-binding protein9, testosterone, and oxandrolone improve nitrogen balance and promote wound healing.2"37z47,82,gg Exogenous administration of recombinant human growth hormone, which increases protein synthesis, has been shown to improve nitrogen balance, preserve lean muscle mass, The anabolic and increase the rate of wound healing.44,98 action of growth hormone appears to be mediated by an increase in protein synthesis, whereas IGF-1 decreases protein degradation. Growth hormone also enhances wound healing by stimulating hepatic and local production of IGF-1 to increase circulating and wound site levels.3g Plasma growth hormone levels; which are decreased following severe burns, can be restored by the administration of recombinant growth hormone (0.2 mg/kg per day) in massively burned children to accelerate skin graft donor site wound healing and shorten hospital stay by more than 25% (Fig. 23-9)." The treatment of severely burned children with recombinant human growth hormone has been shown to be safe and efficacious. Growth hormone given during acute hospitalization maintains growth in severely burned children.83 Height velocity improved during the first 2 years after burn injury in growth hormone-treated patients when compared with control patients. Recombinant human growth hormone also stimulates bone formation and muscle protein synthesis by up-regulation of IGF-1, successfully abating muscle catabolism and ~ s t e o p e n i a . ~ ~ In severely burned patients, muscle anabolism can result from the administration of submaximal dosages of insulin by stimulating muscle protein synthesis. Insulin administration has also been demonstrated to improve skin graft donor site healing and wound matrix f0rmation.2~Testosterone production is greatly decreased after severe burn injury, which may last for months in postpubertal males. Increased protein synthesis with

Placebo Nutropin Protropin Donor site healing time for groups receiving either placebo (normal saline, n = 26) or recombinant growth hormone (Nutropin 0.2 mg/kg/day, n = 20; or Protropin 0.2 mg/kg/day, n = 20). A significant reduction in average healing time is noted with both forms of recombinant growth hormone when compared with control patients (mean f SEM; * P< 0.05 versus placebo). (From Giipin DA, Barrow RE, Rutan RL, et al: Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994;220:19.) I

-

testosterone administration is accompanied by a more efficient utilization of intracellular amino acids derived from protein breakdown and an increase in the inward transport of amino acids. An increase in net protein synthesis is attainable in adults with large burns by restoring testosterone concentrations to the physiologic range.2R An analogue of testosterone with less androgenic effect, oxandrolone, has been used in acute and rehabilitating adult burn patients, with promising results with regard to weight gain. Oxandrolone alone has been shown to enhance protein synthesis efficiency, which improves muscle protein metabolism in severely burned children.gO The use of a beta blocker, propranolol, has been shown to lower resting heart rate and left ventricular work and to decrease peripheral lipolysis while maintaining lean body mass,7without adversely affecting cardiac output or 2~," beta the ability to respond to cold s t r e s ~ . ~ ~ 1Recently, blockade using propranolol during hospitalization has been shown to attenuate hypermetabolic response and reverse muscle protein catabolism in burned children (Fig. 23-10).43 Propranolol was given at a standard starting dose (1.98 mg/kg per day) and then titrated to decrease heart rate approximately 20% from baseline values. After 2 weeks of treatment, resting energy expenditure and oxygen consumption had increased in the control group. In contrast, patients in the proprano101 group had significant decreases in these variables. Concurrently with the decline in energy expenditure, beta blockade also improved the kinetics of skeletal

CHAPTER

Control group (n=12)

.-c

E

Propranolol group (n=12)

Z

0

-

O.lOl

-0.10

At baseline

At 2 wk

,

Mean change from baseline in the net balance of ~nuscleprotein synthesis and breakdown during 2 weeks of treatment with propi~anolol.Valties were obtained from a 5-hour kinetic study using isotopically labeled phenylalanine. Asterisk (*) indicates a significant difference between the two groups (P=0.001 by t-test) and a significant difference between the baseline value and the value at 2 weeks ( P = 0.002 by paired t-test). (From Hcl-ndon DN, Hart DW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223.)

muscle protein. The muscle protein net balance improved by 82% compared with pretreatment baseline values, whereas it decreased only 27% in untreated controls.43 Further, administering propranolol to burned children also receiving human growth hormone has salutary cardiovascular effects, decreases the release of free fatty acids from adipose tissue, and increases the liver's efficiency in handling secreted free fatty acids and verylow-density lipoproteins. Administration of propranolol has also been shown to decrease peripheral lipolysis and fat deposition in the liver of burn patients.43 Ketoconazole is an inhibitor of steroid ring synthesis and blocks the production of cortisol, indicating a potential use in the modulation of hypermetabolism.

cost-effectiveagents for the treatment of the hypermetabolic responses to trauma. Further, the role of nutrition in supporting the hypermetabolic response to trauma is often overlooked, but it clearly plays a part.

23

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393

NUTRITION The metabolic rate of patients with burns increases from 1.5 times the normal rate in a patient with 25% TBSA burns to 2 times the normal rate in those with 40% TBSA burns.3Xhildren are particularly vulnerable to protein-calorie malnutrition because of their proportionally less body fat and smaller muscle mass, in addition to increased metabolic demands. This malnutrition is associated with dysfunction of various organ systems, including the immune system, and delayed wound healing. Therefore, optimal nutritional support must be provided to maintain and improve vital organ functions. Feeding tubes are generally placed under fluoroscopic guidance immediately after the initial evaluation of burns, and enteral nutrition is started within hours after injury. Early enteral feedings have been shown to decrease the level of catabolic hormones, improve nitrogen balance, maintain gut mucosal integrity, and hyperalidecrease overall hospital stay.15~7%xVlthough mentation can deliver sufficient calories, its use in burn patients has been associated with deleterious effects on immune function; small bowel mucosal atrophy, with an increased incidence of bacterial translocalion: and a ~ ~ . ~ ~ nutrition is always predecrease in ~ u r v i v a l .Enteral ferred to parenteral nutrition and is associated with a decreased metabolic rate and lower incidence of sepsis in burn patients. Several formulas are used to calculate caloric requirement in burn patients. Both the Curreri formula (25 kcal/ kg plus 40 kcal/% TBSA burned) and the modified Harris-Benedict formula (calculated or measured resting metabolic rate times injury factor) use the principle of providing maintenance calories plus the additional calories reauired related to the burn size. Similar to fluid resuscitation guidelines, caloric requirements based on total and burned body surface area rather than weight are more appropriate for pediatric burn patients (Table 23-5)."-" The exact nutrient requirements of burn patients are not clear, but it is generally accepted that maintenance of energy requirement and replacement of protein losses are vital. The recommended enteral tube feedings should have 20% to 40% of the calories as protein, 10% to 20% as fat, and 40% to 70% as carbohydrates. Milk is one of the least expensive and best tolerated forms of nutrition, but sodium supplementation may be needed to avoid dilutional hyponatremia. There are also various commercially available enteral formulas, such as Vivonex and PediaSure, to choose from.

Infant and toddler Child

2100 kcal/m2 total 1800 kcal/m2 total 1500 kcal/m2 total

+ 1000 kcal/m2 burned + 1300 kcal/m2 burned

+ 1500 kcal/m2 burned

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Analgesia Burn wound treatment and rehabilitation therapy produce pain in patients of all ages. Infants and children do not express their pain in the same way adults do and may display fear, anxiety, agitation, tantrums, depression, and withdrawal. With older children, allowing them to participate in their own wound care can give them some sense of control and alleviate fear and pain. Various combinations of analgesics and anxiolytic medications are used effectively during procedures and dressing changes (Table 23-6). Successful pain management of burned children requires an understanding that pain is associated with the burn depth and phase of wound healing. Pain management protocols should be tailored to control background pain as well as particular procedurerelated painful stimuli. Physical therapy, which is vital to optimize good functional outcome, can be provided more effectively with appropriate pain control; however, absolute caution must be exercised to prevent any potential complications due to overmedication at the time of exercise therapy. In children as young as 5 years old, patient-controlled analgesia may be an ideal option to provide a steady-state background infusion of narcotic with an additional bolus regimen.'l Burn injuries are traumatic for burned children as well as for their families. Burn care professionals must do everything they can to make the experience as tolerable as possible while assisting burn patients to a successful recovery.

Sedatives and Anxiolytics Ketamine is a commonly used procedural sedativeanesthetic in burn patients. Derived from phencyclidine, it is characterized by dissociative anesthesia and has excellent analgesic properties. Given at a dose of 1.0 to 2.0 mg/kg intravenously or 5.0 to 7.0 mg/kg intramuscularly, the effect is rapid, but with a relatively short

Agent

Dose

Indication

Morphine sulfate

0.05-0.1 mgfkg IV or 0.3 mg/kg PO

Meperidine

1.0-2.0 mgfkg PO or IV

Ketamine

1.0-2.0 mgfkg IV or 5.0-7.0 mgfkg IM

Diazepam Chloral hydrate Midazolam

1.0-2.0 mg PO or IV 250-500 mg PO 0.25-0.5 mgfkg PO or IV

Lorazepam

0.03 mgfkg PO or IV

Acute pain; procedures and dressing changes Acute pain; procedures and dressing changes Surgery; procedures and dressing changes Preoperative; anxiety Preoperative; insomnia Anxiety; used in combination with narcotics Background anxiety

duration of action. In addition, ketamine is frequently used as an anesthetic agent for operative procedures, without compromising airway reflexes. The use of ketamine is contraindicated in patients with increased intracranial pressure. Benzodiazepines are commonly used to control burn-related anxiety as well as to enhance the effects of narcotics for pain control. Lorazepam (Ativan) at a dosage of 0.03 mg/kg orally or intravenously is an effective anxiolytic agent. It is also useful as a hypnotic agent to improve patient restfulness in the acute care setting. Diazepam (Valium) has a longer duration of action than lorazepam, making it useful in more chronic settings. Diazepam also improves muscle relaxation, which can facilitate rehabilitative therapy. Midazolam (Versed) has a rapid onset of action; peak plasma levels are achieved within 30 minutes, with a half-life of 2 to 5 hours. It is commonly used to achieve the desired level of sedation for procedures and dressing changes. Because it induces anterograde amnesia, it is commonly used as a premedication on the day of surgery.

Antibiotics The use of perioperative IV antibiotics has had a tremendous impact in improving the survival of major burn patients in the past 2 decades. Bacteria colonized in a burn eschar can potentially shed systemically at the time of eschar excision, contributing to sepsis and other organ system infection. Empirically, a broad-spectrum IV antibiotic regimen (e.g., vancomycin, third-generation cephalosporins, and penicillins) is given perioperatively to patients with greater than 40% TBSA burns to protect against Streptococcus, Staphylococcus aurew, and Pseudomonas. The antibiotic regimen is subsequently modified, depending on sensitivities identified by quantitative cultures of the excised eschar. In acute burns, a gram-positive coccus is generally the predominant organism involved, but colonization with gram-negative organisms and even fungi is frequently encountered in chronic burn wounds, and these organisms must be covered with appropriate IV antibiotics during excision and grafting. In addition to burn wound sepsis, graft loss may be attributed to the presence of an infected wound at the time of skin grafting or colonization of the grafted bed shortly after surgery. The most common organisms responsible for graft loss are beta-hemolytic streptococci ( S . pyogenes, S. agalactiae, or S. viridans). They are generally sensitive to thirdgeneration cephalosporins and fluoroquinolones. The emergence of multiresistant bacteria, such as methicillinresistant S. aureus, has become a serious problem for burn centers. Therefore, IV antibiotics should be used with diligence, but only for perioperative coverage and treatment of an identified source of infection.

INHALATION INJURY Inhalation injury is a major cause of death in burn patients. The mortality rate for children with isolated cutaneous burns is 1% to 2% but increases to approximately

CHAPTER

40% in the presence of inhalation i n j ~ r y . ~Inhalation ~,~2 injury is caused primarily by inhaled toxins such as fumes, gases, and mists. Although the supraglottic region can be injured by both thermal and chemical insults, tracheobronchial and lung parenchymal injuries rarely occur as a result of direct thermal damage because the heat disperses rapidly in the larynx. Hypoxia, increased airway resistance, decreased pulmonary compliance, increased alveolar epithelial permeability, and increased pulmonary vascular resistance may be triggered by the release of vasoactive substances (thromboxane A2, CSa, and CSa) from damaged epithelium.93 Neutrophil activation plays a critical role in this process, and pulmonary function has been shown to improve with the use of a ligand binding to E-selectins (inhibiting neutrophil adhesion) and anti-interleukin-8 (inhibiting neutrophil chemotaxis). Another significant form of respiratory tract pathology is the sloughing of ciliated epithelial cells from the basement membrane, resulting in exudate formation. The exudate, which consists of lymph proteins, coalesces to form fibrin casts. These fibrin casts are frequently resistant to routine pulmonary toilet and can create a "ball-valve" effect in localized areas of lung, eventually causing barotrauma. The diagnosis is usually made based on clinical history and physical examination findings during the initial evaluation. Victims trapped in a house fire with excessive smoke and fumes are likely to have sustained severe inhalation injury. Facial burns with singed hair and carbonaceous sputum suggest the presence of inhalation injury. Hoarseness and stridor suggest significant airway obstruction, so the airway should be secured immediately with endotracheal intubation. Patients who present with disorientation and obtundation are likely to have elevated carbon monoxide levels (carboxyhemoglobin >lo%). Cyanide toxicity as a result of the combustion of common household items may also contribute to unexplained metabolic collapse. Diagnostic tools, such as bronchoscopy and xenon-133 scanning, are more than 90% accurate in determining the presence of inhalation injury. Fiber-optic bronchoscopic examination of the airway at the bedside (avoiding the need to transport critically injured burn patients to the nuclear medicine department) is usually sufficient to identify airway edema and inflammatory changes of the tracheal mucosa such as hyperemia, mucosal ulceration, and sloughing. It remains the gold standard to confirm the presence of scan with xenon 133 can inhalation inj~ry.~Wentilation also identify regions of inhalation injury by assessing respiratory exchange and excretion of xenon by the lungs.'" The treatment of inhalation injury begins at the scene of the burn accident. The administration of 100% oxygen rapidly decreases the half-life of carbon monoxide. The airway must be secured with intubation in patients exhibiting signs and symptoms of imminent respiratory failure. Aggressive pulmonary toilet with physiotherapy and frequent suctioning is vital to prevent any serious respiratory complications. Humidified air is delivered at high flow, and bronchodilators and racemic epinephrine are used to treat bronchospasm. lV heparin has been shown to reduce tracheobronchial cast formation, improve minute ventilation, and lower peak inspiratory

23

Burns

395

pressures after smoke inhalation. Inhalation treatments such as 20% acetylcysteine nebulized solution (3 mL every 4 hours) plus nebulized heparin (5000 to 10,000 units with 3 mL normal saline every 4 hours) are effective in improving the clearance of tracheobronchial secretions and minimizing bronchospasm, thereby significantly decreasing reintubation rates and r n ~ r t a l i t y . ' ~ , ~ ~ The presence of inhalation injury generally requires increased fluid resuscitation, up to 2 mL/kg per percent TBSA burned more than would be required for the same size burn without an inhalation injury. In fact, pulmonary edema that is associated with inhalation injury is not prevented by fluid restriction; rather, inadequate resuscitation may increase the severity of pulmonary injury by the sequestration of polymorphonuclear cells.40 Steroids have not been shown to be of any benefit in inhalation injury. Prophylactic IV antibiotics are not indicated but are started if there is a clinical suspicion of pneumonia. Early pneumonia is usually the result of gram-positive organisms such as methicillin-resistant S. aureus, whereas later infection is caused by gramnegative organisms such as Pseudomonas. Serially monitored sputum cultures and bronchial washings should guide antibiotic therapy.

NONTHERMAL INJURIES

Chemical Burns Children often accidentally come in contact with various household cleaning products. Treatment of chemical burns involves the immediate removal of the causative agent and lavage with copious amounts of water, taking care to avoid hypothermia and to ensure that the effluent does not contact uninjured areas. Fluid resuscitation is also started. Decontamination is not performed in a tub; rather, the wounds are irrigated toward a drain, such as in a shower. After copious irrigation, wounds should be covered with topical antimicrobial dressing, and appropriate surgical plans should be made. Rapid recognition of the offending chemical agent is crucial to proper management.ZYWhen in doubt, the local poison control center should be contacted to identify the chemical composition of the product involved. The common offending chemical agents can be classified as alkali or acid. Alkalis, such as lime, potassium hydroxide, sodium hydroxide, and bleach, are among the most common agents involved in chemical injuries. Mechanisms of alkali-induced burns are saponification of fat, resulting in increased cell damage from heat, extraction of intracellular water, and formation of alkaline proteinates with hydroxyl ions. These ions induce further chemical reaction in the deeper tissues. Attempts to neutralize alkalis are not recommended, because the chemical reaction can generate more heat and add to the injury. Acid burns are not as common. Acids induce protein breakdown by hydrolysis, resulting in the formation of an eschar, and therefore do not penetrate as deeply as alkaline burns. Formic acid injuries are rare but can result in multiple systemic effects, such as metabolic acidosis, renal failure, intravascular

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hemolysis, and acute respiratory distress syndrome. Hydrofluoric acid burns are managed differently from other acid burns.94 After copious local irrigation with water, fluoride ions must be neutralized with topical application of 2.5% calcium gluconate gel. If not appropriately treated, free fluoride ions can cause liquefaction necrosis of the affected tissues, including bones. Because of potential hypocalcemia, patients should be closely monitored for prolonged QT intervals.

Electrical Burns Electrical burns are rare in children, accounting for only 3% to 5% of all admitted burn patients. Electrical burns are categorized as either high- or low-voltage injuries.50 High-voltage injuries are characterized by varying degrees of local burns and destruction of deep tissues.",84 Electrical current enters a part of the body and travels through tissues with the lowest resistance, such as nerves, blood vessels, and muscles. Heat generated as electrical current passes through deep tissues with relatively high resistance, such as bones, and damages adjacent tissues that may not be readily visible. Skin is mostly spared owing to its high resistance to electrical current. Primary and secondary surveys, including electrocardiograms, should be completed. If the initial electrocardiogram is normal, no further monitoring is necessary; however, any abnormal findings require continued monitoring for 48 hours and appropriate treatment of dysrhythmias when detected.85 The key to the management of electrical burns lies in the early detection and proper treatment of injuries to deep structures. Edema formation and subsequent vascular compromise are common in extremities. Fasciotomies are frequently necessary to avoid potential limb loss. If myoglobin is present in urine, vigorous hydration, with the administration of sodium bicarbonate to alkalinize the urine and mannitol to achieve diuresis and to act as a free radical scavenger, is indicated. Repeated wound exploration and debridement of affected areas are required before ultimate wound closure because there is a component of delayed cell death and thrombosis. The mechanism of electrical burn injury is to overwhelm the cellular systems that operate at millivolt or milliamp levels, so cells that survive the initial injury may slowly die over a week's time as ion gradients deteriorate and thrombosis of the microvasculature proceeds. Electrical injuries may also have a thermal, nonconductive component as the electricity flashes. This is treated as if it were a conventional thermal burn. Low-voltage injury is similar to thermal injury without the transmission of electrical current to deep tissues and usually requires only local wound care.

OUTPATIENT BURNS The majority of pediatric burns are minor, often resulting from scalds involving less than 10% TBSA or contact with hot objects causing small, isolated areas of thermal injury. Such burns are usually partial-thickness

skin injuries and can be treated on an outpatient basis. After an initial assessment, the burn wound is gently washed with water and a mild soap with appropriate pain control. Blisters can be left intact when they are small and unlikely to rupture spontaneously, especially on the palms of the hand, because they provide a natural barrier against the environment and are beneficial to avoid daay dressing changes. Spontaneous resorption of the fluid occurs in approximately 1 week with the re-epithelialization process. Larger areas of blisters should be debrided, and topical antimicrobial dressings applied. Silvadene is most commonly used owing to 2s broad-spectrum antimicrobial properties, as well as its soothing effect on superficial second-degree burns. However, because silver sulfadiazine can imwede ewithelization, its use should be discontinued when healing partial-thicknesswounds are devoid of necrotic tissue and evidence of re-epithelialization is noted. Alternatively, antimicrobial dressings with triple antibiotic ointment (neomycin, bacitracin, and polymyxin B sulfate) or Polysporin, which has no negative effect on epithelialization, are commonly used. For small, superficial partial-thickness burns, nonmedical white Petrolatumimpregnated fine mesh or porous mesh gauze (Adaptic), or fine mesh absorbent gauze impregnated with 3% bismuth tribromophenate in a nonmedicinal petrolatum blend (Xeroform), is usually sufficient, without the need for topical antimicrobials. Superficial burns of the face can be treated with the application of triple antibiotic ointment without any dressings. The frequency of dressing change varies from twice daily to once a week, depending on the size and depth of the burn and the amount of drainage. Those who advocate twice-daily dressing changes base their care on the use of topical antimicrobials whose half-life is about 8 to 12 hours. Others who use petrolatum-based or bismuth-impregnated gauze recommend less frequent dressing changes-once every 3 to 5 days. The use of synthetic wound dressings is ideal for the outpatient treatment of superficial partial-thickness b ~ r n s . ~ % e n applied appropEiately to fresh, partial-thickness wounds, Biobrane adheres to the wound rapidly and is very effective in promoting re-epithelialization in 1 to 2 weeks (see Fig. 23-7). Although daily dressing changes are eliminated, Biobrane-covered wounds should still be monitored closely for signs of infection.

REHABILITATION Acute Therapy Rehabilitation therapy is an essential component of burn care. During the acute phase of burn care, splints are used to prevent joint deformities and contractures. Made of thermoplastic materials, which are amenable to heat manipulation, splints are fitted individually to each patient. Application of splints at all times except during exercise periods can prevent the severe contractures that occur in patients with large burns. Patients are mobilized out of bed immediately after the graft takes, and aggressive physical therapy is provided.

CHAPTER

After t h e acute phase, hypertrophic scar formation is a major concern. Burn d e p t h , patient age, a n d genetic factors all play a n important role i n hypertrophic scar formation. I n general, d e e p second-degree b u r n wounds, requiring 3 weeks o r m o r e to heal, produce hypertrophic scarring. Children a r e m o r e p r o n e t o hypertrophic scar formation than adults are, probably because of t h e high rate of cell mitosis associated with growth. Constant pressure applied 24 hours a day is t h e most effective m e t h o d t o minimize hypertrophic scar formation; pressure garments should b e worn until scars mature. Scar maturation usually occurs 6 t o 18 m o n t h s after injury; in younger patients, scars mature a t a m u c h slower rate. I n addition to splints a n d pressure garments, exercise therapy is a crucial c o m p o n e n t of rehabilitation therapy. Families should receive thorough instruction o n a program of range-of-motion exercises a n d muscle strengthening.

Extended Therapy Burn survivors a n d their families n e e d rehabilitation therapy for extended periods o n both a physical a n d a psychological level. All must deal with feelings ranging from guilt to post-traumatic stress. In o n e study, a g r o u p of surgeons reviewed t h e images of 12 b u r n survivors with 80% o r greater TBSA b u r n e d a n d 70% third-degree burns, a n d predicted their status with respect to scarring a n d future employability. They predicted that all t h e patients would experience difficult psychological adjustments, a n d that many would require multiple operations in t h e reconstructive phase.45-In reality, t h e patients received twice as many operations as predicted, yet three quarters of these children demonstrated normal adjustm e n t a n d emotional growth. W h e n this longitudinal study was followed f o r additional 10 years, t h e children's emotional assessment scores were equal to those of their uninjured peers. T h a t s o few of these survivors developed serious ps~chologicala n d social difficulties is a striking testament to h u m a n resilience.

REFERENCES 1. Ayus JC, Arieff AI: Hyponatremia and myelinolysis. Ann Intern Med 1997;127:163. 2. Baptiste MS, Feck G: Preventing tap water burns. Am J Public Health 1980;70:727. 3. Barillo DJ, Goode R: Fire fatality study: Demographics of fire victims. Burns 1996;22:85. 4. BarretJP, Wolf SE, Desai MH, et al: Cost-efficacy of cultured epidermal autografts in massive pediatric burns. Ann Surg 2000;231:869. 5. Bjerknes R, Vindenes H, Laerum OD: Altered neutrophil functions in patients with large burns. Blood Cells 1990; 16:127. 6. Bjerknes R, Vindenes H, Pitkanen J, et al: Altered polymorphonuclear neutrophilic granulocyte functions in patients with large burns. J Trauma 1989;29:847. 7. Breitenstein E, Chiolero RL, Jequier E, et al: Effects of beta-blockade on energy metabolism following burns. Burns 1990;16:259.

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8. Brigham PA, McLoughlin E: Burn incidence and medical care use in the United States: Estimates, trends, and data sources. J Burn Care Rehabil 1996;17:95. 9. Brink JA, Sheets PW, Dines KA, et al: Quantitative assessment of burn injury in porcine skin with high-frequency ultrasonic imaging. Invest Radio1 1986;21:645. 10. Brown M, Desai M, Traber LD, et al: Dimethylsulfoxide with heparin in the treatment of smoke inhalation injury. J Burn Care Rehabil 1988;9:22. 11. Bucky LP, Vedder NB, Hong HZ, et al: Reduction of burn injury by inhibiting CDIsmediated leukocyte adherence in rabbits. Plast Reconstr Surg 1994;93:1473. 12. Burn Injury Fact Sheet. Washington, DC, National Safe Kids Campaign; 2004. 13. Carter EA, Gonnella A, Tompkins RG: Increased transcellular permeability of rat small intestine after thermal injury. Burns 1992;18:117. 14. Chance WT, Nelson JL, Foley-Nelson T, et al: The relationship of burn-induced hypermetabolism to central and peripheral catecholamines. J Trauma 1989;29:306. 15. Chiarelli A, Enzi G, Casadei A, et al: Very early nutrition r supplementation in burned patients. Am J Clin ~ u t 1990; 51:1035. Chung DH, Evers BM, Townsend CM Jr, et al: Burninduced transcriptional regulation of small intestinal ornithine decarboxylase. Am J Surg 1992;163:157. Chung DH, Evers BM, Townsend CM Jr, et al: Role of polyamine biosynthesis during gut mucosal adaptation after burn injury. Am J Surg 1993;165:144. Cope 0 , Moore FD: The redistribution of body water. Ann Surg 1947;126:1016. DelBeccaro EJ, Robson MC, Heggers JP, et al: The use of specific thromboxane inhibitors to preserve the dermal microcirculation after burning. Surgery 1980;87:137. Demling RH, LaLonde C: Early postburn lipid peroxidation: Effect of ibuprofen and allopurinol. Surgery 1990; 107:85. Demling RH, Mazess RB, Witt RM, et al: The study of burn wound edema using dichromatic absorptiometry. J Trauma 1978;18:124. Desai MH, Herndon DN: Eradication of Candida burn wound septicemia in massively burned patients. J Trauma 1988;28:140. Desai MH, Herndon DN, Broemeling L, et al: Early burn wound excision significantly reduces blood loss. Ann Surg 1990;211:753. Desai MH, Rutan RL, Heggers JP, et al: Candida infection with and without nystatin prophylaxis: An 11-year experience with patients with burn injury. Arch Surg 1992; 127:159. Drost AC, Burleson DG, Cioffi WG Jr, et al: Plasma cytokines following thermal injury and their relationship with patient mortality, burn size, and time postburn. J Trauma 1993;35:335. Du GB, Slater H, Goldfarb IW: Influences of different resuscitation regimens on acute early weight gain in extensively burned patients. Burns 1991;17:147. Ferrando AA, Chinkes DL, Wolf SE, et al: A submaximal dose of insulin promotes net skeletal muscle protein synthesis in patients with severe burns. Ann Surg 1999;229:11. Ferrando AA, Sheffield-Moore M, Wolf SE, et al: Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med 2001;29:1936. Fitzpatrick KT, Moylan JA: Emergency care of chemical burns. Postgrad Med 1985;78:189. Fox CL Jr, Rappole BW, Stanford W: Control of Pseudornonas infection in burns by silver sulfadiazine. Surg Gynecol Obstet 1969;128:1021.

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31. Gallico GG 3rd, O'Connor NE, Compton CC, et al: Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311:448. 32. Gamelli RL, He LK, Liu H: Macrophage suppression of granulocyte and macrophage growth following burn wound infection. J Trauma 1994;37:888. 33. Gerding RL, Emerman CL, Effron D, et al: Outpatient management of partial-thickness burns: Biobrane versus 1% silver sulfadiazine. Ann Emerg Med 1990;19:121. 34. Gilpin DA, Barrow RE, Rutan RL, et al: Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994; 220:19. 35. Goran MI, Peters EJ, Herndon DN, et al: Total energy expenditure in burned children using the doubly labeled water technique. Am J Physiol 1990;259(4 Pt 1):E576. 36. Graves TA, Cioffi WG, McManus WF, et al: Fluid resuscitation of infants and children with massive thermal injury. J Trauma 1988;28:1656. 37. Hart DW, Wolf SE, Ramzy PI, et al: Anabolic effects of oxandrolone after severe burn. Ann Surg 2001;233:556. 38. Heggers JP, Sazy JA, Stenberg BD, et al: Bactericidal and wound-healing properties of sodium hypochlorite solutions: The 1991 Lindberg Award. J Burn Care Rehabil 1991; 12:420. 39. Herndon DN, Barrow RE, Kunkel KR, et al: Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990;212:424. 40. Herndon DN, Barrow RE, Linares HA, et al: Inhalation injury in burned patients: Effects and treatment. Burns Incl Therm Inj 1988;14:349. 41. Herndon DN, Barrow RE, Stein M, et al: Increased mortality with intravenous supplemental feeding in severely burned patients. J Burn Care Rehabil 1989;10:309. 42. Herndon DN, Gore D, Cole M, et al: Determinants of mortality in pediatric patients with greater than 70% fullthickness total body surface area thermal injury treated by early total excision and grafting. J Trauma 1987;27:208. 43. Herndon DN, Hart DW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223. 44. Herndon DN, Hawkins HK, Nguyen TT, et al: Characterization of growth hormone enhanced donor site healing in patients with large cutaneous burns. Ann Surg 1995;221:649. 45. Herndon DN, LeMaster J, Beard S, et al: The quality of life after major thermal injury in children: An analysis of 12 survivors with greater than or equal to 80% total body, 70% third-degree burns. J Trauma 1986;26:609. 46. Herndon DN, Parks DH: Comparison of serial debridement and autografting and early massive excision with cadaver skin overlay in the treatment of large burns in children. J Trauma 1986;26:149. 47. Herndon DN, Ramzy PI, DebRoy MA, et al: Muscle protein catabolism after severe burn: Effects of IGF-l/IGFBP-3 treatment. Ann Surg 1999;229:713. 48. Herndon DN, Stein MD, Rutan TC, et al: Failure of TPN supplementation to improve liver function, immunity, and mortality in thermally injured patients.J Trauma 1987;27:195. 49. Herndon DN, Thompson PB, Traber DL: Pulmonary injury in burned patients. Crit Care Clin 1985;1:79. 50. Hildreth MA, Herndon DN, Desai MH, et al: Caloric needs of adolescent patients with burns. J Burn Care Rehabil 1989;10:523. 51. Hildreth MA, Herndon DN, Desai MH, et al: Current treatment reduces calories required to maintain weight in pediatric patients with burns. J Burn Care Rehabil 1990;11:405.

52. Hildreth MA, Herndon DN, Desai MH, et al: Caloric requirements of patients with burns under one year of age. J Burn Care Rehabil 1993;14:108. 53. Ho-Asjoe M, Chronnell CM, Frame JD, et al: Immunohistochemical analysis of burn depth. J Burn Care Rehabil 1999;20:207. 54. Honeycutt D, Barrow R, Herndon D: Cold stress response in patients with severe burns after beta-blockade. J Burn Care Rehabil 1992;13(2 Pt 1):181. 55. Huang PP, Stucky FS, Dimick AR, et al: Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg 1995;221:543. 56. Hunt JL, Agee RN, Pruitt BA Jr: Fiberoptic bronchoscopy in acute inhalation injury. J Trauma 1975;15:641. 57. Hunt JP, Hunter CT, Brownstein MR, et al: The effector component of the cytotoxic T-lymphocyte response has a biphasic pattern after burn injury. J Surg Res 1998;80:243. 58. Jahoor F, Herndon DN, Wolfe RR: Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients. J Clin Invest 1986;78:807. 59. Jarrett F, Ellerbe S, Demling R: Acute leukopenia during topical burn therapy with silver sulfadiazine. Am J Surg 1978;135:818. 60. Jerath MR, Schomacker KT, Sheridan RL, et al: Burn wound assessment in porcine skin using indocyanine green fluorescence. J Trauma 1999;46:1085. 61. Jeschke MG, Barrow RE, Wolf SE, et al: Mortality in burned children with acute renal failure. Arch Surg 1998;133:752. 62. Kimura R, Traber LD, Herndon DN, et al: Treatment of smoke-induced pulmonary injury with nebulized dimethylsulfoxide. Circ Shock 1988;25:333. 63. Klein GL, Wolf SE, Goodman WG, et al: The management of acute bone loss in severe catabolism due to burn injury. Horm Res 1997;48(Suppl 5) :83. 64. Klimpel GR, Herndon DH, Stein MD: Peripheral blood lymphocytes from thermal injury patients are defective in their ability to generate lymphokine-activated killer (LAK) cell activity. J Clin Immunol 1988;8:14. 65. Laberge LC, Ballard PA, Daniel RK: Experimental electrical burns: Low voltage. Ann Plast Surg 1984;13:185. 66. La1 S, Barrow RE, Wolf SE, et al: Biobrane improves wound healing in burned children without increased risk of infection. Shock 2000;14:314. 67. LeVoyer T, CioE WG Jr, Pratt L, et al: Alterations in intestinal permeability after thermal injury. Arch Surg 1992;127:26. 68. Lindberg RB, Moncrief JA, Switzer WE, et al: The successful control of burn wound sepsis.J Trauma 1965;5:601. 69. Lund CC, Browder NC: The estimation of areas of burns. Surg Gynecol Obstet 1944;79:352. 70. Marano MA, O'Sullivan G, Madden M, et al: Tourniquet technique for reduced blood loss and wound assessment during excisions of burn wounds of the extremity. Surg Gynecol Obstet 1990;171:249. 71. McDonald AJ, Cooper MG: Patient-controlled analgesia: An appropriate method of pain control in children. Paediatr Drugs 2001;3:273. 72. Mileski W, Borgstrom D, Lightfoot E, et al: Inhibition of leukocyte-endothelial adherence following thermal injury. J Surg Res 1992;52:334. 73. Mochizuki H, Trocki 0 , Dominioni L, et al: Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. Ann Surg 1984;200:297. 74. Monafo WW: The treatment of burn shock by the intravenous and oral administration of hypertonic lactated saline solution. J Trauma 1970;10:575. 75. Moyer CA, Brentano L, Gravens DL, et al: Treatment of large human burns with 0.5 per cent silver nitrate solution. Arch Surg 1965;90:812.

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76. Moylan JA .Jr, Wilmore DW, Mouton DE, et al: Early diagnosis of inhalation injury using 133 xenon lung scan. Ann Surg 1972;176:477. 77. Murphy KD, Lee JO, Herndon DN: Current pharmacotherapy for the treatment of severe burns. Expert Opin Pharmacother 2003;4:369. 78. Myers SI, Minei JP, Casteneda A, et al: Differential effects of acute thernial injury on rat splanchnic and renal blood flow and prostanoid release. Prostaglandins Leukot Essent Fatty Acids 1995;53:439. 79. Nwariaku FE, Sikes PJ, Lightfoot E, et al: Effect of a bradykinin antagonist on the local inflammatory response following thermal injury. Burns 1996;22:324. 80. O'Reilly TJ, Spence RJ, Taylor RM, et al: Laser Doppler flowrnetry evaluation of burn wound depth. J Burn Care Rehabil 1989;10:l. 81. Park DH, Hwang JW, Jang KS, et al: Use of laser Doppler flowmetry for estimation of the depth of burns. Plast Reconstr Surg 1998;101:1516. 82. Pierre EJ, Barrow RE, Hawkins HK, et al: Effects of insulin on wound healing. J Trauma 1998;44:342. 83. Ramirez KJ, Wolf SE, Barrow RE, et al: Growth hormone treatment in pediatric burns: A safe therapeutic approach. Ann Surg 1998;228:439. 84. Robson MC, Murphy RC, Heggers JP: A new explanation for the progressive tissue loss in electrical injuries. Plast Reconstr Surg 1984;73:431. 85. Robson MC, Smith DJ: Care of the thermal injured victim. In Jurkiewicz MJ, Krizek TJ, Mathes SJ, et al (eds): Plastic Surgery: Principles and Practice. St Louis, CV Mosby, 1990. 86. Rue I,W 3rd, Cioffi WG, McManus WF, et al: Wound closure and outcome in extensively burned patients treated with cultured autologous keratinocytes. J Trauma 1993; 34:662. 87. Ryan CM, Yar~nush ML, Burke JF, et al: Increased gut permeability early after burns correlates with the extent of burn irljjury. Crit Care Med 1992;20:1508. 88. Saito H, Trocki 0 , Alexander JW, et al: The effect of route of nutrient administration on the ~lutritionalstate, catabolic hormone secretion, and gut mucosal integrity after burn injury. JPENJ Parenter Enteral Nutr 1987;ll:l.

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89. Shamoon H, Hendler R, Sherwin RS: Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans..J Clin Endocrinol Metab 1981;52:1235. 90. Sheffield-Moore M, Urban RJ, Wolf SE, et al: Short-term oxandrolone administration stin~ulatesnet muscle protein synthesis in young nlen. J Clin Endocrinol ~ e t a b 1999;84:2705. 91. Sheridan RL, Tompkins RG: Cultured autologous epithelium in patients with burns of ninety percent or niore of the body surface. .J Trauma 1995;38:48. 92. Tht~mpsonPB, Herndon DN, Traber DI., et al: Effect on mortality of inhalation in-jnry.J Trauma 1986;26:163. 93. Traber DL, Herndon DN, Stein MD, et al: The pulmonary lesion of smoke inhalation in an twine model. Circ Shock 1986;18:311. 94. Trevino MA, Herrmann GH, Sprout WI,: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983; 252361. 95. Vo IIT, Papworth GD, Delarley PM, et al: A study of vascular response to thermal injury on hairless mice by fibre optic confocal imaging, laser Doppler flowmetry and conventional histolo.gy. Burns 1998;24:319. 96. Warden GD: Burn shock resuscitation. WorldJ Surg 1992; 16:16. 97. Warden GD: Fluid resuscitation and early management. In Herndon DN (ed): Total Burn Care. Philadelphia, WB Saunders, 1996, p 53. 98. Wilmore DW, Moylan JA .Jr, Bristow BF, et al: Anabolic and e high caloric feedeffects of human growth h o r m o ~ ~ ings following thermal injury. Surg Gynecol Obstet 1974; 138:875. 99. Wolf SE, Barrow RE, Herndon 1)N: Growth horrnone and IGF-I therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab 1996;10:447. 100. Wolf SE, Ikeda H, Matin S, et al: (;utaneous burn increases apoptosis in the gut epithelium of mice. J Am Coll Surg 1999;188:10. 101. Zedler S, Faist E, Ostermeier B, et al: Postburn constitutional changes in T-cell reactivity occur in CD8+ rather than in CD4+ cells. J Trauma 1997;42:872.

Child Abuse and Birth Injuries -

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Dennis W. Vane

CHILD ABUSE Child abuse encompasses physical abuse, sexual abuse, emotional abuse, and neglect. This maltreatment of children has become a significant focus of attention in our society. The media routinely publish accounts of the alleged traumatic and sometimes fatal abuse of children among all socioecorlomic classes and levels of celebrity. The myth that child abuse and other violence in the home occur only among the poor and the uneducated has been debunked. Child abuse is a worldwide problem that affects all levels of society. Prevention and effective treatment depend on the timely detection of epidemiologic situations that lend themselves to the maltreatment of children. Unfortunately, the "minor" status of children leads to the justifiable issue of the relative rights of parents and guardians. Religious and societal "norms" have created barriers to the identification of victims in many nations. Around the globe, relatively few nations have addressed this problem at all.3 In the United States and Canada, legislation aimed at identifying child abuse and neglect ~* that time, was enacted beginning in the 1 9 6 0 ~ . Since the reporting of child abuse to civil authorities has been mandated for almost all professionals dealing with children. The legislation protects the reporting individual from liability (usually by using the phrase "suspicion of' or "injuries consistent with"), supersedes all professionalclient privilege, and sometimes even imposes penalties for failure to report abuse.45

age groups, maltreatment of children generally increases with age. In teenagers, the incidence of abuse is thought to be twice that in preschool children.54 Patterns of child abuse occur with differing frequencies over the social strata. Sexual and emotional abuse have no socioeconomic associations,whereas physical abuse and neglect are more frequently associated with p o ~ e r t y . ~ ~ Often several types of abuse are perpetrated on the same child or within the same familv. Additionallv. ,, abuse commonly occurs in families with other forms of intrafamilial violence, such as spousal abuse and violence among sibling^.^" Child abuse is a self-perpetuating social and economic problem. Problems with substance abuse and depression are reportedly two to three times more likely in abused children than in the general population, and abused children are likely to be far more physically aggressive with their peers."<3Vt is estimated that approximately 30% of abuse victims eventually abuse their own children.PO Some authors have suggested that this perpetual cycle of abuse is attributable in part to changes in the neuroendocrine system influencing arousal, learning, growth, and the individual's pain threshold.") What is clear is that the incidence of child abuse is significantly underreported, because professional contact or recognition is often required to identify abuse in the first place. Physicians must recognize not only abuse that has already occurred but also the factors indicating a high potential for abuse if this dramatic worldwide problem is to be prevented.

Epidemiology Estimates in the United States indicate that approximately 1.4 million children under the age of 18 suffer some sort of maltreatment every year.54 This represents between 2% and 3% of the population. In about 160,000 children, this maltreatment is considered physically serious or life threatening. Between 1000 and 2000 deaths are attributed to child abuse each year in the United States, and 80% of those children are younger than 5 years. Forty percent of the deaths occur in the first year of life.4R Although deaths occur predominantly in the younger

Presentation Physicians must be aware that abused children are often withdrawn and avoid eye contact with their interviewers. Interviewers must be cognizant of the fact that children often respond with answers that they think will please the interviewer, so care must be taken not to influence the child's responses. Young children are prone to associative fabrication, which may influence or even alter reality. The clinical history in suspected child abuse cases should include a detailed history of the family situation,

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unrelated caregivers, substance abuse in the household, and any history of past abuse. Even with these indicators, child abuse is extremely hard to accurately diagnose. Given the wide spectrum of abuse, presenting symptoms vary accordingly. In the youngest victims, the diagnosis often depends on physical signs such as bruising, patterned burn injuries, retinal hemorrhages, and long bone fractures. Among all children, presentations that should raise a high level of suspicion in the clinician include multiple injuries in different stages of healing; injuries not consistent with the history provided by the caregiver; a history that changes when retold, particularly when the incident was "unwitnessed"; and injuries to the perineum. Wisslow71 provided an excellent summary of the presenting physical injuries in cases of child abuse and neglect (Table 241). In children, essentially any injury can be the result of abuse; however, particular injuries and injury patterns have a high degree of association with abuse.

Traumatic Brain lnjury Head injury is perhaps the most common injury associated with child abuse, and it is certainly the most devastating.

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Penetrating head injury is relatively rare in abuse victims, and most head injuries occur in younger children.36 Blunt injury most commonly manifests as "shaken baby syndrome" or, more accurately, "shaken impact syndrome," in which the insult is caused by an acceleration and deceleration of the brain within the cranial compartment due to violent shaking (Fig. 241). Recent studies indicate that some sort of contact with an object is necessary for the classic brain injury to occur, but that object may be relatively soft and produce no external indication of trauma.21Angular forces created during shaking and eventual percussion against an object result in rotation of the brain within the skull. This causes diffuse axonal injury and tearing of the subdural bridging veins, often resulting in subdural hematoma. Spontaneous subdural hematoma or its occurrence from unintentional trauma is uncommon in children, so its presence should raise the suspicion of child abuse. Acute contact with stationary objects results in the characteristic multiple skull fractures associated with repetitive injury. Secondary brain injury is also frequently associated with abuse, resulting in intracranial hemorrhage, anoxia secondary to apnea, hypoperfusion, cardiac arrest, and potentially herniation of the brainstem." Brain injury secondary to

Subnormal growth Weight, height, or both less than 5th percentile for age Weight less than 5th percentile for height Decreased velocity of growth Head injuries Torn frenulum of upper or lower lip Unexplained dental injury Bilateral black eyes with history of single blow or fall Traumatic hair loss Retinal hemorrhage Diffuse or severe central nervous system injury with history of minor to moderate fall (<3m) Skin injuries Bruise or burn shaped like an object Bite marks Burn resembling a glove or stocking or with some other distribution suggestion an immersion injury Bruises of various colors (in different stages of healing) lnjury to soft tissue areas that are normally protected (thighs, stomach, upper arms) Gastrointestinal or genitourinary injuries Bilious vomiting Recurrent vomiting or diarrhea witnessed only by parent Chronic abdominal or perineal pain with no identifiable cause History of genital or rectal pain lnjury to genitals or rectum Sexually transmitted disease Bone injuries Rib fracture in the absence of major trauma, such as a motor vehicle accident Complex skull fracture after a short fall ( ~ 1 . 2m) Metaphyseal long bone fracture in an infant Femur fracture (any configuration) in a child younger than 1yr Multiple fractures in various stages of healing Laboratory studies Implausible or physiologically inconsistent laboratory results (polymicrobial contamination of body fluids, sepsis with unusual organisms, electrolyte disturbances inconsistent with the child's clinical state or underlying illness, wide and erratic variations in test results) Positive toxicologic tests in the absence of a known ingestion or medication Bloody cerebrospinal fluid (with xanthochromic supernatant) in an infant with altered mental status and no history of trauma

L From Wissow LS: Child abuse and neglect. N Engl J Med 1995;332:1425-1431.

I

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A

I . .

B

A and R, Shaketl baby syndrome is often recognizable by external bruising about the chest, shoulders, and neck caused by the finge1-s and hands.

abuse carries a reported mortality rate of 15% to 38%, which is significantly higher than that of similar injuries caused by unintentional trauma.2' Nonfatal outcomes in abused children with traumatic brain injuries are also significantly worse than in those whose injuries were sustained unintentionally.24 Nonenhanced computed tomography is considered the most appropriate diagnostic tool for the identification of intentional head injury. Intracranial lesions are easily identified, as are the often associated skull fracture^.^^ Although most commonly seen in younger children, head injury associated with child abuse occurs in older children as well. Whereas external signs of trauma are infrequent in younger children, older children usually present with visible injuries secondary to violent external trauma. These injuries are often severe, with poor outcornes.4J The identification of retinal hemorrhage has been deemed almost pathognomonic of child abuse's; however, recent studies indicate that retinal hemorrhage occurs in cases of nonintentional injury as well, including normal vaginal delivery, which can cause compression of the

baby's soft skull.*8,25The presence of retinal hemorrhage from nonintentional injury is so rare, however, that it should stimulate a high level of suspicion for child abuse. When it is identified, the physician should begin an appropriate workup to investigate that possibility.

Fractures It is postulated that approximately 80% of child abuse cases in the United States are identified radiographically.12 Fractures secondary to child abuse can be found in any age group, although fractures in older children are more commonly from high-impact unintentional injury.I0 The presence of a long bone fracture in any child younger than 2 years has a high association with ~-l~ halie historically intentional i n ~ u r y . ~Investigators associated several fracture types with abuse, but it is probably more accurate to state that all fracture types can be associated with multiple causes. Spiral fractures, once reported as the most common type of fracture in abuse victims, have been replaced in more recent studies with al are the result single transverse f r a c t ~ r e s . ~ q p i rfractures

CHAPTER

of torsional force applied to the extremity secondary to rotation of some sort. Transverse fractures are the result of a direct injury to the bone. This information should be used by the evaluating physician in conjunction with the history of injury to determine whether the history coincides with the presenting injury. Diaphyseal fractures of the long bones are the most common fractures associated with child abuse, particularly those of the tibia, femur, and humerus. If the child is not ambulatory, the association between these fractures and abuse is extremely high.46 Epiphyseal-metaphyseal fractures, although much less common than diaphyseal injuries, are reportedly far more specific for intentional injury.17 The forces required to sustain these injuries greatly exceed the forces normally associated with falls and other minor trauma. Epiphyseal-metaphysealfractures are also commonly known as corner fractures or buckethandle fractures. Type 1 fractures of the femur and humerus have a high association with abuse when encountered outside of the neonatal period.26This is particularly true if the history of injury does not contain significant high-force violent trauma. These injuries require considerable force to occur and, when nonintentional, are commonly associated with significant soft tissue damage and other injuries. Other types of Salter-Harris injuries do not appear to have a strong association with intentional abuse. Clavicular fractures can also be associated with abuse, but there is a low specificity. Clavicular fractures of either end rather than the midshaft are usually the result of significant traction or the trauma of shaking5()Rib fractures, in contrast, have an extremely high association with abuse. It is postulated that the relatively elastic rib cage in children prevents most fractures secondary to accidental trauma. When fractures of the ribs do occur, the association with abuse is high-up to 82%.8 Spinal fractures are rare in children, as is cord injury. The difficulty in diagnosing vertebral body injuries and the relatively protected spine make any association with abuse difficult to determine. Suffice it to say that any injury of the spine or spinal cord requires an extremely violent force, and the cause must be carefully investigated. It is critical for any physician treating children to investigate all fractures, particularly in the younger age groups. Minimal trauma does not commonly cause fractures, except when associated with other pathology. Getting an accurate history is critical. The presence of multiple fractures associated with a history of minimal trauma always requires an investigation for potential child abuse. The identification of multiple fractures, particularly when the age of the fractures is different, is almost pathognomonic of abuse. When abuse is suspected, skeletal surveys are indicated. The American College of Radiology has published standards for these survey^.^

Burns Burns are a fairly common indication of child abuse, representing approximately 20% of pediatric burn injuries. Abuse victims often have characteristic patterns of burn infliction that physicians should be aware of.45 Common patterns include circumferential burns,

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Punctate injuries or burns of the extremities caused by a recognizable object such as a fork indicate child abuse. -

4

particularly when the burns are on more than one extremity; "pattern" burns or branding; burns to the buttocks, genitalia, or perineum; and punctate or cigarette burns (Fig. 242). Burn victims who are abused are usually younger than unintentional burn victims and have a history of being burned in the bathroom." The demographics of intentionally burned children are striking. These children are often being raised by single mothers or are in foster care, they are in homes where other children have previously been removed because of abuse, and there is an almost 40% chance that past abuse has already been in~estigated.~" With burns, the history of injury is critical and is often inconsistent with the burn pattern. The burn itself often exhibits uncharacteristic features, such as lack of splash marks from falling liquids, consistent depth throughout the burn rather than the normal "feathering" of depth, and larger surface areas than expected based on the history. These burns, which are often the result of immersion, present with clear lines of demarcation, indicating that the child was unable to move during the incident and was probably restrained. Inflicted burns to the buttocks and perineum often occur in children being toilet trained when a caregiver becomes frustrated over an "accident." The depth of burn is also important. It takes approximately 1.5 seconds to cause a second-degree burn in adult skin immersed in water at 150" F. That is certainly more time than anyone would keep his or her hands immersed volitionally. A complete history and physical examination are necessary in any child seen for burns or the suspicion of abuse. Other signs of abuse are often discernible, such as healed or healing fractures or possibly perineal injuries. Additionally, recent data indicate that some burn injuries mimic chronic skin conditions." Thus, a high level of suspicion must be maintained when clinicians see lesions that d o not present in characteristic locations or do not respond to normal therapy. Given the high incidence of recurrence in burn injury, physicians must ensure that the child is discharged to a safe environment.

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Thoracoabdominal lnjury Fortunately, significant thoracoabdominal injury secondary to child abuse is uncommon, estimated to occur in about 5% of abused children.61 Unfortunately, thoracoabdominal injury is the second leading cause of death in these children, following head injury.55 Any type of blunt or penetrating abdominal injury can be caused intenti0nally.~~~~9-~~~~~~61 Injuries commonly result from severe blows to the abdomen or chest cavity, and as previously stated, rib fractures in children should raise the suspicion of abuse.8 Most important, the clinician must ascertain the history of injury to determine whether the injury is consistent with the mechanism described. For example, recent reports indicate that a simple fall down a flight of stairs does not generate the force or dynamics necessary for a hollow viscus perforation.34 Similarly, significant head injury requires a mechanism generating more force than simply rolling out of bed. Injuries to the perineum should always lead to a consideration of child abuse. Aside from bums to the perineum, discussed previously, injuries resulting from abuse tend to be penetrating in nature. Rectal or vaginal trauma resulting in laceration should routinely be investigated, as should lacerations in the penile and scrota1 region. Abuse may involve retained foreign bodies as well. The physician should always investigate anal and vaginal orifices that appear to be dilated, particularly those that may result in incontinence. Signs of abuse to the perineum are often chronic, and areas of scar and old lacerations should be noted. The radiographic and diagnostic workup for children suffering thoracoabdominal abuse is identical to that for unintentional injury. Recommendations for appropriate scans and diagnostics have been updated by the American Academy of Pediatrics? Management of these injuries is also the same as for unintentional thoracoabdominal i n j ~ r i e s . ~ ~ . ~ ~

BIRTH INJURIES Birth injury is estimated to occur in 6 to 8 of every 1000 live births in the United States, but it is responsible for around 2% of the perinatal mortality.65 Injury most commonly occurs in babies with macrosomia but can also be associated with fetal organomegaly, mass lesions, prematurity, protracted labor, precipitous delivery, breech presentation, and cephalopelvic dissociation. The development and widespread use of prenatal ultrasonography, along with other advances in perinatal care, have allowed the early identification of many of these factors, along with recommendations for the delivery of such high-risk infants.Z8

Soft Tissue Injury The most common birth iniurv encountered is iniurv to the soft tissue. This can present as a hematoma (often cephalohematoma), simple cutaneous bruising, - or fat necrosis manifesting as subcutaneous masses. These lesions resolve spontaneously within months and require no treatment other than reassurance of the parents. J

,

J

Less commonly, lacerations secondary to instrumentation may occur. These lacerations can usually be closed with adhesive strips or cutaneous glue rathkr than sutures. Suturing may be necessary, however, when adhesive closure cannot achieve the appropriate cosmetic result. Fine material should always be used, and healing is usually excellent. Lacerations are rarely deep, but if they are, standard precautions for wound exploration should be followed. Torticollis has been ascribed to birth trauma or intrauterine rnalpositioning.63 The cause is debatable, because torticollis has been found in infants who were delivered by cesarean section as well as in those delivered vaginally. The classic presentation is a small, firm mass in the body of the sternocleidomastoid muscle. The head is tilted toward the mass, with the face classically turned to the contralateral side. Physical therapy performed by the parents is successful in the vast majority of cases, and surgical intervention is rarely indicated. Facial asymmetry may result in untreated lesions.

Fractures The most common fracture associated with birth trauma is clavicular, occurring in about 2.7 of every 1000 bii-th~.5~ The fracture is noticed when the infant does not move the arm or swelling occurs over the clavicle. The fracture is commonly in the midshaft and generally requires no treatment, although some authors recommend figure-ofeight splints or pinning the baby's shirtsleeve to the chest on the affected side.*' Occasionally, because of shoulder dystocia, the clavicle may be intentionally f r a c t ~ r e d . ~ Fractures of the humerus usually occur in either the shaft or the proximal epiphysis. Epiphyseal fractures are difficult to diagnose because of a lack of ossification points in the neonatal epiphysis. Associated neurologic findings may be noted with fractures of the humerus, ,~~ including Erb's palsy and radial nerve p a l ~ y . 9Shoulder dislocation is most likelv not related to birth trauma but rather to intrauterine causes or therapy for Erb's palsy.' Distal fractures and dislocations of the radial head may also occur and are often associated with breech delivery.l~f;6 Proximal fractures of the humerus can be successfully treated by bandaging the arm to the chest in a neutral position for epiphyseal injuries and by strapping the arm to the chest with an abduction device or possibly a posterior splint for shaft fract~res.~Z Birth trauma can cause fractures of the femur at almost any location. Breech delivery and high birth weight are predisposing factors.67 Presentation consists of abnormal rotation of the lower extremity, pain, or swelling. Treatment involves application of a traction device, spica cast, or both.68 Reduction should be close to anatomic, because overgrowth and remodeling of the femur are not usually dramatic.5l

,

Neurologic Injury Brachial plexus injury is the most common neurologic birth injury30 Approximately 21% of these injuries are associated with a shoulder dystocia at birth. Erb's palsy

CHAPTER

24

Child Abuse and Birth Injuries

405

( C 3 t o C 5 ) is t h e m o s t c o m m o n o f t h e brachial plexus Perforation o f t h e esophagus o r cricopharyngeus c a n injuries and usually resolves spontaneously, with little residalso occur. In m o s t cases o f birth trauma t o t h e chest, ual effect. Presentation involves a lack of m o t i o n o f t h e expectant observation is indicated. T h e clinical course affected shoulder, with t h e l i m b adducted and internally dictates t h e n e e d for operative intervention. H i g h perrotated t o t h e prone position. Distal sensation and hand forations o f t h e esophagus and cricopharyngeus can function are usually normal. Even after aggressive physical usually b e treated b y observation o r occasionally therapy, about 2% o f cases are permanent.29 Lower injuries drainage.65 Lower lesions require drainage o r operative of t h e C 6 t o T 1 cervical roots (Klumpke's palsy) present repair. W i t h early identification, results are excellent. with a lack of hand and wrist function. T h e s e lesions may Perforation o f t h e esophagus c a n also result f r o m placeb e accompanied b y Homer's syndrome, with t h e associated m e n t o f a gastric t u b e i n t h e neonatal period. physical findings. Microsurgical repair has b e e n described Liver h e m a t o m a is t h e m o s t c o m m o n intra-abdominal injury secondary t o birth trauma (Fig. 2 4 3 ) . T h e usual for recalcitrant brachial plexus injuries, with relatively presentation is a n e m i a , b u t it c a n also b e shock.27 good success, b u t this should b e reserved only for infants Diagnosis is usually m a d e by ultrasonography, b u t a failing aggressive physical therapy.60 Phrenic nerve paralysis is a c o m m o n l y associated finding and should be invest h o r o u g h investigation m a y b e necessary t o rule o u t tigated whenever brachial plexus injury is identified. o t h e r hepatic masses i n a n e w b o r n . T r e a t m e n t is usually Isolated brachial plexus injury can cause significant shoulexpectant a n d includes v o l u m e resuscitation a n d correcder abnormalities, and therapy should n o t b e d e l a ~ e d . ~ t i o n o f a n y h y p o t h e r m i a o r coagulopathy. Occasionally, Phrenic nerve injury c a n also occur i n i ~ o l a t i o n . ~ ~operative intervention is necessary w h e n t h e baby is Treatment of phrenic nerve injury d e p e n d s o n t h e severity unstable o r c o n t i n u e d h e m o r r h a g e occurs. Hemostatic o f t h e respiratory embarrassment experienced b y t h e a g e n t s a p p e a r t o b e m o r e h e l p f u l t h a n a t t e m p t s at child. Asymptomatic injuries should not b e treated; s u t u r e repair i n stopping hepatic bleeding i n newborns.'' In any case, control o f hepatic h e m o r r h a g e is very diffiinjuries resulting i n respiratory i m p a i r m e n t should b e cult i n this age group. treated with diaphragmatic plication o r o t h e r procedures designed t o reduce t h e paradoxical m o v e m e n t o f S p l e n i c i n j u r y is rare a n d p r e s e n t s m u c h l i k e t h e diaphragm w i t h r e ~ p i r a t i o n . ~ ? h e p a t i c injury. Intra-abdominal b l o o d m a y b e t h e Certainly t h e m o s t devastating neurologic birth injuries o n l y presenting sign, a n d as i n h e p a t i c injury, o t h e r a t m~e n t i n c l u d e s involve t h e central nervous system. Lesions o f t h e cervical pathology m u s t b e ruled o ~ t T .r e ~ e x p e c t a n t observation a n d c o r r e c t i o n o f coagulopathy spine are rare but are devastating w h e n t h e y occur. T h e o r h y p o t h e r m i a . O p e r a t i v e i n t e r v e n t i o n is d i f f i c u l t cause o f injury is usually a vaginal delivery with a b r e e c h a n d usually results i n s p l e n e c t o m y . H e m o s t a t i c agents o r transverse lie.2 As with all cervical spine injuries, h i g h lesions require mechanical ventilation, a n d lower lesions m a y also b e u s e f u l . As w i t h splenic injury, i n j u r y t o t h e adrenal glands have devastating physical sequelae. Survival is poor i n is u n c o m m o n b e c a u s e o f t h e relative protection proneonates with c o m p l e t e transection. Partial injury m a y m i m i c cerebral palsy.40 vided b y t h e thoracic ribs. T h e presentation m a y b e Subdural, subarachnoid, intraventricular, and intrah e m o r r h a g e o r adrenal i n s u f f i c i e n c y i n severe cases. parenchymal bleeds have also b e e n associated with birth Injury c a n also b e identified f r o m calcifications f o u n d on a radiograph t a k e n later i n l i f e . A s w i t h all intratrauma. O u t c o m e is d e p e n d e n t o n t h e e x t e n t of t h e lesion a b d o m i n a l solid organs, investigation o f h e m a t o m a s and t h e presentation. Usually these lesions are secondary requires a w o r k u p t o r u l e o u t o t h e r pathology, s u c h as t o v a c u u m extraction,23,70 which is also implicated as t h e cause o f subgaleal cephalohematoma. Although m o s t underlying tumor. hematomas resolve without incident o r sequelae, approximately 25% have b e e n reported t o cause death i n affected neonates." Traction injury t o t h e internal carotid artery has also b e e n reported i n difficult births. O u t c o m e f r o m these injuries is varied and d e p e n d s o n t h e e x t e n t o f vascular damage and collateral perfusion.62 Similarly, direct injury to t h e optic nerve has b e e n described.39 T h e m o s t c o m m o n central nervous system injury duri n g childbirth is anoxic brain d a m a g e a n d t h e resultant "cerebral palsy." T h e cause is controversial, b u t difficult delivery is a c o m m o n association. T r e a t m e n t o f neurologic b i r t h t r a u m a is usually expectant, with aggressive physical therapy. Recalcitrant peripheral injuries have responded t o surgical repair.

Thoracoabdominal Injury Injuries t o t h e chest are believed t o b e t h e result of pressure o n t h e thoracic cavity. P n e u m o t h o r a x , p n e u m o m e diastinum, a n d chylothorax have b e e n described.sz69

. . A Ultraso~lographyof the abdomen clcarly demonstrates this hepatic hematoma caused by birth trauma, which resolved spontaneously. Lesions like this call be followed by ultrasonography; if they persist, other causes such as neoplasm must be investigated.

I

406

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TRAUMA

REFERENCES 1. Akbarnia BA, Silberstein MJ, Rend RJ, et al: Arthrography in the diagnosis of fractures in the distal end of the humerus in infants. J Bone Joint Surg Am 1986;68:599-601. 2. Allen JP: Birth injury to the spinal cord. Northwest Med 1986;69:323-326. 3. Al-Moosa A, Al-Shaiji J, Al-Fadhli A, et al: Pediatricians' knowledge, attitndes and experience regarding child maltreatment in Kuwait. Child Abuse Negl 2003;27: 1161-1178. 4. Al-Qattan MM: Classification of secondary shoulder deformities in obstetric brachial plexus palsy. J Hand Surg [Br] 2003;28:483-486. 5. American Academy of Pediatrics: Diagnostic imaging of child abuse. Pediatrics 2000;105:1345-1348. 6. American College of Radiology: Standards for Skeletal Surveys in Children. American College of Radiology, 1997. 7. Babbitt DP, Cassidy RH: Obstetrical paralysis and dislocation of the shoulder in infants. J Bone Joint Surg Am 1968; 50:1447-1452. 8. Barsness KA, Cha E, Bensard DD, et al: The positive predictive value of rib fractures as an indicator of nonaccidental trauma in children. J Trauma 2003;54:1107-1110. 9. Bianco AJ, Schlein AP, Kruse RI, et al: Birth fractures. Minn Med 1972;55:471-474. 10. Blakemore LC, Loder RT, Hensinger RN: Role of intentional abuse in children 1 to 5 years old with isolated femoral shaft fractures. J Pediatr Orthop 1996;16:585-588. 11. Blocker SH, TernbergJL: Traumatic liver laceration in the newborn: Repair with fibrin glue. J Pediatr Surg 1986; 21:369-371. 12. Brown T: Radiography's role in detecting child abuse. Radio1 Techno1 1995;66:389-390. 13. Budeni! DL, Farber MG, Mirchandani HG, et al: Ocular and optic nerve hemorrhages in abused infants with intracranial injuries. Ophthalmology 1994;101:559-565. 14. Caffey J : Multiple fractures in the long bones of infants suffering from chronic subdural hematoma. AJR Am J Roentgen01 1946;56:163-173. 15. Cameron CM, Lazoritz S, Calhoun AD: Blunt abdominal injury: Simultaneously occurring liver and pancreatic injury in child abuse. Pediatr Emerg Care 1997;13:334336. 16. Cameron JM, Rae LJ: Atlas of the Battered Child Syndrome. Edinburgh, Churchill Livingstone, 1975. 17. Chapman S: Radiological aspects of non-accidental injury. J R Soc Med 1990;83:67-71. 18. Choi HJ, Lee SY, Yang H, et al: Retinal haemorrhage in vivax malaria. Trans R Soc Trop Med Hyg 2004;98:387-389. 19. Coant PN, Kornberg AE, Brody AS, et al: Markers for occult liver injury in cases of physical abuse in children. Pediatrics 1992;89:274278. 20. De Bellis MD, Putnam FW: The psychobiology of child maltreatment. Child Adolesc Psychiatr Clin N Am 1994; 3:663-678. 21. Deputy S: Shaking-impact syndrome of infancy. Semin Pediatr Neurol 2003;10:112-119. 22. Dodge KA, Bates JE, Petit GS: Mechanisms in the cycle of violence. Science 1990;250:1678-1683. 23. D y e r D: Problems after vacuum-assisted childbirth. Nursing 2002;32:74. 24. Ewing-Cobbs L, Kramer L, Prasad M, et al: Neuroimaging: Physical and developmental findings after inflicted and noninflicted traumatic brain injury in young children. Pediatrics 1998;102:300-307. 25. Forbes BJ, Christian CW, Judkins AR, et al: Inflicted childhood neurotrauma (shaken baby syndrome): Ophthalmic findings. J Pediatr Ophthalmol Strabismus 2004;41:80-88.

26. Forlin E, Guille J, Kumar S, et al: Transepiphyseal fractures on the neck of the femur in very young children. J Pediatr Orthop 1992;12:164168. 27. French CE, Waldstein G: Subcapsular hemorrhage of the liver in the newborn. Pediatrics 1982;69:204-208. 28. Friesen CD, Miller AM, Rayburn WF: Influence of spontaneous or induced labor on delivering the macrosomic fetus. Am J Perinatol 1995;12:63-66. 29. Gherman RB, Ouzounian JG, Goodwin TM: Brachial plexus palsy: An in utero injury? Am J Obstet Gynecol 1999;180:1303-1307. 30. Gherman RB,Ouzounian JG, Satin AJ, et al: A comparison of shoulder dystocia-associated transient and permanent brachial plexus palsies. Obstet Gynecol 2003;102:544548. 31. Heider TR, Priolo D, Hultman CS, et al: Eczema mimicking child abuse: A case of mistaken identity.J Burn Care Rehabil 2002;23:357-359. 32. Holmes SJ, Robins LN: The role of parental disciplinary practices in the development of depression and alcoholism. Psychiatry 1988;51:2436. 33. Hultman CS, Priolo D, Cairns BA, et al: Return to jeopardy: The fate of pediatric burn patients who are victims of abuse and neglect. J Burn Care Rehabil 1998;19:367-376. 34. Huntimer CM, Muret-Wagstaff S, Leland NI,: Can falls on stairs result in small intestine perforations? Pediatrics 2000; 106:301-305. 35. Johnson DL, Boa1 D, Baule R: The role of apnea in nonaccidental head injury. Pediatr Neurosurg 1995;23:305-310. 36. Keenan HT, Runyan DK, Marshall SW: A population-based study of inflicted traumatic brain injury in young children. JAMA 2003;290:621-626. 37. Keller MS: Blunt injury to solid abdominal organs. Semin Pediatr Surg 2004;13:106-111. 38. Keller MS, Stafford PW, Vane DW: Conservative management of pancreatic trauma in children. .J Trauma 1997;42: 1097-1100. 39. Khalil SK, Urso RG, Mintz-Hittner HA: Traumatic optic nerve injury occurring after forceps delivery of a term newborn. J Pediatr Ophthalmol Strabismus 2003;7:146-147. 40. Koch BM: Neonatal spinal cord injury. Arch Phys Med Rehabil 1979;60:378-381. 41. Kogutt MS, Swischuk LE, Fagan CJ: Patterns of injury and significance of uncommon fractures in the battered child syndrome. Radiology 1974;121:143-149. 42. Langer JC, et al: Plication of the diaphragm for infants and young children with phrenic nerve palsy. .J Pediatr Surg 1988;23:749-751. 43. Lee ACW, Ou Y, Fong D: Depressed skull fractures: A pattern of abusive head injury in three older children. Child Abuse Negl 2003;27:1323-1329. 44. Lemperg R, Liliequist B: Dislocation of the proximal epiphysis of the humerus in newborns. Acta Paediatr Scand 1970;59:377-380. 45. Lenoski EF, Hunter KA: Specific patterns of inflicted burn injuries. J Trauma 1977;17:842-846. 46. Loder RT, Bookout C: Fracture patterns in battered children. J Orthop Trauma 1991;5:428-433. 47. Ludwig S, Kornberg AE (eds): Child Abuse: A Medical Reference, 2nd ed. New York, Churchill Livingstone, 1992. 48. McClain PW, SacksJ, Froehlke RG, et al: Estimates of fatal child abuse and neglect, United States, 1979 through 1988. Pediatrics 1993;91:338-343. 49. McKibben L, De Vos E, Newberger EH: Victimization of mothers of abused children: A controlled study. Pediatrics 1989;84:531-535. 50. Merten DF, Radkowski MA, Leonidas JC: The abused child: A radiological appraisal. Radiology 1983;146377-381. 51. Mitchell WC, Coventry MB: Osseous injuries in the newborn. Minn Med 1959;42:1-4.

CHAPTER

52. Moucha CS, Mason DE: Distal humeral epiphyseal separation. Am J Orthop 2003;32:497-500. 53. Nakagawa H, Yamanchi M, Kusuyama T, et al: Cervical as a comemphysema secondary to pneumomediastint~n~ plication of childbirth. Ear Nose Throat.] 2003;82: 948-951. 54. National Center on Child Abuse and Neglect: Study Findings: Study of National Incidence and Prevalence of Child Abuse and Neglect: 1988. Washington, DC, Department of Health and Human Services, 1988. 55. National Pediatric Trauma Registry. Boston, Tufts University. 56. Ng CS, Hall CM, Shaw DG: The range of visceral manifestations of non-accidental injury. Arch Dis Child 1997;77: 167-174. 57. Oppenheim WL, Davis A, Growdon WA, et al: Clavicle fractures in the newborn. Clin Orthop 1990;250:176-180. 58. Pirtan G, Pamberger P, Blab E, et al: Common tasks and problems it1 paediatric tranma radiology. Eur J Radiol 2003;48: 103-124. 59. Perdomo Y, Fiore N, Reyna T: Splenic injury presenting with isolated scrota1 findings in a stable newborn. J Pediatr Surg 2003;38: 1673-1675. 60. Piatt JH: Birth injuries of the brachial plexus. Pediatr Clin North Am 2004;51:421-440. 61. Purdue GF, HuntJL: Burn injuries. In Ludwig S, Kornberg AE (eds): Child Abuse: A Medical Reference, 2nd ed. New York, Churchill Livingstone, 1992, pp 105-116.

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62. Robertson WC, Pettigrew I><::"<:ongenital" Homer's syndrome and carotid dissection. J Neuroimaging 2003;13: 367-370. 63. Sanerkin BG, Edwards P: Birth injury to t h e sternocleidomastoid muscle. J Bone Joint Snrg Rr 1066;48:441. 64. Sartorelli KH, Vane DW: The diagnosis and management of children with blunt injury of the chest. Se~ninPediatr Surg 2004;13:98-105. 65. Schullinger JN: Birth trauma. Pediatr (:lin North Am 1993;40:1351-1358. 66. Siffert RS: Displacement of the distal hurnel-a1epiphysis in the newborn inf'ant.,J Bone Joint Surg An1 191i3;45:165-169. 67. Theodorou SD, Ierodiaconou MN, Mitsou A: Obstetrical fractnre-separation of' the nppel. femoral epiphysis. Acta Orthop Scand 1982;53:239-243. 68. T~twbinR, Crawford AH: Neonatal tra~~rnatic proximal femoral epiphysiolysis. Pediatrics 1!)79;(i3:456-459. S: Neonatal subgaleal hemorrhage 69. Uchil D, Arulk~~maran and its relationship to delivery by vacutlnl extraction. Obstet Gynecol Surv 2003;58:687-693. 70. Whitby EH, Griffiths PD, Ruttcr S, et al: Freq~~ency and natural history of subdnral haernorrhages in babies and relation to obstetric factors. Lancet 2003;362:841i-85l. 71. Wissow LS: Child abuse and neglect. N Engl J Med 1995;332:1425-1431.

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy Matthew J. Krasin and Andrew M. Davidoff

A number of milestones in the evolution of cancer therapy have come from the field of pediatric oncology. The first clear evidence that chemotherapy could provide effective treatment for childhood malignancy occurred in 1950, when Farber4 reported temporary cancer remission in children with acute lymphoblastic leukemia (ALL) treated with the folic acid antagonist aminopterin.41 The first successful use of a multidisciplinary approach to cancer treatment occurred in the 1950s and 1960s through the collaborative efforts of pediatric surgeons, radiation therapists, and pediatric oncologists aiming to improve the treatment of Wilms' tumor in children." Such a multidisciplinary approach is now used throughout the field of oncology. The successful use of a combination of chemotherapeutic agents to cure Hodgkin's disease and ALL during the 1960s led to the widespread use of combination chemotherapy to treat virtually all types of pediatric cancers. Since the late 1980s, neuroblastoma has been the paradigm for the use of therapies of variable intensity, depending on risk stratification determined by clinical and biologic variables, including molecular markers. Other advances in pediatric oncology have included the development of interdisciplinary, national cooperative clinical research groups to critically evaluate new therapies, the efficacy of dose-intensive chemotherapy programs in improving the outcome of advanced-stage solid tumors, and the supportive care necessary to make the latter approach possible. The development and application of these principles and advances have led to substantially increased survival rates for children with cancer and profound improvements in their quality of life. Additionally, advances in molecular genetic research in the past 2 decades have led to an increased understanding of the genetic events in the pathogenesis and progression of human malignancies, including those of childhood. A number of pediatric malignancies have served as models for molecular genetic research. Chromosomal structural changes, activating or inactivating mutations of relevant genes or their regulatory elements, gene

amplification, and gene imprinting may each play a role in different tumor types. In some instances, these genetic events occur early in tumorigenesis and are specific for a particular tumor type, such as chromosomal translocation t(11;22) (q24;q12) in Ewing's sarcoma; other aberrations occur in a variety of different tumor types and are almost always associated with additional genetic changes, such as chromosome l p deletion in neuroblastoma and Wilms' tumor. Some alterations involve oncogenes-genes that, when activated, lead directly to cancer-whereas others involve tumor suppressor genes, whose inactivation allows tumor progression. The result of alterations in these genetic elements, regardless of the mechanism, is disruption of the normal balance between proliferation and death of individual cells. These discoveries have highlighted the utility of molecular analysis for a variety of purposes, including diagnosis, risk stratification, and treatment planning; the understanding of syndromes associated with cancer; genetic screening and genetic counseling; and prophylactic treatment, including surgical intervention. Soon, treatment regimens are likely to be individualized on the basis of the molecular biologic profile of a patient's tumor. In addition, molecular profiling will lead to the development of new drugs designed to induce differentiation of tumor cells, block dysregulated growth pathways, or reactivate silenced apoptotic pathways.

EPIDEMIOLOGY AND SURVIVAL STATISTICS Cancer in children is uncommon; it represents only about 2% of all cancer cases. Nevertheless, after trauma, it is the second most common cause of death in children older than 1 year. Each year, approximately 130 new cases of cancer are identified per million children younger than 15 years (or about 1 in 7000). This means that in the United States, about 9000 children younger than 15 years are diagnosed with cancer each year, in addition

412

PART

III

MAJORTUMORS OF CHILDHOOD

Type of Cancer

Percentage of Total

Leukemia Brain tumors Lymphoma Neuroblastoma Sarcoma Wilms' tumor Germ cell tumors Osteosarcoma Retinoblastoma Liver tumors

30

been outstanding, progress in the treatment of others, such as metastatic neuroblastoma and rhabdomyosarcoma, has been modest. Therefore, there is still a need for significant improvement in the treatment of childhood cancer.

22

15 8 7 6

to 4000 patients aged 15 to 19 years.15*Leukemia is the most common form of cancer in children, and brain tumors are the most common solid tumor of childhood (Table 25-1). Lymphomas are the next most common malignancy in children, followed by neuroblastoma, soft tissue sarcomas, Wilms' tumor, germ cell tumors, osteosarcoma, and retinoblastoma. A slightly different distribution is seen among 15- to 19-year-olds, in whom Hodgkin's disease and germ cell tumors are the most frequently diagnosed malignancies; non-Hodgkin lyrnphoma, nonrhabdomyosarcoma soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, thyroid cancer, and melanoma also occur with an increased incidence. In general, the incidence of childhood cancer is greatest during the first year of life, peaks again in children aged 2 to 3 years, and then slowly declines until age 9. The incidence then steadily increases again through adolescence. Each tumor type shows a different age distribution pattern, however. Variations by gender are also seen. For example, Hodgkin's disease, ALL, brain tumors, neuroblastoma, hepatoblastoma, Ewing's sarcoma, and rhabdomyosarcoma are more common in boys than in girls younger than 15 years, whereas only osteosarcoma and Ewing's sarcoma are more common in boys than in girls older than 15 years. However, girls in the older age group have Hodgkin's disease and thyroid cancer more frequently than boys do. Distribution also varies by race: white children generally have a 30% greater incidence of cancer than do black children. This difference is particularly notable for ALL, Ewing's sarcoma, and testicular germ cell tumors. The probability of surviving childhood cancer has improved greatly since Farber induced the first remissions in patients with ALL. In the early 1960s, approximately 30% of children with cancer survived their disease. By the mid-l980s, about 65% of children with cancer were cured, and by the mid-1990s, the cure rate had increased to nearly 75%.12' These great strides resulted from three important factors: (1) the sensitivity of childhood cancer, at least initially, to available chemotherapeutic agents; (2) the treatment of childhood cancer in a multidisciplinary fashion; and (3) the treatment of most children in major pediatric treatment centers in the context of a clinical research protocol using the most current and promising therapy. Although progress in the treatment of some tumor types such as ALL and Wilms' tumor has

MOLECULAR BIOLOGY OF CANCER During normal cellular development and renewal, cells evolve to perform highly specialized functions to meet the physiologic needs of the organism. Development and renewal involve tightly regulated processes that include continued cell proliferation, differentiation to specialized cell types, and programmed cell death (apoptosis). An intricate system of checks and balances ensures proper control over these physiologic processes. The genetic composition (genotype) of a cell determines which pathway or pathways will be followed in exerting that control. In addition, the environment plays a crucial role in influencing cell fate: cells use complex signal transduction pathways to sense and respond to neighboring cells and their extracellular milieu. Cancer is a genetic disease whose progression is driven by a series of accumulating genetic changes influenced by hereditary factors and the somatic environment. These genetic changes result in individual cells acquiring a phenotype that provides them with a survival advantage over surrounding normal cells. Our understanding of the processes that occur in malignant cell transformation is increasing; many discoveries in cancer cell biology have been made by using childhood tumors as models. This greater understanding of the molecular biology of cancer has also contributed significantly to our understanding of normal cell physiology.

Normal Cell Physiology CeN Cycle Genetic information is stored in cells and transmitted to subsequent generations of cells through nucleic acids organized on chromosomes as genes. A gene is a functional unit of heredity that exists on a specific site or locus on a chromosome, is capable of reproducing itself exactly at each cell division, and is capable of directing the synthesis of an enzyme or other protein. The genetic material is maintained as DNA formed into a double helix of complementary strands. The backbone of each strand is made up of linked sugar and phosphate groups to which complementary bases-a purine (adenine or guanine) and a pyrimidine (cytosine or thymine)-are connected by hydrogen bonds. DNA normally exists in a tightly wound complex maintained by histone proteins in the nucleus. Unwinding of the DNA is required for its activation. The complementary nature of the two DNA strands allows DNA to be exactly replicated during cell division: each strand serves as a template for the synthesis of the second strand. The cell must ensure that synthesized DNA (3 billion base pairs) has been accurately copied. DNA replication errors that go uncorrected potentially alter the function of normal cell regulatory proteins.

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Principles o f Pediatric Oncology, Genetics o f Cancer, and Radiation Therapy

Protein synthesis begins with the transcription of a single strand of messenger RNA (mRNA) from a DNA template. RNA contains the pyrimidine uracil, instead of the DNA base thymine, and a pentose sugar, ribose, instead of the deoxyribose sugar found in DNA. After transcription, the mRNA undergoes modifications that affect its sequence, length, physical form, and stability. Following this, translation of the mRNA template into the sequence of amino acids that constitutes a polypeptide occurs. Additional post-translational modifications can then be made to these newly synthesized proteins. These proteins, whose sequence is dictated by the DNA of a given cell, are responsible for an enormous range of activities within the cell and direct, in particular, the cell's division cycle, by which cells proliferate. The molecular machinery used to control the cell cycle is highly organized and tightly regulated (Fig. 25-1).I34 Normal growth results from the progression of cells

A Mitosis

Resting Phase

apoptosis (death)

3

Growth

terminal differentiation I

.

Synthesis

A, The cell cycle. Normal cell growth proceeds in an orderly fashion, with cells proceeding through the cycle of DNA replication (S) and mitosis (M). These cycles are separated by two intervening phases of growth (G, and G P ) Cells . are signaled to leave the cycle to enter a resting state, to differentiate,or to die. B, Cell signal transduction. Proto-oncogene products (examples in parentheses) are involved in all aspects of signal transduction that move the cell through the cell cycle. The process begins when extracellular growth factors bind to a transmembrane growth factor receptor, thereby inducing the protein kinase activity of the receptor. Other proteins bind to the phosphorylated receptor and transmit a signal to the nucleus through membrane-bound and cytoplasmic messengers. This activates nuclear transcription factors, which bind to DNA and affect the transcription of growth-relatedgenes. GTP, guanosine triphosphate.

413

through cycles of DNA replication (S phase) and cell division or mitosis (M phase). These two phases of the cell cycle are separated by two intervening growth phases (GI and G2). Cells can also temporarily leave the cell cycle and enter a resting state called Go. Signals that stimulate or inhibit cellular growth converge on a set of evolutionarily conserved enzymes that drive cell cycle progression. Two classes of proteins, cyclins and cyclindependent kinases, form complexes that mediate progression through the cell cycle by sequentially phosphorylating target proteins. Cyclin-dependent kinase inhibitors regulate the activity of the cyclin-dependent kinases and serve as a "braking" system for the cell cycle machinery. In addition, various "checkpoints" exist to halt progression through the cell cycle during certain environmental situations or times of genetic error resulting from inaccurate synthesis or damage. Two of the most well-studied participants in the cell cycle checkpoint system are p53 and retinoblastoma (RB) proteins.1" In normal circumstances, cells divide and terminally differentiate, thereby leaving the cell cycle, or they enter a resting state. Inactivation of the effectors of cell cycle regulation or the bypassing of cell cycle checkpoints can result in dysregulation of the cell cycle-a hallmark of malignancy.

Signal Transduction Signal transduction pathways regulate all aspects of cell function, including metabolism, cell division, death, differentiation, and movement. Multiple extracellular and intracellular signals for proliferation or quiescence must be integrated by the cell, and it is this integration of signals from multiple pathways that determines the response of a cell to competing and complementary signals. Extracellular signals include growth factors, cytokines, and hormones; the presence or absence of adequate nutrients and oxygen; and contact with other cells or an extracellular matrix. Signaling mediators often bind to membrane-bound receptors on the outside of the cell, but they may also diffuse into the cell and bind receptors in the cytoplasm or on the nuclear membrane. Binding of a ligand to a receptor stimulates the activities of small-molecule second messengers-proteins necessary to continue the transmission of the signal. Signaling pathways ultimately effect the activation of nuclear transcription factors that are responsible for the expression or silencing of genes encoding proteins involved in all aspects of cellular physiology. Receptors with tyrosine kinase activity are among the most important transmembrane receptors. They are composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular, cytoplasmic, tyrosine kinase domain. The binding of ligand to a receptor may cause a conformational change in the receptor or lead to the linking of the receptoreto one or more other receptors. Either event results in activation of the receptor. The tyrosine kinase domain, in particular, is responsible for conveying signals intracellularly by phosphorylating internal substrates directly or by activating associated tyrosine kinases. Several important transmembrane receptors with protein kinase activity have been identified and grouped

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in families on the basis of structural ~imi1arities.I~~ These families include the epidermal growth factor receptors (EGFRs), fibroblast growth factor receptors, insulin-like growth factor (IGF) receptors, platelet-derived growth factor (PDGF) receptors, transforming growth factor recep tors, and neurotrophin receptors (Trks). Abnormalities of members of each of these families are often found in pediatric malignancies and therefore are thought to play a role in their pathogenesis. Characteristic abnormalities of these receptors often form the basis of both diagnostic identification of certain tumor types and, more recently, targeted therapy for tumors with these specific abnormalities.

Programmed Cell Death Multicellular organisms have developed a highly organized and carefully regulated mechanism of cell suicide in order to maintain cellular homeostasis. Normal development and morphogenesis are often associated with the production of excess cells, which are removed by the genetically programmed process called apoptosis. Cells undergoing apoptosis have distinct morphologic features (plasma membrane blebbing, reduced volume, nuclear condensation), and their DNA is subjected to endonucleolytic cleavage. Apoptosis is initiated by the interaction of "death ligands," such as tumor necrosis factor-a (TNF-a), Fas, and TNF-related apoptosis-inducing ligand (TRAIL), with their respective receptors. This interaction is followed by aggregation of the receptors and recruitment of adapter proteins to the plasma membrane, which activate caspa~es.'~)~ Caspases are a large family of proteases that function in both the initiation of apoptosis in response to proapoptotic signals and the subsequent effector pathway that disassembles the cell. Thus, apoptosis limits cellular expansion and counters cell proliferation. Because cell survival signals may also be activated through pathways mediated by nuclear factor KB, the fate of a cell is determined by the balance between death signals and survival s i g n a l ~ . ~ W t hsignals er arising from cellular stress (e.g., DNA damage, hypoxia, oncogene activation) may also effect cell cycle arrest or apoptosis. An alternative to cell death mediated by receptorligand binding is cellular senescence, which is initiated when chromosomes reach a critical length. Eukaryotic chromosomes have DNA strands of unequal length, and their ends, called telomeres, are characterized by speciesspecific nucleotide repeat sequences. Telomeres stabilize the ends of chromosomes, which are otherwise sites of significant instability.'"Wver time and with each successive cycle of replication, chromosomes are shortened by failure to complete replication of their telomeres. Thus, telomere shortening acts as a biologic clock, limiting the life span of a cell. Germ cells, however, avoid telomere shortening by using telomerase, an enzyme capable of adding telomeric sequences to the ends of chromosomes. This enzyme is normally inactivated early in the growth and development of an organism. Persistent activation or the reactivation of telomerase in somatic cells appears to contribute to the immortality of transformed cells.

Malignant Transformation Alteration or inactivation of any of the components of normal cell regulatory pathways may lead to the dysregulated growth that characterizes neoplastic cells. Malignant transformation may be characterized by cellular dedifferentiation or failure to differentiate, cellular invasiveness and metastatic capacity, or decreased drug sensitivity. Tumorigenesis reflects the accumulation of excess cells that results from increased cell proliferation and decreased apoptosis or senescence. Cancer cells do not replicate more rapidly than normal cells, but they show diminished responsiveness to regulatory signals. Positive growth signals are generated by proto-oncogenes, so named because their dysregulated expression or activity can promote malignant transformation. These protooncogenes may encode growth factors or their receptors, intracellular signaling molecules, and nuclear transcription factors (Table 25-2). Conversely, tumor suppressor genes, as their name implies, control or restrict cell growth and proliferation. Their inactivation, through various mechanisms, permits the dysregulated growth of cancer cells. Also important are the genes that regulate cell death. Their inactivation leads to resistance to apoptosis and allows the accumulation of additional genetic aberrations. Cancer cells carry DNA that has point mutations, viral insertions, or chromosomal or gene amplifications, deletions, or rearrangements. Each of these aberrations can alter the context and process of normal cellular growth and differentiation. Although genomic instability is an inherent property of the evolutionary process and normal development, it is through genomic instability that the malignant transformation of a cell may arise. This inherent instability may be altered by inheritance or exposure to destabilizing factors in the environment. Point mutations may terminate protein translation, alter protein function, or change the regulatory target sequences that control gene expression. Chromosomal alterations create new genetic contexts within the genome and lead to the formation of novel proteins or to the dysregulation of genes displaced by aberrant events. Genetic abnormalities associated with cancer may be detected in every cell in the body or only in the tumor cells. Constitutional or germline abnormalities either are inherited or occur de novo in the germ cells (sperm or oocyte). Interestingly, despite the presence of a genetic abnormality that might affect growth regulatory pathways in all cells, people are generally predisposed to the development of only certain tumor types. This selectivity highlights the observation that gene function contributes to growth or development only within a particular milieu or physiologic context. Specific tumors occur earlier and are more often bilateral when they result from germline mutations than when they result from sporadic or somatic alterations. Such is often the case in two pediatric malignancies, Wilms' tumor and retinoblastoma. These observations led Knudson81 to propose a "two-hit" mechanism of carcinogenesis in which the first genetic defect, already present in the germline, must be complemented by an additional spontaneous

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

415

Oncogene Family

Proto-oncogene

Chromosome Location

Tumor

Growth factors and receptors

Erb 6 2 Trk Src H-ras c-myc N-myc

17q21 9q22 7pll 11~15.1 18q24 2p24

Glioblastoma Neuroblastoma Rhabdomyosarcoma,osteosarcoma, Ewing's sarcoma Neuroblastoma Burkitt's lymphoma Neuroblastoma

Chromosome Location

Tumor

Protein kinase Signal transducers Transcri~tionfactors

Syndrome Familial polyposis coli Familial retinoblastoma WAGR* Denys-Drasht Beckwith-Wiedemannt Li-Fraumeni Neurofibromatosis type 1 Neurofibromatosis type 2 Von Hippel-Lindau

Tumor Suppressor Gene -APC

RE WT1 WT1 WT2 (?) ~ 5 3 NFI NF2 VHL

5q21 13q24 11~13 11~13 11~15 17q13 17q11.2 22q12 3~25-26

Intestinal polyposis, colorectal cancer Retinoblastoma, osteosarcoma Wilms' tumor Wilms' tumor Wilms' tumor, hepatoblastoma, adrenal Multiple (see text) Sarcomas, breast cancer Neurofibroma, neurofibrosarcoma, brain tumor Renal cell cancer, pheochromocytoma, retinal angioma, hemangioblastoma

'Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation. tWilms' tumor, pseudohermaphroditism, mesangial sclerosis, renal failure. ?Multipletumors, hemihypertrophy, macroglossia, hyperinsulinism.

mutation before a tumor can arise. In sporadic cancer, cellular transformation occurs only when two (or more) spontaneous mutations take place in the same cell. Much more common, however, are somatically acquired chromosomal aberrations, which are confined to the malignant cells. These aberrations affect growth factors and their receptors, signal transducers, and transcription factors. The general types of chromosomal alterations associated with malignant transformation are shown in Figure 25-2. Although a low level of chromosomal instability exists in a normal population of cells, neoplastic transformation occurs only if these alterations affect a growth-regulating pathway and confer a growth advantage.

DNA Content Normal human cells contain two copies of each of 23 chromosomes; a normal "diploid" cell therefore has 46 chromosomes. Although cellular DNA content, or ploidy, is accurately determined by karyotypic analysis, it can be estimated by the much simpler method of flow cytometric analysis. Diploid cells have a DNA index of 1.0, whereas near-triploid cells have a DNA index ranging from 1.26 to 1.76. The majority (55%) of primary neuroblastoma cells are triploid or near triploid (e.g., having between 58 and 80 chromosomes), whereas the remainder are near diploid (35 to 57 chromosomes) or near Neuroblastomas tetraploid (81 to 103 chromo~omes).~6 consisting of near-diploid or near-tetraploid cells usually have structural genetic abnormalities (e.g., chromosome l p deletion and amplification of the MYCN oncogene), whereas those consisting of near-triploid cells are characterized by three almost complete haploid sets of

chromosomes with few structural abnormalities.16 Importantly, patients with near-triploid tumors typically have favorable clinical and biologic prognostic factors and excellent survival rates compared with those who have near-diploid or near-tetraploid tumors."'

Chromosomal Translocations Many pediatric cancers, specifically hematologic malignancies and soft tissue neoplasms, have recurrent, nonrandom abnormalities in chromosomal structure, typically chromosomal translocations (Table 25-3). The most common result of a nonrandom translocation is the fusion of two distinct genes from different chromosomes. The genes are typically fused within the reading frame and express a functional, chimeric protein product that has transcription factor or protein kinase activity. These fusion proteins contribute to tumorigenesis by activating genes or proteins involved in cell proliferation. For example, in Ewing's sarcoma the consequence of the t(11;22) (q24;qlZ) translocation is a fusion of EWS, a transcription factor gene on chromosome 22, and FLI-1, a gene encoding a member of the ETS family of transcription factors on chromosome 1 The resultant chimeric protein, which contains the DNA binding region of FLI-I and the transcription activation region of EWS, has greater transcriptional activity than does EWS alone.98 The EWS-FLI-1 fusion transcript is detectable in approximately 90% of Ewing's sarcomas. At least four other EWS fusions have been identified in Ewing's sarcoma; fusion of EWSwith ERG (another ETS family member) accounts for an additional 5% of cases.'S7 Alveolar rhabdomyosarcomas have characteristic translocations between the long arm of chromosome 2 (75% of cases) or the short

416

PART

I1 I

MAJORTUMORS OF CHILDHOOD

Monosomy 14

\

Trisomy

IGain

/

Amplification

Telomere Short Arm

Centromere Long Arm

Telomere

/

d

Interstitial deletion

Transl cation

chromosomal

1

lntra

m >oIal

.

del (1p33)

t(1;14) (p33;q11.2)

inv(14) (q11.2q32)

-

Spectrum of gross chromosomal aberrations using chromosomes 1 and 14 as examples. HSR, homogeneously staining regions (From Look AT, Kirsch IR: Molecular basis of childhood cancer. In Pizzo PA, Poplack DG [eds]: Principles and Practices of Pediatric Oncology. Philadelphia: Lippincott-Raven, 1997, p 38.)

arm of chromosome 1 (10% of cases) and the long arm of Translocations that generate chimeric. proteins with chromosome 13. These translocations result in the fusion increased transcriptional activity also characterize desmoplastic small round cell tumor,88myxoid l i p o s a r ~ o m a , l ~ ~ of PAX3 (at 2q35) or PAX7 (at lp36) with FKHR, a gene encoding a member of the forkhead family of transcription extraskeletal myxoid chrondrosarcoma,27 malignant factors." The EWS-FLJ-1 and PAX7-FKHR fusions appear melanoma of soft parts,l54 synovial sarcoma,28 congenital fibrosarc0ma,14~ cellular mesoblastic nephroma,12' to confer a better prognosis for patients with Ewing's sarcoma and alveolar rhabdomyosarcoma, re~pectively.~,~~ and dermatofibrosarcoma protuberans.109

CHAPTER

25

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Tumor

Fusion Transcript -----

Ewing's sarcoma, primitive neuroectodermal tumor

FLII-EWS ERG-EWS ETVI-EWS EIAF-EWS FEV-EWS WTI-EWS FLl1-EWS SSX1-SM SSX2-SM PAX3-FKHR PAX7-FKHR AJFI-EWS CHOP-TLS(FUS) CHOP-EWS CHN-EWS COLIAI-PDGFB EN6-NJRK3 ? ?

Desmoplastic small round cell tumor Synovial sarcoma Alveolar rhabdomyosarcoma

' 1

Malignant melanoma of soft part (clear cell sarcoma) Myxoid liposarcoma Extraskeletal myxoid chondrosarcoma Dermatofibrosarcoma protuberans and giant cell fibroblastoma Congenital fibrosarcoma and mesoblastic nephroma Lipoblastoma

417

From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 2001;10:106-118.

Proto-oncogene Activation Proto-oncogenes are commonly activated in transformed cells by point mutations or gene amplification. The classic example of proto-oncogene activation by a point mutation involves the cellular proto-oncogene RAS. RASfamily proteins are associated with the inner, cytoplasmic surface of the plasma membrane and function as intermediates in signal transduction pathways that regulate cell proliferation. Point mutations in RAS result in constitutive activation of the RAS protein and, therefore, the continuous activation of the RAS signal transduction pathway. Activation of RAS appears to be involved in the pathogenesis of a small percentage of pediatric malignancies, including leukemia and a variety of solid tumors. Gene amplification (i.e., selective replication of DNA sequences) enables a tumor cell to increase the expression of crucial genes whose products are ordinarily tightly controlled. The amplified DNA sequences, or amplicons, may be maintained episomally (i.e., extrachromosomally) as double minutes-paired chromatin bodies lacking a centromere-or as intrachromosomal, homogeneously staining regions. In about one third of neuroblastomas, for example, the transcription factor and proto-oncogene MYCN is amplified. MYCN encodes a 64kDa nuclear phosphoprotein (MycN) that forms a transcriptional complex by associating with other nuclear proteins expressed in the developing nervous system and other tissues.@Increased expression of MycN increases the rates of DNA synthesis and cell proliferation and shortens the GI phase of the cell cycle.g4The MYCN copy number in neuroblastoma cells can be amplified 5- to 500-fold and is usually consistent among primary and metastatic sites and at different times during tumor evolution and treatment.15 This consistency suggests that MYCN amplification is an early event

in the pathogenesis of neuroblastoma. Because gene amplification is usually associated with advanced stages of disease, rapid tumor progression, and poor outcome, it is a powerful prognostic indicator.l7l1" The cell surface receptor gene ERBB2 is another proto-oncogene that is commonly overexpressed due to gene amplification, an event that occurs in breast cancer, osteosarcoma, and Wilms' tumor.l14 Comparative genomic hybridization studies have shown that a gain of genetic material on the long arm of chromosome 17 (17q) is perhaps the most common genetic abnormality in neuroblastomas: such gain occurs in approximately 75% of primary t u r n ~ r s . ~ ~ W h r o m o s o m e 17q gain is strongly associated with other known prognostic factors but may be a powerful independent predictor a i 17q n most often results of adverse o u t ~ o m e . ~ ~ of from an unbalanced translocation of this region to other chromosomal sites, most frequently l p or 1lq. The term unbalanced indicates that extra copies of 17q are present, in addition to the normal chromosome 17. Although it is unclear what the crucial gene or genes are on 17q and how extra copies of 17q contribute to the malignant phenotype of neuroblastoma, the existence of 17q amplification in neuroblastoma suggests the presence of a proto-oncogene on 17q.

Inactivation of Tumor Suppressor Genes Tumor suppressor genes, or antioncogenes, provide negative control of cell proliferation. Loss of function of the proteins encoded by these genes, through deletion or mutational inactivation of the gene, liberates the cell from growth constraints and contributes to malignant transformation. The cumulative effect of genetic lesions that activate proto-oncogenes or inactivate tumor suppressor genes is a breakdown in the balance between cell

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M ~ J O TUMORS R OF CHILDHOOD

proliferation and cell loss due to differentiation or apoptosis. Such imbalance results in clonal overgrowth of a specific cell lineage. The first tumor suppressor gene to be recognized was the retinoblastoma susceptibility gene, RB. This gene encodes a nuclear phosphoprotein that acts as a "gatekeeper" of the cell cycle. RB normally permits cell cycle progression through the GI phase when it is phosphorylated, but it prevents cell division when it is unphosphorylated. Inactivating deletions or point mutations of RB cause the protein to lose its regulatory capacity. The nuclear phosphoprotein p53 has also been recognized as an important tumor suppressor gene, perhaps the most commonly altered gene in all human cancers. Inactivating mutations of the $153gene also cause the p53 protein to lose its ability to regulate the cell cycle. The p5P gene is frequently inactivated in solid tumors of childhood, including osteosarcoma, rhabdomyosarcoma, brain tumors, anaplastic Wilms' tumor, and a subset of In addition, chemotherapy-resistant neuroblastoma.7~7*~*6 heritable cancer-associated changes in the $153 tumor suppressor gene occur in families with Li-Fraumeni syndrome, an autosomal dominant predisposition for rhab domyosarcoma, other soft tissue and bone sarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinomas.95 Other tumor suppressor genes include Wilms' tumor 1 ( WTI), neurofibromatosis 1 (MI), and von Hippel-Lindau ( VHL). Other tumor suppressor genes are presumed to exist but have not been definitively identified. For example, early karyotype analyses of neuroblastoma-derived cell lines found frequent deletion of the short arm of chromosome 1.18 Deletion of genetic material in tumors suggests the presence (and subsequent loss) of a tumor suppressor gene, but no individual tumor suppressor gene has been identified on chromosome l p . Functional confirmation of the presence of a l p tumor suppressor gene came from the demonstration that transfection of chromosome l p into a neuroblastoma cell line results in morphologic changes of differentiation and ultimately cell senescence.5 Approximately 20% to 35% of primary neuroblastomas exhibit l p deletion, as determined by fluorescent in situ hybridization (FISH),and the smallest common region of loss is located within region 1~36.51Deletion of l p is also common in Wilms' tum0r.~2

Metastasis Metastasis is the spread of cancer cells from a primary tumor to distant sites and is the hallmark of malignancy. The development of tumor metastases is the main cause of treatment failure and a significant contributing factor to morbidity and mortality resulting from cancer. Although the dissemination of tumor cells through the circulation is probably a frequent occurrence, the establishment of metastatic disease is a very inefficient process. It requires several events, including the entry of the neoplastic cells into the blood or lymphatic system, the survival of those cells in the circulation, their avoidance of immune surveillance, their invasion of foreign (heterotopic) tissues, and the establishment of a blood supply to permit expansion of the tumor at the distant site.

Simple, dysregulated cell growth is not sufficient for tumor invasion and metastasis. Many tumors progress through distinct stages that can be identified by histopathologic examination, including hyperplasia, dysplasia, carcinoma in situ, invasive cancer, and disseminated cancer. Genetic analysis of these different stages of tumor progression suggests that uncontrolled growth results from progressive alteration in cellular oncogenes and inactivation of tumor suppressor genes, but these genetic changes driving tumorigenicity are clearly distinct from those that determine the metastatic phenotype. Histologically, invasive carcinoma is characterized by a lack of basement membrane around an expanding mass of tumor cells. Matrix proteolysis appears to be a key part of the mechanism of invasion by tumor cells, which must be able to move through connective tissue barriers, such as the basement membrane, to spread from their site of origin. The proteases involved in this process include the matrix metalloproteinases and their tissue inhibitors. The local environment of the target organ may profoundly influence the growth potential of ~ various cell surface extravasated tumor ~ e l l s . 4The receptors that mediate interactions between tumor cells and between tumor cells and the extracellular matrix include cadherins, integrins (transmembrane proteins formed by the noncovalent association of a and P subunits), and CD44, a transmembrane glycoprotein involved in cell adhesion to hyaluronan.144 Tumor cells must decrease their adhesiveness to escape from the primary tumor, but at later stages of metastasis, the same tumor cells need to increase their adhesiveness during arrest and intravasation to distant sites.

Angiogenesis Angiogenesis is the biologic process of new blood vessel formation. This complex, invasive process involves multiple steps, including proteolytic degradation of the extracellular matrix surrounding existing blood vessels, chemotactic migration and proliferation of endothelial cells, the organization of these endothelial cells into tubules, the establishment of a lumen that serves as a conduit between the circulation and an expanding mass of tumor cells, and functional maturation of the newly formed blood v e ~ s e 1 . 5 0Angiogenesis ~~~~ involves the coordinated activity of a wide variety of molecules, including growth factors, extracellular matrix proteins, adhesion receptors, and proteolytic enzymes. Under physiologic conditions, the vascular endothelium is quiescent and has a very low rate of cell division, such that only 0.01% of endothelial cells However, in response to hormonal are di~iding.~O,~O,l2~ cues or hypoxic or ischemic conditions, the endothelial cells can be activated to migrate, proliferate rapidly, and create lumens. Angiogenesis occurs as part of such normal physiologic activities as wound healing, inflammation, the female reproductive cycle, and embryonic development. In these processes, angiogenesis is tightly and predictably regulated. However, angiogenesis can also be involved in the progression of several pathologic processes in which there is a loss of regulatory control, resulting in persistent growth

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Principles o f Pediatric Oncology, Genetics o f Cancer, and Radiation Therapy

of new blood vessels. Such unabated neovascularization occurs in rheumatoid arthritis, inflammatory bowel disease, hemangiomas of childhood, ocular neovascularization, and the growth and spread of tumors.49 Compelling data indicate that tumor-associated neovascularization is required for tumor growth, invasion, and metasta~is.~.47~4*,~~6 A tumor in the prevascular phase (i.e., before new blood vessels have developed) can grow to only a limited size, approximately 2 to 3 mm3. At this point, rapid cell proliferation is balanced by equally rapid cell death by apoptosis, and a nonexpanding tumor mass results. The switch to an angiogenic phenotype with tumor neovascularization results in a decrease in the rate of a p o p tosis, thereby shifting the balance to cell proliferation and tumor growth.71,gl This decrease in apoptosis occurs, in part, because the increased perfusion resulting from neovascularization permits improved nutrient and metabolite exchange. In addition, the proliferating endothelium may supply, in a paracrine manner, a variety of factors that promote tumor growth, such as IGF-I and IGF-II.G4 In experimental models, increased tumor vascularization correlates with increased tumor growth, whereas restriction of neovascularization limits tumor growth. Clinically, the onset of neovascularization in many human tumors is temporally associated with increased tumor growth,'" and high levels of angiogenic factors are commonly detected in blood and urine from patients ' ~ ~addition, the number with advanced m a l i g n a n ~ i e s .In and density of new microvessels within primary tumors have been shown to correlate with the likelihood of metastasis, as well as the overall prognosis for patients with a wide variety of neoplasms, including pediatric tumors such as neuroblastoma and Wilms' tumor.'JOl It has become increasingly evident that the regulation of tumor angiogenesis is complex: new blood vessel formation occurs as the result of competing pro- and antiangiogenic signals originating in multiple tissues.23 Specific genetic events in certain cancers, such as altered expression of the $153 tumor suppressor gene32Jj3 or the human EGFR gene,8YJj".'" not only affect the cell cycle but also play a role in angiogenesis by modulating key signals (e.g., u p regulating the expression of vascular endothelial growth factor [VEGF] or down-regulating the expression of the endogenous angiogenesis inhibitor thrombospondin 1). Metastasis also appears to be dependent on angiogenesis.45," This dependence is probably due to several factors. First, new blood vessels in the primary tumor provide increased opportunities for the shedding of tumor cells into the circulation. Also, disruption of the basement membrane by proteases released by the proliferating endothelial cells may contribute to the metastatic Finally, successful growth of potential of a t~mor.~9J** metastatic cells in foreign target organs depends on the stimulation and formation of new blood vessels, perhaps even when cells metastasize to the bone marrow.

MOLECULAR DIAGNOSTICS The explosion of information about the human genome has led not only to an improved understanding of the molecular genetic basis of tumorigenesis but also to the

419

development of a new discipline: the translation of these molecular events into diagnostic assays. The field of molecular diagnostics has developed from the need to identify abnormalities of gene or chromosome structure in patient tissues and as a means of supporting standard histopathologic and immunohistochemical diagnostic methods. In most instances, the result of genetic testing confirms light microscopic and immunohistochemistrybased diagnosis. In some instances, however (e.g.,primitive, malignant, small round cell tumor; poorly differentiated synovial sarcoma; lipoblastic tumor), molecular analysis is required to make a definitive diagnosis. The molecular genetic methods most commonly used to analyze patient tumor material include direct metaphase cytogenetics or karyotyping, FISH, and reverse transcriptase polymerase chain reaction (RT-PCR). Additional methods, such as comparative genomic hybridization, loss of heterozygosity analysis, and complementary DNA (cDNA) microarray analysis, may eventually become part of the routine diagnostic repertoire but are currently used as research tools at referral centers and academic institutions. Each standard method is summarized in Table 25-4. As with any method, molecular genetic assays have advantages and disadvantages, and it is important to understand and recognize their limitations. It is also necessary to know the specific type of material required for each molecular assay. Surgeons can best appreciate the fine balance between minimizing the trauma and tissue disruption associated with a biopsy procedure and obtaining enough tissue for diagnosis, molecular genetic studies, and tissue banking for future analysis. The value of molecular genetic analysis of patient tissue is not limited to aiding histopathologic diagnosis. Many of the most important markers provide prognostic information as well. MYCN amplification in neuroblastomas,16 for example, is strongly associated with biologically aggressive behavior. Amplification of this gene can be detected by routine metaphase cytogenetics or by FISH, and current neuroblastoma protocols include the presence or absence of MYCNamplification in their stratification schema. Some fusion gene variants are also thought to influence prognosis. In initial studies, two examples noted to confer relatively favorable prognoses are the type 1 variant fusion of E W F L I l in Ewing's sarcoma or primitive neuroectodermal tumorB and the PAX7-EKHR fusion in alveolar rhabdomyo~arcoma.~ Complementary DNA microarray technology is likely to lead to the discovery of many more prognostically relevant genes. New technologies are emerging that permit accurate, high-throughput analysis or "profiling" of tumor tissue: gene expression can be analyzed by using RNA microarrays, and proteins by using proteomics. These approaches identify a unique "fingerprint" of a given tumor that can provide diagnostic or prognostic information. Proteomic analysis can also identify unique proteins in patients' serum or urine; such a profile can be used for early tumor detection, to distinguish risk categories, and to monitor for recurrence. Microarray analysis has also been used to characterize the response of tumor cells to stimuli such as stress, hypoxia, and therapy by analyzing a tumor cell's entire complement of RNA. The commercial availability of

420

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M.410~TUMORS OF CHILDHOOD

Purpose --

Cytogenetics

Low-resolution analysis of metaphase chromosomes of cells grown in culture

In situ hybridization

Detection of translocations, amplifications, and gene deletions by hybridization of nucleic acid probes to specific DNA or mRNA sequences

PCR and RT-PCR

Extremely sensitive detection of DNA sequences and mRNA transcripts for the demonstration of fusion genes, point mutations, and polymorphisms

L

Advantages

Disadvantages

Does not require a priori knowledge of genetic abnormalities Available in most diagnostic centers

Requires fresh, sterile tumor tissue for growth in culture

Can be applied to chromosomal preparations as well as cytologic specimens, touch preparations, and paraffin sections Morphologic correlation is possible Multiple probes can be assayed at the same time Rapid (usually only 2 days) Highest sensitivity and specificity of all molecular diagnostic techniques DNA sequencing of PCR products can confirm results and provide additional information Requires minimal tissue Versatile; can be applied to fresh tissue as well as formalin-fixed, paraffinembedded tissue Morphologic correlation is possible Presence of normal tissue usually does not affect test results Rapid (usually 3-5days)

Low sensitivity; detects only large structural abnormalities No histologic correlation Slow and technically demanding (may take several weeks to perform) Cannot detect small deletions or point mutations Interpretation can be difficult, especially with formalin-fixed, paraffin-embedded material Only a limited number of specific nucleic acid probes are available commercially Formalin-fixation diminishes sensitivity Combinatorial variability within fusion gene partners requires appropriate redundant primer design to avoid false-negative test results Extreme sensitivity requires exacting laboratory technique to avoid falsepositive test results

-

mRNA, messenger RNA; PCR, polymerasechain reaction; RT-PCR, reverse transcriptase polymerase chain reaction. From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Sernin Pediatr Surg 2001;10:106-118.

various precoated kits and their ease of use have led to widespread application of this approach. The procedure involves the hybridization of complementary strands of labeled DNA or RNA from tumors with known genes or oligonucleotides derived from the genome. The known genes or oligonucleotides are attached to a solid support, the microarray. Hybridization is detected by fluorescence. Once the quality and consistency of sample material can be refined and data management and statistical analyses validated and standardized, gene profiling microarrays will probably be used routinely to analyze pediatric malignancies.

CHILDHOOD CANCER AND HEREDITY Advances in molecular genetic techniques have also improved our understanding of cancer predisposition syndromes. Constitutional gene mutations that are hereditary (i.e., passed from parent to child) or nonhereditary (i.e., de novo mutations in the sperm or oocyte before fertilization) contribute to an estimated 10% to 15% of pediatric cancer~.~Ig Constitutional chromosomal abnormalities are the result of an abnormal number or structural rearrangement of the normal

46 chromosomes and may be associated with a predisposition to cancer. Examples are the predisposition to leukemia seen with trisomy 21 (Down syndrome) and to germ cell tumors with Klinefelter's syndrome (47XXY). Structural chromosomal abnormalities include interstitial deletions resulting in the constitutional loss of one or more " genes. Wilms' tumors may be sporadic, familial, or associated with specific genetic disorders or recognizable syndromes. A better understanding of the molecular basis of Wilms' tumor has been achieved largely through the study of the latter two types of tumors. The WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) provides an easily recognizable phenotype for grouping children likely to have a common genetic abnormality. Constitutional deletions from chromosome llp13 are consistent in children with WAGR s y n d r o m ~and ~ ~ also occur in approximately 35% of those with sporadic Wilms' tumor." A study of a large series of patients identified the gene deleted from chromosome llp13 as WT1.Z This gene encodes a nuclear transcription factor that is essential for normal kidnev and gonadal developmentN8 and appears to act as a tumor suppressor,but its precise role is unclear at this time. Aniridia in patients with WAGR syndrome is thought to

CHAPTER

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

occur after the loss of one copy of the PAX6gene located close to WTl on chromosome 11.143 Denys-Drash syndrome, which is characterized by a very high risk of Wilms' tumor, pseudohermaphroditism, and mesangial sclerosis leading to early renal failure, is associated with germline mutations in the DNA binding domain of WT1.li2 The mutated WT1 protein appears to function by a dominant negative effect. Only 6% to 18% of sporadic Wilms' tumors have WTl r n u t a t i o n ~ . ~ 2 2 ~ ~ ~ In another subset of ~atients with Wilms' tumor, there is loss of genetic material'in a region distal to the WTl locus toward the telomeric end of chromosome 11 (1lp15) .30 It has therefore been suggested that there is a second Wilms' tumor susceptibility gene, tentatively named WT2, in llp15. Loss of heterozygosity at this locus has also been described in patients with Beckwith-Wiedemann syndrome, a congenital overgrowth syndrome characterized by numerous growth abnormalities as well as a predisposition to a variety of malignancies, including Wilms' t~mor.~"SeeChapter 27.) Neurofibromatosis type 1 (NFI) is one of the most common genetic disorders. The NFl protein normally inhibits the proto-oncogene RAS, but in patients with NF1, mutation of one copy of the gene combined with deletion of the other permits uncontrolled RAS pathway activation. These patients are then susceptible to myelogenous disorders, benign tumors, gliomas, and malignant peripheral nerve sheath tumors. An inherited predisposition to pediatric cancers is also associated with Li-Fraumeni syndrome (which results from inactivating mutations of the $153gene and puts patients at risk for osteosarcoma. rhabdomvosarcoma, adrenocortical carcinoma, and brain tumors, among other tumors), familial retinoblastoma (which results from inactivating mutations of the RB gene and puts patients at risk for osteosarcoma as well as retinoblastoma), familial adenomatous polyposis, and multiple endocrine neoplasia syndromes. Another set of inherited risk factors is reprksented by mutations of DNA repair genes (so-called caretaker genes), as seen in xeroderma pigmentosa and ataxia-telangiectasia.80 Understanding these complex syndromes and their pathogenesis is important in efforts to screen for early detection and, possibly, for prophylactic therapy.

GENErIC SCREENING Along with an increased understanding of the molecular basis of hereditary childhood cancer has come the opportunity to identify children who are at high risk of malignancy and, in some cases, to intervene before the cancer develops or when it is still curable. Two examples include familial adenomatous polyposis and familial thyroid cancer. Familial adenomatous polyposis is an autosomal dominant inherited disease in which hundreds to thousands of adenomatous intestinal polyps develop during the second and third decades of life. Mutations of the adenomatous polyposis coli (APC) gene on chromosome 5q21 occur in approximately 80% of kindreds of persons who have the disease.i08."7 These mutations initiate

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the adenomatous process by allowing clonal expansion of individual cells that, over time, acquire additional genetic abnormalities that lead to the development of invasive colorectal carcinoma.~Vrophylacticcolectomy is recommended for patients with this germline mutation, although the most appropriate timing for this intervention in children with familial adenomatous polyposis is controversial. These patients are also at increased risk of hepatobla~toma.~~ Medullary thyroid carcinoma (MTC) is a rare malignancy that may occur sporadically or as part of two syndromes: multiple endocrine neoplasia (type 2A or 2B) syndrome or familial MTC syndrome. In children, MTC is much more likely to occur in association with a familial syndrome. An apparently 100% association between germline RET mutationsio4and MTC guides the recommendation for prophylactic thyroidectomy in affected patients. There is no effective adjuvant treatment other than surgery for MTC, highlighting the need for early intervention. Patients with germline M57' mutations should also be screened for pheochromocytoma, which occurs in 50% of patients with multiple endocrine neoplasia type 2A, and hyperparathyroidism, which occurs in 35% of such patients.72 In addition, patients who are at risk for MTC or have newly diagnosed MTC, as well as their relatives, should be screened for the germline RET mutation so that appropriate surgical and genetic counseling can be given.

GENERAL PRINCIPLES OF CHEMOTHERAPY Cytotoxic agents were first noted to be effective in the treatment of cancer in the 1960s, after alkylating agents such as nitrogen mustard gas, used during World War 11, were observed to cause bone marrow hypoplasia. Chemotherapy is now an integral part of nearly all cancer treatment regimens. The overriding goal of cancer chemotherapy is to maximize tumoricidal effect (efficacy) while minimizing adverse side effects (toxicity). This goal can be difficult to achieve, however, because the dose at which tumor cells are affected is often similar to the dose that affects normal proliferating cells, such as those in the bone marrow and gastrointestinal tract. Despite the early promise of chemotherapy and the observation that most tumor types are initially sensitive to chemotherapy, often exquisitely so, the successful use of chemotherapy is often thwarted by two factors: the development of resistance to the agent and the agent's toxicity to normal tissues. Nevertheless, chemotherapy remains an integral part of therapy when used as an adjunct to treat localized disease or as the main component to treat disseminated or advanced disease. A number of principles and terms are essential to the understanding of chemotherapy as a therapeutic anticancer modality. Adjuuant chemotherapy refers to the use of chemotherapy for systemic treatment following local control of a clinically localized primary tumor, generally by surgical resection or radiation therapy. The goal in this setting is to eliminate disease that is not detectable by standard investigative means at or beyond the primary tumor's site. Neoadjuuant chemotherapy refers

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to chemotherapy delivered before local therapeutic modalities, generally in an effort to improve their efficacy; to treat micrometastatic disease as early as possible, when distant tumors are smallest; or to achieve both of these aims. Induction chemotherapy refers to the use of chemotherapeutic agents as the primary treatment for advanced disease. In general, chemotherapy given to children with solid tumors and metastatic disease at the time of first examination has a less than 40% chance of effecting long-term, disease-free survival. Exceptions include Wilms' tumor with favorable histologic features, germ cell tumors, and paratesticular rhabdomyosarcoma, but most children with metastatic disease are at high risk of disease recurrence or progression. Combination chemotherapy refers to the use of multiple agents, which generally have different mechanisms of action and nonoverlapping toxicities, that provide effective, synergistic antitumor activity and minimal side effects. The efficacy of combination chemotherapy is explained by ~~ states that a the Goldie-Coldman h y p o t h e ~ i s ,which tumor's response to an individual drug reflects the individual tumor cells' sensitivity to that drug. The chance of a tumor developing a resistance phenotype depends on the rate of mutation and the number of tumor cells or tumor size. Once a single tumor cell becomes resistant to a given agent, the tumor can no longer be cured by that agent. Combining agents with different mechanisms of action decreases the likelihood that a tumor cell will develop resistance to any or all agents and is therefore more likely to effect a cure. Pharmacokinetics describes the relationship between time and the plasma concentration of a drug, and drug exposure is quantified by calculating the area under the curve of the graph of drug concentration against time. The pharmacokinetics of a drug is influenced by its absorption, distribution, metabolism, clearance, half-life, and excretion and by the presence of active metabolites. The interpretation of pharmacokinetic data requires an understanding of the relation between plasma concentration of the drug and its anticancer effect. The dose-response curve for a given agent is usually sigmoidal, with a threshold level, lag phase, linear response, and plateau. The slope of the linear phase is often quite steep, and this steepness implies a significant loss of efficacy with a slight dose reduction. Therefore, the delivery of a maximum tolerated dose, to ensure that the dose range of the linear phase has been exceeded, has become a basic principle of chemotherapy. Dose intensity can be maximized by increasing the total dose of an agent or by shortening the interval between doses. Inappropriate dose reduction may lead to residual tumor cells not being eliminated. The therapeutic index is the ratio of beneficial to harmful effects. An emerging theory regarding optimal chemotherapeutic dosages that is somewhat counter to the longstanding and widely used approach of maximum tolerated dose is metronomic dosing. This new approach, which entails the continuous delivery of a low dose of chemotherapeutic agents, may be effective for two reasons. First, because most agents are cell-cycle specific (i.e., they kill only cells that are at specific points in the cell cycle), only a fraction of tumor cells is susceptible

at any given time. Therefore, a longer duration of exposure to an agent may result in more tumor cells being susceptible. Second, metronomic dosing may allow the agent to target the endothelial cells that constitute the expanding tumor vasculature, as well as the tumor cells themselves. The traditional scheduling of cytotoxic therapy-the administration of a maximum tolerated dose, followed by a rest period to allow the recovery of affected normal tissue (notably the bone marrow and gastrointestinal tract)-may also permit the recovery and proliferation of the more slowly dividing endothelial cells in a tumor bed and thereby permit tumor regrowth.20 A metronomic schedule in which cytotoxic drugs are administered continuously or at least more frequently, without a treatment-free interval. and at a lower total dose may therefore be more effective at controlling tumor progression, even if the tumor cells themselves are resistant to the drug.20 This approach appears to be true for cytotoxic drugs and antiangiogenic agents. The rational design of chemotherapy treatment programs and clinical trials involves an understanding of the mechanisms of action of these agents, their metabolism, and their toxicity profiles. Most agents used to treat tumors in children affect the synthesis or function of nucleic acids (DNA or RNA) in malignant and normal cells. Therefore, these agents can kill tumor cells but can also affect normal tissue. The mechanisms of action and side effects of commonly used agents are listed in Table 25-5. Alkylating agents interfere with cell growth by covalently cross-linking DNA and are not cell-cycle specific. Antitumor antibiotics intercalate into the double helix of DNA and break the DNA strands. Antimetabolites are truly cell-cycle specific because they interfere with the use of normal substrates for DNA and RNA synthesis, such as purines and thymidine. The plant alkaloids can inhibit microtubule function (vinca alkaloids, taxanes) or DNA topoisomerases (camptothecins inhibit topoisomerase I; epipodophyllotoxins inhibit topoisomerase 11), and these actions also lead to breaks in DNA strands. Topoisomerases are a class of enzymes that alter the supercoiling of double-stranded DNA. They act by transiently cutting one (topoisomerase I) or both (topoisomerase 11) strands of the DNA to relax the DNA coil and extend the molecule. The regulation of DNA supercoiling is essential to DNA transcription and replication, when the DNA helix must unwind to permit the proper function of the enzymatic machinery involved in these processes. Thus, topoisomerases maintain the transcription and replication of DNA. The common toxic effects of these agents are also listed in Table 25-5. Most toxicity associated with chemotherapy is reversible and resolves with cessation of treatment. Other side effects may be reversed by giving specific antidotes such as leucovorin for toxicity associated with methotrexate. Leucovorin acts in the same way in the body as folic acid does, but it does not negate the therapeutic efficacy of methotrexate. However, some chemotherapeutic agents may have lifelong effects. Of particular concern is that certain drugs can lead to a second malignancy. Most notable is the development of leukemia after the administration of the epipodophyllotoxins and ~yclophosphamide.~45

1 Class of Drug

Agent

Synonyms

Brand Name Mechanism of Action

Common Toxic Effects

Alkylating agents

Carboplatin

CBCDCA

Paraplatin

Cisplatin

CDDC

Platinol

A, H, M (esp. thrombocytopenia), N/V A, N/V, R (significant), ototoxicity, neuropathy

Cyclophosphamide

CTX

Cytoxan

lfosfamide

l FOS

lfex

DTlC

Dacarbazine Temozolomide Nitrogen mustard

Melphalan

Antimetabolites

Temodar Mustargen

L-PAM

Alkeran

Busulfan

Busulfex

Cytarabine

Cytosar

Fluorouracil

Several

Mercaptopurine

Antibiotics

TMZ Mechlorethamine

6-MP

Purinethol

Methotrexate

MTX

Trexall

Dactinomycin

Actinomycin D Cosmegen

Bleomycin

BLEO

Anthracyclines Daunomycin

Daunorubicin Cerubidine

Blenoxane

Platination, intra- and interstrand DNA cross-linking Platination, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking Methylation Methylation

Site of Activation

Method of Elimination

Susceptible Solid Tumors

Renal

BT, GCT, NBL, STS

Renal

BT, GCT, NBL, OS

A, N/V, SIADH, M, R, cardiac, cystitis

Liver

Hepatic, renal (minor)

Broad, BMT

A, CNS, N/V, M, R, cardiac, cystitis

Liver

Hepatic, renal (minor)

Broad

H, N/V, M, hepatic vein thrombosis CNS, N/V, M

Liver

Renal

NBL, STS

Spontaneous

Renal

BT

Spontaneous hydrolysis

BT

Spontaneous hydrolysis

NBL, RMS, BMT

Renal

BMT

Target cell

Biotransformation

Limited

Target cell

Biotransformation, Gastrointestinal renal (minor) carcinomas, liver tumors Biotransformation, Limited renal (minor)

Alkylation, intra- and interstrand DNA, cross-linking Alkylation, intra- and interstrand DNA cross-linking Alkylation, intra- and interstrand DNA cross-linking

A, M (significant), N/V, mucositis, vesication, phlebitis, diarrhea M, N/V, mucositis, diarrhea

Inhibits DNA polymerase, incorporated into DNA Inhibits thymidine synthesis, incorporated into DNA/RNA lnhibits thymidine synthesis, incorporated into DNA/RNA Blocks folate metabolism, inhibits purine synthesis

M, N/V, diarrhea, CNS CNS, N/V, M, cardiac, diarrhea, mucositis, skin, ocular H, M, mucositis

A, H, M, N/V, P mucositis

Target cell

CNS, H, M, R, mucositis, skin

Renal, hepatic (minor)

OS

DNA intercalation, strand breaks DNA intercalation, strand breaks

A, H, M, N/V, mucositis, vesication I? skin, mucositis

Hepatic

RMS, W

Hepatic, renal

GCT

DNA intercalation, strand breaks, free radical formation

A, M, N/V, cardiac, diarrhea, vesication, potentiates XRT reaction

Hepatic

Limited

1

Continued

1

Class of Drug

Plant alkaloids

Susceptible Solid Tumors

Hepatic

Broad

Topoisomerase II inhibitor, A, M, N/V, mucositis, DNA strand breaks neuropathy, diarrhea Topoisomerase II inhibitor, A, M, N/V, mucositis, DNA strand breaks neuropathy, diarrhea

Renal

Broad

Degraded

Broad

Inhibits tubulin polymerization, blocks mitosis Inhibits tubulin polymerization, blocks mitosis

A, SIADH, neuropathy, vesicant

Hepatic

Broad

A, M, mucositis, vesication

Hepatic

GCT

Renal

NBL, RMS

Hepatic, renal (minor)

NBL, RMS

Degraded

Limited

Hepatic, renal (minor)

BT

Synonyms

Brand Name Mechanism of Action

Common Toxic Effects

Adriamycin

Doxorubicin

Adriamycin

DNA intercalation, strand breaks, free radical formation

A, M, N/V, cardiac, diarrhea, mucositis, vesication, potentiates XRT reaction

Epipodophyllotoxins Etoposide

VP-16

VePesid

VM-26

Vumon

Vinca alkaloids Vincristine

VCR

Oncovin

Vinblastine

VLB

Velban

Teniposid

Taxanes Paclitaxel

Taxol

Interferes with microtubule formation

A, M, cardiac, mucositis, CNS, neuropathy

Taxotere

Interferes with microtubule formation

A, neutropenia, cardiac, mucositis, CNS, neuropathy

TPT

Hycamtin

lrinotecan

CPT-11

Camptosar

Topoisomerase I inhibitor, A, H, M, N/V, mucositis, diarrhea, skin DNA strand breaks Topoisomerase I inhibitor, A, H, M, N/V, diarrhea DNA strand breaks

L-Asparaginase

Erwinia

Elspar

Docetaxel

Camptothecins Topotecan

Miscellaneous

Method of Elimination

Agent

Corticosteroids

L-Asparagine depletion, inhibits protein synthesis Nuclear receptormediated apoptosis

Site of Activation

Liver, gastrointestinal tract

CNS, H, coagulopathy, pancreatitis, anaphylaxis Avascular necrosis, hyperglycemia, hypertension, myopathy, pancreatitis, peptic ulcers, psychosis, salt imbalance, weight gain

Liver

Toxic effects: A, alopecia; CNS, central nervous system toxicity; H, hepatotoxicity;M, myelosuppression;N/V, nausea and vomiting; P, pulmonary toxicity; R, renal toxicity; SIADH, syndrome of inappropriate antidiuretic hormone; XRT, radiotherapy.Solid tumors: BMT, conditioningforbone marrow transplantation; BT, brain tumor; EWS, Ewing'ssarcoma; GCT, germ cell tumors; NBL, neuroblastoma; OS, osteosarcoma; RMS, rhabdomyosarcoma;STS, soft tissue sarcoma; W, Wilms' tumor.

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Finally, understanding the metabolism of chemotherapeutic agents is important. Certain agents require metabolism at a specific site or organ for their activation or are eliminated from the body by a specific organ (see Table 25-5). The processes of activation and elimination require normal organ function (e.g., the liver for cyclophosphamide); therefore, children with liver or kidney failure may not be able to receive certain agents.

Risk Stratification Major advances in the variety of chemotherapeutic agents and dosing strategies used to treat pediatric cancers in the past 30 years are reflected in improved patient survival rates. Regimen toxicity (including late effects, which are particularly important in the pediatric population) and therapeutic resistance are the two main hurdles preventing further advancement. As more information about diagnostically and prognostically useful genetic markers becomes available, therapeutic strategies will change accordingly. With molecular profiling, patients can be categorized to receive a particular treatment on the basis of not only the tumor's histopathologic and staging characteristics but also its genetic composition. Some patients whose tumors show a more aggressive biologic profile may require dose intensification to increase their chances of survival. Patients whose tumors do not have an aggressive biologic profile may benefit from the lower toxicity of less intensive therapy. Such an approach may allow the maintenance of high survival rates while minimizing long-term complications of therapy in these patient populations. The paradigm for the use of different therapeutic intensities on the basis of risk stratification drives the management of pediatric neuroblastoma. There is increasing evidence that the molecular features of neuroblastoma are highly predictive of its clinical behavior. Most current studies of the treatment of neuroblastoma are based on risk groups that take into account both clinical and biologic variables. The most important clinical variables appear to be age and stage at diagnosis, and the most powerful biologic factors appear to be MYCN status, ploidy (for patients younger than 1 year), and histopathologic classification. These variables currently define the Children's Oncology Group risk strata and therapeutic approach. At one extreme, patients with low-risk disease are treated with surgery alone; at the other extreme, patients at high risk for relapse are treated with intensive multimodality therapy that includes multiagent, doseintensive chemotherapy; radiation therapy; and stem cell transplantation. Other factors such as 17q gain, l p deletion, caspase 8 inactivation, and TrkA/B expression are currently being evaluated and may help further refine risk assessment in the future. The management of other solid pediatric tumors is also shifting to riskdefined treatment. For example, the next protocol for the management of patients with Wilms' tumor is likely to include risk stratification and therapy adjustment based on molecular analysis of the primary tumor for 16q and l p deletions.

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Targeted Therapy Another major change in the approach to the treatment of cancer has been the concept of targeted therapy. Until recently, the development of anticancer agents was based on the empirical screening of a large variety of cytotoxic compounds without particular regard to disease specificity or mechanism of action. Now, one of the most exciting prospects for improving the therapeutic index of anticancer agents, as well as overcoming the problem of therapy resistance, involves targeted therapy. As the molecular bases for the phenotypes of specific malignancies are being elucidated, potential new targets for therapy are becoming more clearly defined. The characterization of pathways that define malignant transformation and progression has focused new agent development on key pathways involved in the crucial processes of cell-cycle regulation, receptor signaling, differentiation, apoptosis, invasion, migration, and angiogenesis, which may be perturbed in malignant tissues. Information about the molecular profile of a given tumor type can be assembled from a variety of emerging methods, including immunohistochemistry, FISH, RT-PCR, cDNA microarray analysis, and proteomics. This information can then be used to develop new drugs designed to counter the molecular abnormalities of the neoplastic cells. For example, blocking oncogene function or restoring suppressor gene activity may provide tumor-specific therapy. In addition, molecular profiling may lead to the development of drugs designed to induce differentiation of tumor cells, block dysregulated growth pathways, or reactivate silenced apoptotic pathways. Some agents target alterations in the regulation of cell proliferation. Herceptin (trastuzumab) is a monoclonal antibody that binds to the cell surface growth factor receptor ERBBP with high affinity and acts as an antiproliferative agent when used to treat ERBB2overexpressing cancer cells." It is currently being tested against ERBB2-positive tumors such as osteosarcoma and Wilms' tumor. Pediatric high-grade gliomas that overexpress EGFR may be amenable to a similar therapeutic agent, gefitinib (Iressa), a small-molecule inhibitor of EGFR (ERBBI). I 4 In addition, small-molecule tyrosine kinase inhibitors, such as imatinib (Gleevec), designed to block aberrantly expressed growth-promoting tyrosine kinases-ABL in chronic myelogenous leukemial4' and c-KIT in gastrointestinal stromal tumorsyl-are being evaluated in clinical trials. Imatinib may also be useful in treating pediatric tumors in which PDGF signaling plays a role in tumor cell survival and growth. Other kinase inhibitors, such as flavopiridol, target cyclin-dependent kinases that modulate the cell cycle,77whereas rapamycin (sirolimus) inhibits the mammalian target of rapamycin (mTOR), a protein whose activation1y9normally leads to increased translation of proteins necessary for cell proliferation. Inhibitors of farnesyl transferase (the enzyme responsible for the activation of RAS), such as R115777, are also being tested in clinical trials. Although activating mutations are very common in adult malignancies, they are rare in pediatric tumors. However, the RAS pathway is occasionally activated by upstream growth factors or

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oncogenic proteins in such pediatric diseases as juvenile myelomonocytic leukemia, certain brain tumors, and NF1, so agents such as R115777 are being tested against these conditions as well. Also of potential therapeutic utility are small-molecule inhibitors that recognize antigenic determinants on unique fusion peptides or one of the fusion peptide partners in tumors that have chromosomal translocations (e.g., sarcomas). Tumors that depend on autocrine pathways for growth (e.g., overproduction of IGF-I1 in rhabdomyosarcoma or PDGF in dermatofibrosarcoma protuberins) may be sensitive to receptor blocking mediators (e.g., antibodies to the IGF-I1 or PDGF receptor). Other agents target alteration of the cell death and differentiation pathways. Caspase 8 is a cysteine protease that regulates programmed cell death, but in tumors such as neuroblastoma, DNA methylation and gene deletion combine to mediate the complete inactivation of caspase 8, almost always in association with MYCN amp1ifi~ation.l~~ Methylation of cytosine residues in genomic DNA is quite common and usually occurs at cytosine residues adjacent to guanosine. DNA methylation is important in the transcriptional repression or silencing of certain genes, particularly developmentally regulated genes. Caspase 8-deficient tumor cells are resistant to apoptosis mediated by death receptors and doxorubicin; this resistance suggests that caspase 8 may be acting as a tumor suppressor. However, brief exposure of caspase &deficient cells to demethylating agents, such as decitabine, or to low levels of interferon-y can lead to the re-expression of caspase 8 and the resensitization of the cells ;o chemotherapeutic drug-induced a p o p tosis. Histone deacetylase also seems to have a role in gene silencing associated with resistance to apoptosis69; therefore, histone deacetylase inhibitors such as depsipeptide are also b e i n g tested for the treatment of certain pediatric malignancies. Finally, cells with alterations in programmed cell death as a result of the persistence or reactivation of telomerase activity, which somatic cells normally lose after birth, can be targeted by various telomerase inhibitors. An example of targeting cell differentiation comes from neuroblastoma. in which different neurotrowhin receptor pathways appear to mediate the signal for both cellular differentiation and malignant transformation of sympathetic neuroblasts to neuroblastoma cells. ~ e u r o t r o ~ h i are n s expressed in a wide variety of neuronal tissues and other tissues that require innervation. They stimulate the survival, maturation, and differentiation of neurons and exhibit a developmentally regulated ~~ and their Trk pattern of e x p r e s ~ i o n . "Neurotrophins tyrosine kinase receptors are particularly important in the development of the sympathetic nervous system and have been implicated in the pathogenesis of neuroblastoma. Three receptor-ligand pairs have been identified: TrkA, TrkB, and TrkC, which are the primary receptors for nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), re~pectively.~ TrkA appears to mediate the differentiation of developing neurons or neuroblastoma in the presence of nerve growth factor ligand and to mediate apoptosis in the absence of nerve growth factor.90Conversely, the

TrkB-BDNF pathway appears to promote neuroblastoma cell survival through autocrine or paracrine signaling, especially in MYChramplified tumors.lOTrkCis expressed in-apprdximately 25%-of neuroblastomas and is sL-0ng-1~ associated with TrkA e x p r e ~ s i o n .Studies '~~ are ongoing to test agonists of TrkA in an attempt to induce cellular differentiation. Conversely, blocking the TrkB-BDNF signaling pathway with ~rk-specifictyrosine kinase inhibitors such as CEP-751 may induce apoptosis by blocking crucial survival pathways.40,'" This targeted approach has the attractive wotential for increased swecificitv and lower toxicity than conventional cytotoxic chemotherapy.

INHIBITION OF ANGIOGENESIS Because tumor growth and spread appear to be dependent on angiogenesis, inhibition of angiogenesis is a logical anticancer strategy. This approach is particularly appealing for several reasons. First, despite the extreme molecular and phenotypic heterogeneity of human cancer, it is likely that most, if not all, tumor types, including hematologic malignancies, require neovascularization to achieve their full malignant phenotype. Therefore, antiangiogenic therapy may have broad applicability for the treatment of cancer. Second, the endothelial cells in a tumor's new blood vessels, although rapidly proliferating, are inherently normal and mutate slowly. They are therefore unlikely to evolve a phenotype that is insensitive to an angiogenesis inhibitor, unlike the rapidly proliferating tumor cells, which undergo spontaneous mutation at a high rate and can readily generate drugresistant clones. Finally, because the new blood vessels induced by a tumor are sufficiently distinct from established vessels to permit highly specific targeting73J$l angiogenesis inhibitors should have a high therapeutic index and minimal toxicity. The combination of conventional chemotherapeutic agents with angiogenesis inhibitors appears to be particularly effective. The first clinical demonstration that an angiogenesis inhibitor could cause regression of a tumor came with the use of interferon-a in a patient treated for lifeAn increasing threatening pulmonary hernangi~ma.~") number of natural and synthetic inhibitors of angiogenesis, which inhibit different effectors of angiogenesis, have since been identified, and many of these agents have been tested in clinical trials. Minimal toxicity has been observed for these agents. Examples include drugs that directly inhibit endothelial cells, such as thalidomide and combretastatin; drugs that block activators of angiogenesis, such as bevacizumab (Avastin), a recombinant humanized anti-VEGF antibody, or "VEGF trap"; drugs that inhibit endothelium-specific survival signaling, such asvitaxin, an anti-integrin antibody; and drugs with nonspecific mechanisms of action, such as celecoxib and interleukin-12 (IL-12). The National Cancer Institute has set up a Web site that lists all the ongoing clinical trials of angiogenesis inhibitors (http://www.cancer.gov/clinicaltrials/developments/anti-angio-table) . Because antiangiogenic therapy may be only tumoristatic, tumor progression may resume when the growth restrictions of angiogenesis inhibition are discontinued.

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25

Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

Therefore, chronic delivery of antiangiogenic agents may be required. Gene therapy, with its potential for sustained expression, may provide a more practical method than chronic protein administration for the long-term delivery of angiogenesis inhibitors.43

IMMUNOTHERAPY The immune system has evolved as a powerful means to detect and eliminate molecules or pathogens that are recognized as "foreign." However, because tumors arise from host cells, they are generally relatively weakly immunogenic. In addition, malignant cells have evolved several mechanisms that allow them to elude the immune system. These mechanisms include the ability to down-regulate the cell surface major histocompatibility complex molecules required for activation of many of the immune effector cells, to produce immunosuppressive factors, and to variably express different proteins that might otherwise serve as targets for the immune system in a process known as antigenic drift. Nevertheless, because of the large number of mutations and chromosomal aberrations occurring in cancer cells, which results in the expression of abnormal, new, or otherwise silenced proteins, it is likely that most if not all cancers contain unique, tumor-associated antigens that can be recognized by the immune system. Examples include the fusion proteins commonly found in pediatric sarcomas and the embryonic neuroectodermal antigens that continue to be produced by neuroblastomas. Recruiting the immune system to help eradicate tumor cells is an attractive approach for several reasons. First, circulating cells of the immune system have ready access to even occult sites of tumor cells. Second, the immune system has powerful effector cells capable of effectively and efficiently destroying and eradicating targets, including neoplastic cells. Initial efforts to recruit the immune system to recognize and destroy tumor cells by using cytotoxic effector mechanisms that are T-cell dependent or independent focused on recombinant cytokines. Cytokines act by directly stimulating the immune system66 or by rendering the target tumor cells more immunogenic. More recently, however, since the discovery that gene transfer can be used to markedly increase the immunogenicity of a tumor, tumor cellbased vaccine approaches have been used. For example, tumor cells transfected with genes that encode cytokines show a substantial increase in their immunogenicity, which allows them to act as an antitumor vaccine when injected into a Transduced tumor cells appear to be much more immunogenic than low doses of cytokines injected directly into lesions. Because the cytokines are produced locally by the transduced tumor cells, there are none of the adverse effects associated with the administration of cytokines at the high systemic doses needed to induce antitumor responses. This gene transfer approach also permits tumor cell targeting without the identification of specific tumor-associated antigens. Because of the concern that tumor cells may not present antigens appropriately to host immune effector cells, alternative vaccine strategies have been used in which

427

tumor lysates or antigenic peptides are delivered to autologous dendritic cells-the immune system's antigenpresenting cells. This approach can expand specific T-cell populations and mediate tumor regression.54 An extension of this approach using gene-modified, cytokine-expressing dendritic cells is being evaluated in preclinical studies.136Other preclinical studies have shown that the tumor antigen-specific immune response can be further enhanced by the administration of immunostimulatory CpG oligodeoxynucleotides after vaccination with cytokine-expressing tumor ~ e 1 l s . l ~ ~ Neuroblastoma has been the most popular target for immunotherapy in the pediatric population. Clinical trials of the treatment of neuroblastoma by transferring cytokine genes into autologous or allogeneic tumor cells have shown that gene-modified, cytokine-expressing tumor cell vaccines have little toxicity and can induce J2~ an antitumor immune r e ~ p o n s e . ~ ~ J 2Neuroblastoma cells are sensitive to antibody-dependent cell-mediated cytotoxicity, as well as to complement-dependent cytotoxicity.25 Although a particular neuroblastoma antigen has not been defined, murine monoclonal antibodies have been raised against the ganglioside GD2, a predominant antigen on the surface of neuroblastoma cells. These antibodies elicited therapeutic responses,26-65but with substantial toxicity, particularly neuropathic pain."' Because the induction of antibody-dependent cellmediated cvtotoxicitv with anti-GD2 antibodies is enhanced by cytokines such as granulocyte-macrophage colonystimulating factorlll and interleukin-2 (IL-2),67 current antineuroblastoma antibody trials are evaluating the use of a humanized, chimeric anti-GD2 antibody (ch14.18) with these cytokines and a fusion protein (hu14.18:IL2) that consists of the humanized 14.18 antibody linked genetically to human recombinant IL-2.

GENERAL PRINCIPLES OF RADIATION THERAPY Radiation therapy is one of the three primary modalities used to manage pediatric cancers in the modern era. Its use, alone or combined with surgery and systemic chemotherapy, forms the basis of management of many forms of childhood malignancy. Radiation therapy is delivered to an estimated 2000 or more children per year for the primary treatment of tumor types as diverse as leukemia, brain tumors, sarcomas, Hodgkin's disease, neuroblastoma, and Wilms' tumor." Delivery of radiation therapy in the pediatric setting differs from that in the adult setting because of the balance between curative therapy and an anticipated long life span during which long-term morbidity may result from the therapy.

Clinical Considerations Radiation therapy for the management of pediatric cancer is most frequently combined with surgery and chemotherapy as part of a multidisciplinary treatment plan. Although radiation therapy is used as a single modality in adult oncology, the sensitive nature of

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pediatric tumors requires the use of a combined therapy approach to maximize tumor control while minimizing the long-term side effects of treatment. Radiation may be delivered preoperatively, postoperatively (relative to a definitive surgical resection), or definitively without surgical management. Systemic therapy may also be integrated into this management approach.

Definitive Irradiation Definitive radiation therapy is an alternative to surgical resection of primary solid tumors. It is often the only local therapeutic approach for children and adolescents with leukemia or lymphoma.flz52 Although it is considered the only treatment option for unresectable tumors, definitive radiation therapy may be used as an alternative to surgical resection to allow the preservation of an organ or function while maintaining excellent local tumor control. Definitive radiation therapy for rhabdomyosarcoma has been used as an alternative to surgical resection, which has potentially greater morbidity; it has achieved high rates of local tumor control while allowing preservation of function." The Ewing's sarcoma family of tumors may also be considered candidates for definitive radiation therapy as an alternative to surgery. With careful patient selection, excellent local tumor control rates can be maintained while reducing or avoiding the morbidity associated with difficult surgical rese~tions.~~~125

Preoperative lrradiation Preoperative radiation therapy may be used in several situations. Targeting of a localized tumor is straightforward in the preoperative setting, when the tumor has clearly defined margins undisturbed by a surgical procedure. The volume of normal, healthy tissues receiving high doses of radiation may be reduced, because the areas at risk for disease involvement can be better defined. Preoperative radiation therapy has been used in the management of Wilms' tumor to decrease the chance of tumor rupture7j and in the management of nonrhabdomyosarcoma soft tissue sarcoma and Ewing's sarcoma to facilitate surgical resection.34.110 One of the limitations of preoperative radiation, however, particularly in patients with sarcoma, may be the slightly higher incidence of postoperative wound complications.~*~

Postoperative Irradiation Postoperative radiation therapy combined with surgical resection is the most common application of adjuvant radiation treatment in the United States. Despite some degree of difficulty in targeting, a postoperative approach allows a review of the histologic studies of the complete tumor specimen, including identification of the tumor margins and the response to any previous therapy. Wound healing complications appear to be reduced with this approach, and the radiation dose can be more accurately tailored to the pathologic findings after primary resection.

Interactions of Chemotherapy and Radiation Most children's cancers are managed with systemic chemotherapy. In children receiving radiation therapy as well as systemic chemotherapy, issues of enhanced local efficacy and enhanced local or regional toxicity need to be considered. Solid tumors that are frequently treated with combined chemotherapy and radiation therapy include Wilms' tumor, neuroblastoma, and sarcomas. These tumors are subdivided into those in which chemotherapy is given concomitantly with radiation therapfsx6I and those in which it is given sequentially, before or after radiation therapy.",i5,gWhen delivering radiation therapy concurrently with or temporally close to a course of chemotherapy, several issues must be considered.

Chemotherapeutic Enhancement of Local Irradiation Several systemic chemotherapeutic agents used against pediatric tumors may enhance the efficacy of radiation therapy when delivered concomitantly. Cisplatin, 5-fluorouracil, mitomycin C, and gemcitabine, for example, Concomitant are well-known radiation sen~itizers.2~~"~2~ delivery of any of these drugs with radiation therapy may require that they be administered at a dose and schedule different from those typically used when the drugs are delivered alone. Despite the potential of increased toxicity, significant improvements in local tumor control have been shown in randomized studies of concomitant drug and radiation therapy.2~4"

lrradiation Combined with Agents Having Limited or No Sensitizing Effect In the management of pediatric malignancies, radiation is often combined with systemic therapy not to increase its local efficacy but to allow continued delivery of systemic therapy to control micrometastatic or metastatic disease. Agents combined with radiation therapy in this setting are common in the management of pediatric sarcomas and include ifosfamide and etoposide, which are delivered concurrently with radiation therapy for Ewing's sarcoma, and vincristine and cyclophosphamide, which are delivered concurrently with radiation therapy Although local toxicity may for rhabdomyosarcoma.38~~1 be increased by such an approach, this risk is often outweighed by the benefit of continuously delivered systemic therapy, particularly in tumors associated with a high incidence of micrometastatic disease.

Agents That Increase Radiation Toxicity Several agents significantly increase the local toxicity of radiation. For this reason, these agents are not given concomitantly with irradiation and are often withheld for a period after the completion of radiation therapy. The two most notable agents are doxorubicin and actinomycin, both of which can induce significant skin and

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Principles of Pediatric Oncology, Genetics of Cancer, and Radiation Therapy

mucosal toxicity when delivered concurrently with radiation therapy.z4,29The camptothecins (including irinotecan and topotecan) also potentiate mucosal toxicity when delivered concurrently with radiation therapy.58J00 Although this increase in toxicity suggests a possible increase in local efficacy, this benefit has not been noted with current treatment approaches and chemotherapeutic dosing guidelines. For this reason, these agents are avoided during the delivery of radiation therapy and are withheld for 2 to 6 weeks after the completion of treatment. The current era of systemic therapy continues to broaden with the availability of many new agents that target molecular pathways. It is important to consider the possibility of new toxicities when combining novel agents with a known therapy such as radiation.

429

radiation beams from the conventional directions: anterior, posterior, and lateral. Limitations of this approach are related to the ability of conventional radiographs to accurately convey the location of tumor-bearing tissue. Although treatment beams are oriented around the tumor, adjacent normal tissues also receive high doses of radiation. Depending on the accuracy of the delineation of adjacent normal tissues on radiographs, the dose to those tissues may not be known. Radiation is delivered via a photon beam generated by a linear accelerator.

Image-Guided Radiation Therapy

Image-guided radiation therapy comprises a group of techniques that deliver radiation to a defined volume usually delineated by computed tomography (CT) or magnetic resonance imaging (MRI). Relatively low doses may be incidentally delivered to surrounding normal Delivery of Fractionated Radiation Therapy tissues. Radiation therapy may be described as image guided when four criteria are met: (1) three-dimensional Conventional, external beam irradiation is delivered in imaging data (CT or MRI) are acquired with the patient a fractionated form. Fractionation implies daily doses of in the treatment position; (2) imaging data are used to radiation delivered 5 days per week and amounting to the delineate and reconstruct the tumor volume and normal prescribed dose for a particular tumor type. Radiation tissues in three dimensions; (3) radiation beams can be delivered once daily at a fraction size between 1.5 and freely oriented in three dimensions in the planning 2.0 Gy on 5 days per week is considered "conventionally" and delivery processes, and structures traversed by the fractionated. This daily dose is well tolerated by normal beam can be visualized with the eye of the beam; and tissues adjacent to the tumor and appears to effect local tumor control in many tumor systems. (4) the distribution of doses received by the tumor volume and any normal tissue is computable on a pointThere has been interest in the hyperfractionation by-point basis in three-dimensional space. Several of radiation therapy to treat pediatric malignancies, different methods of delivering image-guided photon most notably brain tumors and solid tumors, to try to are currently in use and are discussed here. ,~~ overcome the biologic resistance of m a l i g n a n c i e ~ . ~ ~radiation Although the efficacy of altered fractionation is unproved in the management of children's cancers, there are sevConformal Radiation Therapy eral reasons to consider alternative treatment schedules The delivery of three-dimensional conformal radiation with a documented efficacy equivalent to that of conventherapy allows specific targeting of tumor volumes on tional fractionation. Hyperfractionation, with a dose of the basis of imaging studies performed with the patient less than 1.5 Gy per fraction, may allow the delivery in the treatment position. This method of delivery uses of standard total doses of radiation but with fewer late multiple fields or portals, with each beam aperture effects. Accelerated hyperfractionated radiation therapy, shaped to the tumor volume, and is performed daily. in which the overall treatment time is compressed, may Beam modifiers such as wedges are used to conform the have the benefit of allowing a short course of radiation radiation beam to the tumor and to ensure that the therapy between other therapies, including systemic thertumor volume receives a homogeneous dose. Conformal apy or bone marrow transplantation. This approach has radiation therapy has been intensively studied in adults and is curbeen used in children with neurobla~toma8~ with head and neck cancer, lung cancer, and prostate rently being investigated in the management of Hodgkin's cancer and has been shown to excel when the target disease in patients undergoing bone marrow transplantavolume is convex and crucial structures do not invagition. Alterations of treatment fractionation continue to nate the target volume. Available data demonstrate that be studied in the pediatric setting, but their potential it has low toxicity despite high doses of radiation to the benefit must be weighed against the difficulties of delivtarget volume.10g ering multiple treatments per day, particularly to young children who require general anesthesia for treatment.

Intensity-Modulated Radiation Therapy

Radiation Therapy Treatment Techniques Traditional Radiation Therapy The planning and delivery of traditional, or conventional, radiation therapy are based on nonvolumetric imaging studies (i.e., conventional radiographs). Patients are positioned in a manner that allows the orientation of

Intensity-modulated radiation therapy is another method of delivering external beam radiation that requires imaging of the patient in the treatment position and delineation of target " volumes and normal tissues. Radiation is delivered to the target as multiple small fields that do not encompass the entire target volume but collectively deliver the prescribed daily dose. Intensitymodulated radiation therapy differs from conformal

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radiation therapy in that it (1) increases the complexity and time required for the planning and delivery of treatment; (2) increases the amount of quality-assurance work required before treatment is delivered; (3) increases dose heterogeneity within the target volume, such that some intralesional areas receive a relatively high dose; and (4) can be used to treat concave targets while sparing crucial structures that invaginate the target volume. The last point holds promise for better protecting normal tissue and reducing late toxic effects. Preliminary data from adult patients given intensity-modulated radiation therapy demonstrate its potential for reducing treatment toxicity when applied to pediatric brain tumors and other adult tumors.7"

Brachytherapy Brachytherapy is a method of delivering radiation to a tumor or tumor bed by placing radioactive sources within or adjacent to the target volume, usually at the time of surgical resection and under direct vision. Planning of the dose to be delivered to the target volume is accomplished after resection and may use CT or MRI studies; the appropriate strength of the radioactive source is determined prospectively. Sources commonly used in children include iridium 192 and iodine 125. Brachytherapy may consist of either low dose-rate treatments (approximately 40 to 80 cGy per hour) or high dose-rate treatments (approximately 60 to 100 cGy per minute). Low dose-rate treatments are delivered over a period of days, often while the patient remains hospitalized, whereas high dose-rate treatments are divided into fractions and delivered on several days over 1 to 2 weeks. The primary advantage of brachytherapy is that a radiation source can be placed into or adjacent to the tumor, often at the time of resection. Preoperative planning and cooperation between the surgical and radiation oncology teams are necessary to ensure the appropriate and accurate implementation of brachytherapy. Nonrhabdomyosarcoma soft tissue sarcomas and some rhabdomyosarcomas are the pediatric tumors most commonly treated with brachytherapy.1°2J15 Most other pediatric solid tumors are not amenable to brachytherapy, however, because of the tumor's behavior (e.g., radioresistance) or its anatomic location (e.g., retroperitoneal).

Other Delivery Methods Several other means of delivering radiation to primary tumor sites are used in adult and pediatric oncology. Intraoperative radiation therapy has been used intermittently after resection in the management of localized tumors." Although of limited availability in the United States, intraoperaGve radiation therapy has the distinct advantage of allowing the operative tumor bed to be visible in the operating theater while radiation is delivered, thereby enhancing the accuracy of delivery and providing the opportunity to displace or temporarily move mobile crucial structures (e.g., bowel, bladder) from the field of delivery. The primary limitation of intraoperative radiation therapy is-that it can deliver only a single fraction of radiation, usually in the 10 to 20 Gy range.

Radiation tolerances of normal tissues that cannot be removed from the treatment field must be respected and may limit the ability to deliver an effective treatment dose. Proton radiation therapy and other approaches using heavy charged particles have been investigated at a limited number of centers. The primary benefit of therapy with proton or other heavy charged particle beams is the capacity to end the radiation beam at a specific and controllable depth. This may allow the protection of healthy, normal tissues directly adjacent to tumorbearing tissues.74 However, the use of proton therapy is limited because of the expense of constructing a suitable treatment facility; only a small number of institutions are so equipped. Although interest in proton therapy decreased in the late 1990s, it has now resumed, and several new facilities are currently under construction in the United States. With appropriately designed studies and comparisons with current state-of-the-art imageguided therapy delivered with photon beams, a determination of the potential benefits of this treatment modality may be made.

Palliative Radiation Therapy For many patients, the management of cancer, particularly pediatric cancer, focuses on curative therapy incorporating surgery, radiation therapy, and chemotherapy in a multidisciplinary plan. Despite substantial success in the management of pediatric cancer, many children experience disease recurrence and ultimately die from their malignancy. Although it is far less frequently discussed, palliative radiation therapy is often a valid intervention.68 Implicit in the concept of palliative radiation therapy is that its purpose is to treat a symptom. The ultimate goal of a palliative approach is to maintain quality of life for patients who will not survive their disease while minimizing the number of disruptive interventions they must undergo. Radiation oncologists are often asked to palliate symptoms from painful sites of disease, particularly those with bony involvement, and symptoms resulting from compression of vital structures, including spinal cord, peripheral nerves, and respiratory tract. Delivery of radiation in this setting is identical to that of curative radiation, with radiation delivered on a daily basis. Close attention is paid to the symptoms being palliated, while treatment-related effects are minimized. A palliative course of therapy is highly individualized, and its success or failure depends on the histologic diagnosis, previous therapy, duration of symptoms, and symptom being treated.

Acute and Late Toxicities of Radiation Therapy The treatment-related effects of radiation therapy, both acute and chronic, are well described for pediatric and adult patients, but unfortunately, their incidence and relation to the dose and volume of treatment are poorly ~haracterized.~Wistorically,treatment-related effects have been classified as acute or late; an arbitrary time point of 90 days after the completion of treatment

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defines the division between the two classifications. Current guidelines for assessing adverse events related to treatment no longer recognize this arbitrary distinction, but the use of early and late time points is instructive in the discussion of radiation-related effects. Essentially all such effects originate from within the confines of the treatment beams, usually the high-dose regions of treatment. The most common early and late treatmentrelated effects arising from radiation are listed in Table 25-6. Despite the arbitrary nature of the division into early and late effects, this classification distinguishes effects from which the patient is likely to recover completely from those that are likely to be permanent. Early treatment-related effects, if managed appropriately, will resolve as normal, healthy tissues adjacent to the tumorbearing tissues gradually recover from the effects of radiation. The period of recovery can range from days to months, but the patient is often left with minimal sequelae. Treatment-related effects that are observed later, after the completion of radiation therapy, are more likely to be chronic or permanent. They appear to be related to the normal healing response of healthy irradiated tissue, resulting in the formation of an unwanted effect such as fibrosis. Many late treatment effects can be managed but are not reversible. For children receiving curative therapy, long-term effects are a primary concern and are best managed with a preventive approach. Some of the long-term effects of treatment in children should be ameliorated by limiting the volume of normal tissue irradiated at high doses and by implementing approaches that minimize the radiation dose to adjacent healthy tissues.

1 Organpite Skin Subcutaneous tissue Mucosa Central nervous system

Acute

Chronic

Erythema Desquamation Edema Mucositis Edema Headache

Atrophy Hyperpigmentation Fibrosis Ulceration Necrosis Myelitis Decline in cognition Cataract Retinopathy Dry eye Hypothyroidism Pericarditis Myocarditis Pulmonary fibrosis Necrosis

Eye

Conjunctivitis

Thyroid Heart

-

Lung Bowel

Pneumonitis Nausea Diarrhea

Kidney

-

Bladder

Muscle

Dysuria Urgency Frequency Edema

Bone

-

Nephritis Renal insufficiency Hemorrhagic cystitis

Fibrosis Hypoplasia Premature physis closure Hypoplasia

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GENERAL PRINCIPLES OF STEM CELL TRANSPLANTATION Infusion or transplantation of hematopoietic cells capable of reconstituting the hematopoietic system is used in two broad instances. First, hematopoietic stem cell transplantation (HSCT) can be used to replace missing or abnormal components of a defective hematopoietic system. Second, HSCT can be used to reconstitute elements of the hematopoietic system destroyed by intensive chemotherapy or radiation therapy for solid tumors or disorders of the hematopoietic system itself. The transplanted cells can be the patient's own (i.e., autologous), in which case the cells are obtained before the administration of myelosuppressive therapy, or they may come from a donor (i.e., allogeneic) who is generally an HLA-identical sibling, a mismatched family member, or a partially matched unrelated donor. The latter two circumstances require immunosuppressive and graft engineering strategies to permit successful engraftment and avoid graft-versus-host disease. Hematopoietic progenitor cells are usually obtained from the bone marrow or peripheral blood. They are the crucial component of the transplant because they are capable of self-renewal and, therefore, long-term production of cells of the various hematopoietic lineages. Occasionally, when available, banked umbilical cord blood may be used as the source of hematopoietic stem cells (HSCs). In general, although autologous cells are the safest to use for HSCT, they may be contaminated with tumor cells. Graft-versus-host disease, which may occur with allogeneic HSCT, can be life threatening, but a modest graft-versus-host reaction may be beneficial if directed against the host's tumor cells. Bone marrow is normally harvested from the posterior iliac crest to a total volume of 10 to 20 mL/kg body weight of the recipient. Peripheral blood stem cells are harvested after their mobilization with recombinant granulocyte colony-stimulating factor, given daily for up to a week before harvest. The exact nature of the crucial cellular component responsible for the reconstitution of the hematopoietic system is unknown, but the number of cells having the surface marker CD34 has been shown to be related to the rate of engraftment.g"efore HSCT, the recipient receives a preparative (or "conditioning") chemotherapeutic regimen. This treatment serves several purposes, including killing residual tumor cells, providing immunosuppression for allogeneic HSCT, and providing "space" in the marrow into which transplanted HSCs can engraft. Before reinfusion, the HSC product may be manipulated ex vivo to enrich it for putative progenitor cells (e.g., CD34+ or CD133+ cells), using positive or negative selection methods, to facilitate hematopoietic reconstitution; to remove donor T lymphocytes, thereby decreasing the risk of graft-versus-host disease in allogeneic HSCT, or to purge contaminating tumor cells from the product used inautologous HSCT. Complications of HSCT can be significant. The most common early complication is infection, which results from the transient but profound immunosuppression of the patient, combined with the breakdown of mucosal barriers. Another common complication is veno-occlusive disease, which is characterized clinically by painful

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enlargement of the liver, jaundice, and fluid retention. Ultrasouild examination shows reversal of flow in the portal vein. Liver biopsy samples show a classic histologic appearance of obliterated hepatic venules and necrosis of centrilobular hepatocytes. There is no specific treatment for this condition; only supportive care can be given, and mild or moderate veno-occlusive disease is self-limited. Other acute complications of HSCT include graft-versus-host disease, a process mediated by donor T cells targeting host cells with antigenic disparities, and graft failure. Late complications include chronic graftversus-host disease, endocrine insufficiency, secondary malignancies, growth failure, and other sequelae related to the use of total-body irradiation as part of some preparatory regimens. Nevertheless, despite the toxicity, HSCT is now an integral part of successful therapy for many high-risk malignancies in children.

CLINICAL TRIALS As previously stated, the past 40 years have seen a significant increase in overall survival rates for children with cancer. This increase has been achieved through the development of new drugs and treatment approaches, improved supportive care, and better diagnostic modalities to permit earlier cancer detection. The benefits of these ad\lances have been confirmed by carefully designed and analyzed clinical trials. Because childhood cancer is relatively rare, excellent organization and planning of these trials are essential. In the United States and other participating countries, clinical trials are largely conducted by the Children's Oncology Group, with smaller pilot studies being run by large individual institutions or small consortia. Clinical trials are generally divided into three phases. Phase I studies are designed to evaluate the potential toxicity of a new diagnostic or therapeutic agent. Small numbers of patients are usually required for a phase I study, which typically uses a dose-escalating design in which cohorts of patients are observed for signs of toxicity before they advance to higher doses. The end point of this type of study is generally a determination of the safety of the agent o r the maximum tolerated dose (or both). However, the increasing number of biologic reagents being introduced and tested may require a shift to the assessment of the optimal biologic dose. Enrollment in a phase I toxicity study is often restricted to patients whose disease has not responded to conventional or "standard-oEcare" therapy. Phase I1 trials are conducted to determine whether a new agent or treatment approach is sufficiently efficacious to warrant further study. Phase I1 agents are often given to newly diagnosed patients before they begin o r just after they complete standard therapy. The testing of new agents in an "upfront window" (i.e., before standard therapy) has been shown not to have an adverse effect on the efficacy of delayed standard therapy. Finally, phase 111 studies are designed to compare the efficacy of an experimental therapy with that of standard therapy. They are best done as prospective, randomized trials, but often, because of small patient numbers, a phase 111 study is

done by comparing the efficacy of an experimental therapy with that of standard therapy given to historic control subjects. It is through such systematic assessment of the risks and benefits of new therapies that approaches are rejected o r accepted as the new standard of care and the field of pediatric oncology is advanced.

CONCLUSION Advances in molecular genetic research in the past 2 decades have led to increased understanding of the genetic events in the pathogenesis and progression of human malignancies, including those of childhood. A number of pediatric malignancies serve as models for the molecular genetic approach to cancer. The pediatric experience highlights the utility of molecular analysis for a variety of purposes. Demonstration of tumor-specific translocations by cytogenetics, FISH, and RT-PCR confirms histopathologic diagnoses. Detection of chromosomal abnormalities, gene overexpression, and gene amplification is used in risk stratification and treatment planning. Elucidation of pathways involving tumor suppressor genes has increased our understanding of syndromes associated with cancer and has led the way for genetic screening and counseling and pl-ophylactic surgical intervention. And in the near f i ~ t u r e , translation of the molecular profile of a given tumor will form the basis of a new therapeutic approach. Treatment will be tailored such that patients with biologically highrisk tumors receive intensified regimens to achieve a cure, whereas patients with biologically low-risk tliinors may experience a cure and benefit from the lower toxicity of nonintensive therapy. Elucidation of the complex molecular pathways involved in tumorigenesis will also encourage the production of targeted anticancer agents with high specificity, efficacy, and therapeutic index.

REFERENCES 1. Abramson LP, Grundy PE, Rademaker AW, et al: Increased microvascular density predicts relapse in Wilms' tumor. J Pediatr Surg 2003;38:325-330. 2. A1 Sarraf M, LeBlanc M, Giri PG, et al: <:henloradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase 111 randomized intergroup study 0099. J Clin Oncol 1998;16:1310-1317. 3. Arap W, Pasqualini R, Ruoslahti E: Cancer treatment by targeted d n ~ gdelivery to tumor vasculature in a mouse model. Science 1998;279:377-380. 4. Asher AL, Muleg, Kasid A, et al: Murine tumor cells transduced with the gene for tumor necrosis factor-alpha: Evidence for paracrine immune effects of tumor necrctsis factor against tumors.J Immunol 1991;146:3227-3234. 5. Bader SA, Fasching C, Brodeur GM, et al: Dissociation of sup pression of tumorigenicity and differentiation in vitro rffected by transfer of single human chromosomes into human neuroblastoma cells. Cell Growth Differ 1991;2:245-255. 6. Barbacid M: Neurotrophic factors and their receptors. Curr Opin Cell Riol 1995;7:145-155. 7. Bardeesy N, Falkoff D, Petruzzi MJ, et al: Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbo~~rs p53 gene mutations. Nat Genet 1994;7:91-97.

CHAPTER

25

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Barr FG: The role of chimeric paired box transcription factors in the pathogenesis of pediatric rhabdomyosarcoma. Cancer Res 1999;59:1711s-1715s. Bicknell R, Harris AL: Mechanisms and therapeutic implications of angiogenesis. Curr Opin Oncol 1996;8:60-65. Blankenstein T, Q I ZH, ~ Uberla K, et al: Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer. J Exp Med 1991;173:1047-1052. Bowman L, Grossmann M, Rill D, et al: IL2 adenovectortransduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma. Blood 1998;92:1941-1949. Bowman LC, Grossmann M, Rill D, et al: Interleukin-2 genemodified allogeneic tumor cells for treatment of relapsed neuroblastoma. Hum Gene Ther 1998;9:1303-1311. Bown N, Cotterill S, Lastowska M, et al: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999;340:19541961. Bredel M, Pollack IF, Hamilton RL, et al: Epidermal growth factor receptor expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res 1999;5:1786-1 792. Brodeur GM, Hayes FA, Green AA, et al: Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Cancer Res 1987;47: 4248-4253. Brodeur GM, Maris JM, Yamashiro DJ, et al: Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol 1997;19:93-101. Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastomas cdrre~ateswith advanced disease stage. Science 1984;224:1121-1124. Brodeur GM, Sekhon G, Goldstein MN: Chromosomal aberrations in human neuroblastomas. Cancer 1977;40: 2256-2263. Brooks PC, Silletti S, von Schalscha TL, et al: Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998;92:391-400. Browder T, Butterfield CE, Kraling BM, et al: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:18781886. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor ST1571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139-145. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990;60:509-520. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature 2000;407:249-257. Cassady.JR,Richter MP, Piro AJ, et al: Radiation-Adriamycin interactions: preliminary clinical observations. Cancer 1975; 36946-949. Cheung NK: Immunotherapy: Neuroblastoma as a model. Pediatr Clin North Am 1991;38:425-441. Cheung NK, Burch L, Kushner BH: Monoclonal antibody 3F8 can effect durable remissions in neuroblastoma patients refractory to chemotherapy: A phase I1 trail. In Evans AE, D'Angio C;J, Kundson AG (eds):Advances in Neuroblastoma Research, 3rd ed. Hoboken, NJ: Wiley-Liss, 1991, p 395. Clark], Benjamin H, Gill S, et al: Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superf'amily, in a human myxoid chondrosarcoma. Oncogene 1996;12:229-235. Clark J , Rocques PJ, Crew AJ, et al: Identification of novel genes, SET and SSX, involved in the t(X;18) (p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet 1994;7:502-508.

433

29. Cohen IJ, Loven D, Schoenfeld T, et al: Dactinomycin potentiation of radiation pneumonitis: A forgotten interaction. Pediatr Hematol Oncol 1991;8:187-192. 30. Coppes MJ, Bonetta L, Huang A, et al: Loss of heterozygosity mapping in Wilms' tumor indicates the involvement of three distinct regions and a limited role for nondisjunction or mitotic recombination. Genes Chromosomes Cancer 1992;5:326-334. 31. Coppes MJ, Haber DA, Grundy PE: Genetic events in the development of Wilms' tumor. N Engl J Med 1994;331: 586-590. 32. Dameron KM, Volpert OV, Tainsky MA, et al: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582-1584. 33. de Alava E, Kawai A, Healey JH, et al: EWS-I1211fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 1998;16:1248-1255. 34. Delaney TF, Spiro IJ, Suit HD, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity softtissue sarcomas. Int J Radiat Oncol Biol Phys 2003;56: 1117-1127. 35. Diaz MA, Vicent MG, Garcia-Sanchez F, et al: Long-term hematopoietic engraftment after autologous peripheral blood progenitor cell transplantation in pediatric patients: Effect of the CD34+ cell dose. Vox Sang 2000;79:145-150. 36. Donaldsor~SS, Halperin EC: Subspecialty training and certification for radiation oncology. J Am Coll Radio1 2004; 1:488-492. 37. Donaldson SS, Hudson MM, Lamborn KR, et al: VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial. J Clin Oncol 2002; 20:3081-3087. 38. Donaldson SS, Meza J, Breneman J C , et al: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma-a report from the IRSG. IntJ Radiat Oncol Biol Phys 2001;51:718-728. 39. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-122. 40. Evans AE, Kisselbach KD, Yamashiro DJ, et al: Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin Cancer Res 1999; 5:35943602. 41. Farber S: Chemotherapeutic studies of tumors, including leukemia, in children. Am J Dis Child 1950;79:961-962. 42. Fearon ER, Pardoll DM, Itaya T, et al: Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 1990;60:397-403. 43. Feldman AL, Libutti SK: Progress in antiangiogenic gene therapy of cancer. Cancer 2000;89:1181-1194. 44. Fidler IJ: The organ microenvironment and cancer metastasis. Differentiation 2002;70:498-505. 45. Fidler IJ, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994; 79:185-188. 46. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase 111 randomized intergroup study. J Clin Oncol 1996;14:2527-2539. 47. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:46. 48. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 1992;3:65-71. 49. FolkmanJ: Clinical appli cations of research on angiogenesis. N Engl J Med 1995;333:1757-1763.

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50. Folkman J, D'Arnore PA: Blood vessel formation: What is its molecular basis? Cell 1996;87:1153-1155. 51. Fong CT, Dracopoli NC, White PS, et al: Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: Correlation with N-myc amplification. Proc Natl Acad Sci U S A 1989;86:3753-3757. 52. Friedmann AM, Hudson MM, Weinstein HJ, et al: Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation. J Clin Oncol 2002; 20:3088-3094. 53. Galili N, Davis RJ, Fredericks WJ, et al: Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993;5:230-235. 54. GeigerJD, Hutchinson RJ, Hohenkirk LF, et al: Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 2001;61:8513-8519. 55. Giardiello FM: Gastrointestinal polyposis syndromes and hereditary nonpolyposis colorectal cancer. In Rustgi AD (ed): Gastrointestinal Cancers: Biology, Diagnosis, and Therapy. Philadelphia: Lippincott-Raven, 1995, pp 367-377. 56. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-1733. 57. Golumbek PT, Lazenby AJ, Levitsky HI, et al: Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 1991;254:713-716. 58. Graham MV, Jahanzeb M, Dresler CM, et al: Results of a trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1996;36:1215-1220. 59. Green DM: The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol 2004;22:1366-1372. 60. Green DM, Jaffe N: Wilms' tumor-model of a curable pediatric malignant solid tumor. Cancer Treat Rev 1978; 5:143-172. 61. Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694701. 62. Grundy P, Coppes MJ, Haber D: Molecular genetics of Wilms' tumor. Hematol Oncol Clin North Am 1995;9: 1201-1215. 63. Haas-Kogan DA, Fisch BM, Wara WM, et al: Intraoperative radiation therapy for high-risk pediatric neuroblastoma. Int J Radiat Oncol Biol Phys 2000;47:985-992. 64. Hamada J, Cavanaugh PG, Lotan 0 , et al: Separable growth and migration factors for large-cell lymphoma cells secreted by microvascular endothelial cells derived from target organs for metastasis. Br J Cancer 1992;66:349-354. 65. Handgretinger R, Baader P, Dopfer R, et al: A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother 1992;35: 199-204. 66. Hank JA, Robinson RR,Surfus J, et al: Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. Cancer Res 1990;50:52345239. 67. Hank JA, Surfus J, Gan J, et al: Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus interleukin-2 induces antibodydependent cellular cytotoxicity against neuroblastoma detected in vitro. J Immunother 1994;15:29-37. 68. Harris MB: Palliative care in children with cancer: Which child and when?J Natl Cancer Inst Monogr 2004;144149. 69. Henderson C, Brancolini C: Apoptotic pathways activated by histone deacetylase inhibitors: Implications for the drugresistant phenotype. Drug Resist Update 2003;6:247-256.

70. Hobson B, Denekamp J: Endothelial proliferation in tumours and normal tissues: Continuous labelling studies. Br J Cancer 1984;49:405-413. 71. Holmgren L, O'Reilly MS, Folkman J: Dormancy of micrometastases: Balanced proliferation and apoptosis in . the presence of angiogenesis suppression. Nat Med 1995; 1:149-153. 72. Howe JR, Norton JA, Wells SA Jr: Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: Results of long-term follow-up. Surgery 1993;114:1070-1077. 73. Huang E, Teh BS, Strother DR, et al: Intensity-modulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52:599-605. 74. Hug EB, Sweeney RA, Nurre PM, et al: Proton radiotherapy in management of pediatric base of skull tumors. Int J Radiat Oncol Biol Phys 2002;52:1017-1024. 75. Jereb B, Burgers JM, Tournade MF, et al: Radiotherapy in the SIOP (International Society of Pediatric Oncology) nephroblastoma studies: A review. Med Pediatr Oncol 1994;22:221-227. 76. Kaneko Y, Kanda N, Maseki N, et al: Different karyotypic patterns in early and advanced stage neuroblastomas. Cancer Res 1987;47:311-318. 77. Kaur G, Stetler-Stevenson M, Sebers S, et al: Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 1992;84:1736-1740. 78. Keshelava N, ZuoJ, Waidyaratne NS, et al: p53 mutations and loss of p53 function confer multidrug resistance in neuroblastoma. Med Pediatr Oncol 2000;35:563-568. 79. Kingston JE, Herbert A, Draper GJ, et al: Association between hepatoblastoma and polyposis coli. Arch Dis Child 1983;58:959-962. 80. Kinzler KW, Vogelstein B: Familial cancer syndromes: The role of caretakers and gatekeepers. In Vogelstein B, Kinzler KW (eds): The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998, pp 241-599. 81. Knudson AG Jr: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68: 820-823. 82. Kohl NE, Kanda N, Schreck RR, et al: Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 1983;35:359-367. 83. Koufos A, Grundy P, Morgan K, et al: Familial WiedemannBeckwith syndrome and a second Wilms' tumor locus both map to llp15.5. Am J Hum Genet 1989;44:711-719. 84. Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al: Efficacy of definitive irradiation and multi-agent systemic therapy for localized Ewing's sarcoma family of tumors (ESFT). Int J Radiat Oncol Biol Phys 2003;57:S197. 85. KucharczakJ, Simmons MJ, Fan Y, et al: To be, or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 2003;22:8961-8982. 86. Kusafuka T, Fukuzawa M, Oue T, et al: Mutation analysis of p53 gene in childhood malignant solid tumors. J Pediatr Surg 1997;32:1175-1180. 87. Kushner BH, Wolden S, LaQuaglia MP, et al: Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery. J Clin Oncol 2001;19:2821-2828. 88. Ladanyi M, Gerald W: Fusion of the EM$ and W 1 genes in the desmoplastic small round cell tumor. Cancer Res 1994;54:2837-2840. 89. Laughner E, Taghavi P, Chiles K, et al: HER2 (neu) signaling increases the rate of hypoxia-inducible factor lalpha (HIF-lalpha) synthesis: Novel mechanism for HIF-1mediated vascular endothelial growth factor expression. Mol Cell Biol 2001;21:3995-4004. A

CHAPTER

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90. Levi-Montalcini R: The nerve growth factor 35 years later. Science 1987;237:11541162. 91. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell 1991;64:327-336. 92. Look AT, Hayes FA, Nitschke R, et al: Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 1984;311: 231-235. 93. Look AT, Kirsch IR: Molecular basis of childhood cancer. In Pizzo PA, Poplack DG (eds): Principles and Practices of Pediatric Oncology. Philadelphia: Lippincott-Raven, 1997, p 38. 94. Lutz W, Stohr M, Schurmann J, et al: Conditional expression of N-myc in human neuroblastoma cells increases expression of alpha-prothymosin and ornithine decarboxylase and accelerates progression into Sphase early after mitogenic stimulation of quiescent cells. Oncogene 1996;13: 803-812. 95. Malkin D, Li FP, Strong LC, et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:1233-1238. 96. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoicacid: Children's Cancer Group. N Engl J Med 1999;341:1165-1173. 97. May WA, Gishizky ML, Lessnick SL, et al: Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLIl for transformation. Proc Natl Acad Sci U S A 1993; 90:5752-5756. 98. May WA, Lessnick SL, Braun BS, et al: The Ewing's sarcoma EWS/FLI-I fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol Cell Biol 1993;13:7393-7398. 99. McNeil C: Herceptin raises its sights beyond advanced breast cancer. J Natl Cancer Inst 1998;90:882-883. 100. Mehta VK, Cho C, Ford JM, et al: Phase I1 trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. IntJ Radiat Oncol Biol Phys 2003;55:132-137. 101. Meitar D, Crawford SE, Rademaker AW, et al: Tumor angiogenesis correlates with metastatic disease, N-myc amplification, and poor outcome in human neuroblastoma. J Clin Oncol 1996;14:405-414. 102. Merchant TE, Parsh N, del Valle PL, et al: Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2000;46:427-432. 103. Merchant TE, Zhu Y, Thompson SJ, et al: Preliminary results from a phase I1 trial of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma. Int J Radiat Oncol Biol Phys 2002;52:325-332. 104. Mulligan LM, Kwok JB, Healey CS, et al: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458-460. 105. Nagata S: Apoptosis by death factor. Cell 1997;88:355-365. 106. Nakagawara A, Azar CG, Scavarda NJ, et al: Expression and function of Trk-B and BDNF in human neuroblastomas. Mol Cell Biol 1994;14:759-767. 107. Nguyen M, Watanabe H, Budson AE, et al: Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 1993;85:241-242. 108. Nishisho I, Nakamura Y, Miyoshi Y, et al: Mutations of chromosome 5q21 genes in FA€' and colorectal cancer patients. Science 1991;253:665-669.

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109. O'Brien KP, Seroussi E, Dal Cin P, et al: Various regions within the alpha-helical domain of the COLlAl gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblaitomas. Genes Chromosomes Cancer 1998;23:187-193. 110. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:2235-2241. 111. Ozkaynak MF, Sonde1 PM, Krailo MD, et al: Phase I study of chimeric human/murine anti-ganglioside G(D2) mon- oclonal antibody (ch14.18) with granulocyte-macrophage colonv-stimulating. factor in children with neuroblastoma u immediately after hematopoietic stem-cell transplantation: A Children's Cancer Group Study. J Clin Oncol 2000;18: 4077-4085. 112. PelletierJ, Bruening W, Kashtan CE, et al: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991;67:437-447. 113. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Path01 1997;151:1523-1530. 114. Pinthus JH, Fridman E, Dekel B, et al: ErbB2 is a tumor associated antigen and a suitable therapeutic target in Wilms' tumor. J Urol 2004;172:16441648. 115. Pisters PW, Harrison LB, Leung DH, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14:859-868. 116. Pluda JM: Tumor-associated angiogenesis: Mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 1997;24:203-218. 117. Powell SM, Petersen GM, Krush AJ, et al: Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982-1987. 118. Pritchard-Jones K, Fleming S, Davidson D, et al: The candidate Wilms' tumour gene is involved in genitourinary development. Nature 1990;346:194197. 119. Quesnel S, Malkin D: Genetic predisposition to cancer and familial cancer syndromes. Pediatr Clin North Am 1997;44:791-808. 120. Rabbitts TH, Forster A, Larson R, et al: Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet 1993;4:175-180. 121. Riccardi VM, Sujansky E, Smith AC, et al: Chromosomal imbalance in the aniridia-Wilms' tumor association: 1l p interstitial deletion. Pediatrics 1978;61:604610. 122. Ries LG: Childhood cancer mortality. In Ries LG, Smith MA, Gurney JG, et a1 (eds): Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. National Cancer Institute, 1999, pp 165-169. 123. Risau W: Mechanisms of angiogenesis. Nature 1997;386: 671-674. 124. Robinson BW, Ostruszka L, Im MM, et al: Promising combination therapies with gemcitabine. Semin Oncol 2004; 31:2-12. 125. Rodriguez-Galindo C, Spunt SL, Pappo AS: Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol 2003;40: 276287. 126. Rousseau RF, Haight AE, Hirschmann-Jax C, et al: Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 2003;101:1718-1726.

436

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127. Rubin BP, Chen CJ, Morgan TW, et al: Congenital mesoblastic nephroma t(12;15) is associated with ETVG-NTRK? gene fusion: Cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol 1998; 153:1451-1458. 128. Ruegg C, Yilmaz A, Bieler G, et al: Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Mat Med 1998;4:408-414. 129. Sabers GI, Martin MM, Brunn GJ, et al: Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815-822. 130. Sandler AD, Chihara H, Kobayashi G, et al: CpG oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma. Cancer Res 2003;63:394399. 131. Schnitzer JE: Vascular targeting as a strategy for cancer therapy. N Engl J Med 1998;339:472-474. 132. Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985;313: 1111-1116. 133. Sharpless NE, DePinho RA: Telomeres, stem cells, senescence, and cancer. J Clin Invest 2004;113:160-168. 134. Sherr CJ: The Pezcoller lecture: Cancer cell cycles revisited. Cancer Res 2000;60:3689-3695. 135. Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2002;2:103-112. 136. Shimizu T, Berhanu A, Redlinger RE Jr, et al: Interleukin-12 transduced dendritic cells induce regression of established murine neuroblastoma. J Pediatr Surg 2001;36: 1285-1292. 137. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al: A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 1994;6:146-151. 138. Srivastava A, Laidler P, Davies RP, et al: The prognostic significance of tumor vascularity in intermediate-thickness (0.76-4.0 mm thick) skin melanoma: A quantitative histologic study. Am J Pathol 1988;133:419-423. 139. Svensson T, Ryden M, Schilling FH, et al: Coexpression of mRNA for the full-length neurotrophin receptor Trk-C and Trk-A in favourable neuroblastoma. Eur J Cancer 1997;33: 2058-2063. 140. Teitz T, Wei T, Valentine MB, et al: Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000;6:529-535.

141. Tepper RI, Mule JJ: Experimental and clinical studies of cytokine gene-modified tumor cells. Hum Gene Ther 1994;5:153-164. 142. ThiesingJT, Ohno-Jones S, Kolibaba KS, et al: Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood 2000;96:3195-3199. 143. Ton CC, Hirvonen H, Miwa H, et al: Positional cloning and characterization of a paired box- and homeoboxcontaining gene from the aniridia region. Cell 1991;67: 1059-1074. 144. Toole BP: Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol 1990;2:839-844. 145. van Leeuwen FE: Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment. Baillieres Clin Haematol 1996;9:57-85. 146. Vandesompele J, Van Roy N, Van Gele M, et al: Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization. Genes Chromosomes Cancer 1998;23:141-152. 147. Varanasi R, Bardeesy N, Ghahremani M, et al: Fine structure analysis of the WT1 gene in sporadic Wilms' tumors. Proc Natl Acad Sci U S A 1994;91:35543558. 148. Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 2004;10:789-799. 149. Wai DH, Knezevich SR, Lucas T, et al: The ETV6-N7RK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 2000;19: 906-915. 150. White CW, Sondheimer HM, Crouch EC, et al: Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med 1989;320:1197-1200. 151. Xiong S, Grijalva R, Zhang L, et al: Up-regulation of vascular endothelial growth factor in breast cancer cells by the heregulin-betal-activated p38 signaling pathway enhances endothelial cell migration. Cancer Res 2001;61:1727-1732. 152. Young JL Jr, Ries LG, Silverberg E, et al: Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer 1986;58:598-602. 153. Zhang L, Yu D, Hu M, et al: Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 2000;60: 3655-3661. 154. Zucman J, Delattre 0, Desmaze C, et al: EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet 1993;4:341-345.

Biopsv Techniques for khildren with Cancer James D. Geiger and Douglas C. Barnhart

The importance of biopsy techniques has increased as the use of preoperative chemotherapy has become common for many childhood cancers. In the past, definitive diagnosis was made at the time of surgical resection of the primary tumor. Currently, many children undergo percutaneous or open incisional biopsy rather than initial resection. Moreover, with a better understanding of the molecular changes associated with these malignancies, definitive diagnosis and accurate staging can be accomplished with smaller specimens. This should lead to less morbidity associated with the diagnosis of solid malignancies in children. There has been a progression toward less invasive techniques to obtain a diagnosis-from complete surgical extirpation to incisional biopsy to percutaneous needle biopsy and minimal-access surgery. This change in practice has been driven not only by the evolution of surgical technique but also by an improved understanding of the molecular markers used for both diagnosis and risk stratification in pediatric solid malignancies. Ironically, this progression has complicated rather than simplified the selection of biopsy techniques in individual cases, because multiple factors must be considered. Percutaneous needle biopsy,I"" minimal-access surgical biopsy,'4 and open biopsy are all safe and effective ways of obtaining an initial diagnosis as well as verifying recurrent or metastatic disease. However, the success of these techniques is obviously dependent on individual institutional experience, which must be considered when selecting a biopsy technique. In addition, it is critical to realize that many of the advances in risk stratification and improved therapy for pediatric malignancies have been facilitated by the development of large tumor banks and the associated biolou studies. Without large biopsy specimens, these tumor banks and the development of research cell lines would not have been possible. For a number of tumors, including neuroblastoma, the collection of such specimens is important to further our understanding of the disease. There has been significant progress toward risk-stratified treatment regimens.18 As this stratification becomes

more complex, the type of information needed from biopsy specimens also becomes more individualized. In order to select the biopsy method that will be the least morbid yet yield all the information necessary to stratify an individual patient, the surgeon must be knowledgeable about the stratification schema that will be used for multimodality therapy. This concept can be exemplified by considering two patients with abdominal masses suggestive of neuroblastoma, both of whom have apparent metastatic disease in the bone marrow, and their treatment under the current Children's Oncology Group (COG) schema.57 The first patient is younger than 1 year, and this child's treatment group could be low, intermediate, or high risk. This determination requires N-myc amplification status, International Neuroblastoma Pathology Classification status, and DNA ploidy, which necessitates sampling of the primary lesion. In contrast, an older child with a similar presentation would be classified as high risk. Therefore, one could consider confirming the diagnosis and assigning a risk group based on bone marrow biopsies alone. Clearly, knowledge of multimodality therapy is essential in the selection of a biopsy technique.

HANDLING OF SPECIMENS Historically, most diagnoses were based on the histologic appearance of tumor tissue on permanent sections using hematoxylin and eosin stains. This was supplemented by the use of immunohistochemistry,which could similarly be performed on formalin-fixed specimens. There has been extensive progress in the molecular diagnosis of childhood malignancies, including recognition of genetic aberrations that have both diagnostic and prognostic signifi~ance."~"~l Techniques used to detect these changes include reverse transcriptase-polymerase chain reaction," fluorescent in situ hybridization, microarray a n a l y s i ~and , ~ ~flow cytometry. Inappropriate specimen handling can preclude the completion of these analyses. For example, phenotypic classification of lymphoma cannot be performed using flow cytometry on formalin-fixed lymph nodes. Given the

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rapidly evolving field of molecular diagnosis, it is essential that the surgeon consult with the pathologist regarding specimen handling before performing the biopsy.

PERCUTANEOUS NEEDLE BIOPSY Fine-needle aspiration was first introduced as a technique for obtaining specimens for cytopathology by Grieg and Gray in 1904.l'Jereb et al.Z9reported success with the use of needle biopsy for the diagnosis of pediatric solid tumors in 1978. Subsequently, extensive experience from multiple institutions has confirmed the accuracy and safety of both needle aspiration and core needle biopsy techniques. The appeal of these techniques is that they permit diagnosis without a significant delay in the institution of multimodality therapy and, in some situations, can be performed as outpatient procedures. Needle biopsies are often performed under either general anesthesia or sedation. In selected older children, some sites may be biopsied under local anesthesia alone using these methods.j4 Percutaneous needle biopsies may be performed by palpation in the extremities and other superficial locations, such as lymph nodes. Deeper biopsies require either ultrasonography or computed tomography (CT) guidance. Ultrasonography can be supplemented with Doppler mode; it allows the clear identification of large vessels and other structures and provides real-time visualization Some l core needle devices as the needle is a d ~ a n c e d . ~ also deposit a small air bubble, which allows verification of the site that was biopsied. CT permits clear visualization of the aerated lung10 and is not obscured by bowel gas. It also allows for measurement and planning of the depth of biopsy.lg Decision making regarding image guidance occurs in conjunction with the radiologist; ideally, biopsies should be performed with both modalities.

of molecular techniques and electron microscopy to supplement light microscopy has increased the histiotype specificity of FNAB and may lead to its increased application in pediatric solid m a l i g n a n c i e ~ . 2 ~ - ~ ~ The most straightforward application of FNAB is the verification of metastatic or recurrent disease in the setting of a previously characterized primary tumor.z6 In this context, documenting the presence of malignant cells is often sufficient to guide further clinical decisions. This least invasive biopsy method is particularly appealing in patients who may already be immunologically or otherwise physiologically compromised. There is an increasing body of literature to support the use of FNAB in the diagnosis of sarcomas. Fine-needle " aspirates have provided a definitive diagnosis of osteosarcoma in 65%l2 to 92%32of patients; this technique is as accurate in children as it is in adults. The use of FNAB in soft tissue tumors has been facilitated by the recognition of cytogenetic abnormalities and fusion proteins that are specific to these tumor types.30.31However, caution should be exercised when using FNAB in this setting, because the reported series come from a limited number of institutions with extensive experience in the interpretation of this cytology. FNAB has not been widely used for the diagnosis of small round blue cell tumors of childhood. However, with the increasing availability of ancillary studies such as electron microscopy, immunocytochemistry, DNA ploidy, cytogenetics, and fluorescent in situ hybridization, its use may become more common.3 Use of FNAB for the evaluation of head and neck masses in children has been ~~,~~ reported to have good sensitivity and s p e c i f i ~ i t y .The results of these series should be interpreted with caution, however, because the majority of these aspirates diagnosed reactive lymphadenopathy; the number of new malignant diagnoses was small. Additionally, false-negative results occurred frequently in patients who were ultimately diagnosed with lymphoma in other series (not specifically isolated to the head and neck) .5*

FINE-NEEDLE ASPIRATION BIOPSY Fine-needle aspiration biopsy (FNAB) has the obvious appeal of being the least invasive biopsy technique. It is typically performed using a 22- to 25-gauge needle with multiple passes into the lesion if necessary. Successful diagnosis using FNAB requires coordination with an experienced cytopathologist; to improve the diagnostic yield, the specimens should be examined immediately after they are taken. Additional aspirations may be taken if initial samples are inadequate.52 Large series with fineneedle aspirates in both children and adults have confirmed the safety of the technique.l6s3I Historically, diagnosis using FNAB was based primarily on cytologic appearance with conventional stains and light microscopy. In adult patients with a higher prevalence of carcinomas, FNAB is a popular method of confirming the presence of malignancy in suspicious lesions. In adults, a diagnosis of carcinoma and determination of the primary site are often sufficient to make initial treatment decisions. However, given the fact that multimodality therapy is histiotype specific in pediatric patients, FNAB is used less frequently in children. The recent application

CORE NEEDLE BIOPSY The obvious advantage of core needle biopsy over FNAB is that it provides a large enough sample to allow histologic examination rather than only cytologic examination. Additionally, it can provide sufficient tissue for molecular evaluation. Despite the widespread use of this technique in adults, its application in children is not as common. Several series have reported the efficacy and safety of this technique in more than 280 ~ h i l d r e n . ~ ~ , ~ ~ , ~ ~ , ~ ~ Various core needle devices may be used, typically ranging in size from 14 gaugeM 4 0 18 gauge.lg Needles are designed so that a cutting sheath advances over the core of the needle to obtain a tissue biopsy that is protected within the sheath as the needle is withdrawii. This cutting sheath may be advanced either manually (e.g., Tru-Cut by Allegiance) or by a spring-loaded firing system (e.g., Monopty by Bard) (Fig. 26-1). There are no data directly comparing the quality of specimens obtained with these two types of systems in pediatric malignancies. The faster deployment of the spring-loaded systems may

CHAPTER

Two commonly used core needle biopsy devices. The upper device is a 14gauge Tru-Cut needle (Allegiance). It is advanced into the region of interest, and then the inner needle is advanced. The outer sheath is manually advanced over the inner needle to obtain a core. The lower device is a 16-gauge Monopty biopsy device (Bard). I t is spring-loaded and is activated after the tip is advanced into the region of interest. The spring-loaded mechanism automatically sequentially advances the obturator and the cannula.

result in less crush artifact, which has been demonstrated in pediatric kidney biopsies." Regardless of the system used, visual inspection of the core biopsy is necessary to verify adequate sampling. Many patients in these series required only a single pass to acquire adequate tissue. Repeated passes were made if inadequate initial samples were obtained. Success with core needle biopsy has been demonstrated in a wide variety of anatomic locations, including the neck, mediastinum, lung, peritoneal cavity, liver, retroperitoneum, kidney, adrenal gland, pelvis, and extremitie~.l"s~~~~~s* The diagnostic accuracy in malignant disease observed in four series is summarized in Table 261. The sensitivity of the biopsy technique is acceptable, but there were clearly problematic cases in which the incorrect diagnosis was made. These inaccuracies may have been avoidable with additional clinical history19 or additional sampling. In some of the discordant cases, the uncertainty of the diagnosis was recognized immediately and addressed with repeat percutaneous or open biopsy. Core needle biopsy tends to be more accurate in detecting metastasis or recurrence than for obtaining the initial diagnosis.

Author/Year

No. of Patients (Total/Malignancy)

Klose et a134/1991 Somers et a154/1993

39/16 25/23

Skoldenberg et a151/2002 Guimaraes et a119/2003

110/84 54/54

82 82

Biopsy Techniques for Children with Cancer

439

No patients in these series suffered procedure-related death or required operative intervention for procedural complications. One series reported a significant decrease in hematocrit requiring transfusion in 3% of core needle biopsy procedures, and 10% of patients undergoing a transthoracic biopsy required a thoracostomy tube.s1 Given the risk of pneumothorax and the variability of lesion position with respiration, core needle biopsy of pulmonary lesions merits special consideration. Connolly et al.l0 reported their experience with core needle biopsy of small lung lesions in children in 1999. Biopsies were performed under CT guidance with a coaxial needle system while the child was under general anesthesia. All imagmg studies and biopsies were performed on complete exhalation. Adequate core tissue samples were obtained for diagnosis in 83% of patients, with the average size of the lesion being 9 mm. When adequate cores were not obtained, aspiration cytology was performed and raised the overall diagnostic yield to 94%. Twenty-seven percent of patients had small pneumothoraces, but none were symptomatic or required drainage. Needle track tumor recurrence represents an oncologic complication specific to this biopsy technique. Estimates of - , this complication in adults vary widely, ranging from 3.4%in hepatocellular carcinomas3 to 0.01% in thoracic tumor^.^ The incidence of this complication is influenced by several factors. Immunologic, chemotherapeutic, and radiotherapeutic effects decrease the likelihood of needle track recurrence. The larger needles used for core needle biopsies are associated with a greater risk than are the fine needles used for aspiration.Z1 There are two reported cases of needle track recurrence in children with Wilms' tumors.*

MINIMAL-ACCESS SURGERY The widespread use of minimal-access surgery, including laparoscopy and thoracoscopy, has had a significant impact on general pediatric surgery over the last 15 years. Both techniques are now being used in cancer diagnosis and therapy. Gans and BerciI4reported their initial experience with multiple endoscopic techniques in children in 19'71. Interestingly, one of the chief applications of peritonoscopy that they advocated was to guide the biopsy of metastatic implants. The application of both laparoscopy and thoracoscopy has now grown to include the initial diagnosis of childhood malignancies and the assessment of refractory or metastatic disease.

Sensitivity (%) 100 88

26

Comments Correct histiogenetic classification in all tumors 4 discordant cases, including neuroblastoma diagnosed as ganglioneuroma 1 6 cases failed to yield diagnosis due to inadequate specimen In 4 cases, initial interpretation was changed, including Wilms' tumor diagnosed as neuroblastoma

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Laparoscopy Laparoscopy affords several advantages in the evaluation of the abdominal cavity in children with cancer. First, it provides the opportunity to examine the entire peritoneal cavity and perform a systematic examination of all peritoneal surfaces. The entire length of the bowel can be examined, along with its mesentery and lymph nodes. Multiple biopsies can easily be obtained. The second chief advantage of laparoscopy is the decreased physiologic stress it produces in these children, who may already be critically ill. Finally, as in all minimally invasive procedures, postoperative pain is reduced and recovery is hastened.'Vhe chief disadvantages of laparoscopy are the limited ability to assess retroperitoneal structures and the loss of tactile evaluation of deep lesions. Diagnostic laparoscopy and biopsy have been used in several settings in the management of children with solid malignancie~."~~ Biopsies obtained using laparoscopic techniques have a high rate of success in yielding diagnostic tissue.'"47 1,aparoscopy allows the surgeon to obtain larger tissue samples than may be obtained with core needle biopsy. This is particularly relevant if larger samples are required for biologic studies. In the initial diagnosis, laparoscopy aids in identifying the site of origin of large abdominal masses. Laparoscopy is superior to CT in assessing intraperitoneal neoplasms and for the evaluation of ascites.7 For example, laparoscopy allows the direct determination of whether a pelvic mass arises from the ovary or the bladder neck, which may be difficult to distinguish by radiologic studies. Direct visualization via laparoscopy has been used to assess the resectability of hepatobla~toma.2~ During the course of treatment, laparoscopy may be used to assess for new metastatic disease or to assess for initial tumor response as a secondlook procedure. One area of concern about the use of laparoscopy in cancer patients is port site recurrence. This complication has been observed in a variety of adult malignancies, most notably in adenocarcinoma of the colon and gallbladder.40This complication is most frequently reported after resection of an unexpected gallbladder carcin~ma.~%ases of port site recurrence have also occurred in adults after the resection of liposarcoma2bnd cervical carcinoma.' More recent reports cite a very low rate of port site recurrence in adult patients with upper gastrointestinal") and renal malignancies.15 Data are relatively limited concerning this issue in children. The COG retrospective study of 85 children noted no port site recurrences.Z4 In a survey of Japanese pediatric laparoscopic surgeons, there were no port site recurrences following 85 laparoscopic and 44 thoracoscopic procedures.27 It should be noted, however, that 104 of these tumors were neuroblastomas, with many being detected by mass screening; the general applicability of these data may therefore be limited. Given the differences in tumor biology between adult adenocarcinomas and pediatric neoplasms,which often have a marked response to neoadjuvant therapy, it is difficult to generalize from the adult literature. Certainly, additional surveillance for port site recurrence of pediatric tumors is merited.

Laparoscopy in children is typically performed under general anesthesia to facilitate tolerance of pneumoperitoneum. The only absolute contraindication to laparoscopic evaluation is cardiopulmonary instability that would prevent safe insufflation of the peritoneal cavity. The supine position is used most commonly and affords a complete view of the peritoneal cavity. To facilitate visualization, a 30-degree laparoscope is used, along with at least two additional ports for manipulation and retraction. Ascites should be collected for cytologic analysis, and all peritoneal surfaces should be inspected. Incisional biopsies can be performed using laparoscopic scissors. Hemostasis is achieved using a combination of electrocautery and hemostatic agents (as discussed later in the section on open incisional biopsy) or by tissue approximation via laparoscopic suturing. Biopsy specimens are typically retrieved using a specimen bag. This reduces the chance of specimen destruction during retrieval and may decrease the risk of port site recurrence. Cup biopsy forceps can be used to obtain specimens as well. Core needle biopsies can be directed by laparoscopy and used to sample retroperitoneal, intraperitoneal, or hepatic masses. For deep-seated tumors, such as intrahepatic lesions, laparoscopic ultrasonography can be used to guide biopsy procedures and to compensate for the inability to palpate tissues."sx Complications associated with the laparoscopic dia<posis and treatment of solid tumors in children are infrequent. The need to convert to an unplanned open operation has similarly been low.24,2X,4x

Thoracoscopy Thoracoscopy was first reported by Jacobus in 1910 as a technique for the lysis of pleural adhesions resulting from tuberculosis. The initial experience with its use in children was reported by Rodgers and Talbert in 1976.4? They described nine children, including two oncology patients (Ewing's sarcoma and recurrent Hodgkin's lymphoma). Since this initial report, thoracoscopy has become widely used for the evaluation of thoracic lesions in children, for several reasons. Primarily, postoperative pain associated with thoracoscopic biopsy or resection is markedly decreased compared with conventional open thoracotomy. Moreover, thoracoscopy allows near-complete visualization of all parietal and visceral pleural surfaces, which cannot be accomplished with a thoracotomy. Additionally, in most children, the mediastinum does not contain a significant amount of adipose tissue and therefore can be inspected thoracoscopically. Although primary neoplasms of the lung are rare in children, pulmonary lesions are often a confounding issue in the treatment of children with cancer."?he most common tumor to have early pulmonary metastases is Wilms' tumor. Pulmonary metastases are also common with bone and soft tissue sarcomas, hepatic tumors, teratocarcinomas, and melanomas. Thoracoscopy is frequently used to evaluate for metastases either at the time of initial diagnosis or after follow-up imaging. A common clinical scenario is difficulty in distinguishing an opportunistic

CHAPTER

A

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Biopsy Techniques for Children with Cancer

441

B

Computed tomography (CT) scans obtained at the time of diagnosis of a new abdominal mass in a 5-year-old boy. A, Abdominal and pelvic CT scans show a large leftsided renal mass. B, Chest CT scan demonstrates a single 8-mm pulmonary nodule in the left upper lobe. No other pulmonary lesio~lswere identified. At the time of nephrectomy, a thoracoscopic excisional biopsy of the lung lesion was performed. Final pathology of the kidney demonstrated a stage I1 favorable-histology Wilms' tumor, and the lung pathology showed a hyalini~edgranuloma.

infection from new metastatic lung disease during the course of therapy. In areas with endemic granulomatous disease, thoracoscopy can also be helpful at the time of diagnosis (Fig. 26-2). The diagnostic accuracy of thoracoscopic biopsies in this setting is very high.44,47,4*,j" Mediastinal lesions can also be biopsied or resected '~~~ provides clear using t h o r a c o ~ c o p y . ~Thoracoscopy visualization of both the anterior and posterior mediastinum, even in small children, and we prefer it over mediastinoscopy for the evaluation of mediastinal lesions in children. The only absolute contraindications to thoracoscopy are complete obliteration of the pleural space and inability to tolerate single-lung ventilation when complete collapse of the lung is required. Thoracoscopy in children is typically performed under general anesthesia with mechanical ventilation. Visualization is facilitated by single-lung ventilation, if possible, and supplemented with insufflation. In older children, this may be accomplished with a double-lumen endotracheal tube. In smaller children, the left lung can be isolated by right mainstem bronchial intubation. Left mainstem intubation is difficult, and the tube frequently dislodges into the right side with positioning. Right lung deflation is performed by endotracheal intubation and right bronchial occlusion with either a dedicated bronchial blocker or a Fogarty catheter placed using rigid bronchoscopy. Fogarty catheter size is based on age: #3 for patients 4 years and younger and #5 for those i s be inflated and deflated aged 5 to 12 y e a r ~ . ~ q hmay during the procedure as needed. If selective ventilation is difficult to achieve or poorly tolerated by the patient, low-pressure insufflation (5 to 10 cm of water pressure) with carbon dioxide will assist with visualization. The anesthesiologist must monitor for any adverse effects from this controlled tension pneumothorax. It can

be rapidly evacuated if necessary but is typically well tolerated. Typically, the child is placed in lateral thoracotomy position. Hyperextension of the chest increases the intercostal space and facilitates movement of the thoracoscopy ports. This positioning should be adjusted for mediastinal lesions. For anterior lesions, a more supine position is used; for posterior lesions, the patient is positioned more prone. The initial port is placed at the midaxillary line using blunt dissection. Additional ports are placed under thoracoscopic guidance at sites based on the location of the lesion of interest. A 30-degree thoracoscope is helpful in achieving complete visualization of all pleural surfaces. Complete inspection is also facilitated by the use of multiple port sites. Careful correlation to cross-sectional imaging is essential to successful thoracoscopic sampling, particularly of smaller lesions. Pleura-based or subpleural pulmonary lesions are often apparent when the lung is deflated. These can be resected using endoscopic stapling devices and retrieved using specimen bags. Identification of deeper lesions is more challenging. After complete collapse of the lung, palpation of the parenchyma allows the identification of larger lesions. Biopsy of smaller lesions can be based on anatomic location if CT localization is specific, such as apical, lingular, or basilar lesions. CT-guided localization may be performed preoperatively with placement of a fine wire23 or injection of methylene blue4%r stained autologous blood.36 These localization techniques have been very effective in obtaining accurate diagnoses in ~hildren."9~4" Intrathoracic ultrasonography may be helpful in localizing deeper parenchymal lesions.53However, this technique is not widely used, and assessment of its efficacy in children is limited. In the future, image-guided biopsies will likely be accomplished with intraoperative magnetic resonance imaging or CT guidance.

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After sampling of the tissues is completed, the pneumothorax can be evacuated with a small catheter placed on water seal. Unless extensive pulmonary biopsies are performed or the lung is otherwise diseased, a thoracostomy tube is not required. Most children can be discharged the next day, and chemotherapy can be started pr0mptly.~6 Thoracoscopic techniques are highly effective in achieving a diagnosis. Most pediatric series report success in obtaining accurate diagnostic tissue in almost licatio diagnostic ns thoraall ~ a s e s . 2 4 , ~ ~ ~ ~ ~ ~ ~ W o m pduring coscopy are rare. Pneumothorax or persistent air leak may occur in children with underlying parenchymal lung disease or those requiring high-pressure ventilatory support. There is the potential for injury to subdiaphragmatic organs during initial trocar placement owing to elevation of the diaphragm during single-lung ventilation.

OPEN INCISIONAL BIOPSY Incisional biopsy remains the gold standard with regard to the quality of tissue sampling if complete excision will not be performed. Laparotomy or thoracotomy allows large samples to be obtained under direct vision, which can provide improved diagnosis compared with needle biopsies. For example, in the National Wilms' Tumor Study Group-4, open biopsy was more successful than core needle biopsy at identifying anaplasia.22 Correlation with preoperative imaging allows multiple samples to be obtained if there is inhomogeneity within the tumor that causes concern about sampling error. The ability to obtain larger specimens is beneficial not only in providing tissue for molecular diagnosis and prognosis but also in providing samples for tissue banking and creation of cell lines. Samples obtained from these biopsies provided the clinical material that allowed the development of the molecular diagnostic and prognostic techniques referred to earlier. Further stratification of risk, to allow more precise risk-based therapy, remains a major focus for pediatric oncology trials. Finally, specimens that are tissue-banked from these larger specimens can be used for investigational therapies, such as vaccines, in individual patients. There are several important factors when performing an open biopsy. The initial biopsy should take into consideration the ultimate operative treatment of the tumor. For example, the incision for biopsy of an extremity mass should be oriented parallel to the axis of the limb, and care should be taken to avoid undermining subcutaneous or fascia1planes. This allows subsequent wide local excision to be performed, with minimal additional resection of tissue owing to the biopsy. Likewise, testicular masses should be biopsied only through an inguinal approach; a scrota1 biopsy incision could require the addition of a hemiscrotectomy to the subsequent orchiectomy. Laparotomy for biopsy should be planned to allow subsequent resection through extension of the same incision. Significant distortion of anatomic relations can occur with large retroperitoneal tumors, and attention must be paid to avoid injury to structures such as the ureters, bile

duct, or major vascular structures that may be distracted over the mass. The most common intra-abdominal tumors in children tend to be vascular, and bleeding from the biopsy site is the most common serious complication. Strategies to reduce perioperative hemorrhage include normalization of coagulation parameters preoperatively and adequate operative exposure. Cauterization of the tumor capsule may help control bleeding, but we have found that direct pressure after packing the biopsy site with oxidized cellulose, combined with procoagulants (described later), is more efficient than generous cautery of the biopsy base. If possible, closure of the tumor capsule can aid with hemostasis. Supplements to achieve hemostasis can include topical agents, fibrin sealants, and recombinant factor VIIa. Commercially available topical products include gelatin foam pads, microfibrillar collagen, and oxidized cellulose, which is available as fabric and cottonoid. Fibrin sealants are composed of fibrinogen, thrombin, and calcium; mixture of these components as they are delivered to the tissue results in the rapid formation of a fibrin clot.46 Recombinant factor VIIa was originally developed to treat patients with hemophilia who had developed inhibitors; however, it has increasingly been used to treat patients with severe bleeding without a preexisting bleeding disorder. There are numerous reports of its use in trauma and a randomized trial showing its efficacy in radical prostate~tomy.~" Its effective use to control hemorrhage after biopsy of a hepatoblastoma has been reported," and we have had success in controlling bleeding from a hepatic metastasis from Wilms' tumor. This is an expensive therapy, and although its risks are poorly characterized, initial experience suggests a low rate of thromboembolic complications.~ One of the important roles of a surgeon is providing adequate tissue for diagnosis and risk stratification. Traditionally, the open biopsy served this purpose extremely well and can be accomplished with low morbidity. In the future, the need for open biopsy will diminish with further advances in molecular diagnosis that require only small tumor specimens or perhaps no biopsy of the primary tumor at all. A thorough understanding of the potential diagnoses and their treatment, as well as coordination between the surgeon and oncologist, is critical to determining the appropriate approach in each individual patient.

REFERENCES 1. Abramowicz, M: Novoseven for nonhemophilia hemostasis. Med Lett 2004;46:1181. 2. Agostini A, et al: Port site metastasis after laparoscopy for uterine cervical carcinoma. Surg Endosc 2003;17: 1663-1665. 3. Akhtar M, et al: Fine-needle aspiration biopsy diagnosis of small round cell tumors of childhood: A com~rehensive approach. Diagn Cytopathol 1999;21:81-91. 4. Aslam A, Spicer RD: Needle track recurrence after biopsy of non-metastatic Wilms' tumor. Pediatr Surg Int 1996;ll: 416417. 5. Ayar D, et al: Needle-track metastasis after transthoracic needle biopsy. J Thorac Imaging 1998;13:2-6.

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6. Barro C , et al: Successful use of recombinant factor VIIa for severe surgical liver bleeding in a 5-month-old baby. Haemophilia 2004;10:183-185. 7. Barth RA, et al: A comparison study of computed tomography and laparoscopy in the staging of abdominal neoplasms. Dig Dis Sci 1981;26:253-256. 8. Berber E, Siperstein AE: Laparoscopic ultrasound. Surg Clin North Am 2004;84:1061-1084. 9. Bown N: Neuroblastoma tumour genetics: Clinical and biological aspects. J Clin Pathol 2001;54:897-910. 10. Connolly BL, et al: CT-guided percutaneous needle biopsy of small lung nodules in children. Pediatr Radiol 1999;29: 342-346. 11. Dagher R, et al: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 2001;23:221-224. 12. Dodd LG, et al: Utility of fine-needle aspiration in the diagnosis of primary osteosarcoma. Diagn Cytopathol 2002;27:350-353. 13. Friederich PW, et al: Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: A double-blind placebwontrolled randomised trial. Lancet 2003;361:201-205. 14. Gans SL, Berci G: Advances in endoscopy of infants and children. J Pediatr Surg 1971;6:199-233. 15. Gill IS, et al: Laparoscopic radical nephrectomy in 100 patients: A single center experience from the United States. Cancer 2001;92:1843-1855. 16. Gonzalez-Campora R: Fine needle aspiration cytology of soft tissue tumors. Acta Cytol 2000;44:337-343. 17. Grieg ED, Gray AC: Lymphatic glands in sleeping sickness. BMJ 1904;1:1252. 18. Grosfeld JL: Risk-based management of solid tumors in children. Am J Surg 2000;180:322-327. 19. Guimaraes AC, et al: Computed tomography-guided needle biopsies in pediatric oncology. J Pediatr Surg 2003; 38: 10661068. 20. Gurley AM, et al: The utility of ancillary studies in pediatric FNA cytology. Diagn Cytopathol 1992;8:137-146. 21. Haddad FS, Somsin AA: Seeding and perineal implantation of prostatic cancer in the track of the biopsy needle: Three case reports and a review of the literature. J Surg Oncol 1987;35:184191. 22. Hamilton TE, et al: Open biopsy is superior to needle for detection of anaplasia in patients with Wilms' tumor. Paper presented at the American Pediatric Surgical Association meeting, 2004. 23. Hanninen EL, et al: Computed tomography-guided pulmonary nodule localization before thoracoscopic resection. Acta Radiol 2004;45:284288. 24. Holcomb GW 3rd, et al: Minimally invasive surgery in children with cancer. Cancer 1995;76:121-128. 25. Horiguchi A, et al: Port site recurrence after laparoscopic resection of retroperitoneal liposarcoma. J Urol 1998; 159:1296-1297. 26. Howell LP: Changing role of fine-needle aspiration in the evaluation of pediatric masses. Diagn Cytopathol 2001;24:65-70. 27. Iwanaka T, et al: No incidence of port-site recurrence after endosurgical procedure for pediatric malignancies. Pediatr Surg Int 2003;19:200-203. 28. Iwanaka T, et al: Endosurgical procedures for pediatric solid tumors. Pediatr Surg Int 2004;20:39-42. 29. Jereb B, Us-Krasovec M,Jereb M: Thin needle biopsy of solid tumors in children. Med Pediatr Oncol 1978;4:213-220. 30. Kilpatrick SE, Garvin AJ: Recent advances in the diagnosis of pediatric soft-tissue tumors. Med Pediatr Oncol 1999;32: 373-376.

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31. Kilpatrick SE, et al: Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients. Am J Clin Pathol 2001;115:59-68. 32. Kilpatrick SE, et al: The role of fine needle aspiration biopsy in the diagnosis and management of osteosarcoma. Pediatr Pathol Mol Med 2001;20:175-187. 33. Kim SH, et al: Needle-tract implantation in hepatocellular carcinoma: Frequency and CT findings after biopsy with a 19.5-gauge automated biopsy gun. Abdom Imaging 2000; 25:246-250. 34. Klose KC, et al: CT-guided percutaneous large-bore biopsies in benign and malignant pediatric lesions. Cardiovasc Intervent Radiol 1991;14:78-83. 35. Liu ES, et al: Fine needle aspiration biopsy of pediatric head and neck masses. Int J Pediatr Otorhinolaryngol 2001;60:135-140. 36. McConnell PI, Feola GP, Meyers RL: Methylene blue-stained autologous blood for needle localization and thoracoscopic resection of deep pulmonary nodules. J Pediatr Surg 2002; 37: 1729-1731. 37. Mobley DL, Wakely PE Jr, Frable MA: Fine-needle aspiration biopsy: Application to pediatric head and neck masses. Laryngoscope 1991;I01:469-472. 38. Montorsi M, et al: Laparoscopy with laparoscopic ultrasound for pretreatment staging of hepatocellular carcinoma: A prospective study.J Gastrointest Surg 2001;5:312-315. 39. Mora J, Gerald WL, Cheung NK: Evolving significance of prognostic markers associated with new treatment strategies in neuroblastoma. Cancer Lett 2003;197:119-124. 40. Paolucci V, et al: Tumor seeding following laparoscopy: International survey. WorldJ Surg 1999;23:989-995,discussion 996-997. 41. Pappo AS, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123-2139. 42. Partrick DA, Rothenberg SS: Thoracoscopic resection of mediastinal masses in infants and children: An evaluation of technique and results. J Pediatr Surg 2001;36:1165-1167. 43. Partrick DA, et al: Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization. J Pediatr Surg 2002;37:970-973, discussion 970-973. 44. Rao BN: Present day concepts of thoracoscopy as a modality in pediatric cancer management. Int Surg 1997;82:123-126. 45. Rodgers BM, Talbert JL: Thoracoscopy for diagnosis of intrathoracic lesions in children. J Pediatr Surg 1976;ll: 703-708. 46. Rousou J, et al: Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations: A multicenter study. J Thorac Cardiovasc Surg 1989;97:194203. 47. Saenz NC, et al: The application of minimal access procedures in infants, children, and young adults with pediatric malignancies. J Laparoendosc Adv Surg Tech A 1997;7: 289-294. 48. Sailhamer E, et al: Minimally invasive surgery for pediatric solid neoplasms. Am Surg 2003;69:56&568. 49. Schaeff B, Paolucci V, Thomopoulos J: Port site recurrences after laparoscopic surgery: A review. Dig Surg 1998;15:124134. 50. Shoup M, et al: Port site metastasis after diagnostic laparoscopy for upper gastrointestinal tract malignancies: An uncommon entity. Ann Surg Oncol 2002;9:632-636. 51. Skoldenberg EG, et al: Diagnosing childhood tumors: A review of 147 cutting needle biopsies in 110 children. J Pediatr Surg 2002;37:50-56. 52. Smith MB, et al: A rational approach to the use of fine-needle aspiration biopsy in the evaluation of primary and recurrent neoplasms in children. J Pediatr Surg 1993;28:1245-1247.

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53. Smith MB, et al: A prospective evaluation of an endoscopic ultrasonic probe to detect intraparenchymal malignancy at pediatric thoracoscopy. J Laparoendosc Surg 1996;6: 233-237. 54. Somers JM, et al: Radiologically-guided cutting needle biopsy for suspected malignancy in childhood. Clin Radio1 1993;48:236-240. 55. Tan GM, Tan-Kendrick AP: Bronchial diameters in childrenuse of the Fogarty catheter for lung isolation in children. Anaesth Intensive Care 2002;30:615-618.

56. WaldhausenJH, Tapper D, Sawin RS: Minimally invasive surgery and clinical decision-making for pediatric malignancy. Surg Endosc 2000;14:250-253. 57. Weinstein JL, Katzenstein HM, Cohn SL: Advances in the diagnosis and treatment of neuroblastoma. Oncologist 2003;8:278-292.

Wilms' Tumor Edward PTagge, Patrick B. Thomas, and H. Biemann Othersen, Jr.

Wilms' tumor continues to be a subject of intense interest, involving both clinical and basic science investigations. With the aid of five cooperative protocols by the National Wilms' Tumor Study Group ( M S G ) , there has been marked improvement in survival. In the fourth NWTSG study ( M S - 4 ) , the 2-year relapse-free survival rate for children with low-risk Wilms' tumor exceeded 91%.60 However, there continue to be a variety of unsolved problems. Anaplastic tumors, clear cell sarcomas of the kidney, and rhabdoid tumors of the kidney are still relatively resistant to therapy. Ten percent of patients have prognostic variables, including unfavorable histology, chromosomal loss on l p and 16q, and diploidy. Patients with lung or liver metastases, major tumor spillage during resection, remote lymph node involvement, and bilateral tumors all have worse outcomes. In addition, there is an increasing appreciation of the long-term morbidity of successful cancer therapy in children. Finally, the underlying molecular basis of Wilms' tumor is quite complex and remains unclear. This chapter briefly summarizes the new information available, focusing on the conclusions of NWTS-4, a preliminary discussion of the results of NWTS-5, and an overview of future directions in Wilms' tumor management.

HISTORY Pathologic descriptions of the tumor now known as nephroblastoma were written as early as 1872.44In 1879 Osler realized that physicians were reporting renal tumors in children and giving them different names, though they were all describing the same type of solid tumor.l()Theclassic article was presented in 1899 when Wilms (a surgeon) reviewed the literature and added seven cases of his own, describing the clinical picture that now bears his name.'" Initially, surgical excision was the only therapeutic option, but the prognosis was grim. However, in 1916 radiation therapy was added by Friedlander,5()and Ladd improved the surgical technique, increasing the survival rate to 20%.8Whemotherapywith actinomycin D and vincristine was eventually added, and this combination of surgical excision, postoperative

irradiation, and chemotherapy ushered in the modern era, with a 2-year survival rate of 81% Because Wilms' tumor is an infrequent occurrence in the United States, it was realized that collaborative research was mandatory to obtain statistically significant numbers of patients. Thus the NWTSG was established in 1969. The original membership included institutions from the Children's Cancer Study Group, the Pediatric Division of the Southwest Oncology Group, and the Pediatric Division of the Cancer and Leukemia Group B. The initial goals of the M S G were to improve the survival of children with Wilms' tumor and other renal tumors, to study the long-term outcome of children treated successfully by identifying adverse effects, to study the epidemiology and biology of Wilms' tumor, and to make information regarding successful treatment strategies for Wilms' tumor available to physicians around the world. The therapeutic studies conducted by the NWTSG eventually involved more than 250 pediatric oncology treatment centers in the United States, Canada, and several other countries. During its final years, approximately 450 to 500 patients with Wilms' tumor were entered annually, including 70% to 80% of all cases in the United States. In 2001 the NWTSG merged with the Children's Cancer Group, the Pediatric Oncology Group (POG), and the Intergroup Rhabdomyosarcoma Study Group to form a new national organization, the Children's Oncology Group (COG). Patient entry into the NWTSG clinical trial protocols was completed in 2002, and future clinical trials will be conducted by the renal disease committee of the COG. The "NWTS" designation will still be used for the continuing study of late effects.

EPIDEMIOLOGY Worldwide, Wilms' tumor affects approximately 1 child per 10,000 younger than 15 years.l"I9 Wilms' tumor represents approximately 6% of childhood cancers in the United States, and the total incidence is estimated at 450 to 500 cases a year." Incidence rates appear to be slightly elevated for blacks (both American and African) in comparison to whites but are only half as great among Asians.

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Several case-control studies have suggested that paternal occupation, maternal hormone exposure during pregnancy, or genetic predisposition may increase the risk for Wilms' tumor. The median age at onset is 38 months in the NWTS series, with the onset in girls occurring on average 6 months later than in boys. Patients with bilateral tumors, aniridia, cryptorchism or hypospadias, Beckwith-Wiedemann syndrome, or intralobar nephrogenic rests tend to be diagnosed much younger than average (median age, 17 to 27 months). Those with familial disease or multicentric tumors have intermediate age-at-onset distributions, whereas those with perilobar nephrogenic rests are diagnosed at older ages. Wilms' tumor shows a strong association with certain congenital anomalies: WAGR syndrome (Wilms' tumor, aniridia, genitourinary malformations, and mental retardation), Beckwith-Wiedemann syndrome (an overgrowth syndrome characterized by exomphalos, visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia), and hemihypertr~phy.~~ Urologic anomalies, such as lobular nephromegaly, hypospadias, and cryptorchidism, are often seen with Wilms' tumor. WAGR syndrome is a rare genetic disorder and is associated with a defect in chromosome llp13. Most children with WAGR syndrome are diagnosed at birth because the aniridia is usually obvious. However, less than 1% of children with Wilms' tumor have WAGR syndrome. Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Some of the svoradic cases are caused by large chromosomal deletions involving the Wilms' tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms' tumor. A recent review of cancer and aniridia cases found that patients with sporadic aniridia have a relative risk of 67 (confidence interval, 8.1 to 241 ) of developing Wilms' tumor.66 Denys-Drash syndrome is characterized by pseudohermaphroditism, progressive glomerulopathy, and Wilms' tumor. Genetically it is associated with mutations of the Wilms' tumor 1 ( W T I )gene. More than 90% of patients with Denys-Drash syndrome who carry constitutional intragenic W T l mutations are at high risk for the development of Wilms' tumor. In fact, prophylactic bilateral nephrectomy in two patients with missense mutations in the WTI gene was recently reported.75 A small percentage of Wilms' tumors are familial in nature. The pattern of transmission for hereditary Wilms' tumor is likely autosomal dominant, with incomplete and variable penetrance.lsJl2 Although some familial cases involve mutations in WTI, more are associated with the familial Wilms' tumor genes FWTl at 17q and FWT2 at 19q, for which fine-scale mapping is currently in progress.

MOLECULAR BIOLOGY AND GENEilCS The development of Wilms' tumor is thought to involve changes in a number of genes that function to control

normal kidney development and growth." Roughly 2% of children diagnosed with Wilms' tumor have a relative who was also diagnosed with Wilms' tumor. The occurrence of these rare Wilms' tumor families suggests that an altered gene is important in the development of this nephroblastic tumor. Other factors point to the importance of an underlying genetic predisposition. Wilms' tumors can occur bilaterally in approximately 5% to 10% of affected children.Z9 In addition, nephrogenic rests, potentially premalignant lesions, are found within the kidneys of 30% to 40% of children with Wilms' tumors. Wilms' tumor is an important model for the study of fundamental mechanisms of carcinogenesis. Statistical evidence to support the involvement of a tumor suppressor gene in the pathogenesis of Wilms' tumor was initially provided by Knudson and Strong in 1972.82According to Knudson's hypothesis of tumor suppressor genes, patients with a familial cancer syndrome inherit one chromosome with an inactive tumor suppressor gene locus because of germline mutation. The counterpart tumor suppressor gene on the remaining paired chromosome is subsequently inactivated by a somatic muration, leading to the formation of cancer. Knudson extended his famous two-hit model of carcinogenesis, originally proposed for retinoblastoma, to Wilms' tumor. In this model, children who were susceptible to retinoblastoma or Wilms' tumor were born with a constitutional DNA mutation in one allele of a presumed tumor suppressor gene-so-called loss of heterozygosity (LOH). Thus, only one new genetic event, the deletion or inhibition of the paired allele, would be needed for tumorigenesis to occur. This condition would increase the likelihood of bilateral tumor formation and an earlier age of onset compared with sporadic cases. subsequent review of chromosomal LOH revealed that the maternal allele was lost in 52 of 53 tumors demonstrating this trait.30 This surprising fact implies that chromos~malloss from a tumor is not a random event and that the alleles of the Wilms' tumor suppressor locus are not equivalent. This functional difference between the maternal and paternal alleles of a gene is termed genomic imprinting. However, the genetics of Wilms' tumor are even more complex than originally believed. More recent evidence suggests that some bilateral and multifocal Wilms' tumors may arise from somatic mosaicism rather than a germline mutation, contradicting the central tenet of the two-hit model.6 The biologic pathways leading to the development of Wilms' tumor involve several genetic loci, including two genes on chromosome 1lp--one on chromosome 1lp13 (the Wilms' tumor suppressor gene W T l ), and the other on chromosome 1lp15 (the putative Wilms' tumor suppressor gene WT2). In addition, loci at l p , 7p, 16q, and 17p (the p53 tumor suppressor gene) are believed to harbor genes involved in the biology of Wilms' tumor. More recent studies have localized two familial predisposition genes on chromosomes 19 and 17, but their actual identification is still ongoing. It is also known that predisposition in some families is due to neither WT1 nor the chromosome 19 or 17 genes, implying that other Wilms' tumor predisposition genes exist.

CHAPTER

The mapping of the genetic loci associated with Wilms' tumor resulted from a combination of clinical observations, karyotype analyses, and molecular genetic studies. In 1964 Miller et aLg8reported an association between aniridia and Wilms' tumor. Subsequently, the rare complex of developmental anomalies known as the WAGR syndrome was described, in which more than 30% of affected children developed Wilms' tumor.lol Karyotypic analvsis of those children demonstrated a deletion in the short arm of one copy of chromosome 11 at band 13.116 The observation that the rare WAGR syndrome was invariably associated with interstitial deletions of chromosome~llpl3,and that tumor tissue at this same locus often displayed LOH, ultimately led to the cloning of the first Wilms' tumor gene WTl.2O,52 WT1 is a complex gene encoded by 10 exons. Cells that express WTl produce four distinct WTI messenger RNAs (mRNAs), which reflect alternative splicing patterns of the transcription products of the WTl gene. The WTl protein is between 45 and 49 kD in size, depending on which mRNA splice variant is translated into protein. The carboxyl terminus of the WT1 protein contains four zinc finger domains, which is a protein motif known to facilitate binding to DNA in a sequence-specific pattern. This implies that WT1 is a transcriptional factor regulating yet unknown targeted genes. WT1 has important functions during genitourinary development, evidenced by its highly restricted temporal and spatial expression in glomerular precursors and by the failure of kidney development in WTl-null mice. In addition to its function in genitourinary development, a role in hematopoiesis is suggested by WTl's aberrant expression in a subset of acute human leukemias. WTI is also expressed in mesothelial cells; a specific oncogenic chromosomal translocation fusing the N-terminal domain of the Ewing's sarcoma gene EWS to the three C-terminal zinc fingers of WTl underlies desmoplastic small round cell tumor.86 Ninety percent of patients with the even rarer DenysDrash syndrome harbor germline mutations in WTl. Most are missense mutations resulting in single amino acid s u b stitutions. Microscopic examination of the kidney in patients with the WAGR and Denys-Drash syndromes often reveals intralobar nephrogenic rests.8 The existence of dominant negative mutations of WT1 is supported by the observation of specific constitutional mutations of WTI in children with Denys-Drash syndrome.31J09 Unlike children with the WAGR syndrome, in whom large deletions on 1lp13 are seen,loYthose with Denys-Drash syndrome have only point mutations of the WTl gene.losInterestingly, the phenotypic effects of these constitutional WTI mutations are far more severe than those resulting from complete deletion of WTl, suggesting that the altered WT1 protein in patients with Denys-Drash syndrome is dysfunctional and acts in a dominant-negative f a ~ h i o n . ~ , ~ ~ WTl is mutated in approximately 20% of all patients with Wilms' tumors. The frequency of germline WTl mutations in patients with bilateral Wilms' tumor and of detectable WTl mutations in Wilms' tumor specimens is low. Linkage at the WTl locus has been excluded in most

27

Wilms' Tumor

447

familial cases." Inherited WTI alterations have also been observed in a few small families with Wilms' tumor, but studies of large families have demonstrated that their inherited predisposition to Wilms' tumor is not due to an altered WTl gene. A recent review of cancer cases and aniridia in Denmark found that patients with sporadic aniridia have a relative risk of 67 (confidence interval, 8.1 to 241) of developing Wilms' tumor." However, patients with the WAGR syndrome or Denys-Drash syndrome each account for less than 1% of all children with Wilms' tumor. The role of WTl mutations in patients with unilateral Wilms' tumor not associated with congenital syndromes seems to be limited, because less than 15% have mutations of WTl.5l

In a subset of Wilms' tumors, LOH has been demonstrated for markers at the llp15 locus, with maintenance of heterozygosity for the llp13 Karyotypes of Wilms' tumors have demonstrated DNA loss at the llp15 locus. Here, several genes (IGF2, p577KIP2, H19, KVL.QT1) that regulate somatic growth are subject to dysregulated imprinting, including the gene for Beckwith-Wiedemann syndrome (BWS).This is the location for the putative second Wilms' tumor gene, WT2, which has yet to be cloned.85 BWS may result from overexpression of a gene at l l p 1 5 that normally has only the paternal copy of the gene expressed (a process called genomic imprinting). In fact, karyotypic analysis has demonstrated a constitutional duplication of the paternal l l p 1 5 chromosomal fragment in some children with BWS. Other children with the syndrome have two grossly normal copies of chromosome 11, both inherited from the father (thus there is no maternal copy)-a phenomenon called uniparental i ~ o d i s o m y .It~ is ~ ,believed ~~ that inheritance of two copies of the paternal gene for BWS would double the expression of this gene, resulting in the overgrowth features. Much interest has centered on insulin-like growth factor 2 (IGF2), which resides at llp15, as the candidate WT2 gene because it is subjected to genomic imprinting. However, to date, no direct evidence has implicated this factor in the pathogenesis of BWS or Wilms' tumor. Investigators in Japan identified a paternally expressed imprinted gene, PEG8/IGF2AS, in this locus.lo3It is transcribed in the opposite direction to the IGF2 transcripts, and some gendkic regions are shared with the I G F ~ gene. Interestingly, PEG8/IGF2AS and IGF2 were found to be overexpressed in Wilms' tumor samples, at levels 10 to 100 times greater than in normal kidney tissue neighboring the tumors. These findings imply that PEG8/IGF2AS may be a marker for Wilms' tumor and also suggest the possibility that PEG8/IGF2AS is one of the candidate ~ i l m stumor ' genes.

Additional Wilms' Tumor Loci The existence of an additional Wilms' tumor locus on the long arm of chromosome 16 (16q) has been suggested by

448

PART

III

MAJOR TUMORS OF CHILDHOOD

tumor LOH for 16q in approximately 20% of Wilms' tumor specimens (compared with a 5% background rate).?#-78.9"Preliminary analysis by Grundy et al.69 in 232 patients with Wilms' tumor suggested the LOH for 16q was a statistically important adverse prognostic factor. When compared with patients without LOH, the relapse rate was 3.3 times higher ( P = 0.01), and the mortality rate was 12 times higher ( P < 0.01), in patients with LOH for 16q. The same study also reported LOH for l p in 12% of Wilms' tumor patients, along with relapse and mortality rates that were three times higher than for patients without l p LOH (not statistically significant). Because of these data. NWTS5 studied the effect of LOH for 16a and l p on the prognosis for Wilms' tumor patients. Linkage analyses in four large families with an inherited susceptibility to Wilms' tumor have implicated the existence of yet another Wilms' tumor Genes at 1lp13, 1 lp15, and 16q have been determined not to play a role in the Wilms' tumors of those families, and detailed linkage analyses will be required to determine the chromosomal location of the familial Wilms' tumor gene. Glypican-3 (GPC3) is a heparan sulfate proteoglycan that can bind to growth factors, such as IGF2. One report noted increased exvression of GPC3 in Wilms' tumor and hepatoblastoma, suggesting a growth-promoting or neutral activity for this gene.l" Another study determined the presence of sequence variants of GPC3 in tumor and normal tissue from 41 male patients with Wilms' tumor.138 Two nonconservative single base changes were present in tumor tissue only, implying a possible role for GPC3 in Wilms' tumor develovment. Investigators from Columbia University performed a survey of gene expression in Wilms' tumor using oligonucleotide microarrays,87 identifylng 357 genes differentially expressed between Wilms' tumors and fetal kidneys. Wilms' tumors systematically overexpressed genes corresponding to the earliest stage of metanephric development and underexpressed genes corresponding to later stages. This signature set was enriched in genes encoding transcription factors PAX2I" and HOXA11, as well as the metastasis-associated transcription factor EMF.

CLINICAL PRESENTATION In the past, most children presented with an asymptomatic abdominal mass, usually noted by a family member (Fig. 27-1). The availability of modern imaging techniques, such as ultrasonography (US) and computed tomography (CT), has allowed the early evaluation of abdominal pain and the discovery of nonpalpable renal masses. Early symptoms include microscopic hematuria (in one third of patients) and other urinary disturbances, malaise, weight loss, and anemia. Occlusion of the left renal vein by tumor extension may obstruct the left spermatic vein, with a resultant varicocele. In addition, tumor thrombus may progress up the inferior vena cava into the heart (right atrium) and cause cardiac malfunction. Occasionally, an acute abdominal crisis occurs after rupture of a Wilms' tumor as a result of a relatively minor abdominal injury. The physical examination should include careful palpation of the abdomen and measurement of blood pressure.

.

. Large tumor mass in the superior portion of the kidney. The tumor bulge was felt by a visiting grandmother.

Wilms' tumor usually presents with a round, smooth, palpable flank mass. Patients with Wilms' tumor may have hypertension secondary to tumor production of renin or renal vascular compression by the mass. Finally, it is important to identify genitourinary anomalies and the presence of aniridia or hemihypertrophy.

DIAGNOSIS No definitive diagnostic blood or urine test for Wilms' tumor exists, although there has been interest in the diagnostic utility of vascular endothelial growth factor (VEGF),81hya1uronan:Z and basic fibroblastic growth factor (bFGF).? Advances in imaging technology have improved the ability to detect Wilms' tumor and its precursor, nephroblastomatosis, as well as the spread of tumor to other organs.55 However, in terms of imaging, there is still wide variation in clinical practice compared with the guidelines recommended by the NWTSG. The preferred radiologic method for evaluating children with suspected Wilms' tumor is CT (Fig. 27-2),with US particularly suited for the detection of venous extension. Magnetic resonance imaging (MRI) identifies blood vessel involvement, although it is not one of the NWTSG recommended preoperative studies (Fig. 27-3). CT of the abdomen may also identify lesions in the contralateral kidney or liver. A plain chest radiograph is taken to evaluate for pulmonary metastasis. CT of the chest is controversial because lesions not visible on radiographs but seen on CT are difficult to interpret. A recent study looked at whether identifylng minimal pulmonary metastatic disease by chest CT in patients with Wilms' tumors and normal

CHAPTER

Wilms' Tumor

449

B

A 9

27

-

A, Abdominal computed tomography scan demonstrating a large tumor mass in the left kidney. B, Bivalved left kidney with tumor.

chest radiographs could predict children at increased risk of pulmonary relapse.105 A retrospective analysis of 449 children entered into the United Kingdom Children's Cancer Study Group (UKCCSG) Second Wilms' Tumor Study between July 1986 and September 1991 was performed.

When only stage I patients were analyzed, there was a significant difference between the pulmonary relapse rate of 43% (3 of 7) in the CT-positive group and 10% (5 of 48) in the CT-negative group (P = 0.02). Importantly, 4 of 8 patients with stage I disease with pulmonary relapse died.

SCREENING Children with BWS and idiopathic hemihypertrophy are at increased risk for developing Wilms' tumor. A recent report evaluating patients from the BWS Registry and previously published studies noted that children with BWS and hemihypertrophy benefited from US screening at intervals of 4 months or less,24 although false-positive screening examinations did result in unnecessary surgery. The National Institutes of Health performed a costbenefit analysis of screening for Wilms' tumor and hepatoblastoma in children with BWS.Y%suming that US examinations were performed three times a year from birth until age 7 years, screening a child with BWS from birth until age 4 years resulted in a cost per life-year saved of $9,642; continuing until age 7 years resulted in a cost per life-year saved of $14,740.

PATHOLOGY

.

Coronal section of a magnetic resonance image demonstrating bilateral Wilms' tumors almost totally replacing normal kidney tissue. No vascular involvement was noted on this study.

The classic Wilms' tumor is composed of the three components seen in normal kidney differentiation: blastema, tubules, and stroma (Fig. 27-4). These components are believed to recapitulate the differentiation of the normal nephron unit. Classic Wilms' tumors are known to be heterogeneous with respect to component proportions and to exhibit aberrant adipose tissue, skeletal muscle, cartilage, and bone. Wilms' tumors may also contain only

450

PART

I I1

M q l o ~TUMORS OF CHILDHOOD

distribution of anaplasia and requires that anaplastic nuclear changes be confined to sharply restricted foci within the primary tumor. The overall incidence of anaplasia varies from 3.2% to 7.3%.14J41Anaplasia is rarely seen in tumors of patients younger than 2 years at diagnosis; its incidence increases to about 13% in patients older than 5 years." A higher incidence has recently been reported in female patients and in non-Caucasian patients.l4.'41 Anaplastic Wilms' tumors frequently show aneuploidy and mutations in the tumor suppressor gene p53.Il3

Clear Cell Sarcoma of the Kidney

.

Medium-power microscopic view ( ~ 1 0 0H&E ; stain) of Wilms' turnor with tripartite histology. Epithelial elements consist of tubules (lower right-hand portion of image) and abortive tubular structures. The majority of the slide contains cellular blastema with small round primitive cells with scant cytoplasm. The mesenchymal elements have a looser spindle cell configuration.

one of these components (monophasic Wilms' tumors); such tumors can be difficult to distinguish from other childhood tumors. Other renal tumors that may be clinically confused with Wilms' tumors are congenital mesoblastic nephroma, clear cell sarcoma of the kidney, and rhabdoid tumor of the kidney. Congenital mesoblastic nephromas are lowgrade spindle cell tumors that recur locally but rarely metastasize. Clear cell sarcomas and rhabdoid tumors initially were believed to be variants of Wilms' tumors, and they were included as "unfavorable histology" in NWTSI. However, with better histologic, immunohistochemical, and molecular characterization of these two tumors, it has been found that neither has a relationship to Wilms' tumors. Indeed, both types of tumors have distinct histopathologic characteristics, aggressive behavior, and a poor response to treatment. Although Wilms' tumors have an excellent prognosis, each of the three cellular components can exhibit focal or diffuse anaplasia, which is a major indicator of a poor outcome. The presence of anaplasia is currently the only criterion for "unfavorable histology" in a Wilms' tumor. Anaplasia denotes the presence of gigantic polypoid nuclei within the tumor sample. Recognition of this change requires both (1) nuclei with major diameters at least three times those of adjacent cells, with increased chromatin content; and (2) the presence of multipolar or otherwise recognizably polypoid mitotic figures. The criteria distinguishing focal from diffuse anaplasia were recently modified. The original definition of focal anaplasia was based on the amount of anaplasia present. Any tumor with anaplastic nuclear changes present in less than 10% of microscopic fields was originally designated as having focal anaplasia. This criterion permitted inclusion when anaplasia was present throughout the tumor, albeit at low density, and cases of anaplasia in extrarenal sites or in metastatic deposits. The new definition emphasizes the

Also known as "bone metastasizing renal tumor of childhood,"g4clear cell carcinoma of the kidney is a distinctive renal neoplasm of childhood that has a propensity for a more widespread pattern of metastases than Wilms' tumor, including bone, brain, and soft tissue. This tumor has a high rate of recurrence and mortality, and it is essential that this entity be recognized to facilitate the early administration of more effective chemotherapy regimens than those employed for Wilms' tumor. There are several variants of clear cell sarcoma of the kidney, including the classic pattern, the hyalinizing pattern, and the epithelioid pattern.

Rhabdoid Tumor of the Kidney Rhabdoid tumor of the kidney is a distinctive renal neoplasm most often encountered in infants younger than 1 year; it is uncommon in patients older than It is extremely aggressive and is the most 5 year~.6,1~~ prognostically unfavorable pediatric renal neoplasm. The most distinctive features of rhabdoid tumor of the kidney are large cells with large, vesicular nuclei (Fig. 27-5); a prominent single nucleolus; and the presence of cytoplasmic inclusions composed of whorled masses of intermediate filaments. Another distinctive feature is the aggressive, invasive pattern of this lesion (Fig. 27-6). Rhabdoid tumor of the kidney has a diverse immunohistochemical profile, and the same cell can be positive for many supposedly incompatible epitopes for epithelial, myogenous, neural, and mesenchymal cell types. Features that are helpful in identifying rhabdoid tumor of the kidney include the presence of hypercalcemia and widespread lymphogenous and hematogenous metastases in an infant.

Nephrogenic Rests In a kidney with Wilms' tumor, associated renal develop mental abnormalities called nephrogenic rests (nephroblastomatosis) are often present (Fig. 2777).These rests are small foci of persistent primitive blastemic cells that are normally found in neonatal kidneys.9 The kidneys of virtually all children with inherited susceptibility to Wilms' tumor contain nephrogenic rests, thereby providing evidence of a constitutional defect in kidney development. In addition, 25% to 40% of children with sporadic

CHAPTER

.

High-power microscopic view (x400) of tumor cells with eccentric nuclei and prominent, glassy, inclusion-like eosinophilic cytoplasm. These features merit the descriptor "rhabdoid (muscle like).

Wilms' tumor have nephrogenic rests within the nearby "normal" kidney t i s ~ u e . ~ A report from our group noted that the same somatic mutation of WI'I was present in the Wilms' tumor and in the nearby nephrogenic rests, providing molecular evidence that nephrogenic rests may be premalignant lesions.lo7 The association between nephrogenic rests and the genetic loci implicated in Wilms' tumor may also be reflected in the anatomic location of these premalignant le~ions.~~Wephrogenic rests developing at the periphery of the renal lobe (perilobar nephrogenic rests) are usually found in children with BWS. Intralobar nephrogenic rests, which may arise anywhere in the renal lobe, are typically found in children with aniridia or other features associated with I.Ir7l.Vhese observations suggest that the various Wilms' tumor genes may be

27

Wilms' Tumor

451

.

Low-power microscopic view (x20) of nephrogenic rest, with aggregates of primitive metanephric tissue with dark-staining blastema and primitive tubule formation. Normal tubules are present in the lower left portion of the image.

involved in distinct developmental pathways in the kidney and that their inactivation may interrupt normal kidney development at specific times.

STAGING The following staging system was used in the NWTS-5 protocol and was modified from previous NWTSG trials. Stage I: The tumor is limited to the kidney and is completely resected. It did not rupture and was not biopsied before removal. The renal capsule has an intact outer surface. The vessels of the renal sinus are not involved, and there is no evidence of tumor at or beyond the margins of resection. Stage 11: The tumor extends beyond the kidney but is completely resected. There is regional extension of tumor (i.e., penetration of the renal capsule or extensive invasion of the renal sinus). The blood vessels outside the renal parenchyma, including those of the renal sinus, contain tumor. The tumor was biopsied (except for fine-needle aspiration) before removal, or there was spillage of tumor before or during surgery that is confined to the flank and does not involve the peritoneal surface. There is no evidence of tumor at or beyond the margins of resection. Stage 111: Residual nonhematogenous tumor is present, confined to the abdomen. Any one of the following may occur:

Medium-power microscopic view ( ~ 1 0 0 showing ) "tongue" of tumor within a vascular channel, an indicator of extensive angiolymphatic invasion. I

1. Lymph nodes within the abdomen or pelvis are found to be involved by tumor (renal hilar, para-aortic, or beyond). 2. The tumor has penetrated through the peritoneal surface. 3. Tumor implants are found on the peritoneal surface.

452

PART

III

MAJORTUMORS OF CHILDHOOD

4. Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination). 5. The tumor is not completely resectable because of local infiltration into vital structures. 6. Tumor spill, not confined to the flank, occurred either before or during surgery.

Operative Therapy Despite the advances in multimodal treatment of Wilms' tumor, surgical staging and tumor resection remain the central components of therapyl2"Fig. 27-8). The surgeon must remove the tumor, determine the intra-abdominal stage by lymph node sampling, and carefully examine the liver and the contralateral kidney. Even if the tumor is considered nonresectable, an open biopsy furnishes an adequate sample of the tumor and allows intra-abdominal staging. The surgical guidelines for management of a possible Wilms' tumor have been clearly outlined. A large transabdominal, transperitoneal incision is recommended for adequate exposure. Thoracic extension may occasionally be necessary. The celiotomy must be large enough to avoid excessive tumor manipulation, which has been associated with increased intraoperative tumor spill. Complete exploration of the abdomen is required. The contralateral kidney should be palpated before nephrectomy to exclude bilateral Wilms' tumors. Gerota's fascia must be incised, the kidney turned to visualize its posterior surface, and any suspicious areas biopsied. Then the lateral peritoneal reflection over the tumor is opened, and the colon is reflected medially. The renal vein and inferior vena cava are palpated carefully to rule out extension of the tumor into the vein. Ideally, this determination should be made by preoperative US. If tumor extension is present, this should be removed en bloc with the kidney. Patients with extension of tumor thrombus above the level of the hepatic veins are probably best managed with preoperative chemotherapy to facilitate shrinkage of the intravascular thrombus. An attempt should be made to first expose and ligate the renal vessels to lessen the chance of hematogenous

Stage IV: Hematogenous metastases (e.g., lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present. Pulmonary nodules not detected on chest radiographs but visible on chest CT do not mandate treatment with whole-lung irradiation, and such patients are treated according to the stage of the renal tumor. Stage V: Bilateral renal involvement is present at diagnosis. An attempt should be made to stage each side according to the foregoing criteria, based on the extent of disease before biopsy.

TREATMENT All children with Wilms' tumor should have the benefit of therapy from a team of pediatric physicians consisting of radiologists, pathologists, oncologists, surgeons, anesthesiologists, and radiotherapists. Cosentino et al.33 reported their 25-year experience with Wilms' tumor at Children's Memorial Hospital in Chicago. They noted an increased survival in patients who were treated primarily at their specialized children's hospital compared with those who had surgical excision of Wilms' tumor by general surgeons and general urologists followed by subsequent referral.

A •

-

B A, Schematic of the extent of a large Wilms' tumor. B, Large tumor and left kidney after removal

CHAPTER

spread of tumor cells; however, initial ligation should not be performed if it would be technically difficult or dangerous. The analysis of surgical factors in NWTS-1 and NWTS2 showed that delayed ligation of the renal vein did not produce any deleterious effects.84 However, intraoperative pulmonary embolism has been reported, and early vein ligation may avert this c0mplication.l2~Care should be taken to avoid rupture of the tumor capsule and tumor spill. The adrenal gland may be left in place if it is not abutting the tumor; if it is (as with superior pole lesions), the adrenal gland should be removed with the neoplasm. The ureter is ligated and divided as low as possible because of the risk of urothelial tumor extension. The tumor and the uninvolved portion of the kidney are mobilized and removed intact. Tumors that involve contiguous structures should be biopsied and staged. These patients can be treated with chemotherapy to shrink the tumor, thereby allowing nephrectomy with preservation of the contiguous organs. Radical en bloc resection of nonessential structures (e.g., tail of the pancreas, segment of diaphragm) should be undertaken only if the surgeon is sure that all disease can be completely removed. If residual neoplasm must be left behind, a biopsy should be done, and the site identified with metallic clips. The use of titanium clips is strongly recommended, as ferromagnetic clips can interfere with CT. Clips are best applied by placing a nonabsorbable suture in the structure to be marked and attaching the clip to the suture. Partial nephrectomy is generally not indicated in patients with unilateral Wilms' tumor. Exceptions include children with synchronous or metachronous bilateral disease or solitary kidneys. The recommended approach for these patients is initial biopsy followed by combination chemotherapy before definitive surgical resection. The surgeon should assign a local-regional stage to the tumor based solely on the operative findings. The presence or absence of disease in hilar and regional lymph nodes is an extremely important factor in accurate staging and choice of appropriate therapy. Routine lymph node sampling from the iliac, para-aortic, and celiac areas must be done for accurate staging. Involved or suspicious lymph nodes should be excised, but formal lymph node dissection is not recommended. For accurate staging, it is also important to determine the extent of any peritoneal soilage. The peritoneum is considered "soiled" if there has been a biopsy, there is tumor spill, or the tumor has ruptured. Preoperative incisional or percutaneous needle biopsy using either the anterior or posterior approach is considered local spillage. Incisional biopsy during

Week

0

1

2

3

v

v

v

A

4

5

A

A, dactinomycin (45 !&&/kg);

6

7

8

A

v

v

v

v

453

Wilms' Tumor

operation before nephrectomy is considered local spillage unless, in the surgeon's judgment, the entire peritoneal cavity has been soiled in the process (diffuse spill). Tumors are sometimes adherent to adjacent structures (e.g., colon, spleen, diaphragm). Tumors and adherent tissues that are removed en bloc entail no tumor spill. Those that are removed as separate specimens-the neoplastic tissue having been cut across in the process-are considered to involve tumor spill (local or diffuse). When tumor rupture occurs preoperatively and tumor cells are disseminated throughout the peritoneal cavity, the patient's disease is classified as stage 111, and radiation therapy must be delivered to the entire peritoneal surface (abdomen and pelvis). Tumors may be inoperable because of size, extension into the suprahepatic portion of the inferior vena cava, or other reasons. Past experience in the NWTSG and studies conducted by the Societe Internationale d'oncologie Pediatrique (SIOP) have shown that pretreatmentwith chemotherapy almost always reduces-the bulk of the tumor and renders it resectable."~"~",Ii7~133 It is recommended that all patients undergo initial exploration to assess operability and obtain a biopsy specimen of the tumor, because the staging error rate in nonbiopsied renal masses is 5% to 10%. Patients who are staged by imaging studies alone are also at risk for understaging or overstaging, leading to inappropriate treatment. Once there is adequate reduction in the tumor's size to facilitate nephrectomy, definitive resection should be completed. In general, radiographic re-evaluation should be performed at week 5. Radiographic evidence of persistent disease can occasionally be misleading, because the tumor's failure to shrink could be due to predominance of skeletal muscle or benign elements. 1f the tumor remains inoperable, biopsy of both the primary tumor and accessible metastatic lesions should be performed. Patients with progressive disease have a very poor prognosis and require treatment with a different, more intensive chemotherapy regimen. '21

Chemotherapy Because patients in the United States are treated based on NWTSG protocols, the recently completed NWTS-5 chemotherapy regimens are applied in this section. As a rule, chemotherapy follows radical nephrectomy and lymph node sampling, except in the case of bilateral disease or inoperable tumors. The specific treatment plan varies by stage, patient age, tumor weight, and histology.

9

10

A

v

27

v

V, vincristine (0.05 mg/kg); V*, vincristine (0.067 mglkg).

v

11 12 13 --

14

15

16

17

18

A

A

A

v*

v*

v*

454

III

PART

Week 0

M A ~ O TUMORS R OF CHILDHOOD

1 2 3 4

A

5

D+

6

7

8 9 10 11 12 13 14 15

V

V

A

v v v v

v

v

D+ V V

16 17 18 19 20 21 22 23 24

A

D*

A

v*

v*

v*

D* v*

A

v*

XRT A, dactinomycin (45 pg/kg IV); D*, doxorubicin (1.0 rng/kg IV); D+, doxorubicin (1.5 rng/kg IV); V, vincristine (0.05 mg/kg IV); V*, vincristine (0.067 mg/kg IV); XRT, radiation therapy.

Patients fitting into the following scenarios are treated with nephrectomy and chemotherapy regimen EE-4A (Table 27-I), using dactinomycin and vincristine:

Wilms' tumor.54For more than 30 years, SIOP has recommended that the diagnosis of Wilms' tumor be based on imaging and metabolic exclusion of neuroblastoma, or preoperative percutaneous biopsy, and that treatment . start with chemotherapy to improve the stage distribution and decrease the complication rate. Initial SIOP studies disclosed that preoperative chemotherapy and radiotherapy reduced the incidence of tumor spill at surgery.40 subsequent authors have continued to emphasize the benefits of this approach, stating that preoperative chemotherapy results in easier operations with significantly fewer tumor ruptures and a favorable stage distribution, without putting the patient at increased risk of postoperative morbidity or reduced survival.'2," A recent . prospective SIOP study compared . 4week and &week preoperative chemotherapy in patients older than 6 months with unilateral Wilms' tumor.'" No advantage was found with prolonged preoperative treatment for any of the following factors: percent stage I, intraoperative tumor rupture rate (1% versus 3 % ) , 2-year event-free survival (84%), and 5-year overall survival (92% versus 87%). The NWTSG does not recommend wreowerative needle biopsy of unilateral Wilms' tumor because the sample is small, intra-abdominal staging cannot be done, and needle biopsy may cause local spread, intratumor bleeding, or, rarely, rupture. In addition, NWTSG studies have not shown intraoperative rupture to be a major problem, and treatment without pathologic confirmation may cause diagnostic error. his concern was emphasized b; Zoeller et al.,I4Owho reported both emergency surgery

Stage I, favorable histology, age younger than 24 months, tumor weight less than 550 g. Stage I, favorable histology, age older than 24 months, tumor weight greater than 550 g. Stage I, focal or diffuse anaplasia. Stage 11, favorable histology. Patients fitting into the following scenarios are treated with nephrectomy, abdominal irradiation, and tripledrug chemotherapy regimen DD-4A (Table 27-2): Stage 111, favorable histology. Stage I1 or 111, focal anaplasia. Stage favorable histology or focal anaplasia. (Pulmonary nodules not detected on chest radiographs but visible on CT do not mandate treatment with whole-lung irradiation. The decision to administer whole-lung irradiation is at the discretion of the investigator.) Patients fitting into the following scenarios are treated with nephrectomy, abdominal irradiation using 1080 cGy, and four-drug chemotherapy regimen I (Table 27-3):

L

Stages I1 to IV,diffuse anaplasia. Stages I to IV,clear cell sarcoma of the kidney. There is no universal agreement about the timing of chemotherapy and surgery for resectable unilateral

-Week 0

1 2 3 4 5

6

7

8 9 10

11 12 13

v

v

v

D

D

v

v

v C E

v

v

14 15 16 17 18 19 20 21 22 --- 23 24

D

C*

v C E

v* C*

L

v* C E

D

D

v*

v* C*

C*

C E

.

XRT L P ~ -

--

C, cyclophosphamide (14.7 mg/kg/day x 5 IV); C*, cyclophosphamide (14.7 mg/kg/day x 3 IV); D, doxorubicin (1.5 rng/kg IV); E, etoposide (3.3 mg/kg/day x 5 IV); V, vincristine (0.05 mg/kg IV); V*, vincristine (0.067 rng/kg IV); XRT, radiation therapy.

CHAPTER

performed because of tumor rupture and incorrect diagnosis of renal cell carcinoma in a small cohort of children treated by the SIOP protocol. In the United States, extensive experience has accumulated using preoperative therapy for children with Wilms' tumor. However, preoperative chemotherapy is considered most appropriate for children with bilateral tumors in whom parenchyma-sparing procedures are desirable,"' patients with inoperable tumors, and those with extensive intravascular tumor extension. The NWTSG concern is that patients staged by imaging studies alone are at risk for understaging or overstaging. If one chooses to give preoperative therapy based on imaging alone (with or without a needle biopsy), the local tumor should be considered a stage 111 lesion, and treatment should include regimen DD-4A for patients with favorable or focal anap&sia histology or unknown histology and regimen I for patients with diffuse anaplasia histology. The UKCCSG Wilms' Tumor Study 3 has adopted preoperative chemotherapy for Wilms' tumors but Eequires a prechemotherapy biopsy for histologic diagnosis. A recent review of the usefulness and safety of prechemotherapy biopsy noted that biopsy material was not diagnostic in 4% of patients, and in 12% the biopsy revealed tumors other than Wilms' tumor.13Wf the 182 children who had percutaneous cutting needle biopsy, a fall in hemoglobin (20% of cases) and local pain (19%') were the most-common complications. One child required emergency nephrectomy due to massive intratumoral bleeding, another had tumor rupture and subsequently died, and a third developed a needle tract tumor recurrence 8 months after the biopsy.

Radiotherapy Since the early decades of the 20th century, radiation therapy has played an important role in the management of Wilms' tumor. In the past, high radiation doses and eccentric field arrangements were responsible for significant late toxicity; however, examination of long-term survivors and information obtained from the NWTSG and SIOP studies have allowed us to tailor radiation fields and doses to provide high levels of local tumor control with minimal late effects.39 Patients with stage " I and I1 tumors with favorable histology do not require abdominal irradiation. Children with stage I anaplastic Wilms' tumor do not receive abdominal irradiation, but those with stages I1 to IV do. All ~ a t i e n t swith clear cell sarcoma of the-kidney receive postoperative radiotherapy. All stage I11 patients are given postoperative irradiation totaling 1080 cGy in 6 fractions. Tumor bed irradiation is usedwhen only hilar lymphadenopathy is present or when there is residual disease confined to the flank. The field is extended across the midline to include all the vertebral bodies at the levels concerned, but not far enough to overlap any portion of the contralateral kidney. The portals are extended (e.g., for the entire length of the para-aortic chains) when these nodes are involved. Total abdominal irradiation is given when there is diffuse

27

Wilms' Tumor

455

peritoneal seeding, gross tumor spillage within the abdominal cavity during surgery, or preoperative intraperitoneal rupture. For stage IV patients, infradiaphragmatic irradiation is given if the primary tumor would have qualified as stage 111; otherwise, no abdominal radiotherapy is administered. When stage IV patients have pulmonary metastases, both lungs are treated, regardless of the number and location of visible metastases. The portals cover both lungs, specifically including the apices and posterior inferior portions, and 1200 cGy is administered in 8 fractions.

TREATMENT CHALLENGES lntracaval and Atrial Extension Tumors that extend into the renal vein or vena cava present particular pr0blems.2~ Preoperative US usually demonstrates the extent of any problem accurately. Pulmonary tumor embolus is a risk, and infracardiac caval occlusion and exploration are recommended. When the proximal extent of the thrombus can be clearly established, the vena cava is occluded above that point and opened, and the tumor thrombus is removed. Some prefer to open the cava without proximal occlusion and insert a large-bore, open-ended suction tube into the vein and advance it as the tumor is sucked out. If the tumor is adherent to the wall of the vena cava, removal by balloon catheter is required. A recent report illustrated an unusual case in which the tumor within the cava was tightly adherent to the venous wall and required complete excision of the vena cava and left renal vein and a portion of the iliac system.115 Free-floating and adherent tumors are classified as stage 11, but if the tumor invades the wall of the vein, it should be considered stage 111.49 Most authors agree that tumor growth into the suprahepatic vena cava and atrium requires cardiopulmonary However, if the tumor bypass when managed ~urgically.~~ can be localized and controlled below the atrium, resection without the use of cardiopulmonary bypass may limit morbidity. Lodge et al.90described a technique in which tumor thrombectomy was performed without the use of cardiopulmonary bypass. They used transesophageal echocardiography to localize the tumor thrombus and an upper midline extension of the transverse abdominal incision to obtain intrapericardial control of the inferior vena cava (Fig. 27-9A) before extracting the tumor thrombus from the infrahepatic vena cava (Fig. 27-9B). Previous data showed that primary surgical removal of tumors with intracaval extension is associated with an ~~~ increased incidence of surgical c o m p l i ~ a t i o n s .This was particularly true for those patients with extension above the level of the hepatic veins or even farther into the right atrium. These extensive tumors can be managed with preoperative chemotherapy to facilitate Preoperative shrinkage of the intravascular thrornbu~.l2~ therapy allows the caval tumor extension to shrink or even totally disappear, thereby obviating the need for cardiopulmonary bypass for removal of the tumor thrombus.

456

A

.

PART

III

MAJOR TUMORS OF CHILDHOOD

B -

A, Close-up intraoperative procedure. The surgeon's hand is displacing the liver down, exposing the suprahepatic inferior vena cava below the diaphragm. Just above that, the diaphragm has been incised, along with the pericardium, in anticipation o f intrapericardial control o f the inferior vena cava. B, Intraoperative picture o f extraction o f tumor embolus from the vena cava below the liver.

A recent review detailed the outcomes of children who had intravascular extension into the inferior vena cava or atrium.l2Wf 2731 patients in NWTS-4, 165 (6%) had intravascular extension of Wilms' tumor. The level of extension was the inferior vena cava in 134 (4.9%) and the atrium in 31 (1.1%). Sixty-nine patients (55 with inferior vena cava extension and 14 with atrial extension) received preoperative therapy. Complications during preoperative chemotherapy were seen in five patients. in 39 The intravascular extension of the tumor recressed " of 49 children with comparable pre- and post-therapy radiographic studies, including 7 of 12 in whom the tumor regressed from an atrial location, thus obviating the need for cardiopulmonary bypass. Surgical complicG tions occurred in 36.7% of the children in the atrial group and 17.2% in the inferior vena caval group. The frequency of surgical complications was 26% in the primary resection group versus 13.2% in the group undergoing preoperative therapy. When all the complications of therapy were considered, the incidence of complications among those receiving preoperative therapi was not statistically different from the incidence among those undergoing primary resection. The difference in 3-year relapse-free survival (76.9% for 165 patients with intravascular extension; 80.3% for 1622 patients with no extension) was not statistically significant. Thus, preoperative treatment facilitated resection by decreasing the extent of the tumor thrombus. but the overall fkauencv of complications was similar in both groups.

Bilateral Tumor Patients who present with bilateral Wilms' tumor (stage V) account for approximately 5% of all cases (Fig. 27-10).

The surgical management of these patients remains controversial. Some groups have advocated bilateral nephrectomy followed by transplantation. Another approach uses ex vivo tumor dissection followed by autotransplantation in an attempt to preserve functioning renal tissue.41 However, reviews of children treated with preoperative chemotherapy based on NWTS regimens indicate that they have an excellent prognosis; survival rates for those having a favorable histology exceed 80% at 2 yearsll.'" and 70% at 10 years after diagnosis.I00 However, there is an increased risk of renal failure in these patients. Concerns regarding the impact of hyperfiltration injury on patients

a

-

Abdominal computed tomography scan showing

bilateral Wilms' tumor. The darker-appearing tumor tissue has totally replaced the left kidney and is in the posterior portion o f the right kidney.

CHAPTER

with less than 50% of the renal parenchyma remaining after resection, and the presence of renal failure in 5.4% of long-term survivors of bilateral Wilms' tumor, have resulted in a more conservative surgical approach in these patients. Identifying these patients at the time of initial diagnosis is important to facilitate renal-sparing surgery. The study by Coppes et al.27 identified the joint presence of perilobar nephrogenic rests and intralobar nephrogenic rests, or the presence of perilobar nephrogenic rests in children diagnosed during the first year of life, as important risk factors. These features did not predict all future events, however, and further study is warranted. Patients treated by preoperative chemotherapy have an equivalent survival to those undergoing initial radical surgery, but more renal units can be preserved in those given preoperative chemotherapy. Thus, radical excision of the tumor should not be attempted at the initial operation. Partial nephrectomy or wedge excision can be performed at the initial operation only if all tumor can be removed, with preservation of the majority of renal parenchyma on both sides. Bilateral biopsies should be obtained to confirm the presence of Wilms' tumor in both kidneys and define the histologic type. Discordant pathology may be observed in 4% of cases. Suspicious lymph nodes should be biopsied, and a surgical stage assigned to each side. For patients fitting the following scenarios, chemotherapy regimen EE-4A (see Table 27-1) should be administered after the initial surgical biopsy and staging: Bilateral stage I with favorable histology or focal or diffuse anaplasia. Bilateral tumors, one or both kidneys evaluated as stage 11, with favorable histology. For patients fitting the following scenarios, chemotherapy regimen DD-4A (see Table 27-2) is used: Bilateral stage I1 with focal anaplasia. Bilateral stage I11 or IV with favorable histology or focal anaplasia. Patients with bilateral stage 11, 111, or IV tumor with diffuse anaplasia are treated initially with regimen I (see Table 27-3). The response to therapy should be evaluated after week 5 by CT scan to assess the reduction in tumor volume and the feasibility of partial resection. At the time of the second-look procedure, partial nephrectomy should be done only if it will not compromise tumor resection and only if negative margins can be obtained. If there is extensive tumor involvement precluding partial resection in one kidney, complete excision of tumor from the least involved kidney is performed. If this procedure leaves a viable and functioning kidney, radical nephrectomy is performed to remove the opposite kidney. If there is a possibility that the remaining kidney can be salvaged, only a biopsy should be obtained, and the extent of disease delineated with titanium clips. Additional chemotherapy is then given, and the patient is reassessed before week 12. If there is persistent disease, the patient should receive radiation therapy.

27

Wilms' Tumor

457

Approximately 1% of children with unilateral Wilms' tumor develop contralateral disease. Coppes et al.2' assessed the demographic and histologic features associated with metachronous bilateral Wilms' tumor by reviewing all children registered during the first four NWTSs.27 Fifty-eight of 4669 registered children developed metachronous bilateral Wilm's tumor. The cumulative incidence of contralateral disease 6 years after initial diagnosis decreased from greater than 3% in NWTS-1 to approximately 1.5% in the three subsequent studies (P=0.08). Patients with nephrogenic rests had a significantly increased risk of metachronous disease; this was particularly true for young children (20 of 206 aged younger than 12 months, compared with 0 of 304 aged older than 12 months). A report from the Children's Hospital of Philadelphia reviewed the experience with renal salvage procedures in patients with bilateral Wilms' tumor.2Wrom 1982 to 1997, 23 children with bilateral Wilms' tumor were treated with partial nephrectomy, including 7 who were also treated with brachytherapy. Anaplasia was the most significant factor associated with an unfavorable outcome (P= 0.003). The authors concluded that (1) preoperative chemotherapy followed by nephron-sparing surgery is indicated in patients with bilateral Wilms' tumor, except those with diffuse anaplasia, and (2) brachytherapy should be considered for local disease involving chemoresistant tumors.

Tumor in Horseshoe Kidney Wilms' tumor arising within a horseshoe kidney presents a difficult diagnostic and therapeutic challenge (Fig. 27-1 1A). The incidence of horseshoe kidneys in the general population is 1 in 400.76 Neville et al."" described 41 of 8617 patients (0.48%) enrolled in the NWTSG from 1969 to 1998 who developed a Wilms' tumor in a horseshoe kidney, suggesting that Wilms' tumor is 1.96 times more common in patients with horseshoe kidney than in the general population. In their study, horseshoe kidney was not recognized preoperatively in 13 patients, 10 of whom were evaluated with CT. Primary surgical resection was performed in 26 patients, and 15 children were treated with preoperative chemotherapy after biopsy. Surgical complications occurred in 14.6% of patients, including two urine leaks, two ureteral obstructions, and one ureteral injury. Although 37% of Wilms' tumors arising in a horseshoe kidney were judged inoperable at initial exploration, all were amenable to resection after chemotherapy. Present NWTSG recommendations are as follows: At initial exploration, if the tumor is resectable and involves only one side of the horseshoe kidney, resection is recommended. In bilateral cases, accurate surgical staging should be performed via biopsies of all tumors and any suspicious lymph nodes. The patient should then receive stage-appropriate adjuvant therapy, followed by secondlook surgery approximately 6 weeks later to assess tumor response and perform definitive resection if possible (Fig. 27-llB). Despite the frequency of tumor entrance into the collecting system in these difficult cases, the overall incidence of surgical complications in patients with horseshoe kidneys is similar to that reported for other NWTS patients.11gJ22

458

PART

I I1

M A ~ OTc'MoRS R OF CHI~.DHOOD

B

A

.

.

A, Massive midliile Wilms' tumor in a horseshoe kidney. R, Same tumor after preoperative chcn~otiierapy.Tlwrr has been marked shrinkage, inaking the tumor amenable to resection, leaving two functioning renal unit5 on both sides of the spine.

Partial Nephrectomy Partial nephrectomy for unilateral disease remains controversial. A SIOP report examined the experience with partial nephrectomy for children with renal tumors." Surgical criteria for partial resection included tumor confined to one pole of the kidney and occupying less than a third of the kidney, no invasion of the renal vein or collecting system, and clear margins around the tumor. Using these criteria, 13 of 90 cases were suitable for partial nephrectomy. Of these 13 patients, 5 underwent partial nephrectomy. None of the 5 patients had a positive margin or recurrent local disease, and ipsilateral renal function was preserved in all cases.

No patient with recurrent anaplastic histol~~gy survived. Only three patients received high-dose chemotherapy with autologous stem cell rescue, indicating significant progress in the treatment of recurrent favorable-histology Wilms' tumor using salvage regimens with conventional chemotherapy. Early recognition of recurrence may improve outcome. Researchers from the United Kingdom recently studied serum VEGF levels in 13 children with Wilms' tumor.'* Before surgery, the median VEGF level was 20 ng/mL; by the week after operation, levels had fallen to 1.9 ng/mL (P < 0.001, ANOVA). Six months after tumor resection, three of the children had died. A VEGF level greater than10 ng/mL 3 months after surgery suggested tumor recurrence in the three patients who died.

Recurrent Disease Shamberger et al.u4 reviewed the data for the 100 NWTS 4 patients (out of 2482) who developed local recurrence. The greatest relative risk for local recurrence was observed in patients with stage I11 disease, unfavorable histology, and tumor spill during surgery. Multiple regression analysis indicated that tumor spill and the absence of lymph node biopsy were associated with an increased relative risk of recurrence. Survival after local recurrence was poor, with a 2-year survival rate of 43%. Survival was also dependent on initial stage; those who received more therapy before relapse had a worse prognosis. This study demonstrated that tumor spill results in an increased risk of local relapse and reaffirmed the importance of lymph node sampling so that tumors are neither understaged nor undertreated. A recent retrospective review of 54 patients with recurrent Wilms' tumor observed that the 5-year overall survival estimates were 63.6% for patients treated after 1984, compared with 20.6% for patients treated before 1984.42

PROGNOSTIC FACTORS Histology Early on, the prognostic importance of Wilms' tumor histology was appreciated, with the 12% of Wilms' accounting for more tumors with "unfavorable histolo
27

CHAPTER

prognosis was similar to that of similarly staged patients with favorable histology. Patients with stage IV disease and diffuse anaplasia h a d a 4year relapse-free survival ~~ treatment with the four-drug regirate of 1 6 . 7 %despite men, indicating a need for further intensification of therapy. Recently, mutational analysis of 140 Wilms' tumors showed an association between Wilms' tumors with anaplastic features and the occurrence of p53 mutations.3 because a $153mutation had aiso been identified in a Wilms' tumor with favorable histologic features, it remained to be determined whether p53 alterations can be used as a molecular marker for ana~lasticWilms' tumors or as a marker for an adverse outcome. To address that question, investigators st~idied97 Wilms' tumors for p53 expression and correlated expression with outcome.130 They detected $153in 13 of 97 tumors and found that it was associated with disease relapse (39% versus 17%;P= 0.06) but not anaplasia. Among p53negative patients, only 5% had metastatic disease, compared with 31% of p53positive patients ( P = 0.038). Overall survival at 1 year was 94% for p53negative patients and 85% for p53positive patients ( P = 0.34). In 2002, SIOP noted that certain histologic features that remain after preoperative chemotherapy, such as blastema, are of prognostic significance, whereas others are not. Therefore, in the next SIOP trials and study, a revised classification of renal tumors will be followed for treatment purposes: completely necrotic (low-risk tumors), blastemic (high-risk tumors), and others (intermediate-risk tumors)

ow ever,

Wilms' Tumor

459

Conflicting data were presented by 13 member laboratories of the U.K. Cancer Cytogenetics Group.'Vn a review of 127 abnormal kawotyr>es, univariate survival analysis showed no significant adverse effects for karyotype complexity, l p loss, or 1l p loss. The poor outcome of cases with 16q loss was of borderline significance, and the association between relapse risk and gain of l q material was not significant. Only monosomy 22 was a significant marker of poor outcome (13 cases showing 50% relapse-free survival at 5 years, compared with 79% survival for the remaining 114 cases; P = 0.02). Hing et a1.73 undertook an analysis of comparative cenomic hvbridization of 58 samules of favorabie-histol" ogy Wilms' tumors taken at initial diagnosis or relapse. Gain of l q was significantly more frequent in the relapse group (27 of 46 [59%] versus 5 of 21 [24%]; P = 0.019). This result suggests that identifying l q gain at diagnosis could be used to select patients with an increased risk of relapse who might benefit from early treatment intensification. Lu et al."konfirmed this study, noting that in 18 cases of Wilms' tumor with favorable histology, relative overexpression of genes on the long arm of chromosome 1 was seen in all tumors that relapsed, but in none that remained in remission. >

, x

Gene Expression

Examining the expression of tyrosine kinase (Trk) receptors in 39 children with Wilms' tumor, Eggert et al.46 noted that children with high levels of full-length TrkB mRNA (TrkBfull) had a significantly greater risk of death than children whose tumors had little or no TrkBfull expression ( P = 0.02). The 5-year relapse-free DNA Content survival was 100% for patients with low tumor expression Increased tumor cell DNA content has been correlated of TrkBfull, compared with 65% for those with high with a more favorable prognosis in children with a variety tumor expression of TrkBfull ( P < 0.003). Conversely, children with tumors that expressed high mRNA levels of tumors, including embryonal rhabdomyo~arcoma,~~~ of a functionally inactive truncated TrkB receptor and acute lymphoblastic 1eukemia.l34 neurobla~torna,"~ (TrkBtrunc) had a greater 5-year relapse-free survival than For Wilms' tumor, however, the data have been mixed; did children with low levels of TrkBtrunc (95% versus aneuploidy was associated with a worse prognosis among 68%; P= 0.005). patients with favorable-histology Wilms' tumors in one Ghamen et al." evaluated the prognostic value of variseries70 but not in another.5 More recently, possible chroous apoptosis-associated regulatory proteins, such as Bcl-2, mosomal prognostic factors have been identified by Bax, and Bcl-X, in a group of 61 Wilms' tumors. An Grundy et al.," who evaluated DNA gain and loss for sevincreased expression of Bcl-2 was observed in the eral chromosomal segments. In a study of 232 children blastemic component of increasing pathologic stages, registered during NWTS-3 and NWTS-4, LOH of 16q while a gradual decline of Bax expression was observed. markers was present in 17.2% of tumor tissue and was Univariate analysis showed that blastemic Bcl-2 expression associated with a statistically significantly worse 2-year and the Bcl-2/Bax ratio were indicative of clinical progresrelapse-free and overall survival. LOH of chromosome sion, and blastemic Bcl-2 expression was a prognostic l p markers, present in tumor tissue from 11% of chilmarker for clinical progression, independent of stage. dren with Wilms' tumor, was associated with poorer relapse-free and overall survival rates, which were of borderline statistical significance ( P = 0.08 and 0.12, respectively). In contrast, LOH for l l p markers or duplication Growth Factors of l q , present in 33% and 25% of cases, respectively, was Previous reports noted that the sera and urine of chilnot associated with any difference in outcome. Study of dren with Wilms' tumor often contain increased concenthe prognostic significance of tumor cell DNA content trations of hyaluronan. Using a mouse heterotransplant was continued in NWTS-5, with the hope that newly conmodel, Loworn et aL9' noted that the sera of mice supportfirmed DNA variables will facilitate the tailoring of treating tumor growth had a median hyaluronan concentration ment to anticipated outcome.

1

460

PART

III

MAJORTUMORS OF CHILDHOOD

of 9379 pg/L, compared with a median concentration of The 2 416 pg/L in animals not supporting tumor g r o ~ t h . ~ highest serum hyaluronan concentrations were detected in animals harboring blastema-predominant tumors with an unfavorable histology. Complete resection of established tumors also resulted in the return of serum hyaluronan to preheterotransplant concentrations. Lin et a1.88 measured bFGF levels in preoperative and postoperative urine samples from 97 patients with Wilms' tumor. Urinary bFGF was elevated in 42% of preoperative samples, and higher-stage tumors resulted in higher preoperative levels. Patients with relapse or persistent disease had significantly elevated postoperative bFGF levels. Kayton et a1.81 detected VEGF with increasing frequency and quantity in a mouse model of Wilms' tumor. Lung metastases occurred in 8 of 10 animals with VEGF-positive tumors but in only 3 of 11 animals with VEGF-negative tumors, an association that was statistically significant.VEGF was found in 10 of 12 clinical Wilms' tumor specimens tested. Davidoff et a1.M developed adeno-associatedvirus vectors containing the soluble, truncated form of VEGF receptor-2 (Flk-1), a known inhibitor of endothelial cell activation. Significant antitumor efficacy was observed in two murine models of pediatric kidney tumors. Tumor development was prevented in 10 of 15 mice (67%), with significant growth restriction of tumors in the remaining mice.

OUTCOMES NWTSG Results Five therapeutic studies have been completed: NWTS-1 (1969-1974),NWTS-2 (1975-1979),NWTS-3 (1980-1985), NWTS-4 (19861995), and NWTS-5 (1995-2002). Five-year survival percentages for patients enrolled in NWTS protocols were 79.7% for 1969-1974 enrollees, 81.6% for 1975-1979, 86.3% for 1980-1984, 88.6% for 1985-1989, and 90.4% for 1990-1995. These are among the highest for all childhood cancers. The major conclusions of NWTS-1, -2, and -3 were as follows: 1. Postoperative irradiation therapy of the renal bed is not necessary for stage I tumors or for stage 11 tumors with favorable histology. 2. Survival of patients with stage 111, favorable-histology tumors is best when therapy consists of dactinomycin, vincristine, and doxorubicin combined with 1000 cGy radiation therapy to the flank, or dactinomycin and vincristine combined with 2000 cGy radiation therapy. 3. Cyclophosphamide does not improve the prognosis when added to the treatment of stage IV favorablehistology tumors. As a result of these studies, the 2-year survival rate of children diagnosed with Wilms' tumor rose from 20%47 to 90%."-37 NWTS-4 found that pulse-intensive actinomycin D and doxorubicin dosing is as efficacious as and less toxic than the traditional divided-dose method; it is also more

cost-effective, saving an estimated $790,000 a year.60.61 NWTS-4 also revealed that 6 months of treatment for stage I1 to IV favorable-histologytumors is equivalent to 15 months of treatment. Ritchey et a1.'22 examined the incidence of surgical complications among patients enrolled in NWTS-4. In a random sample of 534 patients, 68 patients (12.7%) experienced 76 complications. Intestinal obstruction was the most common complication (5.1% of patients), followed by extensive hemorrhage (1.9%), wound infection ( 1.9%), and vascular injury (1.5%). Intravascular extension into the inferior vena cava, nephrectomy performed through a flank or paramedian incision, and tumor diameter 10 cm or greater were also associated with an increased risk of surgical complications. NWTS-4 also demonstrated that surgical rupture of the tumor must be prevented, because spills produce an increased risk of local relapse.124 NWTS-5 (also know as POG 9440 and CCG 4941) opened in July 1995 and closed in June 2002. It had a variety of objectives, including to (1) evaluate the importance of various biologic prognostic factors; (2) decrease the morbidity of treatment by limiting initial therapy; (3) improve the survival of patients with unfavorablehistology tumors, including Wilms' tumor with diffuse anaplasia, clear cell sarcoma of the kidney, and malignant rhabdoid tumor of the kidney; and (4) study the biology and pathology of patients who present with bilateral Wilms' tumor. The results from NWTS-5 with regard to the genetic implications for clinical outcome are still being analyzed and have not been published. Of particular interest in NWTS-5 was the management of small stage I tumors. Green and Jaffe,"" in a 1979 review, had suggested that nephrectomy might be adequate therapy for patients younger than 24 months with tumors weighing less than 550 g. A subsequent review of children treated during NWTS-1, -2, and -3 supported the hypothesis that NWTS regimens had not improved the excellent prognosis among this group of children."" Thus a "surgery only" arm was developed for investigation in NWTS-5. By March 31, 1998,69 patients had been entered in the surgery-only treatment arm. Nine patients relavsed: three in the tumor bed or abdomen. one in the pleural space, four in bilateral lungs, and one in the contralateral kidney. The relapse-free survival percentage at 2 years was 82.1%, far below the established relapse-free su-rvivalpercentage cutoff of 95%. Thus the surgery-only trial was suspended.

European Results Results from Europe have been similar to NWTS results. For instance, the results of the UKCCSG Second Wilms' Tumor Study were reported in 2OOO.gg Four-year eventfree survival was as follows: stage 1 with favorable histology, 94%; stage I1 with favorable histology, 91%; and stage 111 with favorable histology, 84%. The outlook for patients with anaplastic or rhabdoid variants was poor. A recent Italian review of 98 nephroblastoma patients treated in three consecutive SIOP trials resulted in a 5-year cure rate of 90%.7Wlinicalcourse was influenced mainly by diffuse anaplasia and, to a minor extent,

CHAPTER

27

Wilms' Tumor

461

be more vulnerable to the delayed adverse sequelae of cancer therapy, such as effects on growth, fertility, and neuropsychological function. Wilms' tumor patients have known risk factors for cardiac, renal, and pulmonary toxicity. NWTS-1 demonstrated that the risk of congestive heart failure persisted for 8 to 12 years or more from the time of anthracycline treatment. Patients treated in NWTS-1 to -4 were reviewed to determine the frequency of congestive heart failure and the risk factors for it following Wilms' tumor treatment with doxorubicin.62 The cumulative frequency of congestive heart failure was 4.4% at 20 years among patients treated initially and 17.4% at 20 years among Specialized Tumors those treated for relapsed Wilms' tumor. The relative risk of congestive heart failure was increased in females A review of 4669 patients treated with NWTS-3 and and by cumulative doxorubicin dose, lung irradiation, NWTS-4 protocols yielded 53 children with BWS.lI1 BWS and left abdominal irradiation. A more recent report patients were more likely to present with lower-stage noted that the most important predictor of worsening tumors (P= 0.0001). The overall survival rate at 4 years cardiac performance was total anthracycline dose: for BWS patients was nearly identical to that of patients patients receiving less than 240 mg/mZ showed no carwithout BWS (89% versus 90%). Twenty-one percent of diac deterioration more than 10 years after the end of patients with BWS had bilateral disease. BWS patients treatment.lZg enrolled in NWTS4 had smaller tumors than those Children with Wilms' tumor are also at risk for renal enrolled in NWTS3 (P=0.02), suggesting that US screendysfunction from a variety of factors, including radiation ing may be efficacious. therapy, use of nephrotoxic chemotherapy agents, a Argani et a1.l reviewed 351 cases of clear cell sarcoma theoretical risk due to hyperfiltration,43 and the possible of the kidney, including 182 cases entered in NWTS-1 to involvement of a genetic component (e.g., patients with -4. Overall survival was 69%, and multivariate analysis Denys-Drash syndrome). In 1996 Ritchey et al.l18 revealed four independent prognostic factors for surreported the spectrum of renal failure in 55 of 5823 vival: treatment with doxorubicin, stage, age at diagnosis, patients treated in NWTS-1 to -4, noting that the risk of and tumor necrosis. renal failure at 16 years was 0.6% for all unilateral-disease The results for children with the WAGR syndrome patients and 13% for bilateral-disease patients. were analyzed and reported by Breslow et al.17 Of the Survivors of childhood cancer are also at increased 8533 patients enrolled between 1969 and 2002 by the risk of developing a second malignant neoplasm, both NWTSG, 64 patients (0.75%) had the WAGR syndrome. leukemias and solid tumors. The cumulative risk at Comparing WAGR and non-WAGR patients, the average 20 years varies between 3% and 10% over several studies birth weights (2.94 and 3.45 kg), median ages at diagnosis and is 5 to 20 times greater than that expected in the (22 and 39 months), percentage with bilateral disease general population.65,*2"he incidence of second malig(17% and 6%),metastatic disease (2% and 13%),favorablenancies following Wilms' tumor in NWTS patients was histology tumors (100% and 92%), and intralobar initially reported in 1988; 15 second malignancies were nephrogenic rests (77% and 22%) all differed. Survival identified among 2438 patients, and the observed-toestimates for WAGR and non-WAGR patients were simiexpected ratio, or standardized incidence ratio, was lar at 4 year (95% versus 92%) but significantly different 8.5.18 These results were updated in 1996, and a similar at 27 years (48% versus 86%). Five late deaths among standardized incidence ratio of 8.4 was observed, with WAGR patients were from end-stage renal disease. 43 second malignant neoplasms occurring. Three breast cancers were found, and the relative risk in multivariate analysis was 12. To help characterize cases of secondary Treatment Morbidity and Mortality acute myelogenous leukemia on NWTSG protocols, Shearer et a1.126 reviewed the 7 patients with that disease An increasing number of children with Wilms' tumor among the 43 identified as having second malignant can expect to be cured, reflecting the undisputed neoplasms. All patients received chemotherapy regimens progress made in the treatment of children with this that included doxorubicin1° or etoposide,' and 6 were renal cancer. However, there is an increasing awareness treated with infradiaphragmatic irradiation. The median standardized of the late effects of cancer therapy.4"he latency period from initial diagnosis of the renal neomortality ratio observed in the' Childhood Cancer plasm to development of secondary acute myelogenous Survivor Study was 9.6 overall and 14.1 for the 5-year surleukemia was 3 years (range, 1.2 to 4 years). vivors of Wilms' tumor. Cumulative mortality was 1.8%, 3.1%, and 5.0% at 10, 15, and 20 years, re~pectively.~~ Radiation therapy has a variety of adverse effects. One study, designed to estimate the reduction in adult stature Some of the effects occur immediately after-treatment induced by radiation therapy of the spine in children (e.g., after the administration of certain chemotherapy) treated for Wilms' tumor, noted that height reductions and are usually transient, but they may become permawere dependent on dose, portal size, and age at treatnent. Although children seem to tolerate acute toxicities children were more often affected. m e n ~ . 7Younger ~ of therapy better than adults do, the growing child may

by lymph node involvement. A total of 2535 cases registered in 34 population-based cancer registries in 16 European countries were included in a recent EUROCARE report.Il0 The overall, 5-year survival of all children diagnosed from 1985 to 1989 was 83%. There was significantly lower survival among patients registered in the formerly socialist countries of Estonia, Poland, and Slovakia; overall European survival was slightly lower compared with results reported from the United States and Australia.

0

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Observed height deficits were 4.1 c m for 5 7 patients who received 15 to 24 Gy a t a mean age of 5 5 months; there was n o height deficit a m o n g 1 6 children who received doses less than 1 5 Gy a t a m e a n age of 83 months. Another retrospective study was undertaken to determine t h e possible effect of radiation therapy, chemotherapy, o r both o n live births, birth weight, a n d frequency of congenital malformations i n pediatric Wilms' tumor survivors." A questionnaire was distributed a m o n g survivors of Wilms' tumor treated in NWTS1 to -4. Respondents reported 427 pregnancies. Women who received flank radiation therapy were a t increased risk of fetal malposition a n d premature labor, a n d t h e offspring of these women were a t risk for low birth weight, premature birth, a n d the occurrence of congenital malformations. Importantly, fertility can b e preserved i n child r e n with Wilms' tumor after upper abdominal radiation therapy (10 to 20 Gy) that does n o t include the entire pelvis.8o

FUTURE DIRECTIONS For the first time since 1969, the NWTS is n o t conducting a clinical trial of treatment protocols. Current a n d future efforts a r e focused o n using the large cohort of former Wilms' t u m o r patients to study the long-term effects of diagnosis a n d treatment in survivors a n d to better understand the pathogenesis a n d cause of Wilms' tumor. T h e NWTS is currently conducting a Late Effects Study (LATE, also known as P O G 9442 a n d CCG 4941L), which o p e n e d i n October 1995, designed to identify treatment-related conditions that may develop in participants who were originally treated in o n e of the five clinical trials. LATE is a federally funded, multi-institutional observational study that follows participants a n d their children throughout their lives t o continue monitoring treatment results a n d possible late effects. T h e specific study objectives include the following:

1. Determine the incidence of life-threatening medical conditions in survivors of Wilms' tumor. 2. Determine mortality rates in former Wilms' tumor

3. Determine the risk of serious pregnancy complications a n d other adverse reproductive events in survivors of Wilms' tumor. 4. Determine the frequency of Wilms' tumor a n d o t h e r cancers i n the children a n d o t h e r family members of Wilms' tumor patients. 5. Identify the most informative subgroups of Wilms' tumor patients for use by molecular biologists a n d epidemiologists. By identifjing the treatment a n d host factors associated with excess mortality, interventions may b e develo p e d to target those a t highest risk. Now that 90% of children with Wilms' tumor a r e being cured, it is most important to focus attention o n t h e duration a n d quality of life in the survivors. Future Wilms' tumor protocols will b e d o n e through the COG. These protocols are still in development a t the time of this writing.

REFERENCES 1. Argani P, Perlman EJ, Breslow NE, et al: Clear cell sarcoma of the kidney: A review of 351 cases from the National Wilms' Tumor Study Group Pathology Center. Am J Surg Pathol 2000;24:418. 2. Argenta PA, Lin RY, Sullivan KM: Basic fibroblast growth factor is a Wilms' tumor marker. Surg Forum 1994; 45:789. 3. Bardeesy N, Falkoff D, Petruzzi MJ, et al: Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 mutations. Nat Genet 1994;7:91-97. 4. Bardeesy N, Zabel B, Schmitt K, et al: WTI mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion. Genomics 1994;21:663-664. 5. Barrantes JC, Muir KR, Toyn CE, et al: Thirty-year population-based review of childhood renal tumours with an assessment of prognostic features including tumour DNA characteristics. Med Pediatr Oncol 1993;21: 2430. 6. Beckwith JB: Wilms' tumor and other renal tumors of childhood: A selective review from the National Wilms' Tumor Study Pathology Center. Hum Pathol 1983;14: 481-492. 7. Beckwith JB: Precursor lesions of Wilms' tumor: Clinical and biological implications. Med Pediatr Oncol 1993; 21:158-168. 8. Beckwith JB: Nephrogenic rests and the pathogenesis of Wilms' tumor: Developmental and clinical considerations. Am J Med Genet 1998;79:268-273. 9. Beckwith JB, Kiviat NB, Bonadio JF: Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumor. Pediatr Pathol 1990;10:1-36. 10. Beckwith JB, Palmer NF: Histopathology and prognosis of Wilms' tumors: Results from the First National Wilms' Tumor Study. Cancer 1978;41:1937-1948. 11. Bishop HC, Tefft M, Evans AE, et al: Survival in bilateral Wilms' tumor-review of 30 National Wilms' Tumor Study cases. J Pediatr Surg 1977;12:631-638. 12. Blann AD, Li JL, Li C, et al: Increased serum VEGF in 13 children with Wilms' tumour falls after surgery but rising levels predict poor prognosis. Cancer Lett 2001;173: 183-186. 13. Blute ML, Kelalis PP, Offord KP, et al: Bilateral Wilms' tumor. J Urol 1987;138:968-973. 14. Bonadio JF, Storer B, Norkool P, et al: Anaplastic Wilms' tumor: Clinical and pathologic studies. J Clin Oncol 1985; 3:513-520. 15. Bown N, Cotterill SJ, Roberts P, et al: Cytogenetic abnormalities and clinical outcome in Wilms' tumor: A study by the UK Cancer Cytogenetics Group and the UK Children's Cancer Study Group. Med Pediatr Oncol 2002; 38:ll-21. 16. Breslow N, Olshan A, Beckwith JB, et al: Epidemiology of Wilms' tumor. Med Pediatr Oncol 1993;21:172-181. 17. Breslow NE, Norris R, Norkool PA, et al: Characteristics and outcomes of children with the Wilms' tumor-aniridia syndrome: A report from the National Wilms' Tunlor Study Group. J Clin Oncol 2003;21:4579-4585. 18. Breslow NE, Olson J, Moksness J , et al: Familial Wilms' tumor: A descriptive study. Med Pediatr Oncol 1996; 27:398-403. 19. Bunin GR, Meadows AT: Epidemiology and Wilms' tumor: Approaches and methods. Med Pediatr Oncol 1993;21: 169-171.

CHAPTER

20. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990;60: 509-520. 21. Canning DA: Is partial nephrectomy appropriate treatment for unilateral Wilms' tumor? J Urol 1999;161:367. 22. Capra ML, Walker DA, Mohammed WM, et al: Wilms' tumor: A 25-year review of the role of preoperative chemotherapy. J Pediatr Surg 1999;34:579-582. 23. Chiappini B, Savini C, Marinelli G, et al: Cavoatrial tumor thrombus: Single-stage surgical approach with profound hypothermia and circulatory arrest, including a review of the literature. J Thorac Cardiovasc Surg 2002; 124:684688. 24. Choyke PL, Siege1 MJ, Craft AW, et al: Screening for Wilms' tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 1999;32: 196-'200. 25. Clayman RV, Sheldon CA, Gonzales R: Wilms' tumor: An approach to vena caval intrusion. Prog Pediatr Surg 1983;15:285-290. 26. Cooper CS, Jaffe WI, Huff DS, et al: The role of renal salvage procedures for bilateral Wilms' tumor: A 15-year review. J Urol 2000;163:265-268. 27. Coppes MJ, Arnold M, Beckwith JB, et al: Factors affecting the risk of contralateral Wilms' tumor development: A report from the National Wilms' Tumor Study Group. Cancer 1999;85:1616-1625. 28. Coppes MJ, Bonetta L, Huang A, et al: Loss of heterozygosity mapping in Wilms' tumor indicates the involvement of three distinct regions and a limited role for nondisjunction o r mitotic recombination. Genes Chron~osomesCancer 1992;5:326-334. 29. Coppes MJ, de Kraker J, van Dijken PJ, et al: Bilateral Wilms' tumor: Long-term survival and some epidemiological features. J Clin Oncol 1989;7:310-315. 30. Coppes MJ, Haber DA, Grundy PE: Genetic events in the development of Wilms' tumor. N Engl J Med 1994;331: 586-590. 31. Coppes MJ, Huff V, Pelletier J: Denys-Drash syndrome: Relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1.J Pediatr 1993;123:673-678. 32. Coppes MJ, Pritchard-Jones K: Principles of Wilms' tumor biology. Urol Clin North Am 2000;27:423-433. 33. Cosentino CM, Raffensperger JG, Luck SR, et al: A 25-year experience with renal tumors of childhood. J Pediatr Surg 1993;28:1350-1355. 34. Crist WM, Kun LE: Common solid tumors of childhood. N Engl J Med 1991;324:461-471. 35. D'Angio GI, Breslow N, Beckwith JB, et al: Treatment of Wilms' tumor: Results of the Third National Wilms' Tumor Study. Cancer 1989;64:349-360. 36. D'Angio GJ, Evans AE, Breslow N, et al: The treatment of Wilms' tumor: Results of the National Wilms' Tumor Study. Cancer 1976;38:633-646. 37. D'Angio GJ, Evans A, Breslow N, et al: The treatment of Wilms' tumor: Results of the Second National Wilms' Tumor Study. Cancer 1981;47:2302-2311. 38. Davidoff AM, Nathwani AC, Spurbeck WW, et al: rAAVmediated long-term liver-generated expression of an angiogenesis inhibitor can restrict renal tumor growth in mice. Cancer Res 2002;62:3077-3083. 39. Davies-johns T, Chide1 M, Macklis RM: The role of radiation thkrapy in the management of Wilms' tumor. Semin Urol Oncol 1999;17:46-54. 40. de Kraker J, Voute PA, Lemerle J, et al: Preoperative chemotherapy in Wilms' tumour: Results of clinical trials

41. 42.

43. 44. 45. 46.

47. 48.

49. 50. 51. 52. 53.

54.

55. 56.

57.

58.

59.

27

Wilms' Tumor

463

and studies on nephroblastomas conducted by the International Society of Paediatric Oncology (SIOP). Prog Clin Biol Res 1982;100:131-144. Desai D, Nicholls G, Duffy PG: Bench surgery with autotransplantation for bilateral synchronctus Wilms' tumor: A report of three cases. J Pediatr Surg 1999;34:632-634. Dome JS, Liu T, Krasin M, et al: Improved survival for patients with recurrent Wilms' tumor: The experience at St. Jude Children's Research Hospital. J Pediatr Hematol Oncol 2002;24: 192-198. Donckerwolcke RM, Coppes MJ: Adaptation of renal function after unilateral nephrectomy in children with renal tumors. Pediatr Nephrol 2001 ;16:568-574. Eberth DJ: Myoma sarcomatodes renum. Virchows Arch Pathctl Anat Physiol 1872;10:518-521. Egeler RM, Wolff JE, Anderson RA, et al: Long-term complications and post-treatment follow-up of patients with Wilms' tumor. Semin Urol Oncol 1999;17:55-61. Eggert A, Grotzer MA, Ikegaki N, et al: Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor. J Clin Oncol 2001;19: 689-696. Farber S: Chemotherapy in the treatment of leukemia and Wilms' tumor. .JAMA 1966;198:826-836. Faria P, Beckwith JB, Mishra K, et al: Focal versus diffuse anaplasia in Wilms' tumor-new definitions with prognostic significance: A report from the National Wilms' Tumor Study Group. Am J Surg Pathol 1996;20:909-920. Federici S, Galli G, Ceccarelli PL, et al: Wilms' tumor involving the inferior vena cava: Preoperative evaluation and management. Med Pediatr Oncol 1994;22:39-44. Friedlander A: Sarcoma of the kidney treated by roentgen ray. Am J Dis Child 1916;12:328-331. Gessler M, Konig A, Arden K, et al: Infrequent nll~tationof the WTl gene in 77 Wilms' tumors. Hum Mutat 1994; 3:212-222. Gessler M, Poustka A, Cavenee W, et al: Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990;343:774778. Ghanem MA, Van der Kwast TH, Den Hollander JC, et al: The prognostic significance of apoptctsis-associated proteins BCL-2, BAX and BCL-X in clinical nephroblastoma. Br.J Cancer 2001;85:1557-1563. Godzinski J, Tournade MF, de Kraker J, et al: The role of preoperative chemotherapy in the treatment of nephroblastoma: The SIOP experience. Societe Internationale d'oncologie Pediatrique. Semin Urol Oncol 1999;17: 28-32. Goske MJ, Mitchell C, Reslan WA: Imaging of patients with Wilms' tumor. Semin Urol Oncol 1909;17:11-20. Graf N, Tournade MF, de Kraker J: The role of preoperative chemotherapy in the management of Wilms' tumor: The SIOP studies. International Society of Pediatric Oncology. Urol Clin North Am 2000;27:443-454. Green DM, D'Angio G J, Beckwith B, et al: Wilms' tumor (nephroblastoma, renal embryoma). In Pizzct PA, Poplack DG (eds): Principles and Practices of Pediatric Oncology, 2nd ed. Philadelphia, JB Lippincott, 1993 pp 713-738. Green DM, Beckwith JB, Breslow NE, et al: Treatment of children with stages I1 to IV anaplastic Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 1994;12:2126-2131. Green DM, Breslow NE, Beckwith JB, et al: Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-histology Wilms' tumors: A report from the National Wilms' Tumor Study. J Clin Oncol 1993;ll: 91-95.

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60. Green DM, Breslow NE, Beckwith JB, et al: Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:237-245. 61. Green DM, Breslow NE, Beckwith JB, et al: Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:37443751. 62. Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 2001;19:1926-1934. 63. Green DM, Jaffe N: The role of chemotherapy in the treatment of Wilms' tunlor. Cancer 1979;44:52-57. 64. Green DM, Peabody EM, Nan B, et al: Pregnancy outcome after treatment for Wilms' tumor: A report from the National Wilms' Tumor Stttdy Group. J Clin Oncol 2002;20: 2506-2513. 65. Green DM, Zevon MA, Reese PA, et al: Second malignant tumors following treatment during childhood and adolescence for cancer. Med Pediatr Oncol 1994;22:1-10. 66. Gronskov K, Olsen JH, Sand A, et al: Population-based risk estimates of Wilms' tumor in sporadic aniridia: A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet 2001;109:11-18. 67. Grundy P, Koufos A, Morgan K, et al: Familial predisposition to Wilms' tumour does not map to the short arm of chron~osome11. Nature 1988;336:374376. 68. Grundy P, Telzerow PE, Paterson MC, et al: Chromosome 11 uniparental isodisomy predisposing to embryonal neoplasms. Lancet 1991;338:1079-1080. 69. Grundy PE, Telzerow PE, Breslow N, et al: Loss of heterozygosity for chromosonles 16q and Ip in Wilms' tumors predicts an adverse outcome. Cancer Res 1994;54:2331-2333. 70. Gururangan S, Dorman A, Ball R, et al: DNA quantitation of Wilms' tumour (nephroblastoma) using flow cytometry and image analysis.J Clin Pathol 1992;45:498-501. 71. Henry I, Bonaiti-Pellie C, Chehensse V, et al: Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature 1991;351:665-667. 72. Henry I, Grandjouan S, Couillin P, et al: Tumor-specific loss of 11p15.5 alleles in del 1lp13 Wilms' tumor and in familial adrenocortical carcinoma. Proc Natl Acad Sci U S A 1989;86:3247-3251. 73. Hing S, Lu YJ, Summersgill B, et al: Gain of l q is associated with adverse outcome in favorable histology Wilms' tumors. Am J Pathol 2001;158:393-398. 74. Hogeboom CJ, Grosser SC, Guthrie KA, et al: Stature loss following treatment for Wilms' tumor. Med Pediatr Oncol 2001;36:295-304. 75. Hu M, Zhang GY, Arbuckle S, et al: Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene. Nephrol Dial Transplant 2004;19:223-226. 76. Huang EY, Mascarenhas L, Mahour GH: Wilms' tumor and horseshoe kidneys: A case report and review of the literature. J Pediatr Surg 2004;39:207-212. 77. Huff V, Compton DA, Chao LY, et al: Lack of linkage of familial Wilms' tumour to chromosomal band llp13. Nature 1988;336:377-378. 78. Huff V, Reeve AE, Leppert M, et al: Nonlinkage of 16q markers to familial predisposition to Wilms' tumor. Cancer Res 1992;52:6117-6120. 79. Jenkner A, Camassei FD, Boldrini R, et al: 111 Renal neoplasms of childhood: A clinicopathologic study. J Pediatr Surg 2001;36:1522-1527.

80. Kalapurakal JA, Peterson S, Peabody EM, et al: Pregnancy outcomes after abdominal irradiation that included or excluded the pelvis in childhood Wilms' tumor survivors: A report from the National Wilms' Tumor Study. IntJ Radiat Oncol Biol Phys 2004;58:13641368. 81. Kayton ML, Rowe DH, O'Toole KM, et al: Metastasis correlates with production of vascular endothelial growth factor in a murine model of human Wilms' tumor. J Pediatr Surg 1999;34:743-747. 82. Knudson AG, Strong LC: Mutation and cancer: A model for Wilms' tumor of the kidney. .J Natl Cancer Inst. 1972;48:313-324. 83. Ladd WE, White RR: Emb~yomaof the kidney (Wilms' tumor). JAMA 1941;117:1859-1863. 84. Leape LL, Breslow NE: The surgical treatment of Wilms' tumor: Results of the National Wilms' Tumor Study. Ann Surg 1978;187:351-356. 85. Lee MP, DeBaun MR, Mitsuya K, et al: Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLZT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor I1 imprinting. Proc Natl Acad Sci U S A 1999;96: 5203-5208. 86. Lee SB, Haber DA: Wilms' tumor and the WT1 gene. Exp Cell Res 2001;264:7499. 87. Li CM, Guo M, Borczuk A, et al: Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchynalepithelial transition. Am J Pathol 2002;160:2181-2190. 88. Lin RY, Argenta PA, Sullivan KM, et al: Diagnostic and prognostic role of basic fibroblast growth factor in Wilms' tumor patients. Clin Cancer Res 1995;1:327-331. 89. Little MH, Williamson KA, Mannens M, et al: Evidence that WTl mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum Mol Genet 1993; 2:259-264. 90. Lodge AJ, Jaggers J, Adams D, et al: Vascular control for resection of suprahepatic intracaval Wilms' tumor: Technical considerations. .J Pediatr Surg 2000;35: 1836-1837. 91. Look AT, Hayes FA, ShusterJ, et al: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastorna. A Pediatric Oncology Group Study. J Clin Oncol 1991;9:581-591. 92. Loworn HN Srd, Savani RC, Ruchelli E, et al: Serum hyaluronan and its association with unfavorable histology and aggressiveness of heterotransplanted Wilms' tumor. J Pediatr Surg 2000;35:1070-1078. 93. Lu YJ, Hing S, Williams R, et al: Chromosome l q expression profiling and relapse in Wilms' tumour. Lancet 2002;360:385-386. 94. Marsden HB, Lawler W: Bone-metastasizing renal tumor of childhood. Br J Cancer 1978;38:437-441. 95. Maw MA, Grundy P, Millow LJ, et al: A third Wilms' tumor locus on chromosome 16q. Cancer Res 1992;52: 30943098. 96. McNeil DE, Brown M, Ching A, et al: Screening for Wilms' tumor and hepatoblastoma in children with BeckwithWiedemann syndrome: A cost-effective model. Med Pediatr Oncol 2001;37:349-356. 97. Mertens A, Neglia J, Yasui Y, et al: Mortality rates and causes of death among 5-year survivors of childhood and adolescent cancer. Proc Am Soc Clin Oncol 1999;19:569a. 98. Miller RW, Fraumeni JG, Manning MD: Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital abnormalities. N Engl J Med 1964;270: 922-930.

CHAPTER

99. Mitchell C, Jones PM, Kelsey A, et al: The treatment of Wilms' tumour: Results of the United Kingdom Children's Cancer Study Group (UKCCSG) second Wilms' tumour study. Br J Cancer 2000;83:602-608. 100. Montgomery BT, Kelalis PP, BLute ML, et al: Extended followup of bilateral Wilms' tumor: Results of the National Wilms' Tumor Study. J Urol 1991;146:514518. 101. Narahara K, Kikkawa K, Kimira S, et al: Regional mapping of catalase and Wilms' tumor-aniridia, genitourinary abnormalities, and mental retardation triad loci to the chronlosome segment llp1305-p1306. Hum Genet 1984;66:181-185. 10'2. Neville H, Ritchey ML, Shamberger RC, et al: The occurrence of Wilms' tumor in horseshoe kidneys: A report from the National Wilms' Tumor Study Group (NWTSG). J Pediatr Surg 2002;37:11341137. 103. Okutsu T, Kuroiwa Y, Kagitani F, et al: Expression and imprinting status of human PEG8/IGF2AS, a paternally expressed antisense transcript from the IGF2 locus, in Wilms' tumors. J Biochem 2000;127:475-483. 104. Osler W: Two cases of striated myo-sarcoma of the kidney. J Anat Physiol 1879;14. 105. Owens CM, Veys PA, Pritchard J, et al: Role of chest computed tomography at diagnosis in the management of Wilms' tumor: A study by the United Kingdom Children's Cancer Study Group. J Clin Oncol 2002;20: 2768-2773. 106. Pappo AS, Crist WM, Kuttesch J, et al: Tumor-cell DNA content predicts outcome in children and adolescents with clinical group 111 embryonal rhabdomyosarcoma. J Clin Oncol 1993;11:1901-1905. 107. Park S, Bernard A, Bove KE, et al: Inactivation of WTl in nephrogenic rests, genetic precursors to Wilms' tumour. Nat Genet 1993;5:363-367. 108. PelletierJ, Bruening W, Kashtan CE, et al: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991;67:437-447. 109. Pelletier J, Bruening W, Li FP, et al: WTl mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 1991;353:431-434. 110. Plesko I, Kramarova E, Stiller CA, et al: Survival of children with Wilms' tumour in Europe. Eur J Cancer 2001; 37:736-743. 111. Porteus MH, Nark001 P, Neuberg D, et al: Characteristicsand outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol2000;18:2026-2031. 112. Rahman N, Arbour L, Houlston R, et al: Penetrance of mutations in familial Wilms' tumor gene FW1. J Natl Cancer Inst 2000;96:650-652. 113. Re GG, Hazen-Martin DJ, Sens DA, et al: Nephroblastoma (Wilms' tumor): A model system of aberrant renal development. Semin Diagn Patho11994;11:126-135. 114. Reeve AE, Sih SA, Raizis AM, et al: Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells. Mol Cell Biol 1989;9:1799-1803. 115. Renaud EJ, Liu D, Pipe SW, et al: Inferior vena cavectomy for nonexcisable Wilms' tumor thrombus. J Pediatr Surg 2001;36:526-529. 116. Riccardi VM, Sujansky E, Smith AC, et al: Chromosomal imbalance in the aniridia-Wilms' tumor association: 1l p interstitial deletion. Pediatrics 1978;61:604610. 117. Ritchey ML: The role of preoperative chemotherapy for Wilms' tumor: The NWTSG perspective. National Wilms' Tumor Study Group. Semin Urol Oncol 1999;17: 21-27.

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118. Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms' tumor patients: A report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 1996;26:75-80. 119. Ritchey ML, Kelalis PP, Breslow N, et al: Surgical complications after nephrectomy for Wilms' tumor. Surg Gynecol Obstet 1992;1992:507-514. 120. Ritchey ML, Kelalis PP, Haase GM, et al: Preoperative therapy for intracaval and atrial extension of Wilms' tumor. Cancer 1993;71:41044110. 121. Ritchey ML, Pringle K, Breslow N, et al: Management and outcome of inoperable Wilms' tumor: A report of National Wilms' Tumor Study-3. Ann Surg 1994;220:683-690. 122. Ritchey ML, Shamberger RC, Haase G, et al: Surgical complications after primary nephrectomy for Wilms' tumor: Report from the National Wilms' Tumor Study Group. J Am Coll Surg 2001;192:63-68. 123. Ross JH, Kay R: Surgical considerations for patients with Wilms' tumor. Semin Urol Oncol 1999;17:33-39. 124. Shamberger RC, Guthrie KA, Ritchey ML, et al: Surgeryrelated factors and local recurrence of Wilms' tumor in National Wilms' Tumor Study 4. Ann Surg 1999;229: 292-297. 125. Shamberger RC, Ritchey ML, Haase GM, et al: Intravascular extension of Wilms' tumor. Ann Surg 2001;234:116-121. 126. Shearer P, Kapoor G, Beckwith JB, et al: Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: A report from the National Wilms' Tumor Study Group. J Pediatr Hematol Oncol 2001;23:109-111. 127. Shurin SB, Gauderer MW, Dahms BB, et al: Fatal intraoperative pulmonary embolization of Wilms' tumor. J Pediatr 1982;101:559-562. 128. Smith MB, Xue H, Strong LC, et al: Forty-year experience with second malisznancies after treatment of childhood cancer: Analysis of outcome following the development of the second malignancy. J Pediatr Surg 1993;28:1342-1348. 129. Sorensen K, Levitt GA, Bull C, et al: Late anthracycline cardiotoxicity after childhood cancer: A prospective longitudinal study. Cancer 2003;97:1991-1998. 130. Sredni ST, de Camargct B, Lopes LF, et al: Immunohistochemical detection of p53 protein expression as a prognostic indicator in Wilms' tumor. Med Pediatr Oncol 2001;37:455-458. 131. Tagge EP, Hanson P, Re GG, et al: Paired box gene expression in Wilms' tumor. J Pediatr Surg 1994;29:134141. 132. Toretsky JA, Zitomersky NL, Eskenazi AE, et al: Glypican-3 expression in Wilms' tumor and hepatoblastoma. J Pediatr Hematol Oncol 2001;23:496-499. 133. Tournade MF, Com-Nougue C, de KrakerJ, et al: Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months: Results of the Ninth International Society of Pediatric Oncology Wilms' Tumor Trial and Study. J Clin Oncol 2001;19:488-500. 134. Trueworthy R, Shuster J,Look T, et al: Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: A Pediatric Oncology Group Study. J Clin Oncol 1992;10:606-613. 135. Vujanic GM, Kelsey A, Mitchell C, et al: The role of biopsy in the diagnosis of renal tumors of childhood: Results of the UKCCSG Wilms' tumor study 3:Med Pediatr Oncol 2003;40:18-22. 136. Vujanic GM, Sandstedt B, Harms D, et al: Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002;38:79-82. 0

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137. Weeks DA, Beckwith JB, Mierau GW, et al: Rhabdoid tunlor of kidney: A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol 1989;13:439-458. 138. White GR,Kelsey AM, Varley JM, et al: Somatic glypican 3 (GPC3) mutations in Wilms' tumour. Br J Cancer 2002; 86:1920-1922. 139. Wilms M: Die Mischgeschwuelste der Niere. In Leipzig, 1899, Arthur Georgi.

140. Zoeller G. Pekrun A. Lakomek M. et al: Wilms' tumor: The problem of diagnostic accuracy in children undergoing preoperative chemotherapy without histological tumor verification. J Urol 1994;151:169-171. 141. Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilms' tumor: A report from the National Wilms' Tumor Study Pathology Center. Hum Pathol 1988;19: 1199-1209.

Neuroblastoma Jay L. Grosfeld

Neuroblastoma is one of the most common solid tumors in infancy and childhood. This neoplasm, of neural crest origin, may arise in the adrenal medulla and along the sympathetic ganglion chain from the neck to the pelvis. The clinical course is quite variable, as this highly malignant tumor demonstrates unusual behavior. Although instances of spontaneous regression and tumor maturation from a malignant to a benign histologic form have been the disease is progressive in many cases. Survival in children with other malignancies, such as Wilms' tumor, rhabdomyosarcoma, acute lymphocytic leukemia, germ cell tumors, Hodgkin's disease, and non-Hodgkin's lymphoma, has been significantly improved by the aggressive use of combined treatment modalities, but the outlook for many children with advanced neuroblastoma remains dismal.'j,27,67,74,77,83,116 This neoplasm exhibits great heterogeneity in its behavior and represents a significant challenge to practitioners caring for affected children. Primitive neuroblasts can be identified in the fetal adrenal gland in the 10th to 12th intrauterine week. The nodules increase in number by 20 weeks' gestation but gradually diminish in number toward the end of gestation. Neuroblastoma in situ in the adrenal gland is seen in 1 of every 260 neonates who die of congenital heart disease and in as many as 1 in 39 infants in the first 3 months of life who die from other causes. The clinical incidence of the tumor is approximately 1 in 7500 to % 2 ~ , ~ ~ , ~ ~is responsible 10,000 ~ h i l d r e n . ~ ~Neuroblastorna for 10% of all childhood tumors and 15% of all cancer deaths. The exact cause remains unknown. There are 700 cases diagnosed annually in the United States. Approximately 40% of cases are diagnosed by age 1 year, 75% by 7 years, and 98% by 10 years.Z7 More than half the patients are younger than 2 years at the time of diagnosis.7Weuroblastoma is slightly more common in boys than in girls, with a ratio of 1.2:1.0.27~74It is the most common intra-abdominal malignancy in newborns. Although a decrease in cancer incidence and mortality has been observed in adults, the incidence of cancer in infants in the United States increased from 189 cases per million to 220 cases per million from 1980 to 1990.1'5 Male infants have an increased rate of central nervous system tumors, neuroblastoma, and retinoblastoma, while girls have an

increased rate of teratoma and hepatoblastoma.nj The embryonal nature of neuroblastoma has been well documented by its identification on prenatal ultrasonography, and the tumor has been known to rarely invade the placenta during the antenatal period.X.'2.~6,~0~,1()9,146,17II226 More than 55 cases of antenatally discovered neuroblastoma have been reported in the literature since the original description by Fenart et al. in 1983." The masses are usually identified during ultrasound examinations performed after 32 weeks' gestation. The earliest reported instance was observed at 18 weeks.10" Mothers of infants with congenital neuroblastoma occasionally experience flushing and hypertension during pregnancy as a result of catecholamine released from the fetal tumor in utero. The neo~lasmhas been described in twins on many occasions, and familial occurrences in both mother and child and father and son have been reported.37.70.171 Concordance for neuroblastoma in twins-during infancy indicates that hereditary factors may be predominant, whereas discordance in older twins suggests that a random mutation may be more important. The median age for the occurrence of familial neuroblastoma is 9 months, in contrast to 18 months in the general population. Maris et al.I4j observed that 20% of patients with familial neuroblastoma have bilateral or multifocal tumors and reported evidence for a hereditary neuroblastoma predisposition locus on chromosome 16~12-13.Neuroblastoma has been observed in infants with Beckwith-Wiedemann syndrome (BWS), neurofibromatosis (von ~ecklin~hausen's disease), Hirschsprung's disease, central hypoventilation syndrome (Ondine's curse), fetal alcohol syndrome, and in offspring of mothers taking phenytoin (fetal hydantoin syndrome) for seizure d i s 0 r d e r s . ~ ~ ~ ~ ~ ~ ~ ~ , ~ ~it~is2unlikely 0 W t h o uthat g h environmental factors play an important role in causing this tumor, neuroblastoma has been noted among infants of mothers receiving medical therapy for vaginal infection during pregnancy and with paternal occupational exposure to electromagnetic fields.27 Neuroblastoma may occur at any site where neural crest tissues are found in the embryo. The neuroblast is derived from primordial neural crest cells that migrate from the mantle layer of the developing spinal cord. Tumors may arise in the neck, posterior mediastinum,

468

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MAJORTUMORSOF CHILDHOOD

Mediastinal 20%

I Neck <5% 1 ::$ ',

8

I Adrenal 50% 1 . - .

Distribution of cases of neuroblastoma at each of the primary tumor sites. Primary tumors most commonly occur in the adrenal gland.

retroperitoneal (paraspinal) ganglia, adrenal medulla, ~ 75% , ~ ~ of , ~cases, ~,~~ and pelvic organ of Z u ~ k e r k a n d l . ~In the tumor is located in the retroperitoneum, in either the adrenal medulla (50%) or the paraspinal ganglia (25%). In 20% of cases, the primary tumor is in the posterior mediastinum. Less than 5% of tumors occur in the neck or pelvis (Fig. 28-1).27,73,74,83Primary intracranial S . addition, ~ ~ , ~ ~a~ cerebral neuroblastoma also O C C U ~ In teratoma in an infant may occasionally contain foci of neuroblastoma. Rare cases of neuroblastoma arising in the bladder have also been reported.60The fate of the neuroblasts can follow one of three clinical pathways: (1) spontaneous regression, (2) maturation by differentiation from neuroblastoma to a benign ganglioneuroma, or most frequently, (3) rapid progression to a highly malignant tumor that is often resistant to treatment.

MASS SCREENING In an effort to identify early cases of neuroblastoma that were amenable to cure, mass screening programs were initiated in Japan in 1985, evaluating urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels in infants a t 6 months of age. These studies'identified a large number of infants with neuroblastoma. The survivalin these cases was exceptionally high compared with the survival in patients who present with clinical disease diagnosed by conventional methods. The Japanese screening effort doubled the actual incidence of neuroblastoma than 1 vear but neither decreased the in-infants vounger , " number of cases observed in older children nor improved Sawada the survival of children older than 1 year.19~27J99~200 et al.199,200reported a 96% survival rate in 170 cases of neuroblastoma identified bv screening.. " These observations suggest that neuroblastomas identified by screening were most likely biologically favorable tumors that spontaneouslv, re~resskd.199 However, a small number of screened " patients have had tumors with unfavorable biologic markers and a poor prognosis, and a few screened patients who tested negative at age 6 months later (at 12 to 18 months of age) developed highly aggressive n e u r o b l a s t o m a ~ . ~ ~ ~ In general, mass screening has provided important information regarding the natural history of this enigmatic tumor and has identified a group of tumors that

clearly regress and represent a biologically favorable form of tumor, in contrast to that noted in older children.147 Prospective, population-based, controlled screening trials in Quebec minimized the rate of false-positive cases but had an overall sensitivitv of onlv 45%.The results A~German ~ study were similar to the findings in J a ~ a n . 2 offered screening to 2.6 million infants between 9 and 18 months of age. This effort identified 149 cases of neuroblastoma in 1800 screened infants, demonstrating a predictive value of 8%.202 The German investigators estimated that two thirds of the tumors detected by screening would have regressed spontaneously. The potential risks were highlighted by the fact that all three children who died in the group detected by screening had localized disease and succumbed from complications of treatment. These studies in North ~ m e r i c aand Europe suggest that screening may result in an overdiagnosis of neuroblastoma and the institution of unnecessary therapies.201 However, the results observed in screening studies are valuable and should help minimize treatment in a substantial subset of infants diagnosed with early-stage neuroblastoma that has an excellent chance of either maturing or spontaneously regressing.239 In a limited trial of expectant observation in 11 patients with localized disease detected by mass screening, all tumors decreased in size during the observation period.2" Oue et al.l69 observed 22 patients with tumors that were identified by screening; 13 (59%) spontaneously regressed, and 9 underwent resection for increasing size. Although none had N-myc amplification, other unfavorable biologic factors were noted in 8 babies, including diploidy, unfavorable histology, and chromosomal deletion ( l p ) ,yet all the babies survived.169Some have suggested that there are compelling medical and psychologi~lreasons (especially among parents in false-positive cases) for the cessation of neuroblastoma screening.54238 Following the cessation of screening elsewhere in the world, the Ministry of Health in Japan discontinued its mass screening program in April 2004.169

CLINICAL PRESENTATION Neuroblastoma is a tumor with multiple clinical manifestations related to the site of the primary tumor, the presence of metastases, and the production of certain metabolic tumor by-products. Fifty percent to 75% of reported cases present with an abdominal mass. The tumor may be hard, nodular, fixed, and painful on palpation. Generalized symptoms including weight loss, failure to thrive, abdominal pain and distention, fever, and anernia.27.73.74.83 Hypertension is found in 25% of cases and is related to the production of catecholamines by the tumor. Instances of hypercalcemia have been observed in association with neuroblastoma, and hernoperitoneum caused by sudden spontaneous rupture of the nedplasm has also been rep0rted.~22~ Neoplasms arising in the upper mediastinum or neck may involve the stellate ganglion and cause Horner's syndrome, characterized by ptosis, miosis, enophthalmos, anhydrosis, and heterochromia of the iris on the affected side.73,74,83 Metastases to the bony orbit may produce

CHAPTER

28

Neuroblastoma

469

An autoimmune phenomenon related to an antigenantibody complex has been suggested.9,19j.207Of interest is the fact that these unusual neurologic symptoms may persist even after tumor resection. Poor school performance and learning deficits are not uncommon-in these children.l95,196 Infants with neuroblastoma, ganglioneuroblastoma, and, occasionally, benign ganglioneuroma may present with intractable diarrhea characterized by watery, exploThe diarrhea is related sive stools and hyp0kalemia.42,~~J2~ to the production of vasoactive intestinal polypeptide . Child with bilateral orbital ecchyrnoses ("panda eyes" (VIP) by the t~mor.%,58,74,12~ These tumors often have or "raccoon eyes") resulting from orbital metastases from somatostatin receptors. neuroblastoma. Neuroblastoma may. spread by direct extension into surrounding structures, lymphatic infiltration, or hematogenous metastases. Regional and distant lymph proptosis or bilateral orbital ecchymosis-often referred nodes, liver, bone marrow, and bone cortex are frequently to as "panda eyes" or "raccoon eyes" (Fig. 28-2). The latin~olved.~2,7~,~7,83~9~~~65 Patients with bone cortex metastases ter finding in a child without a history of trauma should have an ominous prognosis. Bone metastases occur in sites always raise the index of suspicion for the presence of a containing red marrow and involve the metaphyseal areas malignancy. Mediastinal tumors may be associated with of long bones in addition to the skull, vertebral column, pelvis, ribs, and sternum.27~74J7.83Bone lesions may cause respiratory distress, due to the tumor's interference with extreme pain. In some cases, the clinical presentation may lung expansion, and dysphagia caused by extrinsic pressure on the esophagus (Fig. 28-3)..i~66~74~24Wediastinalbe characterized by a child's refusal to walk because of leg and paraspinal retroperitoneal lesions may manifest with pain due to bone metastases. Occasionally, patients with paraplegia related to tumor extension through an interadvanced disease present with a bleeding diathesis related vertebral foramen, resulting in a dumbbell- or hourglassto thrombocytopenia from extensive involvement of bone shaped lesion that may cause extradural compression of marrow and interference with hepatic production of clot8 , 2patients, ~2 cauda the spinal ~ o r d . ~ " ~ ~ 8 p ~ ~In~ ,a~ 9few ting factors by liver metastases. Multiple subcutaneous equina syndrome has also been observed. Pelvic tumors skin nodules and hepatomegaly may occur in infants with may be associated with bladder and bowel dysfunction. stage IV-S neuroblastoma. Hematogenous metastases to Anemia is often related to bone marrow invasion by the the brain, spinal cord, and heart are unusual. Brain metastumor. Excessive catecholamine production by the tases usualiv manifest in older children with headaches tumor may result in flushing, sweating, and irritability. Lung metastases are found on chest and ~eizures.'~Jl~ radiographs in only 4% of patients."' This may be the Acute cerebellar ataxia, characterized by opsomyoclonus result of direct extension to the lung from mediastinal and nystagmus ("dancing eye syndrome"), has been observed.g~1~1~1g5~196~~07 TWOthirds of these cases have lymph nodes or diffuse hematogenow-spread, presenting occurred in infants with mediastinal neuroblastoma. The with a radiographic pattern that may be confused with pulmonary edema or interstitial pneumonia.222 Occasionally, involuntary muscular contractions and random eye movements are unrelated to metastases. The cause of lung involvement by intralymphatic metastases (not seen on chest radiographs) is noted at autopsy. this unusual presentation of neuroblastoma is unknown.

A

B

A, Plain chest radiograph shows the presence of a left upper thoracic tumor. B, Computed tomography scan documents a mass in the posterior nlediastinum that contains calcium, suggestive of a neuroblastoma.

470

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DIAGNOSIS Diagnosis of neuroblastoma is made through a variety of imaging and isotopic studies, serum and urine determinations, and histologc and genetic evaluation of tumor tissue. On the plain abdominal radiograph, approximately 50% of cases may show finely stippled tumor calcification.73,74,77 Radiographs also may show displacement of bowel gas by a mass. Paraspinal widening is commonly found with celiac axis tumors. Chest radiographs may show a posterior mediastinal tumor or paraspinal widening above the diaphragm from extension of an abdominal tumor. Computed tomography (CT) can demonstrate tumor calcification ~ ~ ~ CT in approximately 80% of cases (Fig. 2 8 - 4 ) . *With studies using contrast enhancement, one can often distinguish kidney and liver from adrenal and paraspinal lesions and evaluate for intracranial extension of skull metastases.is??,7Wagnetic resonance imaging (MRI) is extremely useful in detecting intraspinal tumor extension and, in some instances, the tumor's relationship to major vascular structures. Helical (spiral) CT with three-dimensional reconstruction is also a useful method of evaluating this latter relationship. The workup of patients with retroperitoneal tumors includes an initial upright radiograph of the abdomen, an ultrasound examination to distinguish a cystic from a solid lesion, and an evaluation for potential obstruction or compression of the inferior vena cava. As a rule, obstruction of the inferior vena cava in patients with neuroblastoma suggests the presence of an ~,'~ CT is perinitially unresectable l e ~ i o n . ~Abdominal formed with intravenous contrast material so that an intravenous urogram can be acquired during the same In most instances, paraspinal or adrenal neuroblastoma causes lateral or downward displacement of the ipsilateral kidney or ureter (or both). A separate intravenous urogram is not necessary. A long bone survey, isotopic bone scintigraphy (using the bone-seeking isotopes technetium and metaiodobenzylguanidine [MIBG]), and multiple MIBG also bone marrow aspirates are also 0btained.7~,75,77.93 images the primary tumor in the adrenal medulla. Isotopic bone scans show a close correlation with the radiographic

skeletal survey and are occasionally more sensitive." Falsepositive bone scans can occur in cases of recent bone trauma or inflammation. The bone-seeking isotopes are picked up by metastatic foci in the bone and by the punctate calcifications in the primary tumor (Fig. 28-5).73,74 Demonstration of the bone-seeking isotope in a retroperitoneal or posterior mediastinal mass suggests that the lesion is a neuroblastoma. Although angiography was once performed to evaluate many childhood tumors, this test is rarely used today because vascular structures can be readily identified by other imaging studies such as helical CT or magnetic resonance angiography (Fig. 28-6). Pelvic neuroblastoma may manifest with both urinary symptoms and constipation. The tumor, usually palpable on rectal examination, must be differentiated from presacral teratoma, yolk sac tumor, nonosseous Ewing's tumor, and pelvic rhabdomyosar~oma.~~,~s Because neuroblastoma is a tumor derived from neural crest cells, it may secrete hormonal products and is likely a member of the amine precursor uptake and decarboxylation (APUD) family of tumors. More than 90% of children with neuroblastoma have tumors that produce high levels of catecholamines or their by-products. Quantification of catecholamine by-product secretion is Adrenaline, best done by 24hour urine c01lection.l~~ noradrenaline, dopamine, metanephrine, HVA, VMA, and vanillylglycolic acid levels are determined. Children with immature, more undifferentiated tumors tend to excrete higher levels of certain by-products (e.g., HVA).73 Patients with more mature tumors excrete more VMA. In rare instances, however, the tumor does not secrete excessive catecholamines. Prasad et al.177suggested that these are parasympathetic neuroblastomas that secrete increased levels of acetylcholine and fail to metabolize tyrosine to dopamine. Patients with advanced malignancy have elevated urine concentrations of cystathionine and homoserine; increased serum levels of neuron-specific enolase, ferritin, and lactic dehydrogenase; and, in 25%

-

Adoniinal computed tomography shows a retroperitoned1 mass with stippled calcificatioil, consistent with neuroblastoma.

.

1'2'-MIBG scintiscarl shows the presence of bone metastases and uptake of the isotope in a prirrlary tumor in the adrenal gland.

CHAPTER

A

28

471

Neuroblastoma

6

Helical computed tomography scan with three-dimensional reconstruction of a neuroblastoma arising near the celiac axis. A, Anterior view indicates that the tumor does not involve the branches of the celiac axis. B, Lateral view demonstrates that the superior mesenteric artely passes through the tumor. (SPPco1orplale.j

of cases, sera positive for carcinoembryonic antiAlthough these observations are of historgen.m~167~216.'28,'44 ical interest, none of these serum levels are independent prognostic factors, nor are they currently used to determine treatment. Although histologic examination of tissue is the key to the conclusive diagnosis of neuroblastoma, in advanced disease, rosettes of tumor cells in bone marrow aspirate and increased urinary excretion of VMA or other catecholamine by-products are often indicative of the diagnosis. 1mmunolog;lc analysis of bone marrow aspirate may be more sensitive than conventional analysis in detecting tumor ce1ls.l" Serial immunocytologic analysis of peripheral blood samples have also identied circulating neuroblasts, documenting tumor dissemination.

STAGlNG Various staging schemes for neuroblastoma were used in the past, including Evans's criteria from the Children's

1

Stage

IIB 111 IV IV-S

Description

Cancer Group (CCG)," the St. Jude staging system" used by the Pediatric Oncology Group (PO(;), a TNM (tumor, lymph node, metastasis) status system employed by the International Union Contra Cancer in Europe, and the Japanese Neuroblastoma Study Group staiing system. These staging criteria were in basic agreement regarding localized, completely resected lesions; instances of metastasis to the bone cortex; and infant5 with Evans's stage IV-S tumors. They disagreed on other aspects of staging, including Evans's stage 111 cases and the importance of lymph node involvement. In 1988 an international staging - ., system , way devised that established a common set of criteria that could be used worldwide and would permit the accrual of large numbers of cases and valid comparisons of data (Table 28-1) .29 The International Neuroblastoma Staging System (INSS) uses certain features of the POG and CCG sistems 'and identifies distinct prognostic groups. These criteria were revised by Brodeur et al. in 1993.ZHIn 2001 the CCG and POG merged with the National Wilms' Tumor

-

--

--

--

Localized tumor confined to area of origin; complete excision, with or without microscopic residual disease; ipsilateral and contralateral lymph nodes negative (nodes attached to primary tumor and removed en bloc with it may be positive) Unilateral tumor with incomplete gross excision; ipsilateral and contralateral lymph nodes negative Unilateral tumor with complete or incomplete excision; positive ipsilateral, nonadherent regional lymph nodes; contralateral lymph nodes negative Tumor infiltrating across the midline with or without lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement or bilateral infiltration (unresectable) Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, or other organs Localized primary tumor as defined for stage I or II with dissemination limited to liver, skin, or bone marrow (limited to infants younger than 1yr)

From Brodeur GM, PritchardJ, Berthold F, et al: Revision of the internationalcriteria for neuroblastomadiagnosis, stagingand response to treatment. J Clin Oncol 1993;11:1466-1477; Brodeur GM, Seeger RC, BarrettA, et al: Internationalcriteria for diagnosis, staging, and responseto treatment in patients with neuroblastoma.J Clin Oncol 1988;6:1874-1881.

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a high MKI, and a dismal outcome. A report by Shimada et a1?12 documented that both histology and ~ - & c a m ~ l i fication provided prognostic information that was independent of staging. Neuroblastomas with N-myc amplification have a characteristic histopathologic phenotype and a rapidly progressive clinical course. The International Neuroblastoma Pathology Classification (INPC) adopted the Shimada classification ~ - 4 ~age-linked ~~2~~ with some minor m o d i f i ~ a t i o n s . ~ ~This PATHOLOGY AND HISTOLOGY classification is both prognostically significant and bioThe pathologic classification of neuroblastoma has been logically relevant. The current system subdivides the revised, and histologic features of the tumor have been undifferentiated subtype into undifferentiated and poorly 2~2 established that have important prognostic v a l ~ e . l l l ~ 2 ~ ~ ~differentiated tumors; changes the name of stroma-rich, The most useful system developed is the Shimada classiwelldifferentiated tumors to ganglioneuroma maturing; fication, which divides neuroblastic tumors into ageand adds a descriptive Schwannian, stroma-dominant related favorable and unfavorable histologic categories Age remains a critical character to gangli0neuroma.2~~ based on whether the tumor exhibits a stroma-rich or prognostic factor, and the grade of differentiation and MKI have different prognostic effects, depending on the stroma-poor appearance (Table 28-2).2l Stroma-rich tumors are characterized by extensive Schwannian patient's age at diagnosis. Although the presence of calstroma and signs of neuroblastic differentiation (i.e., cification was thought to favorably influence survival, developed nuclear and cytoplasmic features of ganglion further studies demonstrated that calcification does not Favorable cells). Stroma-poor tumors contain immature, undifferhave an independent prognostic impa~t.~~l>208 Shimada histology was associated with an 85% survival entiated neural crest cells and have a high mitotic karyorrhexis index (MKI). The MKI refers to nuclear rate, compared with 41 % for unfavorable histologic types. fragmentations and is determined by the sum of the All ganglioneuroblastoma nodular (GNBn) cases were number of necrotic tumor cells, the number of cells with initially classified as unfavorable tumors. Umehara et al.230 were the first to define subsets of these specific neoplasms mitosis, and the number of cells with malformed, lobulated, that exhibit different behavior. Peuchmaur et al.l73 or pyknotic nuclei per 5000 cells examined. The MKI varies with age; a high MKI value in infants younger than recently revised the INPC by dividing GNBn cases into two prognostic subsets-favdrable and unfavorable. The 18 months is greater than 200/5000 cells, and for those older than 18 months it is greater than 100/5000 cells. All favorable type was associated with an 86% event-free surpatients older than 5 years have unfavorable histology. vival, whereas the unfavorable type (two thirds of cases) Stroma-poor tumors often have N-myc amplification, had only a 32% event-free survival. Children with the favorable subset of GNBn have an overall survival of greater than 90%, compared with 33.2% for the unfavorable GNBn subset (Fig. 28-'7).17' Large cell neuroblastoma has been identified as a distinct phenotype with aggressive clinical behavior.22Vhese tumors have unfavorable histologic features, including monomorphous undifferentiated neuroblasts, a low incidence of calcification, and a high " MKI. Immunohistochemical studies Favorable Unfavorable showed that large cell neuroblastoma cells stained posiAppearance Histology Histology tive for neuron-specific enolase, prodrug gene products, Stroma rich Well differentiated Ganglioneuroblastoma, and tyrosine hydroxylase and were negative for CD99.229 (ganglioneuroma) nodular On gross examination, neuroblastoma usually appears Ganglioneuroblastoma, as a highly vascular purple-gray mass that is often solid intermixed but occasionally cystic. The tumor has an easily ruptured, Stroma poor friable pseudocapsule that may lead to significant hemor(i.e., neurorhage during operative manipulation. The tumor is often blastoma) necrotic, especially the undifferentiated form. Mature MKI <4% MKI >4%or Age < I 8 mo tumors (ganglioneuromas) have a more solid consistency undifferentiated and frequently have a fleshy white color. The histologic MKI >2% or Age 18-60 mo MKI <2% and pattern may be quite variable. Primitive stroma-poor differentiating undifferentiated or poorly differentiated neuroblastomas may be indistinguishable from other None All Age >5 yr small, blue round dell tumors such as Ewing's tumor, rhabdomyosarcoma, or primitive neuroectodermal tumors. The neuroblast is a small round cell consisting MKI, mitotic karyorrhexis index. predominantly of the nucleus without much cytoplasm. From Shimada H, Chatten J, Newton WA Jr, et al: Histopathologic prognostic factors in neuroblastoma: Definition of subtypes of ganglioneuroblastoma and an age-linked Immature, undifferentiated tumors are characterized bv classification of neuroblastoma.J Natl Cancer lnst 1984;73:405-416;Shirnada H, closely packed small spheroid cells without any special Stram DO, Chatten J, et al: Identification of subsets of neuroblastomas by combined arrangement or differentiation.I42 Nuclei may appear histopathologic and N-myc analysis. J Natl Cancer lnst 1995;87:1470-1476. cone shaped and are hyperchromic. Rosette formation Study and Rhabdomyosarcoma Study Group to form the Children's Oncology Group (COG), which now employs the INSS for all cases of neuroblastoma. At my institution, 266 cases of neuroblastoma were staged as follows: 14 (5.2%) stage I, 52 (19.6%) stage II,62 (23.4%) stage 111,117 (44%) stage IV, and 21 (7.8%) stage IV-S.

-"

CHAPTER

International Neuroblastoma Pathology Classification. FH, favorable histology; GNBn, ganaglioneuroblastoma nodular; MKI, mitotic karyorrhexis index; %MKC, mitotic and karyorrhectic cells; UH, unfavorable histology; * classic GNBn (single, macroscopically visible, usually hemorrhagic nodule in stroma-rich, stroma-dominant tissue background; ** MKC 2%, 100 of .5000 cells; MKC 4%, 200 of 5000 cells. (From Peuchmaur M, d ' h o r e ES, Joshi W, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 2003;98:22742281.)

r >50%

t

Neuroblastoma

Absent+Ganglioneuroma maturing subtype

I

Ganglioneuroblastorna nodular classic*

Schwannian development

L

GNBn variant (with or without macroscopic b visible nodule(s)*

0 or >50%

Undifferentiated

+-

Differentiated

I -

Differentiating

. k

may be observed and is considered a sign of early tumor differentiation (Fig. 28-8). The center of each rosette is formed by a tangle of fine nerve fibers. More matureappearing, stroma-rich tumors may contain cells that resemble normal ganglion cells, with an admixture of

. - Hlstolog~cappearance of rosettes of neuroblastoma

FH

b~resentq~an~lioneuroblastoma intermixed

visible nodules

cells from a bone m a r m aspirate, an early sign of tumor dlfferennanon

473

Absent-+Microscopic neuroblastic foci

Neuroblastoma

, .

28

FH

UHIFH

UHIFH

%MKC'*

Age

Any MKI

Any age

UH

>4%

Any age

UH

Any MKI

>1.5 yr

UH

<4%

<1.5 yr

FH

>5 yr

UH

<4%

~ 1 . yr 5

FH

>4%

>1.5 yr

UH

<2%

1.5-5.0 yr

FH

>2%

1.5-5.0 yr

UH

Any MKI

Histology

histologic components characterized by abundant nerve filaments, neuroblastic rosettes, and ganglion cells all seen in a single microscopic field.70."7 On electron microscopy, neurofibrils and electrondense, membranebound neurosecretory granules may be observed. The neurosecretory granusles may be the site of conversion of dopamine to norepinephrine. These ultrastructural findings and genetic identification of the tumor tissue can usually separate neuroblastoma from other small cell tumors. Instances of spontaneous maturation from a highly malignant, undifferentiated neuroblastoma to a ganglioneuroblastoma and subsequently a benign ganglioneuroma have been observed. Ambros et al.11 reported that maturing neuroblastomas consist of both Schwann cells and neuronal cells, including ganglion cells. Schwann cells have normal numbers of chromosomes and triploid flow cytometry, in contrast to other neuronal cells, including ganglion cells.11These observations suggest that Schwann cells may be a reactive population of normal cells that invade a neuroblastoma recruited or attracted by trophic factors and may be responsible for tumor maturation and serve as an antineuroblastoma agent.10J~~2~chwann cells also produce angiogenesis inhibitors that induce endothelial cell apoptosis and may limit tumor growth by restricting angiogene~is.~~.~~

474

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BIOLOGIC AND G E N n I C ALTERATIONS Unique oncogenes are observed in tumors, such as N-myc and ras 0ncogenes.'"2~ Amplification of N-myc (>lo copies) is associated with advanced disease, tumor progression, and a poor outcome, especially in children older than 1 year.'5x7.'!).1.5'2-15X:212 Overexpression of N-myc probably impairs differentiation and promotes the proliferation of N-myc immature neural crest-derived cells.2"z"he proto-oncogene is located on the short arm of chromosome 2p24. Double minutes and long, nonbanding staining regions have been observed at this site and may represent amplified cellular genes. Approximately 30% of patients with neuroblastoma have tumors with N-myc amplification. More than 90% of patients with N-myc amplification have rapidly progressive disease and are reistant to therapy. DNA flow cytometry studies evaluating tumor ploidy indicate that children with diploid tumors have a worse outcome than those with aneuploid (hyperdiploidy or triploidy) turn or^.^^^^^ N-myc amplification is commonly associated with chromosome l p deletion and diploidy.30,89 Diploid tumors are commonly associated with an unbalanced gain of chromosome 17q, even in the absence of N-myc.11~27~"~144 Allelic loss of l l q and 14q and gains of 4q, 6q, l l q , and 18q have also been observed (Table 28-3).27 High expression of the neurotropin Trk-A (a highaffinity nerve growth factor receptor) is associated with a good prognosis and is inversely related to N-myc.lS7Jj8 Trk-A is observed in young infants and in those with stage I and stage IV-S tumors and indicates a very favorable o ~ t c o m e . l "Trk-A ~ ~ ~ is ~ associated with neural cell

Genetic Feature

Associated Factors

Risk Group

N-myc amplification (2p24 locus)

Diploidy or tetraploidy Allelic loss of l p , high Trk-B, advanced disease (stage Ill, IV)

High

More aggressive tumor associated with N-myc amplification Occurs concurrently with N-myc amplification

High Risk related to N-myc

Often associated with N-myc 70%-80%are near diploid tumors associated with disease progression

High

Few associated with N-myc amplification

Intermediate; decreased survival in patients without N-myc amplification

Allelic gain 17q gain Gain at 4q, 6p, 7q, l l q , 18q observed Allelic loss lp36

I

differentiation and tumor regression and may play a role in angiogenic inhibition. The low-affinity nerve growth factor receptor gene is another proto-oncogene that has a prognostic effect similar to Trk-A and probably influences cellular maturation.'"z7Jz() In contrast, high expression of Trk-B with its ligand BDNF may provide an autocrine survival pathway in unfavorable tumors, particularly those ~ ~ ~ ' ~patients ~ have with N-myc a m p l i f i ~ a t i o n . 2 7 ~These more advanced disease, are usually older than 1 year, and have a dismal 0utcome.27J00.~~"rk-C expression has also been identified in neuroblastoma and is usually observed in lower-stage tumors that do not express N-myc.z7,"0 Another gene has been cloned, the multidrug resistance (MDR)-associated protein gene, that is associated with chemotherapy resistance, overexpression of N-myc, and a poor outcome.lm Similarly, elevated P-glycoprotein levels are associated with progressive disease and a poor outcome.""2" Telomerase is increased in tumor cells and maintains cell viability by preserving the telomeres that . ~ ~ ~is~an ~ ~inverse protect the end of c h r o m ~ s o m e sThere relationship between telomerase levels and outcome in neuroblastoma and a direct correlation between telomerase levels and N-myc amplifi~ation.2~ CD44 is a glycoprotein found on the cell surface of a number of tumors, including neuroblastoma. High expression of CD44 is associated with a favorable outcome. In contrast, nm23 overexpression is observed in instances of advanced and The ganglioside GD2 is aggressive ne~roblastoma.14~ found on human neuroblastoma cell membranes, and increased levels are associated with active disease and tumor progression. Gangliosides inhibit the tumorspecific immune response.15'

llq

Correlates with LOH 14q Correlates with LOH l l q , inverse relationship with l p and N-myc Predisposition 16~12-13 Association Chromosome 1 0 (Ret-oncogene) 11~15.5

Intermediate

Familial neuroblastoma Multifocal and bilateral neuroblastoma

Low

Hirschsprung's disease Beckwith-Wiedemannsyndrome

Variable Low

LOH, loss of heterozygosity. Note: This table does not include changes in the genetic expression of Trk-A, -B, and -C; the multidrug-resistant protein gene; telomerase; or others that are covered elsewhere in this chapter.

1

CHAPTER

28

Neuroblastoma

475

Evaluation of the relationship between tumor angiogendisease had operative resection, but many had microesis and outcome in infants with neuroblastoma demonscopic residual disease or tumor that extended into an strates that increased tumor vascularitv characterized bv intervertebral foramen, making complete resection microvessel density correlates with advanced dissemiimpossible. Some of these patients received localized nated disease and the likelihood of metastase~.~~,~9~",ls3 radiotherapy. Others received only operation, despite Angiogenesis is controlled by the balance of humoral the presence of residual tumor; these patients had only a stimulators, inhibitors, and signal transduction pathways.40 75% to 80% cure rate.74,124,164 Angiogenesis is associated with N-myc amplification, unfaBecause of the wide variabilitv in tumor behavior in vorable histology, and poor outcome. Neuroblastoma stage I1 patients with residual disease and the poor surproduces angiogenic factors that induce blood vessel vival of those with more advanced tumors (stages I11 and IV), it became apparent that additional information was growth, including vascular endothelial growth factor required to determine the appropriate treatment. (VEFG), platelet-derived growth factor (PDGF-A), stem cell factor, and their respective receptors Flk-1, PDGFR, During the past 2 decades, a number of biologic and and C-kit.l5 Komuro et a1.'22 demonstrated that high genetic factors have been identified that are important VEGF-A expression correlated with stage IV disease and prognostic indicators and currently influence therapy. suggested that it could be a target for antiangiogenic therBased on the impact of the new INSS, the use of the apy. Kaicker et a1.H' noted that VEGF antagonists inhibit INPC, and the identification of numerous biologic and nkoangiogenesis and tumor growth in e ~ p ~ r i m e n tneual genetic characteristics as risk factors and predictors of roblastoma in athymic mice with xenograft neuroblasoutcome, a risk-based management system has been develNewer treattoma cell line NGP. They also found that thalidomide oped to determine treatment.27~74.208-210~213 suppressed angiogenesis 'and reduced microvessel denment protocols individualize treatment using risk factors sity but not tumor growth. Kim et al."' and Rowe et al.Ig3 as medictors of outcome in an effort to maximize survival. also demonstrated inhibition of tumor growth in experiminimize long-term morbidity, and improve the quality of mental neuroblastoma models using antiangiogenic life. Current protocols are now based on low-, intermedistrategies. Imatinib mesylate, a compound used to treat ate-, and high-risk tumor categorization (Table 28-4). patients with gastrointestinal stromal tumors, has been Good outcomes are associated with stage I, 11, and IV-S shown to decrease the growth of neuroblastoma in vivo patients who are younger than 1 year and have hyperand in vitro, decrease cell viability, and increase apoptosis diploid DNA flow cytometry, favorable histology, less (by ligand-stimulated phosphorylation of C-kit and than one copy of N-myc, high Trk-A expression, and PDGFR) in a severe combined immunodeficiency (SCID) absence of chromosome l p abnormalities. In contrast, a mouse model.15 Davidoff et a1.4Wemonstrated that gene poor prognosis is likely in children older than 1 year with therapy using in situ tumor cell transduction with retroadvanced tumors (stages I11 and IV), more than 10 viral vectors can deliver angiogenesis inhibitors for the copies of N-myc, low Trk-A expression, diploid DNA Flk-1 receptor and restrict tumor-induced angiogenesis ploidy, allelic loss of lp36, and unfavorable histology. and tumor growth. For low-risk patients, surgical excision of the tumor is The Bcl-2 family of proteins is responsible for relaying usually curative and avoids the risks associated with apoptotic signals that influence tumor cell regression chemotherapy. Intermediate-risk patients are usually and is expressed in most neuroblastomas. The Bcl-2 gene treated with surgery and standard chemotherapy. The a protein that prevents neuronal cell death poor prognosis in high-risk patients justifies a much (apoptosis). The level of Bcl-2 expression is high in more intense treatment regimen, including combination advanced cases associated with a poor outcome and low chemotherapy followed by complete surgical excision (if in cases demonstrating tumor apoptosis (regression) and possible), radiation therapy to achieve local control, expression may aiso play a role differentiation. High ~ c l - 2 myeloablative treatments, and bone marrow rescue. .~~ of in acquired resistance to c h e m ~ t h e r a p y Subgroups the Bcl-family include Bcl-xL, which inhibits apoptosis, and Bcl-xS, which induces natural cell death. VEGF upOPERATIVE MANAGEMENT regulates Bcl-2 expression and promotes neuroblastoma cell survival by altering apoptosis and its regulation Complete surgical removal of the primary tumor proteins.14 Elevated caspase levels (enzymes responsible remains an essential component of treatment in the vast for apoptotic signaling) are associated with an improved majority of cases. Operative procedures are performed outcome in neuroblastomas that demonstrate favorable using endotracheal general anesthesia and careful monbiologic features.Y7 itoring. Appropriate large-bore intravenous catheters are placed in the upper limbs. Adequate intravenous access is important because these tumors are quite vascular, and blood loss may be excessive. Body temperature, oxygen satRISK-BASED MANAGEMENT uration, electrocardiogram, and pulse rate are monitored. For many years, the choice of therapy in neuroblastoma The blood pressure must also be carefully monitored intravaried with the extent of disease at the time of diagnosis, operatively to detect sudden hypertension caused by Total excision or the patient's age, and the ~tage.2"~,~~2" excessive catecholamine release from the tumor. excision of as much tumor as possible in localized cases In patients with primary tumors located in the I lesions were resulted in the best outcome~.6~,~"~tage retroperitoneum, the operation is performed through a t i e nstage ts I1 managed by operation a l ~ n e . ~ ~ ~ ~ W a with long, transverse transperitoneal-supraumbilical incision.

476

PART

III

MAJORTUMORS OF CHILDHOOD

INSS Stage

Age

N-myc Status*

I IIA/IIB

0-21 yr >365 days 365 days-21 yr 365 days-21 yr 365 days-21 yr <365 days <365 days >365 days-21 yr >365 days-21 yr >365 days-21 yr <365 days <365 days >365 days-21 yr <365 days <365 days <365 days <365 days

Any Any Nonamplified Amplified Amplified Nonamplified Amplified Nonamplified Nonamplified Amplified Nonamplified Amplified

111

IV

IV-S

Any Nonamplified Nonamplified Nonamplified Amplified

lNPC (Histology)

Favorable Unfavorable Any Any Favorable Unfavorable Any Any Any Any Favorable Any Unfavorable Any

DNA Ploidyt

Risk Group Low Low Low Low High lntermediate High lntermediate High High lntermediate High High Low lntermediate lntermediate High

*N-myc nonamplified=1 copy, amplified >1 copy. tDNA index>l (aneuploid)or=l (diploid). INPC, International Neuroblastoma Pathology Classification; INSS, InternationalNeuroblastomaStaging System. Modified from Children's Oncology Group protocols by LaBerge JM: Neuroblastoma. In O'NeillJA Jr, GrosfeldJL, FonkalsrudEW, Coran AG (eds): Principlesof Pediatric Surgery, 2nd ed. St Louis, Mosby, 2003.

In some cases, a bilateral subcostal chevron incision or a thoracoabdominal incision may be required. The peritoneal space is entered, and on either side, the colon is reflected medially and inferiorly by incising the attachments to the lateral abdominal wall. The spleen and pancreas are mobilized and displaced upward and medially for left-sided tumors. For right-sided tumors, the duodenum and head of the pancreas can be mobilized and retracted medially and the liver attachments divided to improve exposure (Fig. 28-9). In most children with localized disease, all or most of the tumor can be removed successfully. The patient's condition should not be jeopardized by an overzealous surgical attempt at initial resection. En bloc contiguous resection of normal surrounding structures, such as the spleen, stomach, pancreas, and colon, can almost always be avoided. In some cases, it is impossible to separate an adrenal or paraspinal neuroblastoma from the ipsilateral kidney, and nephrectomy may be necessary. It is important to excise any suspicious para-aortic and perirenal lymph nodes for staging purposes. A routine retroperitoneal lymph node dissection is usually not performed. The margins of the tumor resection are marked with titanium clips to guide the port if radiation is required and will reduce the scatter effect noted with other types of metal clips on follow-up CT scan. Because neuroblastoma may have a friable pseudocapsule, careful handling of the tumor during dissection is important to avoid tumor spill and hemorrhage. Neuroblastoma often adheres to or surrounds the great vessels, and special care should be taken to identify and spare the blood supply to important visceral structures, such as the branches of the celiac axis and superior mesenteric artery. Primary adrenal tumors may be fed by

a number of small arteries. The major venous drainage is usually constant, directly to the inferior vena cava on the right side and into the left renal vein and subdiaphragmatic vessels on the left. Although there is no good evidence that partial excision and reduction of tumor bulk favorably affect the prognosis for this highly malignant childhood neoplasm, an improved response to adjunctive therapy has been observed when tumor resection has ~ ~ ~ ~aggressive ~ ~ ~ ~ palliative been a c c o m p l i ~ h e d .Overly debulking that places the child at risk for life-threatening hemorrhage is not indicated. Following a good response to initial chemotherapy, the tumor often shrinks and can be removed during a delayed primary resection or at a second-look operative Inferiorly located paraspinal and primary pelvic tumors often require careful dissection to separate the lesion from the bifurcation of the aorta and inferior vena cava. The tumor frequently extends into the intervertebral foramina (Fig. 28-10). Minimally invasive surgical techniques have also been emvloved for selected cases of n e u r o b l a ~ t o m a . ~ ~ ' Adrenal tumors initially detected by mass screening have been excised laparoscopically by a number of investigators.l23,160 Yamamoto et a1.'3Vescribed three cases of adrenal neuroblastoma in which the lesions were less than 20 mm in diameter. They used a five-trocar technique and kept the intra-abdominal pressure for the pneumoperitoneum less than 4 mm Hg. The well-encapsulated tumors were completely excised; they were placed in a plastic bag and removed through the 10-mm trocar site. All had favorable histology, and none had Nmyc amplification. No recurrences w&e observed. Kouch et al.l25 described laparoscopic resection of six adrenal tumors less than 4 cm in size. There were no conversions L

,

CHAPTER

28

Neuroblastoma

477

Adrer blood

igated adrenal vessels

or tumor recurrence in the abdomen or at the port sites. Iwanaka et a1.107 used laparoscopy for tumor biopsy in advanced cases of neuroblastoma and compared the minimally invasive resection of tumors to open excision via laparotomy. There was no significant difference in the length of procedure or blood loss; however, time to start chemotherapy, interval to postoperative oral intake, and length of hospital stay were less following laparoscopic Lagausie We et al.52 described nine tumor r e ~ e c t i o n . ~ ~ ~ J O cases of adrenal neuroblastoma treated by the laparoscopic approach. Two were detected prenatally, and seven were noted postnatally, including three with stage IV disease. The mean age was 38 months (range, 2 months to 9 years). Complete excision was accomplished in eight children, and one had to be converted to an open procedure. In three cases, one or more lymph nodes were also excised. There were no deaths and one port site infection. These and other reports suggest that in selected cases, laparoscopic biopsy and tumor excision are both safe and effective.32 Mediastinal tumors are usually approached through a standard posterolateral thoracotomy incision. Excision of

A, Tumor of the right adrenal gland. B, The colon attachments are taken down, and the duodenum and head of the pancreas are mobilized and retracted medially. C, The adrenal vessels are controlled and divided, and the tumor is excised. The arterial blood supply of the tumor comes from a number of small vessels from the right renal artery, aorta, and diaphragmatic branches. Venous drainage is usually consistent with direct drainage to the vena cava on the right side. The kidney can often be spared. The tumor bed is displayed at the conclusion of the resection.

the pleura and the endothoracic fascia around the tumor usually allows entry into an appropriate dissection plane. Mobilization of the tumor from the rib edges is accomplished with both sharp and blunt dissection. It is important to identify and either ligate or clip specific intercostal blood vessels feeding and draining the tumor. The tumor may be attached to a number of sympathetic ganglia and intercostal nerves and often extends, in one or more areas, into the intervertebral foramina (Fig. 28-11).4866,155243 It may be impossible to remove every bit of tumor at the foramina1 sites. Small primary tumors have been successfully removed by thoracoscopic techniques. Thoracoscopy is also useful in obtaining tissue for biopsy. In patients with neurologic symptoms (including paraplegia) associated with dumbbell tumors, prompt MRI and an urgent laminotomy to .excise extradural tumor and relieve cord compression are recommended before attempting intrathoracic resection of the tumor. The mediastinal resection can be delayed a short time to allow the patient's neurologic symptoms to improve. If extradural tumor is present on imaging studies but the patient is asymptomatic, chemotherapy is initiated and

478

PART

III

MAJORTUMORS OF CHILDHOOD

-

I A, Lower retroperitoneal paraspinal neuroblastoma and its relationship to the bifurcation of the aorta and ureter. B, Tumor may extend into the vertebral foramina. C, Photograph of the operative field after resection of a right-sided pelvic neuroblastoma. Note the vascular loops placed around the iliac arteries, right iliac vein, and ureter to facilitate a safe dissection. (C, see colmplate.)

may shrink the tumor and avoid the need for laminotomy or laminectomy. The choice of therapy for intraspinal tumor extension is still somewhat controversial. Plantaz et a1.'74 reviewed 42 patients in France and recommended initial chemotherapy followed by surgical removal of residual disease. Yiin et al.242 described 13 cases of neuroblastoma with symptomatic spinal cord

compression and neurologic deficits. Ad1 the patients were treated initially with chemotherapy: three recovered, four improved, and six worsened and became paraplegic. Two of the six recovered after laminectomy. Those authors recommended spinal cord decompression for patients who have neurologic deterioration on chemotherapy. Sandberg et a].'" described the treatment

CHAPTER

--

-

28

Neuroblastoma

479

e A, Right posterolaterai thoracotonly incision used for the excision of a posterior mediastinal neuroblastoma. B, Relationship of the tumor to surrounding tissues. C, The turnor is mobilized and retracted anteriorly, exposing numerous intervertebral extensions. The tumor extensions are divided at the vertebral foramina, leaving small remnants of residual tumor behind. This does not adversely influence the outcome.

Tumor extensions

C

of 46 patients with epidural or neural foramina1 tumor involvement. Nine were low-risk patients with normal neurologic examinations who remained neurologically intact following operation or chemotherapy. Four lowrisk patients with high-grade spinal cord compression improved or remained stable after surgical intervention, but two who were treated with chemotherapy had worsening deficits. Eleven of 12 high-risk patients with normal neurologic examinations and without radiographic high-grade spinal cord compression were treated with chemotherapy and had no neurologic deterioration. Of 16 high-risk patients with high-grade spinal cord compression, 7 of 10 treated initially with chemotherapy and all 6 who underwent initial surgery improved or remained stable. Spinal deformities occurred in 12.5% (2 of 16) treated nonoperatively and in 30% (9 of 30) who underwent operation. The authors concluded that patients with high-risk tumors and spinal involvement but normal neurologic examinations should be offered chemotherapy, with the understanding that a small percentage may require operations for progressive neurologic deficits. Chemotherapy may be avoided in patients with low-risk tumors who can be offered a potentially curative procedure. Patients and their families should be made aware that operative intervention may be associated with subsequent spinal deformity in as many as 30% of cases.Ig8 Cervical neuroblastoma is often localized and has a favorable outcome.n' Haddad et a1.,86 in a study of 43 cervical neuroblastomas, identified four risk factors that were associated with increased operative morbidity: adherence to vascular structures, tumor size, friability, and dumbbell tumors. Imaging studies may show a solid mass with vascular displacement and narrowing.2 Tumors arising in the neck or upper mediastinum often involve

the stellate ganglion. If not present preoperatively, resection may result in postoperative Horner's syndrome.2.7" This is a relatively minor consequence outweighed by complete tumor excision and survival, but the patient's family should be made aware of this possible complication. Special attention should be given to protecting the brachial plexus and the phrenic, vagus, and recurrent laryngeal nerves. Whether additional therapy is necessary for stage I1 tumors depends on the patient's risk assessment based on age, tumor histology, and presence of adverse biologic and genetic factors (e.g., >10 copies of N-myc, chromosome l p deletion, diploid flow cytometry, unfavorable histology).j4Thirteen percent of stage I1 cases have high-risk prognostic factors and require aggressive chemotherapy. Patients with more advanced disease (stage 111) often require more aggressive treatment, including operative resection (if possible), multiagent chemotherapy, and initial local irradiation. Stage I11 tumors in the pelvis or near the celiac axis are often unresectable initially. After chemotherapy, however, the tumor frequently becomes small enough to be excised at a second-look operation.74-83Patients with stage I11 disease have an improved ~ , ~ type ~ of adjuncoutlook after complete r e s e ~ t i o n . jThe tive therapy depends on tumor resectability, histology, and biologic and genetic characteristics affecting risk for that specific neoplasm. Completely resected tumors with favorable prognostic factors may require less intensive chemotherapy. In contrast, patients with incomplete tumor resection are usually treated with local irradiation to the tumor bed and more dose-intensive chemotherapy regimens. Those with high-risk unresponsive tumors may benefit from intensive cytoablative chemotherapy followed by autologous bone marrow transplantation (BMT).31,84,14"14Wigh-risk stage 111 cases can usually be

480

PART

III

MAJORTUMORS OF CHILDHOOD

patients with a complete response to chemotherapy and tumor resection,78,84,218data concerning the biologic characteristics of the surviving patients were often lacking, and an independent effect of gross tumor resection could not be demonstrated.134 More recently, LaQuaglia et a1.135 reviewed 141 INSS stage IV patients and reaffirmed that the rate of gross tumor resection improved with more intense chemotherapy. The probability of local tumor progression was 50% in unresected patients, compared with 10% in those with gross total resection. The overall survival rate was 50% in resected patients, versus 11% in patients with unresected tumors.'" Aggressive surgical management is occasionally associated with late complications in survivors, including ipsilateral atrophy of the kidney following adrenal resection and ejaculatory problems following pelvic tumor excision.l26 Of interest is the very favorable outlook noted in patients with stage 111 and IV tumors arising in the pelvis following complete tumor r e s e c t i ~ n . ~ ~ , ~ ~

predicted by the presence of adverse biologic features, such as age older than 1 year, unfavorable tumor histology, and more than 10 copies of N-rnyc.148J49 The marrow is purged for tumor cells with multiple monoclonal antibodies before BMT.151 Emwlovment of BMT earlv in the management of unresponsive tumors with high-risk biologic factors results in a better outcome than if BMT is attempted as a lastditch effort in patients with progressive disease.149,151,178In recent years, the use of autologous stem cell transplantation has replaced traditional BMT in many childhood cancer facilities. The CCG compared initial resection at diagnosis with delayed primary resection and second-look procedures for initially inoperable stage IV tumors. Complete resection was possible in 62% of the initial group, 77% of delayed primary operations, and 66% of second-look procedures.84 The risk of concomitant nephrectomy and the incidence of postoperative complications were lower in children in the delayed primary resection Because there was no difference in survival among the three groups (40% among complete responders at 3 years), delayed primary resection after chemotherapy was considered the wrocedure of choice in children with stage IV tumors. The role of primary tumor resection in patients with stage IV disease is unsettled. In patients who respond completely or partially to chemotherapy, it has been my practice to perform a delayed primary or second-look operation to remove all possible residual tumor. There are conflicting reports concerning the efficacy of complete resection i n itage IV disease.-~aaseet al.,84 reporting for the CCG, described a survival advantage for stage IV patients with complete resection following delayed primary excision after chemotherapy. In contrast, reports by Kiely1I6and Shorter et al.215 suggest that there is no survival advantage for stage IV patients with complete resection. However, LaQuaglia et a1.,134in a report of 70 stage IV patients, noted that gross tumor resection and a higher-intensity chemotherapy protocol resulted in improved overall survival. Although some studies have shown an improved survival in stage IV 1

,

NEUROBLASTOMA IN INFANCY Infants younger than 1 year at diagnosis have a significantly improved outcome. At the Riley Hospital for Children, the survival rate was 76% for infants younger than 1 year and only 32% for older patients (Fig. 28-12).7Vhisfavorable outlook for patients younger than 1 year extends across all stages, including infants with stage IV metastatic disease. The incidence of stage IV lesions in infants younger than 1 year is 30%, compared with 60% to 70% in older patients.76 ~1tho;gh resection of the primary tumor in stage IV disease is controversial, in my personal experience, the only infant survivors had excision of the primary tumor.76 Similarly, a CCG report described 7 of 11 infants with stage fi disease who had complete delayed primary tumor resection and remained disease free for more than 5 year^.^^,^^ Infants with stage IV disease respond better to chemotherapy than older children do; 50% of Bar graph d e m o n strates t h e improved survival i n infants with neuroblastoma w h o are younger t h a n 1 year.

Percent survival

I

I*

2

Under 1 yr

0

10

20

30

40 Percent

50

60

70

80

CHAPTER

infants have a complete response to treatment, compared with 22% of older children.85 This observation suggests that resolution of metastases may have a greater impact on length of survival than the surgical excision does. Further, this implies that surgical resection is beneficial in some infants and should be a t t e m ~ t e dwhen disseminated disease is controlled by chemotherapy. Paul et al.170 documented a 75% 5-year survival rate in 24 stage IV patients younger than 1 year, compared with a 10% survival rate for older patients with stage TV tumors. Patients were treated with nitrogen mustard, vincristine, dacarbazine, doxorubicin, cyclophosphamide, and cislat tin without BMT. Schmidt et al.204observed a 93% surviva1 rate in infants younger than 1 year with stage IV disease without N-myc amplification; however, those with more than 10 copies of the N-myc oncogene had rapidly progressive disease and often succumbed despite chemotherapy.204 Therefore, more intensive chemotherapy regimens and BMT may be necessary to attain a cure, especially in highly selected infants presenting with adverse biologic markers. 1

STAGE IV-S The most unusual group of patients with neuroblastoma are those infants younger than 1 year with stage IVS disease, characterized by hepatomegaly, subcutaneous nodules, and positive bone marrow, that would otherwise be classified as stage I or 11 primary tumor. Stage IV-S cases account for approximately 30% of patients with neuroblastoma

A

28

Neuroblastoma

481

of these recognized in the first year of life.7"reatment patients is somewhat controversial. Some infants may die as a result of complications of stage IV-S disease rather than tumor progression. Complications of severe hepatomegaly include respiratory insufficiency, caused by significant elevation of the diaphragm by the large, tumor-filled liver; coagulopathy; and renal compromise due to compression by the mass (Fig. 28-13).",45,50,76,236Vomiting may occur because of a change in the gastroesophageal angle related to the diaphragmatic elevation, resulting in gastroesophageal reflux, protein-calorie malnutrition, and aspiration pneumonia. Total parenteral nutrition may be a useful Most fatalities in stage IV-S therapeutic adjunct.l"J",2" cases occur in infants younger than 2 months with severe symptoms related to hepatomegaly, who do not tolerate ~2 therapy as well as older infants d 0 . ~ " ~ Symptomatic hepatomegaly caused by tumor infiltration may benefit from low-dose irradiation to the liver in the range of 600 to 1200 Gy, administered in doses of 100 to 150 Gy/day.21,76s83 Although some early reduction in the size of the liver is seen, and peripheral edema may resolve in a few weeks, complete resolution may take 6 to 15 months.76Resolution of the liver mass is probably related more to the natural course of stage IV-S disease than to radiotherapy. Administration of low-dose cyclophosphamide 5 mg/kg per day is a reasonable treatment alternative. Although some investigators advocate the insertion of a Dacronreinforced Silastic sheet to create a temporary ventral abdominal wall hernia to accommodate the enlarged liver and reduce intra-abdominal pressure, I have not

B

A, Six-week-old infant presented with abdominal dister tio on and hepatomegaly. B, Appearance of the liver at laparotomy. There were multiple metastatic nodules, and the biopsy confirmed the diagnosis of stage IV-S neuroblastoma.

482

PART

III

MAJORTUMORS OF CHILDHOOD

found this technique to be effective.205Mortality due to septic complications after insertion of an external Silastic sheet has been observed.".76 To reduce the risk of infec~~ the use of an tion, Lee and A p p l e b a ~ m lrecommend internal polytetrafluorethylene patch to create a temporary ventral hernia. The graft can be removed in stages as the bulk of the hepatic mass regresses over time. Survival of these unusual infants with remote metastases is greater than 80%, often without specific treatment. Table 82-5 summarizes the results reported in 12 studies of stage IV-S neuroblastoma, with an overall 86% survival rate. Most patients with stage IV-S disease (>go%) have favorable genetic and biologic factors, including high Trk-A expression, no N-myc amplification, favorable histology, and no evidence of allelic loss of chromosome 1p.This suggests that the majority of stage IV-S tumors undergo spontaneous regression. Although most patients with stage IV-S disease do well, Wilson et a1.S6 reported 18 cases with a heterogeneous tumor presentation and a survival rate of only 50%, including three patients with N-myc amplification. The presence of adverse genetic and biologic prognostic factors suggests that this subset of patients ( 4 0 % ) requires more aggressive therapy. Of interest is that infants with multiple subcutaneous nodules seem to have the most favorable outlook. This may be due to increased immunologic activity as a result of tumor being present in multiple ~ i t e s . 7Increased ~ uptake of major histocompatibility complex (MHC) class I antigen by neuroblastoma cells in vitro and in vivo may influence the outcome favorably.22O Infants with stage IV-S disease have normal levels of MHC class I surface antigen expression, whereas those with stages I to IV have low levels.220 Sugio et al.224 reported that down-modulation of MHC class I antigen expression is associated with increased amplification of the N-myc oncogene in patients with advanced disease. In 2002 ~ickversonei a1.'62 described 80 infants with stage IV-S disease from the CCG. Fifty-eight cases were managed without specific therapy. All 44 asymptomatic patients survived without treatment. Symptomatic patients were treated with cyclophosphamide 5 mg/kg

Author (Year) D'Angio et al (1971)45 Breslow et al (1971)23 Nitschke et al (1980)l65 Nickerson et al (1985)163 Blatt et al (1987)21 Wilson et al (1991)236 Suarez et al (1991)223 DeBernardi et al (1992)50 Grosfeld et al (1993)76 Hatchitanda et al (1996)ss Nickerson et al (2000)162 Schleiermacher et al (2003)203 Total

No. of Patients

94 460

per day for 5 days and hepatic radiation at a dose of 4.5 Gy over 3 days. Five of six deaths occurred in symptomatic infants younger than 2 months. Event-free 5-year survival was 86%, and overall survival was 92%. Early intervention is indicated in stage IV-S patients with lifethreatening complications (e.g+, hepatosplenomegaly, coagulopathy, renal failure).76Ja Surgical resection did not alter outcome. More aggressive chemotherapy is also required in those cases in which the tumor demonstrates more than 10 copies of N-myc, chromosome l p deletion, ~2,2~~ of or other adverse biologic m a r k e r ~ . ~ ~ JAmplification N-myc may be observed in 1 of 12 patients with stage IV-S tumors who develop progressive disease and succumb, despite having a favorable prognostic stage. In 2003 Schleiermacher et al.,203in a report concerning 94 babies with stage IV-S neuroblastoma in France, observed an 88% overall survival and recommended a more intensive regimen using cisplatin and etoposide for those who require therapy. Some infants with stage IV-S have survived without resection of the primary tumor (in some, the primary tumor may not be identified). Knowing that resection of the primary tunlor may have some benefit in infants with stage IV tumors, resection of the primary neoplasm should be accomplished when feasible, especially in high-risk stage IV-S cases with any unfavorable characteristics.76

CYSTIC NEUROBLASTOMA Cystic neuroblastomas are relatively rare and are often identified on prenatal ultrasound examinations.227 They characteristically occur in the adrenal gland, and almost all are diagnosed in early infancy (Fig. 28-14). Few are calcified, and only 10% are associated with elevation of

No. of Survivors (%) 14 (88) 18 (95) 11(100) 31 (89) 8 (73) 9 (50) 28 (75) 63 (83) 17 (81) 36 (80) 74 (92) 83 (88) 392 (85)

Photograph of a cystic neuroblastoma of the adrenal gland in a 5-month-old baby that required complete excision. The patient was managed by surgery alone and is a long-term survivor.

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28

Neuroblastoma

483

urinary VMA and HVA levels.187 They are associated with children with resectable localized neuroblastoma with a benign behavior and a favorable outcome. There is favorable biologic and genetic characteristics. For stage I and most stage I1 patients, surgery alone is all that is necsome evidence that these lesions have a tendency to es~ary.6~,7~28Vtage I1 patients with poor prognostic biologic e regress and undergo spontaneous i n v ~ l u t i o n . ~ ~ ~ o m investigators have recommended observation alone, with and genetic factors, however, are at higher risk and should close serial sonogram monitoring of the mass during the be treated more aggressively with multiagent chemotherfirst few months of life to be sure that the tumor mass apy, including cisplatin, doxorubicin (Adriamycin) , cyclophosphamide, and etoposide (W-16). For advanced shrinks, indicating tumor regression. Operative reseccases (stages I11 and IV), the mainstay agents throughout tion should be reserved for those tumors that fail to the 1970s and early 1980s included cyclophosphamide, regress or that increase in size. When resection is indivincristine, and dacarbazine.6lfj4.67 Treatment failures cated, surgery is the only therapy recommended. The received doxorubicin and teniposide (VM-26). COG has initiated a prospective study of observation only Although these chemotherapy protocols did not effecfor cases of cystic neuroblastoma. It uses strict criteria in tively increase the cure rate of stage IV patients, such treatterms of tumor volume (
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and decreases bone marrow tumor involvement, was by screening the number of tyrosine hydroxylase mRNA Reynolds et al.,183,185 in a shown to be usefu1.~51J84~~33 transcripts. phase 111 randomized trial in high-risk patients, showed that high-dose pulse therapy with 13-cis-retinoic acid given after completion of intensive chemoradiation (with RADIATION THERAPY or without auotologous BMT) significantly improved event-free survival. In phase I studies, the cytotoxic synIn general, the role of radiation therapy in the managethetic retinoid 4HPR (fenretinide) achieved multilog ment of neuroblastoma has become more limited in cell kills in neuroblastoma cell lines resistant to transrecent years. Once a mainstay of treatment, radiation and 13-cis-retinoic acid and was better tolerated when therapy is used primarily (1) to control local disease in ceramide modulators were used to reduce toxicity. instances of incomplete tumor resection or local recurFenretinide has also been shown to exhibit antiangiorence, (2) to reduce the tumor burden in preparation genic properties.l86 for BMT, and (3) for palliation in patients with refractory Other high-intensity, compressed chemotherapy proend-stage disease or painful rneta~tases.~3~81~~3,143 tocols include the use of high-dose cyclophosphamide, External beam radiation is associated with considercarboplatin, and etoposide with granulocyte colonyable toxicity in growing children, resulting in growth disstimulating factor to mobilize peripheral blood stem turbance, bony deformity, endocrine deficiency, cells and enhance hematopoietic reconstitution of neuhypoplastic soft tissue changes, skin atrophy, and, of trophils and platelets. The stem cells are harvested by greater concern, secondary malignancies in the radiation leukapheresis for later reinfusion. Mesna is used to avoid portal. Techniques used to decrease radiation-induced high-dose cyclophosphamide-induced hemorrhagic cystitoxicity include hyperfractionating the radiation dose, tis. After dose-intense induction, surgical intervention is which usually does not reduce the desired antitumor employed to resect the primary tumor and any bulky effect, and avoiding the simultaneous administration of metastases. Peripheral blood stem cell infusion is used to chemotherapy agents that may enhance the radiation reconstitute the marrow after myeloablative treatment. effect.133Brachytherapy and intraoperative radiotherapy Immunoglobulin G levels are monitored and replaced can better confine the radiation effect to the target tissue with gamma globulin. Sulfamethoxazole and fluconazole and spare surrounding normal tissue^.^^.^^^ Although are given prophylactically to avoid opportunistic early local control can be achieved, only 38% of stage IV patients given intraoperative radiotherapy survived after Pneumocystis cam'nii and fungal infection. With regard to BMT, patients who receivied purged 3 years. Some patients still require supplemental exterautologous cells responded better than those getting nal beam radiation, and postoperative ureteral stricture, allogeneic cells, mainly because of a higher toxic death renal artery stenosis, and neuropathies have been described.83 Haas-Kogan et a1.80described an experience rate and an increased incidence of graft-versus-host disusing intraoperative radiotherapy in 23 cases of high-risk ease in the latter group.I48Patients with high-risk stage IV disease have a better outcome with BMT, especially if neuroblastoma and noted that this technique was effecO only J ~ ~ in patients who had gross total resection of the they have amplification of the N-myc ~ n c o g e n e . ~ ~ ~ J ~ tive These newer chemotherapy pilot programs resulted in primary tumor." All patients with partial tumor resection improved survival of stage I11 patients older than 2 years had recurrence, despite radiotherapy, and subsequently at diagnosis from 36% to 86%; survival of stage IV died. There are few data to support the efficacy of this patients (older than 1 year) increased from 11% to 37% therapy. Intraoperative radiotherapy is sometimes cumat 3 years of age and was 23% at 6 years of age.148J49 bersome to perform, especially in institutions that do not There is a high risk of Epstein-Barr virus-associated lymhave an operative suite in the radiotherapy department phoproliferative disease with highly immunosuppressive or radiation therapy equipment (including linear acceltherapies.l7WIogeneic BMT, especially when supported erators) in the operating room. Under these circumby T-cell-depleted stem cell products, is a risk factor. stances, after attempted tumor resection, the patient has Although the risk after autologous BMT is low (3.5%), to be transported under general anesthesia for the treatthere is an increased risk when sequentially high-dose ment to take place. chemotherapy is supported by CD34+-selected periphChildren with refractory advanced neuroblastoma with eral blood stem cells. Median time to lymphoproliferawidespread involvement often suffer severe pain due to tive disease was 3 months post transplant. All patients metastases. Kang et a1.lI3 employed targeted radiotherapy with lymphoproliferatiave disease were in the selected using submyeloablative doses of II3l-MIBG to achieve CD34+ group; treatment was with rituximab and gancidisease palliation. The treatment stabilized disease, clovir. In many centers, peripheral blood stem cell transrelieved pain, or improved performance status, with 31% plantation has replaced autologous BMT as the method of patients showing an objective response to treatment. of choice. Obtaining blood can be accomplished on an They concluded that this modality is useful for treating outpatient basis with less pain and anxiety, and stem cell end-stage neuroblastoma. Targeted radiation therapy transplantation is associated with fewer complications with MIBG has also been used in combination with and less toxicity. Tumor cells can be purged from the myeloablative chemotherapy and proton beam radiation sample. Kanold et al.114 reported that ex vivo expansion of for recurrent and refractory neuroblastoma. Proton beam autologous perihperal blood CD34+cells provided a purge therapy has the advantage of delivering radiation more effect in children with neuroblastoma, documented precisely than conventional methods. As it becomes

CHAPTER

more widely available, it may play a greater role in the management of children with neuroblastoma requiring radiation treatrnent.2' Deutsch and T e r ~ a decribed k~~ the use of radiotherapy (300 to 1000 cGy) for palliative treatment of symptomatic metastases to bone. The most common treatment sites were the skull, spine, hip, and femur. Twenty-nine percent of patients survived 1 year or longer (range, 1 to 52 months). Only 8% survived more than 3 years.

IMMUNOTHERAPY In the 1970s and 1980s, it was observed that tumor regression in neuroblastoma suggests that an immunologic mechanism may be involved, resulting from an unusual Lymphocytes from chiltumor-host relation~hip.~J~,~OJ7~ dren with neuroblastoma were observed to inhibit colonies of neuroblasts in culture but not cells from other tumors.20 Sera from patients with progressive disease contain a blocking antibody that prevents a lymphocytemediated cytotoxic response and inhibits lymphocyte .~~~~~ blastogenesis to p h y t o h e m a g g l ~ t i n i n s Lymphocytes from patients with neuroblastoma also have a decreased systemic and in situ natural killer activity.71 In experimenand hyperthertal studies, operative electrocoag~lation~~5 mia resulting from high-intensity focused ultrasonography induced immunity in mice with neuroblastoma. A major problem is that advanced neuroblastoma cells are MHC class I deficient and evade immunorecognition. Although immunotherapy evolved slowly, this has changed with the production of recombinant interleukin-2 (IL-2), a cytokine that can mediate immunoreactivity and cancer regression.lg2 IL-2 is produced by helper T lymphocytes. The interaction of antigens with T lymphocytes activates lymphoid cells to express receptors for IL-2. Stimulation of IL-2 secretion leads to expansion of immune cells and effective immunity. Newer molecular biologic techniques have been developed to identify genes that encode cancer antigens and their immunogenic peptides. Immune cells can be generated against the antigens present on cancer cells that are the potential targets of immune therapy.lg2 Vertuani et al.2" reported that retinoids and T-cellbased immunotherapy may be an effective combination for the treatment of neuroblastoma. Retinoids serve as multistep modulators of the MHC class I presentation pathway and sensitize neuroblastomas to cytotoxic lympho~ytes.l8",~8"2"The use of tumor cell vaccines derived from irradiated cells transduced with IL-2 or interferon, targeted 1121-MIBG therapy, and I'31-labeled anti-GD2 antibody therapy have been attempted alone or in combination with BMT, however, data are not yet available to document the efficacy of these treatments.148Raffaghello et a1.180 employed an anti-GD2 antibody in nude mice with neuroblastoma and noted increased long-term survival and decreased metastatic spread in a dose-dependent manner in treated mice compared with controls. Cheung et a1.3 suggested that immunotherapy using ganglioside GD2 monoclonal antibody should be directed at minimal disease and must be used in conjunction with

28

Neuroblastoma

485

dose-intensive chemotherapy to be effective. Kushner et a1.1" described the management of seven patients who relapsed with widespread disease after initial treatment with surgery alone for locoregional neuroblastoma. They received dose-intensive chemotherapy, anti-GD2 3F8 antibody, and targeted radiotherapy using 1'"-lableled 3F8 if they had assessable disease, or 3F8, granulocytemacrophage colony-stimulating factor, and 13-ci~retinoic acid if they were in remission. Five of the seven patients remained in remission from 4 to 8 years later.'" The same group reported that high-dose cyclophosphamide, irinotecan, and topotecan were effective in achieving remission and inducing an immunologic state conducive to antibody-based passive immunotherapy (using 3F8 antibody) in resistant n e u r o b l a ~ t o m a . ~ ~ ~ Dendritic cells are potential targets for immunotherapy. They can enhance growth and differentiation of CD40activated B lymphocytes, directly affect natural killer cell function, and act as antigen presenters.I8l Redlinger et a1.182 noted that advanced neuroblastoma impairs dendritic cell differentiation and function in adoptive immunotherapy. It has been shown that in neuroblastoma, gangliosides inhibit dendritic cell function. IL-12 is a potent proinflammatory cytokine that enhances the cytotoxic activity of T lymphocytes and resting natural killer cells.l82 In a murine model of neuroblastoma, Shimizu et al.214 demonstrated that IL-12 transduced dendritic cell vaccine (with an adenoviral vector expressing IL-12) resulted in a complete and sustained antitumor response. Tumor regression was associated with a high infiltration of dendritic cells and viable T cells.

PROGNOSIS For many years, the age of the patient and the stage of disease at the time of diagnosis were the two key independent variables determ
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the better the prognosis.142 Others noted that a more mature histology may be associated with the same dismal outcome as in patients with undifferentiated neuroIn patients with metastatic disease, the presence bla~ts.l2~ of more mature elements seemed to improve-the outlook and was associated with increased surviva1.67~77,218 Shimada et a1.211 subsequently classified the histopathology of neuroblastoma -into favorable and unfaGorable types, characterized by a stroma-rich appearance for the former and a stroma-poor appearance for the latter. The Shimada classification was also age related. The impact of Shimada histology class on prognosis proved to be important, especially when associated with other prognostic biologic variables, particularly amplification of the N-myc oncogene and allelic loss on the short arm of chromosome 1 (lp36).2l2 The current INPC (which embraced and modified the Shimada classification) further divided cases into subsets of favorable and unfavorable histologic types and is a highly significant N- mYC independent predictor of progno~is.~~~,~~3,208,212,213 amplification is seen in approximately 30% of neuroblastoma cases and has an important role in modulating the malignant phenotype in neuroblastoma.27J48.157 The prognostic value of N-myc is independent of stage and age. N-myc is associated with a poor response to treatment,-rapidly progressive disease, and a diimal outcome. Although attempts to stimulate tumor maturation with nerve growth factor, adrenergic agonists, papaverine, prostaglandins, exogenous cyclic adenosine monophoswere successful in the laborabhate,-and hwerthermia , tory setting, there was minimal clinical evidence of their usefulness.3"73.Y7-137~234The use of retinoids as a promoter of differentiation. however. has rekindled interest in this concept and has been successful in prolonging survival in advanced cases during clinical trials.151 The addition of cis-retinoic acid to the treatment protocol for high-risk cases of neuroblastoma following BMT or peripheral stem cell transplantation is now standard practice.27 Nakagawara et al.1573158 reported that high levels of the proto-oncogene Trk-A, a receptor for the neurotrophin nerve growth factor, were associated with excellent survival in infants with neuroblastoma. Trk-A receptor is activated by nerve growth factor and may have an important role in spontaneous regression and tumor differenis associated with younger patients, t i a t i ~ n . I ~ ~Trk-A J" lower-stage disease, and absence of N-myc expression. Trk-A also down-regulates angiogenic factor expression and the number of microvessels in neuroblastoma tumor cell lines. Multivariate analysis, however, suggests that Nmyc is a more important independent prognostic factor. In contrast, Trk-B, another neurotropin receptor, is often associated with N-mycamplification and, due to its ligand BDNF, may provide a tumor cell survival or growth advantage.159 The Trk-B-BDNF pathway also contributes to enhanced angiogenesis, tumorigenicity, cell survival, and drug resistance.27~100Trk-C (similar to Trk-A) is identified in lower-stage tumors without N-myc amplification.2' The Bcl-2 oncoprotein is responsible for relaying apoptotic signaling and is expressed by most neuroblastomas. Increased Bcl-2 expression in neuroblastoma is L

associated with inhibition of chemotherapy-induced - , apoptosis and a poor 0 u t c o m e . ~ ~ . 2 ~Decreased ,",~~ expression of caspases (enzymes resoponsible for executing the apoptotic signal) is also associated with a dismal outcome. In contrast, increased expression of caspases in neuroblastomas with favorable biologic features is associated with an improved outcome. Tumors with high CD44 cell surface expression are usually well differentiated and result in improved survival. Cellular DNA content is a predictor of response to chemotherapy in infants with unresectable neuroblastoma. Flow cytometry studies show that hyperdiploidy and triploidy are associated with a favorable outcome, whereas diploid tumors have a poor outcome. Similar to N-myc, DNA ploidy is of prognostic value independent of stage and age, and the two factors (N-myc and ploidy) together provide important complementary prognostic information for infants.ll.27 DNA ploidy flow cytometry correlates well with response to chemotherapy and outcome. The survival rate for patients who present with opsoclonus and nystagmus ("dancing eye syndrome") is approximately 90%. This syndrome is seen more frequently (>60%) in patients with primary mediastinal tumors, in patients with stage I or I1 disease, and in infants younger than 1 year.g1207In addition, these tumors are often more histologically mature. Presence of the dancing eye syndrome in patients who present with advanced tumors and N-myc overexpression, however, is associated with a poor outcome." Despite tumor resection and adrenocorticotropic hormone treatment, the neurologic symptoms in sk-vivors (including learning disabilities and attention deficits) may persist for many years.121,195,1Y6 The outlook is also improved for patients who present with the hypokalemic watery diarrhea syndrome associated Serum VIP with a VIP-producing neurogenic t~mor.~2,58,127 levels can serve as a tumor marker in these cases, in which the tumor often does not secrete catecholamines. These patients frequently have tumors that are more mature and well differentiated (e.g., ganglioneuroblastoma). VIP production has also been observed in cases of benign ganglioneuroma, again suggesting that these lesions have a more benign behavior. Somatostatin receptors are expressed more frequently in tumor tissue from patients with lower-stage disease and favorable histology without N-myc amplification. These observations suggest that somatostatin receptor expression is a favorable prognostic factor.154J7Y Children with advanced neuroblastoma frequently show evidence of protein-calorie malnutrition associated with immunoincompetence, based on anergy to a variety rd of skin test a n t i g e n ~ . ~ ~ " l ~ W c keta a1.18Wemonstrated that patients with stage IV neuroblastoma who were malnourished at diagnosis had more treatment delays and a significantly worse outcome than adequately nourished counterparts with similar disease severity: These observations suggest that a nutritional assessment at diagnosis should be a component of the patient's staging.lS8In addition, Van Eys et al.231and Rickard et a1.'8XJ8%howed that significant nutritional depletion occurs with multimodal cancer therapy and thai total parenteral nutrition -

~

-

CHAPTER

28

Neuroblastoma

487

(low, intermediate, and high) that determine future can replete and maintain the patient's nutritional status treatment protocols. ~isk-basedmanagement permits during intensive tumor therapy. In a recent study, individualized care for each patient based on age, INSS Sala et a1.1" reported that the incidence of malnutrition stage, INPC histology, and biologic and genetic characin children with advanced neuroblastoma was 50%. They teristics that affect the behavior of each t~mor.27,~~,2~" stressed the importance of nutritional status and its This avoids unnecessary and potentially harmful possible influence on the course of the disease and treatment in patients categorized as having low-risk survival. Of interest is a study from Toronto, Canada, that tumors who may do well with surgery alone (and occaimplies that mandatory folic acid fortification of floursionally observation alone in highly selected cases). initially intended to reduce the incidence of neural tube It allows the physician to reserve the most aggressive defects-was associated with a 60% decrease in the incidence of neuroblastoma in the province of O n t a r i ~ . ~ ~ treatment protocols for children with the highest-risk tumors and the most guarded prognosis. At present, the Previously, Laug et a1.l" demonstrated that stage IV outlook is best in low-risk patients: infants younger than patients with a high urinary HVA/VMA ratio have a sig1 year, patients with localized tumors that can be comnificantly worse outlook. A greater production of HVA pletely excised (stages I and 11) with favorable INPC hismay be indicative of a primitive and immature tumor tology and low-risk biologic and genetic factors, and with more malignant potential. Hann et a1.87 reported infants with stage IV-S disease. Infants with cystic neurothat 63% of patients with stage IV disease had high blastomas detected on prenatal sonograms also have a serum ferritin levels, which was predictive of a poor progvery favorable outcome. In patients with stage IV-S disnosis, especially in girls older than 2 years. A number of ease and those with cvstic, multifocal, or bilateral tumors studies showed that neuroblastic tumors produce biologic characteristics, observation alone ~ *favorable *~ increased serum levels of neuron-specific e n ~ l a s e . ~ ~ ~and may be reasonable. Close sonographic monitoring of Zeltzer et a1.*" documented that neuron-specific enolase these cases in the first year of life is important to be sure levels are elevated in 96% of patients with metastatic disthat the tumor shrinks and undergoes regression. ease and that high serum levels are associated with a Increase in tumor size is an indication for operative poor prognosis, particularly in infants. Elevated serum intervention. Intermediate-risk cases include stage I11 lactic dehydrogenase levels are also associated with a patients (according to the INSS) without adverse biopoor prognosis in localized neuroblastoma."6 The proglogic risk factors and stage IV patients younger than nostic role of the multidrug resistance gene ( a - 1 ) in 1 year without biologic risk factors. Problem areas that High levels of the neuroblastoma is controversial.~6~~66 continue to require special attention include (1) infants MDR-associated protein gene (located on chromosome older than 1 year; ( 2 ) high-risk patients, including stage 16), however, is associated with a poor outcome. This I1 patients older than 1 year with high N-myc expression effect is independent of stage, N-myc, and Trk-A status.lG6 and unfavorable histology and those with advanced disAlthough these earlier observations were of interest and ease (stages I11 and IV) and adverse prognostic biologic shed light on the behavior of this enigmatic neoplasm, in and genetic variables; and (3) the prevention and treatthe present era, age, INSS stage, N-myc status, allelic loss ment of complications of aggressive multimodal therapy. at the lp36 locus, unbalanced 17q gain, and INPC are The last include conventional and total-body irradiation now considered the key predictors of outcome for neudamage, immunosuppression, cardiac and renal toxicity, roblastoma. The current survival rates are greater than scoliosis, adverse effect on growth and development, 90% for low-risk cases, 70% to 75% for intermediate-risk delayed sexual maturation, learning disabilities, and the cases, and 25% to 30% for high-risk cases. The overall occurrence of second neoplasms, including renal survival at 3 years is 50%.27 tUmors.27,68,l94 A better understanding of factors influencing tumor regression and differentiation and tumor-host immune SUMMARY AND FUTURE DIRECTIONS interactions is required. In children with high-risk tumors, identifying additional tumor markers and targetThis common pediatric malignancy remains an enigma ing effective monoclonal antibodies against the tumor; because of the high variability in tumor behavior. The developing improved techniques to clear the bone marprimitive neuroblastic tumor may follow one of three row of tumor cells; employing new and more effective possible pathways: spontaneous regression (apoptosis), chemotherapy programs (with or without total-body irradifferentiation and maturation to a benign ganglioneudiation); hematologic rescue with autologous purged roma, or, more commonly, tumor proliferation and peripheral blood stem cell infusions; and using growth rapid malignant progression. Fetal ultrasonography and factors (e.g., granulocyte colony-stimulating factor) and infant screening programs have clearly demonstrated other biologic tumor modulators (cis-retinoic acid) to that some tumors spontaneously regress. Age-related protect against infection and promote regression and histopathologic studies have clarified that some tumors differentiation may control the progression of disease (favorable histology) differentiate and mature, whereas and improve the outlook for this highly malignant others (unfavorable histology) are undifferentiated tumor. Despite some improvements in outcome using neoplasms that respond poorly to treatment and have a high-intensity treatments, the outlook for patients with rapidly progressive course and fatal outcome. advanced disease remains dismal, with less than half Recognition of important biologic (and genetic) charsurviving. Alternative treatment protocols using novel acteristics can categorize these tumors into risk groups

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and less toxic biologically based therapies (targeted proapoptotic, antiangiogenic, and immunotherapies) will no doubt be tested in the next few years in an attempt to improve the outcome of children with advanced neuroblastoma and diminish the toxicity associated with the current high-intensity but relatively ineffective treatment programs. Molecular profiling of the genetic changes that occur in neuroblastoma will likely permit a more concise classification system to predict outcome and further define the choice of specific therapy, which may include targeting the genes, proteins, and signaling pathways responsible for malignant progression of the tumor.27

REFERENCES 1. Abrams HL, Siegelman SS, Adams DF, et al: Computed tomography versus ultrasound of the adrenal gland: A prospective study. Radiology 1982;143:121-128. 2. Abramson SJ, Berdon WE, Ruzal-Shapiro C, et al: Cervical neuroblastoma in eleven infants-a tumor with favorable prognosis: Clinical and radiologic (US, CTR, MRI) findings. Pediatr Radio1 1993;23:253-257. 3. Acharya S, Jayabose S, Kogan S, et al: Prenatally diagnosed neuroblastoma. Cancer 1997;80:304310. 4. Adams GA, Shochat SJ, Smith EI et al: Thoracic neuroblastoma: A pediatric oncology group study. J Pediatr Surg 1993;28:372-377. 5. Adkins ES, Sawin R, Gerbing RB, et al: Efficacy of complete resection for high risk neuroblastoma: A Children's Cancer Group study. J Pediatr Surg 2004;39:931-936. 6. Akeson R, Seeger RC: Interspecies neural membrane antigens on cultured human and murine neuroblastoma cells. J Immunol 1977;118:1995-2003. 7. Allen RW Jr, Ogden B, Bentley FL, Jung AL: Fetal hydantoin syndrome: Neuroblastoma and hemorrhagic disease in a neonate. JAMA 1980;44:14641465. 8. Al-Rashid RA, Cress C: Hypercalcemia associated with neuroblastoma. Am J Dis Child 1979;133:838-841. 9. Altman A, Baehner RL: Favorable prognosis for survival in children with coincident opsomyoclonus and neuroblastoma. Cancer 1976;37:846-852. 10. Ambros IM, Attarbashi A, Rumpler S, et al: Neuroblastoma cells provoke Schwann cell proliferation in vitro. Med Pediatr Oncol 2001;36:163-168. 11. Ambros IM, Zellner A, Roald B, et al: Role of ploidy, chromosome lp, and Schwann cells in the maturation of neuroblastoma. N Engl J Med 1996;334:1505-1511. 12. Anders D, Kindermann G, Pfeifer U: Metastasizing fetal neuroblastoma with involvement of the placenta simulating fetal erythroblastosis. J Pediatr 1973;82:50-53. 13. Beckwith JB, Perrin EV: In-situ neuroblastoma: A contribution to the natural history of neural crest tumors. Am J Pathol 1963;43:1089-1104. 14. Beirle EA, Strande LK, Chen MK: VEGF upregulates bcl-2 expression and is associated with decreased apoptosis in neuroblastoma cells. J Pediatr Surg 2002;7: 467-471. 15. Beppu K, Jaboine J, Merchant MS, et al: Effect of imatinib mesylate on neuroblastoma tumorigenesis and VEGF expression. J Natl Cancer Inst 2004;96:46-55. 16. Bernardi J, et al: Prognostic value of MDRl gene expression in neuroblastoma: Results of a multivariate analysis. Prog Clin Biol Res 1994;385:111.

17. Bernstein I , Hellstrom KE, Wright PW, et al: Immunity to tumor antigens: Potential implications in human neuroblastoma. J Natl Cancer Inst 1976;57:711-715. 18. Berthold F, Kassenbohmer R, Zieschang J: Multivariate evaluation of prognostic factors in localized neuroblastoma. Am J Hematol Oncol 1994;16:107-115. 19. Bessho F, Hashizume K, Nakajo T, et al: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 1991;119:237-241. 20. Bill AH: Immune aspects of neuroblastoma: Current information. Am J Surg 1971;122:142-147. 21. Blatt JB, Deutsch M, Wollman MR: Results of therapy in stage IV-S neuroblastoma with massive hepatomegaly. Int J Radiat Oncol Biol Phys 1987;13:1467-1471. 22. BlattJB, Fitz G, Mirro J: Recognition of central nervous system metastases in children with metastatic primary extracranial neuroblastoma. Pediatr Hematol Oncol 1997;14:233-241. 23. Breslow N, McCann B: Statistical estimation of prognosis for children with neuroblastoma. Cancer Res 1971; 31:1098-1103. 24. Brock CE, Ricketts RR: Hemoperitoneum from spontaneous rupture of neonatal neuroblastoma. Am J Dis Child 1982;136:370-371. 25. Brodeur GM: Molecular basis for heterogeneity in human neuroblastoma. Eur J Cancer 1995;31A:505-510. 26. Brodeur GM: Schwann cells as antineuroblastoma agents. N Engl J Med 1996;334:1537-1539. 27. Brodeur GM: Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-216. 28. Brodeur GM, Pritchard J, Berthold F, et al: Revision of the international criteria for neuroblastoma diagnosis staging and response to treatment. J Clin Oncol 1993;11:1466-1477. 29. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis of staging and response to treatment in patients with neuroblastoma. J Clin Oncol 1988;6: 18741881. 30. Caron H, van Sluis B, de Kraker J, et al: Allelic loss of chromosome l p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 1996;334: 225-230. 31. Caste1 V, Bedal MD, Bezanilla JL, et al: Treatment of stage 111 neuroblastoma with emphasis on intensive induction chemotherapy: A report from the Neuroblastoma Group of the Spanish Society of Pediatric Oncology. Med Pediatr Oncol 1995;34:29-35. 32. Caste1 W, Heidelberger KP, Bromberg J, et al: Expression of the apoptosis-suppressing protein bcl-2 in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol 1993;143:1543-1550. 33. Castleberry RP, Pritchard J, Ambros P, et al: The International Neuroblastoma Risk Groups (INRG): A preliminary report. Eur J Cancer 1997;33:2113-2116. 34. Castleberry RP, Shuster JJ,Smith EI: Pediatric Oncology Group experience with the International Staging System criteria for neuroblastoma. J Clin Oncol 1994;12: 2378-2381. 35. Chan HS, Haddad G, Thorner PS, et al: P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med 1991;325:1608-1614. 36. Chang THT, Prasad KN: Differentiation of mouse neuroblastoma cells in-vitro and in-vivo, induced by cyclic adenosine monophosphate (CAMP).J Pediatr Surg 1976; 112347-858. 37. Chatten J, Voorhees ML: Familial neuroblastoma: Report of a kindred with multiple disorders including

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38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

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50.

51.

52. 53. 54. 55. 56. 57.

58.

neuroblastoma in four siblings. N Engl J Med 1967;277: 1230-1236. Cheung NK: Monclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep 2000;2:547-551. Cheung NK, Kushner BH, Yeh SD, et al: 3F8 Monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase I1 study. Int J Oncol 1998;12:1299-1306. Chlenski A, Liu S, Cohn SL: The regulation of angiogenesis in a neuroblastoma. Cancer Lett 2003;197:47-52. Coldman AJ, Fryer CJ, Elwood JM, Sonley MJ: Neuroblastoma: Influence of age at diagnosis, stage, site and sex on prognosis. Cancer 1980;46:1896-1901. Cooney DR, Voorhees ML, FisherJE, et al: Vasoactive intestinal polypeptide producing neuroblastoma. J Pediatr Surg 1982;17:821-825. Cushing H, Wolbach SB: Transformation of malignant paravertebral sympathicoblastoma into benign ganglioneuroma. Am J Path01 1927;3:203. D'Angio GJ, Evans AE: Experience with cyclic low-dose total body irradiation for metastatic neuroblastoma [abstract]. Proc Am Soc Clin Oncol 1982;23:52. D'Angio GJ, Evans AE, Koop CE: Special pattern of widespread neuroblastoma with a favorable prognosis. Lancet 1971;1:10461049. Dastur DK: Cerebral ganglioglioneuroblastoma: An unusual brain tumor of the neuron series. J Neurol Neurosurg Psychiatry 1982;45:139-142. Davidoff AM, Kandel J:Antiangiogenic therapy for the treatment of pediatric solid malignancies. Semin Pediatr Surg 2004;13:53-60. Davidoff AM, Leary MA, Ng CT, et al: Retroviral vector producer cell mediated angiogenesis inhibition restricts neuroblastoma growth in-vivo. Med Pediatr Oncol 2000;35:638-640. Davidoff AM, Leary MA, Ng CY,et al: Gene therapy mediated expression by tumor cells of the angiogenesis inhibitor Flk-1 results in inhibition of neuroblastoma growth in-vivo.J Pediatr Surg 2001;36:30-36. DeBernardi B, Pianca C, Boni L, et al: Disseminated neuroblastoma (stage IV and IV-S) in the first year of life: Outcome related to age and stage. Italian Cooperative Group on Neuroblastoma. Cancer 1992;70:1625-1633. DeBernardi B, Conte M, Mancini A, et al: Localized resectable neuroblastoma: Results of the 2nd study of the Italian Cooperative Group for Neuroblastoma. J Clin Oncol 1995;13:884893. de Lagausie P, Berribi D, Michon J, et al: Laparoscopic adrenal surgery for neuroblastoma in children. J Urol 2003;170:932-935. Deutsch M, Tersak JM: Radiotherapy for symptomatic metastases to bone in children. Am J Clin Oncol 2004;27:128-131. Dobrovoljski G, Kerbl R, Strobl C, et al: False-positive results in neuroblastoma screening: The parents' view. J Pediatr Hematol Oncol 2003;25:1418. Dole M, Nunez G, Merchant AK, et al: Bcl-2 inhibits chemotherapy induced apoptosis in neuroblastoma. Cancer Res 1994;54:3253-3259. Dreyfus M, Neuhart D, BaldaufJ, et al: Prenatal diagnosis of cystic neuroblastoma. Fetal Diagn Ther 1994;9:269-272. Eggert A, Ikegaki N, KwiatkowskiJ, et al: High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res 2000;6:1900-1908. El-Shafie M, Samuel D, Klippel CH, et al: Intractable diarrhea in children with VIP-secreting ganglioneuroblastoma. J Pediatr Surg 1983;18:3436.

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59. Emery LG, Shields M, Shah MR, et al: Neuroblastoma associated with Beckwith-Wiedemann syndrome. Cancer 1983;52:176-179. 60. Entz-Werle N, Marcellin L, Becmeur F, et al: The urinary bladder: An extremely rare location of pediatric neuroblastoma. J Pediatr Surg 2003;38:E10-E12. 61. Evans AE, Albo V, D'Angio GJ, et al: Cyclophosphamide treatment of patients with localized and regional neuroblastoma: A randomized study. Cancer 1976;38:655-660. 62. Evans AE, D'Angio GJ, Randolph JG: A proposed staging for children with neuroblastoma. Cancer 1971;27: 374378. 63. Evans AE, Gerson J , Schnaufer I,: Spontaneous regression of neuroblastoma. Natl Cancer Inst Monogr 1976;44:49-54. 64. Evans AE, Heyn RN, Newton WA Jr, Leikin SL: Viscristine sulfate and cyclophosphamide for children with metastatic neuroblastoma. JAMA 1969;207:1325-1327. 65. Fenart D, Deville A, Donzeau M, Bruneton JN: Neuroblastome retroperitoneal diagnostique in utero. J Radiol 1983;64:359-361. 66. Filler RM, Traggis DG, Jaffe N, Vawter GF: Favorable outlook for children with mediastinal neuroblastoma. J Pediatr Surg 1972;7:136-143. 67. Finklestein JZ, Klemperer, MA, Evans AE, et al: Multiagent chemotherapy for children with metastatic neuroblastoma: A report from the Children's Cancer Study Group. Med Pediatr Oncol 1979;6:179-188. 68. FleitzJM, Wooten-Gorges SC, Wyatt-AshmeadJ, et al: Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma early in childhood. Pediatr Radiol 2003; 33:540-545. 69. French AE, Grant R, Weitzman S, et al: Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol 2003;74:288-294. 70. Gerson JM, Chatten J, Eisman S: Familial neuroblastomaa follow-up. N Engl J Med 1974;190:487. 71. Gerson JM, Herberman RB: Systemic and in-situ natural killer activity in patients with neuroblastoma. In Evans AE (ed): Advances in Neuroblastoma Research. New York, Raven Press, 1980. 72. Green AA, Hayes FA, Hustu HO: Sequential cyclophosphamide and doxorubicin for induction and complete remission in children with disseminated neuroblastoma. Cancer 1981;48:2310-2317. 73. GrosfeldJL: Neuroblastoma: A 1990 overview. Pediatr Surg Int 1991;6:9-13. 74. Grosfeld JL: Risk based management of childhood solid tumors. J Am Coll Surg 1999;189:407-425. 75. Grosfeld JL, Ballantine TVN, Baehner RL: Experience with "second-look operations in pediatric solid tumors. J Pediatr Surg 1978;13:275-280. 76. Grosfeld JL, Rescorla FJ, West KW, Goldman J: Neuroblastoma in the first year of life: Clinical and biologic factors influencing outcome. Semin Pediatr Surg 1993;2:37-46. 77. GrosfeldJL, Schatzlein M, Ballantine TVN, et al: Metastatic neuroblastoma: Factors influencing survival.J Pediatr Surg 1978;13:59-65. 78. Grosfeld JL, West KW, Weber TR: The role of second-look procedures in the management of retroperitoneal tumors in children. J Pediatr Hematol Oncol 1984;6:441-447. 79. Haas D, Ablin AR, Miller C, et al: Complete pathologic maturation and regression of stage IV-S neuroblastoma without treatment. Cancer 1988;62:818-825. 80. Haas-Kogan DA, Fisch BM, Wara WB, et al: Introperative radiation therapy for high risk neuroblastoma. Int J Radiat Oncol Biol Phys 2000;47:985-992.

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81. Haas-Kogan DA, Swift PS, Eslch M, et al: Impact of radiotherapy for high risk neuroblastoma: A Children's Cancer Group study. Int J Radiat Oncol Biol Phys 2003; 56:28-39. 82. Haase GM: Head and neck neuroblastomas. Semin Pediatr Surg 1994;3:194202. 83. Haase GM, LaQuaglia MP: Neuroblastoma. In Ziegler M, Azizkhan RG, Weber TR (eds): Operative Pediatric Surgery. New York, McGraw-Hill, 2003, pp 1181-1191. 84. Haase GM, O'Leary MC, Ramsay NK, et al: Aggressive surgery combined with intensive chemotherapy improves survival in poor risk neuroblastoma. J Pediatr Surg 1991; 26:1119-1123. 85. Haase GM, Wong KY, deLorimier AA, et al: Improvement in survival after excision of the primary tumor in stage I11 neuroblastoma. J Pediatr Surg 1989;24:194200. 86. Haddad M, Triglia.jM, Helardot P, et al: Localized cervical neurob1astoma:-prevention of surgical complications. Int J Pediatr Otorhinolaryngol 2003;67:1361-1367. 87. Hann JL, et al: Serum ferritin levels as a guide to prognosis in stage IV neuroblastoma [abstract]. Proc Am Soc Clin Oncol 1983;24:72. 88. Hatchitanda Y, Hata J: Stage IV-S neuroblastoma: A clinical, histological and biological analysis. Hum Path01 1996;27:1135-1 138. 89. Hayashi Y, Kanmda N, Inaba T, et al: Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer 1989;63:125-132. 90. Hayes FA, Green AA, CasperJ, et al: Clinical evaluation of sequentially scheduled cisplatin and VM-26 in neuroblastoma: Response and toxicity. Cancer 1981;48:1715-1718. 91. Hayes FA, Green AA, Hustu HO, Kumar ML: Surgicopathologic staging of neuroblastoma: Prognostic significance of regional lymph node metastases. J Pediatr 1983;102:59-62. 92. Hayes F, Green AA, Mauer AM, et al: Correlation of cell kinetics and clinical response to chemotherapy in disseminated neuroblastoma. Cancer Res 1977;37:3766-3770. 93. Heisel MA, Miller JH, Reid BS, Siege1 SE: Radionuclide bone scan in neuroblastoma. Pediatrics 1983;71:206-209. 94. Hellstrom I, Hellstrom KE, Pierce GE, Bill AH: Demonstration of cell bound humoral immunity against neuroblastoma cells. Proc Natl Acad Sci U S A 1968;60: 1231-1238. 95. Hellstrom KE, Hellstrom I: Lymphocyte mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol 1974;18:209-217. 96. Helson L, Ghavimi F, Wu CJ, et al: Carcinoembryonic antigen in children with neuroblastoma. J Natl Cancer Inst 1976;57:725-726. 97. Helson L, Helson C, Peterson RF, Das SK: A rationale for the treatment of metastatic neuroblastoma. J Natl Cancer Inst 1976;57:727-729. 98. Hiyama E, Yokoyama T, Hiyama K et al: Multifocal neuroblastoma: Biologic behavior and surgical aspects. Cancer 2000;88:1955-1963. 99. Hiyama E, Yokoyama T, Ichikawa T, et al: Poor outcome in patients with advanced stage neuroblastoma and coincident opsomyoclonus syndrome. Cancer 1994;74: 1821-1826. 100. Ho R, Eggert A, Hishiki T, et al: Resistance to chemotherapy mediated by TrkB in neuroblastoma. Cancer Res 2002;62:6462-6466. 101. Ho TC, EstroffJA, Kozakewich H, et al: Prenatal detection of neuroblastoma: A ten year experience from the DanaFarber Cancer Institute and Children's Hospital. Pediatrics 1993;92:358-364.

102. Holcomb GW: Minimally invasive surgery for solid tumors. Semin Surg Oncol 1999;7:184192. 103. Holgersen LO, Subramanian S, Kirpekar M, et al: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 1996;31:153-155. 104. Ikeda H, Iehara T, Tsuchida Y, et al: Experience with the International Neuroblastoma Staging System and pathology classification. Br J Cancer 2002;86:1110-1116. 105. Ikeda H, Suzuki N, Takahashi A, et al: Surgical treatment of neuroblastomas in infants under 12 months of age. J Pediatr Surg 1998;33:1246-1250. 106. Ishimoto K, Kiyokawa H, Fujita H, et al: Problems of mass screening for neuroblastoma: Analysis of false negative cases. J Pediatr Surg 1990;25:398-401. 107. Iwanaka T, Arai M, Ito M, et al: Surgical treatment for abdominal neuroblastoma in the laparoscopic era. Surg Endosc 2001;15:751-754. 108. Iwanaka T, Arai M, Kawashima H, et al: Endosurgical procedures for pediatric solid tumors. Pediatr Surg Int 2004;20:39-42. 109. Jennings RW, LaQuaglia MP, Leong K, et al: Fetal neuroblastoma: Prenatal diagnosis and natural history. J Pediatr Surg 1993;28:1168-1174. 110. Jiang TH, Yang CP, Hung IJ, et al: Brain metastases in children with neuroblastoma-a single institution experience. Med Pediatr Oncol 2003;41:570-571. 111. Joshi W, Cantor AB, Altschuler G, et al: Age-linked prognostic categorization based on a new histologic grading system of neuroblastoma. Cancer 1992;69:2183-2196. 112. Kaicker S, McCRudden KW, Beck L, et al: Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma. Int J Oncol 2003;23:1651-1655. 113. Kang TI, Brophy P, Hickeson M, et al: Targeted radiotherapy with submyeloablative doses of 1'"-MIBG is effective for disease palliation in highly refractory neuroblastoma. J Pediatr Hematol Oncol 2003;25:769-763. 114. Kanold J, Halle P, Tchirkov A, et al: Ex-vivct expansion of autologous PB CD34+ cells provide a purge effect in children with neuroblastoma. Bone Marrow Transplant 2003;32:485-488. 115. Kenney LB, Miller BA, Gloeker-Reis LA, et al: Increased incidence of cancer in infants in the United States 1980-1990. Cancer 1998;82:1396-1400. 116. Kiely EM: The surgical challenge of neuroblastoma. J Pediatr Surg 1994;29:128-133. 117. Kim ES, Soffer SZ, Huang J, et al: Distinct response of experimental neuroblastoma to combination antiangiogenic strategies. J Pediatr Surg 2002;37:518-522. 118. King D, Goodman J, Hawk T, et al: Dumbbell neuroblastoma in children. Arch Surg 1975;110:888-891. 119. Kinney H, Faix R, Brazy J: The fetal alcohol syndrome and neuroblastoma. J Pediatr 1980;66:130-132. 120. Kogner P, Barbani G, Dominici C, et al: Co-expression of messenger RNA for Trk protooncogene and low affinity nerve growth factor receptors in neuroblastoma with favorable prognosis. Cancer Res 1993;53:20442050. 121. Koh PS, Raffensperger J, Berry S, et al: Long-term outcome in children with opsoclonus myoclonus and ataxia and coincident neuroblastoma. J Pediatr 1994;125: 712-716. 122. Komuro H, Kaneko S, Kaneko M, et al: Expression of angiogenic factors and tumor progression in human neuroblastoma. J Cancer Res Clin Oncol 2001;127:739-743. 123. Komuro H, Makino S, Tahara K: Laparoscopic resection of an adrenal neuroblastoma detected by mass screening that grew in size during the observation period. Surg Endosc 2000;14:297.

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supportive care or minimal therapy: A Children's Cancer Group study. J Clin Oncol 2000;18:477-486. 163. Nickerson HJ, Nesbit ME, Grosfeld JL, et al: Comparison of stage IV and IV-S neuroblastoma in the first year of life. Med Pediatr Oncol 1985;13:261-268. 164. Ninane J, Pritchard J, Morris Jones PH, et al: Stage I1 neuroblastoma: Adverse prognostic significance of lymph node involvement. Arch Dis Child 1982;57:438-442. 165. Nitschke R, Cangir A, Crist W, Berry DH: Intensive chemotherapy for metastatic neuroblastoma: A Southwest Oncology Group study. Med Pediatr Oncol 1980;8: 281-288. 166. Norris MD, Bordow SD, Marshall GM, et al: Expression of the gene for multidrug resistance associated protein and outcome in patients with neuroblastoma. N Engl J Med 1996;334:231-238. 167. Odelstad L, Pahlman S, Lackgren G, et al: Neuron specific enolase: A marker for differential diagnosis of neuroblastoma and Wilms' tumor. J Pediatr Surg 1982;17: 381-385. 168. Oue T, Fukuzawa M, Kusafuka T, et al: In situ detection of DNA fragmentation and expression of bcl-2 in human neuroblastoma: Relation to apoptosis and spontaneous regression. J Pediatr Surg 1996;31:251-257. 169. Oue T, Inoue M, Yoneda A, et al: Profile of neuroblastoma detected by mass screening, resected after observation without treatment: Results of the Wait and See pilot study. J Pediatr Surg 2005;40:359-363. 170. Paul SR, Tarbell NJ, Korf B, et al: Stage IV neuroblastoma in infants: Long-term survival. Cancer 1991;67:1493-1497. 171. Pegelow CH, Ebbin AJ, Powars D, Towner JW: Familial neuroblastoma. J Pediatr 1975;87:763-765. 172. Perkins DG, Kopp CM, Haust MD: Placental infiltration in congenital neuroblastoma. Histopathology 1980;4: 383-389. 173. Peuchmaur M, d'Amore ES,Joshi W, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 2003; 98:22742281. 174. Plantaz D, Rubie H, Michon J, et al: The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease: A prospective study of 42 patients-results of the NBL 90 study of the French Society of Pediatric Oncology. Cancer 1996;3:521-525. 175. Ponzoni M, Bocca P, Chiesa V, et al: Differential effects of N-4hydroxyphenylretinamide and retinoic acid on neuroblastoma cells: Apoptosis and differentiation. Cancer Res 1995;55:853-861. 176. Powell JL, Buniz NJ, Callahan C, et al: An unexpectedly high incidence of Epstein-Barr virus lymphoproliferative disease after CD34+ selected autologous peripheral blood stem cell transplant in neuroblastoma. Bone Marrow Transplant 2004;33:651-657. 177. Prasad KN, Mandal B, Kumar S: Demonstration of cholinergic cells in human neuroblastoma and ganglioneuroma. J Pediatr 1973;82:677-679. 178. Pritchard J, McElwain TJ, Graham-Pole J: High dose melphalan with autologous bone marrow for treatment of advanced neuroblastoma. Br J Cancer 1982;45:86-94. 179. Qualman SJ, O'Diorisio MS, Fleshman DJ, et al: Neuroblastoma: Correlation of neuropeptide expression in tumor tissue with other prognostic factors. Cancer 1992; 70:2005-2012. 180. Raffaghello L, Marimpietri D, Pagnan G, et al: Anti-GD2 monoclonal antibody immunotherapy: A promising strategy

181. 182. 183. 184. 185. 186. 187. 188. 189. 190.

191. 192. 193. 194. 195.

196.

197. 198. 199. 200. 201.

in the prevention of neuroblastoma relapse. Cancer Lett 2003;197:205-209. Redlinger RE, Shimizu T, Remy T, et al: Cellular mechanisms of interleukin-12 mediated neuroblastoma regression. J Pediatr Surg 2003;38:199-204. Redlinger RE Jr, Mailliard RB, Barksdale EM: Neuroblastoma and dendritic cell function. Semin Pediatr Surg 2004;13:61-71. Reynolds CP: bifferentiating agents in pediatric malignancies: Retinoids in neuroblastoma. Curr Oncol Rep 2000;2:511-518. Reynolds CP, Kane DJ, Einhorn PA, et al: Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 1996;366:203-211. Reynolds CP, Matthay KK, Villablanca JG, et al: Retinoid therapy of high risk neuroblastoma. Cancer Lett 2003;197:185-192. Ribatti D, Raffaghello L, Marimpietri D, et al: Fenretinide as an anti-angiogenic agent in neuroblastoma. Cancer Lett 2003;197:181-184. Richards ML, Gundersen AE, Williams MS: Cystic neuroblastoma of infancy.J Pediatr Surg 1995;30:13541357. Rickard KA, Detamore CM, Coates TD, et al: Effect of nutrition staging on treatment delays and outcome in stage IV neuroblastoma. Cancer 1983;52:587-598. Rickard KA, Grosfeld JL, Kirksey A, et al: Reversal of protein-energy malnutrition in children during treatment of advanced neoplastic disease. Ann Surg 1979;190:771-781. Rill DR, Santana VM, Roberts WM, et al: Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 1994;84:380-383. Riley RD, Heney D, Jones DR, et al: A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res 2004;10:412. Rosenberg SA: Development of effective immunotherapy for the treatment of patients with cancer. J Am Coll Surg 2004;198:685-696. Rowe DH, Huang J, Li J, et al: Suppression of primary tumor growth in a mouse model of human neuroblastoma. J Pediatr Surg 2000;35:977-981. Rubino C, Adjadj E, Guerin S, et al: Long-term risk of second malignant neoplasms after neuroblastoma in childhood: Role of treatment. Int J Cancer 2003;107:791-796. Rudnick C, Khakoo Y, Antunes NL: Opsoclonusmyoclonus-ataxia syndrome in neuroblastoma: Clinical outcome and antineural antibodies-a report from the Children's Cancer Group study. Med Pediatr Oncol 2001;36:612-622. Russo C, Cohn SL, Petruzzi MJ, et al: Long term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: A report from the Pediatric Oncology Group. Med Pediatr Oncol 1997;28: 284288. Sala A, Pencharz P, Barr RD: Children, cancer and nutrition-a dynamic triangle in review. Cancer 2004;lOO: 677-687. Sandberg DI, Bilsky MH, Kushner BH, et al: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 2003;39:291-298. Sawada T, Sugimoto T, Kawakatsu H, et al: Mass screening for neuroblastoma in Japan. Pediatr Hematol Oncol 1991;8:93-109. Sawada T, Todo S, Fujita K, et al: Mass screening of neuroblastoma in infancy. Am J Dis Child 1982;136:710-712. Schilling FH, Parker C: Mass screening in neuroblastoma: The European experience. In Brodeur GM, Sawada T,

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242. Yiin J, Chang CS, Jan YJ, Wang YC: Treatment of neuroblastoma with intraspinal extension. J Clin Neurosci 2003; 10:579-583. 243. Young DG: Thoracic neuroblastoma/ganglioneuroma. J Pediatr Surg 1983;18:37-41. 244. Zeltzer PM, Marangos PJ, Parama AM, et al: Raised neuron specific enolase in the serum of children with metastatic neuroblastoma: A report from the Children's Cancer Study Group. Lancet 1983;2:361-363.

245. Ziegler MM, Vega A, Koop CE: Electrocoagulation induced immunity-an explanation for regression of neuroblastoma. J Pediatr Surg 1980;15:3437. 246. Zimmerman RA, Bilaniuk CT: CT of primary and secondary craniocerebral neuroblastoma. AJR Am J Roentgen01 1980;135:1239-1242.

Nonmalignant Tumors of the Liver Philip C. Guzzetta, Jr.

Primary liver tumors constitute less than 3% of tumors seen in the pediatric population, and only one third of Despite the rarity of those tumors are benign.2~*~~"~66" benign liver tumors, recommendations for diagnostic evaluation and management can be made, based on the experience gained from centers with a relatively large number of patients. Benign tumors may be epithelial (focal nodular hyperplasia, hepatocellular adenoma), mesenchymal (infantile hepatic hemangioendothelioma, cavernous hemangioma, mesenchymal hamartoma), or other (teratoma, inflammatory pseudotumor). Nonparasitic cysts, although not technically neoplasms, are also discussed in this chapter. One of the more interesting aspects of benign liver tumors in children is their predilection to occur in patients with other conditions. Hepatocellular adenomas have long been associated with the use of oral contraceptives in adults. Children are at risk for hepatocellular adenoma when they have received androgen therapy for aplastic anemia, have chronic iron overload from transfusion in P-thalassemia, or have received corticosteroids after renal transplantation.8 Patients with type I glycogen storage disease are at increased risk for hepatocellular adenomahand focal nodular h y p e r p l a ~ i a liver ~ ~ ; hamartomas may occur in children with tuberous sclerosis.33

CLINICAL PRESENTATION Most children with benign liver tumors present with a painless right upper quadrant abdominal mass or hepatomegaly. Symptoms of gastrointestinal compression, such as constipation, anorexia, or vomiting, may also be present. If the mass is painful, the pain is usually dull and aching and is caused by expansion of the liver capsule or compression of the normal surrounding structures. Jaundice and weight loss are uncommon except in infants with infantile hepatic hemangioendothelioma (IHH), and those signs should raise the suspicion that the lesion is malignant. Acute abdominal pain may be caused by bleeding into the mass or into the peritoneum, particularly in hepatocellular adenomas, although this problem is rarely seen in children. Children may present with congestive heart failure (CHF) and thrombocytopenia,

which is known as Kasabach-Merritt syndrome when associated with a vascular anomaly such as IHH." Cutaneous hemangiomas are seen in about half the children with IHH,25,"".%nd the rapid liver enlargement with IHH can cause abdominal compartment syndrome and respiratory distress.52 CHF without significant thrombocytopenia can also be seen with liver arteriovenous malformation (AVM)zO or mesenchymal hamartoma.") Fetal hydrops has been identified by prenatal ultrasonography in some fetuses with IHHZ1 or mesenchymal h a m a r t ~ m a . ~ ~

DIAGNOSIS Laboratory Tests Serum alpha fetoprotein (AFP) is present in very high concentrations at birth (48,000 f 35,000 ng/mL) and rapidly declines to adult levels of less than 10 ng/mL by 8 months of age (Table 29-1).7"hus, in infants younger than 8 months, AFP levels must be interpreted in the context of this dramatic change. Markedly elevated AFP

I Age

No. of Patients

AFP Level f SD (ng/mL)

Premature Newborn Newborn-2 wk 2 wk-l mo 1mo 2 mo 3 mo 4 mo 5 mo 6 mo 7 mo 8 mo From Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants Pediatr Res 1981: 5:50.

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levels in a child with a liver mass almost certainly means that the mass is malignant, although milder elevation may be encountered with some benign lesions such as mesenchymal hamartoma"' or teratoma.'j6As mentioned previously, significant thrombocytopenia associated with a liver mass is usually part of the Kasabach-Merritt syndrome due to IHH. Hypothyroidism may also occur in IHH27; thyroid function tests should be done routinely in these children, because hypothyroidism significantly impacts their management.42

-

-

Imaging Techniques The initial imaging study in a child presenting with an abdominal mass should be a supine radiograph of the abdomen, looking for calcifications within the mass. The next imaging study should be an abdominal sonogram with Doppler spectral analysis, followed by computed tomography (CT) with intravenous contrast (Fig. 29-1).6 Magnetic resonance imaging (MRI) may be indicated, depending on the sonogram and CT scan results, especially when surgical resection is planned and more detailed information about the vascular anatomy relative to the tumor is desired. Arteriography is reserved for children with IHH or, rarely, mesenchymal harnart0ma4.~ with CHF, in whom embolization of the tumor blood supply is needed for treatment. Liver-spleen radionuclide scans are seldom helpful in differentiating liver masses and thus are unnecessary in centers that have CT and MRI. The use of percutaneous biopsy under sonogram or CT guidance in children with benign tumors is generally discouraged (unless excision of the tumor would pose a major risk to the child), because establishing a diagnosis on the basis of a small sample may be problematic for the pathologist, and because resection is the proper therapy for most of these tumors. The findings on imaging studies are discussed in the sections on each individual tumor.

.

-

Contrastenhanced abdominal computed tomogra-

phy scan of a &month-old female infant with a large hemangioendothelioma of the left hepatic lobe. Note the cential area ofnecrosis.

VASCULAR TUMORS

infantile ti^ ~

~

~

~

~

~

i

~

IHH is by far the most common benign liver tumor in children. Increasingly, IHH is being diagnosed prenatally, and similar to affected neonates, the fetus may be asymptomatic or profoundly i11.z1,55Symptomatic children present before 6 months of age 80% of the time, with many presenting in the newborn period.25,"," The most common physical finding is hepatomegaly. The disease has a wide range " of severitv, ,. with some children being " asymptomatic and others having life-threatening CHF, abdominal compartment syndrome, and severe thrombocytopenia. I* most series, the female-to-male ratio is 2:1, and about half the children have a cutaneous hemangioma as well as IHH.1i,'5,9 In infants, IHH, can be reliably diagnosed by abdominal sonogram and dynamic contrast-enhanced CT. Lesions are usually present throughout the liver but may be localized to a few hepatic segrnents.'j8 On ultrasonography, multifocal, echolucent nodules usually have high-flow vessels, while solitary lesions have a more heterogeneous echogenicity.'j Before the administration of intravenous contrast, these lesions have low attenuation on CT; with contrast, they enhance diffusely or ent tripe tally.^ MRI of IHH reveals the extent of disease, the flow characteristics, and .~ the high rate of accuracy in the flow ~ t r u c t u r eDespite diagnosing IHH by imaging techniques, AFP and catecholamine levels should be obtained, because occasionally a hepatoblastoma or stage IV-S neuroblastoma is misdiagnosed as IHH.2" Dehner and Ishak12 identified two microscopic patterns of IHH. Type 1, the more common histologic pattern, is characterized by an orderly arrangement of dilated and compressed endothelium-lined vascular spaces supported by reticulin fibers with benign cytologic features. In their review, 17 of 23 lesions were type 1. Type 2 lesions have a more aggressive histologic appearance, with more complex and irregular branching structures within the vascular lumens. Endothelial cells are more hyperchromatic and pleomorphic than in type 1 lesions, although mitoses are uncommon. In Dehner and Ishak's series, the mortality rate was higher for patients with type 2 than type 1 tumors, but more recent series report a favorable outcome regardless of type. Thus, the histopathology of the tumor does not seem to correlate with prognosis. Management of these tumors depends on the severity of symptoms and the location of the lesion. When the lesion is asymptomatic and little hepatomegaly is present, observation is the appropriate therapy, as long as the diagnosis can be made with a high degree of certainty on the basis of noninvasive radiographic studies. Unless there is serious concern that the lesion is malignant, percutaneous or open biopsy is discouraged because of the risk of significant hemorrhage. Treatment of a symptomatic child is directed first toward uharmacologic " control of the tumor with corticosteroids,25355,59 interferon (IFN),y,18~ i n c r i s t i n e ,or ~~ cy~lophospharnide.2~ Despite initial enthusiasm for IFN therapy for IHH, there aEe concerns about serious side

~

~

CHAPTER

effects with both IFN-alpha 2a3 and IFN-alpha 2b.6 In addition, the therapy takes weeks to months to be effective, which is too long in critically ill neonates to be clinically useful. The success rate of any medical therapy is difficult to assess because of the wide disparity in disease severity and the fact that the usual singlecenter experience is fewer than 20 patients. In my experience, however, very ill neonates with CHF and thrombocytopenia due to diffuse or multifocal lesions are seldom improved with medical therapy alone. Embolization is most effective in children with disease restricted to only a few of the eight hepatic segments,68 but some success has been reported in children with diffuse IHH as we11.6 Diffuse IHH lesions frequently have extrahepatic arterial collaterals arising from the superior mesenteric, phrenic, intercostal, and internal mammary arteries, as well as some blood supply from the portal venous system.6,20This makes complete elimination of the blood flow by embolization virtually impossible. Although hepatic artery ligation was recommended as treatment for IHH in the past, it prevents effective embolization and thus should be avoided. If disease progression occurs despite embolization, hepatic resection11355 or even liver transplantationll,36 may be needed if the child is to survive. Radiation therapy has been used to treat these lesions,5',53 but the long-term effect of hepatic radiation in an infant is unknown, and there is one disturbing report that described three children with angiosarcoma of the liver who had previously been treated for IHH with radiation therapy.lg Estimates of survival rates with IHH are unreliable because of the variability of the disease and the wide range of treatment approaches, but in children younger than 6 months with CHF, reported survival rates are between 45% and 90% for this "benign" tumor.11,25,55

29

Nonmalignant Tumors of the Liver

497

venous system. Similar to patients with hemangioendotheliomas, patients with hepatoportal AVMs usually present before 6 months of age, many in the newborn period, with hepatomegaly, CHF, and a bruit over the liver.14 In older children and adults,. hepatic AVM may occur as part of hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu Angiography is diagnostic, and embolization is therapeutic in some but it is necessary to eliminate the extensive collaterals for successful closure of the AVM.614 Fatal complications from the embolization of liver AVMs have been reported.71 Steroids have no place in the management of these lesions, and AVMs not managed successfully with embolization may be controlled with hepatic arterial ligation.23~24 x

Mesenchymal Hamartoma Mesenchymal hamartoma (MH) usually presents as a painless right upper quadrant abdominal mass in a child Some patients may have eviyounger than 2 years.13,37,64 dence of CHF,45,60 and, similar to IHH, MH has been .~~ proposed that MH diagnosed ~ r e n a t a l l yEdmondson17 arises from a mesenchymal rest that becomes isolated from the normal portal triad architecture and differentiates independently. The tumor grows along bile ducts and may incorporate normal liver tissue. Because the blood vessels and bile ducts are components of the mesenchymal rest, the biologic behavior of the tumor varies with the relative predominance of these tissues within the loose connective tissue stroma (mesenchyma) that surrounds them. Thus, the tumor may present as a predominantly cystic structure (Fig. 29-2) that enlarges rapidly because of fluid accumulation,61 or it may be predominantly vascular and present with CHF.60

Hemangioma Hemangioma is the most common vascular liver tumor in adults; in children, however, hemangiomas are usually incidental findings in asymptomatic patients.12 Hemangomas have widely dilated, nonanastomotic vascular spaces lined with flat endothelial cells and supported by fibrous tissue on microscopic examination.12 Review of the literature on hemangioma in children is problematic, because some authors have called the lesions hemangiomas when the patient's age and clinical presentation were more In addition, consistent with hemangioend~thelioma.~O because the preferred treatment for these lesions is not surgical, there is usually no specimen for the accurate assessment of histopathology. In children, the risk of hemorrhage with hemangiomas is low; thus, unless the patient is having pain or disability from hepatomegaly, no treatment is recommended. In contrast, adults with giant hemangiomas (>4 cm in diameter) are generally treated by resection.lxj7

Arteriovenous Malformation An AVM may occur within the liver parenchyma or outside the liver between the hepatic artery and the portal

- Cross section of a pathology specimen of a left hepatic lobectomy for mesenchymal hamartoma in a 10-month-old male infant.

498

PART

III

MAJORTUMORS OF C H I I . ~ H O O D

. - .

Contrast-enhanced abdommal computed tomography scan of a recurlent ~nesenchymalhamartoma of the right hepatic lobe, prev~ouslytreated by unroofing It was wbsequently managed successfully by pat tlal r ~ g hhepatlc t lobectomy

Von Schweinitz et al." suggested that fat-storing (Ito) cells of the immature liver may be involved in the development of MH. Serum AFP levels are usually normal in children with The radiMH, but they may be mildly ele~ated.~I,*0 ographic features of these tumors are consistent and distinguishing; abdominal sonography and CT demonstrate a single, usually large, fluid-filled mass with fine internal se~tationsand no cal~ifications.~2 Management must be tempered by the understanding ,~ there that MH usually follows a benign c o ~ r s ealthough have been reports of malignant transformation.46.j0 In general, complete operative resection is the procedure of choice, if it can be accomplished safely. Huge lesions or those that involve both lobes may be treated by unroofing and marsupializing the cysts, although the lesion may recur after incomplete resection (Fig. 29-3). MH is an entity distinct from the liver hamartomas associated with tuberous sclerosis. The latter are smaller, multifocal lesions that may be associated with angiomyolipomas in other locations, such as the kidney; they are rarely symptomatic and usually present in children older than 2 or 3 years. These hamartomas have little clinical significance, but their presence may be helpful in diagnosing tuberous sclerosis.33

Hepatocellular Adenoma Although isolated lesions are encountered in childhood, hepatocellular adenoma (HCA) is most commonly observed in adults in association with the use of anabolic corticosteroids or estrogen. HCA has been described in children treated with anabolic steroids and multiple blood transfusions for chronic anemia,s and it is expected in children with type I glycogen storage disease.26 several mechanisms for the developBianchi-roposed ment of HCA in patients with type I glycogen storage disease, including (1) regional imbalance in insulin and

glucagon metabolism, because these hormones are important in the regulation of hepatocyte proliferation and regeneration; (2) response to glycogen overload; and (3) oncogene activation. Microscopic examination of these adenomas reveals hepatocytes in sheets and cords oriented along sinusoids without a ductal component. The cells have glycogenfilled cytoplasm and small nuclei without mitoses. Adjacent liver and vessels are compressed but not invaded. The Children usually do not have coexisting cirrho~is.~ histologic pattern is similar to that of a well-differentiated hepatocellular carcinoma, and development of hepatocelluar carcinoma within an unresected HCA has been rep~rted.~~,~~ In children, HCA generally presents as an asymptomatic hepatic mass. The mass is solid on ultrasonography and CT. Liver enzyme and AFP levels are normal. A feature unique to this lesion is its propensity for intraperitoneal hemorrhage from spontaneous rupture. In adults, intraperitoneal bleeding is almost always seen in patients receiving estrogen therapy, and tumor regression may occur with the cessation of hormone administration. In patients with glycogen storage disease and HCA, tumor regression may occur with the correction of metabolic dist~rbances.~ Because of the known association between HCA and hepatocellular carcinoma, resection of HCA is recommended when it occurs in a child who is not receiving steroids and does not have glycogen storage disease. If resection cannot be accomplished without substantial risk, observation of the lesion while monitoring the serum AFP level may be appropriate. If the AFP level begins to increase or the lesion is significantly symptomatic, and if the risk of resection is unacceptably high, liver transplantation may be the best alternative.

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) in children presents as an irregularly shaped, nontender liver mass. It is frequently found incidentally at laparotomy for another cause or on radiographic studies performed for another indication. The female-to-male ratio for FNH is approximately 4:1.'j3 FNH is occasionally seen with vascular malformations and hemangiomas in the liver,70and it has been postulated that the lesions represent an unusual response to injury or ischemia.17On abdominal sonography, the lesions may be isoechoic, hypoechoic, or hyperechoic to normal liver parenchyma and may be multiple in 10% to 15% of patients. The classic central scar may not be seen on ultrasonography. CT typically shows a hypervascular lesion with a dense stellate central scar. Conventional arteriography or magnetic resonance angiography shows a hypervascular mass with feeding arteries entering the periphery and converging on the central portion of the tumor. Some cases of fibrolamellar hepatocellular carcinoma are radiographically indistinguishable from FNH, which is a cause for concern if the diagnosis is being made without a biopsy.43There are reports of adult patients who have FNH and hepatocellular carcinoma simultaneously.44

.

CHAPTER

29

Nonmalignant Tumors of the Liver

499

Because this lesion is predominantly solid, it is difficult to differentiate it from other benign or malignant tumors by imaging studies. Invariably, the serum AFP level is normal. Fever, leukocytosis, and high C-reactive protein level in a child with a solid liver mass and normal AFP level are suggestive of an inflammatory pseudotumor of the liver. This lesion is thought to be an inflammatory reaction to some insult, although the instigating cause is usually unknown. Because it is difficult to diagnose this lesion without a large biopsy or resection of the lesion, most children undergo resection, which is curative.",54

Nonparasitic Cysts

Surgical view of focal nodular hyperplasia within the left lobe of the liver in a 2-year-old child treated by left lateral lobectomy.

On gross examination, the lesions are nonencapsulated, occasionally pedunculated, and quite firm (Fig. 294). Microscopic examination shows proliferation of hepatocytes and bile ducts and the pathognomonic central fibrosis. These lesions rarely become malignant, and hemorrhage is rare. Therefore, expectant therapy is appropriate when removal might be associated with significant morbidity, the child is asymptomatic, and the diagnosis has been made conclusively by radiographic studies, normal AFP levels, and biopsy.jl

OTHER TUMORS Teratoma There have been fewer than 25 case reports of hepatic teratoma in children.663'2 These children are invariably younger than 1 year, and calcification is usually present within the lesion, helping to differentiate it from other tumors. Some of these lesions have met the criteria for ~l AFP levels may be an intrahepatic fetus in f e t ~ . Serum elevated with a teratoma, but only mildly elevated in comparison to the levels seen with hepatoblastoma. Resection is the procedure of choice for a teratoma because of the risk of malignancy in any immature elements of the tumor.

Inflammatory Pseudotumor Inflammatory pseudotumor of the liver is rare. These lesions are generally seen in children older than 3 years but have been reported in younger children as well.

Nonparasitic cysts of the liver are rare and occur more commonly in adults than in children. Although they may be present and symptomatic at birth, most of these cysts are asymptomatic and are identified incidentally at autopsy or laparotomy. Symptoms are related to abdominal distention or displacement of adjacent structures. These lesions occur with equal frequency in males and females.1Wonparasitic cysts are generally unilocular and lined by cuboidal or columnar epithelium, characteristic of bile ducts. The cyst fluid is typically clear or brown, and bile is rarely present. Pathologic studies suggest that nonparasitic cysts arise from congenital or secondary obstruction of peribiliary glands. These glands normally arise from the ductal plate at the hepatic hilum around the seventh week of gestation and continue to proliferate until adolescence.15 Symptomatic cysts can be effectively treated by simple unroofing, marsupialization," or sclerotherapy.49 If biliary communication is suspected, cholangiography may identify the source and allow the communicating ductule to be oversewn. Cystic dilatation of the intrahepatic ducts may also present as a mass, although jaundice and cholangitis are often associated with this problem. Resection of the affected lobe is the preferred therapy." If MH appears to be completely cystic on imaging, it may be misdiagnosed as a nonparasitic cyst. Post-traumatic bile cysts result from ductal disruption and intrahepatic accumulation of bile. These lesions can be treated by percutaneous drainage or, in some cases, by biliary sphincterotomy to reduce the bile duct pressure and lessen the biliary leak." Resection is rarely necessary for post-traumatic cysts. Multiple parenchymal cysts associated with hereditary polycystic kidney disease are generally asymptomatic and so small that they do not require intervention. Epidermoid cysts differ from other nonparasitic cysts, in that the lining epithelium is squamous rather than cuboidal. This histologic characteristic has led to the theory that these lesions may be foregut bud anomalies trapped in the hepatic substance. Although these lesions are rare, there has been a report of malignant degeneration. Thus, resection is the appropriate m a n a g e r n ~ n t . ~ ~ ACKNOWLEDGMENT The author thanks W. Raleigh Thompson, MD, for his contribution to this chapter in the fifth edition of this book.

500

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MAJORTUMORS OF CHILDHOOD

REFERENCES 1. Baer HU, Dennison AR, Moulton W, et al: Enucleation of giant hemangiomas of the liver. Ann Surg 1992;216:673. 2. Baggenstoss AH: Pathology of tumors of liver in infancy and childhood. In Pack G, Islami A (eds): Tumors of the Liver. New York: Springer-Verlag, 1970, p 240. 3. Barlow CF, Priebe CJ, Mulliken JB, et al: Spastic diplegia as a complication of interferon alpha-2a treatment of hemangiomas of infancy.J Pediatr 1998;132:527. 4. Barnhart DC, Hirschl RB, Garver KA, et al: Conservative management of mesenchymal hamartoma of the liver. J Pediatr Surg 1997;32:1495. 5. Bianchi L: Glycogen storage disease I and hepatocellular tumors. Eur J Pediatr 1993;152:S63. 6. Burrows PE, Dubois J, Kassarjian: Pediatric hepatic vascular anomalies. Pediatr Radiol 2001;31:533. 7. Buscarini E, Buscarini L, Danesino C, et al: Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family. J Hepatol 1997;26:111. 8. Chandra RS, Kapur SP, Kelleher J, et al: Benign hepatocellular tumors in the young: A clinicopathologic spectrum. Arch Pathol Lab Med 1984;108:168. 9. Chang E, Boyd A, Nelson CC, et al: Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol 1997;19:237. 10. Cohen RC, Myers NA: Diagnosis and management of massive hepatic hemangiomas in childhood. J Pediatr Surg 1986;21:6. 11. Daller JA, Bueno J, Gutierrez J, et al: Hepatic hemangioendothelioma: Clinical experience and management strategy. J Pediatr Surg 1999;34:98. 12. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. Arch Pathol 1971;92:101. 13. DeMaioribus CA, Lally KP, Sim K, et al: Mesenchymal hamartoma of the liver. Arch Surg 1990;125:598. 14. Dickman PS, Meza MP, Newman B: Hepatic vascular malformations. Pediatr Pathol Lab Med 1995;15:155. 15. Donovan MJ, Kozakewich H, Perez-Atayde A: Solitary nonparasitic cysts of the liver: The Boston Children's Hospital experience. Pediatr Pathol Lab Med 1995;15:419. 16. Dubois J, Hershon L, Carmant L, et al: Toxicity profile of interferon alfa-2b in children: A prospective evaluation. J Pediatr 1999;135:782. 17. Edmondson HA: Differential diagnosis of tumors and tumor like lesions of liver in infancy and childhood. Am J Dis Child 1956;91:168. 18. Ezekowitz RAB, Mulliken JB, Folkman J: Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456. 19. Falk H, Herbert JT, Edmonds L, et al: Review of four cases of childhood hepatic angiosarcoma-elevated environmental arsenic exposure in one case. Cancer 1981;47:382. 20. Fellows KE, Hoffer FA, Markowitz RI, et al: Multiple collaterals to hepatic infantile hemangioendotheliomas and arteriovenous malformations: Effect on embolization. Radiology 1991;181:813. 21. Gembruch U, Baschat AA, Gloeckner-Hoffmann K, et al: Prenatal diagnosis and management of fetuses with liver hemangiomata. Ultrasound Obstet Gynecol 2002; 19:454. 22. Hata Y, Sasaki F, Matuoka S, et al: Inflammatory pseudotumor of the liver in children: Report of cases and review of the literature. J Pediatr Surg 1992;27:1549. 23. Hazebroek FWJ, Tibboel D, Robben SGF, et al: Hepatic artery ligation for hepatic vascular tumors with arteriovenous and arterioportal venous shunts in the newborn: Successful

management of two cases and review of the literature. J Pediatr Surg 1995;30:1127. Heaton ND, Davenport M, Karani J, et al: Congenital hepatoportal arteriovenous fistula. Surgery 1995;117:170. Holcomb GW, O'Neill JA, Mahboudi S, et al: Experience with hepatic hemangioendothelioma in infancy and childhood. J Pediatr Surg 1988;23:661. Howell RR,Stevenson RE, Ben-Menachem Y, et al: Hepatic adenomata with type 1 glycogen storage disease. JAMA 1976;236:1481. Huang SA, Tu HM, Harney JW, et al: Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185. Hurvitz SA, Hurvitz CH, Sloninsky L, et al: Successful treatment with cyclophosphamide of life threatening diffuse hemangiomatosis involving the liver. J Pediatr Hematol Oncol 2000;22:527. Ingram JD, Yerushalmi B, Connell J, et al: Hepatoblastoma in a neonate: A hypervascular presentation mimicking hemangioendothelioma. Pediatr Radiol 2000;30:794. Ishak KG: Primary hepatic tumors in childhood. In Popper H, Schaffner F (eds): Progress in Liver Diseases, vol 5. New York, Grune & Stratton, 1976, p 636. Ito H, Kishikawa T, Toda T, et al: Hepatic mesenchymal hamartoma of an infant. J Pediatr Surg 1984;19:315. Janes CH, McGill DB, LudwigJ, et al: Liver cell adenoma at the age of 3 years and transplantation 19 years later after development of carcinoma: A case report. Hepatology 1993;17:583. Jozwiak S, Pedich M, Rajszys P, et al: Incidence of hepatic hamartomas in tuberous sclerosis. Arch Dis Child 1992; 67:1363. Kamata S, Nose K, Sawai T, et al: Fetal mesenchymal hamartoma of the liver: Report of a case. J Pediatr Surg 2003;38:639. Kasabach HH, Merritt KK: Capillary hemangioma with extensive purpura: Report of a case. Am J Dis Child 1940;59:1063. Kasahara M, Kiuchi T, Haga H, et al: Monosegmental living-donor liver transplantation for infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1108. Lack EE: Mesenchymal hamartoma of the liver: A clinical and pathologic study of nine cases. Am J Pediatr Hematol Oncol 1986;8:91. Litwin DEM, Taylor BR, Greig P, et al: Nonparasitic cysts of the liver: The case for conservative surgical management. Ann Surg 1987;205:45. Longmire WP, Mandiola SA, Gordon HE: Congenital cystic disease of the liver and biliary system. Ann Surg 1971;174:711. Luks FI, Yazbeck S, Brandt ML, et al: Benign liver tumors in children: A 25 year experience. J Pediatr Surg 1991; 26:1326. Magnus KG, Millar AJW, Sinclair-Smith CC, et al: Intrahepatic fetus-in-fetu: A case report and review of the literature. J Pediatr Surg 1999;34:1861. Mason KP, Koka BV, Eldredge EA, et al: Perioperative considerations in a hypothyroid infant with hepatic haemangioma. Paediatr Anaesth 2001;11:228. Meyers RL, Scaife ER: Benign liver and biliary tract masses in infants and toddlers. Semin Pediatr Surg 2000;9:146. Muguti G, Tait N, Richardson A, et al: Hepatic focal nodular hyperplasia: A benign incidentaloma or a marker of serious hepatic disease? HPB Surg 1992;5:171. , Mulrooney DA, Carpenter B, Georgieff M, et al: Hepatic mesenchymal hamartoma in a neonate: A case report and review of the literature. J Pediatr Hematol Oncol 2001; 23:316.

CHAPTER

46. O'Sullivan MI, Swanson PE, Knolll, et al: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: Report of a case and review of the literature. Pediatr Dev Pathol 2001;4:482. 47. Perez J, Pardo J, Gomez C: Vincristine-an effective treatment of corticoid-resistant life- threatening infantile hemangiomas. Acta Oncol 2002;41:197. 48. Pizzo CJ: Type I glycogen storage disease with focal nodular hyperplasia of the liver and vasoconstrictive pulmonary hypertension. Pediatrics 1980;65:341. 49. Raboei E, Luoma R: Definitive treatment of congenital liver cyst with alcohol. J Pediatr Surg 2000;35:1138. 50. Ramanujam TM, Ramesh JC, Goh DW, et al: Malignant transformation of mesenchymal hamartoma of the liver: Case report and review of the literature. J Pediatr Surg 1999;34:1684. 51. Reymond D, PlaschkesJ, Ridolfi Luthy A, et al: Focal nodular hyperplasia of the liver in children: Review of follow-up and outcome. J Pediatr Surg 1995;30:1590. 52. Ricketts RR, Stryker S, Raffensperger JG: Ventral fasciotomy in the management of hepatic hemangioendothelioma. J Pediatr Surg 1982;17:187. 53. Rotman M, John M, Stowe S, et al: Radiation treatment of pediatric hepatic hemangiomatosis and coexisting cardiac failure. N Engl J Med 1980;302:852. 54. Sakai M, Ikeda H, Suzuki N, et al: Inflammatory pseudotumor of the liver: Case report and review of the literature. J Pediatr Surg 2001;36:663. 55. Samuel M, Spitz L: Infantile hepatic hemangioendothelioma: The role of surgery. J Pediatr Surg 1995;30:1425. 56. SchullingerJN, Wigger HJ, Price JB, et al: Epidermoid cysts of the liver. J Pediatr Surg 1983;18:240. 57. Schwartz SI, Husser WC: Cavernous hemangioma of the liver: A single institution report of 16 resections. Ann Surg 1987;205:456. 58. Scioscia PJ, Dillion PW, Cilley RE, et al: Endoscopic sphincterotomy in the management of posttraumatic biliary fistula. J Pediatr Surg 1994;29:3. 59. Selby DM, StockerJT, Waclawiw MA, et al: Infantile hemangioendothelioma of the liver. Hepatology 1994;20:39.

29

Nonmalignant Tumors of the Liver

501

60. Smith WL, Ballantine TVN, Gonzalez-Crussi F: Hepatic mesenchymal hamartoma causing heart failure in the neonate. J Pediatr Surg 1978;13:183. 61. Srouji MN, Chatten J, Schulman WM, et al: Mesenchymal hamartoma of the liver in infants. Cancer 1978;42:2483. 62. Stanley P, Hall TR, Woolley MM, et al: Mesenchymal hamartomas of the liver in childhood: Sonographic and CT findings. AJR Am J Roentgen01 1986;147:1035. 63. Stocker JT, Ishak KG: Focal nodular hyperplasia of the liver: A study of 21 pediatric cases. Cancer 1981;48:336. 64. Stocker JT, Ishak KG: Mesenchymal hamartoma of the liver: Report of 30 cases and review of the literature. Pediatr Pathol 1983;1:245. 65. Tesluk H, Lawrie J: Hepatocellular ademona: Its transformation to carcinoma in a user of oral contraceptives. Arch Pathol Lab Med 1981;105:296. 66. Todani T, Tabuchi K, Watanabe Y, et al: True hepatic teratoma with high alpha fetoprotein in serum. J Pediatr Surg 1977;12:591. 67. von Schweinitz D, Gomez Dammeier B, Gluer S: Mesenchymal hamartoma of the liver-new insight into histogenesis. J Pediatr Surg 1999;34:1269. 68. Warmann S, Bertram H, Kardorff R, et al: Interventional treatment of infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1177. 69. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512. 70. Whelan TJ, Baugh J, Chandor S: Focal nodular hyperplasia of the liver. Ann Surg 1973;177:150. 71. Whiting JH, Korzenik JR, Miller FJ, et al: Fatal outcome after embolotherapy for hepatic arteriovenous malformations of the liver in two patients with hereditary hemorrhagic telangiectasia. J Vasc Interv Radio1 2000; 11:855. 72. Witte DP, Kissane JM, Askin FB: Hepatic teratomas in children. Pediatr Pathol 1983;1:81. 73. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981;15:50.

Liver lumors James B. Atkinson and Daniel A. DeUgarte

Malignant liver neoplasms account for 1% of all pediatric malignancies and are the third most common intra-abdominal neoplasm after neuroblastoma and nephroblastoma. The two primary malignant neoplasms of the liver are hepatoblastoma and hepatocellular carcinoma. Survival has significantly improved for hepatoblastoma with the advent of new chemotherapy protocols and advances in liver surgery. The prognosis for hepatocellular carcinoma remains poor. Complete resection is required for cure.

EPIDEMIOLOGY Hepatoblastoma and hepatocellular carcinoma have a different incidence, age distribution, genetic basis, and associated risk factors (Table 30-1). From 1979 to 1996, the incidence of hepatoblastoma rose from 0.6 to 1.2 per million U.S. residents younger than 20 years, and that of hepatocellular carcinoma decreased from 0.45 to 0.29 per million.'4 Hepatoblastoma and hepatocellular carcinoma both occur more frequently in male^.^^,^^ Hepatoblastoma usually occurs in children aged 6 months to 3 years, whereas hepatocellular carcinoma occurs in older children and adults.

I

1

Hepatoblastoma Incidence 1.2 cases per million12 Age distribution 6 rno to 3 yr Risk factors Beckwith-Weidemann syndrome Familial adenomatous polyposis Hemihypertrophy Low birth weight26.54 5-yr survival 52% to 75%12,40.47,55

Hepatocellular Carcinoma ---0.29 cases per million12 >5 yr Hepatitis B virus Cirrhosis Liver disease

18%to 28%11.26

1

Hepatoblastoma is associated with Beckwith-Wiedemann syndrome, familial adenomatous polyposis, hemihypertrophy, and low birth weight.l",'",44360,66The most common genetic aberrations involve chromosomes lp, lq, 2q, 4q, 7q, 8q, 12p, 17q, 20, 22q, Xp, and Xq.6"71,7Wepatoblastoma has also been associated with stabilizing mutations of p-catenin and activation of Wnt/p-catenin signaling.6 Up-regulation of insulin-like growth factor 2 has also been observed in hepatoblastomas and may be mediated by the overexpression of PLGAl oncogene, a transcrip~~ tional activator on the 8q c h r o m o ~ o m e .Cytogenetic abnormalities have not led to the identification of a causal factor nor been shown to influence prognosis. The cause of hepatoblastoma remains unclear, but recent theories suggest that hepatoblastoma is derived from a pluripotent hepatic stem cell or oval stem cell that can differentiate into both hepatocytes and biliary epithelial cells. Both hepatoblastoma cells and oval stem cells express markers for these two lineages. Further, the structural features of hepatoblastoma resemble those found in distinct phases of h e p a t ~ g e n e s i s . ~ ' , ~ ~ The association between very low birth weight (VLBW) and hepatoblastoma may be explained by a higher likelihood of genetic abnormalities or the susceptibility of the immature liver to the effects of intensive perinatal therapy (e.g., oxygen, diuretics, radiation). In one study, hepatoblastoma patients had a longer duration of and more aggressive perinatal therapy than did birth weightmatched controls.54VLBW infants may also be at higher risk of developing advanced h e p a t ~ b l a s t o m a . ~ ~ o m e reports have suggested that infants with VLBW or other conditions associated with hepatoblastoma might benefit from screening with serial ultrasound examinations and serum alpha fetaprotein (AFP) monitoring to increase the likelihood of early detection." However, a cost-benefit analysis of screening for hepatoblastoma in high-risk patients must be performed before it is applied routinely. Hepatocellular carcinoma occurs predominantly in the setting of underying liver disease and cirrhosis. In young children, hepatocellular carcinoma has been associated with tyrosinemia and other inherited metabolic disorders.76 The incidence of hepatocellular carcinoma in the United States is higher in Asians and foreign-born children.10.14 In Taiwan, hepatocellular carcinoma occurs

CHAPTER

503

Liver Tumors

elevated serum transaminase levels are occasionally observed.57 Diagnosis is ultimately made with biopsy. An algorithm for the diagnosis and treatment of malignant liver neoplasms is presented in Figure 30-1. The most sensitive laboratory test for hepatoblastoma and hepatocellular carcinoma is serum AFP level. AFP is produced in the fetal liver and yolk sac, and levels decline to adult values during the first 6 months after birth. Although AFP can be used effectively as a tumor marker, it is nonspecific. Serum AFP levels are elevated in over 90% of hepatoblastomas and in approximately 70% of hepatocellular carcinomas.13~" Falsely elevated serum AFP levels can be noted in hepatitis, cirrhosis, hemangioendothelioma, germ cell tumor, testicular tumor and gallbladder carcinoma. Normal AFP levels have been observed with both well-differentiated and immature hepatoblastomas and frequently occur with the fibrolamellar variants of hepatocellular c a r c i n o m a . l ~ JSerum 3 ~ ~ AFP levels can be used to monitor chemotherapeutic efficacy and to detect disease recurrence. Rarely, hepatoblastoma may secrete Phuman chorionic gonadotropin, associated with sexual precocity.

predominantly in hepatitis B viral carriers.14 Hepatitis B vaccinations led to a significant decrease in the rate of hepatocellular carcin0ma.~,"~46A Taiwanese study comparing hepatocellular carcinoma in children and adults demonstrated that hepatitis B viral infection was always present in children (100% versus 80%), the frequency of liver cirrhosis was similar (70%), and the rate of resectability was lower in children (18% versus 56%).1°

CLINICAL FEATURES AND LABORATORY DATA Most patients with liver tumors present with an abdominal mass, and more than two thirds of liver tumors are malignant." Although most patients are asymptomatic, some note abdominal distention, anorexia, weight loss, pain, nausea, and fatigue. An abdominal computed tomography (CT) or ultrasound scan is obtained, which usually reveals a solid liver mass. Laboratory studies should include complete blood cell count, chemistry panel, liver function tests, coagulation profile, and serum AFP levels. Thrombocytosis is present in 60% of cases.7Unemia and

Algorithm for the diagnosis and treatment of a liver mass. AFP, alpha fetoprotein; CBC, complete blood count; CT, computed totnography; CXR, chest radiograph; LFT, liver function tests; MRI, magnetic rcsonance imaging; PT/PTT, prothrombin time/partial thromboplastin time; US, ultrasound.

30

Liver Mass

.

Diagnostic lmaging (US andlor CT)

-w

Solid

Vascular or Cystic

&

J. Staaina Workaroup: Labs (AFP, CBC, LFTs, PTIPTT, Chemistry) CXR Chest CT MRI

*

J. Surgery for Exploration

Resectable

Angiography IResection vs. Obsewation

(+) Metastasis

I

7

Not Resectable

Biopsy

J.

Neoadjuvant Chemotherapy

lmaging Resection

4

I

Not Resectable

3. Chemotherapy (* Chemotherapy for Stage I - Pure Fetal Histology)

Follow-UP

Original AFP

Serial AFP

t

Original AFP Normal

Serial Imaging

1

504

PART

III

M A ~ TUMORS R OF CHII.DHOOD

IMAGING Imaging is helpful both for diagnostic purposes and to assess tumor resectability. Ultrasonography or CT of the abdomen is performed initially to assess the tumor.Z3 A chest radiograph or CT scan of the chest should also be obtained to rule out metastatic disease. Ultimately, imaging should delineate the size and location of tumors, evaluate for metastastic disease, and determine whether vascular invasion of the portal vein, hepatic veins, or inferior vena cava is present. Although advances in imaging have improved the ability to predict resectability, the ultimate assessment is made in the operating room by the surgeon. Ultrasonography is helpful for the initial evaluation and to assess vascular involvement. Liver lesions can be categorized sonographically as solid, cystic, or vascular. Malignant liver neoplasms are usually well-defined hyperechoic (solid) lesions on ultrasonography.15 Color Doppler ultrasonography is helpful in diagnosing venous thrombosis and vascular shunts within the tumor." It has also been used intraoperatively to aid in determining vascular involvement and tumor resectability. CT with intravenous and gastrointestinal contrast enhancement is useful to delineate tumor type, size, and location and to detect regional lymphadenopathy. Abdominal CT usually reveals a mass with low attenuation. Helical CT with three-dimensional reconstruction can be performed in complex cases that require nonstandard resections.

A

Magnetic resonance imaging (MRI) and magnetic resonance angiography are especially helpful in determining the tumor's relationship to the hepatic vasculature and biliary anatomy. Liver tumors have homogeneous hypointensity on T1-weighted images and hyperintensity on T2-weighted images." Three-dimensional reconstruction can significantly enhance the surgeon's ability to predict resectability (Fig. 30-2). Angiography was used in the past to delineate the anatomy of the hepatic vasculature, but with the availability of MRI and contrast-enhanced CT, it is rarely required for the diagnostic evaluation of malignant liver neoplasms. Angiography is used in some cases to perform selective chemoembolization as a therapeutic intervention.

DIFFERENTIAL DIAGNOSIS AND HISTOLOGY Diagnosis is ultimately made with biopsy using percutaneous, laparoscopic, or open approaches. Fine-needle aspiration can be sufficient for diagnosis. Some groups permit the initiation of neoadjuvant chemotherapy based on clinical criteria when those clinical features are highly suggestive of hepatoblastoma or hepatocellular carcinoma.13 However, given the significant error rate in clinical diagnosis, we strongly advocate biopsy in all cases.'" The distribution of malignant and benign primary hepatic tumors of children is shown in Table 30-2. Hepatoblastoma and hepatocellular carcinoma are of

B

A, Magnetic resonance imaging o f a &month-old cklild demonstrates a 10-cm right hepatic mass. B, Magnetic resonance angiography with three-dimensional reconstruction allows image roctation and delineation o f vascular anatomy. Compression o f the intrahepatic vena cava demonstrates unresectability.

CHAPTER

Tumor Malignant Hepatoblastoma Hepatocellular carcinoma Sarcoma Benign Benign vascular tumor Mesenchymal hamartoma Adenoma Focal nodular hyperplasia Other

30

Liver Tumors

505

% of Patients 43 23 6

13 6 2 2 5

Adapted from Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512-537.

epithelial origin and account for more than 90% of malignant liver neoplasms.76Primary liver neoplasms can also be of mesenchymal origin; of these, sarcomas are the most common. Undifferentiated embryonal sarcomas and rhabdomyosarcoma usually occur in children aged 5 to 10 years. They are associated with a normal serum AFP level and are vimentin positive on staining.74Other reported malignancies include the malignant transformation of mesenchymal hamartoma,58 angiosarcoma, cholangiocarcinoma, rhabdoid tumor,"g immature teratoma, and c h o r i o c a r ~ i n o m aMetastatic .~~ disease to the liver is relatively uncommon in children. Histologic classification of hepatoblastomas has minimal predictive value in determining prognosis. Uniform criteria have not been established, but most pediatric pathologists have simplified the classification into epithelial and mixed (epithelial and mesenchymal) types. The epithelial type is subdivided into fetal, embryonal, macrotrabecular, and small cell undifferentiated types.60 Small cell undifferentiated histology may confer an unfavorable outcome.22 Conversely, pure fetal histology (PFH) with minimal mitotic activity (<2 mitoses/l0 400x microscopic fields) has been associated with significantly improved event-free survival (Fig. 30-3).4"7"n fact, adjuvant chemotherapy is no longer routinely recommended by the Children's Oncology Group for children who undergo complete resection of hepatoblastomas with PFH. With respect to hepatocellular carcinoma, it has been proposed by some investigators that patients with a fibrolamellelar variant may have a higher resection rate and improved survival than those with the typical ~ariant.~z,33 However, Katzenstein et a1." observed that although the median survival may be longer, no difference is noted when a stage-for-stage comparison is made between the fibrolamellar variant and other cell types.

STAGlNG Multiple staging systems have been proposed to classify both hepatoblastoma and hepatocellular carcinoma. The system currently used by the Pediatric Oncology

Photomicrograph demonstrates pure fetal histology (PFH) with minimal mitotic activity (<2 mitoses/l0 400x microscopic fields). In stage I hepatoblastoma, PFH has been associated with significantly improved event-free survival.

Group (POG) in the United States and the German Cooperative Pediatric Liver Tumor Study Group is shown in Table 30-3.21,49This classification scheme is based on the postoperative extent of disease. Approximately 5% of hepatoblastomas that are completely resected (stage I) disease is have PFH with low mitotic a~tivity.~Wesidual defined as microscopic (stage 11), macroscopic (stage 111), or extrahepatic or metastatic (stage IV).Approximately 20% of hepatoblastomas have distant metastasis at the , ~ ~ , ~ ~ , ~ ~carcinoma usually time of d i a g n o s i ~ . * ~Hepatocellular presents at a more advanged stage than hepatoblastoma does.lS29 Although the POG staging system is useful in determining the postoperative prognosis, it does not provide information on the preoperative extent of disease. To assess tumor response and resectability before and after neoadjuvant chemotherapy, the International Society of Pediatric Oncology (SIOP) developed the PRETEXT (pretreatment extent of disease) staging ~ y s t e m .The ~ ~ ,PRETEXT ~~ system is based on radiologic findings and describes both the number and the location of involved liver sectors and takes into account invasion of the hepatic and portal veins as well as extrahepatic and metastatic disease (Fig. 30-4). For example, a group 111, p, m tumor has three out of four sectors involved by tumor, with ingrowth of the portal vein and metastasis.

Stage

Description

I* II

Complete resection Microscopic residual tumor Macroscopic residual tumor Distant metastasis

*Stage I hepatoblastoma can be subdivided into (1) pure fetal histology with minimal mitotic activity and (2) all other histologic types.

506

PART

I1I

MAJORTUMORSOF CHILDHOOD

p ' p "v R

L

3 adjoining sectors FREE

" @pp 4

v

A, 2 sectors in one lobe FREE

L medial and R anterior sectors FREE

The SIOP pretreatment grouping system

L

R

p

J

@p @ L lat. sector FREE

A2

R post. sector FREE

number of (PRETEXT) liver involvement of sectors describes involved based the extent on and the takes into account metastasis (m), ingrowth of vena cava (v) and portal vein ( p ) , and extrahepatic (e).

'32 L med. sector FREE R ant. sector FREE

"@'p no FREE sector

@metastases

@ingrowth vena portae

@ ingrowth vena cava

@extrahepatic extension

This staging system has allowed oncologists to compare positioned such that the surgeon has access to the neck, tumor response to different neoadjuvant regimens. chest, abdomen, and groins. In the event that additional Other classification schemes that have been developed access or more extensive exposure is needed, these for hepatoblastoma include those by the ~ a ~ a n e s e areas will be easily accessible within the sterile field. Society of Pediatric Surgeons and TNM classifications.6* The Trendelenburg position lowers the caval and In children, hepatocellular carcinoma also has been hepatic venous pressures and minimizes the risk of air investigated using the POG and PRETEXT staging sysembolism. tems.l"Zg In adults, the Okuda and Barcelona Clinic An initial subcostal incision can be used to evaluate the clas~ifications9"~8 have been used to take into account tumor's location and extent. The remainder of the both the extent of tumor involvement and the severity of abdomen is searched for any evidence of metastatic disease liver disease. not detected by preoperative studies. Once a decision is made to proceed with resection, the incision is extended across the abdomen. In older children, a midline extension toward the xiphoid provides even wider exposure of SURGERY the liver and tumor. The primary goal of surgery is complete anatomic resecThe liver and tumor are completely mobilized from all tion. Resectability can be compromised by multifocality, anatomic attachments. The triangular ligament is divided bilobar involvement, portal vein or vena cava thrombosis, from the left hepatic vein to its termination at the left vascular invasion, para-aortic lymphadenopathy, extendiaphragm. The right lobe of the liver is then retracted sion to the hepatic hilum, and distant metastasis. In from the right diaphragm, and the bare attachments are centrally located tumors, hepatic vein involvement may divided by cautery. As the liver is delivered through the preclude safe resection. In general, nonanatomic liver incision, the remaining attachments of the right adrenal resections should be avoided because of a higher rate gland and several branches of the infrahepatic vena cava of incomplete tumor resection and local relapse.20 When are divided to completely mobilize the liver. histo10,gy demonstrates microscopic residual disease Additional mobilization of the infrahepatic vena cava following resection, reoperation shbuld be strongly conis then performed such that the vena cava above the sidered to extend the margins of resection when anatomorigin of the renal veins to the junction with the hepatic ically feasible. parenchyma is encircled and contrblled with a vessel Successful hepatic resection requires careful planning loop. With complete mobilization of the liver, a final and supportive care. An experienied pediatric zkesthes; assessment of the plan for resection is made. The portal ologist is essential. The first step in the operative structures can be palpated bimanually through the foraprocedure is placement of reliable large-bore venous men of Winslow for evidence of tumor invasion and the cathetes, arterial monitoring lines, and supplemental presence of frequently encountered vascular anomalies. peripheral venous catheters. The patient -should be The retrohepatic vena cava should be assessed for location

CHAPTER

within the hepatic parenchyma or evidence of tumor invasion. Finally, a careful assessment of the relationship between the tumor and the hepatic veins should be made. The accuracy of this assessment may be enhanced by preoperative images and intraoperative ultrasonography. Unexpected invasion of the remaining solitary hepatic vein is the most common cause of positive resection margins, severe intraoperative hemorrhage, and postoperative liver failure due to acute portal hypertension from hepatic vein injury (Budd-Chiari syndrome). Once this assessment is completed, the mobilized tumor and liver can be evaluated for the required resection. Options include a standard right or left hepatic lobectomy, extended right or left lobectomy, or, in rare cases, a central or segmentally based anatomic resection. The sequence of the dissection is similar in all cases. Once the tumor and liver have been mobilized and the surgeon determines that the tumor is resectable, attention is directed to a vascular dissection of the portal structures. The hepatic artery, common bile duct, and portal vein are identified near the duodenum and distal to the branching of the pancreaticoduodenal artery. The gallbladder is dissected from the liver, and the cystic duct is ligated. A vascular dissection of the common duct, hepatic artery, and portal vein is then performed, with identification and ligation of the structures supplying the intended segment or lobe of the liver and tumor. As the hepatic arterial and portal venous branches are ligated, a line of demarcation appears to guide the parenchymal dissection. Once the portal dissection is complete, attention is directed to the retrohepatic inferior vena cava. The liver and tumor are rotated to the left, exposing the course of the vena cava. A tedious and careful dissection of the vena cava is performed beginning distally and working superiorly toward the hepatic veins. Myriad small paired branches can be identified, dissected, and ligated as the vena cava is freed from the hepatic parenchyma. In difficult cases, the Pringle maneuver, clamping across the remaining portal vasculature and clamping the supra- or infradiaphragmatic vena cava, may facilitate dissection. Clamping of the portal structures should be limited to 15 minutes, with the total clamp time not to exceed 60 minutes. At the conclusion of this portion of the surgery, the vena cava will be entirely free except for the major hepatic veins. The final portion of the vascular dissection is the identification and division of the appropriate hepatic veins. The right, middle, and left hepatic veins originate very close to the surface of the liver. The course of the veins is extremely short until they combine into the structure of the atrium of the heart. Before beginning the resection, it is critical that involvement at the hepatic veins has been accurately assessed. Intraoperative ultrasonography can be of great assistance in planning the surgical approach to these important structures. Because the veins branch rapidly after entering the substance of the liver, it is technically much safer to divide them in the parenchyma if the tumor margins allow the use of this technique. Marking the surface of the liver with cautery just distal to the hepatic veins to be divided guides

30

Liver Tumors

507

parenchymal dissection and is safer than attempting extrahepatic ligation of the veins. When the tumor or anatomy does not permit intraparenchymal division of the hepatic veins, wide exposure and careful dissection should be used to isolate and divide the veins. Frequently, this can be delayed until most of the parenchyma has been divided and the specimen is nearly ready for delivery to the pathologist. The surgeon should not hesitate to obtain supradiaphragmatic control of the vena cava when control of the hepatic veins is difficult to achieve. Upon completion of the vascular dissection, a line of demarcation should be visible to guide the parenchymal dissection. Cautery may be used to circumferentially mark the line of resection 3 to 5 mm in deep. Particular care should be taken to mark the course of the parenchymal dissection in the area of the previously dissected portal structures and through the previously identified path to control the hepatic veins. The anesthesiologist should be alerted at this point to prepare for the potential blood loss associated with parenchymal dissection. The parenchymal dissection in the classic operation may proceed with blunt and finger fracture technique or by passing ligatures around bundles of hepatic parenchyma, tying the suture, and cutting through the parenchyma to reveal the vascular and biliary structures. Depending on surgeon preference, the Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, Ohio), the Integra Selector (Integra, Plainsboro, N.J.), or the TissueLink device (TissueLink, Dover, N.H.) may be used to facilitate dissection. Although these devices aid in a precise dissection, the key to a successful and relatively blood-free parenchymal dissection is a complete vascular dissection before dividing the parenchyma. Knowledge of the three-dimensional segmental anatomy of the liver described by Couinard (Fig. 30-5) is essential in planning liver resections (Fig. 30-6). Segmentectomy involves resection of a single segment. A right hepatic lobectomy involves resection of segments V, VI, VII, and VIII and ligation of the right hepatic artery, right portal

The anatomy of the liver is divided into segments as described by Couinard.

508

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Standard anatomic liver resections are based on the segmental anatomy of the liver. Left lobectomy (formerly left lateral segmentectomy) excises segments I1 and 111; left hepatectomy, segments 11, 111, and IV,extended left hepatectomy, segments 11, 111, IV, V, and VIII (and occasionally I); right hepatectomy, segments V, VI, VII, and VIII; and extended right hepatic lobectomy (formerly right trisegmentectomy), segments IV, V, VI, VII, and VIII (and occasionally I). GB, gallbladder; IVC, inferior vena cava; LHV, left hepatic vein; MHV, middle hepatic vein; PV, portal vein; RHV, right hepatic vein.

vein, right hepatic biliary duct, and right hepatic vein. The liver parenchyma is divided through the median portal fissure on a line between the gallbladder fossa and the vena cava. The large distal branch and the smaller branches of the middle hepatic vein supplying these segments must also be divided. An extended right hepatic lobectomy (right trisegmentectomy) includes resection of segments I, IV, and V through VIII. The right and middle hepatic veins are divided. The liver parenchyma is divided along the falciform ligament and left portal fissure. In addition, the branches of the left hepatic artery, portal vein, and hepatic biliary duct to segments I and IV are ligated. Left lobectomy involves resection of segments 11, 111, and N and ligation of the left hepatic artery, left portal vein, left hepatic biliary duct, and left hepatic vein. The liver parenchyma is divided through the median portal fissure. The branches of the middle hepatic vein to segment IV are also divided. A left lateral segmentectomy involves resection of segments I1 and 111. The branches of the left hepatic artery, portal vein, and hepatic biliary duct to these segments are ligated. An extended left hepatic lobectomy (left trisegmentectomy) involves resection of segments I through IV, V, and VIII. The liver

parenchyma is divided along the right portal fissure. The left hepatic artery, left portal vein, left hepatic biliary duct, and left and middle hepatic veins are ligated. The branches of the right hepatic artery, right portal vein, and right hepatic biliary duct to segments V and VIII are also ligated. When only segments IV, V, and VIII are involved with tumor, central hepatic resection (mesohepatectomy) can be performed.34 Branches to the left portal vein to segment IV are divided in the umbilical fissure. The middle hepatic vein and right anterior sectoral pedicles are ligated. Central hepatic resection offers the advantage of preserving normal hepatic parenchyma (either segments 1-11 or VI-VII), which would ordinarily be removed in a standard anatomic resection (i.e., extended right or left lobectomy) . When the tumor is not resectable using standard anatomic resections, novel techniques have been used. Hepatic vein reconstruction using portal vein or synthetic graft has been performed when the hepatic vein or vena cava is involved by tumor.g When all hepatic veins are involved, one approach is to rely on venous outflow through the inferior hepatic vein, allowing resection of all segments except V and VI (we have no personal experience with this technique) .67 In the most challenging cases, tumor resection can be performed ex vivo (on the back table) using methods developed for liver transplantation. Blood flow to the heart is preserved with venovenous bypass. Following hepatectomy, the liver is infused with University of Wisconsin solution and placed in an ice bath. Back-table tumor resection and hepatic vein-vena cava reconstruction are performed before reim~lantation.2~ Upon completion of the resection, adequate hemostasis is achieved. Special attention is given to the raw surface of the remaining liver for both bleeding and bile leak. Drains are placed in the suprahepatic and subhepatic spaces. Complications following hepatic resection include bleeding, subphrenic abscess, biliary fistula, wound infection, and biliary obstruction. Several advances in anesthesia and surgical technique have improved resection rates and decreased perioperative mortality to less than 5%. When the operation is complicated by severe bleeding, total vascular isolation can be achieved by clamping the supra-and infrahepatic inferior vena cava in combination with the Pringle maneu~er.~' Bleeding can then be controlled before proceeding with resection. Vascular staplers can be used to transect hepatic vessels, resulting in reduced operative time and blood loss.77Vascular staplers, ultrasonic dissection, laser, Harmonic Scalpel, finger fracture, sharp dissection, and Kelly clamp have all been used to divide liver parenchyma. Argon beam coagulation and fibrin glue can be used to help control bleeding from the residual liver tissue. Laparoscopic liver resections have also been described in adults45 and have potential applications in children. Standard anatomic resections can lead to the loss of a significant percentage of liver parenchyma: right extended lobectomy, 85%; right lobectomy, 65%; left lobectomy, 35%; segmental or wedge resection, 3% to 15%.

CHAPTER

30

Liver Tumors

509

Most children with otherwise normal liver parenchyma can easily adapt to major resections with compensatory hyperplasia of the remaining liver. However, neonates have immature livers and are particularly susceptible to developing postoperative hepatic insufficiency manifested by hypoglycemia, hypoalbuminemia, and hypoprothrombinemia. Maintenance intravenous fluids contain 10% dextrose. Supplemental albumin and vitamin K can be administered for the first postoperative week. Oral feedings can usually be resumed in 2 to 3 days. Chemotherapy is usually withheld for 3 weeks in patients who have had extensive resections or compromised liver function to permit adequate liver replication to occur.

LIVER TRANSPLANTATION Ultimately, up to 6% of patients with hepatoblastoma will require orthotopic liver transplantation (Fig. 30-7).23,54 Liver trans~lantationshould be considered for everv child presenting with involvement of all four sectors of the liver or involvement of three sectors when complete tumor excision by partial hepatectomy is unlikely. A contraindication to liver-transplantation is the presence of extrahepatic disease following chemotherapy. Several reports describe favorable outcomes following In ~ a t i e n t s liver trans~lantationin children.1,3,32,51,5',54,61 who undergo primary liver transplantation for hepatoblastoma following neoadjuvant chemotherapy, 10-year survival rates of 85% have been achieved.51Tumor recurrence appears to be more frequent in children with a previous attempt at hepatic resection. In patients who undergo "rescue" liver transplantation following partial hepatectomy, the 5-year overall survival is 30% to 50%. positive margins after an initial attempt at resection is associated with a particularly poor prognosis. These results suggest that heroic attempts at partial hepatectomy should be avoided, and liver transplantation should be considered when the potential for complete resection B is in question.51 Computed tomography scan demonstrates a multifocal For hepatocellular carcinoma, liver transplantation hepatoblastoma. Despite a good response to chemotherapy, liver has the thkoretical advantage of removing n6t only the transplantation is the only hope for cure. tumor but also the entire diseased preneoplastic liver. Most centers restrict transplantation for hepatocellular carcinoma to patients with single tumors 5 cm or smaller of lifelong immunosuppression, which may enhance or three nodules 3 cm or smaller.3gThe overall 5-year survival rate following liver transplantation for hepatotumor recurrence or secondary malignancies. cellular carcinoma is 60% to 70% in adult series48 The scarcity of cadaveric donors, especially in the pediatric age group, has led to the use of segmental ADJUVANT THERAPY grafts from living donors or split-liver cadaveric donors. Living, related donor transplantation for tumors has been Although cure ultimately requires complete resection, associated with improved graft survival and outcome.76 chemotherapy remains the mainstay of adjuvant therapy Total hepatectomy in these patients should include for hepatoblastoma and hepatocellular carcinoma. removal of the retrohepatic inferior vena cava. This need Neoadjuvant chemotherapy has been advocated for the has discouraged the use of split livers in this population. purposes of downstaging disease, improving the likeliIn cases in which a segmental graft is used, reconstruchood of complete resection, and ultimately improving tion of the vena cava can be achieved with either a long-term survival.16 The disadvantage of neoadjuvant preserved allogeneic iliac vein or the internal jugular therapy is that nonresponders can experience disease vein procured from the living donor.C4lDisadvantages of progression, and ultimately the tumor can be upstaged transplantation include the associated expense and risks or become unresectable. Therefore, imaging and serum

510

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MATORTUMORS OF CHILDHOOD

AFP levels should be performed routinely to assess for response when neoadjuvant therapy is used. There are several chemotherapeutic regimens. Regimens with cisplatin, vincristine, and 5-fluo;ouracil have had comparable results to those with cisplatin and The SIOP advodoxorubicin, with fewer side effe~ts.2~3~~ cates cis~latinand doxorubicin and attributes better tolerance of this regimen to lower doses of doxorubicin.13 A German study group utilizes cisplatin, ifosfamide, and doxorubicin as its chemotherapeutic regimen.Z1 Results were similar to SIOP's, but toxic-ity was greater. Etoposide (W-16)and carboplatin are used for recurrent or unresponsive disease. Early reports suggest that irinotecan may be a promising chemotherapeutic agent in refractory or relapsed h e p a t ~ b l a s t o m a . ~ , ~ Wofs eantiangiogenic agents, including anti-vascular endothelial growth factor antibody and topotecan, resulted in reduction of tumor volume in ex~erimentalliver tumors.42,43 Neoadjuvant therapy has had a significant impact in improving resectability in hepatoblastoma, but outcomes are less favorable in children with hepatocellular carcinoma. Up to 50% to 70% of stage 111hepatoblastomas can

C

be rendered resectable after neoadjuvant chemotherapy.49 In stage 111 hepatocellular carcinoma, however, resection can be achieved in only 10% to 36% of patients following chemotherapy (Fig. 30-8).l"Z9 Radiation therapy has a limited role in the management of hepatoblastoma and hepatocellular carcinoma. Current cooperative trials provide for permissive use of radiation therauv in chiidren with residual disease. However, the ultimate goal remains complete surgical resection as the only effective for cure. In the hope of avoiding the systemic side effects of standard adjuvant therapies, novel and less toxic treatment modalities have been sought. One proposed strategy that selectively targets tumor cells is suicide gene therapy.27 This strategy involves the expression of a gene that converts a membrane-permeable nontoxic prodrug into a toxic agent (suicide drug) in tumor cells only. For example, in vivo models for hepatocellular carcinoma have used a replication-deficien; adenovirus carrying suicide ,~~ genes such as Escherichia coli c y t ~ s i n e . ~ .A' ~transcriptional control element like that for AFP is used to selectively express the suicide gene in tumor cells. L ,

D

Neoadjuvant chemotherapy can significantly decrease tumor size and ultimately make lobectomy easier and safer. Prominent calcification is seen after chemotherapy, and the right portal vein is noted to be patent.

CHAPTER

30

Liver Tumors

511

ABLATIVE THERAPIES Patients with lesions that cannot be anatomically resected and those who are not candidates for transplantation can be considered for local ablative therapies, including chemoembolization, radiofrequency ablation, percutaneous injection of ethanol, and cryoablation.2,",64 Ablative therapies offer palliation and may prolong survival but rarely achieve a cure. Alternatively, ablative therapies can act as a bridge to transplantation until a suitable donor becomes available. Radiofrequency ablation uses a needle electrode inserted into the tumor that delivers alternating current in the range of radiofrequency waves to cause focal thermal injury. Larger lesions require multiple overlapping applications, each lasting 10 to 20 minutes. Cryoablation uses direct freezing and thawing to cause cell death by protein denaturation, cell membrane disruption, and hypoxia. Intraoperatively, the Pringle maneuver can be performed to decrease the warming effects of larger blood vessels passing through or near the site to be ablated. Usually, two freeze cycles lasting 15 to 20 minutes each are followed by spontaneous thaw cycles. The goal of ablative therapies is to incorporate a l-cm rim of normal tissue. This can be confirmed sonographically by the presence of echogenic microbubbles with radiofrequency ablation or a round, echogenic expanding rim with cryoablation. Intrahepatic arterial chemoembolization has the potential to improve chemotherapeutic response and allow for contralateral liver hyperplasia. The procedure involves angiographic placement of a catheter into the main feeding artery of the tumor. Doxorubicin (Adriamycin) dispersed in lipiodol and cisplatin is infused, and embolization is then performed with Gelfoam." Drug levels within the tumor can reach 50 to 400 times that used in conventional chemotherapy without an increase in systemic toxicity. Reports concerning chemoembolization in children have been limited, but subsequent surgical resectability has been achieved in some case^.^,^^," Complications of chemoembolization include hepatic artery thrombosis and gastric ulceration. Chemoembolization can also be used before transplantation when systemic neoadjuvant chemotherapy has failed.4

1

1 Stage

Hepatocellular Hepatoblastoma Carcinoma

I (pure fetal histology) I (other histologic types) I (hepatocellular carcinoma) II Ill IV

1 0 0 % (n = 9 ) 91% (n = 4 3 ) 1 0 0 % (n = 7) 64% (n = 8 3 ) 25% (n = 4 0 )

I

I

88% (n = 8 ) - (n = 0 ) 8% ( n = 2 5 ) 0% (n = 1 3 )

Data adapted from Ortega JA, Dougless EC, FeusnerJH, et al: Randomizedcomparison of cisplatin/vincristine/Auorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma:A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol2000;18:2665-2675; and Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Hepatocellular carcinoma in children and adolescents: Resultsfrom the Pediatric Oncology Group and the Children's Cancer Group IntergroupStudy. J Clin Oncol2002;20: 2789-2797.

100% ( n = 3) for stage 11, 68% ( n = 25) for stage 111, and 21 % ( n = 14) for stage 1V.a The primary predictor for poor prognosis in hepatoblastoma and hepatocellular carcinoma is metastatic disease.*OJ3,21Multifocality, size, and lack of response to chemotherapy are also predictive of poor prognosis in hepatocellular carcinoma.13 Although metastatic disease portends a worse prognosis, some metastatic lesions have a complete response to chemotherapy. Pulmonary resection should be considered in selected patients with lung lesions that persist after chemotherapy. Following hepatic resection, most patients receive postoperative chemotherapy. Patients should be followed closely to ensure that serum AFP levels return to normal and that the neoplasm does not recur. In those patients who present with normal AFP levels, serial ultrasonography or CT can be performed to screen for recurrence.

CONCLUSION PROGNOSIS AND FOLLOW-UP The 5-year survival rate for hepatoblastoma has markedly improved from 35% 3 decades ago to 75% in some series.14,17,50,flfiThe prognosis for hepatocellular carcinoma remains dismal, with 5-year overall survival rates of that are successfully less than 18% to 28%.l"2"esions resected have a better prognosis, with 91% to 100% 5-year survival in hepatoblastoma and 30% to 54% for hepatoResults for estimated 5-year cellular car~inoma.~0,~"~"57,7s event-free survival reported by the Intergroup Hepatoma Study are summarized in Table 30-4. The German Cooperative Pediatric Liver Tumor Study Group had similar results for disease-free survival in hepatoblastoma (mean follow-up 58 months): 89% ( n = 27) for stage I,

Advances in anesthesia, surgical technique, and chemotherapy have led to a significant improvement in the prognosis of children with hepatoblastoma. Outcomes for hepatocellular carcinoma remain poor. Liver transplantation is useful in patients with unrectable tumors. Continued cooperation of multi-institutional pediatric cancer study groups will be required to achieve additional advances in the treatment of malignant liver neoplasms. ACKNOWLEDGMENT

We are grateful to Marcio Malogolowkin, MD, chair of the Liver Tumor Subcommittee of the Children's Oncology Group and director of the Bone and Soft Tissue Tumor Program

512

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at Children's Hospital, Los Angeles, for his review of the manuscript.

REFERENCES 1. Achilleos OA, Buist LJ, Kelly DA, et al: Unresectable hepatic tumors in childhood and the role of liver transplantation. J Pediatr Surg 1996;31:1563-1567. 2. Ahrar K, Gupta S: Hepatic artery embolization for hepatocellular carcinoma: ~ e c h n i ~ u patient e, selection, a i d outcomes. Surg Oncol Clin N Am 2003;12:105-126. 3. Al-Qabandi W, Jenkinson H, Buckels JA, et al: Orthotopic liver transplantation for unresectable hepatoblastoma: A single center's experience.J Pediatr Surg 1999;34:1261-1264. 4. Arcement CM, Towbin RB, Meza MP, et al: Intrahepatic chemoembolization in unresectable pediatric liver malignancies. Pediatr Radiol 2000;30:779-785. 5. Boechat MI, Kangarloo H, Ortega J, et al: Primary liver tumors in children: Comparison of CT and MR imaging. Radi~lo~gy 1988;169:727-732. 6. Buendia MA: Genetic alterations in hepatoblastoma and hepatocellular carcinoma: Common and distinctive aspects. Med Pediatr Oncol 2002;39:530-535. 7. Cao G, Kuiryama S, Gao.1, et al: Gene therapy for hepatocellular carcinoma based-on tumour-selective suicide gene expression using the alpha-fetoprotein (AFP) enhancer and a housekeeping gene promoter. Eur J Cancer 2001; 37:140-147. 8. Chang MH, Chen CJ, Lai MS, et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336: 1855-1859. 9. Chardot C, Saint-Martin C, Gilles A, et al: Living related liver transplantation and vena cava reconstruction after total hepa~ectomyincluding vena cava for hepatoblastoma. Transplantation 2002;73:90-92. 10. Chen JC, Chen CC, Chen WJ, et al: Hepatocellular carcinoma in children: Clinical review and comparison with adult cases. J Pediatr Surg 1998;33:1350-1354. 11. Clericuzio CL, Chen E, McNeil DE, et al: Serum alphafetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolate hemihyperplasia. J Pediatr 2003; 143:270-272. 12. Craig JR, Peters RL, Edmondson HA, et al: Fibrolamellar carcinoma of the liver; a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 1980;46:372-379. 13. Czauderna P, Mackinlay G, Perilongo G, et al: Hepatocellular carcinoma in children: Results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 2002;20:2798-2804. 14. Darbari A, Sabin KM, Shapiro CN, et al: Epidemiology of primary hepatic malignancies in US children. Hepatology 2003;38:560-566. 15. de Campo M, de Campo JF: Ultrasound of primary hepatic tumours in children. Pediatr Radiol 1988;19:19-24. 16. Evans AE, Land VJ, Newton WA, et al: Combination chemotherapy (vincristine, Adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer 1982;50:821-826. 17. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children with particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey-1974. J Pediatr Surg 1975;lO: 329-337.

18. Feusner J, Plaschkes J: Hepatoblastoma and low birth weight: A trend or chance observation? Med Pediatr Oncol 2002;39:508-509. 19. Finegold MJ: Chemotherapy for suspected hepatoblastoma without efforts at surgical resection is a bad practice. Med Pediatr Oncol 2002;39:484486. 20. Fuchs J, Rydzynski J, Hecker H, et al: The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma-a report from the German Cooperative Liver Tumour Studies HB 89 and 94. Eur J Pediatr Surg 2002;12:255-261. 21. Fuchs J, Rydzynski J, Von Schweinitz D, et al: Pretreatment prognostic factors and treatment results in children with hepatoblastoma: A report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 2002;95:172-182. 22. Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 2001;92:3130-3134. 23. Helmberger TK, Ros PR, Mergo PJ, et al: Pediatric liver neoplasms: A radiologic-pathologic correlation. Eur Radiol 1999;9:1339-1347. 24. Hemming AW, Reed AI, Langhan MR, et al: Hepatic vein reconstruction for resection of hepatic tumors. Am Surg 2002;235:850-858. 25. Hughes LJ, Michels W: Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 1992;43:1023-1025. 26. Ikeda H, Hachitanda Y, Tanimura M, et al: Development of unfavorable hepatoblastoma in children of very low birth weight: Results of a surgical and pathologic review. Cancer 1998;82:1789-1796. 27. Kanai F: Transcriptional targeted gene therapy for hepatocellular carcinoma by adenovirus vector. Mol Biotechnol 2001;18:243-250. 28. Kanai F, Lan KH, Shiratori Y, et al: In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res 1997;47:561-565. 29. Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Hepatocellular carcinoma in children and adolescents: Results from the Pediatric Oncology Group and the Children's Cancer Group Intergroup Study. J Clin Oncol 2002;20:2789-2797. 30. Katzenstein HM, Krailo MD, Malogolowkin MH, et al: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 2003;97:2006-2012. 31. Katzenstein HM, Rigsby C, Shaw PH, et al: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 2002;24:751-755. 32. Koneru B, Flye MW, Bussutil RW, et al: Liver transplantation for hepatoblastoma: The American experience. Ann Surg 1991;213:118-121. 33. Lack EE, Neave C, Vawter GI? Hepatocellular carcinoma: Review of 32 cases in childhood and adolescence. Cancer 1983;52:1510-1515. 34. LaQuaglia MP, Shorter NA, Blumgart LH: Central hepatic resection for pediatric tumors. J Pediatr Surg 2002;37: 98G989. 35. Lau WY, Leung TW, Yu SC, et al: Percutaneous local ablative therapy for hepatocellular carcinoma: A review and look into the future. Ann Surg 2003;237:171-179. 36. Lee CL, KOYC: Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediatrics 1997;991351-353. 37. Liu DC, Vogel AM, Gulec S, et al: Hepatectomy in children under total hepatic occlusion. Am Surg 2003;69:539-541. 38. Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-338.

CHAPTER

39. LlovetJM, Burroughs A, BruixJ: Hepatocellular carcinoma. Lancet 2003;362:1907-1917. 40. Malogolowkin MH, Stanley P, Steele DA, et al: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 2000; 18:1279-1284. 41. Martinez JA, Rigamonti W, Rahier J, et al: Preserved vascular homograft for revascularization of pediatric liver transplant: A clinical, histological, and bacteriological study. Transplantation 1999;68:672-677. 42. McCrudden KW, Hopkins B, Frischer J, et al: Anti-VEGF antibody in experimental hepatoblastorna: Suppression of tumor growth and altered angiogenesis. J Pediatr Surg 2003;38:308-314. 43. McCrudden KW, Yokoi A, Thosani A, et al: Topotecan is anti-angiogenic in experimental hepatoblastorna. J Pediatr Surg 2002;37:857-861. 44. Molmenti EP, Wilkinson K, Molmenti H, et al: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2002;2:535-538. 45. Morino M, Morra I, Rosso E, et al: Laparoscopic vs open hepatic resection: A comparative study. Surg Endosc 2003; 17:19141918. 46. Ni Y-H, Change M-H, Huang L-M, et al: Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001;135:796. 47. Ohashi M, Kanai F, Tateishi K, et al: Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by ElB55k-attenuated adenovirus. Biochem Biophys Res Commun 2001 ;282:529-535. 48. Okuda K, Ohtsuki T, Obata H, et al: Natural history of hepatocellular carcinoma and prognosis in relation to treatment: Study of 850 patients. Cancer 1985;56:918-928. 49. Ortega JA, Douglass EC, Feusner JH, et al: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 2000;18:2665-2675. 50. Ortega JA, Krailo MD, Hans JE, et al: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: A report from the Children's Cancer Study Group. J Clin Oncol 1991;9:2167. 51. Otte JB, Aronson DC, Brown J, et al: Liver transplantation for hepatoblastoma: Results from the International Society of Pediatric Oncology (SlOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 2004; 42:7483. 52. Otte JB, Aronson D, Vraux H, et al: Preoperative chemotherapy, major liver resection, and transplantation for primary malignancies in children. Transplant Proc 2001; 28:2393. 53. Oue T, Fukuzawa M, Kusafuka T, et al: Transcather arterial chemoembolization in the treatment of hepatoblastoma. J Pediatr Surg 1998;33:1771-1775. 54. Oue T, Kubota A, Okuyama H, et al: Hepatoblastoma in children of extremely low birth weight: A report from a single perinatal center. J Pediatr Surg 2003;38:134137. 55. Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 2003;41:78-80. 56. Perilongo G, Brown J, Shafford E, et al: Hepatoblastoma presenting with lung metastases: Treatment results of the first cooperative, prospective study of the International Society of Pediatric Oncology on childhood liver tumors. Cancer 2000;89:1845-1853.

30

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57. Pritchard J, Brown J, Shafford E, et al: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: A successful approach-results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 2000;18:3819-3828. 58. Ramanujam TM, Ramesh JC, Goh DW, et al: Malignant transformation of mesenchymal hamartoma of the liver: Case report and review of the literature. J Pediatr Surg 1999:34:16841686. 59. Ravindra KV, Cullinane C, Lewis IT, et al: Long-term survival after spontaneous rupture of a malignant rhabdoid tumor of the liver. J Pediatr Surg 2002; 10:1488-1490. 60. Rowland JM: Hepatoblastoma: Assessment of criteria for histologic classification. Med Pediatr Oncol 2002:39: 478-483. 61. Ruck P, Xiao JC: Stem-like cells in hepatoblastorna. Med Pediatr Oncol 2002;39:504507. 62. Sasaki F, Matsunaga T, Iwafuchi M, et al: Outcome of hepatoblastoma treated with the JPLT- 1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg 2002;37:851-856. 63. Sato M, Ishida H, Konno K, et al: Liver tumors in children and young patients: Sonographic and color Doppler findings. Abdom Imaging 2000;25:596-601. 64. Scaife CL, Curley SA: Complication, local recurrence, and survival rates after radiofrequency ablation for hepatic malignancies. Surg Oncol Clin N Am 2003;12:243-255. 65. Schnater JM, Aronson DC, Plaschkes J, et al: Surgical view of the treatment of patients with hepatoblastoma: Results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 2002;94:1111-1120. 66. Sindhi R, Rosendale J, Mundy D, et al: Impact of segmental grafts on pediatric liver transplantation: A review of the United Network for Organ Sharing Scientific Registry Data (1990-1996).J Pediatr Surg 1999;34:107-111. 67. Superina RA, Bambini D, Filler RM, et al: A new technique for resecting "unresectable" liver tumors. J Pediatr Surg 2000;35:12941299. 68. Surace C, Leszl A, Perilongo G, et al: Fluorescent in situ hybridization (FISH) reveals frequent and recurrent numerical and structural abnormalities in hepatoblastoma with no informative karyotype. Med Pediatr Oncol 2002; 39:536-539. 69. Szavay PO, Wermes C, Fuchs J, et al: Effective treatment of infantile choriocarcinoma in the liver with chemotherapy and surgical resection: A case report. J Pediatr Surg 2000; 35:11341135. 70. Tanimura M, Matsui I, Abe J, et al: Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res 1998;58:303'2-3035. 71. Terracciano LM, Bernasconi B, Ruck P, et al: Comparative genomic hybridization analysis of hepatoblastomi reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Hum Path01 2003;34:864871. 72. Tsuchida Y, Ikeda H, Suzuki N, et al: A case of welldifferentiated, fetal-type hepatoblastoma with very low serum-alpha-fetoprotein. J Pediatr Surg 1999;12:1762-1764. 73. von Schweinitz D, Hadam MR, Welte K, et al: Production of interleukin-lp and interleukin-6 in hepatoblastoma. Int J Cancer 1993;53:728. 74. Webber EM, Morrison KB, Pritchard SL, et al: Undifferentiated embryonal sarcoma of the liver: Results of clinical management in one center. J Pediatr Surg 1999;34:1641-1644.

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75. Weber RG, Pietsch T, von Schweinitz D, et al: Characterization of genomic alterations in hepatoblastomas: A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Path01 2000;157:571-578. 76. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 1983;14:512-537. 77. Yanaga K, Nishizaki T, Yamamoto K, et al: Simplified inflow control using stapling devices for major hepatic resection. Arch Surg 1996;131:103-106.

78. Zatkova A, Rouillard.JM, Hartmann W, et al: Amplification and overexpression-of the IGFP regulator PLAGI in hepatoblastoma. Genes Chromosomes Cancer 2004;39: 126-137. 79. Zimmerman A: Pediatric liver tumors and hepatic ontogenesis: Common and distinctive pathways. Med Pediatr Oncol 2002;39:492-503.

Gastrointestinal Tumors Patrick A. Dillon and Robert I? Foglia

Primary gastrointestinal (GI) tumors are relatively uncommon in infants and children. GI malignancies account for approximately 1.2% of all pediatric cancer cases.4 The clinical presentation and histopathology of GI tumors in children can differ significantly from those seen in adults. In addition, the discovery of genetic markers and the use of immunohistochemistry have allowed a more thorough identification of these tumors, although these same advances have made it difficult to assess their true incidence. The most common presenting symptoms are nonspecific and include abdominal pain, vomiting, and rectal bleeding. The duration of symptoms is often several weeks before diagnosis, and emergent surgery for intestinal ~ , ~ ~ not a common obstruction may be r e q ~ i r e d .Although diagnosis, the possibility of a GI malignancy should be considered in any child with signs and symptoms of intestinal obstruction, intractable abdominal pain, and alteration in bowel habits or GI bleeding. In addition, children with bowel disorders should receive a detailed and vigorous diagnostic evaluation, including contrast studies, ultrasonography, computed tomography (CT), and endoscopy to both confirm the diagnosis and detect the extent of disease.31

GASTROINTESTINAL STROMAL TUMORS Epidemiology Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract. The incidence is difficult to determine, owing to changes in nomenclature, cellular origin, and diagnostic criteria. Classification has also been hindered by published reports that contain only a few patients, the mixing of benign and malignant tumors, and failure to separate primary and recurrent GISTs.12 In addition, GISTs have been grouped together, regardless of anatomic location, making prediction of their clinical behavior difficult.j7 The median age at presentation is between the 5th and 6th decades of life; these tumors are considered rare in patients younger than 40 years. Gender distribution

is equal. The most common site of origin is the stomach (50% to 70%), followed by the small intestine (20% to 30%),colon or rectum ( l o % ) ,and esophagus ( 5 % ) .The mesentery or omentum may occasionaily be the site of origin for GIST.39,43 GIST is currently classified as a mesenchymal tumor of the GI tract and is thought to originate from the interstitial cell of Cajal, an intestinal pacemaker cell." Historically, smooth muscle tumors such as leiomyomas and leiomyosarcomas and neural tumors such as schwannomas and malignant peripheral nerve sheath tumors have been categorized as GISTs. However, histologic and immunohistochemical features now distinguish GISTs from tumors of smooth muscle origin.

Association with Other Conditions In 1977 Carney et a1.7 reported the rare association of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma in unrelated young women. The patients' young age, the multifocal locations, and the multiple organ involvement raised the possibility of an inherited disorder, but thus far, no genetic link has been identified." primary feature of Carney's triad is gastric stromal tumors. These tumors are usually located along the lesser curve or antrum and produce few local symptoms; continued growth can lead to mucosal ulceration and GI bleeding, and serosal involvement is common. The multifocal nature of the tumor can lead to local recurrence as well as widespread but slowly progressive metastatic lesions. Traditional adjuvant therapy has been unsuccessful in treating metastatic disease.6 Despite the possible development of additional gastric tumors in the remaining stomach, less than total gastrectomy, if feasible, is likely the best initial operation to avoid the complications of total gastrectomy, particularly in teenage patients., Patients treated in this manner should be advised that new gastric tumors may develop and should be re-examined at 3-year intervals. Evaluation for adrenal tumors in patients with gastric stromal sarcomas or pulmonary chondromas (or both) should be considered, and a family history should

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be obtained from patients with Carney's triad. However, family screening and genetic counseling for the disorder are not currently rec~mrnended.~ A subset of GIST has been identified and is commonly referred to as GI autonomic nerve tumor (GANT). There have been very few cases of GANT reported in the pediatric population. However, in small series of pediatric patients, there is a female predominance, and symptoms may include abdominal pain, fullness, emesis, and a palpable abdominal mass." GANT can arise in any part of the GI tract, with the small intestine being the most common site in adults. As is the case with GIST, when GANT occurs in children, it tends to favor the stomach as the primary site of origin." The majority of pediatric patients have localized disease at the time of diagnosis, and surgical resection of the tumor is the treatment of choice. Currently there appears to be no defined role for chemotherapy or radiation. In children, localized disease and small tumor size at the time of diagnosis likely aid in the more favorable long-term prognosis compared with adults. Immunocytochemical and ultrastructural evaluation is required to differentiate these tumors from GIST, and established criteria for malignancy are not currently available for the pediatric p o p ~ l a t i o n . ~ ~

Clinical Presentation At the time of presentation, most patients have experienced some symptoms, most often generalized abdominal pain, dyspepsia, and occult GI bleeding. Irondeficiency anemia, which can be present in children, should prompt an investigation to rule out the GI tract as the source of the anemia." Less commonly, patients present with a palpable abdominal mass or intestinal obstr~ction.~"tandard imaging studies to assist in the diagnosis include plain radiographs and CT; there also appears to be a potential role for whole-body fluorodeoxyglucose positron emiscan be helpful in identifysion tomography.~~ndoscopy ing a tumor mass, especially if the tumor is located in the stomach or the proximal small intestine.

Pathology GISTs are defined as cellular spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumors of the GI tract that express the KIT (CD117, stem cell factor receptor) protein, as detected using immunohistochemistry. Additional cell type markers such as CD34, smooth muscle actin, desmin, and S-100 protein are used to establish a diagnosis of GIST.S%ttempts to predict the outcome of GIST rely on traditional pathologic criteria such as size, stage, extent of tumor invasion into mucosa or surrounding organs, mitotic index, and nuclear pleomorphism. Although these criteria have been useful in predicting GIST behavior, no single feature is consistently reliable when it comes to predicting 0utcorne.2~Morphologic features that are associated with malignant gastric stroma1 tumors include tumor size greater than 7 cm, high cellularity, mucosal invasion, and mitotic count greater than 5 mitoses per 50 high-powered fields. All these

factors must be considered when distinguishing benign from malignant gastric stromal tumors." Recently, a mutation in the c-kit gene on exon 11 was identified in GIST. Patients found to have this mutation showed an increased risk of recurrence and higher mortality compared with GIST patients without the c-kit m ~ t a t i o n . ~ "

Treatment Complete surgical resection of GISTs, along with any possible pseudocapsules, is the recommended approach. Although wide margins are not thought to be necessary, en bloc resection may require complete or partial organ negative removal to achieve clear margin~.~Uchieving pathologic margins is generally not difficult, because GISTs tend to hang from, and do not diffusely infiltrate, the organ of origin. Consequently, wedge resection of the stomach or segmental resection of the intestine provides adequate therapy; wide resection has no known benefit.49 In addition, because the status of the microscopic margins does not appear to be important for survival, vital structures should not be sacrificed if gross tumor clearance has already been attained-'2 GIST rarely metastasizes to lymph nodes, so lyrnphadenectomy is seldom ~ a r r a n t e d . ~ ~ The high rate of local and distant recurrence underscores the need for adjuvant therapy. GIST has traditionally been resistant to radiotherapy and all previously available systemic treatments. However, the ability of imatinib td reduce tumor size significantly has changed the management of GIST. Imatinib is a signal transduction inhibitor that exerts its activity in GIST through the blockade of the adenosine triphosphate binding site of KIT, a transmembrane receptor protein-tyrosine kinase. Imatinib has been successful in treating patients with chronic myeloid leukemia and other Philadelphia chromosome-positive leukemias. The use of imatinib for GIST patients is based on the hypothesis that imatinib can block the constitutive activity of KIT receptor tyrosine kinase in the cells of GISTs.13 With the use of imatinib, surgical resection may be possible for GIST patients with widespread metastatic disease who would otherwise not be candidates for surgery. This therapy may also decrease the incidence of postoperative GIST recurrence and spread and thereby extend lives. Although the trials of adjuvant and neoadjuvant imatinib are ongoing, it appears reasonable to suggest that surgery be considered the first option for patients with resectable GISTs, followed by enrollment in a clinical trial of imatinib as a postoperative adjuvant in cases of incomplete resection, tumor spillage, or other high-risk factors. For cases of recurrent or metastatic GIST, a Gal of imatinib, followed by surgical resection, should be considered.

Survival The long-term survival following surgical resection of GIST varies in published series and is especially difficult to determine in children, because most reports either contain small numbers of patients or include primarily adult patients (Table 31-1). Moreover, given the recent

CHAPTER

Institution

Years Covered

Mayo Clinic MSKCC MCV MDACC MGH MSKCC

1950-1974 1949-1973 1951-1984 1957-1997 1962-1986 1982-1998

No. of Patients Evaluated

31

Gastrointestinal Tumors

No. of Patients Completely Resected (%)

5-Year Survival (%)

52 (48) 20 (53) 30 (59) 99 (52) 40 (73) 80 (40)

50 65 63 48 35 54

517

MCV, Medical College of Virginia; MDACC, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan-KetteringCancer Center.

changes in the recognition and pathologic categorization of these tumors, many older series may contain tumors that are not actually GISTs. Despite these obstacles, several factors appear to be useful in predicting long-term outcome following surgical resection: tumor size, mitotic index, and location (Table 31-2). Improved survival is noted when tumors are less than 5 cm, compared with those 5 to 10 cm; in turn, this intermediate group of tumors has a better prognosis than those greater than 10 cm. Low-grade tumors have a mitotic index of less than 10 per 50 high-powered fields, whereas high-grade tumors have an index of greater than 10 per 50 high-powered fields. Tumor location has also been found to predict prognosis, with gastric tumors having an improved survival compared with GISTs in other locations.46

ESOPHAGEAL AND GASTRIC CANCER Esophageal or gastric cancer in a child is extremely rare. According to Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Statistics Branch, esophageal carcinoma was diagnosed in 10,441 patients between 1988 and 1996. Of those patients, only three (0.03%) were between 10 and 19 years of age, and no patients were younger than 10 years.20

1 ---Factor Size Cellularity Nuclear pleomorphism Necrosis Mitosis Infiltrative growth attern Metastasis c-kit Mutation

Benign*

Malignant

<5 cm Low Absent to minimal Absent < @ Iper 30-50/ HPF Absent

>5 cm High May be prominent Present 1-5 or more per 10/HPF May invade adjacent structures Present Frequently present

Absent Absent

*No single feature is absolutely predictive of benign behavior. Tumor size, mitotic rate, and presence or absence of necrosis appear to be the most important factors in predictingbehavior. HPF, high-powered field, 400x.

Despite the rarity of esophageal cancer, there are known risk factors associated with a predisposition for tumor development. With regard to esophageal adenocarcinoma, the development of Barrett's esophagus secondary to chronic gastroesophageal reflux disease (GERD) is the primary risk factor. Pediatric populations that appear to be at increased risk for the development of Barrett's esophagus secondary to chronic GERD include children with severe neurologic deficits, such as cerebral palsy, and those with congenital defects involving the esophagus, such as esophageal atresia and tracheoesophageal fistula.lVhe overall incidence of Barrett's esophagus has been estimated by Hassall'8 to be 0.02% among young patients with severe GERD and associated risk factors; the incidence of Barrett's changes is probably even lower for those without risk factors. Nevertheless, adenocarcinoma of the esophagus has been documented in adolescents with long-standing GERD, and surveillance with upper endoscopy and multiple stepwise biopsies may benefit those children who have the mucosal changes of Barrett's es~phagus.~" Barrett's changes can also be seen with the retained cervical esophagus following esophageal replacement surgery. A history of this type of surgery requires the control of gastric pH and long-term surveillance endoscopy with biopsy of the retained upper esophageal segment. Depending on the technique and approach, esophageal replacement surgery for patients with esophageal atresia may result in retention of the distal esophageal segment. This remnant can cause severe chronic esophagitis and Barrett's changes requiring surgical resection. Because Barrett's esophagus is a premalignant lesion and can lead to the development of esophageal adenocarcinoma, the distal segment of esophagus should be removed at the time of esophageal replacement surgery.4xThere have also been case reports of esophageal carcinomas arising in children after chemical injuries to the esophagus. Endoscopic follow-up with biopsies should be considered for patients with Barrett's esophagus and for those with chemical injuries to monitor for the development of malignant changes.47 Between 1997 and 2001, the SEER database reported a gastric cancer incidence of 0.1% for patients younger than 20 years rrom a total of 15,274 cases reported.5" Despite the rarity of gastric adenocarcinoma in children, there are several case reports of adenocarcinoma of the

518

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MAJORTUMORS OF CHII.DHOOD

stomach in children as young as 2 '/2 years.'' The tumors can arise from any anatomic location in the stomach38; symptoms may be quite vague but can include epigastric pain, weight loss, vomiting, and anemia. In addition, symptoms associated with esophageal achalasia have been reported in conjunction with gastric adenocarcinoma.'.17

CARClNOlD TUMORS Epidemiology Carcinoid tumors originate from neuroendocrine cells found along the primitive GI tract. These neoplasms originate from the same progeny cells as other GI cells and are part of the amine precursor uptake and decarboxylation (APUD) system.59 Pediatric carcinoid tumors can occur in the GI tract-stomach, small intestine, appendix (most common), and rectum-as well as in extraintestinal sites such as the lung. Although carcinoid tumors of the appendix are rare in children and adolescents, they are nevertheless the most common GI tumor , ~ O incidence is difficult to among this age g r o ~ p . l ~ The assess in the pediatric population because most large series include retrospective data that may exclude certain types of carcinoid tumor, but the reported incidence appears to be in the range of 0.08% to 0.169%,16.52 or approximately 1.14 per million children per year,42 with a slight female predominan~e.2"4~

Although symptoms may be atypical and carcinoid size can be variable, there is no report of carcinoid syndrome ass* ciated with carcinoid tumors confined to the appendix.16.52 In contrast to patients with appendiceal or incidental carcinoid tumors, pediatric patients with extra-appendiceal carcinoid tumors, such as in the lung or liver, are often symptomatic and have diffuse disease at the time of diagnosis. Broaddus et al.5reported that 46% of their patients with extra-appendiceal carcinoids had recurrent tumor or metastasis following the initial diagnosis or disseminated disease at the time of diagnosis.

Treatment For pediatric carcinoid tumors limited to the appendix, surgical resection of the appendix is the treatment of choice and often results in a cure. Long-range follow-up reveals either minimal or no recurrence of disease and The most a rare likelihood of metastatic di~ease.l~,~O~" important factor in surgical decision making for carcinoid tumors of the appendix is the size of the tumor. For carcinoids less than 2 cm in diameter, appendectomy alone is usually adequate. Histologic evidence of invasion into the mesoappendix and tumors that involve the base of the appendix are indications for performance of a right hemicolectomy, regardless of tumor diameter. Carcinoid tumors larger than 2 cm in diameter, those with high-grade malignancies, and goblet cell adenocarcinoids are also indications to proceed with a right hemicolectomy.2"

Diagnosis Pediatric carcinoid tumors are often discovered during an operation for presumed appendicitis or incidentally during surgery unrelated to the carcinoid tumor. Although clinical signs consistent with acute appendicitis or suggestive of a gynecologic pathology may result in exploration, true inflammatory changes of the appendix are often not seen.1° The lack of inflammation may be the result of appendiceal carcinoid tumors typically being located in the distal portion of the appendix; thus, proximal obstruction of the appendiceal lumen is not seen (Fig. 31-1).16,23

Pathology Important pathologic tumor characteristics include size, histologic subtype, mesoappendiceal involvement, and lymph node status. Carcinoids can also be graded as benign, borderline malignant, low-grade malignant, or high-grade malignant, although a more precise and uniform classification system may identify patients who would benefit from more aggressive surgery." Van Eeden et al.js attempted to address this issue by requesting that the World Health Organization apply the current classification of lung neuroendocrine tumors to all neuroendocrine tumors of the GI tract as well.

COLORECTAL ADENOCARCINOMA

,

.

Location of appendiceal carcinoids (%).

Adenocarcinoma of the colon and rectum is the most common cancer of the GI tract, with an annual incidence in the United States of approximately 148,300 cases and 56,600 deaths. The lifetime risk of colorectal cancer in the general population is 5% to 6%.30 Colorectal cancer is the second most common cancer of the alimentary tract in children, following liver tumors. Colorectal cancer is rare in children, however, with an incidence between 1.3 and 2 cases per million lives.41256 Although cancer of the colon has been diagnosed in a child as young as 9 months old, most pediatric cases occur in the second decade of life; the median age at

CHAPTER

Familial polyposis syndromes Inflammatory bowel disease, especially ulcerative colitis Hereditary nonpolyposis syndromes Previous ureterosigmoidostomy Chronic parasitic infection Previous radiation therapy Diet high in fat and low in fiber Possible exposure to environmental chemicals and radiation

diagnosis is 15 to 19 years.35,45,53 The development of carcinoma of the colon appears to be associated with several predisposing factors (Table 31-3). These include a diet high in fat and cholesterol and low in fiber, exposure to environmental chemicals and radiation, polyposis syndromes, inflammatory bowel disease, hereditary nonpolyposis syndromes, urinary diversion with a previous ureterosigmoidostomy, chronic parasitic infection, and previous radiation therapy. The cause of the tumor can be categorized as sporadic in approximately 75% of patients, familial in approximately 10% to 20% of patients who have at least two firstdegree relatives with colon cancer (but no defined genetic pattern), genetic (polyposis syndromes) in approximately 1% of patients, inflammatory bowel disease in approximately 1%, and hereditary nonpolyposis syndromes in approximately 5% to 6%. Although diet has a putative role in the development of colon cancer in adults, no similar studies have been done to support this role in children. Various environmental factors are associated with tumor formation. In one study, exposure to herbicides was found in 10 of 13 children who developed colon cancer.44 Colorectal cancer differs greatly between adults and children. These differences include the presenting signs and symptoms, primary site of the tumor, pathologic findings, stage, and prognosis.

Association with Other Conditions Because the sporadic form of pediatric colorectal carcinoma accounts for approximately '75% of cases, this suggests that 25% of childhood cases have some associated predisposing condition. Sporadic colon cancer in young patients appears to be an aggressive disease whose morphology and natural history differ from those of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and adult colon cancer. Tumor development most likely occurs secondary to tumor suppressor gene involvement, loss of heterozygosity, or a mutational event." Several genetic disorders carry a significant risk for the subsequent development of colon carcinoma and are characterized as polyposis syndromes. They include Gardner's syndrome (adenomatous polyps and soft tissue and bone tumors), Turcot's syndrome (familial

31

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adenomatous polyps and central nervous system tumors), and familial polyposis coli. Both Gardner's syndrome and familial polyposis are autosomal dominant disorders and are associated with adenomatous polyps in both the colon and the small intestine. Bassey3 has shown that the incidence of colon carcinoma in patients with familial polyposis is 50% by 28 years of age and that the eventual likelihood of colon cancer approaches 100%. Patients who have an APC mutation or who have one or more first-degree relatives with familial adenomatous polyposis are at high risk, and screening with flexible sigmoidoscopy should begin by age 10 to 12 years. Patients with colonic polyps, a verified APC germline mutation, or both require annual endoscopic examination. As patients reach their teens and 20s, the increased number of polyps may prevent adequate and safe colonoscopic polypectomy. When this occurs, prophylactic surgery should be performed to remove the affected colon. Surgical options include subtotal colectomy with end ileostomy or ileorectal anastomosis followed by annual endoscopy of the remaining rectum. Currently, many patients are candidates for total abdominal proctocolectomy with a restorative small bowel pouch anal anastomosis. Peutz-Jeghers syndrome is associated with the appearance of hamartomatous polyps. The incidence of colon carcinoma in patients with Peutz-Jeghers syndrome is 2% to 3%. Likewise, juvenile polyposis seems to have an increased potential for the development of colon ~arcinoma.g,2~,5~ Recommendations for colon resection are based on the likelihood of the development of malignancy. The entire surface of the colon can be carpeted with thousands of polyps in these patients. Realistically, the ability to carry out surveillance and identify suspicious lesions is low. There is little question that colectomy is the appropriate treatment for patients with familial polyposis, Gardner's syndrome, and Turcot's syndrome. Because of the relatively low incidence of malignancy with PeutzJeghers syndrome and juvenile polyposis, surveillance is a reasonable strategy. There is a clear-cut and progressively increasing likelihood of the development of colon carcinoma in patients with ulcerative colitis. This risk is approximately 20 times greater than that in the general population and is related to the total length of time a patient has ulcerative colitis.24 After the first 10 years with ulcerative colitis, the likelihood of cancer development increases from 1% to 2% per year.15 Several important features noted in patients with ulcerative colitis who develop colon carcinoma include occurrence at a young age, prevalence of multiple sites of malignancy, and a higher likelihood of malignancy in patients with colitis involving the entire colon than in those with only left-sided colitis.2" Crohn's disease is another type of inflammatory bowel disease in which the risk for colon cancer is up to 20 times greater than that in the general population." The likelihood of malignancy is related in part to the amount of bowel involved. However, cancer can develop in areas of colon that appear grossly normal," which in some ways makes the diagnosis of a malignancy in a patient with Crohn's disease more difficult than in a patient with

520

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ulcerative colitis. Therefore, regular surveillance protocols and random biopsies are especially important. In patients with inflammatory bowel disease, a contrast enema and colonoscopy are the mainstays of surveillance. Biopsies should be performed on any suspicious areas and randomly during the colonoscopy. Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, has an autosomal dominant inheritance and is the most common form of hereditary colorectal can~er.8,~ It' accounts for approximately 1% to 3% of all cases of colorectal cancer and is five times more prevalent than familial polyposis-related colon This type of colorectal cancer usually presents with proximal colon lesions (approximately 70% are proximal to the splenic flexure), and patients develop cancer at a younger age (mean, approximately 45 years) than patients with Hereditary nonpolypocolorectal cancer in genera1.22~~~ sis colorectal cancer is also notable for the development of synchronous and metachronous extracolonic cancers, such as carcinoma of the endometrium, ovary, stomach, small bowel, pancreas, hepatobiliary tract, brain, and upper uroepithelial tract.37 Ureterosigmoidostomy performed for urinary diversion in patients with bladder exstrophy and other genitourinary anomalies is associated with colon cancer. Eraklis and Folkman" reported that 5% of patients with a ureterosigmoidostomy developed colon cancer, in each case at the site of the ureteral implant. Experimental data have implicated chronic inflammation caused by the mixture of feces and urine at the implant site as a cause of the cancer, especially when the urine has been infected. Patients with this type of urinary diversion warrant close follow-up and should undergo annual sigmoidoscopy. Children with a primary cancer treated with radiation are at risk for the subsequent development of colorectal carcinoma in the radiation field. LaQuaglia et al.3" described one patient who had resection of a Wilms' tumor, received radiation to the retroperitoneal area, and subsequently developed cancer of the left colon. Others have reported two cases of colorectal cancer as a second malignancy following treatment of a retroperitoneal rhabdomyosarcoma and a Wilms' tumor, both treated with resection and radiation therapy,14The first child was a 1year-old boy whose retroperitoneal rhabdomyosarcoma was treated with preoperative radiation, surgery, and chemotherapy. At 2 years of age he developed radiation colitis and, subsequently, adenomatous polyps. At age 11 years a rectal adenocarcinoma developed (Fig. 31-2). The second child had a Wilms' tumor treated at 9 months of age with surgery and radiation therapy. He also developed radiation colitis and, subsequently, multifocal adenocarcinoma of the colon 42 years later. Results of immunohistochemical studies were positive for the p53 antigen in both tumors in the latter patient and in the adenomas of the first patient. It is speculated that the radiation caused a p53 mutation, which led to the neoplasia.

Diagnosis In children with colorectal tumors, common presenting symptoms include abdominal pain in almost all patients;

.

-

Contrast enema in an 11-year-old boy who had

previously been treated with radiation for a retroperitoneal rhabdomyosarcoma. The radiograph shows almost complete obstruction in the rectum.

nausea and vomiting in 40% to 70%; and a change in bowel habits and the development of constipation, particularly with left-sided lesions. Physical findings that are often noted in these patients include abdominal distention, tenderness, and a mass. More than half these children have chemical evidence of blood in the stool. A history of rectal bleeding may be elicited in approximately one third of patients and is more prevalent in those with cancer of the left colon and rectum. Significant weight loss affects 20% to 30% of patients. The median length of time from the onset of symptoms to presentation is often several months; at least one report cited almost a year between the onset of sympcan be delayed if the toms and the diagn~sis.~Wiagnosis patient's symptoms are attributed to more common pediatric conditions such as appendicitis, intussusception, or gastroenteritis." Another possible explanation for the delay in diagnosis may be adolescents' tendency to hide symptoms owing to embarrassment." Rectal bleeding, which may also be a sign of benign pathology such as polyps or hemorrhoids, should raise the suspicion for a colorectal malignancy; early diagnosis depends on a high index of suspicion.3' Steinberg et al." considered a

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• Contrast enema in a 14year-old patient who presented with a I-month history of abdominal pain and constipation. Complete obstruction in the transverse colon is demonstrated.

delayed diagnosis to have occurred if the patient's symptoms had been present for longer than 3 months; they found that five of nine patients with colon cancer had had symptoms for 3 to 36 months (mean, 11 months) before the diagnosis of cancer. This delay in diagnosis may be an important factor contributing to the advanced stage of disease in many of these children. On the basis of the signs and symptoms at presentation, two scenarios can develop. In the first, the clinical diagnosis is an acute surgical abdomen caused by appendicitis or peritonitis. In this case, the child is often taken directly to the operating room. The second, more common scenario occurs when intestinal obstruction is diagnosed. Radiographic evaluation usually demonstrates a mass lesion in the colon, and a contrast enema identifies the point of obstruction (Fig. 31-3). Depending on the location of the lesion, sigmoidoscopy or colonoscopy allows biopsy and diagnosis. In adults, most lesions are rectosigmoid in location and can be identified by sigmoidoscopy. In contrast, childhood colorectal cancer is relatively evenly distributed throughout the colon; one third of tumors are located in the right colon."".4" Colonoscopy is often the technique of choice to obtain a biopsy for diagnosis.

Pathologic Characteristics Two characteristics of colorectal tumors differ markedly in children and adults: stage and histologic type of adenocarcinoma. Approximately 40% of adults with colon cancer have tumors in which regional lymph nodes are involved or have distant metastases (Dukes' stage C or D lesions).

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In children, more than 80% of tumors are Dukes' stage C or D.3"45,53In addition, the histologic finding of a mucinous type of adenocarcinoma is found in over half the children with colorectal tumors. The mucinous subtype has an aggressive course and is known to metastasize e a r l ~ . ~ q hisi sat least one order of magnitude greater than the approximate 5% incidence of mucinous adenocarcinoma in adults with colon cancer. There is no obvious reason why this mucinous histologic type is seen so frequently in childhood colon carcinoma. The synergy of the more advanced stage of disease at the time of diagnosis and the increased frequency of a mucinous subtype (which carries a poor prognosis) contributes to the poor prognosis in these patients. The microsatellite status of the lymph nodes is thought to identify distinct pathways of genetic development in pediatric patients with colorectal cancer. Patients with colorectal cancer and high-frequency microsatellite instability were more likely to have multiple synchronous or metachronous colorectal cancers and were diagnosed at a younger age than those with microsatellite ~tability.~" Microsatellite instability is not, however, predictive of a family history of colorectal cancer or of unique phenotypic features.ll The utility of carcinoembryonic antigen (CEA) has been well established in adults with colon cancer, but there is little evidence of a similar utility in pediatric patients. Rao et a1.4"dentified 4 of 20 patients with Dukes' stage C or D lesions who had normal antigen levels at the time of diagnosis.4-n a longitudinal evaluation of these children, CEA levels correlated with an increase or decrease in tumor burden in 60% of patients; unfortunately, the other 40% had normal antigen levels despite progressive disease. At this time, CEA levels have not been shown to correlate well with response to treatment in children.

Treatment The wrimam treatment for colon cancer in children is surgical resection consisting of a wide excision of the involved colon, the mesentery, and the lymphatic drainage area. Unfortunately, resection for cure is possible in only 40% to 69% of pediatric patients; these percentages are much lower than those in adults with colon The ovaries and the omentum are common sites of metastasis. If resection for cure is performed, omentectomy and, in female patients, oophorectomy are appropriate. No specific chemotherapy protocols are available for of chemotherthese children. In most studies, some hn>e , apy was given, and radiation therapy has been used in selected patients. Although anecdotal case reports indicate that one or both of these methods mav result in success, no data document the benefit of either chemotherapy or radiation therapy for cure or palliation. The overall rate and duration of survival among children with colon carcinoma are dismal; studies-often show that less than 5% of patients survive 5 years.* More recently, LaQuaglia et a1.35 reported survival in 8 of 29 patients (28%) with a median follow-up of 4.7 years.

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Survival was directly related to complete resection. I n patients who h a d resection for cure, predictors of survival included n o d e involvement o r high histologic grade. T h e primary aim of treatment i n pediatric colon cancer is complete resection during t h e initial surgery. With t h e p o o r survival even in patients who have undergone complete resection, adjuvant chemotherapy is appropriate. T h e use of chemotherapy, combined with second-look surgery in selected cases, may improve survival.

Summary T h e biolo
REFERENCES 1. Aichbichler BW, Eherer AJ, Petritsch W, et al: Gastric adenocarcinoma mimicking achalasia in a 15-year-old patient: A case report and review of' the literature. J Pediatr Gastroenterol Nutr 2001;32:103-106. 2. Andersson A, Bergdahl L: Carcinoma of the colon in children: A report ofsix new cases and a review of the literature. J Pediatr Surg 1976;11:967-971. 3. Bassey HJR: Familial Polyposis Coli. Baltimore, Johns Hopkins University Press, 1975. 4. Bethel CA, Bhattacharyya N, Hutchinson C, et al: Alimentary tract malignancies in children. J Pediatr Surg 1997;32:1004-1008. 5. Broaddus KR, Herzog CE, Hicks MJ: Neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) presenting at extra-appendiceal sites in childhood and adolescence. Arch Path01 Lab Med 2003;127:1200-1203. 6. Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglictma (Carney triad): Natural history, adrenocortical component, and possible Familial occurrence. Mayo Clin Proc 1999;74:543-552. 7. Carney JA, Sheps SG, Go VL, Gordon H: The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977;296:1517-1518. 8. Chung DC, Rustgi AK: The hereditary nonpolyposis colorectal cancer syndrome: Genetics and clinical implications. Ann Intern Med 2003;138:560-570. 9. Coburn M C , Pricolo VE, DeLuca FG, Bland KI: Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 1995;2:386-391. 10. Corpron CA,Black CT, Herzog CE, et al: A half century of experience with carcinoid tumors in children. Am J Surg 1995;170:60&608.

11. Datta RV, LaQuaglia MP, Paty PB: Genetic and phenotypic correlates of colorectal cancer in young patients. N Engl J Med 2000;342:137-138. 12. DeMatteo RP, LewisJ, Leung D, et al: Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-58. 13. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-480. 14. Densmore TL, Langer JC, Molleston JP, et al: Colorectal adenocarcinoma as a second malignant neoplasm following Wilms' tumor and rhabdomyosarcoma. Med Pediatr Oncol 1996;27:556-560. 15. Devroede GJ, Taylor WF, Sauer WG, et al: Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971;285:17-21. 16. Doede T, Foss HD, WaldschmidtJ: Carcinoid tumors of the appendix in children: Epidemiology, clinical aspects and procedure. Eur J Pediatr Surg 2000;10:372-377. 17. Dokucu AI, Ozturk H, Kilinc N, et al: Primary gastric adenocarcinoma in a 2.5-year-old girl. Gastric Cancer 2002;5:237-239. 18. Eisenberg BL, Judson I: Surgery and imatinib in the management of GIST: Emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465-475. 19. El Serag HB, Bailey NR, Gilger M, Rabeneck L: Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97:1635-1639. 20. Eloubeidi MA, Desmond R, Arguedas MR, et al: Prognostic factors for the survival of patients with esophageal carcinoma in the US: The importance of tumor length and lymph node status. Cancer 2002;95:14341443. 21. Eraklls AJ, Folkman MJ: Adenocarcinoma at the site of ureterosigmoidostomies for exstrophy of the bladder. J Pediatr Surg 1978;13:730-734. 22. Fitzgibbons RJ Jr, Lynch HT, Stanislav GV, et al: Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and 11). Ann Surg 1987;206:289-295. 23. Goede AC, Caplin ME, Winslet MC: Carcinoid tlimour of the appendix. Br J Surg 2003;90:1317-1322. 24. Greenstein AJ, Sachar DB, Smith H, et al: Cancer in universal and left-sided ulcerative colitis: Factors determining risk. Gastroenterology 1979;77:290-294. 25. Greenstein AJ, Slater G, Heimann TM, et al: A comparison of multiple synchronous colorectal cancer in ulcerative colitis, familial polyposis coli, and de novo cancer. Ann Surg 1986;203:123-128. 26. Gryfe R, Kim H, Hsieh ETK, et al: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77. 27. Haider N, Kader M, McDermott M, et al: Gastric stromal tumors in children. Pediatr Blood Cancer 2004;42:186-1 89. 28. Hassall E: Co-morbidities in childhood Barrett's esophagus. J Pediatr Gastroenterol Nutr 1997;25:255-260. 29. Hassall E, Dimmick JE, Magee JF: Adenocarcinoma in childhood Barrett's esophagus: Case documentation and the need for surveillance in children. Am J Gastroenterol 1993;88:282-288. 30. Jemal A, Thomas A, Murray T, Thun M: Cancer statistics, 2002. CA Cancer J Clin 2002;52:23-47. 31. Karnak I, Ciftci AO, Senocak ME, Buyukpamukcu N: Colorectal carcinoma in children. J Pediatr Surg 1999; 34:1499-1504. 32. Kamak I, Kale G, Tanyel FC, Buyukpamukcu N: Malignant stromal tumor of the colon in an infant: Diagnostic difficulties and differential diagnosis. J Pediatr Surg 2003;38:245-247.

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33. Kerr JZ, Hicks MJ, Nuchtern JG, et al: Gastrointestinal autonomic nerve tumors in the pediatric population: A report of four cases and a review of the literature. Cancer 1999;85:220-230. 34. Kindblom LG, Remotti HE, Aldenborg F, Meis-KindblomJM: Gastrointestinal pacemaker cell tumor (GIPACT): Gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152:1259-1269. 35. LaQuaglia MP, Heller G, Filippa DA, et al: Prognostic factors and outcome in patients 21 years and under with colorectal carcinoma. J Pediatr Surg 1992;27:1085-1089. 36. Leichtner AM: Intestinal neoplasms. In Walker WA, et a1 (eds): Pediatric Gastrointestinal Disease. Philadelphia, BC Decker, 1991. 37. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 2003;348:919-932. 38. McGill TW, Downey EC, Westbrook J, et al: Gastric carcinoma in children. J Pediatr Surg 1993;28:1620-1621. 39. Miettinen M, Lasota J: Gastrointestinal stromal tumorsdefinition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1-12. 40. Moertel CL, Weiland LH, Telander RL: Carcinoid tumor of the appendix in the first two decades of life. J Pediatr Surg 1990;25:1073-1075. 41. Odone V, Chang L, Caces J, et al: The natural history of colorectal carcinoma in adolescents. Cancer 1982;49:171&1720. 42. Parkes SE, Muir KR, a1 Sheyyab M, et al: Carcinoid tumours of the appendix in children 1957-1986: Incidence, treatment and outcome. Br J Surg 1993;80:502-504. 43. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF: Gastrointestinal stromal tumors: Current diagnosis, biologic behavior, and management. Ann Surg Oncol 2000; 7:705-712. 44. Pratt CB, Rivera G, Shanks E, et al: Colorectal carcinoma in adolescents: Implications regarding etiology. Cancer 1977;40(5 Suppl) :24642472. 45. Rao BN, Pratt CB, Fleming ID, et al: Colon carcinoma in children and adolescents: A review of 30 cases. Cancer 1985;55:1322-1326. 46. Roberts PJ, Eisenberg B: Clinical presentation of gastrointestinal stromal tumors and treatment of operable disease. Eur J Cancer 2002;38(Suppl5):S37-S38.

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47. Schettini ST, Ganc A, Saba L: Esophageal carcinoma secondary to a chemical injury in a child. Pediatr Surg Int 1998;13:519-520. 48. Shamberger RC, Eraklis AJ, Kozakewich HP, Hendren WH: Fate of the distal esophageal remnant following esophageal replacement. J Pediatr Surg 1988;23:1210-1214. 49. Shiu MH, Farr GH, Papachristou DN, Hajdu SI: Myosarcomas of the stomach: Natural history, prognostic factors and management. Cancer 1982;49:177-187. 50. Skinner MA, Plumley DA, Grosfeld JL, et al: Gastrointestinal tumors in children: An analysis of 39 cases. Ann Surg Oncol 1994;1:283-289. 51. Soper RT: Gastrointestinal neoplasms. In: Ashcraft KW, Holder TM (eds): Pediatric Surgery. Philadelphia, W.B. Saunders, 1993, pp 464469. 52. Spunt SL, Pratt CB, Rao BN, et al: Childhood carcinoid tumors: The St Jude Children's Research Hospital experience. J Pediatr Surg 2000;35:1282-1286. 53. Steinberg JB, Tuggle DW, Postier RG: Adenocarcinoma of the colon in adolescents. Am J Surg 1988;156:460-462. 54. Stemper TJ, Kent TH, Summers RW: Juvenile polyposis and gastrointestinal carcinoma: A study of a kindred. Ann Intern Med 1975;83:639-646. 55. Surveillance, Epidemiology, and End Results (SEER) Program. SEER 1975-2001. SEER Stat Database. Bethesda, Md, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, 2004. 56. Symonds DA, Vickery AL: Mucinous carcinoma of the colon and rectum. Cancer 1976;37:1891-1900. 57. Trupiano JK, Stewart RE, Misick C, et al: Gastric stromal tumors: A clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive clinical behaviors. Am J Surg Pathol 2002;26:705-714. 58. Van Eeden S, Quaedvlieg PF, Taal BG, et al: Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol 2002;33:1126-1132. 59. Van Gompel JJ, Sippel RS, Warner TF, Chen H: Gastrointestinal carcinoid tumors: Factors that predict outcome. World J Surg 2004;28:387-392. 60. Volpe A, Willert J, Ihnken K, et al: Metastatic appendiceal carcinoid tumor in a child. Med Pediatr Oncol 2000; 34:218-220. 61. Weedon DD, Shorter RG, Ilstrup DM, et al: Crohn's disease and cancer. N Engl J Med 19'73;289:1099-1103.

Rhabdomyosarcoma Richard J. Andrassy

Rhabdomyosarcoma (from the Greek rhabdos, meaning "rod"; mys, "muscle"; and sarkos, "flesh") is a primary malignancy in children and adolescents that arises from embryonic mesenchyma with the potential to differentiate into skeletal muscle. Rhabdomyosarcoma (RMS) accounts for more than 50% of all soft tissue sarcomas in children and is thus the most common soft tissue sarcoma. Sarcomas in adults arise mostly in the extremities, whereas RMS in children can occur anywhere there is skeletal muscle, as well as in sites with no skeletal muscle (e.g., urinary bladder, bile ducts). RMS can arise at any site and in any tissue except bone. The most common sites are the head and neck region and the genitourinary tract, with only 20% occurring in the extremities. The original distinction of soft tissue sarcomas and bone sarcomas from epithelial and hematopoietic tumors is attributed to Virchow, who in the mid-1850s propounded a theory of "cellular pathology" that ascribed the origin of tumors to specific types of cells.99 The first case of RMS was described by Webner in 1854 in a 21-year-old patient with a tongue tumor.97 In 1946 Stoutlo"eported a series of adults with a malignant condition of the trunk and limbs. In 1954 Pack et al.79 described a group of children with RMS of the skeletal muscle. In 1958 Horn et al." proposed a classification of this tumor into four subgroups: embryonal, alveolar, botryoid, and pleomorphic. During those early years, surgery was the only therapy available, and radical excision was the standard. Survival rates were poor except in selected sites where total excision was possible by means of radical surgery, such as amputation or pelvic exenteration. Survival rates of 7% to 70% were seen, depending on site.78 In 1950 Stobbe et a1.lo5demonstrated improved outcomes in head and neck sites when radiation therapy was added after incomplete resection of RMS. In 1961 Pinkel et al." advocated adjuvant chemotherapy after complete surgical excision and postoperative radiation therapy, which was the beginning of the multimodal approach to solid tumors. Recognizing the value of this multimodal approach, as well as the relative rarity of these tumors, the leadership of three cooperative pediatric cancer research groups in the United States (the Children's Cancer Study Group and the pediatric sections of the Cancer and Leukemia

Group B and the Southwest Oncology Group), in concert with the National Cancer Institute, formed the Intergroup Rhabdomyosarcoma Study (IRS) Group in 1972 to investigate the therapy and biology of RMS and undifferentiated sarcoma in previously untreated patients younger than 21 years old. Since then, five successive clinical protocols involving almost 5000 patients have been completed: IRM (1972 to 19'78),IRSII (1978 to 1984), IRSIII (1984 to 1991), IRS-lV Pilot (for patients with advanced disease only; 1987 to 1991), and IRS-IV (1991 to 1997).*,2~"x~~,18 Based on lessons learned from these studies, IRS-V was opened in 1997 for patients with low-risk disease (i.e., with a good prognosis for survival) and expanded in 1999 to other patients. Although the trend has been toward far less mutilating surgery, the surgeon plays an important role in initial biopsy and staging, primary re-excision, appropriate wide local resection, and second-look operations. The surgeon should be an early participant in thk multimodal approach to treatment.

EPIDEMIOLOGY RMS is the third most common solid tumor in infants and children, after neuroblastoma and Wilms' tumor. There are approximately 250 to 300 new cases per year in the United States. There is a slightly greater incidence in males compared with females (3:2) and in Caucasians compared with non-Caucasians (12:5). The peak age at presentation is bimodal, with the primary peak occurring between 2 and 5 years of age and the secondary peak between 15 and 19 years. Patients with RMS appear to have a higher incidence of other congenital anomalies." Both RMS and Wilms' tumor are associated with an increased incidence of genitourinary anomalies. RMS is also linked to anomalies of the central nervous system." Patients with von Recklinghausen's neurofibromatosis have an increased risk of RMS.423101 The Li-Fraumeni familial cancer svndrome, first reported in 1969, includes soft tissue sarcomas occurring in siblings and cousins; parents and other relatives have a variety of malignancies, including RMS, adrenocortical

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carcinoma, glioblastoma, breast cancer, and lung cancer."," This svndrome is an autosomal dominant disorder and is frequently associated with a germline mutation of p53.66 Breast cancer in mothers is the major associated malignancy in families of children with soft tissue malignancy.lo7A review of the mothers of 13 children with RMS showed that their risk of breast cancer was 3 to 13.5 times greater than that of controls.13 Other somewhat weaker associations with fetal alcohol syndrome, maternal exposure to marijuana or cocaine, x-ray exposure, and employment as a health care worker have been s ~ g g e s t e d . " , ~ ~ , ~ ~ RMS has also been observed in association with Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on chromosome llp15, where the gene for insulin-like growth factor I1 (IGF-11) is located.28 The two histologic subtypes of RMS-embryonal and alveolar-have distinct genetic alterations that may play a role in the pathogenesis of these tumors. In alveolar RMS, there is a characteristic translocation between the long arm of chromosome 2 and the long arm of chromosome 13, referred to as t(2;13) (q35;q14). This translocation fuses the PAX?gene (believed to regulate transcription during early neuromuscular development) with the FKHR gene (a member of the forkhead family of transcription factors). It is believed that this fusion transcription factor may inappropriately activate the transcription of genes that contribute to a transformed phenotype. The variant t(1;13) (p36;q14) fuses the PAX7 gene located on chromosome 1 with FKHR Patients with tumors expressing the PAX-FKHR fusion tend to be younger and are more likely to present with an extremity lesion, suggesting a distinct clinical phenotype. Polymerase chain reaction assays are now available that allow confirmation of the diagnosis of alveolar RMS based on the presence of these fusion genes.28363,7',H0 Embryonal RMS is known to involve loss of heterozygosity at the l l p 1 5 locus, with loss of maternal genetic information and duplication of paternal genetic information. This is the location of the IGF-IIgene. IGF-I1 has been demonstrated to stimulate the " growth of RMS cells, whereas the blockade of this factor using monoclonal antibodies inhibits tumor growth both in vitro and in vivo.l13 Several other solid neoplasms are associated with genomic deletions on the short arm of chromosome 11, including Wilms' tumor, hepatoblastoma, and neuroblastoma. The MyoD family of genes codes for DNA binding proteins that regulatk the iranscription of DNA sequences encoding myogenic proteins such as desmin, creatine kinase, and myosin."g."' In RMS, the down-regulation of this gene does not occur, so that MyoDl expression l ~ ~biologic signifremains at high levels in tumor ~ e l 1 s .The icance of this overexpression is not clear; however, the detection of high levels of the MyoDl gene product may be used to diagnose RMS.la The c h a n"~ ein a cell's DNA content has been described in a variety of tumors and may have some prognostic significance. The DNA content of embryonal RMS tumors ranges between diploid and hyperdiplbid (1.1 to 1.8 times the normal amount of DNA). It has been reported that diploid embryonal RMS tumors may have

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a worse prognosis than hyperdiploid tumors. Near tetraploidy was associated with alveolar histology.28,53 RAS oncogene mutations have been described in RMS cell lines and tumor specimens. It is not known whether these alterations are involved in RMS tumor pathogenesis or reflect secondary abnormalities that occur during tumor progression.28 Aberrant expression of the M E 1 oncogene in embryonal and alveolar RMS tumor samples and established cell lines has been described. MET encodes the receptor for HGF/scatter factor, which is known to control cell motility and invasion in epithelial cells. It is hypothesized that the overexpression of MET may provide RMS cells with the same property as embryonal myoblasts, allowing them to migrate into surrounding connective tissues.31

PATHOLOGY FWS cells arise from undifferentiated mesodermal tissue and fall into the broader category of the small, round, blue cell tumors of childhood. The differentiation of specific tumor type is accomplished by a combination of light microscopy, immunohistochemical techniques, electron microscopy, and molecular genetic techniques. The characteristic feature that permits a tumor to be classified as RMS is the identification of a myogenic lineage. Typically, this consists of the light microscopic identification of cross-striations that are characteristic of skeletal muscle or rhabdomyoblasts.4,fl3Skeletal muscle or muscle-specific proteins can be identified by immunohistochemical staining. Histologically, RMS is classified as a small, round, blue cell tumor of childhood, a category that also includes neuroblastoma, Ewing's sarcoma, small cell osteogenic sarcoma, non-Hodgkin's lymphoma, and leukemia. Each of the two major subtypes of RMS has a characteristic histologic appearance. Embryonal RMS is the most common histologic subtype, constituting more than 30% of all newly diagnosed tumors. This embryonal subtype, particularly the botryoid and spindle cell variants, was thought to have a much better prognosis, but there is now controversy whether the histologic subtype or the site of the tumor is the strongest indicator of prognosis. Botryoid RMS, described as a "cluster of grapes," is seen in cavitary structures and has a good prognosis. The spindle cell variants arise disproportionately in the paratesticular region but may also be seen in the head and neck, ~ ~ , ~ )subtypes especially the orbit, and the e ~ t r e m i t i e s . These are almost always associated with limited disease, behave less aggressively than the classic embryonal tumors, and have an extremely good prognosis; however, both types account for only 5% to 6% of all MS.") The pathologic description of RMS as a tumor of myogenic lineage was first advanced in 1958 by Horn et aL50 These investigators proposed the first c1,assificationscheme that divided RMS into four different pathologic types (embryonal, botryoid, alveolar, and pleomorphic). This system has been used for decades and was modified into a "universal" system by an international group of pediatric pathologists in 1994. This system ascribes prognostic significance to each histologic subtype by classifying

526

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CLINICAL PRESENTATION

I. Favorable prognosis a. Botryoid b. Spindle cell II. Intermediate prognosis a. Embryonal b. Pleomorphic (rare) Ill. Poor prognosis a. Alveolar (including solid variant) b. Undifferentiated From Asmar L, et at: Agreement among and within groups of pathologistsin the classification of rhabdomyosarcoma and related childhood sarcomas: Report of an internationalstudy of four pathology classifications.Cancer 1994;74:2579.

them into groups with favorable, intermediate, and poor prognoses (Table 32-1) . l The alveolar variant accounts for approximately 20% of tumors and frequently arises in the extremities, trunk, or perineum; these tumors have an unfavorable prognosis." The alveolar variant is characterized by a prominent alveolar arrangement of stroma and dense, small, round tumor cells resembling those of lung tissue. A subtype is the "solid" alveolar RMS, characterized by an architecture of dense cellular sheets lacking any intercellular stroma but with cytologic features identical to those found in the classic alveolar tumors. Undifferentiated sarcoma is a poorly defined category of sarcomatous tumor whose cells show no evidence of myogenesis or other differentiation.75.76 The distribution of histologic subtypes is shown in Table 32-2. A number of monoclonal antibodies have been shown to react with elements of RMS and have been useful in its diagnosis. These include antibodies to desmin, musclespecific actin, sarcomeric actin, and myoglobin. All have been used to confirm the myogenic lineage of cells and, when used in combination, have very good specificity and sensitivity."' MyoDl was mentioned earlier; other nonmyogenic protein products that can be identified in these tumors include cytokeratin, neuron-specific enolase, S-100 protein, and Leu-7.

Histologic Type Embryonal Alveolar Undetermined Undifferentiated Botryoid Extraosseous Ewing's

Percentage

--

53 19 18 7 5 3

From Newton WA, et al: Pathology of rhabdomyosarcoma and relatedtumors. In Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcomaand Related Tumors in Children and Adolescents. Boca Raton, Fla, CRC Press, 1991.

The clinical presentation of RMS depends on the site of origin of
CHAPTER

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527

DIAGNOSIS The diagnosis of RMS is usually made by direct open biopsy. There are no helpful markers or specific imaging studies. The pathologist is expected to identify the histologic subgroups of RMS to allow adequate staging and to direct therapy. For this purpose, several grams of tissue are needed. Biopsies of genitourinary RMS are frequently performed using the endoscope. Needle biopsies that are performed to establish the diagnosis of prostatic RMS are difficult to interpret and must include several cores. Trunk and extremity RMS should have excisional or incisional biopsy, with the incision placed so that it will not interfere with the incision required for subsequent wide local excision. This usually means an axial incision in extremities. Wide local excision with clear margins is the ultimate goal. Regional lymph nodes are evaluated, depending on the location of the primary tumor. Trunk and extremity lesions have a high incidence of lymph node involvement, and sentinel lymph node mapping is advi~ed.~~,74 Patients with RMS require a complete workup before definitive surgery. The preoperative evaluation includes imaging, blood work, and bone marrow evaluation. The complete preoperative or pretreatment evaluation is outlined in Table 32-3. The most important part of the diagnostic process is obtaining adequate tissue for histologic and cytologic diagnosis and classification. This procedure is generally accomplished by open incisional biopsy under general anesthesia.

Staging and Clinical Grouping Pretreatment staging for RMS is performed to stratify the extent of the disease for the purpose of determining

Stage -

Sites

I

Orbit Head and neck (excluding parameningeal) Bladder-nonprostate Bladder-prostate Extremity Cranial parameningeal Other (includes truncal, retroperitoneal, perineal, biliary, intrathoracic) Bladder-prostate Extremity Cranial parameningeal Other (as in stage II) All

II

111

Iv

-,

History and physical examination (height, weight) Measurement of lesion (physical or imaging) Complete blood count, differential, platelets Urinalysis Electrolytes, creatinine, calcium, phosphorus Alkaline phosphatase, lactate dehydrogenase, bilirubin, serum glutamic-pyruvic transaminase Bone marrow biopsy or aspirate Chest radiograph Magnetic resonance imaging (MRI) or computed tomography (CT) of primary tumor CT of chest MRI or CT of head (for head tumors) Bone scan Cerebrospinal fluid cytology (for parameningeal tumors) Electrocardiogram or echocardiogram (selective)

the appropriate treatment regimen as well as to compare outcome. This classification is a modification of the TNM staging system and is based on primary tumor site, primary tumor size, clinical regional node status, and distant metastatic spread (Table 32-4) .58,74 Pretreatment size is determined by external measurement or by magnetic resonance imaging or computed tomography (CT), depending on the anatomic location. The staging is "clinical" and should be done by the responsible surgeon based on preoperative imaging and physical findings. Intraoperative or pathologic results do not affect the stage but do affect the clinical group. The IRS clinical grouping system is based on the pretreatment and operative outcome (Table 32-5). Its basic premise is that total tumor extirpation at the original site is the best hope for cure, and it stratifies patients

Tumor

Size

Nodes

TI or T2

a or b

No or N,

Mo

TI or T2

a

No or N,

Mo

TI or T2

a b

N1 NO. N,I N,

Mo

a or b

NO.NI, Nx

MI

il or T,

Metastasis

Tumor: T,, confined to anatomic site of origin: (a) 5 cm diameter in size, (b) >5 cm diameter in size; T, extension and/or fixation to surroundingtissue: (a) 5 cm diameter in size, (b) > 5 cm diameter in size. Regional nodes: No,regional nodes not clinically involved; N,, regional nodes clinically involved by neoplasm; N,, clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation). Metastasis: M, no distant metastasis; M,, metastasis present.

528

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Group I: Localized disease, completely resected. (Regional nodes not involved-lymph node biopsy or sampling is highly advised [9602] or required [9803, 98021, except for head and neck lesions.) (a) Confined to muscle or organ of origin. (b) Contiguous involvement-infiltration outside the muscle or organ of origin, such as through fascia1 planes. Note: This includes both gross inspection and microscopic confirmation of complete resection. Any nodes that may be inadvertently taken with the specimen must be negative. If the latter are involved microscopically, the patient is placed in group Ilb or Ilc. Group II: Total gross resection with evidence of regional spread. (a) Grossly resected tumor with microscopic residual disease (surgeon believes that all the tumor has been removed, but the pathologist finds tumor at the margin, and additional resection to achieve a clean margin is not feasible [9602] or reasonable [9803, 98021). No evidence of gross residual tumor. No evidence of regional node involvement. Once radiotherapy and chemotherapy have been started, re-exploration and removal of the area of microscopic residual do not change the patient's group. (b) Regional disease with involved nodes, completely resected with microscopic residual. Note: Complete resection with microscopic confirmation of no residual disease makes this different from groups Ila and Ilc. Additionally, in contrast to group Ila, regional nodes (which are completely resected) are involved, but the most distal node is histologically negative. (c) Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual or histologic involvement of the most distal regional node (from the primary site) in the dissection. Note [9602 only]: The presence of microscopic residual disease makes this group different from group Ilb, and nodal involvement makes this group different from group Ila. Group Ill: Incomplete resection with gross residual disease. (a) After biopsy only. (b) After gross or major resection of the primary tumor (>50%). Group IV: Distant metastatic disease present at onset (lung, liver, bone, bone marrow, brain, distant muscle and nodes). Note (9602 only]: The above excludes regional lymph nodes and adjacent organ infiltration, which places the patient in a more favorable grouping (see group 11). The presence of positive cytology in cerebrospinal fluid or pleural or abdominal fluids or implants on pleural or peritoneal surfaces or in the omentum are regarded as indications for placement in group IV.

i Numbers in brackets are the specific study number underthe IRS protocols.

according to tumor resectability. This has led, in the past, to aggressive and often mutilating procedures. This system does not take into account the biologic nature or natural history of the tumor, nor does it account for the experience and the aggressiveness of the operating surgeon. With the more frequent use of biopsy and neoadjuvant chemotherapy, there has been a "shift" from group I or I1 to group 111, with biopsy followed by neoadjuvant therapy. Group assignment is based on intraoperative findings and postoperative pathologic status and includes final pathologic verification of margins, residual tumor, node involvement, and cytologic examination of pleural and peritoneal fluid, when applicable. Both clinical grouping and pretreatment staging have been shown to correlate with outcome.4.27.74 Based on the findings from IRS-I through -IV, risk groups have been established for treatment in IRSV, which combines group, stage, and histology subtype to allocate patients to three different therapeutic protocols according to risk of recurrence (Table 32-6). Low-risk patients have an estimated %year failure-free survival (FFS) rate of 88%; intermediate-risk patients have an estimated %year FFS rate of 55% to ?6%, and high-risk patients have a 3-year FFS rate of less than 30%. Multidisciplinary treatment is recommended, as defined by histologic subtype, primary site, extent of disease at diagnosis, and response to treatment. The goal is to achieve local control with preservation of form and function."'

TREATMENT The approach to the treatment of RMS has been multimodal for more than 30 years. The advances in understanding the biology and treatment of this disease can

Risk Group Stage Clinical Group, Node Status, Site Low

I

Intermediate

I I II 111 IV

High

I, II; No; all favorable sites (orbit, head and neck, nonparameningeal, genitourinary, nonbladder-prostate) Ill; No, N,; orbit only I; No, N,; all other (unfavorable) sites; tumor =5 cm in widest diameter II; N;, all favorable sites (see above) Ill; No, N, N,; all favorable sites except orbit 11, Ill; No, N, N;, all other sites 11, Ill; No, N, N,; all other sites IV; No, N, N,; any site with metastatic disease, including tumor cells in cerebrospinal, pleural, or peritoneal fluid or omental implants

LI -

.-

No,regional nodes not clinically involved; N,, regional nodes clinically involved by neoplasm; N, clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation).

CHAPTER

32

Rhabdomyosarcoma

529

demonstrated the benefits of PRE. In IRS-I and IRS-11, largely be attributed to the IRS (I-V). The surgical treat154 patients with extremity or trunk RMS were initially ment for RMS has become progressively less mutilating placed in clinical group IIa; then 41 patients underwent or surgically aggressive while maintaining the excellent successful PRE and were converted to clinical group I survival statistics of earlier studies. before the onset of adjuvant therapy. These patients were The surgical treatment of RMS is site specific and is compared with 113 patients who had microscopic residual discussed later by individual site. The general principles disease and did not undergo PRE and with 73 patients include complete wide excision of the primary tumor who were free of disease after the initial resection (cliniand surrounding uninvolved margins while preserving cal group I). Among the 41 PRE patients, the 3-year cosmesis and function. Kaplan-Meier survival estimate was 91%, compared with The initial biopsy is generally incisional except in small 74% for group IIa patients not undergoing PRE and 74% lesions, where excisional biopsy is possible. Some lesions for group I patients. This approach may be applicable to have a pseudocapsule that may allow the lesion to be tumors in other locations as well. PRE should be considshelled out, giving the surgeon the false notion that he or ered, even if the margins are apparently normal, if the she has removed the entire lesion. Many sites have gross or initial resection was not a "cancer" operation (i.e., maligmicroscopic residual tumor, and pretreatment re-excision is warranted if this can be done without m ~ t i l a t i o n . ~ ~ nancy was not suspected at the initial excision) ,21349 Biopsy of any lesion may involve reoperation and wide Second-look operations have been used for several excision. Longitudinal incisions are frequently better pediatric tumors to evaluate therapeutic response and to remove any residual tumor after completing initial therthan horizontal incisions on areas such as an extremity. A biopsy to confirm malignancy requires that the biopsy apy. The use of second-look operations was evaluated in IRS-I11 and shown to be beneficial in clinical group I1 tract be excised at the time of reoperation; if the biopsy RMS patient~.l~.~,l~7-llg The performance of a second-look site is inappropriately placed, this excision may require operation changed the response status in a significant much larger incisions or resections than necessary. number of patients; 12% of presumed complete-response Solid tumor biopsies are traditionally divided into patients were found to harbor residual tumor, and 74% excisional biopsies, in which the entire tumor is included of both partial- and no-response patients were recategoin the specimen, and incisional biopsies, in which only a rized as complete responders after operation. The surportion of the tumor is included. In an excisional biopsy, vival rate of these recategorized patients was similar to margins should be carefully marked to allow re-resection that of patients confirmed to be complete responders at should the biopsy reveal a positive margin on review. re-exploration.117,1 Ideally, excisional biopsies are planned to allow resections The general surgical principles learned from IRS-I that will leave behind only negative margins. If such an through -IV and thus considered in IRS-V include the excisional biopsy would result in too large a resection, following: (1) Patients with localized, completely resected incisional biopsy is more appropriate. disease (group I) generally have the best prognosis for If biopsy margins are not carefully marked on both 5-year FFS and overall survival. Patients with metastases the specimen and the operative field (usually by sutures at diagnosis (group IV) have the worst outlook, and or clips), the surgeon's ability to subsequently obtain negthose with group I1 and I11 disease have an intermediate ative margins is severely compromised. For example, an prognosis. Thus, it is preferable to try to remove all visible inappropriate approach to biopsy may lead to further tumor, if doing so is feasible without excessive morbidity. difficulties in the case of testicular masses. Any testicular (2) When a lesion has been resected, primary re-resecmass should be approached through an inguinal rather tion is indicated if the primary operation was not a cancer than a scrotal incision so that proximal control of the cord operation for malignancy. Any question about margin can be obtained and a wide local excision performed status warrants re-resection. Group I (totally resected) without seeding the scrotum with tumor. The proximal patients with embryonal RMS are not subjected to postspermatic cord should be examined for free margins. operative radiation therapy.l2"3) It is desirable to preserve Higher excision may be necessary if tumor is still present. organ function and thus spare such structures as the eye, Biopsy of the tumor through the scrotum may lead vagina, and bladder. Also, patients with tumor at or near to further scrotal resection and increased risk of local these sites have a good prognosis. Primary chemotherapy recurrence. followed by radiation therapy is the recommended Secondary excision after initial biopsy and neoadjuvant approach. Delayed excision of initially unresected tumor therapy has a better outcome than does partial or incommay improve the prognosis by changing a partial plete excision. There has been a shift of patients into response into a complete response after initial shrinkage clinical group 111, but chemotherapy followed by delayed of the tumor by chemotherapy, with or without radiation or second-look surgery allows a better prognosis with less therapy.l17 (4) There is a relationship between age at mutilating surgery. Biopsy of regional nodes, or sentinel diagnosis and likelihood of regional lymph node involvelymph node mapping, is warranted in selected sites, such ment in boys with nonmetastatic paratesticular RMS. as the extremity. Event-free survival in IRS-IV was better for boys younger In some patients with extremity or trunk RMS, initial than 10 years because the nodal relapse rate was lower tumor resection is thought to be complete, but histopathothan in those aged 10 years and older. We now recomlogic review reveals microscopic residual disease corremend performing a modified ipsilateral retroperitoneal sponding to clinical group IIa in the surgical margins. In lymph node dissection in older boys who have no clinical many of these patients, primary re-excision (PRE) is possible, achieving wider disease-free margins. Hays et a1.43 evidence of regional node involvement. If the nodes are

530

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MAIORTUMORS OF CHII.DHOOD

uninvolved, cyclophosphamide and radiation therapy VAC has been the gold standard for combination are withheld; if tumor is present in the nodes, cyclophoschemotherapy in the treatment of most cases of RMS. phamide and radiation therapy are given, in addition to consecutive-large " randomized trials have led to modifications of this combination tailored to specific subgroups vincristine and actinomycin D.120.121 Other considerations for IRS-V include a more aggresbased on clinical group and site of disease. In patients sive approach to evaluating lymph nodes. In the earlier with clinical group I embryonal tumors, results of IRSIII studies,g"57 lymph node involvement was thought to be showed equivalent survival for patients treated with VA rare at most sites, because the nodes were rarely evaluated. only versus VAC.2.5In IRS-IV, patients with clinical group I paratesticular or orbital disease were treated with VA More recent studies suggest that the incidence of involved alone for 2 years. In an IRSV pilot study, VA chemotherapy lymph nodes in patients with primary tumors of the alone was given to patients with "low-risk" disease, includextremity may be higher than initially s u ~ p e c t e d . ~ ~ Sentinel lymph node mapping, using a vital dye such as ing those with stage I, clinical group I or I1 (No)orbital, Lymphazurin blue along with radiolabeled technetium head and neck (nonparameningeal), or genitourinary sulfur colloid, can localize the regional node most likely tract (nonbladder-prostate) disease; those with stage " 11, clinical group I disease; and those with stage I, clinical to contain tumor ~ells.~"he surgeon removes the indicated sentinel node, and the pathologist can thoroughly group I11 (orbit only No) disea~e.2~3~2 When evidence of the efficacy of eto~osideand ifosinvestigate the presence or absence of tumor in that famide for RA4S was recognized,71 this was incorporated node. The sentinel node reflects the status of the nodal into a randomized treatment protocol in IRS-IV. basin. If the node is positive, the nodal basin is irradiated. Randomization of VAC versus VAI versus VIE was The utility of sentinel lymph node mapping is being evaldone for nonmetastatic RMS. Data from IRS-IV indicate uated in IRS-V. that the current standard combination of VAC, with For patients whose tumors are initially deemed unresectable, a second-look procedure should be considered cyclophosphamide at 2.2 g/m2 per dose with granulocyte after initial chemotherapy. Imaging studies have not been colony-stimulating factor, is equally efficacious with consistently reliable in determining the actual response regard to FFS and overall survival, as are VAI and VIE.'" Therapy for patients with intermediate-risk disease to treatment. In IRS-111, 75% of children with group I11 tumors and evidence of partial or no response on imagmay be improved by the introduction of new agents. ing studies either had a pathologically complete response Dose intensification using" known active chemotherapeutic agents should also be considered. Preliminary or were converted to such a response by resection of all remaining tumor. Most (but not all) patients who IRS-IV results have shown an improvement in FFS for intermediate-risk embryonal RMs, probably related showed a complete response on imaging studies were to an increased cyclophosphamide dose.2 Escalation confirmed as having such a response by secondary surgery. of cyclophosphamide from 0.9 g/m' in IRS-111 to Survival was better in those patients who converted to a 2.2 g/m2 in IRS-IV improved the FFS of patients with complete response. Secondary surgery is less beneficial embryonal RMS but not those with alveolar RMS or in children with stage IV disease. Second-look surgery is least useful for tumors in the head and neck but is approundifferentiated RMS.2 Data from IRS-I, IRS-11, and IRS-I11 in 1431 patients priate for tumors in the trunk and limbs. The trend indicate that there is no benefit to adding doxorubicin to toward improved survival in patients converted to a VAC in patients with group 111 and group IV disease, complete response by means of second-look operations has been enduring.~~7~**8 whether analyzed together or within group I11 and group N categories individually.25."%7o,Y'LThe addition of doxorubicin and cisplatin with or without etoposide to the VAC regimen did not improve the outcome for CHEMOTHERAPY patients with advanced disease in IRS-III.2"6"7() Before multimodal therapy, surgery alone for RMS resulted Patients with metastatic disease have a poor prognosis . .. despite aggressive therapy. Intensive, multiagent combiin survival rates of less than 20%. Local micrometastatic disease, nodal disease, or unrecognized or untreated disnations have been used in an attempt to improve survival. tant disease frequently led to early recurrence and subseThe International Society of Pediatric Oncology (SIOP) quent death mainly due to advanced metastatic disease. reported a 53% response rate to a combination of carboplatin, epirubicin, &d vincristine in previously untreated The development of adjuvant and later neoadjuvant patients with metastatic RMS.3" chemotherapy has led to a marked increase in survival. The use of methotrexate in front-line treatment regiThe IRS Group studies have shown progressively better mens offers the potential advantages of relative lack of survival rates with less mutilating surgery and less chemotoxici~y.24.2~.569,70083 additive myelosuppression and a different mechanism of Agents with known activity in the treatment of RMS action. In a phase I1 trial, Pappo et a1.81reported a 33% response rate to high-dose methotrexate.in patients with include vincristine (V), actinomycin D (A), doxorubicin, cyclophosphamide (C), ifosfamide (I), and etoposide (E). previously untreated, advanced-stage RMS. Melphalan and cisplatin were evaluated for their potenTopotecan, a campotothecin analogue that acts as an tial role in patients with locally extensive or metastatic disinhibitor of topoisomerase I, is being examined for its ease and did not improve outcome compared with other potential role in RMS (inhibition of topoisomerase I options in the randomized trials involving patients with inhibits DNA repletion). The IRS Group reported a 45% clinical group I11 or IV disease.2jJo0 response rate to topotecan used in a window setting in -

-

CHAPTER

newly diagnosed patients with nonparameningeal metastatic RMS.8'J11An IRSV pilot for metastatic RMS is currently evaluating topotecan in combination with cyclophosphamide in an up-front window before VAC and radiation therapy. It appears to be active in newly diagnosed patients with metastatic RMS and can be given in combination with VAC.$z Autologous bone marrow transplantation has been used in several of the childhood solid tumors. To date, it has not been of value in patients with metastatic RMS.51,54 In summary, the recommendations for IRS-V, which is presently ongoing, are as follows: Low-risk patients are those with localized embryonal RMS in favorable sites (stage I) or in unfavorable sites (stages I1 and 111) that has been grossly removed. Those with the best prognosis are placed in subgroup A and receive VA with or without radiation therapy. The others, placed in subgroup B, receive VAC with or without radiation therapy. Intermediate-risk patients are those with localized alveolar RMS or undifferentiated sarcoma (stages I to 111) or embryonal RMS (stages I1 and 111) with gross residual disease (group 111) or embryonal RMS with metastases (group IV) younger than 10 years at diagnosis. They are randomized to receive VAC or VAC alternating with vincristine and cyclophosphamide plus topotecan, along with radiation therapy. High-risk patients have embryonal RMS diagnosed at 10 years of age or older, or alveolar RMS or undifferentiated sarcoma at any age younger than 21 years, with metastases at diagnosis (group IV). They receive a trial of irinotecan34 over 6 weeks, followed by VAC. Irinotecan is continued at intervals for those who responded to it initially but is omitted for nonresponders. High-risk patients with cranial parameningeal tumors and meningeal impingement at diagnosis receive VAC without irinotecan.

RADIOTHERAPY Radiotherapy is tailored for specific sites and is based on extent of disease. In some sites, such as the head and neck or pelvis, tumors often cannot be completely removed surgically. Radiation therapy may be used in conjunction with chemotherapy to eradicate residual tumor cells. The guidelines for radiation doses have changed over successive IRS Group studies. The dosage is now tailored to the amount of residual disease (gross or microscopic) and the tumor response. In IRS-IV, radiation therapy was defined by clinical group. Patients with completely resected clinical group I, TNM stage I and I1 tumors received no radiotherapy. Patients with completely resected group I, stage I1 tumors and those with group I1 tumors received conventional external beam radiation to a total dose of 4140 cGv. Clinical group I11 patients were randomized to receive 5040 cGy external beam radiation or hyperfractionated radiotherapy to a dose of 5940 cGy. Based on IRS-IV, there is no indication that giving hyperfractionated radiotherapy with 59.4 Gy in two daily fractions of 1.1 Gy, with

32

Rhabdomyosarcoma

531

a 6-hour interfractional interval, results in a better localregional control rate among children with group I11 tumors than that obtained with 50.4 Gy in 1.8 fractions daily.29230 There is no evidence of a benefit in giving radiation to patients with completely resected, locailesi<ns (group I), provided the histologic subtype is embryonal RMS.lZ3 Graded doses of irradiation are appropriate for all other patients, based on the patient's group at the time of studv entry. Volumes to be irradiated include the wretreatment primary tumor and the regional lymph node area, if involved. Patients with group - IV disease receive radiation therapy to both the primary site and the sites of metastases, within the limits of bone marrow tolerance. An analysis of patients with group I1 disease in IRS-I through -IV showed improved outcome in IRS-I11 and -IV, ~ e r h a i due s to intensi6ed thera~v.I0" Local failure rates for patients with group I11 disease in IRS-I11 and -IV were reviewed in 2000 by the IRS Statistical Office. The rates have remained'stable or improved. In IRS-IV, local failure rates were 2% in orbit primary sites, 16% in cranial parameningeal sites, and 12% in other head or neck sites. Local failure rates were 7% in extremity sites, 19% in genitourinary sites, and 14% in other sites. Current IRS Group results suggest that most patients with cranial parameningeal sarcoma, including those with localized intracranial extension contiguous with the primary tumor at diagnosis, can be successfully managed with systemic chemotherapy and radiation therapy. Radiation therapy is directed to the primary tumor, including any extension, along with a 2-cm margin, including the adjacent meninges. Whole-brain irradiation and intrathecal anticancer agents are not necessary in the absence of diffuse meningeal involvement, such as multiple intracranial metastase~.~~~~~ A summary of the recommendations for radiation therapy in IRS-V include the following: Patients with completely excised embryonal RMS (group I) receive no radiation therapy. However, patients with completely excised (group I) alveolar RMS and undifferentiated sarcoma receive radiation therapy to the primary site.lZ3 Other patients receive radiation therapy as a function of group, histologic subtype, and status of regional lymph nodes or distant metastases. Patients with metastases receive radiation therapy to the primary tumor and to sites of metastases within the limits of bone marrow tolerance.92 x ,

MANAGEMENT BY SITE Head and Neck Head and neck lesions include superficial head and neck, orbit, parotid, buccal, laryngeal, and oropharyngeal locations. The multidisciplinary approach to therapy has allowed less aggressive surgical procedures while maintaining an excellent prognosis at this site. Wide excision is appropriate when feasible, but the possibility of achieving wide margins is restricted to small superficial lesions.47

532

PART

III

MATOR TUMORS OF CHILDHOOD

Tumors of the orbit have an excellent response to ~~~~~l~ residual mass effect on imaging s t u d i e ~ . l ~ "Other therapy because the tumor is usually confined to the bony studies suggested a good correlation between evidence orbit and there is a paucity of lymphatics. Abramson et al.1 of stable residual disease on CT and subsequent local demonstrated that radiation therapy plus chemotherapy relapse and death." This is being investigated further. is the most effective treatment for orbital RMS; this type of therapy ended the need for orbital exenteration. Survival of more than 90% of patients is standard with VA Genitourinary Sites chemotherapy and radiation therapy.25~32J14Metastatic The genitourinary sites include the bladder, prostate, spread to regional nodes is seen in less than 3% of patients? Cervical lymph node biopsy or sentinel lymph paratesticular areas, vagina, uterus, vulva, and, rarely, kidnode mapping does not appear to be warranted unless neys or ureter. RMS is the most common malignancy of nodes are clinically involved. Patients with nodal involvethe pelvic structures in children. Tumors in these locations ment should be treated with the IRS intermediateare considered in two different categories on account of risk protocol. Thus, except for small lid lesions, the role their different prognoses: bladder-prostate versus vulvoof surgery for orbital primary tumors is limited to biopsy vagina, uterus, and paratesticular. These sites accounted a10ne."'~.~2Jl~J~~Orbital exenteration has been used selecfor approximately 25% of cases in IRS-III.2Vn 6% of tively in recurrent disease. those patients with pelvic tumors in IRS-I and -11, the exact site of origin within the pelvis could not be defined. Nonorbital, nonparameningeal sites include superficial and deep tumors that do not impinge on the meninges. Tumors in the vagina and testicular areas have a good For some tumors, such as parotid, laryngeal, oropharynprognosis and are more commonly of embryonal histolgeal, and other deep tumors, surgery is limited to biopsy ogy, often with the botryoid (vaginal) or spindle cell followed by chemotherapy and radiation therapy for (paratesticular) variant. treatment regimen has led to tumor eradication.l1"his Bladder RMS and prostate RMS can be difficult to dissurvival rates of 83%.3,38 tinguish from each other because of their anatomic proxThe need for alkylating agents in orbital and nonorimity and the tumor's tendency to grow to a large size bital head and neck sites has been q ~ e s t i o n e d . ~ ~ " ~ l l ~ ~before l l 6 diagnosis. When this determination is possible, In IRS-111, patients with orbital and nonparameningeal however, it is evident that patients with bladder tumors head and neck tumors who received intensive VA have a better prognosis than those with tumors arising chemotherapy and radiation therapy had the same rate from the prostate.l15 The majority of tumors in these of survival (90%) as did patients in IRS-I1 who received areas are embryonal (71%) or botryoid (20%);2% are of those therapies in conjunction with alkylating agent~.2~,25 alveolar histology.75 The present recommendation for this low-risk group is In IRS-I11 it was found that children with tumors of the to receive VA with or without radiation therapy.27 bladder or prostate who received more intensive Parameningeal tumors are associated with a poor chemotherapy and earlier radiation therapy had a survival prognosis because of the propensity for extension and rate only slightly lower than that of patients with head the presence of abundant lymphatics.3~*0,5fi."6In addition, and neck tumors. This finding contrasts with that of IRS-II.24,25,699,0,87 parameningeal RMS often occurs in hidden sites, which frequently results in delayed diagnosis.32Jl4Jl6 Fifteen Bladder or prostate tumors commonly arise near the percent of patients with parameningeal RMS present area of the trigone and produce symptoms of bladder with metastatic disease.25 Bone erosion is a predictor outlet obstruction or hematuria. Diagnosis is usually made of local relapse." More intensive treatment of paraby cystoscopic evaluation and biopsy, as well as CT or magmeningeal RMS, including VAC chemotherapy, intrathecal netic resonance imaging. Previously, the initial managechemotherapy, and radiation therapy to the entire cranial ment of these tumors in children was usually anterior or neuraxis, has resulted in increased survival.86In patients total pelvic exenteration, followed by chemotherapy and receiving this intensified therapy, the tumor-freesurvival radiation; this treatment produced very good long-term rate increased from 33% to 57%, and the failure rate survival rates, approaching 85% in some series, but it also for local tumor control fell from 28% to 6%.86 The value necessitated a permanent urinary conduit and, in some of prophylactic radiation therapy to the central nervous cases, colostomy.87,90 Today, bladder salvage is an impor~ ~IRS-111, radiation system has been q u e ~ t i o n e d .In tant goal, and less aggressive surgical procedures are therapy and intrathecal chemotherapy were based on c ~ m m o n . Neoadjuvant ~ ~ ~ , ~ ~ chemotherapy and radiathe degree of meningeal involvement, and most patients tion have decreased the rate of exenterative cystectomy received less radiation therapy than that used in from greater than 50% to approximately 30%.44-4"n IRS-11. There was no decrease in progression-free survival IRSIII 50% of patients with bladder RMS received cisplatin among patients in IRS-I11 compared with those in in addition to vincristine-doxorubicin (Adriamycin)IRS-11.24.25 cyclophosphamide or VAC and irradiation. Of 171 children Craniofacial resection for anterior skull-based tumors with primary bladder lesions enrolled in IRSI through -111, of the nasal areas, paranasal sinuses, temporal fossa, and 40 underwent partial cystectomy after receiving neoadjuother such sites should be reserved for surgical teams vant chemotherapy and radiation. Relapse occurred in with expertise in its performance and for secondary pronine patients (seven locally). The Kaplan-Meier estimate cedures when tumor persists after initial chemotherapy of survival rate with a functioning bladder among all and radiation therapy. In some reports, no viable tumor children with bladder or prostate tumors in IRS-I11 was could be found in the resected specimens, despite a 60%. Long-term survival was in excess of 80%.44-46

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Rhabdomyosarcoma

533

Exenteration is no longer the primary treatment for testes and the entire cord, including the atraumatic clamp, RMS of the prostate. This site accounted for about 5% of together; (6) thoroughly irrigate the field. Patients with newly diagnosed cases in IRS-111. The mean age at the time spillage are considered clinical group IIa regardless of of diagnosis was 5.3 years. Most tumors were relatively the completeness of r e s e ~ t i o n . ~ ~ large, had embryonal histology, and were clinically localThe incidence of nodal metastatic disease for paratesized but unresectable without major loss of organ functicular RMS has been reported to be as high as 26% to tion. The 44 patients with group I11 tumors (gross residual 43%.37,77,86,120 During IRS-111, all patients were required disease) were treated according to the IRS-I11 protocol. to undergo ipsilateral retroperitoneal lymph node dissecForty-three of them underwent biopsy only, and one tion. During IRSIV, the retroperitoneal lymph nodes were evaluated with CT. In this study, only those patients with patient had subtotal resection as the initial procedure. The average number of surgical procedures per patient lymph node involvement on CT required surgical evaluation of the lymph nodes. This led to the "down-grouping" was two (range, one to five). Six of the 44 patients had no additional surgery. The second-look procedures performed of about 15% of patients from group I1 (lymph nodes positive) to group I (total resection, no nodal disease). in the other 38 patients included exenteration,14 prostatectomy,4 cystoscopic or perineal needle biopsy? lapaThis effect was higher in adolescents (>30%).This change rotomy with biopsy,6 and subtotal excision with bladder led to fewer patients receiving radiation to the retroperisalvage.%dditional surgery was required for four patients toneum, but also a poorer FFS in IRS-IV and a higher for evaluation of residual mass, postoperative fistula, relapse rate. For patients younger than 10 years, long-term ureteral stricture, or small bowel obstruction. Six patients survival rate did not differ between IRS-I11 and -IV and was excellent (IRS-111, 100%; IRS-IV, 98%). However, with relapse or residual disease underwent additional or treatment in about 30% of adolescents assigned to group I chemotherapy and late exenteration,~rostate~tomy,~ biopsy.? Four of the six were cured, one received treattumor status in IRS-IV failed; those patients required ment for a second malignancy, and the other had residual retreatment, with poor salvage. In IRS-IV, among disease after exenteration. Thus, 36 of the 44 patients patients given retroperitoneal lymph node radiation with group I11 tumors were cured (minimum follow-up, and intensive three-agent chemotherapy, including alky6 years; range, 6 to 11 years), compared with 23 of lating agents, survival at 3 years was 100%. Based on 47 patients in IRS-11. The bladder salvage rate for those these data, the IRS Group resumed recommending cured of their disease was also better (64% versus 57%). retroperitoneal lymph node dissection for all patients Conservative, delayed surgery, performed after intensive older than 10 years. chemotherapy with or without radiotherapy, yields a better This remains controversial, because SIOP no longer recommends retroperitoneal lymph node dissection for cure rate while maintaining a high rate of bladder salvage any patients. Olive et al.77found that chemotherapy was in children with group I11 prostatic RMS.65 effective in eradicating occult micrometastases; thus, they concluded that lymph node dissection was not necessary in completely resected paratesticular RMS treated with Paratesticular Sites multiagent chemotherapy. Paratesticular RMS represents 7% of all childhood RMS Retroperitoneal lymph node dissection is associated and 12% of childhood scrotal tum0rs.l2~Most paratesticuwith significant long-term complications. Heyn et al.48 lar RMS is embryonal, nonmetastatic, and highly curable found it to be associated with intestinal obstruction, loss with multimodal therapy including surgery, multiagent of ejaculatory function, and lower extremity lymphedema. chemotherapy, and, for patients with retroperitoneal There are risks associated with using the more intensive lymph node involvement or incompletely resected disease, chemotherapy protocol as well. Cyclophosphamide is an radiation therapy.80 N-phosphorylated cyclic derivative of nitrogen mustard. Most tumors present as a painless scrotal mass and are Side effects of cyclophosphamide include immunooften easily resected (group I). Survival rates exceed 90% suppression, pulmonary fibrosis, sterility, and testicular for group I and I1 patients.6o," Lesions adjacent to the atrophy in men."' Present recommendations are that all patients with testis or spermatic cord should be removed by orchiectomy and resection of the entire spermatic cord through paratesticular RMS should have thin-cut abdominal and an inguinal incision with proximal control of the sperpelvic CT scans with double contrast to evaluate for evimatic cord. The contralateral testis may be transposed to dence of nodal involvement. Patients aged 10 years and the adjacent thigh, temporarily, when scrotal radiotherapy older receive ipsilateral retroperitoneal nerve-sparing is required. Open scrotal biopsy or tumor spillage should template node dissection. Patients with group I1 disease receive intensified treatment (e.g.,VAC and retroperitoneal be avoided, because inguinal recurrence may follow; lymph node radiation).lQisease in children younger spillage or open biopsy requires scrotectomy with or withthan 10 years can be staged with abdominal thin-cut (5-mm out radiation. If biopsy is warranted before orchiectomy, slices) CT, reserving ipsilateral node d-issectionfor those the following steps should be followed: (1) achieve atraumatic high control of the spermatic cord; (2) mobilize with positive scans. Patients with group I disease should the testis and cord, carefully isolated from the operative receive VA chemotherapy without radiation. Inguinal field; (3) keep the biopsy site closed and the testes covnodes are rarely involved and are biopsied only if clinically ered while awaiting the frozen section report; (4) change positive or if the scrotum is invaded by tumor. Inguinal gowns and gloves and the instruments that were used for nodes are not considered regional; when they are positive, biopsy; (5) if the biopsy report is positive, remove the this places the patient in stage IV (clinical group IV).

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For tumors of the vagina, vulva, and uterus, the general principles followed in IRS-V include biopsy and staging, followed by chemotherapy as directed by stage and group Vulvovaginal and uterine RMS is the most common (i.e., risk category). Second- and third-look operations malignancy of the pediatric female genital system. This with biopsy a i d dystoscopy are common. Distal vaginal tumor generally presents in the first few years of life with lesions may be polypoid or localized and are amenable to vaginal bleeding, discharge, or a vaginal mass. If the tumor primary resection or delayed resection. Rarely is vaginecarises from the vulva, it consists of a firm nodule embedtomy or hysterectomy indicated, except for recurrent or ded in the labial folds, or it may be periclitoric in location. persistent-viable tumor. Lymph node involvement is very Diagnosis is made with incisional or excisional biopsy. rare. Oophorectomy is not done except for direct involveVaginal lesions generally have embryonal or botryoid with advanced or recurrent disease. ~~~~ embryonal histology and have an excellent p r o g n o ~ i s . ~ ment A primary chemotherapy approach with the gold stanVulvar lesions may have alveolar histology, but because dard of VAC, followed by local resectional therapy and most are localized, they also have a good prognosis. occasional use of radiotherapy when indicated, has proVaginal lesions usually arise from the anterior vaginal duced excellent results.lO Patients aged 1 to 9 years fared wall in the area of the embryonic vesicovaginal septum the best (5-year survival of 98%); patients outside of this (urogenital sinus). The bladder, prostatic utricle, prostate, age range benefited from the intensified therapy used and lower vagina all arise from the urogenital sinus. These in IRS-I11 or -IV (5-year survival of 67% in IRS-I and -11, are common sites for RMS in both sexes. versus 90% in IRS-111 and -IV).l0 Before 1972, pelvic exenteration was the accepted surgical approach for vaginal RMS. Beginning in 1972, the IRS Group began to enter patients in prospective clinical trials. The first eight patients with nonmetastatic vagiTrunk nal RMS underwent primary surgical intervention, Primary RMS of the trunk may occur in paraspinal sites, followed by postoperative chemotherapy with VAC. Three the thoracic or chest wall, the abdominal wall, intrapatients also received radiotherapy. Because vaginal RMS abdominal sites, or the pelvis or retroperitoneum. These appeared to be responsive to chemotherapy, IRS-I1 contumors tend to have a higher incidence of alveolar histolsisted of a primary chemotherapy regimen followed by ogy and a somewhat worse prognosis in some site^.^.^^ delayed surgical intervention with or without radiation. These lesions present differently, depending on site, and Fourteen of 20 patients (70%) eventually underwent surare discussed separately. gical resection." During IRS-111, these patients were given primary chemotherapy consisting of VAC plus doxorubicin and Paraspinal Sites cisplatin after initial biopsy (clinical group 111). Only 7 Paraspinal RMS presents as an enlarging mass in the of 23 patients (30%) underwent surgical resection after paravertebral muscle area. This is usually diagnosed by primary chemotherapy. Six of the seven patients had no incisional biopsy and must be distinguished from viable tumor in the resected specimen, and one had extraosseous Ewing's sarcoma, which is more common in maturing rhabdomyoblasts. The presence of rhabdomythis site in our experience. For all truncal tumors, the oblasts may not signify persistent active disease.4Wt M. D. biopsy should be performed in the long axis of the tumor Anderson Cancer Center, we continued chemotherapy (i.e., parallel to the ribs), to allow for wide local excision without resection when rhabdomyoblasts were found. No and rib resection as necessary. viable tumor or rhabdomyoblastswere found after further Most patients with paraspinal lesions require chemotherchemotherapy or subsequent biopsy in these patients. apy before resection, and many require postoperative Only six patients in IRSIII underwent radiotherapy." radiation therapy. Wide local excision is frequently done During IRS-IV, only 3 of 21 patients (14%) underwent in conjunction with a plastic surgeon, who can assist in surgical resection after primary chemotherapy. Three flap closure of the defect. In small children, it may be wise patients had only rhabdomyoblasts, and one patient who to eliminate radiation therapy close to the spine whenever underwent early second-look surgery had rhabdomyoblasts feasible. and a small amount of viable tumor. No patient in IRS-IV had a cystectomy, and all but one patient are still alive with no evidence of disease. Abdominal WaN Early IRS Group studies suggested that patients with This location is relatively rare (
Vulva, Vagina, and Uterus

CHAPTER

and -111, only 105 had primary tumors of the chest wall, pleura, lung, or heart. It has been suggested that these sites have a poor prognosis owing to histology, advanced stage at presentation, and difficulty of local resection. Early studies showed high rates of local and distant relapse." A review of IRS-I1 and -1118 included 84 patients with thoracic sarcomas: 76 chest wall tumors, 3 lung tumors, 4 pleural tumors, and 1 that arose from the heart. Sixty patients (71%) achieved a complete response. Thirty-nine patients had a local relapse, and 22 patients had a distant relapse. Forty-two percent of patients survived. Progression-free survival was not significantly associated with histology, site, clinical group, or IRS number. Overall survival was significantly associated with clinical group, size, and local or distant recurrence but not histology or IRS number by univariate analysis. In a multivariate analysis, only clinical group and local and distant recurrence showed statistical significance. Thus, if survival is to be improved, local tumor control with negative margins must be achieved. Clinical group I1 patients were treated with radiation therapy and had a better survival rate than did those in clinical group I (totally resected and thus no radiation therapy), indicating that the resection may have left microscopic or even gross residual disease. Either second-look surgery or consideration of local radiation therapy for possible residual disease in clinical group I may be indicated to improve survival." Specific surgical management of chest wall RMS includes initial biopsy (longitudinal to ribs) and staging. Following neoadjuvant chemotherapy, the tumor is resected to clear margins, and attached pleura or lung is removed as necessary. If needed, wide local resection can be followed by chest wall reconstruction, usually with a synthetic material covered by a myocutaneous flap. Frequently, tumor size reduction allows resection with primary closure.

Retroperitoneal and Pelvic Sites RMS of the retroperitoneum and pelvis usually presents as a large, bulky tumor whose exact site of origin is difficult to determine.'Vrequently, these tumors invade or involve vital organs or vessels; thus, only biopsy can be performed at the initial exploration. Early IRS Group studies indicated a poor prognosis for these sites.2" Blakely et al.14 reported on 94 patients with group 111 disease from IRS-111 and IRS-IV Pilot and found a 57% FFS rate at 4 years. They found that age younger than 10 years at diagnosis and embryonal histology were favorable -prognostic factors, as was the performance of a debulking procedure before instituting chemotherapy and radiation therapy.14 Recently Raney et al.gQeported on the results of 56 patients with localized retroperitoneal and pelvic RMS. Fifty-four of these patients had gross residual disease (clinical group 111) a t the completion of the initial diagnostic procedure. Two patients underwent grossly complete surgical excision with microscopic involved marginswithout Tgroup IIa) or with (group Cc) tumor-involved regional lymph nodes that were removed before beginning chemotherapy. Only 15 patients (27%) had 50% or more of the tumor removed before

32

Rhabdotnyosarcoma

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beginning chemotherapy and were classified as debulked; the other 41 patients were classified as having biopsy only. Among the 15 patients who underwent debulking of the tumor before chemotherapy or radiotherapy, there have been no treatment failures thus far. In contrast, 15 of the 41 patients who underwent biopsy only developed recurrent sarcoma. Thus, it appears that debulking may be of value when it can be achieved safely and with minimum morbidity. Otherwise, an alternative would be delayed primary excision after shrinkage with chemotherapy.

Biliary Sites Patients with biliary RMS do relatively well with chemotherapy and radiotherapy without aggressive surgiMost patients have the botryoid variant cal rese~tion.8~3104 of embryonal RMS, which responds well to chemotherapy. Although these tumors present with significant obstructive jaundice, biopsy followed by neoadjuvant chemotherapy commonly reduces the jaundice without the need for resection or internal or external biliary drainage. Surgical resection or bypass involves significant complications. Spunt et al.104 reported on 25 patients treated in IRS-I through -IV and found that total resection was rarely possible, external biliary drains were frequently associated with infection, and tumors responded well to combination chemotherapy without aggressive surgical intervention.

Perineal and Perianal Sites RMS of the perineum or anus is a rare sarcoma of childhood with a relatively poor prognosis. Blakely et al.I5 reported on 71 patients treated in IRS-I through -IV. The majority (64%) were at an advanced stage (clinical groups I11 and IV) at initial presentation, and 50% had positive regional lymph node involvement. The 5-year FFS for all patients was 45%, and the overall survival rate was 49%. Characteristics that were associated with significantly improved survival were primary tumor size less than 5 cm, lower (less advanced) clinical group and stage, negative lymph node status, and age younger than 10 years. When the extent of disease was controlled for multivariate analysis, only age younger than 10 years predicted an improved outcome. The 5-year overall survival rate for patients younger than 10 years was 71%, versus 20% for older patients (P < 0.001). Because of the high incidence of regional lymph node involvement, biopsy of clinically suspicious nodes should be done, and sentinel lymph node mapping for nonclinically suspicious nodes should be entertained.

Extremities Primary tumors of the extremity accounted for 19%of RMS in IRS-1117 and 20% in IRS-IV.74 Despite the intensive efforts of the IRS Group, the outcome of extremity RMS remains suboptimal compared with that of RMS in

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MAJORT ~ J M OOF RS CHII.DI~OOD

other sites. Improvements in survival have been seen with subsequent studies, but estimated 5-year survival is about 74% for patients without distant metastatic d i ~ e a s e . ~ Analysis of these studies suggests that the improvement is attributable to the intensification of therapy for patients with a poorer prognosis, while allowing a decrease in therapy for those with a good prognosis. Various prognostic factors have been suggested for extremity RMS in children. The elements of the Lawrence-GehanMstaging system used in IRS-IV are local tissue invasiveness, tumor size, presence of nodal and distant metastases, and site. BecaGse the extremities are relativelv unfavorable sites, no extremity tumors are classified as stage I by this system. A total of 139 patients were entered in IRS-IV with extremity RMS and were assigned a preoperative stage and a clinical group, as follows: stage I1 ( n = 34), stage 111 ( n = 73), stage IV ( n = 32); group I ( n = 31), group I1 ( n = 21), group I11 ( n = 54); group IV ( n = 33). Three-year FFS was 55%, and the overall survival rate was 70%. FFS was significantly worse for patients with advanced disease. Totally resected patients (group I) had a 3-year FFS of 91%.74 Initial treatment consists of biopsy, either incisional or excisional. This should be done in a longitudinal or axial direction to allow for wide local excision. If wide local excision can be accomplished without mutilation, this should be considered. The standard 2-cm margins are arbitrary and are not practical in children. There is little evidence that a clear margin of only a few millimeters involves a higher risk for r&urrence than do larger margins. Amputation is rarely indicated except for larger recurrent or persistent disease. Excision of the entire muscle from origin to insertion, as recommended in the past, is not necessary. The importance of complete resectibn is emphasized, because survival is markedly improved with total excision or microscopic residual only. Careful determination of margin status is extremely important, and reresection at initial or subsequent operation is warranted. Hays et a1.4Wemonstratedthat patients with node-negative extremity and trunk sarcomas who underwent re-excision for micrbscooic residual tumor had a survival rate that was significantly higher than those who did not have reexcision or were reported to have no residual tumor after initial resection. It is our policy to recommend re-excision for all patients referred i o our institution after previous resection, no matter what was previously reported. We have found residual and even gross disease in patients reported to have complete resection (probably because the surgeon was unaware that cancer was present). Lymph node involvement with extremity RMS in IRSI and -11 was only 12%,537,5"57 because few patients actually had lymph node biopsy. LaQuaglia et al." reported 40% incidence of positive nodes. In a review of IRS-IV, Andrassy et al.7 demonstrated that 39% of patients who underwent evaluation of their lymph nodes had histologic confirmation of disease. ~ e v i l l eet a1.,74 in a review of IRS-IV data, found that 50% of biopsied lymph nodes contained disease. Of the patients whose lymph nodes were clinically negative but were biopsied anyway, 17%were found to have microscopic disease. The finding of histologically positive lymph nodes is a statistically significant predictor of FFS. Although lymph node dissection has

a

not improved the survival rate, positive regional nodes should be irradiated to prevent local recurrence. We have used and recommended lymphatic mapping with sentinel node biopsy to evaluate the regional nodes.7K.74 If sentinel lymph node mapping is not available, aggressive sampling is warranted.

COMPLICATIONS Complications of treatment for RMS are varied and extensive. These include chemotherapy toxicity and death, radiation-related acute and long-term complications, and the standard surgical complications of biopsy and resection. Discussion of the specific complications and their treatment is beyond the scope of this chapter. Long-term follow-up of all patients is warranted for delayed complications and second m a l i g n a n c i e ~ . ~ ~

TREATMENT OF METASTATIC DISEASE Metastatic disease most commonly involves the lung (58%), bone (33%), regional lymph nodes (33%), liver (22%), and brain (20%).21 Of the patients enrolled in IRS-111,'" 14% were clinical group IV at the time of diagnosis. Primary sites more likely to have metastases include the extremities (23%), parameningeal sites (13%), and retroperitoneal, trunk, gastrointestinal, and intrathoracic sites. Primarv sites with a low incidence of metastases include the orbit (1.8%), nonparameningeal or nonorbital head and neck (4.5%), and genitourinary sites.g7 Metastatic disease is the single most important predictor of clinical outcome in patients with RMS. The 3-year FFS As menis only 25% in patients with metastatic di~ease.2"7~) tioned previously, regional node metastases vary with the site of the primary tumor (highest in the extremities) and also affect survival. The lung is the most common site of metastatic disease. Patients with only lung metastases appear to have a somewhat better prognosis than do those with metastases in multiple sites or metastases to bone or liver.9"atients with only lung metastases also have a greater incidence of favorable histology and a smaller number of extremity primary tumors." Because RMS is highly chemosensitiv6, resection of numerous metastases is not indicated. In our experience, an isolated single metastasis to the lung has a better prognosis than do multiple metastases. For this reason, it is worthwhile to biopsy a single metastasis to confirm histology. The better prognosis may well be related to the treatment of nonmetastatic lung lesions other than RMS. Persistent or recurrent diseaseafter chemotherapy may warrant resection both for diagnosis and possibly to decrease the tumor burden. Overall, there has been little improvement in the survival of patients with metastatic diskase. They are presently categohzed in stage IV, group IV and are considered high risk. Aggressive chemotherapy and radiation in an attempt to improve survival is being studied. During IRS-IV, 127 eligible patients were treated for metastatic disease with one of two regimens that incorporated a window of either ifosfamide and etoposide with vincristine, dactinomycin,

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Rhabdornyosarcoma

537

10. Arndt CA, et al: What constitutes optimal therapy for patients with rhabdornyosarcoma of the female genital tract? Cancer 2001;91:2454. 11. Asmar L, et al: Agreement among and within groups of pathologists in the classification of rhabdornyosarcoma and related childhood sarcomas: Report of an international study of four pathology classifications. Cancer 1994;74:2579. 12. Beech TR, et al: What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma arising in the abdominal wall? A report from the Intergroup Rhabdornyosarcoma Study Group.J Pediatr Surg 1999;34:668. OUTCOME 13. Birch JM, et al: Excess risk of breast cancer in the mothers of children with soft tissue sarcomas. Br J Cancer 1984; The overall trend has been an increase in survival for each 49:325. subsequent IRS Group study. The survival rate depends 14. Blakely ML, et al: Does debulking improve survival rate in on clinical group, stage, and primary site. The overall advanced-stage retroperitoneal embryonal rhabdomyosar5-year survival rate in IRS-I11was 71%; it was 90% for clincoma? J Pediatr Surg 1999;5:736. ical group I, 80% for clinical group 11, 70% for clinical 15. Blakely ML, et al: Prognostic factors and surgical treatment group 111, and 30% for clinical group IV. The survival guidelines for children with rhabdornyosarcoma of the perrate by pretreatment staging classification was 80% for ineum or anus: A report of Intergroup Rhabdomyosarcoma stage I, 68% for stage 11, 49% for stage 111, and 21% for Studies I through IV, 1972 through 1997. J Pediatr Surg stage IV.lZ4 2003;38:347. 16. Breneman JC, et al: The management of pediatric geniOverall, FFS rates for the patients treated in IRS-IV did tourinary rhabdornyosarcoma. In Vogelzang NJ, et al (eds): not differ from those of similar patients treated in IRSIII; The Comprehensive Textbook of Genitourinary Oncology. the estimated 3-year FFS rate was 76% in IRS-111 and 77% Baltimore, Williams & Wilkins, 1996. in IRS-IV. Three-year FFS rates were improved for patients 17. BrenemanJC, et al: Prognostic factors and clinical outcomes with embryonal RMS treated in IRS-IV compared with in children and adolescents with metastatic rhabdomyosarIRSIII (83% versus 74%). The improvement seemed to be coma: A report from the Intergroup Rhabdomyosarcoma restricted to patients with stage I1 or stage 11-111, group 1-11 Study rV.J Clin Oncol2003;21:78. embryonal RMS. The sites of treatment failure were local 18. Burger RA, et al: Extent of surgery in rhabdornyosarcoma in 93 patients (51%),regional in 30 (17%),and distant in of urogenital structures. Eur Urol 1989;16:114. 58 (32%).Salvage therapy after relapse differed by group. 19. Cavazzana AO, et al: Spindle cell rhabdornyosarcoma. Am J Surg Path01 1992;16:229. Forty-one percent of patients with group 1-11 tumors were 20. Coene IMJH, et al: Rhabdornyosarcoma of the head and alive 3 years after relapse, compared with 22% of those with neck in children. Clin Otolaryngol 1992;17:291. group 111 tum0rs.2~ 21. Cofer BR, et al: Rhabdomyosarcoma. In Andrassy RI (ed): Pediatric Surgical oncology. Philadelphia, WB ~aunders, 1998. REFERENCES 22. Corpron CA, et al: Conservative management of uterine pediatric rhabdornyosarcoma: A report from the Intergroup 1. Abramson DH, et al: The treatment of orbital rhabdomyosarRhabdomyosarcoma Study I11 and IV Pilot. J Pediatr Surg coma with irradiation and chemotherapy. ~ ~ h t h a l m b l o g y 1995;30:942. 1979;86:1330. 23. Crist WM, et al: Soft tissue sarcomas arising in the retroperi2. Anderson GJ, et al: Rhabdornyosarcoma of the head and toneal space in children: A report from the Intergroup neck in children. Arch Otolaryngol Head Neck Surg 1990; Rhabdomyosarcoma Study. Cancer 1985;56:2125. 116:428. 24. Crist WM, et a1 (for the IRS Committee): Prognosis in chil3. Anderson JR, et al: Improved outcome for patients with embrydren with rhabdornyosarcoma: A report of IRS-I and IRS-11. onal histology but not alveolar histology rhabdomyosarcoma: J Clin Oncol 1990;8:443. Results from Intergroup Rhabdornyosarcoma Study IV 25. Crist WM, et al: Intergroup Rhabdornyosarcoma Study (IRS-IV). Proc Soc Clin Oncol 1998;17:526a. (IRS) 111.J Clin Oncol 1995;13:610. 4. Andrassy RJ: Rhabdornyosarcoma. Semin Pediatr Surg 26. Crist WM, et al: Preliminary results for patients with local/ 1997;6:17. regional tumors treated on the Intergroup Rhabdomyosar5. Andrassy RJ: Advances in the surgical management of sarcocoma Study-IV (1991-1997). Proc Am Soc Clin Oncol 1999; mas in children. Am J Surg 2002;184:484. 18:18. 6. Andrassy RJ, et al: Conservative surgical management of 27. Crist WM, et al: Intergroup Rhabdornyosarcoma Study-IV: vaginal and vulvar pediatric rhabdomyosarcoma: A report Results for patients with nonmetastatic disease.J Clin Oncol from the Intergroup Rhabdornyosarcoma Study-111. J Pediatr 2001;19:3091. Surg 1995;30:1034. 28. Dagher R, et al: Rhabdomyosarcoma: An overview. 7. Andrassy RJ, et al: Extremity sarcomas: An analysis of progOncologist 1999;4:34. nostic factors from the Intergroup Rhabdornyosarcoma 29. Donaldson S, et al: Hyperfractionated radiation in children Study (IRS) 111.J Pediatr Surg 1996;31:191. with rhabdomyosarcoma: Results of an Intergroup 8. Andrassy RJ, et al: Thoracic sarcomas in children. Ann Surg Rhabdornyosarcoma Pilot Study. Int J Radiat Oncol Biol 1998;227:170. Phys 1995;32:903. 9. Andrassy RJ, et al: Progress in the surgical management of 30. Donaldson SS, et al: Results from the Intergroup vaginal rhabdornyosarcoma: A 25-year review from the Rhabdornyosarcoma Study-IV randomized trial of hyperIntergroup Rhabdomyosarcoma Study Group. J Pediatr Surg fractionated radiation in children with rhabdomyosar1999;34:731. coma. Int J Radiat Oncol Biol Phys 2000;48:178.

and cyclophosphamide or vincristine, melphalan, and VAC. The estimated overall survival and FFS was 39% and 25%, respectively, at 3 years. Overall survival at 3 years was influenced by histology (47% for embryonal versus 34% for all others) and number of metastatic sites. By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor.17

538

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31. Ferracini R, et al: Retrogenic expression of the MET protooncogene correlates with the in;asive phenotype of human rhabdomyosarcomas. Oncogene 1996;12:1697. 32. Fiorillo A, et al: Multidisciplinary treatment of primary orbital rhabdornyosarcoma: A single institution experience. Cancer 1991;67:560. 33. Frascella E, et al: Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin, and vincristine. Eur J Cancer 1996;32A:821. 34. Furman W, et al: A phase I study of irinotecan (CPT-11) in children with relapsed solid tumors. Proc Am Soc Clin Oncol 1998;17:187a. 35. Gasparini M, et al: Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension. J Clin Oncol 1990;8:1854. 36. Gilles R, et al: Head and neck rhabdomyosarcomas in children: Value of clinical and CT findings in the detection of local regional relapses. Clin Radiol 1994;49:412. 37. Goldfarb B, et al: The role of retroperitoneal lymphadenectomy in localized paratesticular rhabdomyosarcoma. J Urol 1994;152:785. 38. Gross M, et al: Therapy of rhabdomyosarcoma of the larynx. Int J Pediatr Otorhinolaryngol 1988;15:93. 39. Grufferman A, et al: In utero x-ray exposure and risk of childhood rhabdomyosarcoma. paper-presented at the Fourth Annual Meeting of the Society for Epidemiologic Research, June 11, 1991, Buffalo, NY. 40. Grufferman S, et al: Parents' use of recreational drugs and risk of rhabdomyosarcoma in their children. Cancer Causes Control 1993;4:217. 41. Hamilton CR, et al: The management of paratesticular rhabdornyosarcoma. Clin Radiol 1989;40:314. 42. Hartley AN, et al: Patterns of cancer in the families of children with soft tissue sarcoma. Cancer 1993;72:923. 43. Hays DM, et al: Primary re-excision for patients with "microscopic residual" following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 1989;24:5. 44. Hays DM, et al: Partial cystectomy in the management of rhabdomyosarcoma of the bladder: A report from the Intergroup Rhabdornyosarcoma Study. J Pediatr Surg 1990;25:719. 45. Hays DM, et al: Retention of func