Obstetric and Gynecologic Dermatology, Third Edition

Obstetric AND

Gynecologic Dermatology

Martin Black MD FRCP FRCPath Emeritus Professor of Dermatological Immunopathology and Honorary Consultant Dermatologist St. John’s Institute of Dermatology St. Thomas’s Hospital London, UK

CHRISTINA M. AMBROSRUDOLPH MD Associate Professor Department of Dermatology Medical University of Graz Graz, Austria

Libby Edwards

md Associate Professor of Dermatology University of North Carolina, Chapel Hill; Chief of Dermatology, Carolinas Medical Center Mid-Charlotte Dermatology and Research Charlotte, North Carolina, USA

Peter J. Lynch

md Program Director and Frederick G. Novy, Jr. Professor of Dermatology Department of Dermatology University of California, Davis Sacramento, California, USA

MOSBY an imprint of Elsevier Limited © 2008, Elsevier Limited. All rights reserved. First published 2008 For revised editions, replace line above with publication years of previous editions e.g.: First edition 1995 Second edition 2002 The right of Martin Black, Christina Ambros-Rudolph, Libby Edwards & Peter J. Lynch to be identified as authors of this work has been asserted by him/her/them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. ISBN:978-0-7234-3445-0 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author_assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

Preface The first and second editions of this text, which we believe was the first ever to focus specifically on the full range of dermatologic problems encountered in obstetric and gynaecological practice, were very well received. For the third edition all chapters have been thoroughly updated and each presents a basic, sensible approach to a complex subject. We are particularly fortunate to have been able to recruit two eminent dermatologists who have long specialised in vulval dermatoses: Dr. Peter Lynch and Dr. Libby Edwards have brought their considerable expertise together and have completely updated and largely re-written the sections on vulval dermatoses and tumours. All sections are profusely illustrated presenting numerous examples of common and unusual disorders or presentations. It is intended that the format of the illustrations and text will aid the user in comparing images of similar-appearing skin problems encountered in the clinic or office. Further emphasis is also made in the text on practical suggestions for diagnostic approaches as well as outlining detailed and practical suggestions for therapy. In addition I am grateful that my co-worker Dr. Christina Ambros-Rudolph has been able to join us as a co-editor and that Dr. Samantha Vaughan Jones has continued to work closely with us. We believe that this atlas and detailed text will continue to be appreciated by consulting dermatologists and non-dermatologists alike. In particular we feel that this book will continue to be a useful reference for all clinicians who care about women’s health. Martin M. Black; Christina Ambros-Rudolph; Peter Lynch; Libby Edwards.

ix

List of Contributors Christina M. Ambros-Rudolph MD

Diana Hamilton-Fairley MD FRCOG

Associate Professor of Dermatology and Venereology Department of Dermatology Medical University of Graz Graz Austria

Joint Head of Women’s Health Services Delivery Unit Guy’s and St. Thomas’ NHS Foundation Trust St. Thomas’ Hospital London UK

Martin M. Black MD FRCP FRCPath

Rachel E. Jenkins BSc MD FRCP

Emeritus Professor of Dermatological Immunopathology Honorary Consultant Dermatologist St. John’s Institute of Dermatology St. Thomas’s Hospital London UK

Consultant Dermatologist Dermatology Department West Suffolk Hospital Bury St Edmonds Suffolk UK

Peter R. Braude PhD FRCOG F Medsci Professor of Obstetrics & Gynecology Chairman & Head of Department United Medical & Dental Schools of Guy’s & St. Thomas’s Hospital London UK

Libby Edwards MD Associate Professor of Dermatology University of North Carolina, Chapel Hill; Chief of Dermatology Carolinas Medical Center Mid-Charlotte Dermatology and Research Charlotte, NC USA

Emma Fox FRCP Consultant Virologist Department of Infection Guy’s and St. Thomas’ NHS Foundation Trust Guy’s Hospital London UK

Hope K. Haefner MD Professor Department of Obstetrics and Gynecology The University of Michigan Hospitals Ann Arbor, MI USA

Diana N. J. Lockwood BSc MD FRCP Consultant Physician & Leprologist Hospital for Tropical Diseases, Copper Street London UK

Peter J. Lynch MD Program Director and Frederick G. Novy, Jr. Professor of Dermatology Department of Dermatology University of California, Davis Sacramento, CA USA

Eithne MacMahon MD FRCPI MRCPath Consultant in Infectious Diseases and Virology Department of Infectious Diseases and Virology St. Thomas’ Hospital London UK

Lynette Margesson MD Assistant Professor Division of Dermatology Queens University Kingston, ON Canada

Catherine Nelson-Piercy MA FRCP MB BSc FRCOG Consultant Obstetric Physician Women’s Health Services Directorate St. Thomas’ Hospital London UK

xi

List of Contributors

Daghni Rajasingham MBBS MRCOG

Catherine J. M. Stephens MBBS FRCP

Consultant Obstetrician Women’s Health Services Directorate St. Thomas’ Hospital London UK

Consultant Dermatologist Poole Hospital NHS Trust Poole Dorset UK

Jeff K. Shornick MD MHA

Samantha Vaughan-Jones MD FRCP

Private Practice Groton, CT USA

Consultant Dermatologist Department of Dermatology Ashford and St. Peter’s NHS Trust Chertsey Surrey UK

xii

Dedications

To my wife, Aniko. M.B. To my family for encouraging me to go into medicine and to my husband, Johannes, for his love and continuing support. C.A.-R. To my wonderful niece, Amanda Coombs. L.E. I would like to express my gratitude to Eduard G. Friederich, Jr., Raymond W. Kaufman, and Donald J. Woodruff. Their role in helping me to understand genital disease in women cannot be overestimated. They have in addition served as valued colleagues, important mentors, and warm friends. P.L.

xiii

PART: I  Obstetrics

CHAPTER 1

Hormonal Changes during Puberty, Pregnancy, and the Menopause Peter Braude Diana Hamilton-Fairley

Introduction This chapter summarizes the hormonal changes that occur during puberty, the menstrual cycle, pregnancy, and the menopause, and how these changes affect the skin physiologically. All children go through the bewildering hormonal changes that the transition from child to adult necessitates. However, it is only the female who will continue to experience a changing hormonal milieu – either cyclically, with the monthly production of an egg followed by menses, or the effects of pregnancy if conception takes place. Then, for the last third of their lives, women face the consequences of a reduction in estrogen levels following the menopause. Although the hormonal events immediately preceding the menopause are turbulent, once the climacteric is reached, it too may cause its problems. Most women are aware of the changes taking place in their skin at these different stages in their lives.

Hypothalamic–pituitary axis An understanding of the interrelationship between the hypothalamus, the pituitary gland, and the ovary is imperative if the cyclical and long-term hormonal changes occurring in women are to be appreciated. Situated above the pituitary gland, the hypothalamus initiates the release of the polypeptides that regulate ovarian function. The ovary cannot produce mature fertile oocytes (eggs) if the signals from the pituitary gland never start, cease prematurely, or are disordered. The female reproductive cycle is regulated precisely via biologic feedback mechanisms from the ovary, which alter the activity of the hypothalamus and pituitary. Normal physiologic changes in the functioning of the hypothalamic–pituitary axis result in the hormonal changes that occur during the four main reproductive endocrine phases of

Chapter 

1

Hormonal Changes during Puberty, Pregnancy, and the Menopause

a woman’s life: puberty, menstruation, pregnancy, and the climacteric. As menarche (the first period) is one event during the years of puberty, so menopause (the final period) marks one event during the years of declining reproductive function (the climacteric or menopause).

Puberty Puberty describes the physiologic, morphologic, and behavioral changes that occur in a child as the gonads mature from the infantile to the adult state that affects most of the organs of the body in both sexes. These physiologic changes can be divided into two main groups: growth and hormonal. Although the changes start at different chronologic ages in different individuals, the sequence of events is similar. In girls the start of puberty is strongly weight-related, with the mean body weight being 47 kg at menarche. Although the age of menarche has declined from 17 years in 1840 to 13.5 years in the 1940s, and is now 12.5 years in the United States, the mean body weight at menarche seems to have remained constant.

Growth spurt The adolescent growth spurt is an acceleration of growth in most skeletal dimensions. The peak height velocity (PHV) is 9–10 cm per year and lasts for about 2 years. There is no difference in the PHV of girls and boys, and both sexes grow between 25 and 28 cm during puberty. However, girls start their growth spurt 2 years earlier than boys, at which time they are 10 cm shorter than when boys start theirs. This accounts for the difference in adult height between the sexes. This large increase in height is mediated by an increase in growth hormone (GH) production by the pituitary gland. The greatest increase in the frequency and amplitude of GH takes place at night in a similar fashion to luteinizing hormone (LH) pulses (Figure 1.1).

Hormonal changes The hormonal changes of puberty produce two main effects: maturation of the ovary so that reproduction can occur, and development of secondary

sexual characteristics (breasts, axillary and pubic hair). During childhood, serum levels of the gonadotrophins – LH and follicle-stimulating hormone (FSH) – are low. During early to mid-puberty, however, there is a striking increase in the magnitude and frequency of LH pulses at night during sleep (see Figure 1.1). In late puberty, there is an increase in magnitude during the day, but not as marked as at night. Only when puberty is complete do the LH pulses lose their diurnal variation and settle into an adult pattern, with pulses approximately every 90 minutes during the follicular phase, and between 120 and 180 minutes in the luteal phase. These events are probably initiated by the maturation of the hypothalamus and the onset of secretion of gonadotrophin-releasing hormone (GnRH). However, it is impossible to prove the exact sequence of events initiating puberty because the experiments required would be unethical in humans. The increase in both LH and FSH activity has a trophic effect on the ovary, stimulating the production of estradiol. The primordial follicles (the oocyte and surrounding support cells), present from birth, begin to mature into antral follicles lined by granulosa cells. This process of maturation takes about 10 weeks. LH acts mainly on the theca cells which surround the follicles, causing them to produce testosterone, which is then converted by an aromatase into estradiol in the granulosa cells under the influence of FSH. The increase in estradiol secretion stimulates breast development. The five stages of breast develop­ment take about 4 years to complete (Figure 1.2). Menarche (the first menstruation) usually occurs once breast development is quite well advanced – between stages III and IV1. Rapid breast development or increase in breast size, common during pregnancy and less common on the oral contraceptive pill, may cause stretch marks to develop, especially in the lateral margins of the breast, which may be of concern, particularly to younger women. Several other changes also occur, which are important in understanding the physiologic changes in the skin. The first is adrenarche. This

Puberty

Sleep Awake stages REM

Prepuberty

II IV LH (mIU/mL)

Figure 1.1  Luteinizing hormone (LH) levels during puberty. Changes in the pulse frequency and amplitude of luteinizing hormone during puberty. REM, rapid eye movement.

10 8 6 4 2 0

Sleep Awake stages REM

Mid to late puberty

II IV LH (mIU/mL)

18 16 14 12 10 8 6 4 2 0

2200

0200

0600

1000

1400

1800

2200

24-hour clock

Figure 1.2  Breast development. The Tanner stages I–V of breast ­development.

I – Prepubertal

III – Enlargement

II – Breast budding

IV – Secondary mound formed by areola

V – Single contour of breast and areola



Chapter 

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Hormonal Changes during Puberty, Pregnancy, and the Menopause

is an increase in the production of adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), which starts at about 8 years of age and continues until 13–15 years of age in both sexes. This increase is thought to stimulate the development of axillary and pubic hair, as hair growth and changes in sebum secretion are modulated predominantly by androgens in both sexes. Pubic and axillary hair growth usually starts before the breasts change following the increase in adrenal androgen levels, but reaches the mature stage at around the same time. The testosterone level increases in girls, as in boys, under the influence of LH, but most of it is converted into estradiol. During puberty, the concentration of the main binding protein of the sex hormones (sex hormone-binding globulin, SHBG) declines in both sexes, despite the increase in estradiol concentrations in girls2. SHBG has a greater affinity for testosterone than for estradiol, with the result that, in most girls, more than 90% of circulating testosterone is bound to SHBG, thus limiting the effect that testosterone may have peripherally. The decrease in SHBG seems to be mediated by an increase in insulin concentration, which has been demonstrated in both sexes3.

Polycystic ovary syndrome There is a group of girls who produce an excess of testosterone accompanied by morphologic changes in their ovaries, a phenomenon known as polycystic ovaries (PCO)4. Typically these girls never establish regular menstruation and have increased hair growth, usually of a male pattern, with an abdominal escutcheon, moustache, or other facial hair growth (Figure 1.3). They may also develop acne. Many girls with acne and/or hirsutism have polycystic ovary syndrome. These girls also have higher insulin concentrations and lower SHBG concentrations than their weightmatched contemporaries5. A lower SHBG concentration, together with an increased circulating testosterone level, will lead to an increased free testosterone level. It is the fraction of free testosterone that is thought to be active peripherally on the skin, sebaceous glands, and hair follicles.

Figure 1.3  Polycystic ovary syndrome. Facial hirsutism ­associated with polycystic ovary syndrome.

Acne Testosterone has major effects on the hair follicle and sebum secretion. Acne vulgaris6 (Figure 1.4) and hirsutism are never seen in prepubertal children with normal adrenal function, providing further evidence that puberty-related changes trigger these events. Although there is no evidence of increased androgen production in men with acne, most women with acne do have increased ovarian androgen production and a reduced SHBG concentration. Undoubtedly, genetic factors also play an important part in determining which girls will suffer and which will not. The pilosebaceous gland becomes more differentiated, increases in size, and changes its sebum composition. These changes are most marked on the scalp and around the nose, chin, and cheeks, as well as on the upper chest and

The menstrual cycle

Follicular phase

Figure 1.4  Acne vulgaris.

back (see Chapter 2). Acne tends to reach a peak during puberty and before sexual maturity. It is therefore thought that the adrenal glands provide the initial stimulus.

The menstrual cycle The menstrual cycle is divided into two phases which are named as viewed from two different standpoints: • The follicular and luteal phases – according to events in the ovary • The proliferative and secretory phases – according to changes that take place in the endometrium As endometrial changes are dependent on the hormonal changes occurring in the ovary, the terms “follicular phase” and “luteal phase” will be used in this chapter.

A few days before the onset of menstruation, the level of FSH starts to rise under the stimulation of GnRH secreted from the hypothalamus (Figure 1.5). This causes several antral follicles to start producing estradiol. As these follicles fill with fluid produced by the granulosa cells, which lie as a single layer around each follicle, they become visible on an ultrasonographic scan. In order to produce estradiol, the granulosa cells utilize testosterone produced by the theca cells, which lie as a second monolayer around the follicle. In the early follicular phase, the granulosa cells carry receptors for FSH, whereas the theca cells are stimulated by LH. The estradiol produced by the ovary is released into the circulation. The pituitary has an abundance of estradiol receptors; their activation results in the inhibition of both LH and FSH production in the mid follicular phase. The granulosa cells also produce inhibin, a protein that augments the negative feedback of estradiol on FSH. This protein is also produced by the corpus luteum following ovulation. As a result of this effect, the smaller follicles stop growing and undergo atresia. By this stage, only one follicle (but, occasionally, two or more) has reached a diameter of about 10–12 mm, and is called the dominant follicle. The granulosa cells of the dominant follicle develop LH receptors and so become receptive to both LH and FSH. The follicle increases in diameter by 2 mm/day. The estradiol concentration rises faster and the granulosa cells begin to accumulate in several layers over the oocyte.

Oocyte release When the follicle reaches a diameter of around 18–20 mm, and the estradiol concentration reaches 800–1000 pmol/L, the biofeedback on the pitu­ itary is reversed. This results in a rapid rise in hormone concentrations, predominantly of LH and to a lesser extent of FSH. In turn, this leads to a luteinization of the granulosa cells and consequently they begin to produce progesterone in preference to estradiol. This change leads to the rupture of the follicle wall, and the oocyte is released into the peritoneum about 24–36 hours



Chapter

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Hormonal Changes during Puberty, Pregnancy, and the Menopause



14 10 6

Luteal phase

Menstruation

18

Follicular phase

Menstruation

36 34 32 20 16 12 8 4 0

mIU/mL

LH

FSH

2 −6

−4

−2

1

3

5

−4

7

−2

0

2

4

−4

−6

6

−2

3

1

5

7

Ovarian activity E2pmol/L 1000

40

750

17β-Estradiol

30

Progesterone

500

20

250

10 26

28

2

4

6

8

10

12

14

16

18

20

22

Ovulation One complete menstrual cycle

24

26

28

2

4

Progesterone (nmol/L)

0

Day of menstrual cycle

Note: pmol are standard units

Figure 1.5  Hormonal changes of the menstrual cycle. LH, luteinizing hormone; FSH, follicle-stimulating hormone.

after the LH surge. The follicular phase ends with release of the oocyte, and varies in length from 12 to 16 days.

Luteal phase Oocyte release marks the start of the luteal phase. Following release of the oocyte, the granulosa cells reseal the defect in the wall within a few hours, forming the corpus luteum. The granulosa (now luteal) cells produce progesterone, and this reaches a peak concentration 5–8 days after ovulation. The effect of progesterone on the endometrium is to increase the surface area of the endometrial glands and their blood supply by causing them to become spiral. They also start to produce large amounts of glycogen, an essential nutrient for the early days of embryo development if fertilization takes place. If the oocyte is fertilized and implantation occurs, then progesterone levels remain high. These levels are maintained by human chorionic gonadotrophin (hCG) produced by the trophoblastic elements of the embryo as the primitive placenta invades the endometrium. If fertilization

does not occur, the concentration of LH is insufficient to maintain production of progesterone by the corpus luteum. The levels decline and the endometrium becomes ischemic; its superficial layers slough off. This, together with bleeding from the spiral arterioles that supplied the endometrium, produces menstruation. Thus, the cycle has come full circle to the hormonal and endometrial states found at its beginning. The whole process then begins again.

Skin changes Skin changes during the menstrual cycle are usually temporary and of minor importance. They include an increase in sebum production before menses, which may lead to acneiform eruptions on the face and occasionally on the back. Knowledge of the hypothalamic, pituitary, and ovarian hormonal changes is useful in under­ standing therapies to modify or ablate the hormonal mileu. There is a range of superactive GnRH analogs (buserelin, goserelin, nafarelin, etc.), which can be given by daily nasal spray or by monthly depot injections, whose effect (after a brief

Pregnancy

stimulation of FSH output) is competitively to block the GnRH receptor and thus abolish FSH and LH production. This effectively renders the woman reversibly menopausal, such that events attributable to the cyclicity of the menstrual cycle can be investigated, such as cyclic pain, eruptions, or progesterone sensitivity (see Chapter 2). This regimen should not be employed for more than 6 months at a stretch because of the estrogendepleting effect and thus its potentially adverse effect on bone loss.

Pregnancy During the first few weeks of pregnancy, progesterone concentrations increase. Progesterone is initially produced by the corpus luteum, which is maintained by the production of hCG from the trophoblast of the conceptus. hCG has been found in the maternal circulation almost immediately after fertilization and rises to a peak by 60–90 days of gestation. The concentration of hCG doubles every 2–3 days until this time, then gradually declines to a plateau level for the remainder of the pregnancy. The corpus luteum continues to produce progesterone, 17-hydroxyprogesterone, estrone, and estradiol, producing a rise in the concentration of all these hormones. In addition, hCG is responsible for the production of inhibin and relaxin by the corpus luteum. Inhibin reduces FSH concentrations so that folliculogenesis is arrested once the embryo has become implanted into the endometrium. It may also act as a growth factor for the early embryo. Relaxin is thought to act in synergy with progesterone to reduce the contractility of the uterine myometrium. The concentrations of both of these hormones rise in parallel with the concentration of hCG, but they are produced only for a limited period by the ovary. From around 7 weeks’ gestation, they are produced by the decidual fetal membranes and placental tissues. Similarly, ovarian steroid hormone production declines from 7 weeks’ gestation, with the placental unit taking over this function. This explains why pregnancies fail if the corpus luteum is removed before 8 weeks, but continue unharmed if the pregnancy has reached 9 weeks’ gestation.

Table 1.1  Hormones Produced by the Fetal–Placental Unit Peptides

Inhibin Relaxin Human placental lactogen

Neuropeptides

Gonadotrophin-releasing hormone Corticotrophin-releasing hormone Thyroid-releasing hormone

Steroid hormones

Progesterone Androgens Estradiol Estrone Estriol

Peptide growth factors

Insulin-like growth factors I and II

The placenta The placenta is a complex organ. Not only does it provide nutrients and excrete waste products from the fetus, but it also modifies the maternal metabolism at various stages of pregnancy via hormones. The placenta reaches structural maturity by the end of week 12 of pregnancy. The functional unit is the chorionic villus, which consists of a central core of loose connective tissue and abundant capillaries. These connect to the fetal circulation and provide a large surface area in contact with the maternal uterine circulation. Around this central core are two layers of trophoblast, an outer syncytium (syncytiotrophoblast), and an inner layer of discrete cells (cytotrophoblast). The fetus and placenta form an interdepen­ dent partnership which regulates the endocrine­metabolic processes during pregnancy. This fetal-placental unit therefore becomes an endocrine system, producing a large number of different hormones (Table 1.1). Several placental products have been measured over the years in the search for a marker for placental insufficiency. These include estriol and human placental lactogen (hPL), the concentrations of which rise steadily throughout pregnancy. But, as



Hormonal Changes during Puberty, Pregnancy, and the Menopause

70 Progesterone

6

60

Estradiol 4

50

hPL

40

Estriol

30 20

2

10

hCG 0

0

40

Day of gestation

80

120

180

200

240

210 180 150 120

Progesterone (ng/mL)

8 Estriol (ng/mL)/Estradiol (ng/mL)

Human chorionic gonadotropin (hCG) (µg/mL)

10

1

Human placental lactogen (hPL) (µg/mL)

Chapter

Figure 1.6  Hormonal changes during pregnancy. Changes in the production of progesterone, estradiol, estriol, human chorionic gonadotropin, and human placental lactogen.

90 60 30

280

(Mean duration of pregnancy=278 days)

their normal ranges are very large, they have not proved clinically useful in predicting the outcome of pregnancy. Following the baby’s birth, all the hormone levels return to normal within a few days. The production of hCG, progesterone, estriol, estradiol, and hPL during pregnancy is shown in Figure 1.6. Despite our ability to measure these hormones during pregnancy, the role that they play in maintaining pregnancy and/or initiating parturition is still poorly understood.

Skin changes in pregnancy Striae gravidarum

Striae gravidarum are linear purple-red lesions which over time lose their pigmentation and atrophy, leaving scar-like tissue. They can cause itching and discomfort and affect 50–90% of women during pregnancy. The underlying etiology has always been unclear, with two principal theories. The first is the association with stretching of the skin causing disruption to the collagen fibers and elastin in the dermis as the uterus grows. However a small study has shown that a significant number of women develop striae gravidarum before 24 weeks7. The other is hormonal change, as in Cushing’s syndrome and steroid therapy. There is little research in this area but the strongest association with the development of striae gravidarum is the presence of striae on the thighs or breasts prior to pregnancy. It appears that the group at highest risk of developing severe striae is teenagers8.

Melasma

Melasma (chloasma) is known as the “mask of pregnancy” as it causes an increase in pigmentation of facial skin, particularly over the cheeks. It is associated with hormonal change as it occurs in 70% of women during pregnancy, in 5–34% of those using the oral contraceptive pill, and has been reported in women using hormonal creams, some cosmetic products, and certain types of drugs. It usually clears once pregnancy is over, confirming its hormonal origins9.

The climacteric and the menopause The menopause (cessation of menses) marks the end of a woman’s reproductive life. The average age for the end of menses in the United Kingdom is 50.3 years. During the perimenopausal years (the climacteric) there is an increase in circulating FSH levels and a decrease in estradiol concentrations10. The negative feedback of estradiol on FSH still occurs, but the resting concentration of FSH is higher than in younger women. The concentrations of FSH at the mid-cycle surge and in the late luteal phase are also greater. LH levels tend to remain within the normal range until the cessation of menses. Ovulatory cycles may still occur with increased levels of FSH, providing evidence that the ovary gradually becomes less responsive to gonadotrophins. The timing of menses may become more irregular, and most cycles become anovulatory, as the ovaries become

The climacteric and the menopause

depleted of antral follicles11,12 and no longer respond to FSH. Estradiol levels decline until they are so low that the endometrium no longer undergoes proliferation, and becomes atrophic. The endometrium is no longer shed and menses cease. As well as a decline in estradiol levels, androgen levels also decrease from an average of 1.6 to 0.5 nmol/L. This reduction in androgen levels has been used to explain the decrease in libido sometimes experienced by postmenopausal women. As a secondary effect of reduced estradiol concentrations, FSH and LH levels rise, owing to a lack of negative feedback on the pituitary gland. While the postmenopausal ovary produces minimal estradiol, it continues to produce quite significant amounts of testosterone and, to a lesser extent, androstenedione, produced by the stromal cells of the ovary. These androgens, predominantly adrenal andro­ stenedione, are converted peripherally by aromatase into estrone. The extent to which this happens depends on age and weight (fat mass). Heavier women have higher conversion rates and circulating estrogen concentrations than slim women. The average percentage of conversion in menopausal women is 2.8%, double that found in premenopausal women. The relative change in balance between estrogen and androgen production in older women13,14 may account for the increased incidence of hirsutism in this group.

Skin changes after the menopause The predominant process is progressive atrophy of the dermis and architectural changes leading to folds and wrinkles. The extent to which this occurs varies from individual to individual and depends on genetic and environmental factors. The generalized aging process of the skin involves the vagina and vulva too. Estradiol is essential to the maintenance of the elasticity and lubrication of the vagina. Most of the changes in the vulva and vagina associated with the menopause are secondary to low estradiol concentrations, as they can be reversed by the topical application of estradiol. In areas such as the vulva and vagina, which are protected from ultraviolet light, the epidermis becomes very thin. There is a reduced

11

Figure 1.7  Fused labia. This condition occurred secondary to postmenopausal skin changes.

number of capillaries within the skin and elastotic changes occur in the arterioles. With time, the withdrawal of estrogens causes the vaginal skin to lose its folds, and the vaginal epithelium becomes thin and friable, making it more susceptible to trauma, with the result that it bleeds. This is a very common cause of postmenopausal bleeding, especially in the older woman. The atrophic changes that affect the vulva predispose it to trauma, often secondary to excessive itching. This may lead to ulceration or scar formation as the wounds heal. In a few women, this leads to fusion of the labia majora (Figures 1.7 and 1.8). Hormone replacement therapy (HRT) has been shown to increase surface lipid concentrations and the water-holding capacity of the skin. This change may improve the function of the skin as a

Chapter

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Hormonal Changes during Puberty, Pregnancy, and the Menopause

hormonal milieu is important in understanding the etiology of certain skin-related complaints. However, it is equally important not to apportion a physiologic explanation for many other conditions that come and go – often regardless of changes in the woman’s serum endocrinology. This is particularly true in pregnancy.

12

References

Figure 1.8  Surgical correction of fused labia. The same patient as in Figure 1.7, after surgical opening.

barrier and reduce skin dryness. There is also evidence that HRT can increase the collagen content in the dermis by up to 6.5%15.

Conclusion A woman’s skin is affected by the many hormonal changes that occur during her lifetime. The degree to which each individual is affected depends on genetic and environmental factors. There is sound research to support the hormonal basis for some skin changes. An appreciation of the prevailing

  1. Tanner, J. M. and Whitehouse, R. H. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch. Dis. Child. 1976; 51: 170–179.   2. Cunningham, S. K., Loughlin, T., Culliton, M., et al. Plasma sex hormone binding globulin levels decline during the second decade of life irrespective of pubertal status. J. Clin. Endocrinol. Metab. 1984; 58: 915–918.   3. Smith, C. P., Archibald, H. R., Thomas, J. M., et al. Basal and stimulated insulin levels rise with advancing puberty. Clin. Endocrinol. 1988; 28: 7–14.  4. Balen, A. H., Conway, G. S., Kaltsas, G., et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum. Reprod. 1995; 10: 2107–2111.   5. Burghen, G. A., Givens, J. R., and Kitabchi, A. E. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J. Clin. Endocrinol. Metab. 1980; 50: 113–116.  6. Brown, S. K. and Shalita, A. R. Acne vulgaris. Lancet 1998; 351: 1871–1876.   7. Chang, A. L., Agredano, Y. Z., and Kimball, A. B. Risk factors associated with striae gravidarum. J. Am. Acad. Dermatol. 2004; 51: 881–885.   8. Atwal, G. S. S., Manku, L. K., Griffiths, C. E. M., et al. Striae gravidarum in primiparae. Br. J. Dermatol. 2006; 155: 965–969.   9. Elling, S. V. and Powell, F. C. Physiological skin changes in the skin during pregnancy. Clin. Dermatol. 1997; 15: 35–43. 10. Gougeon, A. Ovarian follicular growth in humans: ovarian ageing and population of growing follicles. Maturitas 1998; 30: 137–142. 11. Lee, S. J., Lenton, E. A., Sexton, L., et al. The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles. Hum. Reprod. 1988; 3: 851–855. 12. Faddy, M. J. and Gosden, R. G. A mathematical model of follicle dynamics in the human ovary. Hum. Reprod. 1995; 10: 770–775. 13. Richardson, S. J. and Nelson, J. F. Follicular depletion during the menopausal transition. Ann. N.Y. Acad. Sci. 1990; 592: 13–20. 14. Rannevik, G., Jeppsson, S., Johnell, O., et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995; 21: 103–113. 15. Hall, G. and Phillips, T. J. Estrogen and skin: the effects of estrogen, menopause and hormone replacement therapy on the skin. J. Am. Acad. Dermatol. 2005; 53: 555–568.

PART: I  Obstetrics

CHAPTER 2

Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis Martin M. Black Catherine J. M. Stephens

Introduction The activity of many skin diseases fluctuates in relation to the menstrual cycle. Some eruptions are confined to the premenstrual period and are considered as part of the premenstrual syndrome. Furthermore, many chronic dermatoses also flare premenstrually. Since the menstrual cycle is controlled by the sex hormones, premenstrual deterioration is thought to be an effect of progesterone, the predominant circulating hormone of the premenstrual period. Hypersensitivity to progesterone can be demonstrated in some of these cases, when the condition is known as autoimmune progesterone dermatitis1. However, hypersensitivity to estrogens may also occur (autoimmune estrogen dermatitis), although it is rarer than with progesterone2.

Sex hormones and the skin The skin is highly sensitive to the effects of the sex steroid hormones, both estrogen and progesterone, as well as to androgens. Estrogens have been shown to suppress sebaceous activity but have little or no effect on the apocrine glands. They increase dermal hyaluronic acid levels with a consequent increase in the water content of the dermis and slow the breakdown of dermal collagen, possibly by increasing the conversion of soluble collagen to the insoluble form. Estrogens also stimulate epidermal melanogenesis, accounting for the transient hyperpigmentation that commonly occurs premenstrually, particularly around the eyes and nipples, and they have also been shown to slow the rate of hair growth. Estrogens alone appear to possess anti-inflammatory properties and will reduce the cutaneous response in delayed hypersensitivity reactions.

Chapter 14

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Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis

The way in which natural progesterone affects the skin is less clear. The vascularity of the skin is greatly increased during the second half of the menstrual cycle and there is increased sebaceous gland activity, producing seborrhea and, frequently, mild premenstrual acne. Although the mechanism of action is not known, these are both likely to be effects of progesterone.

The perimenstrual dermatoses The premenstrual syndrome Perimenstrual eruptions fall into three categories. An eruption recurring cyclically, and confined to the premenstrual period, may be considered part of the premenstrual syndrome (PMS) (Table 2.1). A specific endocrine etiology for PMS has not yet been defined. Changes in endorphins, prostaglandins, and prolactin3 have all been implicated, but because of the temporal association of symptoms with the luteal phase of the menstrual cycle an abnormality of progesterone is strongly suspected3. Several hypotheses for a progesteronerelated effect have been proposed, but not proven, including progesterone deficiency4, a relative imbalance of estrogen and progesterone levels, and a progesterone allergy5. Acne vulgaris is one of the most common disorders treated by dermatologists. It is a disease of the pilosebaceous unit leading to the formation of open and closed comedones, papules, pustules, nodules, and cysts. The noninflammatory lesions

are open comedones (blackheads) and closed comedones (whiteheads). Papules and pustules constitute the superficial inflammatory lesions, and cysts and nodules, and occasionally deep pustules, make up the deep lesions. In most patients several types of acne lesions are present simultaneously. In mild acne, scattered comedones and/or papules with a few pustules predominate. In moderate acne more papules and pustules are present (Figure 2.1), whereas nodulocystic lesions usually predominate in severe acne. Mild facial acne is reported by up to 70% of women during the premenstrual period, often accompanied by excessive greasiness of the scalp. Perioral dermatitis, which is common in teenage girls, is quite frequently cyclical. In addition, edema of the hands and feet, and more rarely patchy pigmentation of the skin, may occur transiently as part of PMS.

Table 2.1  The Premenstrual Syndrome Seborrhea, acne vulgaris Edema, weight gain Nausea, vomiting Constipation, frequency of micturition Breast fullness/tenderness Headache, migraine Excitability, irritability Lethargy, malaise, depression

Figure 2.1  Acne vulgaris. Premenstrual flares are extremely common.

The perimenstrual dermatoses

If premenstrual acne requires treatment, a topical antiseptic–keratolytic preparation (e.g., benzoyl peroxide) or antibiotic (e.g., clindamycin 1% solution) is usually helpful, but suppression of ovulation, and thus the postovulatory surge of progesterone, can also be effective. The choice of oral contraceptive pill is also important, as some synthetic progestogens (e.g., norethisterone, levonorgestrel) tend to make acne worse (­Figure 2.2). For any acne-prone patient, a combined pill ­ containing gestodene, desogestrel, or norgestimate is recommended. These progestogens appear not to have a stimulatory effect on sebaceous glands. Conversely, they raise levels of sex hormone-­binding globulin, so reducing the level of free testosterone, producing a clinical antiandrogenic effect6. Although a progestogen is frequently prescribed for symptoms of PMS in which a functional deficit of natural progesterone is suspected4, it currently has no place in the management of premen­ strual acne.

Premenstrual exacerbation of existing dermatoses Many women complain of cyclical premenstrual worsening of existing dermatoses (Table 2.2). This is a common phenomenon. Inflammatory disorders, particularly of the face, become more active and irritable premenstrually, in part due to the hormonal effects of increased cutaneous vascularity, seborrhea, and dermal edema. Acne vulgaris (see Figure 2.1), rosacea (Figure 2.3), and the

various forms of lupus erythematosus (Figure 2.4) are notable examples. Premenstrual flares are also well recognized in young women with psoriasis, atopic eczema (Figure 2.5), lichen planus, dermatitis herpetiformis7, pompholyx, and urticaria. Pemphigoid (herpes) gestationis may persist postpartum, classically falling into a pattern of premenstrual exacerbations8. Herpes simplex and aphthosis, although frequently recurrent, are often not strictly cyclical.

Table 2.2  Chronic Dermatoses that may Flare ­Premenstrually Acne vulgaris Acne rosacea Lupus erythematosus Psoriasis Atopic eczema Lichen planus Dermatitis herpetiformis Pompholyx Urticaria Erythema multiforme Pruritus vulvae Pemphigoid gestationis

Norethisterone May cause acne Levonorgestrel

Gestodene Desogestrel

Improve acne

Norgestimate

Figure 2.2  Synthetic progestogens used in the combined oral contraceptive pill which may affect acne.

Figure 2.3  Acne rosacea may flare premenstrually.

15

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Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis

16

Autoimmune progesterone dermatitis Autoimmune progesterone dermatitis (AIPD) is a rare condition characterized by recurrent premenstrual exacerbations of a dermatosis in which sensitivity to progesterone can be demonstrated1.

History

Figure 2.4  Subacute cutaneous lupus erythematosus.

The first case report of a cyclical eruption in which an allergy to endogenous sex hormones was suggested was by Géber9, who in 1921 reported a case of menstrual urticaria in which the eruption could be reproduced by autoinjection of premenstrual serum. The concept of sex hormone sensitization was extended in 1945 when Zondek and Bromberg10 described several patients with conditions related to menstruation and the menopause, including cases of cyclical urticaria. They demonstrated positive delayed hypersensitivity reactions to intradermal progesterone in affected patients but not in healthy controls, evidence of passive cutaneous transfer of skin reagins, and clinical suppression by desensitization. In 1951, Guy et al.11 reported a patient with premenstrual urticaria who reacted strongly to intradermal injections of extracts of corpus luteum and was later successfully treated by desensitization. The term “autoimmune progesterone dermatitis” was eventually introduced in 1964 by Shelley et al.12, who were also the first to document a partial response to estrogens, and cure by oophorectomy.

Clinical manifestations

Figure 2.5  Atopic eczema is frequently less manageable premenstrually. Here, the dermatitis involves the eyelids as well as more typical areas such as the antecubital and popliteal fossae.

Increased cutaneous vascularity and the increased metabolic rate that occurs ­premenstrually will aggravate pruritic conditions (e.g., eczema and pruritus vulvae) and, in general, tolerance of a dermatosis is often lowered in women with premenstrual tension at this time of the cycle.

Various clinical morphological features are described, including eczema (Figure 2.6)13–15, erythema multiforme (Figures 2.7 and 2.8)10,15–18, urticaria (Figure 2.9)11,15,19–21 , pompholyx15–22, stomatitis23, and a dermatitis herpetiformis-like eruption (Figure 2.10)7 (Table 2.3). Other unusual variants include cases resembling erythema annulare centrifugum and cyclical episodes of purpura with petechiae24,25.The eruptions do not appear to differ morphologically or histologically from the noncyclical variants. The condition is confined to ovulating women. Onset is usually in early adult life, occasionally after a normal pregnancy, and the duration is very variable, with

Autoimmune progesterone dermatitis 17

Figure 2.6  Autoimmune progesterone dermatitis. Flexural lichenified eczema.

Figure 2.7  Autoimmune progesterone dermatitis.

Figure 2.9  Autoimmune progesterone dermatitis. ­Polycyclic urticarial lesions.

the menstrual cycle, peaks premenstrually, and regresses spontaneously with the menstrual flow. Skin lesions are less florid, or the skin may be clear during the first half of the cycle. By definition, the eruption recurs clinically during every ovulatory cycle, but the diagnosis may be difficult to make when menses are irregular and in association with endometriosis26.

Mechanism of sensitization

Figure 2.8  Erythema multiforme.

s­ pontaneous ­ remissions occurring. Two-thirds of patients have been exposed to exogenous progesterone in the form of the oral contraceptive pill prior to the eruption15. Typically the dermatosis appears to flare during the second half of

The mechanism by which women become sensitive to their own progesterone is not known. One frequently quoted hypothesis is that previous use of exogenous progestogens induces allergy to endogenous progesterone. It is suggested that synthetic progesterone is sufficiently antigenic to act as a stimulus for antibodies which then cross-react with natural progesterone and perpetuate the immune response premenstrually15. However, not all women with AIPD have been exposed to synthetic

Chapter

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Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis

18

Table 2.3  Autoimmune Progesterone Dermatitis Eczema Erythema multiforme Urticaria/angioedema Pompholyx Stomatitis Dermatitis herpetiformis Erythema annulare centrifugum

Severity of eczema

Nonspecific papular erythema

10 9

Menses

8 7 6 5 4 3 2 1 0

Figure 2.10  Autoimmune progesterone dermatitis. Excoriated papules over the elbows resembling dermatitis herpetiformis.

December 1985

January 1986

February 1986

Figure 2.11  Autoimmune progesterone dermatitis. Patient’s diary cards confirm recurrent premenstrual exacerbations of eczema.

­ rogestogens. Schoenmakers et al.27 suggested p that steroid cross-sensitivity could be an alternative sensitizing mechanism after demonstrating cross-sensitivity on cutaneous testing between ­hydrocortisone and 17-hydroxyprogesterone in five of 19 corticosteroid-sensitive women, two of whom had features of AIPD. Stephens et al.28 were, however, unable to demonstrate steroid cross­sensitivity in five patients with AIPD and obtained no positive reactions to 17-hydroxyprogesterone.

spontaneous improvement or clearing during pregnancy has been reported in other cases13,19,20. Pregnancy is known to ameliorate many allergic states; therefore it is suggested that there is a low maternal immunological reaction during pregnancy, probably due to the raised cortisol levels that occur. It is also possible that the gradual rise in the hormone levels during pregnancy brings about hormonal desensitization in some individuals.

Pregnancy

Evidence for progesterone sensitivity

In three cases, onset or a worsening of the eruption has been reported during pregnancy18,29,30, as well as premenstrual exacerbations. This is not unexpected, as progesterone and estrogen levels rise steadily throughout pregnancy. Two cases were associated with spontaneous abortion. ­ However,

All patients with AIPD show cyclical premenstrual exacerbations of the eruption (Figure 2.11), which, with the use of accurate diary cards, may be shown to correspond to the postovulation rise in serum progesterone concentration. In addition, the eruption is frequently resistant to ­conventional

Autoimmune progesterone dermatitis 19

Figure 2.13  Autoimmune progesterone dermatitis. Skin necrosis commonly occurs at sites of progesterone ­intradermal testing.

have been associated with a serum-binding factor to 17-hydroxyprogesterone32,33.

Progesterone intradermal tests

Figure 2.12  Progesterone intradermal testing demonstrating irritant reactions with necrosis at test sites. Such results cannot be interpreted.

therapy, irrespective of clinical type, but responds to anovulatory drugs. This implies sex hormone sensitivity, but not necessarily an antibody­mediated reaction to progesterone. Hypersensitivity to progesterone may be demonstrated by controlled intradermal tests, intramuscular or oral progesterone challenge, or the demonstration of circulating antibodies to progesterone14,31 or the corpus luteum19,31. Two cases

Intradermal tests using synthetic progesterone are reported to show an immediate positive urticarial reaction in some cases, but more frequently a delayed hypersensitivity reaction. Intradermal tests, although frequently used, in the authors’ experience are unpredictable because of the insolubility of progesterone in water, and the fact that all diluents are highly irritant. Reactions are often difficult to interpret, and false-positive reactions can occur (Figure 2.12). Furthermore, skin necrosis at test sites, producing scarring, often occurs (Figure 2.13). However, a persistent late reaction confined to test sites implies progesterone sensitivity. Recommended procedures for progesterone ­Intradermal tests

Various dilutions of progesterone solution 0.2 mL, plus controls of diluent alone, are injected intradermally into the anterior aspect of the forearm to produce a well-defined raised bleb. Pure progesterone powder is solubilized using a 60% ethanol– saline mixture to produce 1%, 0.1%, and 0.01% test solutions. Ethanol–saline (60%) alone and normal saline should be used as controls.

Chapter 20

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Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis

Estrogen sensitivity may be investigated concurrently using ethinylestradiol and the same diluent. Readings should be made every 10 minutes for half an hour then every 30 minutes for the first 4 hours, and at 24 and 48 hours. Immediate irritant reactions to diluent alone may occur, in which case all early reactions at test sites should be discounted. A positive reaction to progesterone is said to occur if a persistent wheal-and-flare reaction is present exclusively at the progesterone test sites, between 24 and 48 hours (Figure 2.14).

Intramuscular and oral progesterone challenge Challenge with intramuscular progesterone has been reported in six cases and produced a flare of the eruption in all six patients. Testing should be undertaken during the first half of the ­ menstrual cycle

when the eruption would normally be quiescent, and the patient observed carefully as severe exacerbations of urticaria with angioedema, although extremely uncommon, have been reported. The authors have used Gestone 25 mg/mL successfully for intramuscular challenge. Placebo-controlled oral challenge may also be of value, again if performed during the first half of the menstrual cycle. Dydrogesterone 10 mg daily for 7 days or levonorgestrel 30 μg made up to 500mg capsules with lactose, one per day for 7 days followed by 7 days of lactose-only capsules, may be used. Oral challenge is less reliable, as the eruption may not flare dramatically and may therefore be difficult to interpret.

Challenge following chemical oophorectomy The optimum test for AIPD, to be recommended only if the patient is so severely affected as to be considering surgical oophorectomy, is to perform a chemical oophorectomy using subcutaneous injections of a luteinizing hormone-releasing hormone (LHRH) antagonist over a 6-month period, and document clearance of the eruption alongside hormonal confirmation of absence of ovulation. Goserelin 3.6 mg by subcutaneous injection may be used for this purpose. If progesterone challenge then produces a flare of the eruption, this is ­substantial evidence for progesterone sensitivity.

Treatment

Figure 2.14  Positive progesterone intradermal test results. Persistent wheal and flare at two progesterone test sites.

The majority of patients with AIPD encountered have failed to respond to conventional treatment modalities, although oral prednisone (prednisolone) in moderately high doses may bring about control13,17,22. Many patients, however, respond well to conjugated estrogens, presumably as a result of suppression of ovulation and hence the postovulatory rise in progesterone level. In practice, however, estrogen therapy is often not appropriate in view of the patient’s age. When estrogen therapy is unsuccessful, the antiestrogen anovulatory drug tamoxifen may be tried. Tamoxifen 30 mg has caused complete remission,13,18,34, but with consequent amenorrhea. A lower dose was achieved in one patient, with return of ­ menstruation but not the rash. No side-effects were encountered.

References

The anabolic androgen danazol (200 mg twice daily started 1–2 days before the expected date of menses, and continuing for 3 days thereafter) has proved highly effective in two patients35. In severe cases, when the patient is unable to tolerate medical treatment, oophorectomy will clear the eruption and cure the disease12,36. Suppression of AIPD urticaria by chemical oophorectomy using the LHRH analog buserelin has been reported37. In the authors’ experience, many cases of AIPD slowly settle spontaneously after a period of successful treatment.

Autoimmune estrogen dermatitis It is known that estrogen sensitivity can cause a clinical syndrome very similar to AIPD. The range of clinical expression includes papulovesicular eruptions, eczema, urticaria, localized pruritus (vulval or anal), and generalized pruritus. The condition is rarer than AIPD, but the hallmark of autoimmune estrogen dermatitis is the cyclical premenstrual flare2. In some cases, the inflammatory papulovesicles are localized to the neck, upper trunk, and arms. This localization may reflect estrogen receptor density, which is highest in the skin of the face and surrounding areas38. Intradermal tests are necessary to establish the diagnosis. It is essential that intradermal test materials are injected subepidermally to raise a superficial bleb and minimize rapid lymphatic removal. Shelley et al.2 recommend using sterile aqueous suspensions of pure estrone (0.1 mL in a 1:1000 dilution) to be injected with a tuberculin syringe with a 27-gauge needle. Persistence of a papule for more than 24 hours is considered a positive test result. Oral challenges may also be done with ethinylestradiol, but a positive result may only support the concept of an estrogen-aggravated dermatitis. To show true sensitization, intradermal skin tests are needed. Autoimmune estrogen dermatitis has been demonstrated in a patient presenting with urticaria in early pregnancy39. As with APID, treatment of autoimmune estrogen dermatitis has been successful with tamoxifen (10 mg twice daily), which may need to be administered only intermittently to control the eruption. Ultimately, the condition is likely to go into remission.

21

References   1. Herzberg, A. J., Strohmeyer, C. R., and Cimillo-Hyland, V. A. Autoimmune progesterone dermatitis. J. Am. Acad. ­Dermatol. 1995; 32: 335–338.   2. Shelley, W. B., Shelley, E. D., Talanin, N. Y., et al. Estrogen dermatitis. J. Am. Acad. Dermatol. 1995; 32: 25–31.   3. Strickler, R. C. Endocrine hypothesis for the aetiology of premenstrual syndrome. Clin. Obstet. Gynaecol. 1987; 30: 377–383.   4. Dalton, K. The Premenstrual Syndrome and Progesterone Therapy. 2nd edn. Year Book Medical Publishers, Chicago, 1984.   5. Maxson, W. S. The use of progesterone in the treatment of PMS. Clin. Obstet. Gynaecol. 1987; 30: 465–477.   6. Anonymous. Starting oral contraceptives – which, when and how? Drug Ther. Bull. 1992; 30: 41–44 (erratum in Drug Ther. Bull.1992; 30: 56).   7. Leitao, E. A. and Bernhard, J. D. Perimenstrual nonvascular dermatitis herpetiformis. J. Am. Acad. Dermatol. 1990; 22: 331–334.   8. Holmes, R. C. and Black, M. M. The specific dermatoses of pregnancy – a reappraisal with specific emphasis on a proposed simplified clinical classification. Clin. Exp. Dermatol. 1982; 7: 65–73.   9. Géber, H. Einege Daten zur Pathologie der Urticaria ­menstruationalis. Dermatol. Z. 1921; 32: 143–150. 10. Zondek, B. and Bromberg, Y. M. Endocrine allergy: ­allergic sensitivity to endogenous hormones. J. Allergy 1945; 16: 1–16. 11. Guy, W. H., Jacobs, F. M., and Guy, W. B. Sex hormone ­sensitisation (corpus luteum). Arch. Dermatol. 1951; 63: 377–378. 12. Shelley, W. B., Prencel, R. W., and Spoont, S. S. Autoimmune progesterone dermatitis: cure by oophorectomy. J.A.M.A. 1964; 190: 35–38. 13. Stephens, C. J. M., Wojnarowska, F. T., and Wilkinson, J. D. Autoimmune progesterone dermatitis responding to tamoxifen. Br. J. Dermatol. 1989; 121: 135–137. 14. Jones, W. N. and Gordon, V. H. Autoimmune progesterone eczema: an endogenous progesterone hypersensitivity. Arch. Dermatol. 1969; 99: 57–59. 15. Hart, R. Autoimmune progesterone dermatitis. Arch. ­Dermatol. 1977; 113: 426–430. 16. Stone, J. and Downham, T. Autoimmune progesterone ­dermatitis. Int. J. Dermatol. 1981; 20: 50–51. 17. Torras, H., Fenaudo, H., and Mallolas, J. Postovulation ­dermatitis (dermatitis caused by progesterone). Med. Cutan. Ibero Lat. Am. 1980; 8: 15–21. 18. Wojnarowska, F., Greaves, M. W., and Peachey, R. D. ­Progesterone induced erythema multiforme. J.R. Soc. Med. 1985; 78: 407–408. 19. Farah, F. S. and Shbaklu, Z. Autoimmune progesterone ­urticaria. J. Allergy Clin. Immunol. 1971; 48: 357–361. 20. Georgouras, K. Autoimmune progesterone dermatitis. Aust. J. Dermatol. 1981; 22: 109–111. 21. Tromovitch, T. and Heggli, W. Autoimmune progesterone ­urticaria. Calif. Med. 1967; 106: 211–212. 22. Anderson, R. H. Autoimmune progesterone dermatitis. Cutis. 1984; 33: 490–491. 23. Berger, H. Ulcerative stomatitis caused by endogenous ­progesterone. Ann. Intern. Med. 1955; 42: 205–208. 24. Halery, S., Cohen, A. D., Lunenfield F., et al. Autoimmune progesterone dermatitis manifested as erythema annulare ­centrifugum. J. Am. Acad. Dermatol. 2002; 47: 311–313.

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Perimenstrual Skin Eruptions, Autoimmune Progesterone Dermatitis, Autoimmune Estrogen Dermatitis 25. Wintzen, M., Goor-van Egmond, M. B. T., and Noz, K. C. Autoimmune progesterone dermatitis presenting with purpura and petechiae. Clin. Exp. Dermatol. 2004; 29: 316. 26. Baptist, A. P. and Baldwin, J. L. Autoimmune progesterone ­dermatitis in a patient with endometriosis.: case report and review of the literature. Clin. Mol. Allergy 2004; 2: 10–15. 27. Schoenmakers, A., Vermorken, A., Degreef, H., et al. ­Corticosteroid or steroid allergy. Contact Dermatitis 1992; 26: 159–162. 28. Stephens, C. J. M., McFadden, J. P., Black, M. M., et al. ­Autoimmune progesterone dermatitis. Absence of contact ­sensitivity to glucocorticoids, oestrogen and 17-OHprogesterone. Contact Dermatitis 1994; 31: 108–110. 29. Mayou, S. C., Charles-Holmes, R., Kenney, A., et al. A premenstrual eruption treated with bilateral oophorectomy and hysterectomy. Clin. Exp. Dermatol. 1988; 13: 114–116. 30. Bierman, S. M. Autoimmune progesterone dermatitis of pregnancy. Arch. Dermatol. 1973; 107: 896–961. 31. Veda, T., Matuda, M., Yambe, H. et al. Two cases of autoimmune progresterone dermatitis. In Wilkinson, D. S., Mascaro, J. M., and Orfanos C. E. (eds). Clinical Dermatology. The CMD Case Collection, pp. 214–215. Schattauer Stuggart, New York, 1987. 

32. Pinto, J. S., Sobrinho, L., da Silva, M. B., et al. ­Erythema multiforme associated with autoreactivity to 17 ­hydroxyprogesterone. Dermatologica 1990; 26: 159–162. 33. Cheesman, K. L., Gaynor, L. V., Chatterton, R. T.Jr., et al. ­Identification of a 17-hydroxyprogesterone-binding ­immunoglobulin in the serum of a woman with periodic rashes. J. Clin. ­Endocrinol. Metab. 1982; 55: 597–599. 34. Nabai, H. and Rahbari, H. Autoimmune progesterone ­dermatitis treated with tamoxifen. Cutis 1994; 54: 161–162. 35. Shahar, E., Bergman, R. and Pollack, S. Autoimmune ­progesterone dermatitis: effective prophylactic treatment with danazol. Int. J. Dermatol. 1997; 36: 708–711. 36. Ródenas, J. M., Herranz, M. T., and Tercedor, J. Autoimmune progesterone dermatitis: treatment with oophorectony. Br. J. Dermatol. 1998; 139: 508–511. 37. Yee, K. C. and Cunliffe, W. J. Progesterone-induced urticaria: response to buserelin. Br. J. Dermatol. 1994; 130: 121–123. 38. Hasselquist, M. B., Goldberg, N., Schroeter, A. et al. Isolation and characterisation of the estrogen receptor in human skin. J. Clin. Endocrinol. Metab. 1980; 50: 76–82. 39. Lee, A. Y., Lee, K. H. and Lim, Y. G. Oestrogen urticaria ­associated with pregnancy. Br. J. Dermatol. 1999; 141: 774.

PART: I  Obstetrics

CHAPTER 3

Physiologic Skin Changes of Pregnancy Samantha Vaughan Jones Pregnancy induces a number of changes in the skin, hair, and nails which are regarded as physiological. It is important to recognize that these changes occur so they are not confused with true skin diseases. The physiological changes can be divided into several categories (Table 3.1).

Hyperpigmentation Localized or generalized hyperpigmentation occurs to some extent in 90% of pregnant women. These changes are most prominent in patients with darkly pigmented skin, although they occur to some degree in fair-skinned individuals. Perhaps the most familiar example is the darkening of the lower abdominal midline, the linea alba. This is described in obstetric textbooks as an early change of pregnancy, but it may not be apparent until several months’ gestation, especially in a first pregnancy. The midline streak usually proceeds from the symphysis pubis to the umbilicus, and can extend to the xiphoid process (Figures 3.1–3.4). It tends to appear earlier in subsequent pregnancies. The nipples and areolae become pigmented (see Figures 3.2–3.4), as do the external genitalia and the axillae (Figure 3.5). Darkening of the neck is particularly bothersome to some patients (Figure 3.6), but this gradually fades postpartum, along with other pigmentary changes. Striae (“stretch marks”) are common, and may darken in susceptible individuals (Figure 3.7), along with other scars, nevi, and freckles although these pigmentary changes tend to regress postpartum. Vulvar melanosis may also develop during pregnancy (Figure 3.8). This increased melanogenesis is Table 3.1  Physiologic Changes in Skin, Hair, and Nails Hyperpigmentation

Hair and nail changes

Melasma

Vascular changes

Striae distensae

Apocrine/eccrine gland activity

Pruritus gravidarum

Immunological skin changes

Chapter

3

Physiologic Skin Changes of Pregnancy

typical, the entire central face is affected in most patients, including the forehead, cheeks, upper lip, nose, and chin. It occurs in the second trimester in three-quarters of pregnant women and in one-third of those taking oral contraceptive pills (OCPs). Melasma is thought to be due to hormonal influences, and is worsened by sun exposure. It usually fades within a year after pregnancy or discontinuation of OCPs. Histologically, excessive melanin deposition is seen either in the epidermis or dermal macrophages2. Melasma is persistent in approximately 30% of patients, whether induced by pregnancy or estrogencontaining OCPs. Epidermal pigment (accentuated by Wood’s light examination) is most responsive to bleaching with topical hydroquinone creams and tretinoin after pregnancy. During pregnancy, treatment should include potent sunscreen and avoidance of ultraviolet radiation and irritant cosmetics.

24

Striae distensae

Figure 3.1  Hyperpigmentation. Darkening of the linea alba from the symphysis pubis to the xiphoid process during pregnancy. (Reproduced from C. M. Lawrence and N. H. Cox Color Atlas and Text of Physical Signs in Dermatology   (Fig. 6.28), Wolfe, London, 1993.)

thought to be a result of increased levels of alpha and beta-melanocyte-­stimulating hormone (MSH), betaendorphin, estrogen, and progesterone1. Some dark-skinned people (male and female) have pigmentary demarcation lines (also called Voigt or Futcher lines) along the outer portion of the upper arms and/or posterior legs. These may not have been noticed by the patient until the general darkening of pigment during pregnancy makes them more prominent (Figures 3.9 and 3.10).

Melasma Melasma (formerly called chloasma, or the “mask of pregnancy”) is symmetrical macular hyperpigmentation of the face (Figure 3.11). This can occur in three patterns – centrofacial, malar, or mandibular, depending on the distribution of pigmentation. Although the malar pattern is ­considered

The so-called stretch marks, which occur in almost all pregnant women during the second and third trimester, are linear, pink-to-purplish, atrophic lines that develop at right angles to the skin tension lines on the abdomen, breasts, buttocks, thighs, and groin (Figures 3.12 and 3.13). They are the same as those seen in patients with Cushing’s syndrome, steroid therapy, and rapid changes in body weight. They are uncommon in black or Asian women and there may be a familial predisposition3. The red coloration typically becomes flesh-colored or pale with time (with or without topical creams of various kinds) but, although the atrophic lines may be thinner after delivery, they do not disappear completely. The effects of topical tretinoin, 0.1% or 0.025% cream on the appearance of striae is still debated, with conflicting results in the literature4,5. As this is a topical retinoid it is contraindicated during pregnancy and may also have an irritant effect.

Hair and nail changes Hirsutism – profuse growth of body hair – is seen in most pregnant women. It is more noticeable in women with dark and/or abundant body hair. It is thought to be due to increased ovarian production of androgens during pregnancy. The short lanugo

Hair and nail changes 25

Figures 3.2–3.4  Hyperpigmentation. Three different patterns of skin darkening in African Americans, as seen immediately postpartum. Note the differences in striae formation on the abdomen and breasts, as well as patterns of pigmentation of the linea nigra, nipples, and areolae.

Figure 3.6  Hyperpigmentation. Darkening of the neck in an African American woman. This is cosmetically distressing to some patients, but will fade slowly.

Figure 3.5  Hyperpigmentation. Pseudoacanthotic pigmentation of the axilla in another African American woman, who also had darkening of the vulva.

Figure 3.7  Striae distensae. Pigmentation of new striae that have developed during pregnancy; older striae remain pale.

Chapter

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Physiologic Skin Changes of Pregnancy

26

Figure 3.8  Vulvar melanosis. This benign change developed during pregnancy and did not require treatment.

Figure 3.10  Pigmentary demarcation lines. These lines, also known as Voigt or Futcher lines, can be seen on the posterior legs. They were not noticed by the patient until they darkened during pregnancy.

Figure 3.9  Pigmentary demarcation line. This can be seen on the upper arm. It has become more prominent during pregnancy.

hairs give the skin a “furry” appearance; however, these disappear postpartum with the development of telogen effluvium. Other diagnoses such as polycystic ovary syndrome and androgen-­secreting ovarian tumors should be excluded if marked hirsutism persists postpartum. Treatment is with reassurance and if necessary cosmetic removal (depilatory creams, electrolysis, or ruby laser) after pregnancy. Telogen effluvium results in the loss of terminal scalp hairs about 1–5 months postpartum; this hair loss can last for up to 1 year or more before regrowth occurs6 (Figure 3.14). The best explanation for this phenomenon is that pregnancy interrupts the normal hair-shedding cycle, with a higher proportion of hairs remaining in the anagen (growing) phase during pregnancy. The

Hair and nail changes 27

Figure 3.12  Striae distensae. These are striae, or stretch marks, over a fair-skinned abdomen. (Reproduced from   G. M. Levene and C. D. Calnan Color Atlas of Dermatology (Fig. 464), Mosby-Wolfe, London, 1994.)

Figure 3.11  Melasma. The “mask of pregnancy” in a typical distribution on the central face. (Reproduced from C. M. Lawrence and N. H. Cox Color Atlas and Text of Physical Signs in Dermatology (Fig. 6.27), Wolfe, London, 1993.)

­ roportion of hairs which enter the telogen (shedp ding) phase is reduced, thus creating thicker hair growth until delivery6. Following delivery, the hair follicles rapidly resume their normal pattern of hair loss (telogen), resulting in excessive shedding of hair. In most cases this hair loss is generally ­diffuse but can occur in a frontoparietal pattern with so-called male-pattern alopecia. However, patients can be reassured that baldness will not occur. Nail changes usually begin in the first trimester. Brittleness or softening may be seen, as may faster growth. Transverse and longitudinal grooving and distal onycholysis have all been noted during pregnancy but the pathogenesis of these changes is not clear. Longitudinal melanonychia has also been described7.

Figure 3.13  Striae distensae. Nonpigmented striae in an African American woman.

Figure 3.14  Telogen effluvium.

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Physiologic Skin Changes of Pregnancy

28

Figure 3.15  Pyogenic granuloma on the lip.

Figure 3.17  Hemorrhoids and vulvar varicosities ­developing during pregnancy.

Figure 3.16  Pyogenic granuloma on the gingiva. (Reproduced from W. R. Tyldesley Color Atlas of Oral Medicine   (Fig. 146), Mosby-Wolfe, London, 1994.)

Vascular changes The vascular system of a pregnant woman undergoes profound changes to accommodate the fetus and its growth. There is a marked increase in blood volume, vascular dilatation, capillary permeability, and neovascularization8. Pyogenic granulomas can develop on mucosal sites (Figures 3.15 and 3.16) or on digits. Varicosities occur to some extent in almost half of all pregnancies (Figure 3.17), and are particularly troublesome in the perianal area (hemorrhoids) and on the legs. Leg and ankle edema is common and may also be

Figure 3.18  Vascular spider.

accompanied by swelling of the hands and eyelids. For varicosities and swelling of the legs, supportive care with leg elevation and elastic stockings is recommended. Patients should avoid prolonged standing or sitting.

Immune system changes

Spider angiomas (nevus araneus, spider nevus) usually develop in the first and second trimesters. Easily recognized by a central red punctum with radiating branches on the upper body, they may be seen in two-thirds of pregnant white women (Figure 3.18). Palmar erythema is also common in about the same number of patients, localized to the thenar or hypothenar eminences (Figure 3.19). The etiology of both is unknown, but is thought to be associated with estrogen or angiogenic factors. These changes usually resolve postpartum. Unilateral nevoid telangectasia syndrome is a collection of spider nevi in a dermatomal distribution, often on the face and neck, and has been described in pregnancy, alcoholic liver disease, and oral contraceptive therapy9,10.

29

Eccrine/apocrine gland activity Eccrine gland activity is increased in pregnancy, leading to an increase in hyperhidrosis and dyshidrotic eczema, while apocrine gland activity is reduced so that Fox–Fordyce disease and hidradenitis suppurativa often improve. Sebaceous gland activity is increased, especially in the third trimester, which can trigger the onset or an exacerbation of acne vulgaris. The sebum excretion rate increases in pregnancy and normalizes after delivery11. In 30–50% of pregnant women brown papules appear on the areolae in early pregnancy. These are Montgomery’s tubercles, which result from hypertrophy of the sebaceous glands but do not persist postpartum.

Immune system changes There are key changes in the immune system during pregnancy which enable the fetus to survive. These changes may help to explain the effects of pregnancy on the skin and the increased susceptibility to certain skin diseases during pregnancy12. The TH2 (subset of CD4+ cells) cytokine pattern is associated with antibody responses ­suggesting that TH2-type cytokines predominate in the ­regulation of the maternal immune response. Interleukins (IL-3, IL-4, IL-5, IL-10, and IL-13) are all TH2 cytokines. Animal studies have shown that these cytokines can be detected in the placenta in

Figure 3.19  Palmar erythema.

all three trimesters of pregnancy. IL-10 suppresses TH1-mediated cellular immunity. The switch from TH1 to TH2 cytokine profile within the placenta thus allows fetal tolerance despite the presence of paternal major histocompatibility complex antigens12. There is also negative feedback so that TH2 cytokines will suppress the production of TH1 cytokines (Figure 3.20). During pregnancy the immune response is therefore biased towards antibody production and away from cell-mediated immunity to enable the fetus (allograft) to survive and to prevent fetal rejection. This may explain the apparent increase in autoimmune skin disease and increased incidence of skin infections. It may also explain why there is often an improvement in psoriasis (TH1mediated) while atopic eczema (TH2-mediated) is exacerbated.

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Physiologic Skin Changes of Pregnancy

30

Antigen-presenting dentritic cells

IL-12

DC1

DC1

pre-Th

pre-Th

?

IL-12

IL-4

Th1

TNF-β

IFN-γ

Th2

IL-4 IL-10

IL-5 IL-13

Macrophages

B cells

Cell-mediated immunity and inflammation

Antibody-mediated immunity

Figure 3.20  Diagram showing TH1and TH2 pathways with negative feedback. (Reproduced from jkimball.ultranet.)

References   1. Wong, R. C. and Ellis, C. N. Physiologic skin changes in pregnancy. J. Am. Acad. Dermatol. 1984; 10: 929–940.   2. Sanchez, N. P., Pathak, M. A., Sato, S., et al. Melasma: A clinical, light microscopic, ultrastructural and immunofluorescent study. J. Am. Acad. Dermatol. 1981; 4: 698–710.

  3. Chang, A. L. S., Agredano, Y. Z., and Kimball, A. B. Risk factors associated with striae gravidarum. J. Am. Acad. Dermatol. 2004; 51: 881–885.   4. Elson, M. L. Treatment of striae distensae with topical tretinoin, Dermatol. Surg. Oncol. 1990; 16: 267–270.   5. Pribanich, S., Simpson, F. G., Held, B. et al. Low dose tretinoin does not improve striae distensae: a double blind, placebo­controlled study. Cutis 1994; 54: 121–124.   6. Winton, G. B. Skin diseases aggravated by pregnancy J. Am. Acad. Dermatol. 1989; 20: 1–13.   7. Fryer, J. M. and Werth, V. P. Pregnancy-associated hyperpigmentation: longitudinal melanonychia. J. Am. Acad. Dermatol. 1992; 26: 493–494.   8. Chanco Turner, M. L. The skin in pregnancy. In Burrow, G. N. and Duffy, T. P. (eds) Medical Complications During Pregnancy, 5th edn, pp. 453–468. W. B. Saunders, Philadelphia, 1999.   9. Woollons, A. and Darley, C. R. Unilateral naevoid telangiectasia syndrome in pregnancy. Clin. Exp. Dermatol. 1996; 21: 459–460. 10. Wilkin, J. K., Smith, J. G., Cullison, D. A. and et al Unilateral dermatomal superficial telangiectasia. Nine new cases and a review of unilateral dermatomal superficial telangiectasia, J. Am. Acad. Dermatol. 1983; 8: 468–477. 11. Graham-Brown, R. A. C. Pregnancy, childbirth and the puerperium. In Rook, A., Wilkinson, D. S., and Ebling, F. J. G. Textbook of Dermatology, 6th edn. pp 3268–3275 Oxford: Blackwells; 1998. :3268–3275. 12. Garcia Gonzales, E., Ahued-Ahued, R., Arrayo, E., et al. ­Immunology of the cutaneous disorders of pregnancy. Int. J. Dermatol. 1999; 38: 721–729.

PART: I  Obstetrics

CHAPTER 4

A Systematic Approach to the Dermatoses of Pregnancy Christina M. Ambros-Rudolph Martin M. Black Introduction Cutaneous symptoms and signs are not uncommon during pregnancy. The physiologic signs of pregnancy (see Chapter 3) often involve the skin or mucous membranes, and can sometimes provide contributory evidence of pregnancy. Although pruritus is the principal cutaneous symptom in pregnancy, itching in itself is not diagnostically helpful. Thus, a full clinical history and a thorough clinical examination are essential to confirm, or exclude, the possibility of any coexisting dermatosis or infestation. The clinical implications of pruritus in pregnancy are outlined in Table 4.1. Chapter 10 describes the effect of pregnancy on other skin disorders. This chapter considers the difficult nomenclature of the specific dermatoses of pregnancy.

Historical background The specific dermatoses of pregnancy represent a heterogeneous group of severely pruritic inflammatory dermatoses closely related to pregnancy and/or the immediate postpartum period. For decades, they have caused great diagnostic confusion. Prior to 1982, the terminology became increasingly confused, with several names being used for similar clinical conditions 1–10(Tables 4.2 and 4.3). The authors have extensively reviewed all the existing literature and have studied a large group of patients comprehensively, covering all the existing disease entities. Similar work was done by Holmes and Black before they published their proposals in 198211 and 198312 of a simplified clinical classification of the specific dermatoses of pregnancy. This classification subdivided the specific dermatoses of pregnancy into four groups: (1) pemphigoid (herpes) gestationis (PG); (2) polymorphic eruption of pregnancy (PEP; synonymous: pruritic urticarial papules and plaques of pregnancy, PUPPP); (3) prurigo of pregnancy (PP); and (4) pruritic folliculitis of pregnancy (PF). Whereas in the

Chapter 32

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A Systematic Approach to the Dermatoses of Pregnancy

Table 4.1  Clinical Implications of Pruritus in Pregnancy Normal skin (‘pruritus gravidarum’)

Table 4.2  Historical List of Specific Dermatoses   of Pregnancy as Described by Various Authors

Disorder

Reference

Year

Herpes gestationis

Milton1

1872

Herpes impetigiformis ­(impetigo herpetiformis)

Hebra2

1872

Prurigo gestationis

Besnier et al.3

1904

Erythema multiforme

Gross4

1931

Prurigo annularis

Davis5

1941

Toxemic rash of   pregnancy

Bourne6

1962

Papular dermatitis of ­pregnancy

Spangler et al.7

1962

Early- and late-onset   prurigo of pregnancy

Nurse8

1968

Pruritic urticarial papules and plaques of pregnancy

Lawley et al.9

1979

Pruritic folliculitis of ­pregnancy

Zoberman and Farmer10

1981

Pre-existing skin condition Skin condition coincidentally acquired in pregnancy Specific dermatoses of pregnancy Pemphigoid gestationis (PG) Polymorphic eruption of pregnancy (PEP) Intrahepatic cholestasis of pregnancy (ICP) Atopic eruption of pregnancy (AEP)

United States the terms “herpes gestationis” and PUPPP are still preferred, in Europe the names PG (points to the autoimmune pathogenesis and avoids any possible association with herpesvirus) and PEP (points to the morphological spectrum) are widely accepted. Unfortunately, except for PG, no reliable criteria exist to differentiate the specific dermatoses of pregnancy13. From time to time “new” disease entities have been reported in the literature, but to date they have remained essentially anecdotal single case reports. Impetigo herpetiformis, for example, is now considered to be a variant of pustular psoriasis (see also Chapter 10). Alcalay et al.14 proposed the term “linear IgM dermatosis of pregnancy,” and described a single case of an intensely pruritic follicular papular eruption, which occurred in the third trimester. Linear deposition of IgM was noted at the dermoepidermal junction, but this disappeared after delivery. However, on clinical grounds, their case would have fitted well into the category of PF. Nevertheless, the proposed, simplified, clinical classification by Holmes and Black has gained wide international acceptance13. For example, a prospective study of 3192 pregnant women with pruritus found that only seven cases could not be classified into a particular subgroup, according to the classification15. In 1998 Shornick16 proposed a further adaptation of the classification by Holmes and Black. He suggested that PF belonged in the group of PP, for all patients with PF in the original report17 were thought to have papular dermatitis ­clinically and were solely classified as being different by their

histopathological features (i.e., sterile ­folliculitis). Since the original description, only a few more cases of PF have been reported and papular dermatitis is nowadays known to belong to the group of PP. Most importantly, Shornick further included intrahepatic cholestasis of pregnancy (ICP; synonymous: obstetric cholestasis) within his classification scheme16. This entity had usually been omitted from classifications of pregnancy dermatoses, as it is not a primary dermatosis but associated with only secondary skin lesions due to scratching. Shornick postulated that failure to appreciate ICP in a pregnant woman with pruritus and excoriated papules probably accounted for some of the confusion in terminology16. The importance of considering ICP within a classification of pregnancy dermatoses has also been supported by Roger et al.15, who in their series observed a high incidence of ICP associated with significant fetal risk and impaired pregnancy outcome. Thus, it seems sensible to include ICP in such a classification, as it is an important ­differential diagnostic

Historical background 33

Table 4.3  Differential Diagnosis of the Specific Dermatoses of Pregnancy

Laboratory Findings

Risks/ Complications

Diagnosis

Clinical Signs

Management

Pemphigoid ­gestationis (PG)   (see Chapter 5)

Erythema, wheals, and ­blisters on abdomen ­(periumbilical involvement), palms, soles, elsewhere

DIF positive (BMZ   of skin and   amnion)

Mother: discomfort and increased risk   of other autoimmune diseases Fetus: blisters,   small-for-date babies

Prednisolone   (0.5–2 mg/kg per day), ­plasmapheresis

Polymorphic   eruption   of pregnancy (PEP) (see Chapter 6)

Papulourticarial rash on ­abdomen (common on striae, periumbilical ­sparing), later polymorphous features

DIF negative

None, other   than mother’s ­discomfort

Moderately potent   topical corticosteroids, ± oral antihistamines

Intrahepatic ­cholestasis of ­pregnancy (ICP)   (see Chapter 7)

Pruritus with only ­secondary skin changes due to scratching ­(excoriations – prurigo lesions)

DIF negative Elevated total   serum bile acid   levels

Mother: discomfort Fetus: fetal distress, prematurity, stillbirth

Ursodeoxycholic acid (15 mg/kg per day)

Atopic eruption of pregnancy (AEP)   (see Chapter 8)

20% exacerbation   of pre-existing atopic eczema; 80% first   manifestation of atopic   skin lesions (E-type, P-type)

DIF negative ±   elevated total   serum IgE   levels

None, other than mother’s discomfort

Moderately   potent topical corticosteroids, ± oral antihistamines

DIF, direct immunofluorescence; BMZ, basement membrane zone; IgE, immunoglobulin E.

consideration associated with potential fetal risk which can increase if the diagnosis is delayed or overlooked. While all authors agreed that PG, PEP, and ICP were distinct entities with stereotypic immunopathological, clinical, or laboratory findings, the group of PP has remained unclear. Even though it has been repeatedly suggested since the first description by Besnier et al.3 that there might be a link to atopy, Holmes and Black12 were the first to postulate that PP might merely be the result of pruritus in atopic pregnant women rather than a distinct entity. Of interest, a prospective study on pruritic skin diseases in pregnancy demonstrated a high prevalence of atopic eczema18. It was the most common skin problem in pregnancy encountered in their series of 200 patients, making it a crucial differential diagnostic consideration that had not been acknowledged by either of the classifications so far.

A recent retrospective study on over 500 pregnant patients with pruritus was able to demonstrate conspicuous overlap in clinical presentation and histopathological findings between pregnant patients with eczema in pregnancy, PP, and PF (together 50% of the total patient collective)19. Based on these observations, all patients with eczema, PP, and PF were summarized within a new disease complex, which the authors termed “atopic eruption of pregnancy” (AEP), following the term “polymorphic eruption of pregnancy.” The term AEP seems preferable to “eczema in pregnancy” or the mere descriptive terms PP or PF, as it describes more accurately the variable manifestations of this disease encountered in pregnancy. This results in a new, rationalized classification of the specific dermatoses of pregnancy as follows: • Pemphigoid gestationis • Polymorphic eruption of pregnancy • Intrahepatic cholestasis of pregnancy • Atopic eruption of pregnancy

Chapter 34

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A Systematic Approach to the Dermatoses of Pregnancy

Table 4.4  Common Skin Disorders that may Mimic   Dermatoses of Pregnancy

Disorder

Clinical Details

Allergic Urticaria (hives)

Does not blister, lesions transient

Drug eruption

Ingestion of medication

Contact dermatitis

Pattern, history of allergen

Common Skin Eruptions Pityriasis rosea

Oval, slightly scaly plaques on trunk, “herald patch” may precede rash by 1–2 weeks. May mimic ­secondary syphilis;   consider serum test for syphilis

Erythema nodosum

Tender red nodules on   shins and lower legs, occasionally seen with pregnancy

Milaria

“Prickly heat,” tiny vesicles on extremities or trunk in hot weather

Insect bites and scabies

Flea bites are most often   on legs, sometimes blister   in sensitive patient.   Scabies has linear papules   in fingerwebs, elbows, areolae

There are a number of other skin disorders that may present during pregnancy and may closely mimic the specific dermatoses of pregnancy (Table 4.4). These should always be considered in the differential diagnosis.

Algorithmic approach to the pregnant woman presenting with pruritus Pruritus is the leading symptom of the specific dermatoses of pregnancy, but may also occur in other dermatoses coinciding by chance with

­ regnancy, including urticaria, drug eruption, p contact ­dermatitis, pityriasis rosea, milaria, and scabies, which have first to be excluded. Then, the four specific dermatoses of pregnancy need to be differentiated. Unequivocal diagnostic tests, namely, immunofluorescence and laboratory investigations, are only available for PG and ICP. However, a pregnant woman with severe pruritus and skin lesions requires urgent clinicopathologic correlation on her condition as well as possibly associated fetal risks, ideally at the first visit before laboratory and biopsy reports are available. A retrospective analysis of a large patient collective revealed the following significant differences which facilitate their discrimination19. Primigravidae and multiple-gestation pregnancies are particularly frequent in patients with PEP. A history of previous pregnancies affected with similar skin changes is typically given in patients with ICP, which is the only disease in that pruritus is the sole presenting symptom, followed by exclusively secondary skin lesions in all patients. While PG, PEP, and ICP characteristically present in late pregnancy, AEP starts significantly earlier, and onset before the third trimester occurs in 75% of patients. Finally, abdominal involvement of skin lesions is stereotypical for PG and PEP, whereas predominant effects on the extremities is observed in ICP patients, compared to equal involvement of trunk and limbs in AEP.

Conclusion It is clear that there is still much to be done in elucidating the pathogenesis of the specific dermatoses of pregnancy. Until this happens, the authors suggest that the simplified clinical classification proposed above should be used. The authors have designed an algorithm which provides a guide to the differential diagnosis, investigation, and treatment of the specific dermatoses of pregnancy (Figure 4.1)19. This will usually provide sufficient clinical diagnostic information to advise and manage the patient. The following chapters deal with each of the specific dermatoses of pregnancy in greater detail.

Conclusion 35 Pruritus in pregnancy

without rash

ICP

Exclusively secondary skin lesions due to scratching (excoriations/prurigo) IMF: non-specific H&E: non-specific LAB: elevated total serum bile acid levels Fetal distress, prematurity, stillbirth

with rash

Non-specific for pregnancy

Steroids, antihistamines, ursodeoxycholic acid

Coinciding skin diseases Specific for pregnancy

Early onset (<3rd trimester) trunk and limbs involved

AEP

20% exacerbated atopic dermatitis 80% first manifestation (E-type/P-type) IMF: non-specific H&E: non-specific LAB: ± elevated serum IgE levels No fetal risk Steroids, antihistamines

PEP Late onset (3rd trimester, pp) predominant abdominal involvement

Papulo-urticarial eruption Onset within striae distensae Periumbilical sparing IMF: non-specific H&E: non-specific LAB: non-specific No fetal risk Steroids, antihistamines

PG

Vesiculo-bullous eruption on urticated erythema Periumbilical involvement IMF: linear C3 along BMZ H&E: ± subepidermal blister LAB: positive indirect IMF Small-for-date babies Steroids, antihistamines

Figure 4.1  An algorithmic approach to the pregnant woman presenting with pruritus19. ICP, intrahepatic cholestasis of pregnancy; AEP, atopic eruption of pregnancy; PEP, polymorphic eruption of pregnancy; PG, pemphigoid gestationis; IMF, ­immunofluorescence; H&E, histopathology; LAB, laboratory findings; pp, postpartum; BMZ, basement membrane zone.

Chapter 36

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A Systematic Approach to the Dermatoses of Pregnancy

References   1. Milton, J. L. The Pathology and Treatment of Disease of the Skin, p. 205. Robert Hardwicke, London, 1872.   2. Hebra, F. Herpes impetiginiformis. Lancet 1872; i: 399–400.   3. Besnier, E., Brocq, L., and Jacquet, L. La Pratique Dermatologique, p. 75. Masson, Paris, 1904.   4. Gross, P. Erythema multiforme gestationis. Arch. Dermatol. Syphilis 1931; 23: 567.   5. Davis, J. H. T. Prurigo annularis. Br. J. Dermatol. 1941; 53: 143–145.   6. Bourne, G. Toxaemic rash of pregnancy. Proc. R. Soc. Med. 1962; 55: 462–464.   7. Spangler, A. S., Reddy, W., Bardavil, W. A., et al. Papular dermatitis of pregnancy. J.A.M.A. 1962; 181: 577–581.   8. Nurse, D. S. Prurigo of pregnancy. Australas. J. Dermatol. 1968; 9: 258–267.   9. Lawley, T. J., Hertz, K. C., Wade, T. R., et al. Pruritic urticarial papules and plaques of pregnancy. J.A.M.A. 1979; 241: 1696–1699. 10. Zoberman, E. and Farmer, E. R. Pruritic folliculitis of pregnancy. Arch. Dermatol. 1981; 117: 20–22. 11. Holmes, R. C. and Black, M. M. The specific dermatoses of pregnancy: a reappraisal with special emphasis on a proposed simplified clinical classification. Clin. Exp. Dermatol. 1982; 7: 65–73.

12. Holmes, R. C. and Black, M. M. The specific dermatoses of pregnancy. J. Am. Acad. Dermatol 1983; 7: 104–110. 13. Borradori, L. and Saurat, J. H. Specific dermatoses of pregnancy: towards a comprehensive view? Arch. Dermatol 1994; 130: 778–780. 14. Alcalay, J., Ingber, A., Hazaz, B., et al. Linear IgM dermatosis of pregnancy. J. Am. Acad. Dermatol 1988; 18: 412–415. 15. Roger, D., Vaillant, L., Fignon, A., et al. Specific pruritic diseases of pregnancy: a prospective study of 3192 pregnant women. Arch. Dermatol. 1994; 130: 734–739. 16. Shornick, J. K. Dermatoses of pregnancy, Semin. Cutan. Med. Surg. 1998; 17: 172–181. 17. Zoberman, E. and Farmer, E. R. Pruritic folliculitis of pregnancy. Arch. Dermatol. 1981; 117: 20–22. 18. Vaughan Jones, S. A., Hern, S., Nelson-Piercy, C., et al. A prospective study of 200 women with dermatoses of ­pregnancy correlating the clinical findings with hormonal and immunopathological profiles. Br. J. Dermatol. 1999; 141: 71–81. 19. Ambros-Rudolph, C. M., Müllegger, R. R., Vaughan Jones, S. A., et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J. Am. Acad. Dermatol. 2006; 54: 395–404.

PART: I  Obstetrics

CHAPTER 5

Pemphigoid (Herpes) Gestationis Rachel E. Jenkins Jeff Shornick Etiology Pemphigoid gestationis (PG) is a rare autoimmune bullous disease that occurs during pregnancy and the puerperium, being associated occasionally with trophoblastic tumors, hydatidiform mole, and choriocarcinoma1. Historically it has been known by many names, with Milton first applying the term “herpes gestationis” in 1872 (Table 5.1). Clinically and immunopathologically, PG is closely related to the pemphigoid group of bullous disorders and therefore the term “pemphigoid gestationis” is preferable to “herpes gestationis,” which may otherwise encourage confusion with virus-mediated disease. Despite a clinical resemblance to herpetic lesions, viral studies of PG have been consistently negative.

Clinical features PG is estimated to complicate 1 in 40 000–60 000 pregnancies1. The disease has no racial predisposition, although there is evidence that the incidence may vary according to the incidence of human leukocyte antigen (HLA)-DR3 and DR4 in different populations2. Table 5.1  Historical Terminology of Pemphigoid ­Gestationis

Term

Original Citation

Pemphigus gravidarum

von Martius, 1829

Pemphigus pruriginosus

Chausit, 1852

Herpes circinatus bullosus

Wilson, 1867

Pemphigus hystericus

Hebra, 1868

Herpes gestationis

Milton, 1872

Dermatitis multiformis gestationis

Allen, 1889

Pemphigoid gestationis

Holmes and Black, 1982

Chapter 38

5

Pemphigoid (Herpes) Gestationis

Onset of disease PG may develop at any time from 9 weeks’ gestation to 1 week postpartum, but usually presents during the second and third trimesters. Approximately 18% present in the first trimester, 34% in the second trimester, and a further 34% in the third trimester3. Initial presentation postpartum may be “explosive” and occurs in approximately 14% of women, but onset more than 3 days postpartum makes PG unlikely as the diagnosis3. The disease is likely to recur, usually with an earlier onset and more florid expression. When PG develops during the middle trimester there is often a period of relative remission in the last few weeks of pregnancy, but this is frequently followed by abrupt relapse postpartum1,3,4. Occasionally, subsequent pregnancies are unaffected. Such “skip pregnancies” have an incidence of approximately 8% but remain unpredictable on a prospective basis using available data3. What is clear, however, is that recurrence is not universal. Previous reports have suggested that such pregnancies may be more likely following a change in partner or when the mother and fetus are fully compatible at the HLA-D locus, but this is certainly not always the case1,5.

Rash of pemphigoid gestationis The disease typically presents with pruritic, erythematous, urticated papules and plaques which may become target-like, develop into annular wheals, or become polycyclic. Progression to clustered vesicobullous lesions on erythematous skin usually occurs within days to weeks of the initial onset of pruritus. Bullae may appear de novo on otherwise clinically uninvolved skin. Blisters are usually tense and contain serous fluid; however, pustules may be seen, albeit rarely. In 90% of patients the eruption is initially confined to the periumbilical area (Figures 5.1–5.3) with later spread to the abdomen (Figures 5.4–5.6), thighs (Figure 5.7), palms, and soles (Figure 5.8)3. The condition often becomes widespread but the face (Figure 5.9) and oral mucosa are usually spared. The blisters tend to resolve first, with the plaques of erythema persisting longer. In the absence of secondary infection, resolution usually occurs without scarring.

Figure 5.1  Early pemphigoid gestationis at 28 weeks’ ­gestation. Pruritic polycyclic urticarial lesions have ­developed periumbilically.

Figure 5.2  Early pemphigoid gestationis around the umbilicus. The urticarial lesions are beginning to develop vesicles.

Figure 5.3  Pemphigoid gestationis.The periumbilical involvement is now clearly bullous.

Natural history Occasionally there is spontaneous clearing of the disease during the latter part of pregnancy, only to flare at the time of delivery. Postpartum flares of disease are seen in 50–75% of patients,

Clinical features 39

Figure 5.4  Pemphigoid gestationis at 34 weeks’ gestation. Pruritic urticarial lesions involve the entire abdomen.

Figure 5.6  Pemphigoid gestationis. The same patient as in Figure 5.5. Small bullae are developing within the areas of urticated erythema.

Figure 5.7  Severe pemphigoid gestationis, involving the anterior thighs.

Figure 5.8  Pemphigoid gestationis. Large bullae developing on soles. Figure 5.5  Pemphigoid gestationis. Pruritic urticarial ­lesions are spreading to involve the breasts.

t­ ypically beginning within 24–48 hours of delivery. The duration of postpartum flares is variable but usually ranges from weeks to several months of involvement. Some patients have been reported with disease activity for as long as 11–12 years6.

The duration of continued disease activity beyond delivery is variable and there is no correlation between disease activity and serum antibody titers. As the disease begins to resolve, recurrences associated with the menstrual cycle are common. Some women (20–50%) develop recurrences

Chapter

5

Pemphigoid (Herpes) Gestationis

40

Figure 5.9  Severe pemphigoid gestationis, showing bulla and urticarial facial lesions.

if treated with oral contraceptives (estrogens or progestogens).

Hydatidiform mole and choriocarcinoma PG is rarely associated with trophoblastic tumors such as hydatidiform mole and choriocarcinoma1, which are most commonly produced by a diploid contribution of paternal chromosomes and have neither fetal tissue nor amnion7. Interestingly, there are no reports of PG-like disease in men with choriocarcinoma. This malignancy is relatively common and biochemically similar to normal pregnancy. Cytogenetic studies have demonstrated that the chromosomes in choriocarcinoma in men are also entirely of paternal origin7. It would, therefore, appear that placental tissue is required for the initial development of disease, not simply the presence of germinal tissue or the actual presence of fetus.

Fetal and neonatal disease Some 5–10% of infants born to mothers with PG have cutaneous lesions1. Transient urticarial or vesicular lesions are most common and resolve spontaneously within around 3 weeks, presumably

Figure 5.10  Mother-to-fetus transmission. The mother has severe pemphigoid gestationis, but only mild transient disease is present in the neonate. (Courtesy of Professor Ernesto Bonifazi, Bari, Italy.)

as transferred maternal antibodies are catabolized (Figure 5.10). Long-term sequelae of disease have not been reported in children born to affected mothers, nor has an increased frequency of other autoimmune diseases. Neonatal PG results from the passive transfer across the placenta of maternal immunoglobulin (Ig) G antibasement membrane zone (BMZ) autoantibodies. These antibodies may be demonstrated in cord blood and neonatal skin. Subclinical disease is probably common since direct immunofluorescence (IF) of fetal skin is routinely positive despite a lack of clinically apparent ­disease. By the end of the first month of life, infants’ skin biopsy specimens are normal and circulating IgG antiBMZ autoantibodies can no longer be detected. There has been controversy about whether or not PG is associated with an increase in fetal ­morbidity

Pathology

or mortality rate. In 1969 Kolodny remarked that there was no evidence of an increased incidence of stillbirth or spontaneous abortion associated with PG8. Lawley et al.9 reviewed 41 cases of immunologically confirmed PG and, by contrast, reported increased fetal morbidity and mortality rates. This review, however, relied extensively on published cases. A study of 50 pregnancies affected by PG demonstrated a slight increase in the frequency of infants that were small for dates and, because such infants have increased mortality and morbidity rates, these authors concluded that the fetal prognosis in PG was impaired10. A more recent large study found no evidence of an increased rate of spontaneous abortion or significant mortality but did demonstrate an increased incidence of both prematurity and small-for-dates babies with PG11. These observations would be consistent with low-grade placental dysfunction.

41

Figure 5.11  Thyrotoxicosis (Graves disease) in the same patient as in Figure 5.9. Thyrotoxicosis developed 10 years after the onset of severe pemphigoid gestationis.

Associated autoimmune diseases Figure 5.12  Direct immunofluorescence in pemphigoid gestationis. Bright linear deposition of C3 in the basement membrane zone and along the epidermal side of salt-split skin (pemphigoid pattern).

A few patients with PG have been reported to have additional autoimmune diseases (e.g., alopecia areata and Crohn’s disease) but this is unusual. However, a recent study of 87 patients with PG reported that 13.8% also had Graves disease3 ­(Figure 5.11). Graves disease is known to be associated with DR3, with a 0.4% female prevalence. This study also documented a slight increase in other autoantibodies in patients with PG, including antithyroid antibodies and platelet antibodies. In addition there is a 25% incidence of autoimmune diseases in the relatives of those with PG, particularly Graves disease, Hashimoto thyroiditis, and pernicious anemia12.

neutrophils, or occasional lymphocytes may be seen to line up along the BMZ. The presence of eosinophils is the most constant feature in PG, being seen in nearly every case. Early urticarial lesions are characterized by epidermal and marked papillary dermal edema. Subepidermal separation results from basal cell necrosis, leading to subepidermal bullae. Severe edema of the papillary dermis may result in bulbous, teardrop-shaped dermal papillae.

Pathology

Immunopathology

Histopathology The histopathology of PG classically shows subepidermal blistering, eosinophils within the blister fluid, and an edematous upper dermis that contains a mixed, perivascular, lymphohistiocytic infiltrate admixed with eosinophils, although these characteristic findings are seen in only a minority. More common findings include ­spongiotic vesicle formation or eosinophilic spongiosis. ­Eosinophils,

The most characteristic finding in PG is linear deposition of C3, with or without IgG, along the BMZ of perilesional skin. Direct IF demonstrates C3 in the BMZ of clinically uninvolved skin in all patients with PG (Figure 5.12) and linear IgG deposition in about 25%. IgG deposition may be demonstrable in patients with negative routine IF with refined multistep techniques. For example, the use of splitskin specimens, chemically separated through the lamina lucida, demonstrates IgG deposits in the

Chapter 42

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Pemphigoid (Herpes) Gestationis

lamina lucida even when conventional direct IF is negative. There appears to be no difference in disease expression in patients who have deposition of complement alone compared with those who have IgG in addition to complement. The herpes gestationis factor, now known as PG factor, is an IgG1 autoantibody directed against a normal cell surface component of cutaneous BMZ1. By contrast, in bullous pemphigoid (BP) the predominant autoantibody is IgG4 subclass. Circulating anti-BMZ IgG is detected in about 25% of patients using an indirect IF technique and binding is to the epidermal side of sodium chloride split skin; titers tend not to correlate with disease severity. There have been a few reports of atypical IF staining in patients with PG, the significance of which is yet to be established13,14.

Immunogenetics PG has previously been shown to be associated with the HLA antigens DR3 and DR4: 61–80% of patients express DR3, 52–53% express DR4, and 43–50% express both, compared with 3% of normal controls15. Advances in molecular analytical techniques such as restriction fragment length polymorphism (RFLP) and sequence-specific oligonucleotide probing have allowed the identification of HLA alleles previously difficult to define by serologic assays. HLA-DRB1*0301 (DR3) and DRB1*0401/040X (DR4; the X denoting the combined subtypes of DR4 other than 0401) have, for instance, been shown to be associated with PG16. There is no obvious relationship between HLA type and clinical severity, onset, duration, or recurrence, nor is there any relationship between HLA type and the presence or absence of IgG along the BMZ by direct IF. A significant increase in the frequency of paternal HLA-DR2 antigens has also led to the conclusion that both paternal HLA type and maternal HLA antibodies are important in the development of PG. The major histocompatibility complex (MHC) class II genes (DR, DP, and DQ) are located immediately adjacent to the class III genes which encode the complement components C4, with the multiple isomers of C4A and C4B, factor B and C2. The nonfunctioning C4 null allele is always present in patients with PG17. The

C4A rather than the C4B null allele is seen and may impair immune complex degradation. However, because the C4 locus is adjacent to the DR locus on chromosome 6, with strong linkage disequilibrium, it is extremely difficult to determine what is the primary genetic marker in PG – DRB1*0301, DRB1*0401/040X, or a C4 null allele.

Immunopathogenesis Studies using immunoelectron microscopy have demonstrated that anti-BMZ IgG is directed towards a component just below the hemidesmosome in the upper lamina lucida of the BMZ. Immunoprecipitation has previously demonstrated that the majority (more than 95%) of BP sera react with a 230-kDa epidermal polypeptide known as BPAg118, with about 50% also reacting with a second epidermal antigen of 180 kDa, known as BPAg219. The majority of PG sera recognize BPAg2 and some react to both BPAg2 and BPAg1. Cloning and sequencing have demonstrated that the two antigens are distinct gene products of different chromosomal locations, BPAG1 at locus 6p11-1220 and BPAG2 at locus 10q24.321. BPAG2 has recently also been identified as COL171A122. PG and BP, therefore, appear to share antigenic determinants, but in PG antibodies directed against the 180-kDa antigen are prevalent whereas in BP antibodies to the 230-kDa antigen are more common. Immunoelectron microscopy using immunogold techniques has shown that BPAg2 is a type II transmembrane constituent of the hemidesmosome with collagenous segments in its extracellular domain and, for this reason, is also known as type XVII collagen23. BPAg1, on the other hand, is an intracellular, cytoplasmic plaque component24. The actual target epitope in PG has been localized to the NC16A region of the BPAg2 extracellular domain, positioned immediately adjacent to the plasma membrane of hemidesmosomes25. This immunodominant epitope is recognized by more than 50% of BP sera and 70% of PG sera. It has been further mapped to a 16-amino-acid peptide. Since BPAg1 is restricted to the intracellular compartment of the basal keratinocyte, it is not directly accessible to circulating antibodies. Anti-BPAg1 autoantibodies would, therefore, be

Treatment

their partner’s antigens, and this may be a clue to the etiology of the disease. Anti-HLA antibodies may develop as a consequence of a placental bleed, which may then result in the partial destruction of the placenta, thereby exposing cryptic antigens and leading to the production of IgG autoantibody.

Differential diagnosis Figure 5.13  Placental immunology in pemphigoid gestationis. Linear binding of pemphigoid gestationis antibody to amniotic basement membrane.

predicted to arise as a secondary event in response to an initial insult to the basal keratinocyte. In contrast, BPAg2 is a transmembrane protein and is recognized by both PG and BP autoantibodies. Therefore, anti-BPAg2 autoantibodies may play an initiator role in subepidermal blister formation in PG and BP. Circulating autoantibodies in both PG and BP are likely to access this newly defined antigenic site on the surface of intact keratinocytes. Circulating autoantibodies which bind to skin cross-react with the basement membranes of chorionic epithelium and amnion, and immune complexes are found to be deposited in the placenta during the course of most cases of PG (Figure 5.13). In addition there is aberrant expression of MHC class II antigens in the placenta on amniochorionic stromal cells and trophoblastic cells which are derived from paternal genes26. This is not so in the skin, where only complement components (with or without IgG) are seen along the BMZ. These placental cells may be exposed to the maternal immune system, as it is known that in some anchoring villi there are focal deficiencies in the syncytiotrophoblast27. The cross-reactivity may be explained by the common origin of skin and amnion from the ectodermal germ layer. In PG there is a universal presence of anti-HLA antibodies, which are mainly directed against class I antigens28. The actual role of these antiHLA antibodies in the primary pathogenesis of PG is unknown but their presence does imply that women with PG are more able than normal women to mount an allogeneic response against

Differentiation of PG from other cutaneous bullous eruptions is usually not difficult, especially once blisters have begun to develop (see Chapters 4 and 6). The vesicles and bullae found only in PG distinguish it from other pregnancy-related dermatoses such as atopic eruption of pregnancy. Nonclassical presentations could, however, easily be confused with polymorphic eruption of pregnancy (PEP) (Table 5.2) and other autoimmune bullous diseases (e.g., BP) (Table 5.3), dermatitis herpetiformis, or linear IgA disease. Bullous systemic lupus erythematosus also needs to be considered. BP is unusual in the child-bearing age group; dermatitis herpetiformis and linear IgA disease can be differentiated by routine histology or IF (Table 5.4). In most clinical settings the most important differential diagnosis is between prebullous PG and PEP. Although eosinophils are more commonly seen in PG, they may also be present in PEP, and the key to differentiating the two diseases is IF29. There is a new commercially available immunosorbent assay directed at the NC16a domain which is highly sensitive and highly specific in differentiating PG from PEP30. It is potentially a valuable tool in the serodiagnosis of PG and provides further evidence that the NC16a domain of BP180 contains the primary target epitopes of PG autoantibodies and that antibodies to NC16a are not present in PEP. Other diseases to be considered in the differential diagnosis include erythema multiforme, contact dermatitis, and bullous drug eruptions.

Treatment The aim of therapy in patients with PG is to relieve pruritus, suppress blister formation, and prevent erosions, secondary infection, and scarring

43

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Table 5.2  Differences Between Polymorphic Eruption   of Pregnancy and Pemphigoid Gestationis

Feature

Polymorphic Eruption of Pregnancy

Incidence

Common (1:150)

Pemphigoid Gestationis Very rare   (1:50 000)

Primiparous

80%

50%

Multiple ­pregnancy

+

–

Morphology Erythematous papules Target lesions Vesicles Bullae

+

+

+ + –

+ + +

Prominent striae

+

–

Periumbilical lesions

–

+

Fetal prognosis

Normal

Impaired

Recurrence   in subsequent pregnancies

–

+

Direct IF for C3   at BMZ

–

100%

Indirect IF for C3 at BMZ

–

HLA associations

Table 5.3  Comparison of Bullous Pemphigoid and ­Pemphigoid Gestationis

Bullous Pemphigoid

Pemphigoid Gestationis

Similarities Clinical

Widespread pruritic bullous eruption

Histo­ pathology

Subepidermal bullae containing ­numerous eosinophils

Direct IF

Deposition of C3 and IgG at the BMZ

Indirect IF

Circulating complement fixing IgG1 autoantibody

Immunogold ­electron ­microscopy

Deposition of the reaction product ­  below hemidesmosome at NC16A   domain of BPAg2 (180 kDa)

Treatment

Invariable response to systemic ­corticosteroids

Differences Sex

Male:female (1:1)

Female

Age

Over 60 years

15–45 years

Etiologic ­associations

Unknown

Pregnancy, ­hydatidiform   mole, chorio­ carcinoma

80%

Predilection for umbilicus

No

Yes

–

DR3, DR4

Hormonal ­modulation

No

Yes

Associated ­autoimmune conditions

–

+

HLA ­associations

?

DR3, DR4

Etiology

Unknown

Autoantibody   to BMZ of skin and placenta

IF, immunofluorescence; C3, third component of complement; BMZ, basement membrane zone; HLA, human leukocyte antigen.

of lesional sites. In mild cases of PG careful but aggressive use of topical fluorinated corticosteroids combined with emollients and systemic antihistamines is adequate. Once bullae have developed, however, it is usually necessary to use systemic steroids1,3,4. A good response to

IF, immunofluorescence; C3, third component of complement; BMZ, basement membrane zone; IgG1, immunoglobulin G1; BPAg2, bullous pemphigoid antigen-2; HLA, human leukocyte antigen.

­ rednisolone (e.g., 40 mg daily) is common, with p control of pruritic symptoms, cessation of new vesicle formation, and clearing within 10 days. Some patients receive greater symptomatic relief from divided doses of daily corticosteroids. Once these patients’ disease is controlled, they can be converted to single morning doses of corticosteroids. If no new lesions develop 3 days after having ­commenced 40 mg prednisolone, the dose should be held constant for 1–2 weeks and then gradually

Treatment

Table 5.4  Immunofluorescence Findings for Differential Diagnosis of Pemphigoid Gestationis

Diagnosis

Direct IF

Indirect IF

Pemphigoid ­gestationis

Linear IgG (25–30%) and C3 (100%) at BMZ

Circulating IgG (20%) against   BMZ; PG factor   in 25–50%

Bullous ­pemphigoid

Linear IgG (50–90%) and C3 (80–100%) at BMZ

Circulating IgG (70%) against   BMZ

Dermatitis ­herpetiformis

Granular papillary deposition of IgA (100%)

No circulating   IgA but 70%   have antismooth­muscle autoantibody

Linear IgA   bullous dermatosis (adult and childhood)

Linear deposition of IgA at BMZ   (90%)

Circulating IgA against BMZ   (adult 50%, ­childhood 75%)

Pemphigus

Intercellular IgG

Circulating ­intercellular IgG

IF, immunofluorescence; Ig, immunoglobulin; C3, third component of complement; BMZ, basement membrane zone; PG, pemphigoid ­gestationis.

decreased. If new lesions continue to develop after 3 days, the dose should be doubled and the guidelines as stated above followed. Some degree of disease activity (e.g., one or two new lesions developing every few days) is acceptable because much higher doses of prednisolone may be required to suppress all disease activity completely. Patients should, therefore, be tried on ever-lower doses of medication once the disease is controlled. The minimum effective dose of systemic corticosteroids should be used. It is important to remember that many patients improve during the latter part of pregnancy, only to have a recurrence at the time of delivery. Doses higher than 80 mg prednisolone are exceptional. The initial dose can often be reduced rapidly to maintenance levels (e.g., 10 mg daily). As postpartum exacerbations are frequent, it is usual to anticipate this by increasing the ­steroid dose temporarily immediately after ­delivery. Some patients may require reinstitution of their medication postpartum following ­ quiescence of the ­disease during the latter part of the third trimester

KEY POINT BOX Pemphigoid gestationis Diagnosis: • Clinical appearance Vesiculobullous eruption on urticated erythema, papules and plaques Conspicuous abdominal involvement with periumbilical affection No association of skin lesions to striae distensae • Postpartum flare in 75%; neonatal skin involvement in 5–10% (mild, transient, due to passive transfer of maternal antibodies) • Positive direct immunofluorescence with linear C3 (100%) and IgG (25–30%) at BMZ; positive indirect immunofluorescence (20–100%)

Differential Diagnosis: Polymorphic eruption of pregnancy Atopic eruption of pregnancy Bullous autoimmune eruption coinciding with pregnancy Urticaria Drug eruption Erythema multiforme

Management: Treatment aims to relieve pruritus, suppress blister formation, and prevent erosions and scarring. Pre-bullous stage: potent topical corticosteroids combined with emollients and systemic antihistamines. Bullous stage: high-dose systemic corticosteroids (prednisolone, 0.5–1mg/kg daily) to be tapered once disease activity is controlled; increase dose immediately after delivery to prevent postpartum flare. Cases unresponsive to systemic corticosteroids: during pregnancy: plasmapheresis; after pregnancy: full range of other immunosuppressive therapy possible. Patients and their offspring should be managed coordinately by dermatologists, obstetricians, and neonatologists. They should also be informed about the significant risk of PG to flare with oral contraceptive use and to recur in subsequent pregnancies. C3, complement three; IgG, Immunoglobulin G; BMZ, basement ­membrane zone.

of pregnancy. Although systemic steroids do not appear to affect fetal prognosis, the mother must be carefully monitored as diabetes mellitus and hypertension may appear. If PG should prove unresponsive to corticosteroids, or if these drugs are contraindicated in a particular patient, then plasmapheresis may be considered. It has been used with apparent success

45

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in a patient during pregnancy and also in a patient with PG persisting postpartum, thereby supporting claims for a circulating pathogenic factor in PG. There are no major technical ­ difficulties in performing plasmapheresis during pregnancy, and in fact it has an established role in the treatment of rhesus disease for the removal of maternal rhesus antibodies. Other treatments have been tried in PG, including pyridoxine31, dapsone, and ritodrine32. Such approaches have not been entirely empiric. Dapsone is unhelpful and is now contraindicated during pregnancy as it can cause hemolytic disease of the newborn. In 1984 MacDonald and Raffle32 reported a case of complete remission of severe PG when ritodrine, a ß-­sympathomimetic drug, was used for the ­treatment of premature labor. Alternative drugs such as gold, methotrexate, and cyclophosphamide have been reported in the literature33. None is useful prior to term and the experience with each has been variable. Goserelin, a luteinizing hormone-releasing hormone analog, has been used in severe, long-standing PG with chemical oophorectomy leading to complete remission34. Intravenous IgG has been used with apparent success in a few isolated patients35. The use of second-line “steroid-sparing” drugs during pregnancy is not advisable because of the ­possible teratogenic effects. Systemic corticosteroids, therefore, remain the mainstay of treatment. Skin lesions in affected infants of patients with PG are transient and resolve as maternal autoantibodies are catabolized. Lesions in these infants usually require no specific therapy other than simple wound care. Infants of patients with PG who were treated with systemic steroids during pregnancy, however, should be assessed by a neonatologist for evidence of ­adrenal insufficiency.

References   1. Jenkins, R. E., Shornick, J. K. and Black, M. M. Pemphigoid gestationis. J. Eur. Acad. Dermatol. Venereol. 1993; 2: 163–173.   2. Garcia-Gonzalez, E., Castro-Llamas, J., Karchmer, S., et al. Class II major histocompatibility complex typing across the ethnic barrier in pemphigoid gestationis. A study in Mexicans. Int. J. Dermatol. 1999; 38: 46–51.   3. Jenkins, R. E., Hern, S., and Black, M. M. Clinical features and management of 87 patients with pemphigoid gestationis. Clin. Exp. Dermatol. 1999; 24: 255–259.

  4. Engineer, L., Bhol, K., and Ahmed, A. R. Pemphigoid gesta­ tionis: a review. Am. J. Obstet. Gynecol. 2000; 183: 483–491.   5. Cozzani, E., Basso, M., Parodi, A., et al. Pemphigoid gestationis post partum after changing husband. Int. J. Dermatol. 2005; 44: 1057–1058.   6. Jenkins, R. E., Vaughan Jones, S. M., and Black, M. M. Conversion of pemphigoid gestationis to bullous pemphigoid; two refractory cases highlighting this association. Br. J. Dermatol. 1996; 135: 595–598.   7. Berkowitz, R. S. and Goldstein, D. P. Chorionic tumors. N. Engl. J. Med. 1996; 335: 1740–1748.   8. Kolodny, R. C. Herpes gestationis. A new assessment of ­incidence, diagnosis, and fetal prognosis. Am. J. Obsetet. ­Gynecol. 1969; 104: 39–45.   9. Lawley, T. J., Stingl, G., and Katz, S. I. Fetal and maternal risk factors in herpes gestationis. Arch. Dermatol. 1978; 114: 552–555. 10. Holmes, R. C. and Black, M. M. The fetal prognosis in ­pemphigoid gestationis (herpes gestationis). Br. J. Dermatol. 1984; 110: 67–72. 11. Shornick, J. K. and Black, M. M. Fetal risks in herpes gesta­ tionis. J. Am. Acad. Dermatol. 1992; 26: 63–68. 12. Shornick, J. K. and Black, M. M. Secondary autoimmune diseases in herpes gestationis (pemphigoid gestationis). J. Am. Acad. Dermatol. 1992; 26: 563–566. 13. Hashimoto, T., Amagai, M., Murakami, H., et al. Specific detection of anti-cell surface antibodies in herpes gestationis sera, Exp. Dermatol. 1996; 5: 96–101. 14. Vaughan Jones, S. A., Bhogal, B. S., Black, M. M., et al. A typical case of pemphigoid gestationis with a unique pattern of intercellular immunofluorescence. Br. J. Dermatol. 1997; 136: 245–248. 15. Shornick, J. K., Stastny, P. and Gilliam, J. N. High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestationis. J. Clin. Invest. 1981; 68: 553–555. 16. Shornick, J. K., Jenkins, R. E., Artlett, C. M., et al. Class II MHC typing in pemphigoid gestationis. Clin. Exp. Dermatol. 1995; 20: 123–126. 17. Shornick, J. K., Artlett, C. M., Jenkins, R. E., et al. Complement polymorphism in herpes gestationis: association with C4 null allele. J. Am. Acad. Dermatol. 1993; 29: 545–549. 18. Stanley, J. R., Hawley-Nelson, P., Yuspa, S. H., et al. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981; 24: 897–903. 19. Labib, R. S., Anhalt, G. J., Patel, H. P., et al. Molecular ­heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J. Immunol. 1986; 136: 1231–1235. 20. Sawamura, D., Nomura, K., Sugita, Y., et al. Bullous ­pemphigoid antigen (BPAG1): cDNA cloning and mapping of the gene to the short arm of chromosome 6. Genomics. 1990; 8: 722–726. 21. Li, K., Sawamura, D., Guidice, G. J., et al. Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium. J. Biol. Chem. 1991; 266: 24064–24069. 22. Li, K., Tamai, K., Tan, E. M. L., et al. Cloning of type XVII collagen, J. Biol. Chem. 1993; 268: 8823–8834. 23. Guidice, G. J., Squiquera, H. L., Elias, P. M., et al. Identification of two collagen domains within the bullous pemphigoid auto-antigen, BP 180, J. Clin. Invest. 1991; 87: 734–738. 24. Stanley, J. R., Tanaka, T., Muellers, S., et al. Isolation of complementary DNA for bullous pemphigoid antigen by use of patients’ autoantibodies, J. Clin. Invest. 1988; 82: 1864–1870. 25. Kitajima, Y. Adhesion molecules in the pathophysiology of ­bullous diseases, Eur. J. Dermatol. 1996; 6: 399–405.

References 26. Kelly, S. E., Fleming, S., Bhogal, B. S., et al. Immunopathology of the placenta in pemphigoid gestationis and linear IgA disease, Br. J. Dermatol. 1989; 120: 735–743. 27. Vince, G. S. and Johnson, P. M. Materno-fetal immuno­biology in normal pregnancy and its possible failure in recurrent ­spontaneous abortion? Hum. Reprod. 1995; 10: 107–113. 28. Shornick, J. K., Jenkins, R. E., Briggs, D. C., et al. Anti-HLA antibodies in pemphigoid gestationis (herpes gestationis), Br. J. Dermatol. 1993; 129: 257–259. 29. Castro, L. A., Lundell, R. B., Krause, P. K., et al. Clinical experience in pemphigoid gestationis: report of 10 cases. J. Am. Acad. Dermatol. 2006; 55: 823–828. 30. Powell, A. M., Sakuma-Oyama Y., Oyama N., et al. Usefulness of BP180NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in different­ iating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch. Dermatol. 2005; 141: 705–710.

31. Fosnaugh, R. P., Bryan, H. G., and Orders, R. L. Pyridoxine in the treatment of herpes gestationis. Arch. Dermatol. 1961; 84: 90–95. 32. MacDonald, K. J. S. and Raffle, E. J. Ritodrine therapy associated with remission of pemphigoid gestationis, Br. J. Dermatol. 1984; 111: 630. 33. Castle, S. P., Mather-Mondrey, M., Bennion, S., et al. Chronic herpes gestationis and antiphospholipid antibody syndrome successfully treated with cyclophosphamide. J. Am. Acad. Dermatol. 1996; 34: 333–336. 34. Garvey, M. P., Handfield-Jones, S. E. and Black, M. M. ­Pemphigoid gestationis: response to chemical oophorectomy with goserelin. Clin. Exp. Dermatol. 1992; 17: 443–445. 35. Hern, S., Harman, K., Bhogal, B. S., et al. A severe persistent case of pemphigoid gestationis treated with intravenous ­immunoglobulins and cyclosporin. Clin. Exp. Dermatol. 1998; 23: 185–188.

47

PART: I  Obstetrics

CHAPTER 6

Polymorphic Eruption of Pregnancy Christina M. Ambros-Rudolph Martin M. Black Introduction Polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy (PUPPP), is one of the most common gestational dermatoses, affecting about one in 160 pregnancies. It is essentially a self-limiting, papular, urticarial eruption of late pregnancy and/or the puerperium. Polymorphous features may be present and include vesicles, target lesions, polycyclic wheals, a widespread toxic erythema-like appearance, and eczematous changes.

Historical background As PEP has a very variable clinical morphology1, it is not surprising that various terms have been used to describe it. The disease was initially reported as “toxemic rash of pregnancy”2, but as the case was not associated with pre-eclampsia, the term was little used. Since then other descriptive terms have been used, including “prurigo of late pregnancy”3, “toxic erythema of pregnancy”4, and “PUPPP”5,6. Although the term “PUPPP” is still widely used, particularly in the United States, it is generally agreed that PUPPP and PEP are identical dermatoses7. This discussion will refer to PEP, because it encapsulates the full range of clinical morphologic expressions, including papules, plaques, target lesions, polycyclic erythematous wheals, vesicles, with occasional small bullae, and eczematous changes.

Etiology PEP is an inflammatory dermatosis associated solely with pregnancy. No associations have been found with atopy, pre-eclampsia, or autoimmune phenomena1, and the frequency of human leukocyte antigens (HLAs) in women with PEP is also normal1,6. The striking association of PEP with abdominal striae observed mainly in the late pregnancy of primigravidae has favored rapid, late abdominal wall distension with consecutive damage to connective tissue as

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an ­ important aspect in the development of PEP. A reaction to abdominal distension has also been implicated by the greater likelihood in PEP of higher maternal weight gain8 and an increased incidence of twins9,10 or multiple pregnancies8,11,12. Associations with higher neonatal birth weight or particular fetal sex, however, have not been confirmed, but a more recent study suggests a higher incidence of male fetuses and cesarian deliveries8,12. A prospective study of 44 patients with PEP showed low serum cortisol levels compared with controls, suggesting a hormonal influence11, although the relevance of this is currently not clear. No evidence has been found to implicate autoimmune mechanisms11–14, nor have circulating immune complexes been found6. A preliminary study of male DNA detection in PEP indicated that fetal cells can migrate to maternal skin during pregnancy15. Whether this initiates the inflammatory responses in PEP remains speculative as these findings have not been substantiated by others. Although PEP is now a well-recognized entity, it is perhaps surprising that there is little substantial information about its etiology, and factors such as parity, multiple pregnancy, and paternity may well need further consideration16.

Figure 6.1  Early polymorphic eruption of pregnancy at 38 weeks’ gestation in an Asian primigravida. Pruritic urticaria in striae distensae. Note the periumbilical sparing.

Clinical features The great majority of patients with PEP are primigravidae, and the development of PEP in a subsequent pregnancy is very likely to coexist with excessive maternal weight gain or multiple pregnancies11,16,17. The characteristic time of onset is between weeks 36 and 39 of gestation, but lesions may also develop in the immediate postpartum period (15%)8 or occasionally in the late second trimester. There is no particular maternal age at which PEP is likely to develop6. The mean duration of the eruption is 6 weeks, but the eruption is usually not severe for more than 1 week1. The eruption begins with pruritic urticarial papules, usually in association with striae distensae (Figures 6.1–6.4); however, these papules can rarely develop on the abdomen without striae (Figure 6.5). Earlier reports of PEP indicated that the lesions consisted almost exclusively of urticarial papules and plaques5. However, the morphology

Figure 6.2  Polymorphic eruption of pregnancy at 37 weeks in a primigravida. Prominent pruritic urticarial lesions are present in striae distensae on the abdomen and thighs.

Figure 6.3  Polymorphic eruption of pregnancy in striae distensae. Close-up of Figure 6.2, showing confluent urticarial papules in striae distensae. Some papules occur adjacent to the striae.

Clinical features 51

Figure 6.4  Polymorphic eruption of pregnancy in striae distensae. The pruritic eruption developed early (26 weeks) in a triplet pregnancy.

Figure 6.6  Polymorphic eruption of pregnancy with urticarial lesions and small vesicles on the abdomen, sparing striae distensae.

Figure 6.5  Polymorphic eruption of pregnancy at 36 weeks’ gestation in a primigravida. Urticarial papules on the upper abdomen in the absence of striae distensae.

Figure 6.7  Polymorphic eruption of pregnancy morphology. “Pinpoint-sized” vesicles are present, on top of the urticarial papules within striae distensae.

of the eruption may vary greatly throughout its duration1,11 and exhibits a characteristic change with disease progression8. While pruritic urticarial papules and plaques are the main morphological features at disease onset (98%), more than onehalf of the patients (51%) develop polymorphous features later on8. These include tiny vesicles, in 17–40% of patients (Figure 6.6), often on top of the papules overlying striae (Figure 6.7). In a small number of cases, these vesicles may coalesce to form smaller bullae18. Target-like lesions and annular or polycyclic wheals are present in 6–20% of cases (Figure 6.8). In 70% the lesions become confluent and widespread, resembling a toxic erythema (Figure 6.9). The Koebner or isomorphic response in PEP is common1, but facial involvement is very rare19,20. As the eruption slowly

Figure 6.8  Polymorphic eruption of pregnancy morphology. Target-like and annular polycyclic lesions resembling erythema multiforme.

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52

Figure 6.9  Polymorphic eruption of pregnancy morphology. Toxic erythema-like eruption on lower legs.

Figure 6.11  Polymorphic eruption of pregnancy morphology. Urticarial lesions on the buttocks.

Figure 6.10  Polymorphic eruption of pregnancy morphology. Extensive urticarial lesions on the back.

resolves, the great majority of cases exhibit fine scaling and crusting, reminiscent of eczema1,8. The eruption begins characteristically (97%) on the lower abdomen8, but often spares the periumbilical area (see Figures 6.1 and 6.2). Other commonly affected sites include the thighs, back (Figure 6.10), buttocks (Figure 6.11), and the extensor surfaces of the arms (Figure 6.12). It is most unusual to see the hands and feet affected21, but, if they are, the condition may resemble scabies (Figure 6.13) or pemphigoid (herpes) gestationis (PG). Mucosal lesions have not been described. In more severe PEP the erythema may confluently involve the entire abdomen, thighs, and even elsewhere (Figure 6.14). In view of the widespread clinical morphology in PEP, an attempt has been made to classify the clinical features. Aronson et al.22 have categorized the clinical features into three types: mainly urticarial papules and plaques

Figure 6.12  Polymorphic eruption of pregnancy morphology. Urticarial lesions on the upper arms.

(type I); nonurticarial erythemas, papules, vesicles, or excoriations (type II); and combinations of the two forms (type III). However, except for clinical appearance and distribution, the three groups did not differ significantly with regard to onset, parity, and histological/immunofluorescence findings.

Prognosis

Figure 6.13  Polymorphic eruption of pregnancy morphology. Acral urticarial and vesicular lesions resembling scabies.

Direct immunofluorescence (DIF) in PEP is characteristically negative for linear C3 and ­immunoglobulin (Ig) G deposition along the basement membrane zone (BMZ). However, some investigators have reported equivocal DIF findings in PEP, such as minimal C3 deposition along the BMZ, perivascular C3 and fibrin in the dermis6,19,21, and in one case antiepidermal cell surface antibodies24. DIF can rarely show a speckled band of IgM deposition along the BMZ11, but indirect immunofluorescence is consistently negative. Saurat25 has stressed the importance of performing DIF in patients with PEP, because some cases may be undistinguishable clinically from prebullous PG.

Differential diagnosis

Figure 6.14  Severe polymorphic eruption of pregnancy. The abdomen, thighs, and forearms are involved.

Therefore, this subclassification has not gained wide acceptance.

Histopathology and immunofluorescence Histopathologic examination of lesional skin usually reveals a spectrum of nonspecific findings, including a mild to moderate, superficial and mid dermal, perivascular, lymphohistiocytic infiltrate, with a variable number of eosinophils present. Spongiosis and marked papillary dermal edema may be present, leading to subepidermal vesicle formation23. Epidermal changes include acanthosis, hyperkeratosis, and/or parakeratosis and are usually more pronounced in older lesions. The histopathologic changes in PEP may considerably overlap with those seen in PG.

As PEP may have a variable clinical morphology, it may be confused with several disorders, including PG, drug eruptions, allergic reactions, scabies, and erythema multiforme (Table 6.1). The following comparison may help to differentiate between PEP and PG: • Examination of striae distensae is important because lesions overlying striae are found in 90% of patients with PEP but are seldom prominent in PG • Although vesicles are commonly found in patients with PEP, they are unlikely to be larger than 2–3 mm in diameter. However, once vesicles occur in PG, they usually evolve rapidly into larger tense bullae • Involvement of periumbilical skin is observed in only 10% of patients with PEP, whereas it is a common finding (84%) in PG1 • Nevertheless, it is firmly recommended that DIF is performed for all patients with PEP to avoid any diagnostic confusion with PG

Prognosis Apart from the discomfort of the pruritic urticarial eruption, the maternal prognosis is unaffected. However, the number of multiple pregnancies in patients with PEP appears to be increased significantly8–11. The largest study on PEP reported multiple pregnancies in 13% of 181 patients8, compared to an expected prevalence of approximately

53

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Table 6.1  Polymorphic Eruption of Pregnancy Diagnosis Clinical appearance Papulourticarial rash starting within striae distensae Conspicuous abdominal involvement with periumbilical sparing Development of polymorphous features (vesicles, ­erythema, target, and eczematous lesions) later on Association with first pregnancy, high maternal weight gain, and multiple pregnancies Direct immunofluorescence is negative Differential Diagnosis Pemphigoid gestationis Atopic eruption of pregnancy Urticaria Drug eruption Erythema multiforme Scabies Management Basic therapy with oil baths and emollients with additives such as 1–2% menthol or urea

described29. In this report, however, the ­possibility of PG has not been ruled out by immunofluorescence investigations. Thus, the fetal skin is usually not affected by PEP.

Management The disease is self-limiting without serious sequelae, and so only symptomatic treatment is usually required. Basic therapy should consist of oil baths and/or emollients with additives such as 1–2% menthol or urea. Most patients can obtain relief with the use of moderately potent topical corticosteroid creams (e.g., clobetasone butyrate 0.05%, or hydrocortisone butyrate 0.1%), either singly or combined with small doses of chlorphenamine maleate (4 mg at night). However, with the exception of coratadine and cetirizine, which seems to be safe during the second and third trimester, the newer nonsedating antihistamines are still not recommended in pregnancy30. More severe cases of PEP with a distressing degree of pruritus can be safely treated with oral prednisolone, the steroid of choice in pregnancy. A tapering dose of prednisolone, 30 mg daily for 7–14 days, should be sufficient. A patient with severe PEP, unresponsive to therapy, was dramatically improved within 2 hours after delivery by cesarean section31.

Moderately potent topical corticosteroid (e.g., clobetasone butyrate 0.05%, or hydrocortisone-17-butyrate 0.01%) in tapering dose for 7–14 days If additional antipruritic therapy is required: chlorpheniramine maleate 4 mg or coratadine 10mg or cetirizine 10 mg at night Severe cases: tapering dose of prednisolone, 30 mg daily, for 7–14 days

1% in the general population. This finding is in line with the results of a recent meta-­analysis of studies published between 1981 and 1999 comprising a total of 282 PEP cases, of which 29 (11.7%) were multiple-­gestation pregnancies.26 Carruthers’ experience indicated that resolution of the eruption in PEP appeared to be unrelated to delivery of the infant27, and it is generally agreed that fetal prognosis is normal1,5,6,8,11,12,21,28. Only one possible case of transient neonatal PEP involvement has been

References   1. Charles-Holmes, R. Polymorphic eruption of pregnancy. Semin. Dermatol. 1989; 8: 18–22.   2. Bourne, G. Toxemic rash of pregnancy. Proc. R. Soc. Med. 1962; 55: 462–464.   3. Nurse, D. S. Prurigo of pregnancy. Aust. J. Dermatol. 1968; 9: 258–267.   4. Holmes, R. C., Black, M. M., Dann, J., et al. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br. J. Dermatol. 1982; 106: 499–510.   5. Lawley, T. J., Hertz, K. C., Wade, T. R., et al. Pruritic urticarial papules and plaques of pregnancy. J.A.M.A. 1979; 241: 1696–1699.   6. Yancey, K. B., Hall, R. P. and Lawley, T. J. Pruritic urticarial papules and plaques of pregnancy. J. Am. Acad. Dermatol. 1984; 10: 473–480.   7. Alcalay, J. and Wolf, J.E. Pruritic urticarial papules and plaques of pregnancy: the enigma and the confusion. J. Am. Acad. Dermatol. 1988; 19: 1115–1116.   8. Rudolph, C. M., Al-Fares, S., Vaughan-Jones, S. A., et al. Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients. Br. J. Dermatol. 2006; 154: 54–60.

References   9. Cohen, L. M., Capeless, E. L., Krusinski, P. A., et al. Pruritic urticarial papules and plaques of pregnancy and its relationship to maternal–fetal weight gain and twin pregnancy. Arch. Dermatol. 1989; 125: 1534–1536. 10. Bunker, C. B., Erskine, K., Rustin, M. H. A., et al. Severe polymorphic eruption of pregnancy occurring in twin pregnancies. Clin. Exp. Dermatol. 1990; 15: 228–231. 11. Vaughan Jones, S. A., Hern, S. A., Nelson-Piercy, C., et al. A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br. J. Dermatol. 1999; 141: 71–81. 12. Regnier, S., Fermand, V., Levy, P., et al. A case-control study of polymorphic eruption of pregnancy. J. Am. Acad. Dermatol. 2008; 58: 63–67. 13. Alcalay, J., Ingber, A., Kafri, B., et al. Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy. Am. J. Obstet. Gynecol. 1988; 158: 417–420. 14. Callen, J. P. and Hanno, R. Pruritic urticarial papules and plaques of pregnancy (PUPPP): a clinicopathologic study. J. Am. Acad. Dermatol. 1981; 5: 401–405. 15. Aractingi, S., Berkane, N., Bertheau, P., et al. Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet 1998; 352: 1898–1901. 16. Powell, F. C. Parity, polypregnancy, paternity and PUPPP. Arch. Dermatol. 1992; 128: 1551. 17. Beckett, M. A. and Goldberg, N. S. Pruritic urticarial plaques and papules of pregnancy and skin distension. Arch. Dermatol. 1991; 127: 125–126. 18. Holmes, R. C., McGibbon, D. H., and Black, M. M. Polymorphic eruption of pregnancy with subepidermal vesicles. J.R. Soc. Med. 1984; 77: 22–23. 19. Carruthers, A. Facial involvement in pruritic urticarial papules and plaques of pregnancy. J. Am. Acad. Dermatol. 1987; 17: 302. 20. Alcalay, J., David, M. and Sandbank, M. Facial involvement in pruritic urticarial papules and plaques of pregnancy, J. Am. Acad. Dermatol. 1986; 15: 1048.

21. Vaughan Jones, S. A., Dunnill, M. G. S, and Black, M. M. Pruritic urticarial papules and plaques of pregnancy. (polymorphic eruption of pregnancy): two unusual cases. Br. J. Dermatol. 1996; 135: 102–105. 22. Aronson, I. K., Bond, S., Fielder, V. C. et al. Pruritic urticarial papules and plaques of pregnancy: clinical and immunopathologic observations in 57 patients. J. Am. Acad. Dermatol. 1998; 39: 933–939. 23. Holmes, R. C., Jureka, W., and Black, M. M. A comparative histopathological study of polymorphic eruption of pregnancy and herpes gestationis. Clin. Exp. Dermatol. 1983; 8: 523–529. 24. Trattner, A., Ingber, A, and Sandbank, M. Antiepidermal cell surface antibodies in a patient with pruritic urticarial papules and plaques of pregnancy. J. Am. Acad. Dermatol. 1991; 24: 306–308. 25. Saurat, J. H. Immunofluorescence biopsy for pruritic urticarial papules and plaques of pregnancy. J. Am. Acad. Dermatol. 1989; 20: 711. 26. Kroumpouzos, G. and Cohen, L. M. Specific dermatoses of pregnancy: an evidence-based systematic review. Am. J. Obstet. Gynecol. 2003; 188: 1083–1092. 27. Carruthers, A. Pruritic urticarial papules and plaques of ­pregnancy. J. Am. Acad. Dermatol. 1993; 29: 125. 28. Alcalay, J., Ingber, A., David, M., et al. Pruritic urticarial papules and plaques of pregnancy: a review of 21 cases. J. Reprod. Med. 1987; 32: 315–316. 29. Uhlin, S. R. Pruritic urticarial papules and plaques of pregnancy. Involvement of the mother and infant. Arch. Dermatol. 1981; 117: 238–239. 30. Schaefer, F., Spielmann, H., Velter, K. Arzneiterordnung in Schwaugerschaft und Stillzert. 7. Auflage, Urban & Fischer, Elsevier Verlag; Munich; 2006. 31. Beltrani, V. P. and Beltrani, V. S. Pruritic urticarial papules and plaques of pregnancy: a severe case requiring early delivery for relief of symptoms. J. Am. Acad. Dermatol. 1992; 26: 266–267.

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PART: I  Obstetrics

CHAPTER 7

Intrahepatic Cholestasis of Pregnancy Christina M. Ambros-Rudolph Introduction Intrahepatic cholestasis of pregnancy (ICP; synonymous: obstetric cholestasis) represents a rare form of genetically linked, hormonedependent reversible cholestasis1. It typically presents in the second half of pregnancy and resolves rapidly after delivery. Clinically, it is characterized by severe pruritus in the absence of primary skin lesions. Secondary skin changes, due to scratching, follow with disease progression and include excoriations and prurigo lesions. Biochemically, elevation of total serum bile acid levels is diagnostic. ICP is particularly prevalent in South America (Chile, Bolivia) and Scandinavia, whereas incidence rates of 0.1–1.5% have been described for Central Europe and Northern America. There is a positive family history in up to 50% of cases. In contrast to the other dermatoses of pregnancy, ICP is associated with significant fetal risk (Table 7.1)1.

Historical background Although ICP had been addressed as an important differential diagnostic consideration in most comprehensive studies of pregnancyrelated disorders, it was usually omitted from the classification of specific dermatoses of pregnancy as it is not a primary dermatosis but associated with only secondary skin lesions due to scratching. Shornick2, in 1998, was the first to include it in the category of specific dermatoses of pregnancy, along with pemphigoid gestationis, polymorphic eruption of pregnancy, and prurigo of pregnancy. He postulated that failure to appreciate ICP in a pregnant woman with Table 7.1  Fetal Risks Associated with Intrahepatic Cholestasis of Pregnancy

Fetal Risks

Prevalence1

Premature births

19–60%

Intrapartal fetal distress Abnormal intrapartum heart rate Meconium staining of ­amniotic fluid

22–33%

Stillbirths

1–2%

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pruritus and excoriated papules, in retrospect, had certainly accounted for some of the confusion in terminology. The importance of considering ICP within a classification of pregnancy dermatoses has also been supported by Roger et al.3, who in their series observed a high incidence of ICP associated with significant fetal risk and impaired pregnancy outcome. Also the most recent classification of pregnancy dermatoses4, based on the results of a large retrospective study on more than 500 pregnant women with pruritus, includes ICP within this category.

Etiology The etiology of ICP appears to be multifactorial. Potential contributing factors include a genetic predisposition interacting with the effects of estrogen and progesterone metabolites on bile secretory mechanisms5. The central role of hormonal factors is supported by the higher incidence of cholestasis in twin pregnancies and the fact that predisposed women often suffered from pruritus when taking oral contraceptives. Historically, ICP has been associated with the cholestatic effect of estradiol metabolites, in particular 17ß-estradiol glucuronide. Progesterone metabolites, however, play an even more important role in its pathogenesis. Their profile in serum and urine from patients with ICP differs significantly from that seen in normal pregnancy and may be related to malfunction of biliary canalicular transporters normally responsible for their secretion from hepatocytes into bile. Several of these transporters have recently been characterized. Mutations in the ABCB4 gene, encoding a member of the ATP-binding cassette (ABC) family of membrane transporters, and variants in the ATP8B1 gene have been identified in a small number of patients with ICP6. Thus, it has been suggested that genetically linked mild malfunction of canalicular transporters, which causes no problem outside pregnancy, may lead to clinical symptoms of cholestasis when the transporters’ capacity to secrete substrates is exceeded – as occurs with the high levels of sex hormones produced in pregnancy7. Besides hormonal and genetic factors, environmental factors may also

contribute to the pathogenesis of ICP. This is based on the observation of a seasonal variability of incidence, an incomplete recurrence at subsequent pregnancies, as well as a decrease in the prevalence of ICP in Sweden and Chile in association with improved nutritional (i.e., selenium) supply over the past decades8,9. Only very recently, an increased intestinal permeability (“leaky gut”), which has been demonstrated in several liver diseases, was also detected in ICP patients10. Reyes and co-workers10 postulate that a leaky gut may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts. The exact pathophysiologic relevance of these findings, however, has yet to be determined.

Clinical and laboratory findings The disorder typically presents in the late second or third trimester of an otherwise normal pregnancy, although initial presentation as early as 8 weeks’ gestation has been reported. Intense generalized itching occurs, which is invariably worse at night, and persists throughout the duration of pregnancy. At onset, pruritus is often localized, particularly to the palms and soles. The result of physical examination correlates with disease duration. Although it is usually normal at disease onset and during the very first days, secondary skin changes, due to scratching, may be observed with disease progression. These vary from few subtle linear excoriations and occasional scratch marks, when the patient presents shortly after onset of pruritus, to severe and widespread prurigo, in case of presentation several weeks after disease onset (Table 7.2). The most commonly involved body sites are the shins and lower arms, but also buttocks and abdomen may be affected (Figures 7.1–7.6). Although jaundice is often quoted as a common finding in ICP, it occurs, in fact, in only 10% of cases, complicating the most severe and prolonged episodes11. If present, jaundice may be associated with steatorrhea and subsequent vitamin K deficiency, which may lead to an increased risk of intra- and postpartum haemorrhage. In most patients, pruritus disappears promptly after

Clinical and laboratory findings 59

Table 7.2  Intrahepatic Cholestasis of Pregnancy Diagnosis Clinical appearance Severe pruritus in late pregnancy without primary skin lesions: resolves rapidly after delivery Secondary skin changes due to scratching followed   by disease progression They vary from excoriations to prurigo lesions, ­correlating with duration of pruritus Elevated total serum bile acid levels (> 11 μmol/L) are diagnostic Positive family history (50%), recurrence with successive pregnancies and oral contraception (40–70%) Differential Diagnosis Dermatoses of pregnancy (in particular, P-type atopic eruption of pregnancy) Scabies Allergic reaction Coinciding viral and/or bacterial rashes With jaundice: see Table 7.2 Management Oral treatment with ursodeoxycholic acid (UDCA)   15 mg/kg per day until delivery

Figure 7.1  Intrahepatic cholestasis of pregnancy with   a 2-week history of pruritus. Subtle excoriations and tiny prurigo lesions due to scratching are present on the shins. Copyright © 2007. American Medical Association.

Patient consent necessary as drug is not yet licensed in pregnancy Close obstetric surveillance (weekly cardiotocograph monitoring from 34 weeks’ gestation on; obstetric   decision on eventual active management) Counseling of the patient on associated fetal risks, family history, and recurrence with successive pregnancies and oral contraception In case of protracted pruritus after delivery, refer for further hepatologic evaluation to exclude chronic liver disease

delivery within 1–2 days. However, a protracted course of the disease may exceptionally occur and should always lead to close monitoring of these patients to exclude chronic liver disease.6,12 Recurrences during subsequent pregnancies as well as with oral contraception are common and occur in about 70% of cases with a similar course.

Figure 7.2  Intrahepatic cholestasis of pregnancy with   a 2-week history of pruritus. Close-up of Figure 7.1.

A typical biochemical finding is of markedly increased levels of total serum bile acids which are the most sensitive indicator of ICP and usually precede the abnormalities of other liver tests. In healthy pregnancies, total serum bile acids are

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60

Figure 7.3  Advanced intrahepatic cholestasis of pregnancy with widespread excoriations and prurigo lesions on the shins. Pruritus in intrahepatic cholestasis of pregnancy leads to exclusively secondary skin changes due to ­scratching. Copyright © 2007. American Medical Association.

Figure 7.4  Severe intrahepatic cholestasis of pregnancy with long-standing history of pruritus for several weeks. Extensive, partly inflamed purigo nodules on the shins of an Egyptian primigravida at 32 weeks’ gestation.   Copyright © 2007. American Medical Association.

slightly higher in pregnant (6.6 ± 0.3 μmol/L) than in nonpregnant women (5.7 ± 0.4 μmol/L)13, and levels up to 11.0 μmol/L are accepted as normal in late gestation14. Among routine liver function tests, raised transaminases, in particular alanine aminotransferase, and gamma-glutamyltransferase levels are sensitive parameters for ICP and occur in 20–60% and 30% of patients, respectively11,15. Hyperbilirubinemia is only detected in 10–20% of cases. An upper abdominal ultrasound, which usually reveals normal findings, may be considered in ICP patients with abdominal symptoms; liver and skin biopsies are unnecessary. The differential diagnosis of ICP includes primarily the other specific dermatoses of pregnancy. While pemphigoid gestationis and polymorphic eruption of pregnancy can be easily ruled

out by the absence of primary skin changes, the distinction between ICP and atopic eruption of ­pregnancy (AEP), in particular P-type AEP, can be a challenge. The most important diagnostic clue to discriminate ICP with prurigo lesions from those associated with AEP is the gestational age. Whereas ICP manifests in late pregnancy, AEP ­presents ­significantly earlier, with 75% onset before the third trimester4. Elevation of total serum bile acids will confirm the diagnosis. Other differential diagnoses of ICP are listed in Table 7.3.

Fetal risks For pregnant women with ICP, quality of life can be significantly impaired by itching, jaundice, and fat malabsorption, but the prognosis for the mother is

Management 61

Figure 7.5  Severe intrahepatic cholestasis of pregnancy. Same patient as in Figure 7.4. Prurigo nodules are also ­present on the extensor surfaces of arms and hands.

good. In contrast, ICP is a condition with possible lethal outcome for the unborn child if not handled with care. Fetal risks include premature births in 19–60% of affected pregnancies, intrapartal fetal distress in 22–33% of deliveries, and stillbirths in 1–2%1. The cause of fetal ­morbidity in ICP is not fully understood, but acute placental anoxia due to abnormal uterine contractility and vasoconstriction of chorionic veins as well as impaired fetal cardiomyocyte function by elevated bile acid levels seem to play a central role16,17. An increased flux of bile acids from the mother to the fetus and a reduced ability of the fetus to eliminate bile acids across the placenta in ICP have been observed18,19 and high bile acid levels have been found to be associated with more frequent occurrence of fetal distress20, in particular with levels exceeding 40 μmol/L21. Intensive fetal surveillance is therefore recommended.

Figure 7.6  Resolution of intrahepatic cholestasis of ­pregnancy 3 weeks after start of ursodeoxycholic acid ­treatment. Same patient as in Figure 7.4, exhibiting ­postinflammatory ­hyperpigmented residual lesions after resolution of pruritus. Copyright © 2007. American Medical Association.

Obstetric management of patients with ICP varies widely over the world. Most authors agree that weekly fetal cardiotocographic registrations are valuable, at least from 34 weeks’ gestation on. The demonstration that the majority of intrauterine deaths occur from 37 weeks’ gestation22,23 has suggested that active management with elective delivery at 37 weeks may help prevent intrauterine death in affected pregnancies. Overall, obstetric management consists in weighing the risk of premature delivery against the risk of sudden death in utero.

Management Since fetal prognosis correlates with disease severity, treatment aims at the reduction of bile acids in order to prolong the pregnancy and reduce both

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Table 7.3  Differential Diagnosis of Intrahepatic   Cholestasis of Pregnancy (ICP) ICP without Jaundice Dermatoses of pregnancy (in particular, P-type atopic eruption of pregnancy) Allergic reaction Scabies Coinciding viral and/or bacterial rashes ICP with Jaundice Viral hepatitis Acute fatty liver of pregnancy Pre-eclampsia with increased liver enzymes Hyperemesis gravidarum Hyperbilirubinemic states Drug icterus Bile duct obstruction Hemolytic and metabolic diseases

fetal risk and maternal symptoms. Systemic treatment with antihistamines, epomediol, silymarine, phenobarbital, and activated charcoal have had limited success1. The role of S-­adenosylmethionine in ICP treatment is still a matter of debate and dexamethasone suppression of ­ fetoplacental estrogen production was effective in a small uncontrolled trial1,24. Anion exchange resins such as colestyramine bind bile acids and interrupt their enterohepatic circulation. Since ICP and colestyramine may independently lead to vitamin K deficiency, ICP patients who are treated with anion resins must receive parenteral substitution of fat-soluble vitamins. Because of the increased risk of antepartal fetal hemorrhage and intra- and postpartal maternal bleedings, as well as the minor effect on pruritus, colestyramine, nowadays, is not considered first-line therapy for ICP1. Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic nontoxic bile acid that has been successfully used to improve clinical and liver function abnormalities in a variety of cholestatic

liver diseases. Although it is not licensed for this indication – indeed, it is officially contraindicated for use in pregnancy – nevertheless, for the time being, it remains the treatment of choice for patients with ICP22,25–28. The recommended dose is 15 mg/kg per day both to reduce symptoms and improve fetal outcome. UDCA ­ stimulates the excretion of hydrophobic bile acids and other potentially hepatotoxic compounds and sulfated progesterone metabolites. Although the exact mechanism of action is still unclear, there is evidence that it corrects maternal serum bile acid profile13, decreases the passage of maternal bile acids to the fetoplacental unit, and improves the function of the bile acid transport system across the trophoblast19. It represents a valuable ­contribution to fetal well-being and outcome and has been shown to reduce premature labor, fetal distress, and fetal deaths22,25,26.

References   1. Lammert, F., Marschall, H. U., Glantz, A., et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J. Hepatol. 2000; 33: 1012–1021.   2. Shornick, J. K. Dermatoses of pregnancy. Semin. Cutan. Med. Surg. 1998; 17: 172–181.   3. Roger, D., Vaillant, L., Fignon, A., et al. Specific pruritic diseases of pregnancy: a prospective study of 3192 pregnant women. Arch. Dermatol. 1994; 130: 734–739.   4. Ambros-Rudolph, C. M., Vaughan-Jones, S. A., Müllegger, R. R., et al. The specific dermatoses of pregnancy revisited and reclassified. Results of a retrospective two-center study on 505 pregnant patients. J. Am. Acad. Dermatol. 2006; 54: 395–404.   5. Reyes, H. and Sjövall, J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann. Med. 2000; 32: 94–106.   6. Ropponen, A., Sund, R., Riikionen, S., et al. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 2006; 43: 723–728.   7. Milkiewicz, P., Williamson, C., Weaver, J., et al. Obstetric cholestasis. Br Med J 2002; 324: 123–124.   8. Berg, B., Helm, G., Petersohn, L., et al. Cholestasis of pregnancy. Clinical and laboratory studies. Acta Obstet. Gynecol. Scand. 1986; 65: 107–113.   9. Reyes, H., Báez, M. E., González, M. C., et al. Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals in Chile. J. Hepatol. 2000; 32: 542–549. 10. Reyes, H., Zapata, R., Hernández, I., et al. Is a leaky gut involved in the pathogenesis of intrahepatic cholestasis of ­pregnancy? Hepatology 2006; 43: 715–722. 11. Riosecco, A. J., Ivankovic, M. B., Manzur, A., et al. Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am. J. Obstet. Gynecol. 1994; 170: 890–895. 12. Leevy, C. B., Koneru, B., and Klein, K. M. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997; 113: 966–972.

References 13. Brites, D., Rodrigues, C. M., Oliveira, N., et al. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J. Hepatol. 1998; 28: 91–98. 14. Carter, J. Serum bile acids in normal pregnancy. Br. J. Obstet. Gynaecol. 1991; 98: 540–543. 15. Milkiewicz, P., Gallgher, R., Chambers, J., et al. Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment. J. Gastroenterol. Hepatol. 2003; 18: 1283–1286. 16. Sepulveda, W. H., Gonzalez, C., Cruz, M. A., et al. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur. J. Obstet. Gynecol. Reprod. Biol. 1991; 42: 211–215. 17. Williamson, C., Gorelik, J., Eaton, B. M., et al. The bile acid taurocholate impairs rat cardimyocyte function: a proposed mechanism for intra-uterine fetal death in obstetric cholestasis. Clin. Sci. 2001; 100: 363–369. 18. Heikkinen, J., Ylöstalo, P., Mäentausta, O., et al. Bile acids in maternal serum, umbilical cord serum and amniotic fluid of healthy women, women with pruritus and patients with intrahepatic cholestasis of pregnancy. J. Obstet. Gynecol. 1983; 4: 17–20. 19. Serrano, M. A., Brites, D., Larena, M. G., et al. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta, J. Hepatol. 1998; 28: 829–839. 20. Laatikainen, T. J. Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis. Am. J. Obstet. Gynecol. 1975; 122: 852–856.

21. Glantz, A., Marschall, H. U. and Mattsson, L. A. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–474. 22. Davies, M. H., da Silva, R. C. M. A., Jones, S. R., et al. Fetal mortality associated with cholestasis of pregnancy and the ­potential benefit of therapy with ursodeoxycholic acid. Gut. 1995; 37: 580–584. 23. Williamson, C., Hems, L. M., Goulis, D. G., et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. Br. J. Obstet. Gynaecol. 2004; 111: 676–681. 24. Hirvioja, M. L. and Tuimala, R. The treatment of intrahepatic cholestasis of pregnancy by dexamethasone. Br. J. Obstet. ­Gynaecol. 1992; 99: 109–111. 25. Palma, J., Reyes, H., Ribalta, J., et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J. Hepatol. 1997; 27: 1022–1028. 26. Zapata, R., Sandoval, L., Palma, J., et al. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience. Liver Int. 2005; 25: 548–554. 27. Kondrackiene, J., Beuers, U. and Kupcinskas, L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005; 129: 895–901. 28. Ambros-Rudolph, C.M., Glatz M., Trauner M., et al. The importance of serum bile acid level analysis and treatment with ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case series from central Europe. Arch. Dermatol. 2007; 143: 757–762.

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PART: I  Obstetrics

CHAPTER 8

Atopic Eruption of Pregnancy Christina M. Ambros-Rudolph Samantha Vaughan Jones

Introduction Atopic eruption of pregnancy (AEP) has recently been introduced as a new disease complex among the specific dermatoses of pregnancy. It encompasses eczema in pregnancy, prurigo of pregnancy, and pruritic folliculitis in pregnancy, as a large retrospective study on more than 500 pregnant patients with pruritic skin diseases has demonstrated significant overlap between these three conditions1. AEP is by far the commonest pregnancy dermatosis, accounting for approximately 50% of pruritic rashes in pregnancy. Its clinical spectrum includes eczematous and papular lesions in patients with a personal and/or family history of atopy. Although AEP manifests throughout pregnancy, affecting all three trimesters, it usually presents much earlier than the other specific dermatoses of pregnancy (75% onset before the third trimester)1. AEP usually responds quickly to therapy and fetal prognosis is not endangered.

Historical background Atopic eczema is a chronic, relapsing, pruritic dermatitis, affecting 1–5% of the general population. The prevalence of this condition appears to be increasing, possibly because of environmental changes.2–4 Several previous studies have shown an exacerbation of eczema during pregnancy5. Kemmett and Tidman5 noted that 50 of 150 atopic women reported a premenstrual exacerbation of the symptoms of atopic dermatitis. Similarly, in 50 women with previous pregnancies, pregnancy had had an adverse effect in 52% of cases, usually in the first and second trimesters5. In a recent prospective study of 200 women with rashes in pregnancy, eczema was found to be the commonest pregnancy dermatosis, accounting for 36% of the total number of cases6. So far, these important findings had not been acknowledged by any of the classifications on pregnancy dermatoses. Since the very first reports, however, there had been doubt that prurigo of pregnancy and pruritic folliculitis of pregnancy represented distinct entities. Holmes

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and Black7 suggested that prurigo of pregnancy may simply result from pruritus in atopic women rather than being a distinct entity. Going back to the first description of prurigo of pregnancy, by Besnier et al. in 19048, it must be acknowledged that “prurigo” at that time was the term applied to describe the condition known as atopic dermatitis nowadays. A comprehensive retrospective study recently evaluated anamnestic, clinical, and histo/immunopathologic data in a series of more than 500 pregnant patients with pruritic skin changes. Significant overlap, both clinically and histopathologically, was demonstrated among patients with eczema, prurigo, and pruritic folliculitis of pregnancy (see Chapter 9)1. Based on these observations, the term “atopic eruption of pregnancy” has been introduced, resulting in a simplified classification of pregnancy dermatoses, as outlined in Chapter 4.

Figure 8.1  Exacerbated eczema in pregnancy. Severely inflamed scaly areas with lichenification and erosive fissures on neck and anterior chest.

Etiology Pregnancy is known as an immunologic state where a natural homeostasis exists between antigenically different tissues. To prevent fetal rejection, normal pregnancy is characterized by a lack of strong maternal cell-mediated immune function and TH1 cytokine production (e.g., interleukin (IL)-12, interferon-gamma) and a dominant humoral immune response and TH2 cytokine production (e.g., IL-4, IL-10)9. These distinct changes in TH1/TH2 cytokine balance are considered responsible for the remission in predominant TH1-driven autoimmune diseases during pregnancy and their characteristic deterioration in the postpartum period, as observed in rheumatoid arthritis or multiple sclerosis, compared to a flare in pregnancy of mainly TH2-driven autoimmune diseases, such as systemic lupus erythematosus10. As atopic dermatitis overall is considered to be a TH2-dominant disease, which accounts especially for acute lesions,11,12 it has been postulated that the TH2 shift associated with pregnancy may favor the exacerbation of atopic dermatitis during pregnancy as well as the manifestation of AEP. Howarth13 postulated that the persistence of this placental TH2 drive may be a major factor in the increasing prevalence of allergic disease over the past 30–40 years.

Figure 8.2  Exacerbated eczema in pregnancy. Lichenified skin with excoriations involving the antecubital fossa and other parts of the arm.

Clinical and diagnostic features In 20% of cases, there is an exacerbation of preexisting atopic dermatitis with the typical clinical appearance. Acute lesions, such as pruritic, erythematous papules and vesicles, or extensive weeping areas covered with serous exudates may be present as well as subacute and chronic features, including excoriated papules and plaques, scaling, and lichenification (Figures 8.1–8.3). Eighty percent of patients, however, experience atopic skin manifestations for the first time ever during pregnancy, or after a long remission (i.e., childhood eczema). Most patients will give a ­ positive personal history of atopy or a family history of asthma, eczema, or hayfever in a

Clinical and diagnostic features 67

Figure 8.4  Mild atopic eruption of pregnancy (E-type). Discrete eczematous patches on the abdomen of a ­primigravida at 26 weeks’ gestation.

Figure 8.3  Exacerbated eczema in a primigravida at 17 weeks’ gestation. Erythrodermic state, involving the whole body.

first-degree relative. Morphologically, two-thirds of patients display patchy eczematous changes (E-type AEP) (Figures 8.4–8.7), whereas one-third present with papular lesions (P-type AEP) (Figures 8.8–8.12)1. The latter occur as prurigo lesions or disseminated, small erythematous papules. Typical atopic sites such as face, neck, anterior chest, and flexural surfaces of extremities are often involved. Overall severe dryness of the skin and frequent atopic “minor features” according to Hanifin and Rajka14 are common findings. Histopathology is nonspecific and varies with clinical presentation; direct and indirect immunofluorescence are negative. Total serum immunoglobulin (Ig) E levels are elevated in 20–70% of cases. Differential diagnosis includes in particular the other specific dermatoses of pregnancy (Table 8.1). The sparing of striae distensae and the significantly earlier presentation will help to differentiate AEP

Figure 8.5  Advanced atopic eruption of pregnancy (E-type). Nummular eczematous lesions are involving the anterior chest, breasts, and the upper abdomen.

from polymorphic eruption of pregnancy, whereas normal total serum bile acid levels are the clue to discriminate AEP from intrahepatic ­cholestasis of pregnancy. Furthermore, dermatoses coinciding with pregnancy, such as scabies, pityriasis rosea,

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Figure 8.7  Atopic eruption of pregnancy involving the whole abdomen. Widespread scaly erythematous areas over the abdomen at 23 weeks’ gestation.

Figure 8.6  Advanced atopic eruption of pregnancy (E-type). Same patient as in Figure 8.5. Nummular eczematous lesions are also present on the back of the patient.

allergic rashes, and drug eruptions, as well as viral and/or bacterial exanthemata must be excluded.

Prognosis Skin lesions in AEP usually respond quickly to therapy, and mostly a marked improvement occurs during pregnancy. Recurrences in subsequent pregnancies are common. Fetal prognosis is not endangered but atopic skin changes may develop in the infant later on.

Management A patient with AEP should try to avoid local heat and contact with irritants such as soap and detergents. The mainstay of treatment is keeping the skin moisturized. Basic therapy using emollients adapted to the skin’s state are central. It is important to find

Figure 8.8  Mild atopic eruption of pregnancy (P-type). ­Disseminated tiny erythematous papules on and around the breasts in a multigravida at 29 weeks’ gestation.

an emollient that suits the individual patient. Urea (3–10 %) and antipruritic additives (menthol, polidocanol) can be safely employed during pregnancy. Additional drying of the skin through washing, bathing, or showering can be avoided by using mild, nonalkaline synthetic detergents capable of replacing lipids and showering with bath oils. Patients may also soak for 10–15 minutes daily in a lukewarm bath with such additives. Emollient cream or ointment should afterwards be applied to the skin while still damp from the bath. In pregnancy, only the weakest possible topical corticosteroid should be applied for routine maintenance, but in acute exacerbations high-potency class 1 or 2 corticosteroids may be applied for a

Management 69

Figure 8.9  Mild atopic eruption of pregnancy (P-type). Same patient as in Figure 8.8. Tiny papules and scaling erythema also involve the neck.

Figure 8.12  Severe atopic eruption of pregnancy (P-type) with widespread inflamed papules on the trunk and limbs. A patch of excoriated eczema on the left wrist at the watch strap site suggests underlying nickel allergy. Figure 8.10  Mild atopic eruption of pregnancy (P-type). Same patient as in Figure 8.8. Discrete papules are also present on the flexural aspects of the arm.

Figure 8.11  Atopic eruption of pregnancy with papular lesions and excoriations on hips and buttocks. Same patient as in Figure 8.7.

few days, with a slow return to a low-potency steroid. The new topical immunomodulators such as tacrolimus and pimecrolimus are not approved for use in pregnancy15. Occasionally, systemic corticosteroids are required for a short period in severe AEP. Prednisolone, 30 mg daily, may be required initially, with the dose tapered over 1 week. If needed for longer, maintenance dose should not exceed 10 mg/day in the first trimester, as a slightly increased incidence of cleft palates is otherwise debated16. As corticosteroids in AEP are usually used as short-time therapy (less than 4 weeks), side-effects (particularly maternal hypertension and gestational diabetes mellitus) need not be expected. In rare cases with high-dose therapy over many weeks, fetal growth should be monitored by ultrasound. Should this therapy be continued up to delivery, possible ­adrenal insufficiency of the newborn must be kept

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70 Table 8.1  Atopic Eruption of Pregnancy Diagnosis Clinical appearance  Atopic skin changes exacerbating during pregnancy or evolving for the first time in pregnancy   20% present as exacerbated atopic dermatitis  80% experience first manifestation of atopic skin ­changes which include eczematous features (two-thirds; E-type AEP) and/or papular lesions (one-third; P-type AEP) A positive personal and/or family history of atopy (atopic eczema, hayfever, asthma) and/or elevated total serum immunoglobulin E levels are characteristic May present throughout pregnancy; however, most often (75%) before the third trimester; recurrence in subsequent pregnancies is common Differential Diagnosis Pemphigoid gestationis Polymorphic eruption of pregnancy Intrahepatic cholestasis of pregnancy Pityriasis rosea Scabies Drug eruption Contact dermatitis Management Basic therapy with oil baths and emollients to keep the skin moisturized is central; emollients should be adapted to the skin’s state and may contain additives such as ­menthol, polidocanol, or urea Apply weakest possible topical corticosteroid for ­routine maintenance and high-potency class 1 or 2 ­corticosteroids for a few days for acute exacerbation In severe cases prednisolone, 30 mg daily, tapered over 1 week may be needed If additional antipruritic therapy is required, use ­chlorpheniramine maleate 4 mg or coratadine 10 mg or cetirizine 10 mg at night In case of secondary bacterial infections use systemic (penicillin, erythromycin) or topical antibiotics (mupirocin, fusidic acid) Ultraviolet B irradiation is an additional helpful and safe therapeutic option in pregnancy

in mind and treated accordingly. Small amounts of corticosteroids also pass into the breast milk, although low doses of prednisolone (e.g., 5 mg daily) are unlikely to have an adverse effect on the infant. Systemic antihistamines, such as ­ hydroxyzine, chlorphenamine, and promethazine, are often required for pruritus, and are safe when used in pregnancy. Apart from coratadine and ­cetirizine, which are safe in the second and third ­trimester16, the newer ­nonsedating antihistamines are still not recommended in pregnancy. Systemic antibiotics are often necessary in AEP because of secondary bacterial infections, especially with Staphylococcus aureus. Penicillin, erythromycin, and cephalosporins are safe to use in pregnancy; penicillinase-resistant penicillins (e.g., ampicillin) are recommended for skin infections15. Topical antibiotics, such as bacitracin or neomycin, are sometimes used, but may cause skin sensitization. Mupirocin and fusidic acid seem to be less sensitizing, but are more expensive. Both ultraviolet B (UVB) irradiation and photochemotherapy using psoralens with long-wave ultraviolet irradiation (PUVA) may be useful adj­ uncts in treating chronic atopic eczema. Although UVB is safe in pregnancy, PUVA should not be used as a first-line treatment because of its potential adverse effects on the fetus. Occasionally, immunosuppressive agents, such as azathioprine and cyclosporine A, are required for severe eczema. These drugs should only be used with great caution during pregnancy17.

Nipple eczema Breastfeeding can sometimes be a problem because of nipple eczema (Figure 8.13). Painful fissures may develop and become secondarily infected with bacteria, particularly S. aureus. Anatomic features, such as relatively flat nipples, contribute to the development of this problem. Nipple eczema is treated with frequent application of moisturizers and a topical corticosteroid of mild potency, such as hydrocortisone. A topical corticosteroid combined with a topical antibiotic is useful for eczema that has become infected by bacteria. A systemic antibiotic, such as erythromycin, may then be required.

References 71

Figure 8.13  Nipple eczema. Dry, scaly, erythematous areas on the nipple, with painful fissures.

Figure 8.15  Hand eczema. Widespread excoriations and lichenification on the dorsal aspects of the hands 6 weeks after delivery.

Figure 8.14  Hand eczema. Erythematous scaly areas on the dorsal and lateral aspects of the fingers and hands with few excoriations.

Figure 8.16  Pompholyx eczema. Presenting with numerous vesicles on the lateral aspects of the fingers during pregnancy.

Hand eczema Hand eczema may be exacerbated during the puerperium because of the constant exposure to irritants used in providing care for young children (Figure 8.14–8.16). Once the skin barrier has been broken, only minor re-exposure to the irritant is needed to keep the eczema active. Treatment is prophylactic and aimed at protecting the hands from all skin irritants by using rubber gloves. Topical corticosteroids of moderate potency (class 4 or 5), such as betamethasone valerate 0.1% cream, are needed, and emollients should be applied ­ frequently. Contact dermatitis should be suspected in patients who fail to improve with standard treatment, but patch testing should be delayed until breastfeeding has stopped.

References   1. Ambros-Rudolph, C. M., Müllegger, R. R., Vaughan Jones, S. A., et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J. Am. Acad. Dermatol. 2006; 54: 395–404.   2. Williams, H. C. Is the prevalence of atopic dermatitis increasing? Clin. Exp. Dermatol. 1992; 17: 385–391.   3. Charman, C. Atopic eczema. Br. Med. J. 1999; 318: 1600–1604.   4. Butland, B. K., Strachan, D. P., Lewis, S., et al. Investigation into the increase in hay fever and eczema at age 16 observed between 1958 and 1970 British birth cohorts. Br. Med. J. 1997; 315: 717–721.   5. Kemmett, D. and Tidman, M. J. The influence of the menstrual cycle and pregnancy on atopic dermatitis. Br. J. Dermatol. 1991; 125: 59–61.   6. Vaughan Jones, S. A., Hern, S., Nelson-Piercy, C., et al. A prospective study of 200 women with dermatoses of pregnancy correlating the clinical findings with hormonal and immunopathological profiles. Br. J. Dermatol 1999; 141: 71–81.

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Atopic Eruption of Pregnancy   7. Holmes, R. C. and Black, M.M. The specific dermatoses of pregnancy. J. Am. Acad. Dermatol. 1983; 7: 104–110.   8. Besnier, E., Brocq, L., and Jacquet, L. La Pratique Dermatologique, vol. 1, p.75Masson, Paris, 1904.   9. Wilder, R. L. Hormones, pregnancy, and autoimmune disease, Ann. N.Y. Acad. Sci. 1998; 840: 45–50. 10. Elenkov, I. J. and Chrousos, G. P. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity, Ann. N.Y. Acad. Sci. 2002; 966: 290–303. 11. Kang, K., Poster, A. M., Nedorost, S. T., et al. Atopic dermatitis. In: Bolognia, J. L., Jorizzo, J. L., Rapini, R. P., et al. (eds) Dermatology, pp. 199–214. Mosby, New York, 2003. 12. Akdis, M., Trautmann, A., Klunker, S., et al. T cells and effector functions in atopic dermatitis. Curr. Allergy Asthma Rep. 2002; 2: 1–3.

13. Howarth, P. H. ABC of allergies. Pathogenic mechanisms: a rational basis for treatment. Br. Med. J. 1998; 316: 758–761. 14. Hanifin, J. M. and Rajka, G. Diagnostic features of atopic eczema, Acta Dermatol. Venereol. Suppl. (Stockh.)1980; 92: 44–47. 15. Weisshaar, E., Diepgen, T. L., Luger, T. A., et al. Pruritus in pregnancy and childhood – do we really consider all relevant differential diagnoses? Eur. J. Dermatol. 2005; 15: 320–331. 16. Schaefer, C., Spielmann, H., and Velter, K. Arzneiverordnung in Schwangerschaft und Stillzeit,. 7. Auflage, Urban & Fischer, ­Elsevier Verlag; Munich; 2006. 17. Weatherhead, S., Robson, S. C., and Reynolds, N. J. Eczema in pregnancy. Br. Med. J. 2007; 21: 152–154.

PART: I  Obstetrics

CHAPTER 9

The Papular and Pruritic Dermatoses of Pregnancy Christina M. Ambros-Rudolph Martin M. Black Samantha Vaughan Jones Introduction The papular and pruritic dermatoses of pregnancy encompass three historical disease entities that are described in the same chapter because each of the terms applied is still quoted in the literature: (1) prurigo of pregnancy; (2) papular dermatitis of pregnancy; and (3) pruritic folliculitis of pregnancy. Significant overlap between them and the lack of unequivocal clinical or diagnostic features, as available in pemphigoid gestationis, polymorphic eruption of pregnancy, and intrahepatic cholestasis of pregnancy, have led to considerable doubt that they were all distinct clinical entities. Indeed, papular dermatitis of pregnancy was the first to be no longer regarded as a distinct condition but to belong in the spectrum of prurigo of pregnancy. And prurigo of pregnancy and pruritic folliculitis of pregnancy, according to the most recent classification of pregnancy dermatoses1, are now summarized within a new disease complex that has been termed atopic eruption of pregnancy (AEP: see Chapter 8). This chapter shortly outlines the historical background and clinical characteristics of each entity.

Prurigo of pregnancy In 1904, Besnier et al. first introduced the term “prurigo gestationis”’ to include all patients with pregnancy-related dermatoses, other than those with herpes gestationis2. At that time, “prurigo” was the term used to describe atopic dermatitis; Besnier was the first to describe the association between atopic dermatitis, allergic rhinitis, and asthma3,4. Costello, in 1941, coined the term “prurigo gestationis of Besnier” and estimated an incidence of 2%5. The condition was first clearly outlined by Nurse in 1968, who termed it “early-onset” prurigo of pregnancy, in contrast to a late form, that is nowadays known as polymorphic eruption of pregnancy6. Nurse

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74

Figure 9.2  Prurigo of pregnancy – reclassified P-type atopic eruption of pregnancy. Excoriated papules on the lower legs.

Figure 9.1  Prurigo of pregnancy – reclassified P-type ­atopic eruption of pregnancy. Diffuse prurigo papules ­scattered on the abdomen and extensor limb surfaces.

described accompanying eczematous features in most of his 31 patients with early-onset prurigo. But it was Holmes and Black in 1983 who first suggested that prurigo of pregnancy would result from pruritus gravidarum in women with atopic diathesis rather than being a distinct entity7. They based their argument on the finding that 18% of pregnancies are complicated by pruritus8 and that 10% of the population displays atopy9. It might therefore be expected that both conditions would coincide in about 2% of pregnancies. In a large retrospective study on more than 500 pregnant patients with pruritus, 45/49 (92%) patients originally diagnosed with prurigo of pregnancy met the preset criteria of atopic eczema1. The remaining 4 patients all showed multiple minor criteria of atopy, as outlined by Hanifin and Rajka10, and shared histopathological features with eczema. Based on these observations, prurigo of pregnancy

was included in a new disease complex that was termed “atopic eruption of pregnancy” and summarizes all patients formerly labeled as eczema in pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy. Clinically, the lesions formerly described as prurigo of pregnancy today represent the “P-type” variant of AEP (see Chapter 8). Lesions, then and now, are described as discrete erythematous or skin-colored papules, which are extremely pruritic, with the result that an excoriated surface soon develops over the papules. The papules tend to be small and are seldom larger than 0.5 cm in diameter. Characteristically, the papules appear on the extensor surfaces of the extremities and trunk (Figures 9.1–9.3). The histological features of prurigo of pregnancy have not been studied systematically, and consequently the diagnosis has been made on clinical criteria alone. Where biopsies have been performed, the pathology usually shows nonspecific findings such as mild acanthosis, parakeratosis, and surface excoriation. A mixed perivascular infiltrate is found, often containing eosinophils and some neutrophils7. Direct immunofluorescence (DIF) is negative7. Prurigo of pregnancy has always been considered a benign disorder, as is AEP nowadays. However, the patient may find the persistent pruritus distressing. Symptomatic relief of pruritus can usually be achieved with moderately potent topical corticosteroid creams and oral antihistamines at night.

Papular dermatitis of pregnancy

Figure 9.3  Prurigo of pregnancy – reclassified P-type atopic eruption of pregnancy. More extensive inflamed erythematous papules on lower legs.

Papular dermatitis of pregnancy Papular dermatitis of pregnancy was first described by Spangler et al.11 in 1962. They identified a group of patients, who they thought could be differentiated from patients with prurigo of pregnancy, both clinically and biochemically. They stressed the high fetal risk which they considered to be preventable by appropriate therapy. There has been considerable doubt, however, that papular dermatitis of pregnancy was an entity separate from more widespread examples of prurigo of pregnancy. Nor was it likely that the disorder carried an appreciable fetal risk12. Spangler et al.11 originally described 12 patients with papular dermatitis. The eruption occurred throughout pregnancy from 11 weeks’ gestation to term. The condition was described as a generalized papular eruption over the trunk, arms, legs, and even the face. The papules were 3–5 mm in

diameter and excoriated. Rahbari13 later described 16 cases and noted that the papules could have an erythematous, urticated appearance before excoriation. Spangler et al.11 estimated an incidence of about one in 2400 pregnancies and expressed concern about the high fetal mortality rate (27–37%). In recent years, very few new cases of papular dermatitis have been reported14,15. The similarity of the eruption to prurigo of pregnancy12 and pruritic folliculitis of pregnancy, both clinically and histopathologically, has been noted15. The few immunofluorescence observations made in papular dermatitis have been negative15. Spangler et al.11,16 also reported a raised chorionic gonadotropin concentration, lowered plasma cortisol levels, and reduced urinary estriol levels in patients with papular dermatitis of pregnancy. Owing to the increased fetal mortality rate they found, they recommended systemic administration of either prednisone (prednisolone), up to 200 mg daily, or diethystilbestrol 600–2500 mg daily. They claimed that these therapies cleared the dermatosis within a few days and reversed the potential fetal loss. In 1971, however, Spangler et al. 16 withdrew their statement because of a newly recognized association between administration of ­ diethylstilbestrol and the development of vaginal carcinoma during adolescence in female offspring17. Subsequently, others did not find a high fetal loss and recommended “conservative treatment” and reported on the beneficial use of tapering doses of prednisone13–15. A comprehensive reappraisal of the startling claims of Spangler et al.11,16 has cast considerable doubt on the nosology of papular dermatitis7. A large prospective study of 200 women with dermatoses of pregnancy found no cases that conformed to the diagnosis of papular dermatitis of pregnancy. In addition, hormonal investigation did not confirm Spangler’s original findings, and fetal prognosis was found to be normal18. It is generally understood now that the cases of papular dermatitis described represented more widespread and severe cases of prurigo of pregnancy11. The main reason for the separate classification of papular dermatitis of pregnancy was based on the findings of raised urinary chorionic gonadotropin, low urinary cortisol, and low urinary estriol levels11,16

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which have not been confirmed by any other study. Furthermore, the fetal mortality rate in the original report of Spangler et al.11 was probably overestimated for the following reasons: 1. The interpretation of fetal deaths that occurred in pregnancies preceding the development of papular dermatitis was not justified, and exaggerated the fetal risk. 2. Their data included spontaneous abortions without reference to the period of gestation. This is important because spontaneous abortions in the first trimester are not uncommon in a normal population. Now that a comprehensive prospective study of pruritic papular dermatoses with biochemical data18 has been published, the diagnosis of papular dermatitis of Spangler can be laid to rest.

them separately as a new entity. Biochemical findings at that stage were not presented. Later on, there was speculation as to whether pruritic folliculitis of pregnancy may be associated with biochemical abnormalities. Wilkinson et al.20 reported a patient in whom serum androgen levels were raised. However, a comprehensive report of 12 patients with pruritic folliculitis showed no significant increase in serum androgen concentration when compared with levels in matched normal pregnant controls21. The present authors have seen a number of patients with a similar widespread eruption consisting of small erythematous papules and ­pustules (Figures 9.4–9.6). The authors’ views are that the clinical appearance of pruritic folliculitis of pregnancy may be divided into two groups: the first group comprises cases of pruritic folliculitis which

Pruritic folliculitis of pregnancy The term “pruritic folliculitis of pregnancy” was first introduced by Zoberman and Farmer in 198119. They described 6 patients who had developed a pruritic, follicular, papular eruption between the fourth and ninth months of pregnancy, which then resolved within 2–3 weeks of delivery. The lesions were principally small, follicular, erythematous papules, distributed widely over the upper trunk, mimicking papular dermatitis of pregnancy. Characteristic histopathologic findings, i.e., a sterile folliculitis, however, led the authors to classify Figure 9.5  Acneiform eruption in pregnancy. A close-up of Figure 9.4 shows small follicular papules and pustules.

Figure 9.4  Acneiform eruption in pregnancy. Diffuse small monomorphic acneiform papules and pustules present on the patient’s back.

Figure 9.6  Acneiform eruption in pregnancy. Involvement of the upper chest.

References

are very similar to the monomorphic type of acne occurring after the administration of systemic corticosteroids or progestogens7. It is therefore possible that these cases are a form of hormonally induced acne rather than a specific dermatosis of pregnancy. Thus, we suggest they should be referred to as “acne” or “acneiform eruption” in pregnancy. In fact, review of the literature shows that many case reports of pruritic folliculitis of pregnancy, in retrospect, fit very well into this category. This is further substantiated by the demonstration of nonsterile folliculitis due to microorganisms such as Gram-positive cocci or Pityrosporum ovale in some of these cases22. The other group comprises cases of pruritic folliculitis which overlap significantly with eczema in pregnancy, in particular the follicular variant seen in atopic dermatitis, as has been pointed out recently1. This has led to the incorporation of these cases of pruritic folliculitis of pregnancy into the newly introduced disease complex of AEP (see Chapter 8)1.

References   1. Ambros-Rudolph, C. M., Müllegger, R. R., Vaughan Jones, S. A., et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J. Am. Acad. Dermatol. 2006; 54: 395–404.   2. Besnier, E., Brocq, L., and Jacquet, L. La Pratique Dermatologique, vol. 1,p. 75 Masson, Paris, 1904.   3. Besnier, E. Première note et observations preliminaires pour servir d’introduction a l’étude des prurigos diathésiques. Ann. Dermatol. Syphilis 1892; 3: 634.   4. Kang, K., Poster, A. M., Nedorost, S. T., et al. Atopic dermatitis. In: Bolognia, J. L., Jorizzo, J. L., Rapini, R. P., et al. (eds) Dermatology, p.199–214. Mosby, New York, 2003.   5. Costello, M. J Eruptions of pregnancy. N.Y. State J. Med. 1941; 41: 849–855.

  6. Nurse, D. S. Prurigo of pregnancy. Australas. J. Dermatol. 1968; 9: 258–267.   7. Holmes, R. C. and Black, M.M. The specific dermatoses of pregnancy. J. Am. Acad. Dermatol. 1983; 8: 405–412.   8. Kasdon, S. C. Abdominal pruritus in pregnancy. Am. J. Obstet. Gynecol. 1953; 65: 320–324.   9. Rapaport, H. G., Appel, S. J. and Szanton, V. L. Incidence of allergy in a pediatric population. Am. J. Allergy 1960; 18: 45–49. 10. Hanifin, J. M. and Rajka, G. Diagnostic features of atopic eczema. Acta Dermatol. Venereol. Suppl. (Stockh.) 1980; 92: 44–47. 11. Spangler, A. S., Reddy, W., Bardawill, W. A., et al. Papular dermatitis of pregnancy. J.A.M.A. 1962; 181: 577–581. 12. Black, M. M. Prurigo of pregnancy, papular dermatitis of pregnancy and pruritic folliculitis of pregnancy. Semin. Dermatol. 1989; 8: 23–25. 13. Rahbari, H. Pruritic papules of pregnancy. J. Cutan. Pathol. 1978; 5: 347–352. 14. Michaund, R. M., Jacobson, D., and Dahl, M. V. Papular ­dermatitis of pregnancy. Arch. Dermatol. 1982; 118: 1003–1005. 15. Nguyen, L. Q. and Sarmini, O. R. Papular dermatitis of pregnancy: a case report. J. Am. Acad. Dermatol. 1990; 22: 690–691. 16. Spangler, A. S. and Emerson. K. Estrogen levels and estrogen therapy in papular dermatitis of pregnancy. Am. J. Obstet. Gynecol. 1971; 110: 534–537. 17. Herbst, A. L., Ulfelder, H., and Poskanzer, D. C. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women, N. Engl. J. Med. 1971; 284: 878–881. 18. Vaughan Jones, S. A., Hern, S., Nelson-Piercy, C., et al. A prospective study of 200 women with dermatoses of ­pregnancy correlating the clinical findings with hormonal and immunopathological profiles. Br. J. Dermatol. 1999; 141: 71–81. 19. Zoberman, E. and Farmer, E. R. Pruritic folliculitis of pregnancy. Arch. Dermatol. 1981; 117: 20–22. 20. Wilkinson. S. M., Buckler, H., Wilkinson, N., et al. Androgen levels in pruritic folliculitis of pregnancy. Clin. Exp. Dermatol. 1995; 20: 234–236. 21. Vaughan Jones, S. A., Hern, S., and Black, M. M. Pruritic ­folliculitis and serum androgen levels. Clin. Exp. Dermatol. 1999; 24: 392–395. 22. Parlak, A. H., Boran, C., and Topcuglu, M. A. Pityrosporum ­folliculitis during pregnancy. J. Am. Acad. Dermatol. 2005; 52: 528–529.

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PART: I  Obstetrics

CHAPTER 10

Effect of Pregnancy on Other Skin Disorders Samantha Vaughan Jones Martin M. Black

Introduction Pregnancy causes immunologic, endocrine, metabolic, defined, and vascular changes in the pregnant woman which modify her responses to skin diseases. Both the obstetrician and the dermatologist need to be aware of this if they are to provide optimal management during pregnancy. Particular attention should be given to any medication administered to a pregnant or nursing woman; the reader is advised to consult published guidelines and/or review articles1–6.

Psoriasis Psoriasis affects 1.5–2% of the general population. It is an inflammatory disorder characterized by red scaly plaques on the skin. The nails are often involved and about 7% of patients have an associated seronegative inflammatory arthritis which may be debilitating. Local injuries to the skin, such as cuts, burns, or other skin infections, often lead to localized psoriasis at the site of injury (Koebner phenomenon).

Types of psoriasis In plaque-type psoriasis, the commonest form of psoriasis, there are well-demarcated erythematous plaques with adherent silver scales on the surface. The lesions are most common on the extensor surfaces of the elbows and knees, the sacral area (Figure 10.1), and the scalp (Figure 10.2). The groin may also be involved. Guttate (drop-like) psoriasis is characterized by scattered pink papules, which are of uniform size and flare in crops mainly on the trunk (Figure 10.3) and proximal extremities. It often follows an upper respiratory infection, especially with streptococci. In erythrodermic psoriasis, the skin is red with a fine desquamative scale present, often over its entire surface. There are several forms of pustular psoriasis, in which small sterile pustules appear either on pre-existing plaques or de novo on normal skin. Most patients with pustular ­psoriasis have

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Figure 10.2  Psoriasis affecting the scalp. Thick scales are seen on the scalp and hairline, and smaller plaques on the forehead.

Figure 10.1  Plaque-type psoriasis. Chronic, well-defined, slightly raised erythematous plaques, covered by a silver scale, are present, especially over the buttocks and extensor surfaces.

had psoriasis previously. Generalized pustular psoriasis (von Zumbusch) may be life-threatening, and treatment is urgently required (Figure 10.4). Fever, arthralgia, and leukocytosis often accompany the eruption. Pustular psoriasis of the palms and soles (palmoplantar pustulosis) consists of sterile itchy pustules on an erythematosquamous background. The effect of pregnancy on psoriasis is unpredictable, although in most cases it improves. In up to 15% of women psoriasis worsens. It can also flare postpartum, usually within 3–4 months of birth. CD4-positive T-helper cells are capable of differentiating from an initial common state into two distinct types called TH1 and TH2 lymphocytes (see Chapter 3). These subtypes differ in their cytokine secretion. TH1 lymphocytes secrete interferon-gamma and interleukin-2, whereas TH2

Figure 10.3  Guttate psoriasis. Small drop-like lesions occur in a shower-like distribution over the trunk and limbs, as shown here on the leg. The eruption occurs suddenly, often after a throat infection, and usually has a good prognosis. (Courtesy of Dr I. R. White, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK.)

lymphocytes secrete interleukins-3, 4, 5, 10, and 13. There is negative feedback so that a TH1 response inhibits the TH2 pathway and vice versa (see ­Figure 3.20 in Chapter 3). In psoriasis proinflammatory TH1 cytokines are upregulated and play

Psoriasis

Figure 10.4  Generalized pustular psoriasis of von ­Zumbusch. The skin is red and sore with sheets of small sterile pustules erupting on the trunk.

a key role in the mechanisms of chronic inflammation. In pregnancy there is a shift from TH1 to TH2 immunity in the placenta that promotes fetal survival by decreasing the TH1 responses involved in rejection of the fetus as an allograft 7.Thus during pregnancy many of the TH1-mediated autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis improve by downregulation of the TH1 proinflammatory cytokine response8–10. It has previously been postulated that high levels of progesterone would correlate with improvement of psoriasis11. In a recent study comparing 47 pregnant women with psoriasis with 27 controls (nonpregnant women with psoriasis), high levels of estrogen correlated with an improvement in psoriasis whereas progesterone levels did not correlate with psoriatic change12.

Management The treatment of psoriasis ranges from the application of mild tar products to the use of immunosuppressive agents. The location of lesions is important in selecting appropriate and effective therapy. Drugs with direct therapeutic effects are used together with emollients, which will soften the skin and aid the removal of scale. Dithranol is the standard topical treatment for most cases of plaque psoriasis. However, it should be used with

caution as it can irritate the skin and stain clothing. It is therefore essential to start with a low concentration and increase the dose gradually. Patients with fair skin do not tolerate dithranol as well as darker-skinned patients. Coal tar ointment in concentrations up to 20% is often used, but as it is messy to apply and has a strong odor it is not very popular with patients. Topical calcipotriol, a vitamin D3 metabolite, may be used for mild to moderately severe plaque psoriasis, but the total topical application should be less than 100 g weekly to minimize possible hypercalcemia. Topical corticosteroids may be required in some forms of psoriasis, such as guttate psoriasis. Side-effects may arise with long-term treatment, and a rapid relapse may occur on withdrawal (rebound phenomenon). Topical retinoids should be avoided because of a theoretical risk of teratogenicity. Phototherapy (ultraviolet B (UVB) and psoralen with ultraviolet A (PUVA)) may be given as adjuncts to topical therapy, with special considerations for the pregnant patient (see below).

Pregnancy Topical dithranol, tar, calcipotriol, topical corticosteroids, and topical tacrolimus appear to be safe choices for control of localized psoriasis in pregnancy13. UVB is the safest treatment for extensive psoriasis during pregnancy when topical therapy is not practical. Short-term use of cyclosporine during pregnancy is probably the safest option for the management of severe psoriasis that has not responded to topical therapy or phototherapy or for severe pustular psoriasis in pregnancy13,14.

Ultraviolet B and psoralen with ultraviolet A UVB irradiation is safe in pregnancy, but the patient should be aware that UVB can increase the size and number of benign pigmented nevi. Narrowband UVB (TL01) has recently been successfully used for the treatment of generalized pustular psoriasis of pregnancy15. The use of PUVA may carry a risk of mutagenesis and teratogenesis, and neither systemic nor topical (bath) PUVA should be used as a first-line treatment in pregnancy. However, a large study by ­Gunnarskog et al.16 found no increased risk of spontaneous or induced abortions, nor an increased risk

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of congenital malformation or infant death, including pregnancies conceived following PUVA treatment. The study, however, found an increased number of low-birthweight infants in pregnancies begun following PUVA treatment. It therefore seems possible that PUVA treatment may cause germ cell mutations, resulting in chromosome anomalies or point mutations. Prenatal diagnosis should therefore be offered to women who become pregnant after PUVA treatment. Topical PUVA (bath PUVA) is safe to use in pregnancy.

Table 10.1  Key Points for Psoriasis in Pregnancy Psoriasis generally improves in pregnancy (60%) Topical corticosteroids, dithranol, tar, calcipotriol, and topical tacrolimus are safe in pregnancy for localized disease Phototherapy (ultraviolet B (UVB), narrowband UVB and psoralen with ultraviolet A (PUVA)) can be used in more extensive disease Severe pustular psoriasis may need oral corticosteroids or cyclosporine

Systemic drugs

Oral retinoids and methotrexate are contraindicated

Systemic drugs are sometimes required to treat psoriasis. Retinoic acid (acitretin) is highly teratogenic and should be used with caution (see below). Several cytotoxic drugs have been used for psoriasis, including methotrexate, hydroxyurea, and azathioprine. Methotrexate and hydroxyurea are known teratogens and must therefore be avoided in pregnancy, and azathioprine may be teratogenic. Cyclosporine A can be used with caution in pregnancy and during breastfeeding and is a safer alternative to oral retinoids17 or methotrexate. The newer biological treatments – ­ antitumor necrosis factor agents and efalizumab – are not currently licensed for use in psoriasis during pregnancy18.

Biological therapies (antitumor necrosis factor agents and efalizumab) are not currently licensed for use in ­psoriasis during pregnancy

Course of disease

Maternal constitutional upset – with fever, delirium, tetany, vomiting, and diarrhea

The hormonal changes in pregnancy do appear to influence the severity of psoriasis (Table 10.1)19. About 75% of women notice a significant change in their psoriasis during pregnancy, with 60% showing improvement and 15% an exacerbation; 80% of these will experience a postpartum flare of their diseases, usually within 4 months of delivery11. Pregnancy may also be a risk factor for psoriatic arthritis20.

Impetigo herpetiformis Impetigo herpetiformis is generally regarded as a very rare, acute, pustular form of psoriasis precipitated by pregnancy (Table 10.2). It can affect pregnant women with no previous history of psoriasis. The onset is usually in the third trimester,

80% of affected patients will flare postpartum

Table 10.2  Key Points for Impetigo Herpetiformis A form of pustular psoriasis in pregnancy Presents in the third trimester and may recur in subsequent pregnancies (earlier onset and with increased severity) Increased risk of stillbirth, neonatal death, and fetal ­abnormalities due to placental insufficiency

Hypocalcemia due to hypoparathyroidism (reduced ­intestinal absorption of vitamin D) Treatment is with oral corticosteroids or cyclosporine Recent evidence suggests treatment with vitamin D and calcium may be helpful

and the disease tends to persist until delivery but may continue thereafter. The eruption characteristically begins in the flexures with small sterile pustules on areas of acutely inflamed skin. These then extend centrifugally on to the trunk (Figure 10.5) and around the umbilicus (Figure 10.6) or form plaques with green-yellow pustules. The eruption may advance

Acne vulgaris 83

Figure 10.6  Impetigo herpetiformis. Sterile pustules around the umbilicus.

Figure 10.5  Impetigo herpetiformis. Sterile pustules ­develop on acutely inflamed skin and coalesce together on the trunk.

and become widespread, involving the tongue, buccal mucosa, and sometimes the esophagus. Constitutional symptoms are common, including fever, delirium, vomiting, diarrhea, and tetany due to hypocalcemia. Death may occur as a result of cardiac or renal failure. The main obstetric problem in impetigo herpetiformis is placental insufficiency, with an increased risk of stillbirth, neonatal death, and fetal abnormalities21. The disease characteristically recurs with each pregnancy, with earlier onset and increased morbidity21. Between pregnancies, patients are free of the disorder and have no manifestations of psoriasis. The disease may also be exacerbated by oral contraceptives22 and has also been described in association with Staphylococcus aureus lymphadenitis23. In severe cases, termination of pregnancy is required; the

i­ mpetigo herpetiformis usually resolves soon afterwards. Although the etiology of this condition is still unclear, a recent report showed extremely low levels of epidermal skin-derived antileucoproteinase/elafin in a patient with impetigo herpetiformis24. An association with hypoparathyroidism and reduced intestinal absorption of vitamin D is thought to be the mechanism for reduced serum calcium levels25. A recent case of impetigo herpetiformis with compensatory hyperparathyroidism and normocalcaemia has been described26. Oral corticosteroids are the treatment of choice for impetigo herpetiformis, but the results are generally unsatisfactory. Cyclosporine has also been used successfully in treating this condition27. Calcium and vitamin D have also been used successfully in treatment28. If the disease persists postpartum and is severe then oral retinoids may be used for treatment.

Acne vulgaris Although acne may improve in pregnancy, it is occasionally exacerbated (Table 10.3). This usually causes management problems, as most antiacne drugs are contraindicated during pregnancy. However, topical antiacne therapy, other than topical retinoic acid and salicylic acid, does not seem to be teratogenic. Topical antiacne therapy which contains salicylic acid should be used cautiously or avoided during pregnancy and lactation as these products can cause salicylism, and absorption from breast milk in nursing infants could in

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theory cause bleeding29. Animal data support the avoidance of topical known teratogens such as retinoids and salicylic acid in pregnant women29. Acne conglobata developing 10 days postpartum has recently been reported30. Acne neonatorum has also been described with a family history of hyperandrogenism31. Acne rosacea often flares during pregnancy and may also require treatment with topical or systemic antibiotics. There is a rare severe variant called rosacea fulminans (or pyoderma faciale) presenting in pregnancy which is characterized by a severe facial eruption with papules, nodules, pustules, and erythema. This normally requires treatment with oral erythromycin and oral corticosteroids. A recent case of rosacea fulminans complicated by stillbirth has been reported32.

Management The treatment of acne depends on the type of acne involved. If only comedones are present, a keratolytic agent such as benzoyl peroxide (2.5–10% cream, lotion, or gel) or azaleic acid cream 20% should be used to remove the surface keratin and unplug the follicular openings. These drugs are safe to use in pregnancy but products containing topical salicylic acid are best avoided29. Topical retinoic acid has been reported as causing multiple congenital defects33. Ultraviolet light has an effect similar to that of topical keratolytics, but should be avoided in pregnancy.

Antibiotics Long-term antibiotic therapy is usually required for inflammatory lesions with papules, pustules, or nodules. However, acne is slow to improve and beneficial effects are not usually seen for at least 2–3 months, with gradual improvement after 6–12 months of therapy. Maintenance treatment must be continued until the acne improves. Oral tetracycline is associated with maternal liver toxicity and deciduous tooth staining in the infant and tetracycline has also been associated with congenital anomalies34. Oral erythromycin is safe in pregnancy and is given at a dose of 250–500 mg twice daily34,35. Topical antibiotics are almost as effective as systemic antibiotics, but they may lead to the selection of resistant bacteria on the skin surface and to contact-allergic eczema. However, as there is negligible systemic absorption, this approach is safe in pregnancy. Examples include topical erythromycin (Stiemycin, Eryacne, Benzamycin, and Zineryt, which contains zinc in addition to erythromycin to reduce bacterial resistance and increase efficacy) and tetracycline (Topicycline, which is no longer available in the United States). The use of topical clindamycin during pregnancy has been associated with pseudomembranous colitis36 and, in order to reduce systemic absorption, topical clindamycin phosphate is preferable to the hydrochloride salt. These topical preparations should be applied once or twice daily to the face and/or upper trunk.

Systemic drugs Table 10.3  Key Points for Acne in Pregnancy Acne vulgaris often flares in the third trimester when sebaceous gland activity increases Topical benzoyl peroxide and azaleic acid appear safe for use in mild comedonal acne Erythromycin is the safest oral and topical antibiotic for treatment of acne in pregnancy Systemic and topical retinoids are contraindicated in pregnancy Rosacea fulminans can flare in pregnancy and usually requires treatment with oral erythromycin and oral ­corticosteroids

Systemic antiandrogens and isotretinoin (Accutane, Roaccutane) are totally contraindicated in pregnancy. Vitamin A derivatives, such as oral isotretinoin, etretinate, and acitretin (Neotigason), are all potent teratogens and must not be used by those who are pregnant or who may become pregnant during the course of treatment. The most common teratogenic effects include nervous system anomalies, ear and eye deformities, cleft palate, renal and urogenital tract abnormalities, skeletal malformations, and toxic hepatocellular damage. Although isotretinoin is rapidly cleared and is not stored in tissue, pregnancy should be avoided until 2 months after the drug has been ­discontinued.

Erythema nodosum

However, etretinate and its ­ metabolite ­ acitretin (Neotigason) are a potential hazard for 2 years after therapy has been stopped because of their very slow elimination from the body.

Hidradenitis suppurativa Hidradenitis suppurativa is a chronic cutaneous disease caused by the occlusion and rupture of follicular units, in which the resulting inflammatory response may secondarily involve the apocrine glands. Recurrent lesions develop in the axillae (Figure 10.7), groin, and perineal areas, with the formation of abscesses and with draining sinuses and progressive scarring. In extreme cases, the entire vulva may be affected over many years, resulting in gross ­ scarring and

deformity, often associated with substantial ­psychosexual problems. The condition may remit during pregnancy as a result of reduced apocrine gland activity37 but a recent review showed no consistent relationship between hidradenitis suppurativa and pregnancy in 38 women38.

Management Management often involves the use of long-term systemic antibiotics, such as erythromycin or tetracycline. However, tetracycline should be stopped before a planned pregnancy. If antibiotics are unsuccessful, alternatives include oral acitretin (which must also not be used in pregnancy) or surgery, where all the apocrine glands in the affected areas are excised. The carbon dioxide laser has been used to treat this condition, with considerable success39. Although repeated treatments may be necessary, the clearance rate and cosmetic results are excellent.

Erythema nodosum Erythema nodosum is a reactive inflammation of the subcutaneous fat, which is secondary to a wide variety of underlying conditions (Table 10.4). It can also occur de novo in pregnancy40. Table 10.4  Underlying Conditions of Erythema Nodosum Infections Streptococcus spp. Tuberculosis Leprosy Coccidiomycosis Drug Allergies Sulfonamides Oral contraceptives Other Disorders Sarcoidosis Figure 10.7  Hidradenitis suppurativa. Painful pustules and nodules are present, with sinus and scar formation in the axilla.

Inflammatory bowel disease Antiphospholipid syndrome

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labor by inhibiting prostaglandin synthetase. Systemic ­ corticosteroids, if not contraindicated by an underlying infectious disease, are necessary in some cases. Treatment of the underlying disease or removal of the inciting drugs is essential. Erythema nodosum may be a presenting feature of coccidiomycosis in pregnancy and can be associated with an improved disease outcome41,42. Three cases of erythema nodosum have recently been described in association with the antiphospholipid syndrome43.

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Bullous disorders Pemphigus

Figure 10.8  Erythema nodosum. Large, painful, shiny, erythematous plaques on the anterior aspect of the lower leg. The lesions are initially bright red in color and then become purple and fade like a bruise. (Courtesy of Dr. A. C. Pembroke, King’s College Hospital, London, UK.)

It presents with the sudden onset of ill-defined, tender, erythematous nodules or plaques, distributed symmetrically over the anterior legs (Figure 10.8). Lesions may also develop over the calves, arms, trunk, and face. Fever, malaise, and arthralgias may precede or accompany the eruption. Lesions usually resolve in 6–8 weeks.

Management Treatment is supportive and includes bed-rest and mild analgesics such as paraceta­mol. Nonsteroidal anti-inflammatory agents should not be used in pregnancy, especially in the third ­trimester. This is because they may constrict the ductus arteriosus in utero, or inhibit or ­ prolong

Pemphigus vulgaris and foliaceus are rare autoimmune bullous dermatoses both characterized by autoantibodies directed against desmosomal antigens, desmoglein 3 (130 kDa) and desmoglein 1 (160 kDa) respectively. These antigens are both transmembrane glycoproteins of desmosomes belonging to the cadherin supergene family of cell adhesion molecules. Pemphigus may develop or worsen during pregnancy and be transmitted to the fetus. In the literature there are many welldocumented pregnancies in women with immunopathologically confirmed pemphigus vulgaris. Fetal prognosis is variable, with three possible outcomes: 1. Normal delivery with birth of a healthy infant 2. Transient neonatal pemphigus with blisters and erosions in the neonate, usually lasting a few weeks only. This is due to transplacental passage of immunoglobulin (Iga) antibodies 3. Fetal demise with stillbirth or spontaneous abortion There does not appear to be a direct correlation between severity of maternal disease and extent of neonatal involvement. Women in remission have given birth to neonates with extensive disease44. Conversely women with active pemphigus have delivered disease-free babies45–47. Unfortunately there are cases of fetal demise associated with maternal pemphigus48,49. It is therefore important that obstetricians and dermatologists maintain close antenatal and postnatal care of the mother and child. Flaccid blisters of the skin (Figure 10.9) and mucous membranes

Bullous disorders

pemphigoid gestationis, and so skin biopsy with immunofluorescence studies is required for an accurate diagnosis4. Enzyme-linked immunosorbent assay using recombinant desmoglein 3 can also confirm the diagnosis50.

Management

Figure 10.9  Pemphigus vulgaris. Superficial flaccid blisters on the upper trunk rupture easily, leaving erosions. Blisters may become secondarily infected with bacteria and become crusted. (Courtesy of Dr. A. C. Pembroke, King’s College Hospital, London, UK.)

develop, and are often widespread. The blisters rupture rapidly, leading to generalized erosions, crusting, and often secondary bacterial infections. Maintenance of normal fluid balance in severe pemphigus during pregnancy is extremely important. The presentation of pemphigus during pregnancy is extremely rare, although pregnancy has been reported to precipitate or aggravate the condition4. Changes in disease activity are more prevalent in the first or second trimester, and in most cases the disease continues chronically postpartum. It has been suggested that the improvement seen in pemphigus in the third trimester is due to a rising endogenous cortisol production and consequent immunosuppression. The clinical presentation of pemphigus can be very similar to that of

Pemphigus during pregnancy is usually treated with high doses of prednisone. Steroid doses as high as 100 mg prednisone daily may be required for initial control, with dose tapering thereafter. A potent topical corticosteroid cream, such as 0.05% clobetasol propionate, can be applied directly to lesions. Immunosuppressants, such as cyclophosphamide, azathioprine, methotrexate, and gold, are best avoided. Azathioprine has not been associated with teratogenicity, but it could theoretically affect the immune system of the fetus or neonate. It is not recommended in breastfeeding mothers. Methotrexate is a potent teratogen, particularly if taken during the first trimester, causing multiple skeletal and neurologic defects and cleft palate. Although it is secreted in relatively low concentrations in breast milk, breastfeeding is not usually recommended. There are few data on the safety of cyclosporine A in pregnant patients with a skin condition. A study of pregnant women taking cyclosporine A following organ transplantation suggested a low risk of teratogenic effects. As cyclosporine A passes into breast milk, there is a potential risk of hypertension, nephrotoxicity, and malignancy in breastfed neonates. Cyclophosphamide is teratogenic, leading to skeletal defects and dysmorphic features. Pemphigus antibody titers may help in assessing disease activity and planning effective treatment. If high antibody titers occur, transplacental transfer of pemphigus antibody and transient fetal pemphigus are probably more likely4. Plasmapheresis and plasma exchange have been used but there is a risk of a rebound increase in circulating levels of pemphigus antibody51,52. There appears to be, therefore, a need for continued plasmapheresis after delivery, with immunosuppressant adjunctive treatment (e.g., azathioprine) making this an option of last resort. High-dose intravenous immunoglobulins have also been used in treating

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autoimmmune bullous diseases, including pemphigus, and appear to be more effective if given as adjunctive therapy (91% response) rather than as monotherapy (56% response rate)53. However further assessment of this treatment is required using double-blind placebo-controlled trials.

Table 10.5  Key Points for Pemphigus in Pregnancy Autoimmune bullous disease with autoantibodies ­directed against desmosomes – desomoglein 3 (pemphigus vulgaris) and desmoglein 1 (pemphigus foliaceus)

Maternal and fetal mortality and morbidity

Presents with flaccid blisters and erosions on trunk, limbs, and mucosal surfaces

Severe cases of disseminated cutaneous disease have been associated with fetal death. Stillborn infants of mothers with pemphigus have been found to have skin lesions and immunofluorescence findings consistent with the disease48,49. Cases of well-controlled or mild disease are not usually associated with a significant risk of maternal and fetal morbidity or mortality. The mode of delivery needs careful consideration in each case. The trauma of vaginal delivery may result in the extension and worsening of erosions, while problems with wound healing in patients on longterm steroid therapy make cesarean section less attractive46.

Skin biopsy necessary to distinguish from pemphigoid gestationis

Neonatal pemphigus Neonatal pemphigus results from transplacental transmission of maternal pemphigus IgG autoantibody (Table 10.5). Active pemphigus during pregnancy does not necessarily result in neonatal pemphigus. A recent report described a case in which the infant of a mother with purely oral disease was born with widespread cutaneous neonatal pemphigus54. This can be explained by the desmoglein compensation theory. In neonatal skin the distribution of desmoglein 3 is in a similar pattern to adult mucosal epithelia but different from that in adult epidermis55. Hence the clinical presentation and antibody titers in the mother do not predict the severity of the disease in the neonate. Neonatal pemphigus foliaceus has also recently been described56. Most neonates who develop blisters require no therapy, as the blisters usually heal spontaneously within 2–3 weeks46. No progression to adult pemphigus vulgaris has been described, unlike neonatal lupus erythematosus which is associated with placental transmission of anti-Ro antibodies. Breastfeeding is not absolutely contraindicated, although local blister formation

Direct immunofluorescence is positive with intercellular pattern of immunoglobulin G binding Treatment is generally with high-dose oral prednisolone Second-line prescription for severe cases – plasma­ pheresis, high-dose intravenous immunoglobulins, plasma exchange Vaginal delivery can exacerbate vulval erosions, but ­cesarean section scar may also heal poorly due to erosions Neonatal pemphigus is seen due to passive transfer of maternal antibodies, but is a transient eruption lasting only a few weeks

may occur with the potential risk of passive transfer of antibody to the infant46.

Dermatitis herpetiformis Dermatitis herpetiformis is an autoimmune vesicular disorder characterized by grouped, intensely pruritic vesicles, which are distributed symmetrically over the elbows, knees, buttocks, shoulders, and scalp (Figure 10.10). There is usually histologic and/or symptomatic evidence of gluten-sensitive enteropathy. The characteristic immunofluorescence feature of this disease is the presence of granular deposits of IgA in the upper papillary dermis.

Management Dapsone administration – the treatment of choice – produces dramatic relief from pruritus within 24 hours and stops new lesion formation within 72 hours. Dapsone is probably safe in pregnancy6,57. Most patients respond to an initial dose of 100 mg daily. Those intolerant of dapsone should be tried on sulfapyridine 1–2 g daily. As

Bullous disorders

membrane. It resembles dermatitis herpetiformis clinically, but sometimes lesions similar to bullous pemphigoid develop on the trunk and limbs. Unlike dermatitis herpetiformis, there is no associated gluten-sensitive enteropathy. Linear IgA disease may improve in pregnancy but a relapse may be seen postpartum58. The disease does not appear to affect fetal outcome adversely. Treatment is similar to that of dermatitis herpetiformis, with dapsone or sulfapyridine, but some patients may need a combination of dapsone and prednisone.

Porphyria cutanea tarda

Figure 10.10  Dermatitis herpetiformis. Grouped, itchy, polymorphic lesions on the extremities, such as axillae, as shown here. Vesicles are excoriated, leaving urticarial papules.

Porphyria cutanea tarda (PCT) is the most common type of porphyria and occurs in both autosomal-dominant and acquired forms. The disorder is due to a defect in uroporphyrinogen decarboxylase activity. This results in a characteristic increase of uroporphyrin and 7-carboxyporphyrin in the urine, and increased isocoproporphyrin in the stool. Patients present with skin fragility, erosions, vesicles, bullae, and milia on sun-exposed areas, especially the dorsum of the hands (Figure 10.11) and forearms. Other cutaneous changes include facial hypertrichosis, periorbital hyperpigmentation, scarring alopecia, and dystrophic calcification with ulceration.

Pregnancy dapsone may produce severe hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, patients should be screened before dapsone therapy is instituted. Ideally, patients with dermatitis herpetiformis should adhere to strict gluten-free diet, preferably for 6–12 months, before conception. This may obviate the need for dapsone during pregnancy. As dapsone is secreted in breast milk and produces hemolytic anemia in infants, patients taking dapsone should be discouraged from breastfeeding.

Linear IgA disease This is a rare, acquired, subepidermal blistering disorder. It has been defined on the basis of its unique immunopathologic finding of linear deposits of IgA along the cutaneous basement

Although PCT is known to be affected adversely by estrogen, iron, and alcohol, there are conflicting reports about the effects of pregnancy (Table 10.6). Case reports of patients whose illness was not exacerbated by pregnancy have led to speculation that endogenous estrogens may be less harmful than exogenous compounds59,60. However, other cases show findings of clinical and biochemical deterioration of disease, with increases in plasma and urine porphyrin levels during pregnancy61,62. In the nonpregnant individual, premenstrual exacerbation is a recognized feature of many of the porphyrias and the gonadotropin-releasing hormone analog, buserelin acetate, has been successfully used to treat hereditary coproporphyria by temporarily suppressing ovulation and menstruation63. However, this drug is contraindicated during pregnancy.

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Table 10.6  Porphyria Cutanea Tarda and Pregnancy Commonest porphyria with defect in uroporphyrinogen decarboxylase activity Presents with skin fragility, vesicles, milia, and bullae on sun-exposed sites, especially dorsum of the hands and forearms Facial hypertrichosis, periorbital hyperpigmentation, scarring alopecia are also seen Exacerbated by pregnancy, oral iron supplements, oral contraceptives, and alcohol Sunlight avoidance and high-factor sunblock ­recommended Severe cases may need venesection if ferritin levels high Oral hydroxychloroquine not recommended in pregnancy due to its teratogenicity

­ earing loss, intellectual impairment, and neoh natal convulsions. Other less commonly applied therapies, such as cholestyramine, activated charcoal, and intravenous deferoxamine administration, are also contraindicated in pregnancy.

Erythema multiforme

Figure 10.11  Porphyria cutanea tarda. Sun-exposed areas, such as the dorsum of the hand and fingers, are most severely affected. Minimal trauma results in erosions and blisters.

Management The avoidance of sunlight and use of an opaque sunblock, such as zinc oxide, are helpful. Venesection or phlebotomy, with careful monitoring of hematocrit, has been used successfully to treat PCT during pregnancy. In this procedure, 500 mL of blood is removed weekly or twice weekly until the hemoglobin level has fallen to 10–11 g/dL or serum iron concentration to 50–60 mg/dL. Chloroquine is contraindicated in pregnancy because of its teratogenicity; it causes multiple defects in the fetus, including neurosensory

This disorder is characterized by acute, self-limiting, but often recurrent, episodes of erythematous maculopapular lesions, which may develop into classical target or iris lesions, or may blister. The lesions are typically distributed symmetrically on the extremities, especially the hands (Figure 10.12), and on the extensor aspects of the forearms and legs. The frequency of mucosal involvement varies widely, between 25% and 60%, with affected organs including the mouth, eyes, pharynx, esophagus, genitalia, and anus. Severe cases (Stevens–Johnson syndrome) may develop significant complications affecting the eyes, mouth, and vulva, such as visual impairment secondary to keratitis with conjunctival scarring (Figure 10.13). Severe cases with Stevens–Johnson syndrome can be difficult to distinguish from druginduced toxic epidermal necrolysis. There are several causes of erythema multiforme, such as herpes simplex or mycoplasmal infections, and sensitivity to drugs, especially to

Neoplasia 91

Figure 10.13  Stevens–Johnson syndrome. Severe blistering and ulceration of the conjunctiva result in corneal scarring. Table 10.7  Causes of Erythema Multiforme Infections Mycoplasma pneumoniae Herpes simplex I and II Histoplasma capsulatum Epstein–Barr virus Drugs Figure 10.12  Erythema multiforme. Well-circumscribed erythematous lesions occur on the hands, as shown here, and feet. The central area of the lesion is more involved than the periphery so it appears like a target. Blisters may develop in the center of the lesions.

Sulfonamides Anticonvulsants Allopurinol Nonsteroidal anti-inflammatory drugs

long-acting sulfonamides. Pregnancy may also cause erythema multiforme, and vaginal stenosis has been described in severe Stevens–Johnson syndrome in pregnancy64. Systemic corticosteroids, such as prednisone 30–40 mg daily, are sometimes required, particularly in Stevens–Johnson syndrome. The dose should be gradually reduced after a few days. Erythema multiforme can flare in pregnancy and may be associated with Mycoplasma pneumoniae infections and herpes simplex virus (HSV; Table 10.7). There is evidence of increased HSV shedding during pregnancy65 and a prophylactic 6-month course of acyclovir has been shown to be effective in the prevention of recurrent erythema multiforme66.

Neoplasia Basal cell epithelioma and squamous cell carcinoma are both very rare in pregnancy, as they tend to be disorders of the elderly population. Gorlin’s syndrome (basal cell nevus syndrome) is a rare autosomal-dominant inherited condition, in which numerous basal cell carcinomas develop in a much younger age group; there are few reports in pregnant women. The disorder certainly does not appear to affect this group specifically.

Benign melanocytic nevi It is known that pre-existing benign pigmented nevi may darken temporarily during pregnancy owing to increased levels of melanocyte-­stimulating

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Figure 10.15  Superficial spreading malignant melanoma. The pigmented lesion is a slightly raised plaque with an irregular outline and irregular pigmentation.

Figure 10.14  Benign melanocytic nevi. Multiple nevi on trunk have evenly distributed pigment and each nevus has a regular outline. (Courtesy of Dr A. D. M. Bryceson, Hospital for Tropical Diseases, London, UK.)

­ ormone67. There is some debate as to whether h benign melanocytic nevi increase in number and size during pregnancy (Figure 10.14). In one report 10% of women reported some enlargement or color change in their nevi during pregnancy (most in the first trimester of pregnancy); no significant histological changes were found when compared with nonpregnant women67. Another study of 22 women found no significant change in measured size of their 129 nevi during pregnancy68. A further histopathological study of 128 nevi removed from 86 pregnant white women showed no lesions suspicious of melanoma. There was however a mild degree of histopathological atypia or activation in the lesions associated with pregnancy compared to lesions removed from nonpregnant female controls69. There is no current evidence that pregnancy induces malignant transformation of pre-existing nevi. In a more recent study which looked at dermoscopy of nevi in pregnancy in 21 women, 9.5% increased in diameter and there were dermoscopic changes in 19% of nevi, although no changes suspicious of melanoma were observed70.

Figure 10.16  Nodular malignant melanoma. A nodule has developed in the center of an irregularly outlined pigmented lesion. The nodule itself appears to be relatively amelanotic.

Malignant melanoma Melanoma represents the fourth commonest cancer in pregnancy, accounting for about 8% of all malignant tumors arising in gestation71. However 30–35% of women with melanoma are of childbearing age. The influence of pregnancy on the prognosis of malignant melanoma (Figures 10.15 and 10.16) has previously been controversial (Table 10.8). Many early observations suggested a link between hormones, immune changes, and malignant melanoma. However four recent large studies have demonstrated no data to support a more advanced stage, thicker tumors, increased metastases to lymph nodes, or a worsened survival72–75. As in nonpregnant patients, prognosis continues to be determined mainly by tumor thickness. Transplacental transmission of melanoma to the fetus

Miscellaneous conditions

Table 10.8  Key Points for Malignant Melanoma in Pregnancy Fourth commonest cancer in pregnancy Prognosis is determined by site and thickness of tumor Pregnancy does not alter 5-year survival Transplacental metastatic spread occurs and the placenta should be examined for metastases postpartum Chemotherapy is indicated for rapidly progressive ­metastatic melanoma

is extremely rare, and maternal melanoma usually has no adverse effects on the fetus76,77. Slingluff and Seigler published a series of 100 cases of pregnancy-associated malignant melanoma78. Although they found a higher incidence of thicker tumors and nodal involvement compared with matched controls, overall mortality was not statistically different78. It has been suggested that a poor prognosis could be due to a delay in diagnosis because nevi can undergo modification in pregnancy, a quicker progression due to the relative immunosuppression during pregnancy or due to the tumor’s hormonal sensitivity. Further studies however have not found that pregnancy worsened the outcome of malignant melanoma or affected survival72,74.

Management Treatment for melanoma in pregnant women is no different from treatment in other patients. Surgical excision of primary lesions and clinically involved lymph nodes should be performed. Therapeutic termination in a woman who has a concurrent malignant melanoma and pregnancy has shown no benefit in inducing maternal tumor regression79. When melanoma occurs during pregnancy, a clinical and histologic examination of the placenta should be performed postpartum because the possibility of transmission of transplacental metastatic disease to the fetus does exist76,79. Chemotherapy may be indicated for rapidly progressive metastatic melanoma and is not necessarily associated with an adverse fetal prognosis80,81.

Timing of pregnancy Women from whom malignant melanomas have been excised should be counseled about future pregnancies. It has been observed that 83% of patients with metastatic disease present within 2 years of the initial diagnosis of primary malignant melanoma. Women should therefore be recommended to consider delaying pregnancy by at least 2 years after diagnosis75. Generally, women with melanoma should be advised about pregnancy on the basis of thickness and site of tumor and evidence of vascular spread, not hormonal status.

Cutaneous T-cell lymphoma Cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) is a chronic, slowly evolving, T-cell lymphoma mainly involving the skin. The earliest lesions are flat, erythematous, slightly scaly patches, which gradually thicken to form plaques. Sometimes tumors may develop. Pregnancy may exacerbate the disease82. Early lesions may respond to potent topical steroids and UVB light, but PUVA should be avoided, if possible, because of the potential teratogenic effects of methoxypsoralen. Therapy with cytotoxic agents is generally contraindicated during pregnancy, especially in the first trimester. A case has previously been described in whom alpha-interferon treatment was given in the third trimester of pregnancy, inducing a remission of disease and prolongation of the pregnancy83. In a further case report of stage IVb MF, pregnancy did not appear to worsen the prognosis or course of the disease84.

Miscellaneous conditions Sarcoidosis Sarcoidosis is a multisystem, granulomatous disorder of unknown etiology, which most commonly affects young adults in their reproductive years. Approximately 0.02–0.06% of pregnant women have sarcoidosis85. Both specific and nonspecific cutaneous lesions are associated with sarcoidosis. Specific lesions include papules, nodules (Figure 10.17), plaques (lupus pernio) (Figure 10.18), ichthyotic scaling, hypopigmentation, atrophy, ulcers,

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Figure 10.18  Lupus pernio. Thickened purple plaques ­occur on the nose and are caused by granulomatous involvement of the dermis and subcutaneous fat.

Figure 10.17  Sarcoidosis. Annular pigmented plaques on the face. Nasal infiltration may be extremely disfiguring and difficult to treat. In West Indians, red-brown nodules are especially common around the nose.

and scar infiltration. The nonspecific lesions are not actually granulomas, but skin changes that are characteristically associated with sarcoidosis, the most common of which is erythema nodosum.

Pregnancy Active sarcoidosis usually improves during pregnancy and relapses postpartum86. In cases of already inactive disease, the condition remains inactive87,88. The positive effects of pregnancy on sarcoidosis may be due to an increased level of circulating free cortisol, and the postpartum relapse may represent a rebound phenomenon, as is usually seen after cessation of corticosteroid therapy. Improvement in some pregnant patients with sarcoidosis may be related to spontaneous resolution of the disease.

The frequency of abortions, obstetric complications, or congenital abnormalities is not increased by the presence of sarcoidosis85. Generally, the obstetric management of pregnancy, labor, and delivery does not differ from that for a normal patient. In some cases, however, such as those with advanced pulmonary disease or extrapulmonary lesions, exacerbations may occur and patients should be followed carefully. Disease activity should be carefully assessed soon after delivery in all patients who have, or have had, sarcoidosis87,88.

Pyoderma gangrenosum There have been six reports of pyoderma gangrenosum in pregnancy to date associated with leukemia, lupus erythematosus, antiphospholipid syndrome, and three idiopathic cases. In approximately 50% of cases there is an associated underlying systemic disease, most commonly myelodysplasia, inflammatory bowel disease, and rheumatoid arthritis89. Investigations should be carried out during pregnancy to exclude these. Most cases respond to either high-dose systemic corticosteroids or cyclosporine89. In one case this condition was a complication of cesarean section for delivery90. Another patient reported developed marked pyoderma gangrenosum with pathergy but responded well to cyclosporine91. The diagnosis of pyoderma gangrenosum should always be considered in cases of apparent wound infection unresponsive to antibiotics90. Early diagnosis and

Miscellaneous conditions

treatment of this condition will drastically alter prognosis.

95

Acrodermatitis enteropathica This is a rare autosomal-recessive condition with reduced serum zinc levels92. Acquired zinc deficiency can occur in patients with an inadequate intake of zinc, such as those receiving long-term parenteral nutrition without zinc ­supplementation, those who have zinc malabsorption, and those with increased losses of zinc. It is characterized by dermatitis, diarrhea, and alopecia. The dermatitis is vesiculobullous and eczematous, and develops on the acral areas of the extremities and periorificial sites, such as the mouth, anus, and genital areas. Paronychia and scalp alopecia are seen. Acrodermatitis enteropathica flares during pregnancy, with a further decrease in serum zinc concentration93. This fall in zinc level is not entirely due to increased fetal demands, because zinc levels also decrease and the disease flares with oral contraceptive use4. Estrogens must therefore have an important primary role4. The skin eruption may resemble impetigo herpetiformis or pemphigoid gestationis. Having first appeared in childhood, the skin disease reappears early during pregnancy, progressively worsens until delivery, and then clears spontaneously postpartum. Most pregnancies have produced normal offspring4. Zinc supplementation (e.g., zinc sulfate 200 mg three times daily) to maintain normal serum zinc levels seems to be effective in preventing adverse fetal effects and can be given safely in pregnancy. There have been reports of pregnancies in patients with acrodermatitis enteropathica, which resulted in congenital abnormalities in the offspring. Oral zinc supplementation may prevent this by providing normal zinc levels and it may also clear the skin manifestations in the mother93.

Neurofibromas Women with neurofibromatosis are thought to experience a higher than expected rate of firsttrimester spontaneous abortion (21%), stillbirth (9%), and intrauterine growth retardation in pregnancy (13%)94. Genetic counseling is mandatory because of the disabilities that may be precipitated

Figure 10.19  Neurofibromatosis. Large neurofibromas have developed on the upper arm.

by pregnancy and because of the rare possible deformities associated with neurofibromatosis, an autosomal-dominant disorder. Elective termination of pregnancy may be necessary in severely affected patients. During pregnancy, the skin lesions of neurofibromatosis may appear for the first time, or may increase in both size and number. Large, plexiform neurofibromas may enlarge (Figure 10.19) and then hemorrhage into the core of the tumor. In most cases, the lesions regress postpartum. Of greater importance is the effect of pregnancy on the vascular system of patients with neurofibromatosis. Major blood vessels may rupture and hypertension may occur95. One study looked at the outcome of 105 women with neurofibromatosis type 1 and pregnancy96. It found that 60% of women reported growth of new neurofibromas during pregnancy and 52% noticed enlargement of existing neurofibromas whereas

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18% of women noticed no change. However in this study there was no increase in pre-eclampsia, preterm delivery, intrauterine growth retardation, stillbirth, or abortion as previous studies suggest96. Patients with neurofibromatosis also have an increased risk of perinatal complications, so close monitoring of pregnancy is mandatory97.

Conclusion Obstetricians and dermatologists working together should be able to recognize and manage skin diseases in pregnant women. They should be aware of the often modified expression of disease in this special group of patients, and should also realize that therapeutic options are inevitably altered by the pregnant condition. It is important that patients with inherited disorders are counseled about the genetic nature of their condition, and if necessary the dermatologist and geneticist should offer counseling before conception.

References   1. Chanco Turner, M. L. The skin in pregnancy. In: Burrow, G. N. and Duffy, T. P., eds. Medical Complications During Pregnancy, 5th edn. Philadelphia: W.B. Saunders; 1999; 453–468.   2. Vaughan Jones, S. A. and Black, M. M. Skin diseases in pregnancy. Medical Disorders in Obstetric Practice, ed: DeSwiet, M., 4th edn. London: Blackwells; 2002; 566–577.   3. Winton, G. B. and Lewis, C. W. Dermatoses of pregnancy, J. Am. Acad. Dermatol. 1982; 6: 977–998.   4. Winton, G. B. Skin diseases aggravated by pregnancy, J. Am. Acad. Dermatol. 1989; 20: 1–13.   5. Reed, B. R. Pregnancy, drugs and the dermatologist, Curr. Probl. Dermatol: 29–80. VI.   6. Stockton, D. L. and Paller, A. S. Drug administration to the pregnant or lactating woman: a reference guide for dermatologists, J. Am. Acad. Dermatol. 1990; 23: 87–103.   7. Garcia Gonzales, E., Ahued-Ahued, R., Arrayo, E., et al. ­Immunology of the cutaneous disorders of pregnancy, Int. J. Dermatol. 1999; 38: 721–729.   8. Wilder, R. L. Hormones, pregnancy and autoimmune disease, Ann. N.Y. Acad. Sci. 1998; 840: 45–50.   9. Elenkov, I. J. and Chrousos, G. P. Stress hormones, proinflammatory and anti-inflammatory cytokines and autoimmunity, Ann. N.Y. Acad. Sci. 2002; 966: 290–303. 10. Raychaudhuri, S. P., Navare, T., Gross, J., et al. Clinical course of psoriasis during pregnancy, Int. J. Dermatol. 2003; 42: 518–520. 11. Boyd, A. S., Morris, L. F. and Phillips, C. M. Psoriasis and pregnancy: hormone and immune system interaction, Int. J. Dermatol. 1996; 35: 169–172. 12. Murase, J. E., Chan, K. K., Garite, T. J., et al. Hormonal effects on psoriasis in pregnancy and post partum, Arch. Dermatol. 2005; 141: 601–606.

13. Tauscher, A. E., Fleischer, A. B. , Phelps, K. C., et al. Psoriasis and pregnancy, J. Cutan. Med. Surg. 2002; 6: 561–570. 14. Finch, T. M. and Tan, C. Y. Pustular psoriasis exacerbated by pregnancy and controlled by cyclosporin A, Br. J. Dermatol. 2000; 142: 582–584. 15. Vun, Y. Y., Jones, B., Al-Mudhaffer, M., et al. Generalised pustular psoriasis of pregnancy treated with narrowband UVB and topical steroids, J. Am. Acad. Dermatol. 2006; 54: S28–S30. 16. Gunnarskog, J. G., Kallen, A. J. B., Lindelof, B. G., et al. Psoralen photochemotherapy (PUVA) and pregnancy, Arch. Dermatol. 1993; 129: 320–323. 17. Die-Smulders, C. E. M., Sturkenboom, M. C., Veraart, J., et al. Severe limb defects and craniofacial anomalies in a fetus conceived during acitretin therapy, Teratology. 1995; 52: 215–219. 18. Smith, C. H., Anstey, A. V., Barker, J. N. W. N., et al. Biologic interventions for psoriasis, Br. J. Dermatol. 2005; 153: 486–497. 19. Mowad, C. M., Margolis, D. J. and Halpern, A. C. Hormonal influences on women with psoriasis, Cutis. 1998; 61: 257–260. 20. McHugh, N. J. and Laurent, M. R. The effect of pregnancy on the onset of psoriatic arthritis, Br. J. Rheumatol. 1989; 28: 50–52.

Impetigo Herpetiformis 21. Lotem, M., Katzenelson, V., Rotem, A., et al. Impetigo herpetiformis: a variant of pustular psoriasis or a separate entity?, J. Am. Acad. Dermatol. 1989; 20: 338–341. 22. Oumeish, O. Y., Farraj, S. E. and Bataineh, A. S. Some aspects of impetigo herpetiformis, Arch. Dermatol. 1982; 118: 103–105. 23. Rackett, S. C. and Baughman, R. D. Impetigo herpetiformis and Staphylococcus aureus lymphadenitis in a pregnant adolescent, Pediatr. Dermatol. 1997; 14: 387–390. 24. Kuijpers, A. L. A., Schalkwijk, J., Rulo, H. F. C., et al. ­Extremely low levels of epidermal skin-derived antileucoproteinase/elafin in a patient with impetigo herpetiformis, Br. J. Dermatol. 1997; 137: 123–129. 25. Ott, F., Krakowski, A., Tur, E., et al. Impetigo herpetiformis with lowered serum level of vitamin D and its diminished intestinal absorption, Dermatologica. 1982; 164: 360–365. 26. Wolf, R., Tartler, U., Stege, H., et al. Impetigo herpetiformis with hyperparathyroidism, J. Eur. Acad. Dermato. Venereal. 2005; 19: 743–746. 27. Imai, N., Watanabe, R., Fujiwara, H., et al. Successful treatment of impetigo herpetiformis with oral cyclosporine during pregnancy, Arch. Dermatol. 2002; 138: 128–129. 28. Michel, J. L., Gentil-Perret, A., Perrot, J. L., et al. Vitamin D2: a treatment for impetigo herpetiformis, Nouv. Dermatol. 1999; 18: 205.

Acne Vulgaris 29. Akhavan, A. and Bershad, S. Topical acne drugs: review of clinical properties, systemic exposure and safety, Am. J. Clin. Dermatol. 2003; 4: 473–492. 30. Van Pelt, H. P. A. and Juhlin, L. Acne conglobata after pregnancy, Acta Dermatol. Venereol. (Stockh.). 1999; 79: 169. 31. Bekaert, C., Song, M. and Delvigne, A. Acne neonatorum and familial hyperandrogenism, Dermatology. 1998; 196: 453–454. 32. Lewis, V. J., Holme, S. A., Wright, A., et al. Rosacea fulminans in pregnancy. Br. J. Dermatol. 2004; 151: 917–919. 33. Lipson, A. H., Collins, F. and Webster, W. S. Multiple congenital defects associated with maternal use of topical tretinoin, Lancet. 1993; 341: 1352–1353. 34. Rothman, K. F. and Pochi, P. E. Use of oral and topical agents for acne in pregnancy, J. Am. Acad. Dermatol. 1988; 16: 431–442.

References 35. Cunliffe, W. J. Treatment for acne in a pregnant women, J. Ind. Med. Assoc. 1990; 88: 26. 36. Van Hoogdalem, E. J. Transdermal absorption of topical antiacne agents in man: review of clinical pharmacokinetic data, J. Eur. Acad. Dermatovenereol. 1998; 11: S13–S19.

56. Hirsch, R., Anderson, J., Weinberg, J. M., et al. Neonatal ­pemphigus foliaceus, J. Am. Acad. Dermatol. 2003; 49: S187–S189.

Hidradenitis Suppurativa

57. Kahn, G. Dapsone is safe during pregnancy, J. Am. Acad. Dermatol. 1985; 13: 838–839. 58. Collier, P. M., Kelly, S. E. and Wojnarowska, F. W. Linear IgA disease and pregnancy, J. Am. Acad. Dermatol. 1994; 30: 407–411.

37. Jemec, G. B., Hedenheim, M. and Nielsen, N. H. Hidradenitis suppurativa – characteristics and consequences, Clin. Exp. Dermatol. 1996; 21: 419–423. 38. Barth, J. H., Layton, A. M. and Cunliffe, W. J. Endocrine factors in pre- and postmenopausal women with hidradenitis suppurativa, Br. J. Dermatol. 1996; 134: 1057–1059. 39. Dalyrumple, J. C. and Monaghan, J. M. Treatment of hidradenitis suppurativa with the carbon dioxide laser, Br. J. Surg. 1987; 74: 420.

Erythema Nodosum 40. Bartelsmeyer, J. A. and Petrie, R. H. Erythema nodosum, estrogens, and pregnancy, Clin. Obstet. Gynecol. 1990; 33: 777–781. 41. Arsura, E. L., Kilgore, W. B. and Ratnayake, S. N. Erythema ­nodosum in pregnant patients with coccidiomycosis, Clin. Infect. Dis. 1998; 27: 1201–1203. 42. Braverman, I. M. Protective effects of erythema nodosum in coccidiomycosis, Lancet. 1999; 353: 168. 43. Nekhlyudov, L., Gradzka, M., Conti-Kelly, A. M., et al. ­Erythema nodosum associated with antiphospholipid antibodies: a report of three cases, Lupus. 2000; 9: 641–645.

Pemphigus 44. Tope, W. D., Kamino, H., Briggaman, R. A., et al. Neonatal pemphigus vulgaris in a child born to a woman in remission, J. Am. Acad. Dermatol. 1993; 29: 480–485. 45. Hern, S., Vaughan Jones, S. A., Setterfield, J., et al. Pemphigus vulgaris in pregnancy with favourable fetal prognosis, Clin. Exp. Dermatol. 1998; 23: 260–263. 46. Goldberg, N. S., DeFeo, C., and Kirshenbaum, N. Pemphigus vulgaris and pregnancy: risk factors and recommendations, J. Am. Acad. Dermatol. 1993; 28: 877–879. 47. Kalayciyan, A., Engin, B. and Serdaroglu, S. A retrospective analysis of patients with pemphigus vulgaris associated with pregnancy, Br. J. Dermatol. 2002; 147: 396–397. 48. Terpestra, H., de Jong, M. C. J. M. and Klokke, A. H. In vivo bound pemphigus antibodies in a stillborn infant: passive intrauterine transfer of pemphigus vulgaris? Arch. Dermatol. 1979; 115: 316–319. 49. Wasserstrum, N. and Lavros, R. K. Transplacental transmission of pemphigus, J.A.M.A. 1983; 249: 1480–1482. 50. Okubo, S., Sato, C., Abe, R., et al. The use of ELISA to detect desmoglein antibodies in a pregnant woman and fetus, Arch. Dermatol. 2003; 139: 1217–1218. 51. Shieh, S., Fang-Yisheng, V., Becker, J. L., et al. Pemphigus, pregnancy and plasmapheresis, Cutis. 2004; 73: 327–329. 52. Piontek, J. O., Borberg, H., Sollberg, S., et al. Severe exacerbation of pemphigus vulgaris in pregnancy: successful treatment with plasma exchange, Br. J. Dermatol. 2000; 143: 455–456. 53. Jolles, S. A Review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders, Clin. Exp. Dermatol. 2001; 26: 127–131. 54. Campo, V. A., Muniz, F., Mascaro, J. M., et al. Neonatal pemphigus vulgaris with extensive mucocutaneous lesions from a mother with oral pemphigus vulgaris, Br. J. Dermatol. 2002; 147: 801–805. 55. Wu, H., Wang, Z. H., Yan, A., et al. Protection against pemphigus foliaceus by desmoglein 3 in neonates, N. Engl. J. Med. 2000; 343: 31–33.

Linear IgA Disease

Porphyria Cutanea Tarda 59. Marks, R. Porphyria cutanea tarda, Arch. Dermatol. 1982; 118: 452. 60. Urbanek, R. W. and Cohen, D. J. Porphyria cutanea tarda; pregnancy versus estrogen effect, J. Am. Acad. Dermatol. 1994; 31: 390–392. 61. Baxi, L. V., Rubeo, T. J., Katz, B., et al. Porphyria cutanea tarda and pregnancy, Am. J. Obstet. Gynecol. 1983; 146: 333–334. 62. Rajka, G. Pregnancy and porphyria cutanea tarda, Acta. Dermatol. Venereol. (Stockh.). 1984; 64: 444–445. 63. Yamamori, I., Asai, M., Tanaka, F., et al. Prevention of premenstrual exacerbation of hereditary coproporphyria by gonadotropin-releasing hormone analogue, Int. Med. 1999; 38: 365–368.

Erythema Multiforme 64. Graham-Brown, R. A. C., Cochrane, G. W., Swinhoe, J. R., et al. Vaginal stenosis due to bullous erythema multiforme (Stevens–Johnson syndrome), Br. J. Obstet. Gynaecol. 1981; 88: 1156–1157. 65. Osborne, N. G. and Adelson, M. D. Herpes simplex and human papillomavirus genital infections; Controversy over obstetric management, Clin. Obstet. Gynaecol. 1990; 33: 801. 66. Schofield, J. K., Tatnall, F. M. and Leigh, I. M. Recurrent erythema multiforme: Clinical features and treatment in a large series of patients, Br. J. Dermatol. 1993; 128: 542.

Moles and Melanoma 67. Sanchez, J. L., Figueroa, L. D. and Rodriguez, E. Behaviour of melanocytic nevi during pregnancy, Am. J. Dermatopathol. 1984; 6(suppl. 1): 89–91. 68. Pennoyer, J. W., Grin, C. M., Driscoll, M. S., et al. Change in size of melanocytic nevi during pregnancy, J. Am. Acad. Dermatol. 1997; 36: 378–382. 69. Foucar, E., Bentley, T. J., Laube, D. W., et al. A histopathologic evaluation of nevocellular nevi in pregnancy, Arch. Dermatol. 1985; 121: 350–354. 70. Gunduz, K., Koltan, S., Sahin, M. T., et al. Analysis of melanocytic nevi by dermoscopy during pregnancy, J. Eur. Acad. Dermato. Venereal. 2003; 17: 348–351. 71. Pavidlis, N. A. Co-existence of pregnancy and malignancy, Oncologist. 2002; 7: 279–287. 72. O’Meara, A. T., Cress, R., Xing, G., et al. Malignant melanoma in pregnancy. A population-based evaluation, Cancer 2005; 103: 1217–1226. 73. Wiggins, C. L., Berwick, M. and Newton-Bishop, J. Malignant melanoma in pregnancy, Obstet. Gynecol. Clin. North Am. 2005; 32: 559–568. 74. Lens, M. B., Rosdahl, I., Ahlbom, A., et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma, J. Clin. Oncol. 2004; 22: 4369–4375. 75. MacKie, R. M. Pregnancy and exogenous hormones in patients with cutaneous malignant melanoma, Curr. Opin. Oncol. 1999; 11: 129–131.

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Effect of Pregnancy on Other Skin Disorders 76. Altman, J. F., Lowe, L., Redman, B., et al. Placental metastasis of maternal melanoma, J. Am. Acad. Dermatol. 2003; 49: 1150–1154. 77. Asai, J., Takenaka, H., Ikada, S., et al. Congenital malignant melanoma; a case report, Br. J. Dermatol. 2004; 151: 693–697. 78. Slingluff, C. L. and Seigler, H. F. Malignant melanoma and pregnancy, Ann. Plast. Surg. 1992; 28: 95–99. 79. Ferreira, C. M. M., Maceira, J. M. P. and de Oliveira Coelho, J. M. C. Melanoma and pregnancy with placental metastases, Am. J. Dermatopathol. 1998; 20: 403–407. 80. Dipaola, R. S., Goodin, S., Ratzell, M., et al. Chemotherapy for metastatic melanoma during pregnancy, Gynecol. Oncol. 1997; 66: 526–530. 81. Johnston, S. R. D., Broadley, K., Henson, G., et al. Management of metastatic melanoma during pregnancy – a difficult case, Br. Med. J. 1998; 316: 848–851.

88. Chapelon, A. C., Ginsburg, C., Biousse, V., et al. Sarcoidosis and pregnancy. A retrospective study of 11 cases, Rev. Med. Int. 1998; 19: 305–312.

Cutaneous T-cell Lymphoma

Acrodermatitis Enteropathica

82. Vonderheid, E. C., Dellatorre, D. L. and van Scott, E. J. ­Prolonged remission of tumor-stage mycosis fungoides by topical immunotherapy, Arch. Dermatol. 1981; 117: 586–589. 83. Echols, K. T., Gilles, J. M. and Diro, M. Mycosis fungoides in pregnancy: remission after treatment with alpha interferon in a case refractory to conventional therapy: a case report, J. Matern. Fetal Med. 2001; 10: 68–70. 84. Castelo-Branco, C., Torne, A., Cararach, V., et al. Mycosis fungoides and pregnancy, Oncol. Rep. 2001; 8: 197–199.

92. Bronson, D. M., Barsky, R. and Barsky, S. Acrodermatitis ­enteropathica, J. Am. Acad. Dermatol. 1983; 9: 140–144. 93. Brenton, D. P., Jackson, M. J. and Young, A. Two pregnancies in a patient with acrodermatitis enteropathica treated with zinc sulphate, Lancet. 1981; 2: 500–502.

Sarcoidosis 85. Abarquez, C., Pandya, K. and Sharma, O. P. Sarcoidosis and pregnancy, Sarcoidosis J. 1990; 7: 63–66. 86. Eggelmeijer, F. and Dijkmans, B. A. Sarcoidosis post partum: a description of four cases, Br. J. Rheumatol. 1989; 28: 270–271. 87. Selroos, O. Sarcoidosis and pregnancy: a review with results of a retrospective survey, J. Intern. Med. 1990; 227: 221–224.

Pyoderma Gangrenosum 89. Sergent, F., Joly, P., Gravier, A., et al. Pregnancy: a possible etiology of pyoderma gangrenosum. A case report and review of the literature, J. Gynaecol. Obstet. Biol. Reprod. (Paris). 2002; 31: 506–511. 90. Steadman, U. A., Brennan, T. E., Daman, L. A., et al. Pyoderma gangrenosum following cesarean delivery, Obstet. Gynaecol. 1998; 91: 834–836. 91. Sassolas, B., Le Ru, Y., Plantin, P., et al. Pyoderma gangrenosum with pathergic phenomenon in pregnancy, Br. J. Dermatol. 2000; 142: 827–828.

Neurofibromatosis 94. Weissman, A., Jakobi, P., Zaidise, I., et al. Neurofibromatosis and pregnancy. An update, J. Reprod. Med. 1993; 38: 890–896. 95. Braude, P. B. and Bolan, J. C. Neurofibromatosis and spontaneous hemothorax in pregnancy: two case reports, Obstet. Gynecol. 1984; 63(Suppl.): 35–38. 96. Dugoff, L. and Sujansky, E. Neurofibromatosis type 1 and pregnancy, Am. J. Med. Genet. 1996; 66: 7–10. 97. Segal, D., Holcberg, G., Sapir, O., et al. Neurofibromatosis in pregnancy, Eur. J. Obstet. Gynecol. Reprod. Biol. 1999; 84: 59–61.

PART: I  Obstetrics

CHAPTER 11

Connective Tissue Diseases in Pregnancy Daghni Rajasingam Catherine Nelson-Piercy Introduction The connective tissue diseases are multisystem disorders characterized by circulating nonorgan-specific autoantibodies. Many of them are more prevalent in women of child-bearing age, so are not uncommonly encountered in pregnancy. Pregnancy is associated with suppressed cell-mediated immunity. Thus connective tissue diseases in general may remit or improve during pregnancy. However, this is not universal; for example, systemic lupus erythematosus (SLE) may flare or present in pregnancy, with disastrous consequences.

Rheumatoid arthritis Up to 75% of women with rheumatoid arthritis experience improvement of both joint and extra-articular features during pregnancy1, although fewer than 20% are in complete remission2. Improvement usually begins during the first trimester, and rheumatoid nodules may disappear. However, 90% of those who experience remission suffer postpartum exacerbations, and there is an increased incidence of rheumatoid arthritis onset in the postpartum period. Pregnancy does not cause reactivation of the symptoms of quiescent juvenile rheumatoid arthritis. The majority of patients with active disease will experience improvement or total remission in the second half of pregnancy and more than 50% of patients will flare postpartum3. Infants of women who also have anti-Ro antibodies are at risk of neonatal lupus (see below). The relative safety of drugs used to treat connective tissue disease in pregnancy4 is shown in Table 11.1.

Systemic lupus erythematosus The prevalence of SLE is approximately 1 per 1000 women, but may be increasing. SLE flares may be difficult to diagnose during pregnancy because many features, such as hair fall, edema, facial erythema,

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Table 11.1  Drug Treatment of Connective Tissue Disease in Pregnancy4

Drug

Relative Safety

Prednisone

Safe (especially in doses of 20 mg daily or less)

Sulfasalazine

Safe (folate supplementation is necessary before and throughout pregnancy)

Aspirin (low doses)

Safe (doses above 150 mg/day should be discontinued before 32 weeks’   gestation)

Nonsteroidal anti-  inflammatory drugs

Relatively contraindicated (use steroids in preference and stop before   32 weeks if essential)

Heparin

Safe (although osteoporosis is a risk with prolonged high doses   of unfractionated heparin)

Gold

Contraindicated

Azathioprine

Safe

Hydroxychloroquine

Safe

Penicillamine

Contraindicated

Methotrexate

Contraindicated

Cyclophosphamide

Contraindicated

Warfarin

Relatively contraindicated (avoid during weeks 6–12)

Fondaparinux

Contraindicated during pregnancy and breastfeeding

Leflunomide

Contraindicated during pregnancy and breastfeeding

Tacrolimus

Safe especially at low doses

Mycophenolate mofetil (MMF)

Contraindicated during pregnancy

Infliximab

Contraindicated in pregnancy and breastfeeding

fatigue, anemia, raised erythrocyte sedimentation rate, and musculoskeletal pain, also occur in normal pregnancy. About 60% of women with SLE have a flare during pregnancy or the puerperium, compared with about 40% of nonpregnant women over the same time period5. Cutaneous flares are the most common (Figures 11.1–11.3), followed by joint symptoms. Disease flares must be managed actively. Corticosteroids are the drug of choice4, but do not prevent flares. They should not be prescribed prophylactically, nor the dose increased for that purpose. Pregnancy does not seem to jeopardize renal function in the long term for women with lupus nephritis, although SLE

Figure 11.1  Florid erythema of the palms. Pregnancy­related palmar erythema may confuse the diagnosis of lupus vasculitis.

Systemic lupus erythematosus 101

Figure 11.3  Lupus vasculitis of the soles. This young woman had marked lupus vasculitis of the soles of the feet, which had been confused with a fungal dermatosis by her family physician. Table 11.2  Features that Distinguish Renal Flare   in Lupus Pregnancy from Pre-eclampsia Evidence of clinical lupus activity in other systems Rising titer of anti-DNA antibodies Evidence of alternate pathway of complement activation (i.e., ↓C3 or ↓C4) Presence of cellular casts on urine microscopy Figure 11.2  Peripheral lupus vasculitis. Vasculitic eruptions in lupus in pregnancy commonly affect the peripheries, especially the tips of the fingers and toes.

nephropathy may manifest for the first time in pregnancy. There is a greater risk of deterioration in patients with a higher baseline serum creatinine level. A renal flare may be ­difficult to distinguish from pre-eclampsia, as hypertension, proteinuria, thrombocytopenia, and renal impairment are all features of both (Table 11.2). SLE is associated with an increased risk of spontaneous abortion, fetal death, pre-eclampsia, preterm delivery (60%), and intrauterine growth restriction (IUGR)6. These adverse outcomes are associated with the presence of anticardiolipin antibodies (aCLs) or lupus anticoagulant (LA) (antiphospholipid antibodies; aPLs), lupus nephritis or hypertension, and either active disease at the time of conception or first presentation of SLE during pregnancy. In the absence of these features, the risk of adverse outcome is not increased.

Absence of other features of pre-eclampsia (e.g., intrauterine growth retardation, abnormal liver function test results, hyperuricemia)

Neonatal lupus syndromes About 30% of patients with SLE have anti-Ro antibodies. They are most common in mothers with predominantly cutaneous lupus and with Sjögren’s syndrome. These antibodies cross the placenta and may cause immune damage in the fetus. The commonest manifestation (5% risk if antiRo-positive) is cutaneous neonatal lupus. The eruption (Figure 11.4) usually appears in the first 2 weeks of life. The typical lesions tend to be geographical, annular, erythematous, and scaly, and occur over the face, scalp, or other light-exposed skin. The rash disappears spontaneously within 6 months and scarring is unusual. The risk of congenital heart block is less (2–3% risk if anti-Ro-positive), and is usually detected in utero at around 18–20 weeks. The perinatal

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Table 11.3  Clinical Criteria for Antiphospholipid   Syndrome8 Diagnostic Criteria One or more of: Thrombosis (venous or arterial) Recurrent pregnancy loss (fetal death > 10 weeks, three   or more miscarriages at < 10 weeks) Premature birth before 34 weeks due to pre-eclampsia   or intrauterine growth retardation Additional Clinical Features Figure 11.4  Cutaneous neonatal lupus. This baby shows the classic appearance of neonatal lupus.

Thrombocytopenia and hemolytic anemia

mortality rate is increased, with 20% of affected children dying in the early neonatal period. Most infants who survive this period do well, although 50–60% require a pacemaker. The risk of a second child being born with heart block is 25%, rising to 50% after two or more affected babies7.

Cerebral involvement (particularly epilepsy, cerebral infarction, chorea, and migraine)

Antiphospholipid syndrome The combination of either aCLs or LA with one or more of the characteristic clinical features (Table 11.3) is known as the antiphospholipid syndrome (APS)8. Livedo reticularis (Figure 11.5) is the typical skin sign but is not invariably present. Indolent cutaneous ulcers (Figure 11.6) are a rare feature. APS may complicate SLE, but many patients have primary APS with no features of SLE. Patients with primary APS should not be labeled as having “lupus,” but the antibodies should be regarded as markers for a high-risk pregnancy. Previous poor obstetric history is an important predictor of fetal loss. Many of the adverse outcomes described (early-onset pre-eclampsia, IUGR, placental abruption, stillbirth) are the end result of abnormal placentation, supporting the hypothesis that placental failure is the mechanism by which aPLs are associated with late loss9. The risk of recurrent thrombosis in patients with APS may reach 70%10. Management of pregnancy in women with APS includes low-dose aspirin (75 mg) and low-molecular-weight heparin, which

Livedo reticularis

Heart valve disease (particularly mitral valve) Hypertension Pulmonary hypertension Leg ulcers

Figure 11.5  Livedo reticularis. This is a cutaneous hallmark of antiphospholipid antibodies. As well as miscarriage and thrombosis, these antibodies may be associated with cardiac murmurs due to valvular vegetations.

reduce fetal mortality. In patients with recurrent miscarriage, a high success rate is achieved when low-dose aspirin is used. The addition of lowmolecular-weight heparin does not significantly improve pregnancy outcome11. Thromboprophylaxis with heparin is essential for those with previous thrombosis. Pregnancy ­complicated by SLE

Dermatomyositis and polymyositis 103

Figure 11.7  Dermatomyositis. Periorbital violescent (heliotrope) rash with associated edema.

Figure 11.6  Cutaneous ulcers and atrophie blanche. Cutaneous ulcers, especially on the lower legs, which are notoriously persistent, are a less usual manifestation of antiphospholipid syndrome.

or APS requires expert care and a team approach by obstetricians, physicians, and hematologists. Close monitoring of both mother and fetus is essential.

Scleroderma It has been postulated that fetal antimaternal graft-versus-host reactions may be involved in the pathogenesis of scleroderma, which has clinical similarities to chronic graft-versus-host disease since persistent fetal microchimerism is more common in women with scleroderma than control women12. Pregnancy may have an etiological role in scleroderma13. Successful pregnancy is now reported to occur in 70–80% of patients14. The risks of adverse outcome are highest for women with early diffuse

disease. Pregnancy can accelerate pre-existing renal damage15. Progressive cutaneous disease is unusual during or immediately after pregnancy. Raynaud’s phenomenon usually improves as a result of vasodilation and increased blood flow. Reflux esophagitis often worsens, related to the decreased lower esophageal tone. Arthralgia usually worsens. There is no evidence that pregnancy worsens cardiac or respiratory disease, although those with severe pulmonary fibrosis and pulmonary hypertension are at extremely high risk of postpartum deterioration, as with pulmonary hypertension from any cause.

Dermatomyositis and polymyositis Dermatomyositis and polymyositis are rare in pregnancy. Dermatomyositis is a subacute systemic weakness of the proximal limb and trunk muscles associated with skin lesions (Figures 11.7 and 11.8). There may be increased rash activity, proximal muscle weakness16 or subcutaneous calcification in polymyositis during pregnancy (Figures 11.9 and 11.10). In an analysis of all the case reports, nearly half the women had established myositis before becoming pregnant and about 35% developed the disease during pregnancy17. Pre-existing dermatomyositis or polymyositis probably presents no increased risk to either mother or fetus, but the fetal mortality rate is increased when onset or relapse occurs during pregnancy18. Forty-three percent of pregnancies in women with active disease resulted in fetal

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Figure 11.8  Dermatomyositis (Gottron papules). Erythematous purple papules on the dorsal aspects of the metacarpophalangeal and interphalangeal joints.

Figure 11.10  Polymyositis. Radiograph of the knee of the patient shown in Figure 11.9, showing calcification of subcutaneous tissue in the lower thigh.

Figure 11.9  Polymyositis. Acceleration of subcutaneous calcification, shown here at the elbow, was noted by this young woman with polymyositis during pregnancy. The disease remained inactive in other respects.

death and 33% were associated with IUGR and premature delivery. A significant improvement can usually be expected in the puerperium17, but occasionally dermatomyositis can present in the postpartum phase19 .

Pregnancy should be planned at a time of remission16, and the patient should be closely monitored throughout the pregnancy for clinical and laboratory signs of disease exacerbation. Prednisone, administered in a minimally effective dosage, is the mainstay of treatment for dermatomyositis and polymyositis.

Ehlers–Danlos syndrome Although Ehlers–Danlos syndrome and pseudoxanthoma elasticum are not regarded as “connective tissue” diseases in the sense described above, they are included in this chapter for convenience. Ehlers–Danlos syndromes I–X are a group of inherited disorders of collagen ­ metabolism,

Ehlers–Danlos syndrome 105

Table 11.4  Key Points for the Pregnant Patient Rheumatoid arthritis

Usually improves in pregnancy Often deteriorates postpartum Use corticosteroids rather than   nonsteroidal anti-inflammatory drugs

Systemic lupus erythematosus

Pregnancy outcome is affected by: Presence or absence of anti-Ro and   antiphospholipid antibodies (aPLs) The activity of the disease and medications used Presence or absence of hypertension and renal involvement

Scleroderma

Women with limited scleroderma without   organ involvement do better than those with diffuse disease12. Women with early (less than 4 years) diffuse   scleroderma are at highest risk for renal crisis both in and   outside pregnancy14, and premature delivery.

Ehlers–Danlos syndrome

Women with Ehlers–Danlos types I (classic or gravis)   and IV (ecchymotic or arterial) are particularly likely to   develop dangerous complications during pregnancy. Catastrophic complications in patients with type I or IV   disease are most likely to occur during labor, delivery, or in   the first few days postpartum. Cesarean section may not result in fewer complications than vaginal delivery23.

Pseudoxanthoma elasticum

The main complication during pregnancy is gastrointestinal (particularly gastric) bleeding with massive hematemesis24,25. Hypertension should be treated aggressively in view of the risks related to cerebral and cardiovascular disease. Careful control of blood pressure may help to reduce the risk   of hemorrhage.

characterized by fragile skin and blood vessels, easy bruising, skin hyperelasticity, and joint hypermobility. Obstetric problems include postpartum bleeding, poor wound healing and dehiscence, vaginal and perineal lacerations, bladder and uterine prolapse, and abdominal hernia20–22 (Table 11.4). There is an increased risk of premature rupture of the membranes and cervical incompetence, and perineal delivery has been described23. A favorable outcome for pregnancy has been reported for type II (mitis) and type X (fibronectin abnormality), and possibly mild forms of the disease20. Women with Ehlers–Danlos types I (classic or gravis) and IV (ecchymotic or arterial) are particularly likely to

develop complications during pregnancy. Ehlers– Danlos type IV has a high risk of death to the mother of 25%. This is mainly caused by rupture of the aorta or uterus22. Rupture and dissection of the pulmonary artery, and rupture of the bowel, especially with type IV disease, also explain the increased maternal mortality rate. Avoidance or early termination of pregnancy should be recommended in type IV disease, for which the reported maternal mortality rate (albeit probably an overestimate due to reporting bias) is 20–25%21,22. It is thus important to categorize the patient’s condition accurately to enable accurate counseling regarding pregnancy. There are no indications that cesarean delivery offers less risk for the patients.

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Figure 11.11  Pseudoxanthoma elasticum. The skin is loose and thickened, like that of a plucked chicken. This is a rather subtle clinical change. The sides of the neck are characteristic sites.

However patients with type IV disease should be counseled to have a cesarean because of the high risk of uterine rupture23.

Pseudoxanthoma elasticum Pseudoxanthoma elasticum is an inherited disease characterized by widespread degeneration of elastic tissue involving the skin (Figures 11.11), eye (angioid streaks and loss of central vision), gastrointestinal tract, and blood vessels. Patients who want to get pregnant should be warned about the possibility of disease exacerbation, complications to the fetus, and the risk of genetic transmission to the child24. The main complication for the woman is that of gastrointestinal hemorrhage. The fetus is particularly susceptible to IUGR. Delivery does not usually present with any further complications25. Arterial hypertension and thromboembolic disease seem to increase after multiple pregnancies. Patients have premature vascular disease, and pseudoxanthoma elasticum is a model for accelerated aging.

References   1. Nelson, J. L. and Ostensen, M. Pregnancy and rheumatoid arthritis, Rheum. Dis. Clin. North Am. 1997; 23: 195–212.   2. Barrett, J. H., Brennan, P., Fiddler, M., et al. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy, Arthritis Rheum. 1999; 42: 1219–1227.

  3. Ostenson, M. Pregnancy in patients with a history of juvenile rheumatoid arthritis, Arthritis Rheum. 1991; 34: 881–887.   4. Ostenson, M., Khamashta, M. A, Lockshn, M., et al. Antiinflammatory and immunosuppressive drugs and reproduction, Arthritis Res. Ther. 2006; 8: 209.   5. Khamashta, M. A. Systemic lupus erythematosus and pregnancy, Best Pract. Res. Clin. Rheumatol. 2006; 20: 685–694.   6. Schmutz, J. -L. Dermatological diseases influenced by pregnancy, Presse Med. 2003; 32: 1809–1812.   7. Buyon, J. P., Hiebert, R., Copel, J., et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry, J. Am. Coll. Cardiol. 1998; 31: 1658–1666.   8. Wilson, W. A., Gharavi, A. E., Koike, T., et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop, Arthritis Rheum. 1999; 42: 1309–1311.   9. Langford, K. and Nelson-Piercy, C. Antiphospholipid syndrome in pregnancy, Contemp. Rev. Obstet. Gynaecol. 1999; June: 93–98. 10. Lakasing, L., Bewley, S. J. and Nelson-Piercy, C. Management of antiphospholipid syndrome in pregnancy. In: Khamastha, M. A. (ed) Hughes Syndrome: The Antiphospholipid Syndrome, 2nd edn, pp. 555–567. Springer, London, 2006. 11. Farquharson, R. G., Quenby, S., and Greaves, M. Antiphospholipid syndrome in pregnancy: a randomized controlled trial of treatment, Obstet. Gynaecol. 2002; 100: 408–413. 12. Artlett, C. M., Smith, B., and Jimenez, S. A. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis, N. Engl. J. Med. 1998; 338: 1186–1191. 13. Black, C. M. Systemic sclerosis and pregnancy, Baillieres Clin. Rheumatol. 1990; 4: 105–124. 14. Steen, V. D. Pregnancy in systemic sclerosis, Scand. J. Rheumatol. 1998; 27(Suppl 107): 72–75. 15. Steen, V. D. Scleroderma and pregnancy, Rheum. Dis. Clin. North Am. 1997; 23: 133–147. 16. Ishii, N., Ono, H., Kawaguchi, T., et al. Dermatomyositis and pregnancy. Case report and review of the literature, Dermatologica. 1991; 183: 146–149. 17. Ohno, T., Imai, A. and Tamaya, T. Successful outcomes of pregnancy complicated with dermatomyositis. Case reports, Gynecol. Obstet. Invest. 1992; 33: 187–189. 18. Silva, C. A., Sultan, S. M. and Isenberg, D. A. Pregnancy outcome in adult-onset idiopathic inflammatory myopathy, Rheumatology. 2003; 42: 1168–1172. 19. Kanoh, H., Izumi, T., Seishima, M., et al. A case of dermatomyositis that developed after delivery: the involvement of pregnancy in the induction of dermatomyositis, Br. J. Dermatol. 1999; 141: 877–900. 20. Winton, G. B. Skin diseases aggravated by pregnancy, J. Am. Acad. Dermatol. 1989; 20: 1–13. 21. Rudd, N. L., Nimrod, C., Holbrook, K. A., et al. Pregnancy complications in type IV Ehlers–Danlos syndrome, Lancet. 1983; i: 50–53. 22. Lurie, S., Manor, M. and Hagay, Z. J. The threat of type IV Ehlers–Danlos syndrome on maternal well-being during pregnancy: early delivery may make the difference, J. Obstet. Gynaecol. 1988; 18: 245–248. 23. Georgy, M. S., Anwar, K., Oates, S. E., et al. Perineal delivery in Ehlers–Danlos syndrome, Br. J. Obstet. Gynaecol. 1997; 104: 505–506. 24. Ramos-e-Silva, M., Periera, A. L. C., Oliviera, G. B., et al. ­Connective tissue diseases:pseudoxanthoma elasticum, ­anetoderma, and Ehlers–Danlos syndrome in pregnancy, Clin. Dermatol. 2006; 24: 91–96. 25. Bercovitch, L., Leroux, T., Terry, S., et al. Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum, Br. J. Dermatol. 2004; 151: 1011.

PART: I  Obstetrics

CHAPTER 12

Infectious Diseases in Pregnancy Eithne MacMahon Emma Fox Diana Lockwood This chapter focuses on those acute and chronic infections that may have adverse consequences for the fetus or neonate, or warrant special attention and/or management during the course of pregnancy. The viral exanthems will be considered first, followed by notes on the dermatological manifestations of human immunodeficiency virus (HIV). The viral vulvar infections (herpes simplex virus (HSV) and human papillomavirus (HPV)) are considered next and leprosy is discussed in the concluding section.

Viral exanthems and pregnancy Introduction The viral exanthems, which cause mild disease in childhood, may be asymptomatic or give rise to severe disease in the expectant mother. Dermatologic manifestations generally take the form of a vesicular or maculopapular-type rash (Table 12.1). Primary maternal infection during pregnancy may have potentially serious consequences for the fetus or newborn (Table 12.2). The fetus may be infected in utero, giving rise to congenital infection, or acquire infection perinatally, with presentation in the neonatal period. The major risk period for exposure of the fetus or neonate depends on the viral etiology and the timing of maternal infection1. Table 12.2 summarizes measures to minimize maternal and fetal sequelae following exposure or infection. Practical points noted below supplement the tabular information.

Varicella-zoster virus (VZV) Primary infection with VZV causes chickenpox (varicella) (Figure 12.1) and induces VZV-specific immunoglobulin (Ig) G, which persists for life2. Reactivation, typically occurring decades later, results in shingles (zoster). In temperate climes, where approximately 90% of adults are VZV-seropositive, varicella is uncommon during pregnancy and may be further reduced by VZV vaccination policies. In contrast, primary infection is delayed in subtropical and tropical ­climates, where

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Table 12.1  Viral Exanthems in Pregnancy: Maternal Infection

Laboratory Diagnosis in Mother

Primary Viral Infection

Incubation Period to Rash

Clinical Features in Mother

Dermatological Manifestations

Varicella-zoster virus

7–23 days2

Varicella Increased risk   of ­complications, ­including ­pneumonitis2 Increased mortality rate in pregnancy?

Vesicular rash2  Lesions progress rapidly   (­maculopapular → vesicles→  pustules →crusting) Itchy Centripetal ­distribution Scalp lesions Oral ulceration

Lesion scrapings2: Electron microscopy Tzanck smear Antigen detection Culture Polymerase chain ­reaction (PCR)

Rubella

13–20 days3

Fever Rash Lymphadenopathy Arthropathy (finger joints, wrists, knees, ankles) Up to 25% of cases asymptomatic

Maculopapular rash3: pinpoint→confluent exanthem

Specific IgM3

Parvovirus B19 Fifth disease Erythema ­infectiosum Slapped-cheek ­syndrome

18 days4 (8 days to Rash ­nonspecific symptoms) Acute symmetric arthropathy: finger joints (metacarpophalangeal, proximal interphalangeal joints), wrists, ankles, knees, elbows, axial spine, hips.   Aplastic crisis   in patients with ­hemoglobinopathy Up to 50% ­asymptomatic

Maculopapular rash4: discrete→confluent → central clearing “lacy”/ reticular pattern

Specific IgM4

Enterovirus infection

2–40 days5

Maculopapular or vesicular5

Stool5: culture PCR

Majority ­asymptomatic5

about 50% of women may be susceptible2. Primary VZV infection may be severe in adults, and associated with greater morbidity and mortality during pregnancy1 (see Table 12.1). Although aciclovir is not licensed for use in pregnancy, it has been used extensively without adverse effects and should be considered in confirmed cases2 (see Table 12.2).

In contrast to primary infection with VZV, there is no evidence that shingles/zoster in pregnancy presents any risk to the fetus or neonate6. The possibility of underlying HIV infection should, however, be considered in prospective mothers who suffer a recurrent attack, or cutaneous or visceral dissemination of shingles.

Viral exanthems and pregnancy 109

Table 12.2  Viral Exanthems in Pregnancy: Consequences for the Fetus/Neonate

Primary Viral Infection

Stages of Pregnancy at which Maternal Infection may Harm Fetus or Neonate

Varicella-zoster virus (VZV)

Rubella

Parvovirus B19 Fifth disease Erythema infectiosum Slapped-cheek syndrome

Manifestations in Fetus or Neonate

Specific Prevention or Management

0–20 weeks

Congenital varicella   (1–2%)6 Manifestations ranging from skin scarring or limb hypoplasia to severe multisystem involvement

VZIG administration to seronegative mother within 72 hours postexposure may prevent or ameliorate maternal infection6. Treat confirmed maternal varicella early with aciclovira p.o. or i.v. for pneumonitis or other complications2

13–40 weeks

Shingles in infancy (1–2%)6

–7 to +7 days from delivery

Neonatal varicella

VZIG prophylaxis to neonate if mother develops varicella rash within the period of 7 days before to 7 days after delivery, or infant of seronegative mother has maternal or other VZV contact before 28 days7 Treat neonatal ­varicella with i.v. aciclovir

0–8 weeks

Spontaneous abortion   (< 20%)3

HNIG may be offered to seronegative pregnant ­contacts of rubella for whom termination is ­unacceptable

0–12 weeks

Congenital rubella ­syndrome Therapeutic abortion3 (85%)3: Sensorineural ­deafness Congenital heart defects Retinopathy, cataract Microphthalmia Microcephaly Psychomotor retardation

13–16 weeks

Congenital rubella3: Sensorineural deafness Retinopathy

0–20 weeks

Mid-trimester abortion 4–6 weeks later (incidence increased by 9%)8 (Continued)

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Table 12.2  Viral Exanthems in Pregnancy: Consequences for the Fetus/Neonate—cont’d

Primary Viral Infection

Stages of Pregnancy at which Maternal Infection may Harm Fetus or Neonate

(Parvovirus B19 continued)

9–20 weeks

Manifestations in Fetus or Neonate

Specific Prevention or Management

Hydrops fetalis after 2–12 weeks (3%)8

Monitor for hydrops fetalis and consider intrauterine transfusion9

Congenital red-cell aplasia?6 Enterovirus infection

Perinatal period

Neonatal infection; variable severity: Asymptomatic →  fulminant multisystem ­disease5,10: Meningoencephalitis Myocarditis Pneumonitis Hepatitis Pancreatitis Disseminated intravascular coagulation

Consider HNIG adminis­ tration to neonates   born within 5 days of ­maternal infection   (­efficacy unproven)10  Infection control measures   to prevent nosocomial spread   from index case5

aUnlicensed

in pregnancy. VZIG, varicella zoster immune globulin; p.o., orally; i.v., intravenously; HNIG, human normal immunoglobulin.

Figure 12.1  Varicella (chickenpox). Multiple, discrete, vesi­ culopustular, and maculopapular lesions on day 5 of rash.

Figure 12.2  Rubella. Discrete and confluent erythematous maculopapular lesions are present.

Maculopapular rashes

be considered in the differential diagnosis of maculopapular rashes.

Rubella (Figure 12.2), parvovirus B19, and enterovirus infections may all present with red rashes, which in practice are clinically indistinguishable3,4,5. Neither a past history nor a current clinical diagnosis is reliable, and laboratory confirmation is required during pregnancy1. The arthropathy associated with both rubella and parvovirus B19 may persist for some weeks3,4. The possibility of HIV seroconversion should always

Rubella Rubella (see Table 12.1) is currently a rare disease in women in many countries as a result of successful vaccination programs3. Congenital rubella syndrome (see Table 12.2) continues to be a problem in developing countries, however, partly as a result of unsatisfactory vaccination strategies11. Where

Human immunodeficiency virus

therapeutic abortion is considered following rubella in the first trimester, the diagnosis should be confirmed by testing a second blood sample for specific IgM and/or a rise in specific IgG. Congenital rubella is diagnosed by the detection of rubella-specific IgM in cord or infant blood3. Rubella reinfection has been described in seropositive individuals3. Reinfection in the first 16 weeks of pregnancy carries an 8% or lower risk of fetal infection, but fetal malformations are rare3.

111

Parvovirus B19 Primary parvovirus B19 infection is most common between 4 and 10 years of age. Whereas seropositivity is almost universal among adults in developing countries, about 40% of women in the developed world remain susceptible4. Parvovirus B19 infects red cells via the erythrocyte P antigen, classically causing a biphasic illness, the period of infectivity coinciding with the first phase of fever, mild anemia, and nonspecific symptoms4. In the second phase, coinciding with specific IgG and IgM production, rash and arthropathy are the main features (see Table 12.1). One or other phase, or both phases, may be subclinical. Joint involvement occurs in 80% of women with rash, and arthropathy may be the sole feature. The rash may wax and wane for some weeks after onset4. Primary infection during pregnancy is associated with an excess fetal loss of 9% and with nonimmune hydrops fetalis (fetal anemia in the absence of hemolysis) in 3% of fetuses 2–12 weeks following maternal illness8 (Figure 12.3). Intrauterine transfusion has been used to treat fetal hydrops9 (see Table 12.2).

Enteroviruses Enteroviral infections occur frequently in healthy adults, usually without symptoms. Symptomatic infection may be associated with rubelliform or vesicular rashes5 (see Table 12.1). Some 1–2% of pregnant women may be excreting enteroviruses at term, with a high risk of transmission5. ­Neonatal infection presents at 3–7 days of age as an illness of wide-ranging severity. Coxsackie B viruses and echoviruses types 6, 7, and 11 have been associated with severe or fatal neonatal infection5,10 (see Table 12.2).

Figure 12.3  Parvovirus B19 infection. Hydropic fetus f­ ollowing primary infection during pregnancy. (Reproduced from the slide collection of the late Dr James C. Booth, St George’s Hospital Medical School, London, UK.)

Human immunodeficiency virus HIV infection is often associated with dermatologic manifestations, although less so since the introduction of highly active antiretroviral therapy (HAART).12 Many of these dermatoses occur commonly in the HIV-negative population but in HIV disease may present atypically and can be harder to treat. Other skin diseases are indicative of severe opportunistic infections. The majority are not usually altered by pregnancy. The ability to recognize them, however, is crucial as knowledge of a pregnant woman’s HIV status allows her to take up recognized interventions to reduce mother-to-child transmission of HIV.13 Although antenatal HIV testing should be recommended to all pregnant women, uptake is variable, and the diagnosis may not be

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made until the woman presents with symptoms and/or a history of associated manifestations.

Folliculitis Itchy, excoriated, follicular papules and pustules on the face, trunk, and upper arms are typical of eosinophilic folliculitis (Figure 12.4), which is almost diagnostic of advanced HIV infection. Treatment includes immune reconstitution with HAART, systemic antibiotics, antihistamines, antifungals, or phototherapy.14 Other causes of folliculitis include Staphylococcus aureus and Pityrosporum ovale.

Kaposi sarcoma Kaposi sarcoma commonly affects homosexual men but can also affect women, particularly those from endemic areas. Human herpesvirus 8 is the causative agent. Lesions appear as patients become more immunosuppressed, but can occur early. Cutaneous lesions are usually purple-brown macules, nodules, or plaques (Figure 12.5). Oral lesions may be visible, often indicating visceral or pulmonary involvement. Histologic examination confirms the diagnosis and differentiates the condition from bacillary angiomatosis, which it may resemble. Treatment involves immune reconstitution with HAART, with radiotherapy, local or systemic chemotherapy when required.15

Figure 12.4  Eosinophilic folliculitis affecting the right cheek.

Varicella-zoster virus HIV should be considered in patients with shingles. It may occur early in the course of HIV infection before the onset of other signs or symptoms. Multidermatomal involvement occurs, usually associated with significant immunosuppression. Atypical presentations include verrucous lesions (Figure 12.6) and indolent ulcers. Prolonged suppressive aciclovir treatment may be required for persistent or recurrent disease.15

Genital conditions Genital warts may be associated with immunosuppression, and HIV should be considered in women with extensive recalcitrant genital warts and multifocal genital intraepithelial neoplasia. Similarly, frequent recurrent herpes simplex virus (HSV) infection may be a presenting symptom. Lesions may be extensive with advanced immunosuppression.15

Figure 12.5  Cutaneous Kaposi sarcoma of the upper arm.

Other conditions Facial molluscum contagiosum is suggestive of advanced HIV infection. Seborrheic dermatitis, tinea, ichthyosis, and psoriasis are frequently seen in patients with HIV infection. Rarely, cutaneous cryptococcosis or histoplasmosis occurs. Drug eruptions are associated with some antiretroviral drugs.

Herpes simplex virus

Figure 12.6  Verrucous lesions of varicella-zoster virus.

Herpes simplex virus Genital herpes simplex infection in the mother may have severe consequences for the neonate. Although this book is concerned with the presence of dermatologic manifestations, it must be emphasized that maternal genital herpes ­infection warrants consideration even in the absence of genital lesions, past or present. Furthermore, disseminated neonatal herpes infection and herpes encephalitis may present in the absence of mucocutaneous lesions. Genital herpes can be caused by either HSV-2 or HSV-116,17. These closely related herpes viruses are characterized by lifelong persistence in the host following primary infection, the establishment of latency in neuronal ganglia, and intermittent reactivation. HSV-2 is predominantly sexually transmitted, first acquired in adolescence or early adulthood and associated with symptoms “below the waist.” In contrast, HSV-1 is classically acquired in childhood and is associated with disease “above the waist,” with primary infection manifest as gingivostomatis and clinical reactivation as “cold sores.” In practice there is considerable cross-over, with up to 50% of initial presentations of genital herpes attributable to HSV-118.

Genital herpes Epidemiology

Serological testing, using assays that can discriminate between HSV-1 and HSV-2, has indicated that enumeration of clinical cases grossly ­underestimates the prevalence of genital herpes

infection. Between 1988 and 1994, the seroprevalence of HSV-2 infection in persons aged 12 years or over in the United States was 21.9%, a 30% increase compared with the late 1970s19. Yet fewer than 10% of seropositive individuals reported a history of genital herpes infection19. Female sex, black race or Mexican-American ethnic background, older age, less education, poverty, cocaine use, and a greater lifetime number of sexual partners were independent predictors of infection. The prevalence of HSV-2 infection in the United Kingdom is considerably less, with values ranging from 3% (male blood donors) to 23% (sexually transmitted disease clinic patients)17. These figures necessarily underestimate the size of the problem, as sexually acquired HSV-1 is not considered18. Clinical features

Primary genital herpes is defined as genital infection with either HSV-1 or HSV-2 in an individual without previous HSV-1 or HSV-2 infection17,20. It may pass unnoticed or present clinically after an incubation period of 2–12 days. First-episode (initial) genital herpes is the first recognized attack of genital herpes in an individual previously infected with HSV-1 or HSV-217,20. Primary or first-­episode genital herpes presents with multiple painful lesions on the external genitalia, buttocks, cervix, vagina, and/or rectum. The initial blisters soon rupture to form shallow ulcers with erythematous margins (Figures 12.7 and 12.8). There is often dysuria and even urinary retention. Symptomatic primary genital infection may be accompanied by constitutional symptoms of fever, malaise, myalgia, and lymphadenopathy. There are large quantities of replicating virus in the genital tract, and viral excretion continues for 3 weeks on average. HSV is not cleared, but persists in a latent state in the local sensory ganglion, reactivating periodically. Acquisition of genital infection may be asymptomatic, but then present clinically for the first time months or years later. Previous HSV-1 infection does not reduce the rate of HSV-2 infection, but significantly increases the likelihood of asymptomatic seroconversion18. Recurrent genital herpes is the second or subsequent episode of clinical disease. Recurrent attacks

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114

Figure 12.7  Genital herpes. Multiple discrete vulvar ulcers.

generally become progressively less frequent and less severe over time. Symptomatic recurrences are fewer and less frequent with genital HSV-1 infection, so that HSV-2 accounts for 95% of recurrent cases21. Asymptomatic or unrecognized herpes reactivation is the rule, however, with viral shedding estimated to occur in 1% of HSV-2-seropositive subjects on any given day regardless of any history of genital herpes22. Diagnosis and treatment

Table 12.3 lists the techniques available to detect viruses in patients with suspected herpes infection. The oral antiviral agents aciclovir, valaciclovir, and famciclovir are effective in reducing the severity and duration of symptoms during attacks and in suppressing clinical recurrences. Aciclovir has also been shown to suppress subclinical shedding and may therefore have a role in preventing transmission23. Herpetic skin lesions may be invasive

Figure 12.8  Genital herpes. Cervical lesions identified by speculum examination.

and persistent in individuals with HIV-1 infection, who may ultimately develop resistance to antiviral agents17. Genital herpetic infection promotes transmission of HIV infection and vice versa.

Neonatal herpes Neonatal herpes occurs far less frequently than genital herpes infections in women of child­bearing age. In the United Kingdom the incidence is 1 in 60 000 live births17, compared with more than 1 in 5000 in the United States16. The variable incidence of neonatal herpes in different countries cannot be explained adequately by differences in the prevalence of HSV-2 infection, or underreporting of neonatal cases16. HSV infection in the neonate may result from intrauterine, perinatal, or postnatal transmission of HSV-1 or HSV-2. Postnatal transmission from staff or family members with active herpetic infections accounts for about 10% of cases. Some 85%

Herpes simplex virus

Table 12.3  Techniques for Viral Detection in Material from Suspected Herpetic Lesions

Table 12.4  Clinical Presentation of Neonatal Herpes Localized to the skin, eye, and/or mouth

Electron microscopy Immunofluorescence Antigen detection Virus culture

Encephalitis with or without skin, eye, and/or mouth involvement Disseminated infection that involves multiple organs, ­including central nervous system, lung, liver, adrenals, skin, eye, and/or mouth

Nucleic acid amplification/detection techniques

are acquired perinatally by contact with infected maternal secretions during vaginal delivery. The incubation period of neonatal herpes is 5–21 days. Intrauterine transmission is implicated in the 5% of infants with neonatal herpes presenting on the day of birth following rupture of membranes for less than 24 hours or born by cesarean section initiated before membrane rupture24,25. Clinical features

Infection may be limited to the portals of viral entry (skin, eyes, mouth) or progress to involve the brain and/or other organs16 (Table 12.4). In localized presentation, cutaneous lesions appear at sites of trauma (e.g., the presenting part, scalp electrode sites, etc). Lesions usually appear at 1–2 weeks but are sometimes present at birth24,25. Vesicular lesions are usually 1–2 mm in diameter, but may be larger and have an erythematous base with clear or slightly cloudy fluid (Figure 12.9). More pustular lesions have been confused with bullous impetigo or erythema toxicum. Prompt diagnosis and treatment are required as untreated neonates may develop encephalitis or disseminated infection. Survival is 100% when neonates with localized infection receive intravenous aciclovir therapy. The relative proportions of cases with localized versus disseminated disease may reflect early recognition and treatment of localized infection26. Disseminated infection presents during the first month of life with signs and symptoms suggestive of overwhelming bacterial infection, including liver dysfunction, bleeding diathesis, and respiratory distress16. The central nervous system subgroup accounts for about one-third of cases26 presenting

Figure 12.9  Neonatal herpes. Lesions on the foot of an infant with fatal disseminated infection.

between 10 and 28 days of age with nonspecific symptoms of fever and irritability followed by seizures. Disseminated and central nervous system infection in the neonate frequently presents in the absence of skin lesions. The initial nonspecific symptoms and signs, together with the lack of a maternal history of genital herpes, may contribute to diagnostic delay. Although aciclovir therapy reduces the mortality rate in both disseminated and central nervous system cases, a large proportion of survivors suffer substantial long-term sequelae16.

Risks of vertical transmission Both symptomatic and asymptomatic viral shedding can result in HSV transmission during vaginal birth. Despite the anxieties of mothers with a history of genital herpes, their risk of perinatal infection is very small. In two prospective studies of 64 such women with recurrent HSV-2 at labor (the majority asymptomatic), there was one case (less than 2%) of neonatal herpes27,28. The women at greatest risk of transmitting infection to their babies are those who first acquire ­ genital HSV

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in pregnancy, most often without their knowledge. Asymptomatic first-episode maternal genital herpes is the source of infection in 60–70% of infected newborns28. In a prospective study of 7046 pregnant women seronegative for HSV-1 and/or HSV-2, 94 (1.3%) acquired genital HSV infection during pregnancy. When adjusted for a 40-week gestation, an estimated 2.1% seroconverted during pregnancy. Among the 64 HSV-2 and 30 HSV-1 infections, subclinical cases were of similar frequency: 64% overall29. Neonatal herpes infection occurred in four of nine infants born to women who had acquired genital HSV infection shortly before labor. In contrast, among a ­further 51 pregnancies (including nine earlier third­trimester infections) where the timing of maternal primary infection was known, there were no cases of neonatal or congenital infection29. Maternal seroconversion before labor is thought to account for these observations29,30.

within 6 weeks of delivery, as the risk of viral shedding in labor is very high29,30. If vaginal delivery is unavoidable, or the membranes have been ruptured for more than 4 hours before a cesarean section, administration of aciclovir to the mother and baby may be indicated30. Vaginal procedures such as application of scalp electrodes, fetal blood sampling, or instrumental delivery should be avoided, as damage to the baby’s skin may be the portal of entry for infection20,30. Viral swabs from the oropharynx, eyes, and surface sites for HSV detection should be collected from babies born to mothers with first-episode genital herpes to allow early identification of infected babies. Consideration should be given to immediate commencement of intravenous aciclovir treatment pending test results, and the baby closely monitored for early signs of neonatal herpes: lethargy, poor feeding, fever, and skin lesions.

Management of genital herpes in pregnancy Diagnosis and antiviral therapy

Pregnant women with symptoms or lesions suggestive of genital herpes should have appropriate samples taken to confirm the diagnosis (see Table 12.3 and Figure 12.10). First-episode genital herpes warrant referral to a genitourinary physician and oral or intravenous antiviral therapys as ­clinically indicated30. Aciclovir, valaciclovir, and famciclovir are all effective but are not licensed for use in pregnancy. The available data suggest that aciclovir (and, by inference, its more bioavailable prodrug valaciclovir) is likely to be safe. Prospective registration of cases with the Aciclovir in Pregnancy Register from 1984 failed to find any evidence that it is teratogenic31. Aciclovir crosses the placenta, concentrates in amniotic fluid and breast milk, and reaches therapeutic levels in the fetus32. There are no data to support the use of famciclovir in pregnancy. First-episode genital herpes during pregnancy

Cesarean section should be considered for all women who develop first-episode genital herpes in the third trimester of pregnancy30. This particularly applies to those whose symptoms first appear

Figure 12.10  Laboratory diagnosis. Immunofluorescent detection of herpes simplex virus in cellular material scraped from the base of a lesion.

Human papillomavirus

First-episode genital herpes in the first and second trimesters presents a lesser risk of perinatal transmission29 and, providing delivery does not ensue, it has been suggested that the pregnancy may be managed expectantly and vaginal delivery anticipated30. Continuous oral aciclovir in the last 4 weeks of pregnancy may prevent recurrence at term and hence the need for delivery by cesarean section30,33.

History of recurrent genital herpes prior to current pregnancy Women with recurrent genital herpes can be reassured that the risk of transmission of infection to their babies is very small. Screening tests to detect asymptomatic shedding during late gestation and at term are not recommended20,30. Vaginal delivery is recommended in the absence of lesions20,30 and prodromal symptoms20 at delivery. Cesarean delivery has been recommended for women with a history of recurrent infection who have genital lesions or prodromal symptoms at onset of labor20. The risk:benefit ratio of this approach has been called into question, and cessation of this practice has not resulted in any increase in the number of cases34. In a study of suppressive aciclovir in late pregnancy, there was no significant reduction in the number of cesarean section deliveries but clinical recurrences were significantly reduced, although some asymptomatic shedding was detected in women receiving aciclovir33. Recent guidance advises that prophylactic aciclovir be offered to women who would opt for cesarean section in the event of a clinical recurrence at labour30,33. ­Following vaginal delivery in the presence of active herpetic lesions, samples may be collected from the neonate to facilitate early identification of herpes simplex exposure, and parents advised to report any early signs of infection.

found to be at risk of contracting primary HSV-2 infection from their HSV-2-positive partners. The risk was unsuspected in over half these women as their partners had no history of genital herpes36. One woman seroconverted during pregnancy. The cost:benefit ratio of this approach has been the subject of considerable debate35,37. In the meantime, pregnant women and their partners should be asked whether either has a history of genital herpes. Where a woman has no history but her partner does, the couple should be warned to avoid sexual intercourse at the time of any recurrences. The use of condoms throughout pregnancy should be advised to minimize the risk of infection30. Clear, tactful explanations about genital herpes, the risk of acquisition of infection, and possible consequent adverse outcome of pregnancy should be given.

Human papillomavirus HPV is the cause of genital warts (condylomata acuminata) (Figure 12.11), and types 16, 18, and other high-risk types are linked etiologically with cervical carcinoma. There is no known association between HPV and any adverse outcome of pregnancy, but perinatal transmission of HPV types 6 and 11 has been implicated in juvenile laryngeal papillomatosis38. Given the rarity of this condition and the high prevalence of asymptomatic HPV infection, cesarean section has not been advocated in women with genital warts. Although recent ­ evidence suggests that high-risk types are

Prevention of genital HSV acquisition during pregnancy Routine antenatal type-specific HSV antibody testing has been advocated as a means of preventing neonatal herpes35. In a prospective study of 190 pregnant women, in which samples were also available from their partners, 18 (9.5%) were

Figure 12.11  Genital warts. Florid condylomata acuminata occupying the perineum.

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often transmitted vertically, no adverse consequences have yet been observed39. Most genital HPV infection is asymptomatic but genital warts are said to grow more rapidly in pregnancy, when they may become florid or hemorrhagic. Rarely, they may cause obstruction sufficient to warrant delivery by cesarean section. A variety of approaches are currently available for the treatment of genital warts. With the exception of imiquimod, an immune response modifier that should not be used in pregnancy, all share tissue destruction as their mode of action. Podophyllin may be teratogenic and is contraindicated throughout pregnancy, but topical therapy with trichloroacetic acid (90%) may be used safely. Other approaches suitable for use in pregnancy include cryotherapy, laser, and other surgical methods. Recurrence of warts after treatment remains a problem. The antiviral agent cidofovir in topical formulation holds promise for the treatment of warts in the future.

Pregnancy and leprosy There is a paucity of contemporary data on leprosy and pregnancy; Lockwood and Sinha40 have recently reviewed all published data on leprosy and pregnancy. Most studies were done in the days before multidrug therapy, with inappropriate controls, and are difficult to interpret. Pregnancy results in depression of cell-mediated immunity by the fetoplacental unit; thus, theoretically, the pregnant patient with leprosy may be at risk of new disease, relapse, and reactions. An Ethiopian study41 of 120 pregnancies in 154 patients suggested that reactivation of leprosy does occur during pregnancy, whereas a Venezuelan42 study of 54 pregnancies did not find this, and data from large field studies do not show an excess of pregnant women amongst newly diagnosed patients.

Reactions There is a clear temporal association between parturition and the development of type 1 reactions, when cell-mediated immunity returns to prepregnancy levels. In the Ethiopian study, 60% of type 1 reactions occurred during the ­postpartum

and lactation phase, with 42% of pregnancies in patients with borderline lepromatous leprosy being complicated by a type 1 reaction41. In the same cohort, patients with lepromatous leprosy experienced erythema nodosum leprosum reactions throughout pregnancy and lactation42,43. Erythema nodosum leprosum in pregnancy is associated with early loss of nerve function, compared with nonpregnant individuals. Neuritis is an important complication of pregnancy and parturition, as significant numbers of women may develop nerve damage associated with pregnancy and lactation. Thus, pregnant and newly delivered women should have regular neurologic examination. Without appropriate treatment, the patient risks developing nerve damage and disability.

Management Multidrug therapy of rifampin, dapsone, and clofazimine is safe during pregnancy. Clofazimine crosses the placenta, and babies may be born with mild clofazimine pigmentation. Leprosy reactions should be treated with prednisolone, 40–60 mg daily for 2 weeks, followed by a steady reduction in dose. Thalidomide is totally contraindicated in woman planning pregnancy, because it is teratogenic. Whenever possible, before they become pregnant, patients should be told that there is a significant risk that their condition will deteriorate after delivery. Ideally, pregnancies should be planned when leprosy is well controlled.

References   1. Remington, J. S., Klein, J. O., Bakar, C., and Wilson, C. B. Infectious Diseases of the Fetus and the Newborn Infant, 6th edn. W. B. Saunders Company, Philadelphia, 2006.   2. Breuer J. Varicella zoster. In Zuckerman, A. J., Banatvala, J. E., Pattison, J. R., Griffiths, P. D., and Schoub, B. D. (eds) Principles and Practice of Clinical Virology, 5th edn, pp. 53–83. John Wiley & Sons, Ltd., Chichester, 2004.   3. Best, J. M. and Banatvala, J. E. Rubella. In Zuckerman, A. J., Banatvala, J. E., Pattison, J. R., Griffiths, P. D., and Schoub, B. D. (eds) Principles and Practice of Clinical Virology, 5th edn, pp. 427–457. John Wiley & Sons, Ltd., Chichester, 2004.   4. Brown, K. E. Human parvoviruses. In Zuckerman, A. J., Banatvala, J. E., Pattison, J. R., Griffiths, P. D., and Schoub, B. D. (eds) Principles and Practice of Clinical Virology, 5th edn, pp. 703–720. John Wiley & Sons, Ltd., Chichester, 2004.   5. Minor, P. D., and Muir, P. Enteroviruses. In Zuckerman, A. J., Banatvala, J. E., Pattison, J. R., Griffiths, P. D., and Schoub, B. D. (eds) Principles and Practice of Clinical Virology, 5th edn, pp. 467–489. John Wiley Wiley & Sons, Ltd., Chichester, 2004.

References   6. Enders, G., Miller, E., Cradock-Watson, J., et al. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet. 1994; 343: 1548–1551.   7. Miller, E., Cradock-Watson, J. E., and Ridehalgh, M. K. S. Outcome in newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet. 1989; ii: 371–373.   8. Miller, E., Fairley, C. K., Cohen, B. J., et al. Immediate and long term outcome of human parvovirus B19 infection in pregnancy. Br. J. Obstet. Gynaecol. 1998; 105: 174–176.   9. Fairley, C. K., Smoleniec, J. S., Caul, O. E., et al. Observational study of effect of intrauterine transfusions on outcome of fetal hydrops after parvovirus B19 infection. Br. Med. J. 1995; 346: 1335–1337. 10. Modlin, J. F. Echovirus infections of newborn infants. Pediatr. Infect. Dis. J. 1988; 7: 311–312.   11. Banatvala, J. E. Rubella – could do better?. Lancet. 1998; 351: 849–850. 12. Calista, D., Morri, M., Stagno, A., et al. Changing morbidity of cutaneous diseases in patients with HIV after the introduction of highly active antiretroviral therapy including a protease inhibitor. Am. J. Clin. Dermatol. 2002; 3: 59–62. 13. European Mode of Delivery Collaboration Elective caesarean­section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet. 1999; 353: 1035–1039. 14. Ellis, E. and Scheinfeld, N. Eosinophilic pustular folliculitis: A comprehensive review of treatment options. Am. J. Clin. Dermatol. 2004; 5: 189–197. 15. Aftergut, K. and Cockerell, C. J. Update on the cutaneous manifestations of HIV infection. Dermatol. Clin. 1999; 17: 445–471. 16. Arvin, A. M. and Whitley, R. J. Herpes simplex virus infections. In Remington, J. S. and Klein, J. O. (eds) Infectious Diseases of the Fetus and Newborn Infant, 5th edn, pp. 425–546. W. B. Saunders Company, Philadelphia, 2001. 17. Drake, S., Taylor, S., Brown, D., et al. Improving the care of patients with genital herpes. Br. Med. J. 2000; 321: 619–623. 18. Langenberg, A. G. M., Corey, L., Ashley, R. L., et al. A prospective study of new infections with herpes simplex virus type 1 and type 2. N. Engl. J. Med. 1999; 341: 1432–1438. 19. Fleming, D. T., McQuillan, G. M., Johnson, R. E., et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N. Engl. J. Med. 1997; 337: 1105–1111. 20. American College of Obstetricians and Gynecologists Management of herpes in pregnancy. Clinical management guidelines for obstetrician-gynecologists. Int. J. Gynaecol. Obstet. 2000; 68: 165–173. 21. Benedetti, J., Corey, L. and Ashley, R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann. Intern. Med. 1994; 121: 847–854. 22. Wald, A., Zeh, J., Selke, S., et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 2000; 342: 844–850. 23. Wald, A., Zeh, J., Barnum, G., et al. Suppression of subclinical shedding of herpes simplex virus type 2 with aciclovir. Ann. Intern. Med. 1996; 124: 8–15. 24. Stone, K. M., Brooks, C. A., Guinan, M. E., et al. National surveillance for neonatal herpes simplex virus infections. Sex. Transm. Dis. 1989; 16: 152–156. 25. Koskiniemi, M., Happonen, J. -M., Järvenpää, A. -L., et al. Neonatal herpes simplex virus infection: a report of 43 patients. Pediatr. Infect. Dis. J. 1989; 8: 30–35. 26. Whitley, R. J., Corey, L., Arvin, A., et al. Changing presentation of herpes simplex virus infection in neonates. J. Infect. Dis. 1988; 158: 109–116.

27. Prober, C. G., Sullender, W. M., Yasukawa, L. L., et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N. Engl. J. Med. 1987; 316: 240–244. 28. Brown, Z. A., Benedetti, J., Ashley, R., et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N. Engl. J. Med. 1991; 324: 1247–1252. 29. Brown, Z. A., Selke, S., Zeh, J., et al. The acquisition of herpes simplex virus during pregnancy. N. Engl. J. Med. 1997; 337: 509–515. 30. Low-Beer, N.M. and Kinghorn, G.R. on behalf of the Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists. Green-top Guideline No. 30. Management of genital herpes in pregnancy. Royal College of Obstetrics and Gynaecologists, London, September 2007. http://www.rcog.org.uk/resources/Public/pdf/ greentop30_genital_herpes0907.pdf (accessed 28 April 2008) 31. Centers for Disease Control Pregnancy outcomes following systemic prenatal aciclovir exposure – June 1, 1984–June 30, 1993. MMWR. Morb. Mortal. Wkly. Rep. 1993; 42: 806–809. 32. Frenkel, L. M., Brown, Z. A., Bryson, Y. J., et al. Pharmacokinetics of aciclovir in the term human pregnancy and neonate. Am. J. Obstet. Gynecol. 1991; 164: 569–576. 33. Brocklehurst, P., Kinghorn, G., Carney, O., et al. A randomised placebo controlled trial of suppressive aciclovir in late pregnancy in women with recurrent genital herpes infection. Br. J. Obstet. Gynaecol. 1998; 105: 275–280. 34. Van Everdingen, J. J., Peeters, M. F. and ten Have, P. Neonatal herpes policy in The Netherlands. Five years after a consensus conference. J. Perinat. Med. 1993; 21: 371–375. 35. Brown, Z. A. HSV-2 specific serology should be offered routinely to antenatal patients. Rev. Med. Virol. 2000; 10: 141–144. 36. Kulhanjian, J. A., Soroush, V., Au, D. S., et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N. Engl. J. Med. 1992; 326: 916–920. 37. Wilkinson, D., Barton, S. and Cowan, F. HSV-2 specific serology should not be offered routinely to antenatal patients. Rev. Med. Virol. 2000; 10: 145–153. 38. Arvin, A. M. and Maldonado, Y. A. Other viral infections of the fetus and newborn (human papillomavirus (condyloma acuminatum), Epstein-Barr virus, human herpesvirus 6, influenza A and B, respiratory syncytial virus, lymphocytic choriomeningitis virus, molluscum contagiosum, rabies virus). In ­Remington, J. S. and Klein, J. O. (eds) Infectious Diseases of the Fetus and Newborn Infant, 5th edn, pp. 855–866. W. B. Saunders Company, Philadelphia, 2001. 39. Mant, C., Cason, J., Rice, P., et al. Non-sexual transmission of cervical cancer-associated papillomaviruses: an update. Papillomavirus Rep. 2000; 11: 1–5. 40. Lockwood, D. N. J. and Sinha, H. H. Pregnancy and leprosy: a comprehensive literature review. Int. J. Lepr. 1999; 67: 6–12. 41. Duncan, M. E., Melsom, R., Pearson, J. M., et al. The association of pregnancy and leprosy I; new cases, relapse of cured patients and deterioration in patients on treatment during pregnancy and lactation – results of a prospective study of 154 pregnancies in 147 Ethiopian women. Lepr. Rev. 1981; 52: 245–262. 42. Ulrich, M., Zulueta, A. M., Caceres-Dittmar, G., et al. Leprosy in women: characteristics and repercussions. Soc. Sci. Med. 1993; 37: 445–456. 43. Duncan, M. E. and Pearson, J. M. H. The association of pregnancy and leprosy III, erythema nodosum leprosum. Lepr. Rev. 1984; 55: 129.

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PART: iI  Gynecologic Dermatology

CHAPTER 13

Vulvar Anatomy Hope Haefner

Introduction The vulva is the area of the female body located between the genitocrural folds laterally, the mons pubis anteriorly, and the anus posteriorly. The internal border of the vulva is represented by the hymeneal ring. The vulva has a variety of appearances, dependent on the age and ethnicity of the patient.

Embryology The urogenital and alimentary systems share a common reservoir, the cloaca, until 5 weeks’ gestation. This is derived from the caudal region of the hindgut (Figure 13.1), and is separated from the surface by the cloacal membrane. Between 5 and 7 weeks’ gestation, the mesoderm migrates distally to become the urogenital septum, dividing the cloaca into the larger urogenital sinus and the anorectal canal. The septum eventually fuses with the cloacal membrane to produce the anal membrane and the urogenital membrane, with the genital tubercle superiorly (Figure 13.2). The close embryologic derivation of the vulva and anus is reflected in the common blood supply and nerve supply of these areas, and the numerous dermatologic conditions that affect both organs in a similar manner. By about 7 weeks, the cloacal membrane is divided into a urogenital membrane and an anal membrane (Figure 13.3), with an anterior genital tubercle, two symmetric genital folds, and two genital swellings. At 8–9 weeks’ gestation, if testes are present, Leydig cells begin producing testosterone. If the target cells in the external genitalia contain the enzyme 5-alpha-reductase, testosterone is converted into dihydrotestosterone, and by 10 weeks’ gestation, male structures develop. If no testosterone is produced, or the reductase enzyme is not found in the epithelial cells, a vulva develops1. The entire conversion to female structures is completed by 20 weeks’ gestational age. The hymen is a remnant of the urogenital membrane. Several variations in the embryologic development of the hymen may occur and

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Allantoic diverticulum

Hindgut S2

Pelvic splanchnic nerve

S3 S4

Cloaca

Pudendal nerve

Cloacal membrane

Figure 13.1  The cloaca at about 5 weeks of intrauterine life.

Urachus

Urorectal septum

S2 S3 S4

Urogenital sinus Anorectal canal

The normal vulva

Genital tubercle Urogenital membrane

Perineal body

Anal membrane

Figure 13.2  The cloaca after the seventh week of intrauterine life.

a

b

result in microperforations, fenestrations, bands, septa, and differences in rigidity and/or elasticity of the tissue. There are various types of hymeneal perforations. In rare cases, the hymen may be imperforate, causing the retention of menstrual blood behind it and giving rise to a hematocolpos (Figure 13.4). The secondary sex characteristics appear earlier in the male fetus than in the female fetus, probably reflecting the earlier functional activity in the testis. The Y chromosome induces the gonad to become a testis in the genetically male fetus. The differentiation of the external genitalia in the female occurs because this male-determining effect is not present. Androgen contact with the epithelium at this time results in an androgenic influence on the external genitalia. Reasons for androgenization in the female include drug or exogenous hormone intake, placental aromatase deficiency, maternal androgenic tumors, and congenital adrenal hyperplasia. The end result is female pseudohermaphrodite with ambiguous genital development1.

The vulva contains the following structures that form the female external genitalia (Figures 13.5 and 13.6), including: • Mons pubis • Labium majus

c

Genital tubercle

Figure 13.3  Stages in the development of external ­genitalia in the female: (a) at 5 weeks; (b) at 7 weeks; (c) at 12 weeks.

Clitoris

Genital fold (labium minus)

Genital tubercle

Genital swelling (labium majus)

Cloacal membrane

Urogenital groove

Urogenital membrane

Perineal body Anal membrane Anus

Embryology

• Interlabial sulcus • Labium minus • Prepuce of the clitoris (clitoral hood) • Frenulum of the clitoris • Clitoris • Vestibule • Bartholin (greater vestibular) gland and duct • Vestibular gland and duct • Urethral orifice • Skene gland and duct • Posterior fourchette • Fossa navicularis • Perineal body (perineum) • Anus

Labia majora The labia majora correspond to the scrotum in the male, and form two thick folds of skin lateral to the labia minora. They consist of adipose and fibrous tissue. Anteriorly, the labia minora fuse to form the mons pubis overlying the pubic bone; posteriorly, they blend into the perineal skin. On

It is important to understand the anatomy of the vulva and to appreciate pathologic abnormalities that occur in the various locations of the vulva. Table 13.1 outlines some of the various pathologic abnormalities that may occur at the corresponding anatomic locations of the vulva.

Mons pubis The mons pubis overlies the symphysis pubis. It is covered with pubic hair. Hair growth begins at puberty and the amount of hair reaches that of an adult by late adolescence. Hair distribution over the vulva is shaped like an inverted triangle, with the base located at the upper mons pubis. The amount of pubic hair decreases after menopause. The underlying tissue of the mons pubis is composed primarily of adipose tissue.

Figure 13.4  Imperforate hymen resulting in the accumulation of menstrual blood.

Figure 13.5  Schematic diagram of the vulva (© 2007 Dawn Danby and Paul Waggoner).

Figure 13.6  Schematic diagram of the vulva (© 2007 Dawn Danby and Paul Waggoner).

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Table 13.1  Anatomic Locations with Site-Specific ­Corresponding Conditions Mons pubis

Pediculosis pubis

Urethral orifice

Skene duct cyst Prolapse Caruncle Diverticulum

Labium majus

Syringoma

Interlabial sulcus

Papillary hidradenoma

Labium minus

Lichen sclerosus Labial hypertrophy Labial agglutination

Bartholin gland orifice and duct

Bartholin’s cyst or abscess

Vestibule

Vestibulodynia Mucous cyst

Hymen

Imperforate hymen

Anus

Condylomata acuminata Preinvasive or invasive vulvar conditions

Perineum

Obstetrical injuries

Genitocrural folds

Yeast infections Intertrigo

Clitoris

Hypertrophy

Prepuce

Abscess

histology, a stratified squamous epithelium is noted. The labia majora contain numerous hair follicles, as well as apocrine, eccrine, and sebaceous glands. The apocrine glands (scent glands) are tubular structures which pass through a full cycle of secretory stages (low cuboidal to secretory, then back to low cuboidal). The eccrine glands (sweat glands) contain cells which secrete and change minimally during the conversion process. The eccrine glands have smaller lumina than apocrine glands. Sweat glands are functional throughout life. The sebaceous glands are alveolar holocrine glands. They do not contain lumina.

Interlabial sulcus The interlabial sulcus is the area between the labium majus and the labium minus.

Labia minora The labia minora are two portions of skin, which lie medial to the labia majora. The lateral portions of the inner labia minora contain tiny sebaceous glands, which are seen as small yellow-white, slightly elevated, smooth areas (Fordyce spots) when the skin is stretched (Figure 13.7). The labia minora are devoid of hair follicles and adipose tissue. The labia minora are hyperpigmented in the adult and may vary considerably in size.

Prepuce and frenulum of the clitoris Anteriorly, each labium minus is divided into two parts. One part passes over the clitoris, forming the prepuce (foreskin). The other part joins beneath the clitoris, forming the frenulum. Posteriorly, the labia minora form a lip of skin known as the fourchette.

Clitoris The clitoris includes the erectile bodies (paired bulbs and paired corpora, which are continuous with the crura) and the glans clitoris2. The clitoris becomes engorged and highly sensitive during sexual activity. Traditionally it was believed to be innervated by the pudendal nerve; however, there are branches of the ilioinguinal and genitofemoral nerves which lie close to the clitoris and most likely are involved with clitoral sensation, too. Histologic evaluation of clitoral tissue reveals erectile tissue and venous channels that are surrounded by smooth muscle. The anatomy of the clitoris has been studied using unenhanced magnetic resonance imaging (MRI)3,4. In the study by O’Connell and DeLancey3, clitoral anatomy was shown most clearly in the axial plane. The sagittal and coronal planes are complementary to the axial plane. The bulbs of the clitoris are not well described in anatomical textbooks. MRI clearly shows the extensive relationship between the urethra and bulbs, and also reveals how these structures are intimately related to the crura and corpora forming the root of the clitoris. The exact role that the bulbs play in urethral support and sexual function is unclear. In some cases the clitoris

Embryology 127

Figure 13.7  Fordyce spots.

Hart’s line

Hymen

Figure 13.9  Separation of the labia minora reveals the vestibule. The vestibule is the area between Hart’s line and the hymen.

Figure 13.8  Clitoromegaly.

can become anatomically enlarged. Clitoromegaly is demonstrated in Figure 13.8.

Vestibule The vestibule extends from the clitoral frenula to the posterior commissure and laterally to Hart’s line. Hart’s line is where the nonkeratinized transitional

epithelium of the vestibule joins the keratinized surface of the labia minora (Figure 13.9). The urethra (anteriorly), the ducts of Skene glands (lateral to the urethra), the ducts of Bartholin glands (posterolaterally), and the vestibular ducts open into the vestibule. The minor vestibular duct openings are located in a semicircular area between Hart’s line and the hymen. The number of minor vestibular glands varies from 1 to 100, but usually averages between 2 and 10 in examined vestibulectomy specimens1. Micropapillomatosis (Vestibular Papillae)

Smooth, finger-like projections on the vestibule are known by several names, including micropapillomatosis, vestibular papillae, vulvar squamous papillomatosis, and micropapillomatosis labialis. Figure 13.10 shows the classic appearance of this normal vulvar variation. At times this condition

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Vulvar Anatomy

128

Figure 13.10  Micropapillomatosis of the vestibule.

has been confused with condylomata acuminata. One way to differentiate micropapillomatosis from condyloma is that micropapillomatosis has a single projection from a single base whereas condyloma tends to have a broad base with several projections coming off the base.

Bartholin duct openings The Bartholin duct openings are located at the posterior base of each bulb, about two-thirds of the way down the lateral wall (at approximately the 5:00 and 7:00 positions of the vestibule). The ducts are attached to the mucus-secreting Bartholin glands. The glands contain columnar epithelium. The ducts are found to have transitional epithelium, whereas the openings of the ducts contain squamous epithelium. The Bartholin ducts are generally not palpated; however they may become blocked, resulting in a cyst or abscess.

Urethra The urethra lies between the clitoris and the vagina, measuring 3–5.5 cm in length. The diameter of the undilated urethra is about 6 mm. It extends from the external orifice to the neck of the bladder. It has everted edges. The epithelial lining of the female urethra varies depending on the location. The distal two-thirds are composed of stratified squamous epithelium, while the proximal onethird is composed of transitional cells.

Skene duct openings The ducts adjacent to the urethra (paraurethral ducts) are the Skene ducts. They extend cephalad, dividing into many smaller branches which

Figure 13.11  Repair of episiotomy. (Reproduced from E. M. Symonds and M. B. A. Macpherson Color Atlas of Obstetrics and Gynaecology (Fig. 10.1), Mosby-Wolfe, London, 1994.)

terminate in the lateral and inferior urethral walls.

Posterior fourchette Posteriorly, the labia minora blend with the labia minora, forming the fourchette.

Fossa navicularis The fossa navicularis or posterior fossa is a depression in the lower part of the vestibule. It is surrounded anteriorly by the hymen, posteriorly by the fourchette, and laterally by the labia minora. The histology of the fossa navicularis contains squamous mucosa overlying a thick lamina propria of fibrous tissue and smooth muscle.

Perineal body The fibromuscular perineal body is formed from the common insertion of the superficial muscles of the perineal pouch. Both support the lower part of the vagina, dividing it from the anal canal. The perineal body is often the subject of trauma at delivery, as a result of tearing or episiotomy (Figure 13.11).

Blood supply

Dorsal artery of clitoris

Superficial external pudendal artery

Deep artery of clitoris

Figure 13.12  The blood and nerve supply of the vulva.

Femoral artery Deep external pudendal artery

Perineal artery

Artery of the bulb

Inferior rectal artery

Anus The opening of the rectum is the anus. It is important to examine the anus as part of the vulvar examination. Several conditions affecting other areas of the vulva can also affect the anus.

Blood supply Arteries The vulva is supplied by branches of the internal iliac and femoral arteries. The internal pudendal artery (Figure 13.12), a terminal branch of the internal iliac (hypogastric) artery, provides much of the blood supply to the vulva. Entering the buttock beneath the gluteus maximus muscle, it arches around the ischial spine, passes through the lesser sciatic notch, and approaches the perineum in the roof of the ischiorectal fossa, lying in company with the pudendal nerve in the pudendal (Alcock) canal. The named terminal branches, from posterior to anterior, are as follows: • The inferior rectal artery passes medially from the pudendal canal to supply the anal canal and sphincter • The perineal and transverse perineal branches pass anteromedially over the ischiorectal fossa,

Internal pudendal artery

and pierce the superficial perineal muscles to supply the anal and vaginal sphincters, anterior fibers of the levator ani muscle, and the skin of the perineal body and posterior labia • The artery to the vestibular bulb passes through the urogenital diaphragm to the bulb of the vestibule • The dorsal artery of the clitoris terminates in the glans of the clitoris whereas the deep artery of the clitoris supplies the crus There is also blood supply from the superficial and deep external pudendal arteries, which arise from the femoral artery.

Veins The internal pudendal vein drains the majority of the perineum. Some blood is drained by the deep dorsal vein of the clitoris and returns to the vesical plexus or by the external pudendal vein into the great saphenous vein5. There is also drainage to the internal pudendal plexus, which terminates in the internal pudendal vein. This latter vein drains into the internal iliac vein. The upper vaginal venous plexus joins the uterine and cervical vaginal veins that drain into the internal iliac veins. The external pudendal vein drains the labium majus and empties into the great saphenous vein.

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Pudendal nerve leaves the pelvis through the greater sciatic notch

Nerve behind ischial spine – anesthetized here in pudendal black Dorsal nerve of clitoris

Nerve enters canal by passing through lesser sciatic notch

Superficial inguinal lymph nodes

Para-aortic nodes

External iliac nodes

Deep inguinal (femoral) nodes Inferior rectal nerve

Perineal nerve

Figure 13.13  The nerve supply of the vulva.

Figure 13.14  Schematic diagram of the lymphatics of the vulva.

Nerve supply The major nerves of the vulva include the pudendal nerves, the genitofemoral nerves (L1 to L2), and ilioinguinal nerves (L2). The majority of the vulva is supplied by branches of the pudendal nerve (S3–S5). The course of the pudendal nerve and other vulvar nerves are illustrated in Figures 13.12 and 13.13. Over 40% of pudendal nerves have multiple trunks6,7. Recognized branches include: • The inferior rectal nerve, supplying the external anal sphincter and the perianal skin • The perineal nerve, divided into a superficial branch (supplying the skin over the perineal body) and a larger deep branch, supplying the levator ani muscle, the external sphincters, the vaginal muscles, and ultimately the erectile tissue of the bulb • The dorsal nerve of the clitoris courses just beneath the pubic arch, diverging laterally toward the puboischial ramus The nerves of the vulva communicate extensively and there is considerable overlap with the ilioinguinal nerve anteriorly, the posterior cutaneous nerve of the thigh centrally, and the anococcygeal nerve posteriorly.

Special sensory nerve endings, such as tactile corpuscles of Meissner, are abundant on the vulva, particularly in the labia minora and clitoris. Nonmyelinated nerve fibers support the sweat glands, blood vessels, and muscle fibers of the vulvar skin. Both myelinated and nonmyelinated sensory nerves are found within the dermis. The nonmyelinated fibers terminate just at or above the dermal–epidermal junction. They are primarily responsible for the sensations of itching and light pain, whereas the myelinated fibers transmit sensations of deep pain, pressure, and heat. The vulva, in common with the lower back, buttock, perineum, and anus (below the mucocutaneous junction), drains via superficial lymphatic channels to the superficial inguinal (groin) nodes. These lie just distal to the inguinal ligament on each side. From here, drainage occurs through the saphenous opening in the fascia lata femoris to the deep inguinal (femoral) nodes that lie in the femoral triangle (Figure 13.14). A constant feature is the medially placed Cloquet node, guarding the entrance to the femoral canal. Lymph channels then pass beneath the inguinal ligament to reach the external iliac nodes, and subsequently the common iliac nodes,

References

Superficial dissection

Symphysis pubis

Deeper dissection

Ischiocavernosus muscle

External urethral sphincter

Bulbocavernosus muscle

Vestibular bulb

Figure 13.15  Dissection of the perineum demonstrating the muscles of the vulva.

Deep transverse perineal muscle

Superficial transverse perineal muscle

Bartholin gland Perineal body

Ischial tuberosity

Levator ani muscle

Fat in ischiorectal fossa

Sacrotuberous ligament

Gluteus maximus muscle Coccyx

and then the para-aortic nodes. Drainage from the labia occurs predominantly to the ipsilateral inguinal nodes, whereas midline structures, the fourchette, and particularly the clitoris may drain bilaterally.

Muscles The vulva can be thought of as being composed of anterior and posterior triangles divided by a line connecting the two ischial tuberosities. The muscles are outlined in Figure 13.15. The bulbocavernosus muscles originate at the deep surface of the inferior margin of the pubic arch, then course posteriorly along the lateral surfaces of the vaginal introitus to insert in the central tendon of the perineum (perineal body) between the posterior vaginal fourchette and the anus. The vestibular bulbs become engorged during sexual arousal. The levator ani muscles are deep to the perineal membrane anteriorly, and form the deep margin of the posterior compartment. Surrounding the anus are superficial skin folds created by subcutaneous attachments of the extrinsic anal sphincter fibers8.

External anal sphincter

References 1. Anatomy and histology of the normal female lower genital tract. In Ferris, D.G., Cox, J.T., O’Connor, D.M., et al. (eds) Modern Colposcopy Textbook and Atlas, 2nd edn, Iowa: ­Kendall/Hunt Company; 2004. 2. O’Connell, H. E., Sanjeevan, K. V., and Hutson, J. M. Anatomy of the clitoris. J. Urol. 2005; 174: 1189–1195. 3. O’Connell, H. E. and DeLancey, J. O. L. Clitoral anatomy in nulliparous, healthy, premenopausal volunteers using unenhanced magnetic resonance imaging. J. Urol. 2005; 173: 2060–2063. 4. Puppo, V. Clitoral anatomy in nulliparous, healthy, premenopausal volunteers using unenhanced magnetic resonance imaging. J. Urol. 2006; 175: 790–791. 5. Netter, F. H. Atlas of Human Anatomy, 3rd edn. Icon Learning Systems, Teterboro, New Jersey, 2003. 6. Gruber, H., Kovacs, P., Piegger, J., et al. New, simple, ultrasoundguided infiltration of the pudendal nerve: topographic basics. Dis. Colon Rectum. 2001; 44: 1376–1380. 7. Mahakkanukrauh, P., Surin, P., and Vaidhayakarn, P. Anatomical study of the pudendal nerve adjacent to the sacrospinous ligament. Clin. Anat. 2005; 18: 200–205. 8. Metz, S. Vulvar–vaginal reconstruction. Available online at http://www.emedicine.com/med/topic3340.htm Jun 2006.

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PART: II  Gynecologic Dermatology

CHAPTER 14

Lichen Sclerosus Libby Edwards

Lichen sclerosus is the classic, pruritic, chronic dermatosis of the postmenopausal vulva.

Epidemiology and clinical manifestations Lichen sclerosus is recognized most often on the vulva of postmenopausal women, with prepubertal girls representing a significant minority. Lichen sclerosus is seen in all age groups, but it is often less symptomatic in premenopausal and postpubertal females who do not have the additive effect of an atrophic, hypoestrogenic vagina. Lichen sclerosus occurs very occasionally on the glans penis of men, and it occurs rarely as an isolated finding on extragenital skin in either gender. Lichen sclerosus is a common disease, reported in about 3% of incontinent women in a nursing-home environment1. Another survey discovered that 1.7% of women presenting to a gynecologist’s office were found to have lichen sclerosus2. In addition, a vulvar clinic in England found lichen sclerosus to be the most common disease evaluated and treated, occurring in 39% of those patients3. There is a slight familial tendency, but the risk for the development of lichen sclerosus in family members is not known. Itching is the most common presenting symptom of women with lichen sclerosus. Pruritus is frequently excruciating, and scratching often produces tearing and purpura because the affected skin is extremely fragile. The patient then experiences pain from the erosions, particularly with urination, sexual activity, or with attempted sexual activity. Pain with defecation due to fissured perianal lichen sclerosus, and resulting fecal retention and constipation are common, particularly in young girls. Classically, well-developed lichen sclerosus presents as sharply demarcated white plaques encompassing the modified mucous membranes of the vulva, perineal body, and perianal skin (Figure 14.1). Most often, lichen sclerosus begins around the clitoral hood but, despite prominent involvement of the perineal body and perianal skin, it does not generally affect the keratinized, hair-bearing labia majora

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Figure 14.1  Classic lichen sclerosus manifested by a white, sharply demarcated plaque encompassing the modified mucous membranes as well as the perineal body; the skin is shiny and crinkled with loss of the labia minora and partial agglutination of the clitoral hood.

(Figures 14.2 and 14.3). Distant extragenital disease has been reported in a minority of women. A series of 250 women examined in this author’s office showed 6% with extragenital disease of keratinized skin and no oral or vaginal lesions (abstract still in press; presented at XIX World Congress of International Society for the study of Vulvovaginal Disease, July 2007, Alaska). The most common locations for extragenital disease are upper arms, back, and chest (Figure 14.4). Lichen sclerosus usually, but not always, spares the mucous membrane of the vestibule, and it has been reported only rarely in the mouth4. There is only one report of vaginal lichen sclerosus5. Lesions of the mouth or the vagina suggest an alternative or additional diagnosis. Although many skin diseases present with white skin on moist mucous membranes or modified mucous membranes, the hallmark of lichen sclerosus is a characteristic texture change of the white plaques. Although the pathognomonic ­ texture

Figure 14.2  Lichen sclerosus preferentially affecting the periclitoral skin and the perineal body.

change is that of a crinkling or cellophane papertype appearance, some lesions exhibit a smooth, waxy surface, and others manifest nonspecific irregular, hyperkeratotic white skin ­(Figures 14.5– 14.7). Rubbing and scratching sometimes produce thickening of the skin (lichenification) and superimposed lichen simplex chronicus can obscure diagnostic texture changes of the lesions (Figure 14.8). Fragility is a hallmark of lichen sclerosus, manifested by purpura, erosions, and fissuring (Figures 14.9–14.12). Extragenital lesions show even more striking texture changes because of the dry nature of the skin. Sometimes, follicular plugging is visible in these lesions. Long-standing and severe disease is associated with resorption of vulvar architecture, with loss of the labia minora, and the clitoris is buried under the scarred clitoral hood (Figures 14.13 and 14.14). Sometimes, side-to-side anterior and/or posterior adhesions eventuate in narrowing of the introitus (Figure 14.15). Squamous cell carcinoma occurs in up to 5% of women with untreated lichen sclerosus (Figure 14.16)6. The primary risk factors for

Diagnosis and differential diagnosis 135

Figure 14.3  The periclitoral area is often the first area affected, and edema and smooth, shiny skin are early skin changes of lichen sclerosus.

Figure 14.4  The extragenital lichen sclerosus on this woman was on her upper back, and shows the crinkled texture and purpura typical for this disease.

the development of squamous cell carcinoma are elderly age of patients (probably an indication of longer duration of disease) and the presence of hyperkeratotic lesions (Figure 14.17)7. Lichen sclerosus is sometimes associated with patchy hyperpigmentation of the modified mucous membranes and vestibule (Figure 14.18). This ­pigment change ranges from mild, poorly demarcated, tan patches to wild, irregular, ­ variegate brown and black patches indistinguishable from malignant melanoma. Pigmentary changes are nearly always benign, but biopsy and follow-up are prudent, since case reports of atypical nevi and melanoma in the setting of lichen sclerosus suggest that there may be an association8–10. Also, benign pigmented lesions in the setting of vulvar lichen sclerosus sometimes appear atypical histologically, confounding the differentiation of benign from malignant11. Women with lichen sclerosus have an increased prevalence of hypothyroidism12, and many clinicians find that their lichen sclerosus patients appear

to be more likely to exhibit concomitant vitiligo or lichen planus, although data are scant13,14.

Diagnosis and differential diagnosis Lichen sclerosus can be confused with other white diseases of the vulva as well as other diseases that exhibit tendency to scar. Lichen simplex chronicus and lichen planus are diseases that sometimes present with white vulvar plaques, and lichen planus produces resorption of vulvar landmarks indistinguishable from lichen sclerosus. The presence of prominent vestibular erosions and the common occurrence of accompanying oral and vaginal lesions suggest the diagnosis of lichen planus. Vitiligo is often mistaken for lichen sclerosus, but this disease presents with depigmentation only, with no symptoms, texture change, scale, erosions, or evidence of rubbing or scratching. Genital warts and vulvar intraepithelial neoplasia 3 are sometimes white, but these are ­ usually well-formed papules that are less symmetrical

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Figure 14.5  This cellophane paper crinkling of perianal skin is nearly pathognomonic for lichen sclerosus.

than lichen sclerosus. Cicatricial pemphigoid and pemphigus vulgaris are erosive diseases that produce resorption of vulvar architecture that is indistinguishable from lichen sclerosus, but white color and texture change are usually absent or subtle. Although white plaques of the vulva are relatively common and nonspecific, and although scarring of the vulva that is identical to lichen sclerosus can occur with other diseases, the diagnosis of lichen sclerosus can often be made on the grounds of morphology. The characteristic crinkled or cellophane paper change, when present, is diagnostic, particularly in the setting of hypopigmentation and agglutination. When the diagnosis is not perfectly clear, a biopsy is indicated.

Laboratory findings and histology The classic histological changes of lichen sclerosus are most often found in areas of hypopigmentation and texture change. Lichen sclerosus of modified mucous membrane skin usually shows

Figure 14.6  Smooth, hypopigmented, nearly waxy skin also occurs in some women with lichen sclerosus, as has occurred on the medial labia majora of this patient.

­ yperkeratosis and thinning of the epidermis with h loss of rete pegs. Early disease shows a lichenoid infiltrate of mononuclear cells at the dermal– epidermal junction with hydropic degeneration of the basal cell layer. The diagnostic histologic hallmark of well-established lichen sclerosus is hyalinization of the upper dermis; a hazy, acellular substance reminiscent of gelatin (Figure 14.19). The histology of hyperpigmented patches shows one of two different entities. The first is postinflammatory hyperpigmentation, with increased melanin both in the basal cell layer and within macrophages in the upper dermis. The ­second histologic pattern is that of genital melanosis, also called genital lentiginosis. Genital melanosis displays elongation of the rete pegs with increased melanin in the basal cell layer. Neither lesion should show melanocytic atypia. Early and mild lichen sclerosus can be harder to identify histologically. Findings are subtle, and abnormalities occur first around adnexal

Pathogenesis 137

Figure 14.7  More long-standing disease is likely to manifest as hyperkeratotic or macerated skin. The perineal body is an area especially prone to thickened lichen sclerosus.

s­ tructures. These abnormalities typically show acanthosis and hyperkeratosis with hypergranulosis. Interfollicular epithelium sometimes shows acanthosis and areas of thickening of the basement membrane. The hyalinization of the dermis may be confined to the far upper dermis and may be accompanied by dilated vessels. The inflammatory response is variable, and dermal melanophages may be present. Because only some of these findings occur in each patient, and because they are generally focal and poorly developed, serial sections as well as periodic acid–Schiff staining may be required for identification15. Women with classic findings of lichen sclerosus may not require biopsy for diagnosis, but even these patients sometimes benefit from a diagnostic biopsy report in their records. Many women experience complete resolution of skin findings with therapy, and they or future physicians are prone to discontinue therapy inappropriately by mistakenly disbelieving the initial diagnosis.

Figure 14.8  Superimposed thickening and purpura from rubbing have occurred in this patient.

Otherwise, no other laboratory testing confirms this diagnosis, but patients should be evalu­ ated for hypothyroidism, which is very common. Screening for autoantibodies shows higher titers in both patients and family members than the background population16,17. Patients with lichen sclerosus and family members are also more likely to exhibit human leukocyte antigen (HLA) DQ717.

Pathogenesis The pathogenesis of lichen sclerosus is poorly understood but is probably multifactorial, including autoimmune, genetic, and environmental factors, and some have suggested an infectious cause as well. Autoimmune factors are indicated by several observations. First, the histology is similar to that of other autoimmune diseases, namely lupus erythematosus, lichen planus, and graft-versushost disease. Second, patients with lichen sclerosus are more likely to exhibit other ­autoimmune

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Figure 14.9  Purpura in the setting of white, crinkled skin is classic for lichen sclerosus.

Figure 14.10  Fissures are common in women with lichen sclerosus, especially within natural skin folds.

diseases, including thyroid disease, vitiligo, lichen planus, and graft-versus-host disease, and several studies have shown an increase in autoantibodies in both affected patients and in their families16–19. Autoantibodies directed against the extracellular matrix and against the basement membrane have been identified in women with lichen sclerosus, and

Figure 14.11  The thin, fragile skin of lichen sclerosus is more prone to inflammation, fissuring, erosion, and ­secondary infection as a result of minor irritants. This ­patient has a secondary staphylococcal skin infection.

may be pathogenic or may be ­epiphenomena20,21. Evidence for cell-mediated autoimmunity has been reported. Immunohistological evidence exists for immune dysfunction at all levels of the skin; CD4 and CD8-type lymphocytes are found in inflammatory infiltrates and there is HLA DR expression around keratinocytes, suggesting that keratinocytes might be involved in antigen presentation22. However, some studies show no evidence for cellular or humoral immunological abnormalities23,24. Clustering of lichen sclerosus in family members suggests genetic factors, and there is a fairly strong and well-known correlation of lichen sclerosus and the presence of HLA DQ717,18. More specific studies of HLA haplotypes show that HLA DR and DQ or some of their haplotypes are likely to confer risk for, or protection from, vulvar lichen sclerosus25. The fact that lichen sclerosus is most common in females, especially in prepubertal girls and

Therapy and prognosis 139

Figure 14.12  Irregular erosions in this patient with lichen sclerosus were produced by scratching.

postmenopausal women, indicates a likely role for hormones, and several studies show decreases in androgen receptors in vulvar skin affected with lichen sclerosus26. There have been reports of an association of lichen sclerosus with Borrelia bergdorferi in Europe, but not in the United States. Environmental factors probably play a role in the pathogenesis of lichen sclerosus. This disease is usually localized to the vulva, but has no predilection for other skin folds. Excision with grafting of extragenital skin regularly results in recurrence. One instance of lichen sclerosus of vulvar skin that was transplanted to the back resulted in resolution of the transplanted skin27. Lichen sclerosus exhibits the Koebner phenomenon, in which the disease is precipitated by local irritation or injury. Therefore, common irritants such as incontinence, infection such as candidiasis, irritant contact dermatitis due to overwashing, and sexual activity may help to precipitate and worsen the disease.

Figure 14.13  Agglutination of the labia minora and partial agglutination of the clitoral hood often occur in advanced lichen sclerosus.

Therapy and prognosis The treatment of lichen sclerosus is a topical ultrapotent corticosteroid. Although topical compounded 2% testosterone was once first-line therapy, double-blind, placebo-controlled trials have shown no significant benefit to testosterone. One trial reported substantial improvement in 66.6% of 58 patients receiving topical testosterone compared to 75% of patients using petrolatum, which was not statistically significant28. In contrast to clobetasol, even when symptoms improve, the basic color and texture of the skin are not changed by topical testosterone29. Also, immunohistologic abnormalities do not change with testosterone therapy29,30. A three-armed controlled and blinded study showed clear superiority of clobetasol over testosterone and vehicle (Figure 14.20)31. These studies were performed with Temovate brand clobetasol propionate. Other ultrapotent corticosteroids that can be substituted are

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Figure 14.14  Ongoing agglutination is clear on the ­anterior vulva of this woman with lichen sclerosus.

Figure 14.15  Anterior midline agglutination of the vulva has produced early narrowing of the introitus.

­ alobetasol (Ultravate), betamethasone dipropioh nate in optimized vehicle (Diprolene), and difluorasone diacetate (Psorcon). The ointment vehicle is preferred because the alcohols and preservatives in creams are often irritating and burn with application. This author, with no data to substantiate this opinion, finds that some forms of generic clobetasol are irritating to some patients, and preferentially prescribes Temovate ointment when women do not improve as expected. The corticosteroid is applied very sparingly to affected areas twice daily until the texture normalizes, which is generally 3–4 months, with the perineal body often clearing last. Symptoms generally clear quickly, but medication should not be administered according to symptoms, but rather according to the clinical appearance of the skin. As skin texture normalizes in different areas of the vulva, medication can be decreased to thrice weekly in those areas. Extragenital lichen sclerosus can be treated in the same fashion, but it responds less well to therapy.

Occasionally, patients do not respond to corticosteroid therapy or develop side-effects to corticosteroid therapy. These women sometimes benefit from a change to a calcineurin inhibitor32,33. Tacrolimus (Protopic) and pimecrolimus (Elidel) have been reported in multiple small series as useful for some patients with lichen sclerosus, and one large trial of 84 patients showed that 43% treated with tacrolimus cleared their lichen sclerosus, and 34% improved33. These medications have several advantages over corticosteroids: calcineurin inhibitors do not produce atrophy, steroid dermatitis, or steroid rosacea. These medications are used regularly twice daily and careful application is not important; a regular schedule and no need to use a mirror and light in application contribute to ease of use and compliance. Disadvantages include the irritating nature of tacrolimus, which often burns with application, and the slower onset of action. Lichen sclerosus is less likely to respond to tacrolimus and pimecrolimus than to ultrapotent corticosteroids, but those patients who do well

Therapy and prognosis 141

Figure 14.16  This 89-year-old woman with excruciatingly pruritic undiagnosed lichen sclerosus presented with this painful nodule, found to represent an invasive squamous cell carcinoma on biopsy.

Figure 14.17  Recalcitrant hyperkeratotic lichen sclerosus is the morphology most at risk for transformation into squamous cell carcinoma.

experience the same normalization of skin color. A final concern is the recent Food and Drug Administration warning regarding carcinogenesis. The prolonged use of systemic tacrolimus is known to predispose to lymphoreticular malignancies and

Figure 14.18  Patchy hyperpigmentation is very common in lichen sclerosus, most visible after therapy.

Figure 14.19  The hyalinized dermis of this biopsy is characteristic and pathognomonic of well-established lichen sclerosus; hyperkeratosis and the chronic inflammatory infiltrate are characteristic as well.

skin cancers, but there are no reports of topical calcineurin inhibitors associated with malignancy in those not already at risk. However, clinicians should remember that lichen sclerosus carries an increased risk of vulvar squamous cell carcinoma

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Figure 14.20a  Topical ultrapotent corticosteroids are extremely beneficial for lichen sclerosus; before therapy, these white plaques are typical for lichen sclerosus. Figure 14.20b  After therapy, the skin exhibits normal color and texture.

A

B

and there is a possibility that the caregiver could be held responsible in that event. Patients should be carefully educated in this regard. Historical therapies whose effects have never been confirmed with controlled trials, and whose use have generally been abandoned, include oral retinoids, potassium aminobenzoate, and topical estrogen and progesterone. Excision and grafting, carbon dioxide laser, and cryotherapy have also been used and abandoned. Newer suggested therapies based on case reports or small open series include calcipotriene, mid-potency corticosteroids, and oral antibiotics34,35. Ultraviolet (UV) light, both UVA1 and psoralens with UVA, have been tried, primarily for extragenital disease due to practicality and the risk of increasing the risk of genital squamous cell carcinoma36,37. Small series have suggested laser-mediated photodynamic therapy and focused ultrasound therapy as possible therapies, and there are case reports of the use of pulsed-dye laser38–40.

Special issues Estrogen deficiency Prepubertal girls and postmenopausal women not using estrogen replacement present the additional problem of estrogen deficiency and a superimposed second cause of atrophy, magnifying symptoms

and fragility. Postmenopausal women generally benefit from the use of estradiol (Estrace) cream, 1 g, inserted in the vagina three nights a week, but intravaginal estrogen creams are not appropriate for young girls.

Prepubertal girls Generally, ultrapotent topical corticosteroids are not indicated for children. However, ultrapotent topical corticosteroid ointments have been used successfully and safely for prepubertal vulvar lichen sclerosus. There is no evidence that topical estrogen or topical progesterone, previous ­standard therapies for girls, benefits lichen sclerosus beyond their moisturizing properties. The fragility that results in tearing and purpura is sometimes mistaken for sexual abuse. The careful clinician recognizes the white discoloration and the history of itching that indicate the correct diagnosis. However, the presence of lichen sclerosus does not exclude sexual abuse in children with other signs of mistreatment.

Eroded, excoriated, macerated skin Vulvar lichen sclerosus skin that exhibits erosions, excoriations, and maceration is likely to burn with the application of topical therapies, particularly creams, and the risk for secondary infection (especially candida) with the application of the

Special issues Figure 14.21a and b  Prepubertal girls, postmenopausal women without estrogen replacement, macerated skin, and hyperkeratotic skin are most likely to respond to topical corticosteroids with secondary infection and irritant dermatitis, as occurred in this child.

A

B

c­ ortico­steroid is increased (Figure 14.21). Those patients with extreme ­ irritation sometimes benefit from the addition of an oral antistaphylococcal/antistreptococcal antibiotic, bedtime sedation to prevent nighttime scratching, tepid tap-water soaks, and a bland emollient such as petrolatum as well as the initiation of a topical corticosteroid.

Hyperkeratotic lesions Hyperkeratotic lesions of lichen sclerosus occur most often in older women and in those with longstanding disease. Hyperkeratotic lesions respond less well to topical corticosteroids, partly because the thickness inhibits absorption, and sometimes because these lesions are progressing down the pathway towards malignant transformation, even though routine biopsies may show no evidence of dysplasia (Figure 14.22). Hyperkeratotic lesions (and erosions) unresponsive to an ultrapotent topical corticosteroid applied regularly for 1 month require biopsy. Those lesions which show no evidence of dysplasia can be treated with 0.1–0.5 mL of an intralesional corticosteroid such as triamcinolone acetonide ­ (Kenalog) 10 mg/mL, injected directly into the lesion. Alternatively, hyperkeratotic lesions have been reported to respond to topical tretinoin (Retin-A)41. Tretinoin cream 0.025% can be applied very, very sparingly to affected areas, but this agent is extremely irritating and usually poorly tolerated on the vulva. Keratotic lichen

Figure 14.22  Hyperkeratotic lesions of lichen sclerosus should be treated aggressively and biopsied when recalcitrant because of their tendency to evolve into squamous cell carcinoma.

sclerosus is sometimes resistant to the above treatments as well as to topical corticosteroids. These areas are often best managed by conservative excision, both because this may be the only successful therapy, and because recalcitrant ­ hyperkeratotic

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lesions may be malignant ­precursors, even in the absence of histologic dysplasia.

Compliance Some patients have difficulty remembering to use medication three times a week long-term and some women are not able to apply medication carefully due to obesity or infirmity. Young girls may not be capable of applying an ultrapotent corticosteroid in the appropriate amount and to the appropriate area. In these patients, clinicians may be tempted to try lower-potency corticosteroids. However, daily use of a safer, lower-potency topical corticosteroid does not generally control lichen sclerosus sufficiently, and side-effects of less-than-exact application may occur nonetheless. These patients sometimes benefit from twice-daily ongoing tacrolimus, which produces no atrophy. Without ongoing therapy, most patients experience recurrence, with a recent study quoting 84% of women manifesting recurrent disease42. Early information from this study suggests that ­treatment of lichen sclerosus minimizes the risk of secondary squamous cell carcinoma42. This is a logical, although not yet proven, assumption, since well-controlled lichen sclerosus generally does not progress to the keratotic lesions most often associated with malignancy. Most patients with lichen sclerosus experience rapid resolution of symptoms with the use of an ultrapotent topical corticosteroid, and return of normal color and texture to the skin over weeks to months of daily therapy. Except for one report, clinicians find that scarring is permanent. ­Gradual dilation or surgical release of adhesions that produce narrowing of the introitus benefit some people after the skin disease is well controlled. Elderly women, those at most risk for hyperkeratotic disease at presentation, tend to experience partial but not complete resolution of signs and symptoms. All women should be followed every 6–12 months for recurrence of disease, side-effects of therapy, and the occurrence of a secondary malignancy, but elderly women, those who do not experience complete clearing with corticosteroids, and women with hyperkeratotic lesions should be followed more frequently.

Lichen sclerosus See Table 14.1. Table 14.1  Lichen Sclerosus Diagnosis Clinical appearance White crinkled or waxy plaques Purpura and erosions common Resorption of labia minora and clitoral hood late Absence of oral and vaginal disease Confirmed on biopsy Differential Diagnosis Lichen simplex chronicus Lichen planus Vitiligo Flat genital warts Vulvar intraepithelial neoplasia/squamous cell ­carcinoma Management Ultrapotent corticosteroid such as clobetasol propionate .05% sparingly bid until texture normalized (2–4 months) Nighttime sedation initially to prevent scratching Treat and suppress infections, minimize irritants Monthly follow-up while on daily corticosteroid Thrice-weekly ultrapotent corticosteroid chronically When controlled, twice-yearly surveillance for ­recurrence, steroid side-effects, and squamous cell carcinoma

References   1. Leibovitz, A., Kaplun, V., Saposhnicov, N., et al. Vulvovaginal examinations in elderly nursing home women residents. Arch. Gerontol. Geriatr. 2000; 31: 1–4.   2. Goldstein, A. T., Marinoff, S. C., and Stodon, C. K. Prevalence of vulvar lichen sclerosus in a general gynecology practice. J. Reprod. Med. 2005; 50: 477–480.   3. Cheung, S. T., Gach, J. E., and Lewis, F. M. A retrospective study of the referral patterns to a vulval clinic: highlighting educational needs in this subspecialty. J. Obstet. Gynaecol. 2006; 26: 435–437.

Further reading   4. Mendonoca, E. F., Ribeiro-Rotta, R. F., Silva, M. A., et al. Lichen sclerosus atrophicus of the oral mucosa. J. Oral Pathol. Med. 2004; 33: 637–640.   5. Longinotti, M., Schieffer, Y. M. and Kaufman, R. H. Lichen sclerosus involving the vagina. Obstet. Gynecol. 2005; 106: 1217–1219.   6. Tasker, G. L. and Wojnarowska, F. Lichen sclerosus. Clin. Exp. Dermatol. 2003; 28: 128–133.   7. Jones, R. W., Sadler, L., Grant, S., et al. Clinically identifying women with vulvar lichen sclerosus at increased risk of squamous cell carcinoma: a case-controlled study. J. Reprod. Med. 2004; 49: 808–811.   8. Rosamilia, L. L., Schwartz, J. L., Lowe, L., et al. Vulvar melanoma in a 10-year-old girl in association with lichen sclerosus. J. Am. Acad. Dermatol. 2006; 54: S52–S53.   9. Hassanein, A. M., Mrstik, M. E., Hardt, N. S., et al. Malignant melanoma associated with lichen sclerosus in the vulva of a 10-year-old. Pediatr. Dermatol. 2004; 21: 473–476. 10. Carlson, J. A., Mu, X. C., Slominski, A., et al. Melanocytic proliferations associated with lichen sclerosus. Arch. Dermatol. 2002; 138: 77–87. 11. El Shabrawi-Caelen, L., Soyer, H. P., Schaepppi, H., et al. Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge. J. Am. Acad. Dermatol. 2004; 50: 690–694. 12. Birenbaum, D. L. and Young, R. C. High prevalence of thyroid disease in patients with lichen sclerosus. J. Reprod. Med. 2007; 52: 28–30. 13. Carli, P., De Magnis, A., Mannone, F., et al. Vulvar carcinoma associated with lichen sclerosus. Experience at the Florence, Italy, Vulvar Clinic. J. Reprod. Med. 2003; 48: 313–318. 14. Di Fede, O., Belfiore, P., and Cabibi, D. Unexpectedly high frequency of genital involvement in women with clinical and histological features of oral lichen planus. Acta Dermatol. Venereol. 2006; 86: 433–438. 15. Regauer, S., Liegl, B., and Reich, O. Early vulvar lichen sclerosus: a histopathological challenge, Histopathology, 2005; 47: 340–347. 16. Meyrick, R. H., Ridley, C. M., McGibbon, D. H., et al. Lichen sclerosus at atrophicus and autoimmunity – a study of 350 women. Br. J. Dermatol. 1988; 118: 41–46. 17. Powell, J., Wojnarowska, F., Winsey, S., et al. Lichen sclerosus premenarche: autoimmunity and immunogenetics. Br. J. Dermatol. 2000; 142: 481–484. 18. Aslanian, F. M., Marques, M. T., Matos, H. J., et al. HLA markers in familial lichen sclerosus. J. Dtsch Dermatol. Ges. 2006; 4: 842–847. 19. Shaffer, J. P., McNiff, J. M., Seropian, S., et al. Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft­versus-host disease: expanding the sclerodermoid spectrum. J. Am. Acad. Dermatol. 2005; 53: 591–601. 20. Howard, A., Dean, D., Cooper, S., et al. Circulating basement membrane zone antibodies are found in lichen sclerosus of the vulva. Australas. J. Dermatol. 2004; 45: 12–15. 21. Chan, I., Oyama, N., Neill, S. M., et al. Characterization of IgG autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Clin. Exp. Dermatol. 2004; 29: 499–504. 22. Farrell, A. M., Marion, P., Dean, D., et al. Lichen sclerosus: evidence that immunological changes occur at all levels of the skin. Br. J. Dermatol. 1999; 140: 1087–1092. 23. Scrimin, F., Rustja, S., Radillo, O. C., et al. Vulvar lichen sclerosus: an immunologic study. Obstet. Gynecol. 2000; 95: 147–150. 24. Foldes-Papp, Z., Reich, O., Demel, U., et al. Lack of specific immunological disease pattern in vulvar lichen sclerosus. Exp. Mol. Pathol. 2005; 79: 176–185. 25. Gao, X. H., Bardnardo, M. C., Winsey, S., et al. The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB 10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated

DRB10301/04/DQB10201/02/03 haplotype protects from vulva lichen sclerosus. J. Invest. Dermatol. 2005; 125: 895–899. 26. Clifton., M. M., Garner, I. B., Kohler, S., et al. Immunohistochemical evaluation of androgen receptors in genital and extragenital lichen sclerosus: evidence for loss of androgen receptors in lesional epidermis. J. Am. Acad. Dermatol. 1999; 41: 43–46. 27. Whimster, L. W. Personal communication. In Jeffcoate, T.N.A. The dermatology of the vulva. J. Obstet. Gynaecol. Commonw. 1962; 68: 888. 28. Sideri, M., Origoni, M., Spinaci, L., et al. Topical testosterone in the treatment of vulvar lichen sclerosus. Int. J. Gynaecol. Obstet. 1994; 46: 53–56. 29. Cattaneo, A., De Marco, A., Sonni, L., et al. [Clobetasol versus testosterone in the treatment of lichen sclerosus of the vulvar region.] Minerva Ginecol. 1992; 44: 567–571. 30. Carli, P., Bracco, G., Taddei, G., et al. Vulvar lichen sclerosus. Immunohistologic evaluation before and after therapy. J. ­Reprod. Med. 1994; 39: 110–114. 31. Bracco, G. L., Carli, P., Sonni, L., et al. Clinical and histologic effects of topical treatments of vulval lichen sclerosus. A critical evaluation. J. Reprod. Med. 1993; 38: 37–40. 32. Stritmatter, H. J., Hengge, U. R., and Blecken, S. R. Calcineurin antagonists in vulvar lichen sclerosus. Arch. Gynecol. Obstet. 2006; 274: 266–270. 33. Hengge, U. R., Krause, W., Hofmann, H., et al. Multicentre, phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br. J. Dermatol. 2006; 155: 1021–1029. 34. Ronger, S., Viallard, A. M., Meunier-Mure, F., et al. Oral ­calcitriol: a new therapeutic agent in cutaneous lichen sclerosis. J. Drugs Dermatol. 2003; 3: 23–28. 35. Cattaneo, A., De Magnis, A., Botti, E., et al. Topical mometasone furoate for vulvar lichen sclerosus. J. Reprod. Med. 2003; 48: 444–448. 36. Beattie, P. E., Dawe, R. S., Ferguson, J., et al. UVA1 therapy for genital lichen sclerosus. Clin. Exp. Dermatol. 2006; 31: 343–347. 37. Brenner, M., Herzinger, T., Berking, C., et al. Phototherapy and photochemotherapy of sclerosing skin diseases. Photodermatol. Photoimmunol. Photomed. 2005; 21: 157–165. 38. Alexiades-Amenakas, M. Laser-mediated photodynamic therapy. Clin. Dermatol. 2006; 24: 16–25. 39. Li, C., Bian, D., Chen, W., et al. Focused ultrasound therapy of vulvar dystrophies: a feasibility study. Obstet. Gynecol. 2004; 104: 915–921. 40. Greve, B., Hartschuh, W., and Raulin, C. [Extragenital lichen sclerosus and atrophicus-treatment with pulsed dye laser.] Hautarzt 1999; 50: 805–808. 41. Virgili, A., Corazza, M., Bianchi, A., et al. Open study of topical 0.025% tretinoin in the treatment of vulvar lichen sclerosus. One year of therapy. J. Reprod. Med. 1995; 40: 614–618. 42. Renaud-Vilmer, C., Cavelier-Balloy, B., Porcher, R., et al. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch. Dermatol. 2004; 140: 709–712.

Further reading Funaro, D. Lichen sclerosus; a review and practical approach. ­Dermatol. Ther. 2004; 17: 28–37. Powell, J. J. and Wojnarowska, F. Lichen sclerosus. Lancet 1999; 353: 1777–1783. Smith, Y. R. and Haefner, H. K. Vulvar lichen sclerosus: pathophysiology and treatment. Am. J. Clin. Dermatol. 2004; 5: 105–125.

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CHAPTER 15

Lichen Planus Libby Edwards Lichen planus is a relatively common disease that exhibits multiple morphologies, depending upon the location and severity.

Epidemiology and clinical manifestations Formerly believed to be very uncommon, vulvovaginal lichen planus is now either recognized much more often or has become more common. Lichen planus of any site occurs in about 1% of people, and approximately 57% of women with oral lichen planus exhibit vulvovaginal disease, which is often asymptomatic1,2. Vulvovaginal lichen planus occurs in several different morphologic forms and individual patients often present with several variants concomitantly (Table 15.1). These include erosive disease; white, reticulate lacy striae; sheets of white epithelium; and, on nonmucous membrane skin, red, or dusky red-brown papules. Most common on vulvovaginal skin is erosive lichen planus, which exhibits characteristic but nonspecific symptoms and signs. Patients generally report introital irritation, burning, superficial dyspareunia, and, sometimes, itching. About two-thirds of women with erosive genital lichen planus experience oral lichen planus usually associated­ with oral pain3. On physical examination, erosive lichen planus typically­ exhibits relatively well-demarcated vestibular erosions, with late disease manifested by scarring and resorption of normal landmarks (Figures 15.1– 15.3). Many women also experience erosions of the labia minora, Table 15.1  Usual Morphologic Variants of Vulvovaginal Lichen Planus Mucous membrane/modified mucous membrane disease   Erosions   White, reticulate, lacy striae   Solid white epithelium Keratinized cutaneous lichen planus   Dusky red, shiny, flat-topped papules

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Figure 15.1  This sharply demarcated erosion of the posterior fourchette with surrounding white epithelium is typical of erosive lichen planus.

Figure 15.2  Erosive lichen planus well localized to the vestibule, with surrounding, patchy, white epithelium, and narrowing of the introitus due to midline agglutination anteriorly.

medial labia majora, and any area of the modified mucous membranes (Figure 15.4). Agglutination of the labia minora is common, as are adhesions which bury the clitoris. Erosive disease sometimes produces midline fusion of the vestibule, with

Figure 15.3  Erosions and white striae (arrow) accompanied by generalized scarring and loss of labia minora, with the ­clitoris buried under the clitoral hood.

resultant narrowing of the ­introitus (Figure 15.5). Rectal involvement is common (Figure 15.6). Erosive vulvar lichen planus is usually accompanied by vaginal and oral lichen planus, the “vulvovaginal–gingival syndrome.” Erosive vaginal lichen planus presents as superficial vaginal erosions or deep vaginal redness. Vaginal secretions are grossly and microscopically purulent (Figure 15.7). The yellowish or green discharge microscopically shows multiple white cells (mostly neutrophils), parabasal and basal cells (immature epithelial cells) shed from the base of erosions, and a marked decrease in lactobacilli, leading to an alkaline pH. Just as vulvar lichen planus results in scarring, synechiae of the vagina sometimes occur, occasionally resulting in complete closure of the vagina. An examination of the mouth of a woman with erosive vulvovaginal lichen planus usually reveals white, lacy papules and striae and/or erosions on the posterior buccal mucosae (Figure 15.8). Often, women with erosive vulvovaginal lichen planus experience associated erosions and intense ­redness

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Figure 15.4  At times, lichen planus is more extensive, ­affecting all areas of the vulva and extending to hair­bearing skin.

of the gingivae (Figure 15.9). The tongue is sometimes involved, with white, hyperkeratotic surface epithelium and/or erosions (Figure 15.10). Esophageal erosive lichen planus is becoming more recognized and can produce strictures that interfere with swallowing4. Although vulvar lichen planus is most often accompanied by vaginal and oral disease, some women exhibit disease in only one or two of these three sites. Also, some patients experience involvement in additional areas, including the rectal mucosa and the esophagus. Like the vagina, esophageal adhesions and stenosis can occur. The extra-­auditory canals and nasal mucosa are uncommonly affected. Occasionally, women with erosive vulvovaginal disease experience extragenital lichen planus, with dusky red papules on keratinized skin, destruction of nails, or scalp involvement producing scarring alopecia. A second morphological presentation of vulvovaginal lichen planus is the classic, lacy, white

Figure 15.5  Erosions, white papules, and marked narrowing of the introitus are present in the patient with lichen planus.

epithelium (Figures 15.11 and 15.12). Although this classic mucosal lichen planus is much less common than erosive lichen planus, this form is pathognomonic for lichen planus. This manifestation is characterized by white striae, often forming fern-like or reticulate plaques. These distinctive plaques are frequently accompanied by vaginal lichen planus. Oral lichen planus occurs in this setting as well. Fairly often, mucosal vulvar lichen planus is characterized by a third morphology, that of uniformly white epithelium which often surrounds erosions (Figures 15.13 and 15.14). White lesions of lichen planus, whether fern-like or solid, are always located on mucous membrane or moist modified mucous membrane skin rather than on dry, keratinized skin. Women with white papules and plaques are most likely to experience itching.

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Figure 15.6  Perianal lichen planus is common,   and is ­morphologically similar to vulvar lichen planus.

Figure 15.8  Often, erosive vulvar lichen planus is accompanied by classic white, lacy striae of the buccal mucosae, sometimes accompanied by erosions.

Figure 15.7  This wet mount of vaginal secretions of a patient with vaginal lichen planus shows large numbers of immature, parabasal cells, a remarkable number of white blood cells, and a lack of lactobacilli.

Yet another morphology of lichen planus occurs on dry, keratinized skin, presenting as dusky red, flat-topped, shiny papules (Figure 15.15). Extragenital lichen planus can occur almost anywhere, although facial involvement is extraordinarily uncommon. Only about 3–5% of women with erosive vulvovaginal lichen planus experience ­nonmucous membrane disease.

Diagnosis and differential diagnosis The differential diagnosis of lichen planus depends upon the presenting morphology. Erosive lichen planus most closely resembles ­mucosal

blistering diseases, because the fragile blisters on mucosal surfaces erode as they form, leaving nonspecific erosions (Table 15.2). Diseases to be ruled out include cicatricial pemphigoid, pemphigus vulgaris, fixed drug eruption, and blistering forms of erythema multiforme (Stevens–Johnson syndrome and toxic epidermal necrolysis). Occasionally, herpes simplex virus (HSV) infection can resemble lichen planus, but erosions from HSV vesicles are usually clustered, small, and localized. These blistering diseases are differentiated by the onset, setting, presence of characteristic extragenital lesions, and, often, results of both routine and direct immunofluorescent biopsies. Plasma cell vulvitis (Zoon’s vulvitis, vulvitis plasmacellularis) is a vulvar skin disease that resembles erosive ­vulvar lichen planus, exhibiting deep red plaques that often appear erosive clinically, but reveal the correct diagnosis histologically. A lichenoid drug eruption is a peculiar reaction to any of several medications. This ­condition

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Figure 15.11  Although classic, well-formed white, lacy, reticulate striae are uncommon.

Figure 15.9  Gingival lichen planus can be manifested by well-demarcated erosions as in this patient, or diffuse beefy red gingivae, or by white striae.

Figure 15.12  Typical white striae can occur on perianal skin as well.

Figure 15.10  Women with erosive vulvar lichen planus sometimes experience concomitant lichen planus of the tongue, frequently manifested by diffuse white epithelium, often with irregular hyperkeratosis and erosions.

resembles lichen planus both clinically and histologically, and is sometimes indistinguishable from lichen planus. Discontinuation of the medication should, in that case, effect resolution of the disease.

The white, lacy papules of lichen planus are generally not confused with any other diseases, although mucosal lupus erythematosus can rarely show this morphology. A biopsy for routine histology and direct immunofluorescence can differentiate the two. Lichen planus manifested by solid white epithelium most often mimics lichen sclerosus and lichen simplex chronicus, although lichen sclerosus usually shows a distinctive crinkled texture. Both immunobullous diseases and lichen sclerosus sometimes produce agglutination of vulvar architecture that is indistinguishable from lichen ­planus; and both some blistering diseases, as well as lichen planus, can scar the vagina closed.

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Figure 15.14  These white plaques surrounding mucous membrane erosions are typical but not specific for lichen planus.

Figure 15.13  Lichen planus can exhibit white, generalized epithelium that mimics lichen sclerosus.

Laboratory and histology There are no pertinent laboratory abnormalities. The differentiation of lichen planus from other similar diseases is made on clinical grounds with correlation of morphology and setting, and the diagnosis is confirmed on biopsy. The biopsy should be performed from a white lesion, but when there is no white epithelium, the edge of an erosion should be sampled. The twisting of a punch instrument sometimes shears the fragile epithelium; a snip or shave biopsy usually minimizes mechanical damage (see Appendix 2). The presence of the epithelium is required for a histologic diagnosis of lichen planus. The different morphologies of lichen planus exhibit different histologic appearances. Erosive vulvar lichen planus is characterized by thinning of the epidermis, with loss of rete pegs. An upper

Figure 15.15  These erythematous, flat-topped papules of extragenital lichen planus generally do not accompany vulvar disease.

dermal mononuclear infiltrate abuts the epidermis and produces vacuolar degeneration of the basal cell layer. Scattered necrotic keratinocytes, called cytoid bodies, are characteristic. Hyperkeratosis and thickening of the granular cell layer are common (Figure 15.16). Thickened lichen planus shows, not thinning of the epithelium, but rather regular acanthosis and more impressive hyperkeratosis. Unfortunately, because lichenoid inflammation (an upper dermal mononuclear infiltrate with liquefaction degeneration of the basal cell layer) is a common inflammatory reaction on the vulva, biopsies are frequently characteristic but nondiagnostic. A biopsy negative for lichen planus does not rule out this diagnosis.

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Table 15.2  Lichen Planus Diagnosis Clinical appearance (some or all) Erosions White lacy papules Solid white papules or plaques Prominent scarring Presence of oral and vaginal lesions Confirmed on biopsy Differential diagnosis Bullous disease – cicatricial pemphigoid, pemphigus vulgaris, fixed drug eruption, toxic epidermal necrolysis, Stevens–Johnson syndrome

Figure 15.16  A biopsy of lichen planus shows a chronic inflammatory infiltrate in the upper dermis that abuts and damages the basal cell layer of the epidermis. The epidermis can be thickened with hyperkeratosis, as is seen here, or, as oftentimes occurs on mucous membranes, the epidermis can be thin.

Plasma cell vulvitis Lichenoid medication reaction Lichen sclerosus Lichen simplex chronicus

An association with hepatitis C has been reported by some, but other studies have not borne out this association5–7. Some clinical hepatologists maintain that severe lichen planus is more likely to show serologies showing hepatitis C infection.

Management Topical corticosteroids bid to vulva Hydrocortisone acetate suppository in vagina hs, then taper as possible Prevent and treat yeast with fluconazole when needed Systemic therapy includes hydroxychloroquine, ­methotrexate, azathioprine, mycophenolate mofitil, etanercept

Pathogenesis Lichen planus is generally believed to be a disease of cell-mediated autoimmunity. Several factors suggest this pathogenesis. First, the biopsy and clinical presentation of lichen planus are essentially identical to that of graft-versus-host disease, and lichen planus exhibits histologic similarities to other autoimmune diseases, such as lupus erythematosus and lichen sclerosus. Second, the primary useful therapies are immunosuppressive medications. Also, medications can induce lichen planus, suggesting a hyperimmune mechanism.

Therapy and prognosis As is true for all vulvar diseases, supportive care is important, especially in this disease that is sometimes difficult to control. Patient education regarding the chronic nature of lichen planus and management of patient expectations are crucial. Patients should be counseled that, except for firstline topical corticosteroids, individual therapy is trial and error, and time to improvement is slow. Patients should be counseled in the avoidance of irritants. Most common are the application of anticandidal creams and topical anesthetics such as benzocaine and diphenhydramine, and washing too frequently or with harsh soaps. Because this disease is most common in postmenopausal women, patients often experience superimposed epithelial thinning of an atrophic vagina. The addition of a topical estrogen intravaginally, such as 1 g estradiol cream three nights a week, minimizes discomfort and scar formation. Also, in order to minimize narrowing of the introitus and vaginal adhesions, a dilator should be inserted into the vagina daily if the patient is not sexually active.

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There are no studies that evaluate the therapies of lichen planus in any meaningful way, so that recommendations are based on small open series of patients and the personal impression of clinicians8. Specific therapy of lichen planus consists of immunosuppressive medications. First-line therapy is topical corticosteroids8. Papular lichen planus, which displays white epithelium, usually responds well to topical corticosteroids. Erosive lichen planus, however, can be much more difficult to control. Almost no well-designed clinical trials that evaluate therapies for vulvovaginal lichen planus have been reported. Although the mainstay of specific therapy for lichen planus is topical corticosteroids, lichen planus is only moderately steroid-responsive. Ultrapotent preparations are most effective and are well tolerated, including clobetasol propionate (Temovate), halobetasol propionate (Ultravate), diflorosone acetate (Psorcon), or betamethasone dipropionate in augmented vehicle (Diprolene). An ointment is preferred, particularly on eroded skin, since the alcohol and preservatives in cream vehicles can burn. The medication is applied sparingly twice daily. During initial daily application, patients should be monitored every 4–6 weeks to assess for improvement and for adverse reactions. When the disease is managed, the frequency of dosing can be tapered to the least frequent use that controls the process, often about three times a week. Treatment of the vagina is extremely important, both for patient comfort and to minimize the risk of vaginal adhesions. Corticosteroids are the treatment of choice for vaginal lichen planus as well as vulvar disease. No corticosteroid preparations are specifically formulated for use in the vagina. However, hydrocortisone acetate 25 mg rectal suppositories can be inserted in the vagina nightly9, or 1 g clobetasol or another potent topical corticosteroid ointment can be inserted into the vagina with an applicator. There is only trivial absorption of topical corticosteroids from the vulva, but corticosteroids are sometimes absorbed from the vaginal epithelium in significant amounts. When disease is adequately controlled, the frequency of dosing should be tapered from nightly to the least frequent dosing that controls the disease.

A cortisol stimulation test is useful to detect significant systemic absorption in those women requiring prolonged nightly ultrapotent corticosteroid instillation. The use of intravaginal corticosteroids, especially in the setting of topical vaginal estrogen, increases the risk of vulvovaginal candidiasis. Weekly oral fluconazole 150 mg until the disease is controlled minimizes that risk. Therapy of oral lichen planus is also important for the comfort of the patient, and the treatment of oral lichen planus is easily within the scope of the clinician who treats the vulva and vagina. Oral and gingival inflammation and erosions are painful and interfere with eating anything other than bland foods. In addition, gingival lichen planus predisposes to loss of teeth. An ultrapotent topical corticosteroid, with gel formulations often preferred by patients for the mouth, applied three or four times a day initially, sometimes effects very significant improvement. The use of topical corticosteroids applied under dental molds can be more effective. These are usually easily available from dentists who fashion these as a reservoir for chemicals to whiten teeth, and serve as a good delivery system when the edges of the molds that overlap the gingivae are not trimmed. Medication is applied to the gingiva and then the patient is instructed to sleep in the mold, preventing removal of the medication by saliva. The treatment of oral lichen planus with immunosuppressant medications sometimes results in oral candidiasis that is confused with flaring of lichen planus. Small, open-label, clinical series suggest that vulvovaginal lichen planus which does not adequately improve with topical corticosteroids sometimes responds well to topical tacrolimus 0.1% (Protopic)10,11. This calcineurin inhibitor is a nonsteroidal immune suppressant. Tacrolimus is irritating and frequently produces intolerable burning when applied to the vulva, although the application of compounded formulations rather than Protopic has anecdotally been said to be less uncomfortable for some patients (personal communication, Lynnette Margesson). A second limiting factor to the use of calcineurin inhibitors is a recent concern regarding carcinogenicity12. The chronic, systemic administration of tacrolimus

Therapy and prognosis

has been associated with lymphoma and nonmelanoma skin cancers, producing concern by some clinicians regarding its use in a disease that already predisposes to squamous cell carcinoma. Finally, the beneficial effects of tacrolimus in lichen planus are relatively slow in onset, requiring several weeks to effect improvement, and the effect appears to be more evident for oral than vulvovaginal disease. However, patients who can tolerate the application of tacrolimus and who understand that the risk of cancer using this medication is probably very low (probably less than the risk of squamous cell carcinoma occurring in uncontrolled lichen planus), this medication can be useful. Pimecrolimus (Elidel) is a similar medication, but with fewer reports than tacrolimus. Combination therapy in general, and topical calcineurin inhibitor and corticosteroids in particular, can be useful for some13. Topical cyclosporine has been reported to be useful for oral lichen planus and has been used for vulvovaginal disease14. Patients with more severe erosive lichen planus usually require systemic antimetabolites or immunosuppressive medications for maximal control of disease. The only predictably useful systemic treatment is corticosteroid therapy. Although chronic therapy is unsafe, a short trial of 40–60 mg each morning for 1–3 weeks sometimes reasonably effects healing so that topical therapies can be tolerated and perhaps maintain control. Hydroxychloroquine (Plaquenil) 200 mg bid has historically been used as one of the first-line systemic therapies for lichen planus, at least partly because of its ease of administration and monitoring15. Methotrexate at a dose of 15–25 mg each week has proven useful in some patients16. Other medications that have been reported anecdotally to be beneficial in case reports or in small series for lichen planus on some areas of the body include etanercept, infliximab, retinoids, mycophenolate mofetil, cyclosporine, cyclophosphamide, and azathioprine16–19. The use of multidrug therapy rather than monotherapy generally produces the best results in women with severe disease. There is also a report that extracorporeal photochemotherapy has been useful20. Lichen planus is a chronic disease which generally does not remit, although it clears in the occasional patient. The use of topical and, often,

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Figure 15.17  Chronic lichen planus has a definite premalignant potential; this woman exhibits white plaques of vulvar intraepithelial neoplasia 3.

systemic therapy usually controls discomfort on a day-to-day basis. However, lichen planus generally exhibits relative flares and remissions at least partly due to infections, stress, activities, irritants, and estrogen deficiency. With disease management, sexual activity becomes comfortable in some, but not all, patients. The occasional patient with vaginal synechiae will not, even after control of the disease, be intercourse-active. Surgery in these women can be performed to lyse adhesions of the vaginal canal, but restenosis is usual. Various techniques to maintain patency have been tried, including long-term placement of a vaginal mold, and the use of an acellular dermal graft21. Chronic erosions and thickened, hyperkeratotic areas are the lesions at highest risk for the development of a secondary squamous cell carcinoma both on the vulva and in the mouth (Figure 15.17). Therefore, chronic, nonhealing erosions, particularly those that are firm to palpation, and chronic hyperkeratotic nodules or plaques should

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be assessed regularly for the development of squamous cell carcinoma. Lichen planus-­associated squamous cell carcinoma has not yet been reported in the vagina. Chronic ulcers and keratotic lesions that do not clear promptly with topical or intralesional corticosteroids require biopsy diagnosis/removal. Patients should be regularly monitored for the development of squamous cell carcinoma, for side-effects of medications, and for scarring. Patients who are well controlled should be seen twice yearly, and those who are poorly managed should be seen more often. With aggressive care, most patients experience marked improvement but not complete clearing of erosive disease22.

References   1. Eisen, D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J. Am. Acad. Dermatol. 2002; 46: 207–214.   2. Belfiore, P., De Fede, O., Cabibi, D., et al. Prevalence of vulval lichen planus in a cohort of women with oral lichen planus: an interdisciplinary study. Br. J. Dermatol. 2006; 155: 994–998.   3. Kirtschig, G., Wakelin, S. H. and Wojnarowska, F. Mucosal vulval lichen planus: outcome, clinical and laboratory features. J. Eur. Acad. Dermatol. Venereol. 2005; 19: 301–307.   4. Shenfine, J. and Preston, S. R. Lichen planus in the eoesohagus: are we missing something? Eur. J. Gastroenterol. Hepatol. 2006; 18: 1043–1045.   5. Harman, M., Akdeniz, S., Dursun, M., et al. Lichen planus and hepatitis C virus infection: an epidemiologic study. Int. J. Clin. Pract. 2004; 58: 1118–1119.   6. Cooper, S. M., Kirtschig, G., Jeffery, K. J., et al. No association between hepatitis B or C viruses and vulval lichen planus in a UK population. Br. J. Obstet. Gynaecol. 2004; 111: 271–273.   7. Chainani-Wu, N., Lozada-Nur, F., and Terrault, N. Hepatitis C virus and lichen planus; a review. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2004; 98: 171–183.   8. Cribier, B., Frances, C. and Chosidow, O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch. Dermatol. 1998; 134: 1521–1530.   9. Anderson, M., Kutzner, S., and Kaufmanh, R. H. Treatment of vulvo-vaginal-lichen planus with vaginal hydrocortisone ­suppositories. Obstet. Gynecol. 2002; 100: 359. 10. Byrd, J. A., Davis, M. D., and Rogers, R. S., Recalcitrant symptomatic vulvar lichen planus: response to topical tacrolimus.3rd. Arch. Dermatol. 2004; 140: 715–720. 11. Kirtschig, G., Van Der Meulen, A. J., Ion Lipan, J. W., et al. Successful treatment of erosive vulvovaginal lichen planus with topical tacrolimus. Br. J. Dermatol. 2002; 147: 625–626.

12. Berger, T. G., Duvic, M., Van Voorhees, A. S., et al. The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J. Am. Acad. Dermatol. 2006; 54: 818–823. 13. Jensen, J. T., Bird, M. and Leclair, C. M. Patient satisfaction after the treatment of vulvovaginal erosive lichen planus with topical clobetasol and tacrolimus: a survey study. Am. J. Obstet. Gynecol. 2004; 190: 1759–1763. 14. Conrotto, D., Carbone, M., Carrozzo, M., et al. Ciclosporin vs. clobetasol in the topical management of atrophic and erosive oral lichen planus: a double-blind, placebo-controlled trial. Br. J. Dermatol. 2006; 154: 139–145. 15. Eisen, D. Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial. J. Am. Acad. Dermatol. 1993; 28: 609–612. 16. Nylander Lundqvist, E., Wahlin, Y. B., and Hofer, P. A. Methotrexate supplemented with steroid ointments for the treatment of severe erosive lichen ruber. Acta Dermatol. Venereol. 2002; 82: 63–64. 17. Lear, J. T. and English, J. S. Erosive and generalized lichen planus responsive to azathioprine. Clin. Exp. Dermatol. 1996; 21: 56–57. 18. Verma, K. K., Mittal, R. and Manchanda, Y. Azathioprine for the treatment of severe erosive oral and generalized lichen planus. Acta Dermatol. Venereol. 2001; 81: 378–379. 19. Frieling, U., Bonsmann, G., Schwartz, T., et al. Treatment of severe lichen planus with mycophenolate mofetil. J. Am. Acad. Dermatol. 2003; 49: 1063–1066. 20. Guyot, A. D., Farhi, D., Ingen-Housz-Oro, S., et al. Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases. Br. J. Dermatol. 2007; 156: 553–556. 21. Stany, M. P., Winter, W. E. Elkas, J. C., et al. The use of ­acellular dermal graft for vulvovaginal reconstruction in a patient with lichen planus. Obstet. Gynecol. 2005; 105: 1268–1271. 22. Cooper, S. M. and Wojnarowska, F. Influence of treatment of erosive lichen planus of the vulva on its prognosis. Arch. ­Dermatol. 2006; 142: 289–294.

Further reading Eisen, D. The evaluation of cutaneous, genital scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1999; 88: 431–436. Kirtschig, G., Wakelin, S. H., and Wojnarowska, F. Mucosal vulval lichen planus: outcome, clinical and laboratory features. J. Eur. Acad. Dermatol. Venereol. 2005; 19: 301–307. Moyal-Barracco, M. and Edwards, L. Diagnosis and therapy of anogenital lichen planus. Dermatol. Ther. 2004; 17: 38–46. Pelisse, M. The vulvo-vaginal-gingival syndrome: a new form of erosive lichen planus. Int. J. Dermatol. 1989; 28: 381–384.

PART: II  Gynecologic Dermatology

CHAPTER 16

Vulvar Pruritus and Lichen Simplex Chronicus Peter J. Lynch

The skin and modified mucous membranes of the vulva are amply endowed with slow-conducting, unmyelinated sensory nerve fibers that terminate within the upper dermis and lower epidermis. When triggered, these nerve fibers carry either pain or itching to the sensory cortex. It is not completely understood why stimulation sometimes conveys pain and, at other times, itching. However, it has recently been shown that there is a subset of these nerve fibers that are physiologically restricted to the conduction of itching. Since the most common triggers for the stimulation of these nerve endings are the environmental factors of heat, sweating, friction, and other forms of mild trauma, it is easy to see why women are more likely to experience vulvar pruritus than pruritus at most other body sites. Vulvar itching occurs in either a primary or secondary setting. In the primary form of pruritus, itching initially develops in normalappearing, disease-free tissue. In the secondary form of pruritus, itching develops as a component of an underlying vulvar disorder such as candidiasis, lichen sclerosus, tinea cruris, psoriasis, or vulvar intraepithelial neoplasia (VIN). Primary pruritus can be viewed as “the itch that rashes” whereas secondary pruritus can be considered as “the rash that itches.” Since itching provokes scratching and rubbing in either setting, the clinical presentation may appear similar in both the primary and secondary setting. When women present with the symptom of vulvar pruritus, clinical examination may or may not reveal abnormalities. Occasionally, early in the course of the problem, the vulva appears entirely normal. Most often, however, there is visible evidence of scratching and rubbing. Sometimes, as indicated above, there may also be changes suggesting the presence of an underlying condition such as candidiasis or one of the vulvar dermatoses. Only the primary form of itching will be reviewed in this chapter. Secondary pruritus, associated with underlying disorders, will be discussed as these conditions are covered elsewhere in the book. Nevertheless, it is extremely important to understand that treatment for itching and scratching is the same in both the primary and secondary setting. For that reason it

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is ­permissible and appropriate to initiate antipruritic therapy even when the two types of pruritus cannot initially be separately identified. Unfortunately, the primary form of pruritus has been associated with major problems in terminology. At various times, in various countries, and by various specialists this form of vulvar itching has been termed “pruritus vulvae,” “eczema,” “atopic eczema,” “atopic dermatitis,” “neurodermatitis,” “hyperplastic dystrophy,” “squamous cell hyperplasia,” or “lichen simplex chronicus.” This has, not surprisingly, led to widespread misunderstanding and confusion. With this in mind, some discussion of these terms seems warranted. “Pruritus vulvae” is, of course, self-explanatory but it is not very useful since a simple translation of a patient’s symptom into Latin does nothing to enhance understanding of the disorder. Moreover, it does nothing to differentiate the primary and secondary forms of pruritus. “Eczema” derives from the Greek word for “boiling out” and thus refers to acute, exudative inflammation of the skin. The term “eczema” used alone is sometimes substituted as a shorthand term for atopic eczema. But gradually the use of “eczema” has become less specific and today it is generally used as a synonym for “dermatitis.” Hence the two terms “atopic eczema” and “atopic dermatitis” are also now synonymous. The terms “atopic dermatitis” and “atopic eczema” were originally only used when there was clinical evidence of atopy (allergic rhinitis, hay­ fever, or asthma) present in the patient and/or the immediate family. Later, the definition of atopy also included elevated total immunoglobulin (Ig) E, elevated antigen-specific IgE, and eosinophilia. Because of this restricted use, in instances where the eruption had the same clinical characteristics as atopic dermatitis but where atopy could not be identified, the term “neurodermatitis” was used instead. However “neurodermatitis” carries the connotation of psychological disturbance that may or may not be present. Moreover it is a term often troubling to patients. Increasingly the atopic and the nonatopic forms of primary pruritus are now being described as “extrinsic” (i.e., allergic) atopic dermatitis and “intrinsic’ (i.e., nonallergic) atopic dermatitis1.

The term “lichen simplex chronicus,” for all practical purposes, can be considered as the localized form of either extrinsic or intrinsic atopic dermatitis. It is a time-honored, morphologically descriptive term and it is not biased toward a specific etiology or pathophysiology. As such, “lichen simplex chronicus” is the term I have chosen to use for primary, localized chronic scratching and rubbing of the vulva.

Lichen simplex chronicus Epidemiology and clinical manifestations Pruritus, especially of the anogenital region, is one of the most common conditions encountered in both men and women. In a clinic devoted to vulvar disease, itching was the single most frequent presenting symptom, occurring in 70% of patients2. In another vulvar specialty clinic, “dermatitis” was found in 25% of patients and was, after lichen sclerosus, the second most common condition encountered3. And, in an audit of 114 nonneoplastic vulvar biopsies, lichen simplex chronicus was identified in 35% of the specimens and was the most frequent condition diagnosed4.

Patient history By the time that a patient appears in the office, she usually indicates that her itching has been present for weeks or even months. She will also usually state that the level of the itching is severe and intractable. Most patients admit that they respond by scratching, even though they try as hard as possible not to do so. Some also acknowledge that “it feels good to scratch” while others find the itching so troublesome that they scratch until pain caused by the scratching replaces the sensation of itching. Still others are embarrassed by their scratching and either minimize the frequency with which they scratch or deny that they scratch at all. In any event, when itching leads to scratching, the fingernails further stimulate the cutaneous nerve endings. This increases the sensation of itching and leads to even more scratching. In short order a vicious cycle of itching and scratching develops. The presence of this “itch–scratch” cycle is highly characteristic for the presence of

Lichen simplex chronicus

lichen simplex chronicus and can be viewed as its single most defining characteristic. Thus, in order to diagnose lichen simplex chronicus, one must demonstrate the presence of the itch–scratch cycle. This can be done by asking the patient whether scratching occurs at the subconscious level during the day and/or takes place at night while sleeping. Since patients may be unaware of nighttime scratching, the presence of this feature can also be identified through the confirmatory history of a bed partner or by the presence of blood flecks on the sheets or under the patient’s fingernails. I have called this nighttime scratching the “Penelope phenomenon” by analogy with Homer’s epic poem describing Odysseus’s wandering and subsequent long delay in reaching his home after the Trojan war. Penelope, the wife of Odysseus, continued to hope for his safe return and told her suitors that she would only consider remarriage after she finished weaving a traditional funeral shroud for her deathly ill father-in-law. With this in mind, she wove productively during the day but, to delay completion of the shroud, she arose at night and unraveled much of what she had woven the day before. The analogy, of course, refers to the fact that nighttime scratching undoes almost all of the benefit of a treatment program that only reduces scratching that occurs during the day. Additional aspects of the patient’s history that should be sought include the presence of deleterious environmental factors such as sweating, the wearing of menstrual napkins, the rubbing of clothing, and the application of various medications. These environmental factors act much like scratching in that they may stimulate the nerve endings and thus play a role in establishing the itch–scratch cycle. Psychological factors play an important part for many patients with lichen simplex chronicus5,6. Few patients volunteer the presence of anxiety and/or depression but, when directly asked, many will admit that their itching and resultant scratching are much worse when they are under stress. Based on long-term experience, I believe that these factors are frequently underrecognized and that they should be inquired about, and addressed if found, in all patients with lichen simplex chronicus.

Examination Lichen simplex chronicus, as an eczematous disease, is characterized by the standard morphology of eczematous diseases: poorly marginated, red, scaling papules and plaques (Figure 16.1). Epithelial disruption in the form of excoriations, weeping, and crusting is present initially; lichenification and pigmentary alteration develop in patients with long-standing disease. The papules and plaques are bright red initially but develop a dusky, brown-red color as time passes. Note, however, that in dark-skinned individuals, the red color may be masked by the patient’s normal brown pigmentation (Figure 16.2). The margination of the lesion, that is, the transition from abnormal to normal tissue, occurs somewhat gradually, resulting in indistinct ­margination. Scale is present but, because of the moisture normally

Figure 16.1  Red, lichenified, poorly demarcated plaques that are classic for lichen simplex chronicus. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 5-1), New York: Churchill Livingstone; 1994.)

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Figure 16.2  Thickness from rubbing and irregular erosions from scratching are typical of lichen simplex chronicus; as with most black patients, redness is not appreciated despite marked inflammation. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 5-4), New York: Churchill Livingstone; 1994.)

present in the anogenital region, it may be visually inapparent. In this situation the scale may be only detectable as a slight roughness on palpation. As the course of the lichen simplex chronicus becomes more chronic, the surface, when moist, may whiten (see below) (Figure 16.3). Excoriations are superimposed on the underlying inflamed red plaques and they may be superficial or deep. These scratch marks can be clinically differentiated from other causes of erosions and ulcers by their angular and linear shapes (Figure 16.4). Excoriations are accompanied by exudation (“weeping”) that leaves slightly yellow or even blood-colored stains on underwear. As the water portion of the exudate evaporates, the plasma proteins remain in place and form crusts. These crusts may be yellow or, if blood is also present, they may

Figure 16.3  This woman with lichen simplex chronicus exhibits redness, accentuation of skin markings of lichenification, scale, and fissuring. The thickened skin appears white from hydration. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 5-7), New York: Churchill Livingstone; 1994.)

have red, blue, or black hues. Crusts almost always contain bacteria but a decision as to whether or not the bacteria represent infection, as opposed to colonization, must be made on other clinical evidence. Excoriations are, of course, due to scratching. Lichenification, on the other hand, is the protective, callus-like, thickening of the skin due to rubbing (Figure 16.5). When the involved tissue is picked up between the thumb and finger, this thickening is readily palpable. Lichenified tissue is usually dusky red in color but when this process occurs in a moist area, such as the anogenital region, the thickened stratum corneum (which is very hydrophilic) turns white, obscuring some of the redness (Figure 16.6). This white color ­represents the same process through which the ventral ­fingertips turn white after prolonged exposure to

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Figure 16.6  This white, thick skin demonstrates the white discoloration of hydrated hyperkeratosis, a nonspecific ­finding seen with any cause of thick skin in a naturally wet area. Figure 16.4  Multiple erosions, most of which are irregular in shape, are typical of excoriations, and are present here in a background of lichenification.

Figure 16.5  Not only do the thick, shiny skin of lichenification and the linear erosion occur as a result of rubbing and scratching, but the hair has been rubbed off.

water. In some instances this thickened tissue loses flexibility, in which case linear fissures develop. This is very similar to the fissuring that occurs on the heels of women who regularly wear openheeled sandals.

The presence of inflammation activates melanocytes. This process accounts for the replacement of the original bright redness with a slowly developing brown-red color (Figure 16.7). And, after the inflammation resolves, the brown color remains for a considerable period of time. This process is known as postinflammatory hyperpigmentation and one can consider this darkening as analogous to the tanning that occurs following sunlight-induced inflammation. However, if the inflammation is sufficiently severe, the melanocytes are destroyed instead of being activated. In this situation, and in the setting of deep excoriation that removes the melanocytes, the outcome is that of postinflammatory hypopigmentation. The distribution of lichen simplex chronicus is usually most prominent over the labia majora but involvement of the labia minora, mons pubis, upper inner thighs, and the perianal area is not uncommon (Figure 16.8).

Diagnosis and differential diagnosis The diagnosis of lichen simplex chronicus is usually established on a clinical basis due to the highly characteristic findings described above.

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disorder). Often, when the patient is first seen, this distinction is not possible and, counterintuitively, biopsy at this juncture is not usually helpful. The best approach is to treat the itch–scratch cycle such that rubbing and scratching no longer occur. If examination after the itch–scratch cycle has been broken reveals only normal-appearing tissue, one can assume that the disorder was one of primary lichen simplex chronicus. Otherwise, if underlying abnormalities remain, the process is presumably secondary. In this situation the underlying disorder must then be identified. This can be done clinically, by biopsy, by potassium hydroxide, or by culture. Moreover, once a diagnosis is established, the identified condition must be treated to ­ prevent rapid recurrence of the superimposed lichen ­simplex chronicus. The underlying disorders most often encountered include candidiasis, lichen sclerosus, tinea cruris, psoriasis, contact dermatitis, human papillomavirus infection (warts), and VIN (Table 16.1).

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Figure 16.7  Redness in darkly complexioned patients ­appears as hyperpigmentation, which is accentuated by the activation of melanocytes from inflammation from rubbing.

Figure 16.8  Although the labia majora are the most ­common site of lichen simplex chronicus, other areas, such as the modified mucous membranes, can be affected as well.

­ ncommonly, biopsy will be necessary. Also, when U a diagnosis of lichen simplex chronicus is established, it is necessary to determine whether the process is primary (arising de novo from normal skin) or secondary (superimposed on an underlying

Histology and laboratory tests The early lesions of lichen simplex chronicus histologically reveal prominent intercellular edema (termed “spongiosis” or “spongiotic dermatitis”) in the epidermis. Inflammatory cells, primarily lymphocytes, are found both perivascularly and diffusely spread throughout the dermis. As lichen simplex chronicus becomes more chronic, the amount of spongiosis decreases and the epidermis thickens with prominent elongation and widening of the epidermal rete ridges. This epidermal acanthosis is accompanied by both orthokeratotic and parakeratotic thickening of the stratum corneum. The dermal inflammatory process remains and mild fibrosis of the papillary dermis develops. Note that the histological findings at the chronic end of the lichen simplex chronicus spectrum overlap somewhat with those found in psoriasis. For this reason pathologists sometimes hedge between the identification of psoriasis and lichen simplex chronicus and return a diagnosis of “psoriasiform dermatitis.” In this situation it is up to the clinician to arrive at the correct diagnosis using clinicopathologic correlation. Aside from histological examination, no other laboratory tests are necessary.

Lichen simplex chronicus

Therapy

r­ eflection of this type IV process, patch tests to various antigens are frequently positive7. Unfortunately these positive reactions rarely correlate with identifiable antigens present in the patient’s anogenital environment. For this reason we do not encourage routine patch testing in patients with lichen simplex chronicus. When patients ask why they have developed the itching and subsequent rash, I indicate that they have inherited a predilection to have dry, itchy skin. Recent evidence suggests that, at the molecular level, this may occur as a result of a mutation in the gene for filaggrin which leads to a defective barrier layer that in turn allows for easy stimulation of the cutaneous nerve fibers responsible for itch and light pain8.

Bathtub soaks and lubrication

Therapy and prognosis

Table 16.1  Lichen Simplex Chronicus Diagnosis Intractable itching and scratching Evidence of nighttime scratching (the itch–scratch cycle) Visible excoriation and/or lichenification Atopic background helpful but not required Differential Diagnosis Clinical: rule out underlying vulvar dermatoses and vulvar intraepithelial neoplasia Microscopic: rule out psoriasis

Mid- to high-potency topical steroids Hydroxyzine or doxepin in early evening Consider systemic steroids Consider daytime selective serotonin reputake inhibitors

Pathogenesis Many triggers initiate primary vulvar pruritus and the subsequently developing lichen simplex chronicus. These include the environmental factors discussed above and, frequently, the ­ elements of anxiety and/or depression5,6. However, it is important to remember that these are only triggers. Once the itch–scratch cycle has started, lichen simplex chronicus takes on a life of its own, regardless of whether or not the triggers remain in place. The actual cause of primary vulvar pruritus and lichen simplex chronicus is unknown. As stated earlier, a majority of patients with these problems can be identified as being atopic. That is, they have a personal or immediate family history of allergic rhinitis, allergic conjunctivitis, hayfever, and/or asthma. All of these aspects of atopy occur as a result of IgE-mediated sensitivity to specific antigens but this is not true of the eczematous lesions occurring in this setting. Instead, atopic dermatitis and its localized variant, lichen simplex chronicus, are due to a T-cell-mediated process. As a

Left untreated, lichen simplex chronicus waxes and wanes over months to years but rarely completely resolves spontaneously. For the most part there are no long-term adverse medical consequences associated with the presence of lichen simplex chronicus but the possibility that chronic lichen simplex chronicus could be a predisposing factor for the development of vulvar squamous cell carcinoma has been raised9,10. Therapy, on the other hand, is usually quite successful. But, even when completely successful, patients must be warned that, once treatment has been stopped, the likelihood of recurrence is extremely great. Specifically, patients should be told that recurrence is an expected part of the natural history of the disease and that it does not represent treatment failure. Treatment for lichen simplex chronicus falls into four categories: (1) identification and resolution of environmental or psychological triggers together with treatment of any underlying dermatological problems that might be found; (2) restoration of an intact epidermal barrier layer; (3) reduction of associated inflammation; and (4) break-up of the itch–scratch cycle. Identification of underlying disease and other triggers

Sometimes when a patient is first examined, it is apparent that an underlying disease is present. For instance, the typical vaginal discharge or satellite

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pustules of candidiasis might be present or, on the other hand, there may be typical plaques of psoriasis present at other skin sites. But, more often, it is not clear on initial examination whether or not there is an underlying disorder. In this situation, it is necessary to treat the itch–scratch cycle. In so doing, the background “noise” caused by the scratching and rubbing resolves, leaving a clearer picture as to whether or not some other disease is also present. When an underlying disorder can be identified it should, of course, be treated not only to relieve the patient of symptoms and signs associated with this disease, but also to reduce the likelihood that the underlying condition would once again trigger rapid recurrence of the lichen simplex chronicus. The anogenital area is a warm moist area and this condition acts as a trigger for the development of itching. It is very difficult to make changes that will influence that fact but some of the following may prove helpful: use of looser outer clothing (skirts rather than pants); use of less occlusive underwear (cotton or polyester blends); sitting on cloth, rather than vinyl, surfaces; use of a perforated “cushion” for sitting in the car; shift from menstrual napkins to tampons; discontinuation of panty liners; and reduction in the number and aggressiveness of unnecessary attempts at hygiene. Fingernails should be cut short twice a week and, after cutting, the sharp edges should be rounded off by filing from top to bottom rather than from side to side. Remind patients that the hair dryer is not a medical instrument and should not be used for drying of the anogenital area. It is not necessary to change the brand of laundry detergent or to double-rinse underwear. Don’t wait for patients to mention psychological factors. Ask them directly whether or not there are stressful (family, social, financial, sexual, or workrelated) factors occurring in their lives. If these are identified, it may be additionally useful to look for specific signs of anxiety or depression. These should, of course, be treated if such are identified. Restoration of the epidermal barrier layer

The epidermal barrier layer is located at the outermost aspect of the epidermis just under the stratum corneum. It is formed of tightly fitting epidermal

cells (“bricks”) held together by desmosomes and keratinocyte-derived lipids (“mortar”). An intact barrier layer protects the sensory nerve endings, which terminate within the epidermis, from being triggered by noxious environmental events. This barrier layer fails to function when fingernails disrupt it and when epidermal edema (spongiosis) forcefully separates the epidermal cells. Improvement of barrier layer function leads to the restoration of a physiological environment for the nerve endings and helps to dampen the transmission of itch signals to the sensory cortex. Improvement in barrier layer function can be accomplished most quickly through the use of soaks. Tell the patient to fill the bathtub with water and then sit in the tub for 20 minutes at a time. Tap water is fine; there is no need to use commercially prepared soaking solutions or to add additional ingredients such as bath oil. The water should be drawn at a temperature comfortable for the patient. Very hot and very cold water do ­anesthetize the nerve endings but this is a very temporary event and is usually followed by rebound-type itching. These soaks can be repeated several times per day, as necessary. Unfortunately, the effect of bathtub soaks is very transient. Once the tissue dries, the nerve endings are once again exposed. For this reason lubricants should be applied immediately after soaking so as to retard the evaporative loss of water. The lubricant to be used depends on the preferences of both the clinician and the patient. In general pure petrolatum products (such as Vaseline) work well but are too “sticky” and greasy to be acceptable to patients. Hand creams (those that are solid rather than liquid) also work very well and are much more acceptable. The product chosen should not contain humectants (such as lactic acid, glycolic acid, ammonium lactate, or urea) as these tend to cause stinging and burning. The brand of lubricant used is unimportant. The patient can try whatever she has on hand. Otherwise, some timehonored brands frequently recommended by dermatologists include Aquaphor, Cetaphil, Eucerin, Lubriderm, Nivea, and Vaseline Intensive Care. These products should be applied frequently, directly after each soak, and each time the patient urinates.

Lichen simplex chronicus Reduction of inflammation

Inflammation is always present in lichen simplex chronicus. In light-skinned patients this will be apparent because of visible redness. However, in darker-skinned individuals, the natural pigmentation will mask the intensity of the redness and shift the color to a darker, red-brown color. The presence of inflammation is detrimental because it leads to spongiosis and resultant barrier layer dysfunction. Inflammation is also associated with the release of cytokines that may have irritating properties. Note, however, that the cytokine histamine plays a very limited role in this inflammation and for that reason the oral administration of antihistamines does not reduce inflammation to any significant degree. Corticosteroids represent the most potent and appropriate agents for the reduction of inflammation. Topical steroids

The use of steroids topically represents the safest approach as there is very little risk of significant systemic absorption when they are applied to a limited area such as the vulva. Historically, dermatologists have recommended using only low-potency products such as hydrocortisone for the anogenital region. Unfortunately these products have little therapeutic effect. It has gradually become apparent that stronger products are equally safe and much more effective. I generally start with fluocinonide (Lidex) 0.05% ointment and if necessary move up to the superpotent category of clobetasol propionate (Temovate) 0.05% ointment. It is almost always wisest to start by using the ointment, rather than the cream, forms of these steroids. Ointments sting less and add a lubricating effect. Later on, after healing is under way, one can switch to a cream vehicle if the patient prefers. Topical steroids should be applied twice daily. Only a small amount, generally about the size of a lead pencil erasure, should be used for each application. The use of a larger amount leads to unwanted spread to nonvulvar tissue and increases the likelihood of adverse effects, such as striae formation, skin atrophy, and telangiectasia. Ordering these steroids in small amounts such as 30 g is desirable. This amount is sufficient for several

weeks of use and helps to convince the patient to apply the agent sparingly. Other topical anti-inflammatory agents

Over the last 5 years two nonsteroidal topical agents have been heavily promoted for the treatment of atopic dermatitis. These products, tacrolimus (Protopic ointment) and pimecrolimus (Elidel cream) have a very limited place in the treatment of lichen simplex chronicus. They are comparable in efficacy only to low- and mid-potency steroids, they sting on application, they are very costly, and they are accompanied by a Food and Drug Administration “black box” warning about the possible induction of malignancy. Their use might be warranted in the event of complete failure of potent topical steroids. Systemic steroids

If there is little or no improvement using topical steroids for 3 weeks, it is worth considering systemic steroids. Most dermatologists prefer a short-term course (“burst”) of either prednisone or prednisolone. These two agents are essentially interchangeable and are administered in similar dosage. A typical approach would be to use either product in a single morning dose of 40 mg for 7 days followed by 20 mg for 7 additional days. No further taper would be necessary. However, I prefer the intramuscular injection of triamcinalone (Kenalog) in a dose of 80 mg administered deep into the buttock. Both routes of administration are effective and both are safe. I prefer the intramuscular injection because there are no compliance issues, there are no patient or pharmacy errors in dosing, the slow taper of this depot-type product leads to little or no disease rebound and, for any one course of therapy, the overall dose of steroid received is lower. Breaking the itch–scratch cycle

Failure to interrupt the itch–scratch cycle is the most common mistake made in the treatment of lichen simplex chronicus. Lack of attention to this aspect almost always results in suboptimal treatment. And, of course, since the scratching occurs at the subconscious level or while asleep, the patient is powerless to break the cycle herself.

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Vulvar Pruritus and Lichen Simplex Chronicus Nighttime scratching

As indicated above, nighttime scratching is extre­ mely common and interferes with sleep patterns11. Antihistamines have historically been used to reduce itching and scratching12, even though there is little scientific evidence for their efficacy13. Originally, the rationale for their use was the desirability of their antihistaminic effect. However, newer information, together with documentation that the new, nonsedating antihistamines are relatively ineffective, suggests that their efficacy depends primarily on their sedative effect. Almost all dermatologists suggest the use of hydroxyzine (Atarax, Vistaril) but other sedating-type antihistamines such as diphenhydramine (Benadryl) also work well. Either of these agents is started in a low dose (10–25 mg) taken approximately 2 hours prior to the expected hour of sleep. Given then, rather than at bedtime, reduces early-morning drowsiness and increases patient acceptability. The dosage is increased by 10–25 mg each week (still given as a single earlyevening dose) until the patient recognizes that her nighttime scratching has ceased or until side-effects (dryness of the mouth, blurred vision, or morning sleepiness) prevent further increase. Generally, the point of maximum benefit occurs between 50 and 75 mg. The maximum daily dose should not exceed 150 mg. If hydroxyzine fails or side-effects are unacceptable, I switch to the tricyclic antidepressant and antihistaminic product doxepin. As was true for hydroxyzine, the efficacy of this product appears to depend in large part on its sedative effect. Dosing is carried out exactly the same as for hydroxyzine. Daytime scratching

The use of nighttime therapy is often sufficient to control daytime itch and scratching as well. However, if daytime scratching persists, morning therapy may be necessary. I choose not to use the agents discussed above because of drowsiness and safety concerns regarding driving and machinery operation. Instead I prefer the selective serotonin reuptake inhibitors (SSRIs). They are quite effective, even though the mechanism through which they work is poorly understood. When prescribing SSRIs, I indicate that these agents are approved

for obsessive-compulsive disorders (OCD) and that one’s incessant scratching can be viewed as a type of OCD. I most often use citalopram (Celexa), starting with 10–20 mg taken each morning. This dose can be increased at weekly intervals to a maximum daily dose of 60 mg. Other SSRI agents such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) also work quite well.

References   1. Park, J. -H., Choi, J. -H., Namkung, W. -S., et al. Characteristics of extrinsic vs. intrinsic atopic dermatitis in infancy: correlations with laboratory variables. Br. J. Dermatol. 2006; 155: 778–783.   2. Sullivan, A. K., Staughair, G. J., Marwood, R. P., et al. A multidisciplinary vulva clinic: the role of genito-urinary medicine. J. Eur. Acad. Dermatol. Venereol. 1999; 13: 36–40.   3. Ball, S. B. and Wojnarowska, F. Vulvar dermatoses: lichen sclerosus, lichen planus and vulval dermatitis/lichen simplex chronicus. Semin. Cutan. Med. Surg. 1998; 17: 182–188.   4. O’Keefe, R. J., Scurry, J. P., Dennerstein, G., et al. Audit of 114 non-neoplastic vulvar biopsies. Br. J. Obstet. Gynaecol. 1995; 102: 780–786.   5. Chuh, A., Wong, W., and Zawar, V. The skin and the mind. Aust. Fam. Physician 2006; 35: 723–725.   6. Krishnan, A. and Koo, J. Psyche, opioids, and itch: therapeutic consequences. Dermatol. Ther. 2005; 18: 314–322.   7. Virgili, A., Bacilieri, S. and Corazza, M. Evaluation of contact sensitization in vulvar lichen simplex chronicus. J. Reprod. Med. 2003; 48: 33–36.   8. Palmer, C. N. A., Irvine, A. D., Terron-Kwiatkowski, A., et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genet. 2006; 38: 441–46.   9. Micheletti, L., Scurry, J., Bogliatto, F., et al. Premalignant aspects of the vulvar non-epithelial disorders (formerly the vulvar dystrophies). CME J. Gynecol. Oncol. 2005; 10: 157–168. 10. Nascimento, A. F., Granter, S. R., Cviko, A., et al. Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma? Am. J. Surg. Pathol. 2004; 28: 638–643. 11. Koca, R., Altin, R., Konuk, N., et al. Sleep disturbance in patients with lichen simplex chronicus and its relationship to nocturnal scratching: a case control study. South. Med. J. 2006; 99: 482–485. 12. O’Donoghue, M. and Tharp, M. D. Antihistamines and their role as antipruritics. Dermatol. Ther. 2005; 18: 333–340. 13. Klein, P. A. and Clark, R. A. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch. Dermatol. 1999; 135: 1522–1525.

Further reading Lynch, P. J. Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol. Ther. 2004; 17: 8–19. Weichert, G. E. An approach to the treatment of anogenital pruritus. Dermatol. Ther. 2004; 17: 129–133.

PART: II  Gynecologic Dermatology

CHAPTER 17

Vulvar Dermatoses: Papulosquamous Diseases Libby Edwards

Inflamed, scaling skin diseases fall into two morphologic groups; papulosquamous disease and eczematous disease. Papulosquamous diseases are well demarcated and usually show little evidence of rubbing and scratching. Eczematous disease is characterized by poorly demarcated borders, and either excoriations or thickening from rubbing (lichenification) are generally prominent. Any papulosquamous or eczematous disease can affect the vulva. Some dermatoses are either more common on the vulva or require a modification of therapy in this area as compared to the usual treatments used on extragenital skin. These more common or problematic conditions are discussed in this chapter.

Psoriasis Psoriasis is a disease of autoimmune etiology which exhibits several different morphological variants. One variant of psoriasis, pustular psoriasis, is closely related to Reiter’s syndrome. The histology and morphologic appearance of these diseases can be identical, and they are often not strictly separable, existing on a spectrum.

Epidemiology and clinical manifestations Psoriasis occurs in approximately 1–3% of the population1. Anogenital involvement is common and usually accompanied by disease on other areas of the body. Psoriasis occurs in all races, and at all ages, but most patients exhibit lesions before the age of 30 years. Obesity and alcoholism are more prevalent in patients with psoriasis. Some patients complain of intense pruritus, others describe pain with fissuring and cracking of the skin, and still others have no symptoms. Most women are troubled by the appearance of the skin and the remarkable proliferation of scale, with embarrassing flakes of skin left on chairs and in the bed. The clinical appearance of psoriasis varies as this disease occurs in several major patterns (Table 17.1). Most common is psoriasis

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Table 17.1  Morphologic Variants of Psoriasis Psoriasis vulgaris – well-demarcated scaling, large   plaques with predilection for elbows, knees, scalp Guttate psoriasis – 0.5–2 cm, lightly scaling, widely ­scattered plaques Inverse psoriasis – moist, deep red plaques in skin folds Erythrodermic psoriasis – generalized erythema and scale Pustular psoriasis – erythematous plaques of pustules   and crusting

Figure 17.2  Psoriasis vulgaris shows a predilection for the elbows and knees, and the identification of classic disease on extragenital skin such as this helps to guide the diagnosis of nonspecific genital morphology. (Reproduced from L. Edwards Dermatology in Emergency Care (Fig. 14.1), New York: Churchill Livingstone; 1997.)

Figure 17.1  These well-demarcated papules and plaques with heavy white, adherent scale are typical of untreated psoriasis on dry, keratinized skin. Figure 17.3  Psoriasis on the vulva and within other skin folds lacks the dense white scale of psoriasis occurring elsewhere, and is more likely to show shiny or glazed skin.

vulgaris (common psoriasis, or plaque-type psoriasis). Psoriasis vulgaris is manifested by classic well-demarcated, red plaques covered with dense, silvery scale (Figures 17.1 and 17.2). In skin folds, however, the scale is more subtle, often with a shiny

or glazed texture (Figure 17.3) Psoriasis vulgaris shows a predilection for elbows, knees, and scalp, although it can occur in all areas. Psoriasis exhibits the Koebner phenomenon, in which the disease preferentially affects areas of trauma

Psoriasis 169

Figure 17.4  Small, discrete, scaling papules of guttate psoriasis generally lack the dense white scale of psoriasis vulgaris. (Reproduced from L. Edwards Dermatology in Emergency Care (Fig. 14.2), Churchill Livingstone.)

Figure 17.5  These well-demarcated, shiny plaques are classic for vulvar psoriasis.

or inflammation. This partially explains the ­distribution of elbows, knees, and genital skin – all areas prone to friction and mild trauma. Many patients also exhibit tiny pits on the fingernails, a relatively specific sign of psoriasis. A second form of psoriasis, guttate psoriasis, appears as 0.5–2-cm round, red, scaling papules and small plaques (Figure 17.4). Scalp and nail disease are less common, and this form of psoriasis does not prominently affect anogenital skin, elbows, knees, or scalp. Inverse psoriasis consists of disease that preferentially affects skin folds, including the axillae, inframammary skin, crural creases, and

Figure 17.6  The thickened skin of psoriasis appears white in skin folds, where chronic moisture regularly makes thick skin appear white. Skin fold psoriasis both mimics and sometimes coexists with candidiasis. Cultures and response to therapy are often required to differentiate these   conditions.

a­ nogenital area. Inverse psoriasis consists of moist plaques that are deeply red, with very subtle scale (Figures 17.5–17.7). The thickened skin in skin folds is often macerated and appears white. The gluteal cleft and umbilicus are characteristically also involved. Often, classic elbow, knee, and scalp psoriasis are absent. A fourth form of psoriasis, erythrodermic psoriasis, is any form of psoriasis which generalizes, resulting in widespread, nonspecific erythema and scale. Erythrodermic psoriasis generally lacks the typical heavy, silvery scale. Erythrodermic psoriasis is indistinguishable from any widespread dermatosis, such as generalized eczema or a medication allergy. The final form of psoriasis is pustular psoriasis, which appears as plaques of pustules that eventuate into crusted plaques. These can be generalized or occur primarily on the hands, feet, and genital skin. The skin findings of pustular psoriasis are indistinguishable from those of Reiter’s syndrome (Figures 17.8 and 17.9). Arthritis is more common with pustular psoriasis than with other forms. Except for guttate psoriasis, all variants of psoriasis frequently exhibit anogenital involvement, and inverse psoriasis nearly always affects the vulva and crural creases. Psoriasis usually affects hair-bearing, nonmucous membrane anogenital

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Figure 17.7  Vulvar psoriasis often presents as poorly demarcated red plaques that are indistinguishable from lichen simplex chronicus, contact dermatitis, and seborrheic dermatitis, so that correlation with abnormalities on other skin surfaces, biopsies, and response to therapy may be required for definitive diagnosis.

Figure 17.8  Pustular psoriasis consists of plaques or ­pustules; the fragile pustules rupture almost immediately, leaving small, coalescing erosions (small arrows).   Surrounding pustules (bold arrows) are also present in this patient, who was originally misdiagnosed with resistant yeast ­infection.

skin. However, pustular psoriasis rarely occurs on the modified mucous membranes of the vulva, the vaginal epithelium, and ectocervix.

similar to psoriasis but generally is less well demarcated. Seborrheic dermatitis is very uncommon on the vulva, but appears similar clinically and histologically, with red, moist, finely scaling red plaques on the vulva and crural creases. Seborrheic dermatitis is regularly accompanied by typical seborrhea of the scalp, central face, and other skin folds. The red, rough plaques of irritant and allergic contact dermatitis sometimes resemble psoriasis, but are classically less well demarcated and unaccompanied by signs of extragenital psoriasis. The above diseases are differentiated by culture, the identification of characteristic lesions elsewhere, and response to therapy. Often, psoriasis coexists with one of these diseases, especially

Differential diagnosis Diseases that mimic genital psoriasis include candidiasis, which is also characterized by red, intertriginous plaques, but candidiasis is usually accompanied by small satellite papules and collarettes, and a positive fungal preparation or culture. Clearing with anticandidal therapy confirms that diagnosis. Tinea cruris, although uncommon in women, sometimes appears indistinguishable from anogenital psoriasis. Lichen simplex chronicus of the labia majora and mons is ­ morphologically

Psoriasis

Table 17.2  Psoriasis Diagnosis   Clinical appearance   Red, well-demarcated, scaling or moist plaques   Usually absent on modified mucous membrane and vagina   Frequent involvement of scalp, nails, elbows, knees   Confirmed on biopsy when not classic Differential Diagnosis Figure 17.9  Acral red plaques of pustules and coalescing crusted papules representing ruptured pustules are characteristic of keratoderma blenorrhagica, the cutaneous eruption of Reiter’s syndrome. This is clinically and histologically identical to skin disease of pustular psoriasis. (Reproduced from L. Edwards Dermatology in Emergency Care (Fig. 7.8), Churchill Livingstone.)

candidiasis, lichen simplex chronicus, and contact dermatitis (Table 17.2).

Laboratory findings and histology Mild psoriasis is usually unaccompanied by laboratory abnormalities. Patients with pustular psoriasis are likely to exhibit a leukocytosis, and those with psoriatic arthritis may exhibit characteristic radiographs. Early lesions and the edges of progressing lesions of psoriasis are the most likely to show diagnostic changes of psoriasis, whereas late lesions are often nonspecific. Classic histology shows regular elongation of the rete pegs with thickening of the lower portion of the pegs, as well as thinning of the suprapapillary epidermis, hyperkeratosis, and parakeratosis. A chronic inflammatory infiltrate is present in the dermis, but the diagnostic finding is that of small collections of neutrophils (microabscesses) in the epidermis and within the parakeratotic stratum corneum. Pustular psoriasis exhibits much larger pustules that are clinically visible. Often, however, psoriasis is chronic and the histology is nonspecific, yielding a histologic “diagnosis” of psoriasiform dermatitis. This is a description rather than a diagnosis, indicating features of both psoriasis and eczema, but diagnositic of neither. This biopsy report neither proves nor disproves the diagnosis of psoriasis.

  Reiter’s syndrome   Lichen simplex chronicus   Candidiasis   Irritant and allergic contact dermatitis   Tinea cruris   Seborrheic dermatitis   Erythrasma Management   Topical corticosteroids, triamcinolone 0.1% ointment ­applied twice daily and tapered when possible, or the more potent clobetasol propionate ointment used twice daily and tapered quickly to once three times a week   Topical calcipotriene cream 0.005% twice daily   Systemic medications for severe recalcitrant ­disease, ­including methotrexate, retinoids, cyclosporine, ­etanercept, infliximab, efalizumab, etc.

Pathogenesis Psoriasis is an immunologically mediated disease characterized by a T-cell inflammatory infiltrate2. This T-cell-mediated type 1 autoimmune process and the resulting cytokines ultimately produce an increased turnover of keratinocytes, thickening of the epidermis, and scale. The predilection for the development of psoriasis is partly inherited.

Therapy and prognosis Vulvar psoriasis is usually controllable with topical therapy. Corticosteroids, the elimination of irritants, and careful attention to secondary

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i­ nfection, particularly Candida, produce sufficient benefit for most women with anogenital psoriasis. An ultrapotent topical corticosteroid such as clobetasol ointment is applied very sparingly once or twice daily, tapering the application to the least frequent dosing that controls the disease, usually about three times a week. The areas most often affected with psoriasis, the hair-bearing labia majora, crural crease, perianal skin, and medial thighs, are the areas that atrophy very easily. Patients who require ongoing daily therapy should be managed with a lower-potency topical corticosteroid, and, if needed, calcipotriene (Dovonex) cream. Other topical agents, such as tar, salicylic acid, and anthralin, are too irritating for use on anogenital skin. Tacrolimus and pimecrolimus are useful in some patients, and although somewhat irritating, some women tolerate them well, particularly after the skin is partially controlled with a topical corticosteroid. Patients who are not adequately controlled with topical therapy require treatment with systemic agents such as methotrexate, acitretin, or one of the new biological agents, including etanercept, infliximab, efalizumab, adalimumab, and alefacept. Psoriasis cannot be cured, but it can be controlled. Psoriasis of the anogenital skin is usually more easily controlled than psoriasis of other areas, but corticosteroid side-effects are also more prominent here so that ongoing surveillance is indicated. Secondary anogenital malignancy has not been reported, but deforming arthritis is a known sequela and there is recent evidence that the inflammation of psoriasis may predispose to coronary artery disease3.

Reiter’s syndrome Reiter’s syndrome is a multisystem disease classically characterized by urethritis, conjunctivitis, and arthritis, but often includes skin disease, iritis, keratitis, fever, and malaise. The skin lesions show a predilection for the hands, feet, and genital skin, and these are clinically and histologically indistinguishable from pustular psoriasis (see Figures 17.8 and 17.9). Psoriasis and Reiter’s syndrome are closely related, existing on a spectrum.

Reiter’s syndrome occurs almost exclusively in men, and there is a hereditary predisposition. Hands and feet often exhibit red plaques of pustules or crusting from ongoing evolution of ruptured pustules. The glans of circumcised males shows similar scaling, crusted plaques, whereas the glans of uncircumcised men exhibits white annular or arcuate papules and plaques (balanitis circinata). The rare woman with Reiter’s syndrome generally exhibits cervicitis, sometimes characterized by white, arcuate papules of the cervix and modified mucous membranes, as well as inflamed scaling plaques of keratinized skin. Abnormal inflammatory Papanicolaou smears sometimes occur. Oral lesions can occur, but are less common. Arthritis usually affects larger joints, such as the knees, in an asymmetric fashion. Back pain associated with ankylosing spondylitis and sacroiliitis is common. Pustular psoriasis is the primary disease in the differential diagnosis of cutaneous manifestations of Reiter’s syndrome. These diseases are closely related, and, at times, indistinguishable. Pustular psoriasis is less likely to exhibit human leukocyte antigen (HLA) B27 positivity, inflammatory eye disease, ankylosing spondylitis, and urethritis/ cervicitis. The urethral discharge in men with the associated arthritis suggests disseminated gonococcemia, and the crusted plaques of the vulva mimic candidiasis. The diagnosis of Reiter’s syndrome is made by the characteristic constellation of signs as described above, including oligoarthritis (especially of the knees and ankles), urethritis or cervicitis, conjuncitivitis, pustular, scaling or crusted plaques of the genitalia and, often, hands and feet, inflammation of the tendon and ligament insertion of the Achilles tendon, and mouth ulcers. Unfortunately, most people with Reiter’s syndrome experience “incomplete” Reiter’s syndrome, exhibiting only a few signs, at least initially, and there are no diagnostic tests. Laboratory abnormalities include the identification of HLA B27 positivity and characteristic radiographic changes of joint disease. Histology is identical to that of pustular psoriasis, showing acanthosis, and neutrophils in the epidermis, coalescing into pustules.

Tinea cruris

The etiology of Reiter’s syndrome includes a genetic predisposition, as evidenced by the usual HLA B27 positivity, and a trigger such as an infection, especially Yersinia, Shigella, or human immunodeficiency virus (HIV), that provokes an immunologic response. The treatment of the vulvar manifestations of Reiter’s syndrome is identical to that of psoriasis. Most patients require systemic therapy for other aspects of the disease, as listed above for psoriasis. Some patients experience self-limited disease, whereas others are afflicted with chronic, disabling illness.

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Tinea cruris Tinea cruris, also called “jock itch,” is a cutaneous fungal infection of hair-bearing skin.

Epidemiology and clinical manifestations Occurring primarily in men, particularly in the setting of tinea pedis and fungal nail infections, tinea cruris is a disease of postpubertal individuals, and it occurs more often in humid and warm climates. The most common symptom associated with tinea cruris is pruritus, especially on the proximal, medial thighs. In addition, the rash is unsightly to some. Pain is generally not associated. Classic tinea cruris presents as well-demarcated, red, lightly scaling plaques covering the proximal, medial thighs, with accentuation of the scale peripherally that produces an annular configuration (Figure 17.10). Generally, tinea cruris does not prominently affect the labia majora or mons, except in women using topical corticosteroids or who are otherwise immunosuppressed. Tinea cruris affecting skin with terminal hair sometimes involves the follicular epithelium (fungal folliculitis), resulting in red nodules, pustules, and/or crusted papules within the more typical plaques of tinea cruris. Tinea cruris does not affect the modified mucous membranes of the vulva. Individuals using topical corticosteroids on their tinea cruris may exhibit tinea cruris that is morphologically atypical (tinea incognito), showing poorly demarcated borders, coalescing arcuate plaques, and fungal folliculitis. At these times, the

Figure 17.10  Tinea cruris appears as red plaques on the proximal thighs and mons pubis, showing peripheral accentuation of redness and scale that confers an annular morphology.

peripheral accentuation of scale may be less obvious (Figure 17.11).

Differential diagnosis All causes of red vulvar plaques should be considered in the differential diagnosis (Table 17.3). These include lichen simplex chronicus, psoriasis, candidiasis, contact dermatitis, and seborrheic dermatitis. A microscopic examination of a fungal preparation of skin confirms the diagnosis by showing branching hyphae without budding yeast. Uncertain or recalcitrant cases can be confirmed by dermatophyte culture.

Laboratory abnormalities and histology The only laboratory abnormality seen in patients with tinea cruris is a positive fungal culture, or a fungal preparation of scale revealing dermatophytosis microscopically.

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Table 17.3  Tinea Cruris Diagnosis   Clinical appearance   Red, well-demarcated, scaling plaques on proximal,   medial thighs, sometimes extending to buttocks or mons   Peripheral scale   Frequent association with onychomycosis or tinea pedis   Confirmed on microscopic examination of potassium hydroxide preparation, culture, or response to therapy Figure 17.11  Tinea cruris treated with topical corticosteroids exhibits atypical morphology and is called tinea incognito. The plaques may lack the usual annular configuration, are often poorly demarcated, and exhibit papules and crusts that represent invasion of the dermatophyte into hair follicles, producing fungal folliculitis. (Reproduced from   C. M. Lawrence and N. H. Cox Color Atlas and Text of Physical Signs in Dermatology (Fig. 6.27), Wolfe, London, 1993.)

Differential Diagnosis   Lichen simplex chronicus   Candidiasis   Irritant and allergic contact dermatitis   Seborrheic dermatitis   Erythrasma

A biopsy of tinea cruris is generally not required for diagnosis. However, histology shows organisms within the stratum corneum that are most easily visualized using special stains such as the periodic acid–Schiff reaction. There are often also changes of dermatitis, to include spongiosis.

Management Mild disease without evidence of fungal folliculitis   Any azole cream, terbenafine cream, or ciclopirox cream used twice daily until clear

Pathogenesis

More extensive disease, or folliculitis

The cause of tinea cruris is infection with a dermatophyte, with Tricophyton rubrum, T. mentagrophytes, or Epidermophyton floccosum being the most common. These are indistinguishable microscopically.

  Oral azoles, in many different schedules, including:

Therapy and prognosis

  Oral terbinafine 250 mg daily until clear

The treatment of tinea cruris consists of the administration of any of several antifungal oral or topical medications. All azoles are effective, whereas nystatin exhibits no activity against tinea. Terbinafine (Lamisil) and ciclopirox (Loprox) are active agents as well. These are applied once or twice a day, and are appropriate therapy when tinea cruris is mild, limited in extent, and shows no signs of fungal folliculitis. When abundant coarse hair or folliculitis is present, or when tinea is extensive, patients respond best to oral medication. Options include the azoles, fluconazole (Diflucan)

  Fluconazole 100–200 mg weekly for 2–4 weeks   Itraconazole 100 mg daily for 2 weeks   Ketoconazole 200 mg daily until clear

  Oral griseofulvin 500 mg twice daily until clear

100–200 mg weekly for 2–4 weeks, or itraconazole (Sporonox), 100 mg/day or ketoconazole, 200 mg/ day until clear. Griseofulvin 500 mg twice daily is effective as well, but nausea and headaches are often limiting side-effects. Oral terbinafine 250 mg daily until clear is effective and well tolerated. All of these medications, except for griseofulvin, also treat Candida in case of a misdiagnosis. Patients should be advised that recurrence can occur, particularly in the setting of ­onychomycosis.

Pityriasis versicolor (tinea versicolor) 175

Figure 17.12  The tan-pink, finely scaling, well-demarcated plaques on the proximal medial thighs without an annular appearance are typical of erythrasma.

These patients should be instructed to restart a topical azole cream or terbinafine cream immediately with the first sign of recurrence.

Erythrasma Erythrasma is a superficial bacterial infection produced by Corynebacterium minutissimum. Occurring more often in men than women, erythrasma presents as well-demarcated, pink, lightly scaling plaques primarily on the proximal, medial thighs (Figure 17.12). This condition can be asymptomatic or associated with pruritus. Erythrasma is most often confused with tinea cruris but it also resembles psoriasis, candidiasis, lichen simplex chronicus, and seborrheic dermatitis. The diagnosis is confirmed by coral pink fluorescence when the skin is illuminated with a Wood’s lamp. Treatment includes oral erythromycin, or topical erythromycin solution 2% or clindamycin cream applied twice daily until clearing. Erythrasma can recur.

Figure 17.13  Pityriasis versicolor (tinea versicolor) is characterized by well-demarcated pink, tan, or hypopigmented coalescing papules. Scale is present but subtle and often only visible when the skin is gently scratched.

Pityriasis versicolor (tinea versicolor) Pityriasis versicolor is a superficial yeast infection that does not preferentially affect vulvar skin, but its common location on the trunk sometimes extends to the mons and other nonmucous membrane skin. Patients usually experience no symptoms, but an occasional person describes itching. Morphologically, lesions can be pink, tan, brown (especially in patients of color), or white, hence its name “versicolor.” Flat, small papules with scale so subtle that it is often overlooked are well demarcated and tend to coalesce, especially on the mid-chest and mid-back (Figure 17.13). The organism sometimes produces folliculitis (pityrosporum folliculitis), primarily on the trunk. The diagnosis can be confirmed on a fungal preparation of skin. Short, curved hyphae and clusters of irregular buds are typical. Biopsies are not performed to diagnose this process, but

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histology shows abundant organisms in the stratum corneum, usually without accompanying inflammation. Pityriasis versicolor is produced by the organism Malassezia furfur; the previous term “tinea” versicolor is a misnomer, being a yeast form rather than dermatophyte. The treatment consists of oral or topical antifungal medications. All azoles and terbinafine are useful topically when applied once or twice daily. Extensive disease can be treated with oral itraconazole 200–400 mg daily for 1 week, fluconazole 400 mg for one dose, or ketoconazole 200 mg daily for 5–7 days. Griseofulvin and oral terbinafine are not useful. These therapies are faster, less irritating, and more cosmetically acceptable than selenium sulfide lotion, which was standard therapy in the past. However, regardless of therapy, recurrence is very common, and retreatment or intermittent suppression is to be expected.

Pityriasis rosea Pityriasis rosea is a common, innocuous, selflimited rash that primarily affects the trunk, but sometimes prominently includes the lower abdomen, hair-bearing areas of the vulva, and proximal thighs. Pityriasis rosea occurs most often in children and young adults, and it is often asymptomatic, although some patients experience itching. This eruption begins with a well-demarcated, often round and annular, pink, scaling plaque called a “herald patch.” The appearance of this lesion is followed by multiple 1–2-cm, fairly well-­demarcated, oval papules and plaques with subtle scale, whose long axis lies in natural skin lines (Figure 17.14). This sometimes produces, on the back, a “fir tree” configuration. Pityriasis rosea most closely resembles secondary syphilis. However, pityriasis rosea does not produce the lymphadenopathy or the palmar/ plantar skin lesions regularly seen with secondary syphilis. Pityriasis rosea is definitively differentiated by syphilis serology. There are no accompanying laboratory abnormalities. A biopsy is characteristic but not diagnostic, and shows patchy parakeratosis, mild

Figure 17.14  Oval, pink, lightly scaling papules that lie with the long axis along skin lines are classic for pityriasis rosea. An annular rim of scale (collarette) is often present on some lesions as well, as seen here on the posterior thigh and buttock.

acanthosis, spongiosis, and an upper dermal inflammatory infiltrate with a small admixture of lymphocytes, eosinophils, and hystiocytes. Exocytosis, dyskeratotic keratinocytes, and erythrocytes in the dermal papillae are sometimes present. The cause of pityriasis rosea is unknown. A nonspecific immunological response to a viral infection, an association with any of several herpes viruses, and a reaction to medication have all been postulated. There is no reasonable therapy that clears the eruption. For the patient who experiences pruritus, a mid-potency topical corticosteroid such as triamcinolone 0.1% cream or ointment generally improves itching, but not the appearance of the rash. For nongenital areas, sunlight sometimes improves the eruption, as can a tanning bed or medical-grade ultraviolet light therapy. Generally, the most reasonable therapy is time, as the eruption usually resolves within several weeks to 2 months. Recurrences are possible.

Plasma cell vulvitis (vulvitis plasmacellularis, Zoon’s vulvitis, vulvitis circumscripta plasmacellularis) Plasma cell vulvitis is a distinctive clinical and histologic picture that occurs on mucous membranes and modified mucous membranes, particularly the

Plasma cell vulvitis 177

Figure 17.15  The mucous membrane location and deep red-rust color of this well-demarcated patch is very   characteristic of plasma cell vulvitis.

Figure 17.16  Occasionally plasma cell vulvitis exhibits a speckled morphology, but still shows deep red or   brown-red color.

vulva. Plasma cell mucositis was first recognized on the glans penis, and has since been described on other mucous membrane surfaces, including the lips, gingivae, esophagus, trachea, and larynx4.

purpura (Figure 17.17). Generally, only the vulva is affected, with the oral mucosa spared.

Epidemiology and clinical manifestations Plasma cell vulvitis is an uncommon condition, but not as rare as many believe. There are no known associations or predisposing factors. Patients usually describe irritation, burning, and dyspareunia, although the severity of symptoms is quite variable. The lesions occur most often on mucous membranes of the vestibule and periurethral epithelium, but can also occur on the modified mucous membranes of the labia minora. Plasma cell vulvitis consists of one or more well-demarcated deeply red, nonscaling plaques (Figures 17.15 and 17.16). These plaques often have a shiny surface that suggests erosion. The red color is especially distinctive, showing a deep red-brown hue, sometimes with speckling, due to hemosiderin from

Differential diagnosis Any cause of red plaques of the mucous membranes and modified mucous membranes of the vulva can be considered in the differential diagnosis (Table 17.4). However, lichen simplex chronicus, contact dermatitis, seborrheic dermatitis, and psoriasis are less well demarcated, less deeply erythematous, and generally affect only the dry, keratinized skin surfaces. The superficial erosions of lichen planus and fixed drug eruption are the diseases most often confused with plasma cell vulvitis. Finally, vulvar intraepithelial neoplasia (VIN) 3 can be indistinguishable from plasma cell vulvitis. Histologically, the plasma cell infiltrate of plasma cell vulvitis can suggest a diagnosis of syphilis. Definitive differentiation between plasma cell vulvitis and the above diseases is made by biopsy, by correlation with other skin findings, by the onset, and by serology to rule out syphilis when indicated.

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Table 17.4  Plasma cell vulvitis Diagnosis Clinical appearance Deep red, glistening plaques on mucous membranes Confirmed on biopsy Differential Diagnosis Erosive lichen planus Fixed drug eruption Figure 17.17  A petechial appearance is common in women with plasma cell vulvitis.

Laboratory manifestations and histology The histology of plasma cell vulvitis is characteristic, showing a dense band-like inflammatory infiltrate of plasma cells associated with a thinned epidermis, sometimes with missing upper layers or even erosion. Epidermal cells are somewhat flattened, with intercellular edema. Extravasation of red blood cells occurs, and hemosiderin is sometimes present. Because a predominance of plasma cells is a nonspecific and common finding on vulvar skin, the presence of these cells in small numbers is not sufficient to make the diagnosis. The percentage of plasma cells is the single best criterion (greater than 50% is usual, and fewer than 25% is a nonspecific finding5).

Pathogenesis The cause of plasma cell vulvitis is unknown. Some believe it to be pathogenetically related to, or even a manifestation of, lichen planus. The nature of the biopsy suggests an immunologically mediated, inflammatory process, but poor response to antiinflammatory therapy and its stable, unchanging nature are unusual for an inflammatory process.

Therapy and prognosis There is no predictably effective treatment for plasma cell vulvitis. Women without significant symptoms do not require therapy. First-line therapy consists of an ultrapotent topical corticosteroid such as clobetasol propionate ointment applied sparingly twice daily6,7. An intralesional

Vulvar intraepithelial neoplasia 3 Management Topical corticosteroids, clobetasol ointment applied   twice daily and tapered to three times a week Intralesional corticosteroid such as triamcinolone acetate (Kenalog), diluted to 3–10 mg/mL

corticosteroid, such as triamcinolone acetonide (Kenalog) 3–10 mg/mL, 0.2–0.8 mL, is sometimes beneficial4. Topical cyclosporine and imiquimod have been used successfully, but irritation can be limiting8,9. Topical misoprostol was reported to be useful as well10. There are several reports of successful treatment of plasma cell balanitis with tacrolimus, but this may be less useful on the vulva11,12. In addition, the Food and Drug Administration warning regarding the possibility of carcinogenicity emphasizes the necessity of a biopsy-proven differentiation of plasma cell vulvitis from VIN 3.

Lupus erythematosus Lupus erythematosus is a highly variable autoimmune disorder that affects skin, and, often, other organ systems, especially the joints, kidneys, and central nervous system. Cutaneous lupus erythematosus occurs most often on the face and sunexposed surfaces of the skin. However, this disease can occur on any skin surface, including mucous membranes. Cutaneous lupus erythematosus can present as any of several morphologic variants. Chronic cutaneous lupus erythematosus (discoid lupus

Vulvar intraepithelial neoplasia 3

erythematosus) presents as 1–3-cm very inflammatory, fairly well-demarcated plaques, often with central scale/crust. These gradually evolve to display hypopigmented or depigmented central scarring with permanent loss of hair. This occurs most often on the face and scalp but can occur on any epithelial surface, including the vulva. Subacute cutaneous lupus erythematosus is manifested by well-demarcated, red, scaling plaques without scarring or crusting. Subacute cutaneous lupus erythematosus occurs primarily on dorsal arms and upper trunk. Acute cutaneous lupus erythematosus is associated with more severe systemic disease, and it occurs as red, usually poorly demarcated, dusky plaques with fine or no scale. A survey of 121 patients with lupus erythematosus showed mucous membrane involvement in general to be more common than previously believed, and two of 42 women (about 5%) with chronic cutaneous lupus erythematosus exhibited vulvar lesions, but none of the women with systemic lupus erythematosus had vulvar involvement13. The differential diagnosis of cutaneous lupus erythematosus of the vulva includes other inflammatory and desquamative processes, including lichen planus, psoriasis, lichen simplex chronicus, and contact dermatitis. The diagnosis of cutaneous lupus erythematosus is made by biopsy. Histology varies with the form of cutaneous lupus erythematosus sampled, but all show a mononuclear patchy and periappendageal dermal inflammatory infiltrate and edema. Hallmarks are hydropic degeneration of the basal cells of the epidermis and follicles, and disruption of the basement membrane. The management of cutaneous lupus erythematosus includes an evaluation for systemic disease as well as careful patient education regarding the impact of serious disease, and the more minor repercussions of chronic cutaneous lupus erythematosus. Specific treatment includes topical corticosteroids which improve but do not eliminate lesions, and hydroxychloroquine 200 mg twice daily ongoing. Other medications include chloroquine, quinicrine, isotretinoin or acitretin, thalidomide, or antimetabolites such as azathioprine or cyclophosphamide. Generally, chronic ­cutaneous lupus erythematosus is not related to

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Figure 17.18  Vulvar intraepithelial neoplasia (VIN) 3 has several forms, and the red form appears inflammatory or erosive, mimicking plasma cell vulvitis and lichen planus. This patient with lichen sclerosus and a history of squamous cell carcinoma removed by vulvectomy in the past has recently developed VIN 3.

severe ­ systemic disease, but this disease requires ongoing therapy to maintain control.

Vulvar intraepithelial neoplasia 3 (Bowen’s disease, squamous cell carcinoma in situ: discussed primarily in chapter 23) VIN 3 represents squamous cell carcinoma in situ, and it mimics inflammatory dermatoses. This condition is often asymptomatic, but sometimes presents with itching or burning/irritation. VIN 3 occurs in two clinical forms. First are small red, white, or brown, well-demarcated papules and plaques associated with human papillomavirus infection (bowenoid papulosis) and most often found in sexually active young individuals. Second are larger plaques (Bowen’s disease), occurring primarily in postmenopausal women, usually unassociated with human papillomavirus infection, and often associated with lichen sclerosus. These are covered with scale when occurring on dry, hair-bearing skin. When the mucous membranes are affected, lesions may be deep red and mimic erosions (Figure 17.18). The differential diagnosis of the larger red plaque includes candidiasis, lichen planus, plasma cell vulvitis, psoriasis, and eczema. Human ­papillomavirus-associated VIN 3 most resembles

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genital warts or seborrheic keratoses. Treatment includes laser, cryotherapy, and excision, as well as topical fluorouracil and imiquimod, used offlabel. Because of the risk of invasive squamous cell carcinoma, these patients should be carefully followed for complete resolution and for recurrence, since recurrence is common.

References   1. Myers, W. A., Gottlieb, A. B., and Mease, P. Psoriasis and psoriatic arthritis: clinical features in disease mechanisms. Clin. Dermatol. 2006; 24: 438–447.   2. Liu, Y., Krueger, G., and Bowcock, A. M. Psoriasis: genetic associations in immune system changes. Genes Immun. 2007; 8: 1–12.   3. Ludwig, R. J., Herzog, C., Rostock, A., et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br. J. Dermatol. 2007; 156: 271–276.   4. Yang, J. H., Lee, U. H., Jang, S. J., et al. Plasma cell cheilitis treated with intralesional injection of corticosteroids. J. Dermatol. 2005; 32: 987–990.   5. Virgili, A., Levratta, A., Marzola, A., et al. Retrospective histopathologic reevaluation of 18 cases of plasma cell vulvitis. J. Reprod. Med. 2005; 50: 3–7.   6. Yoganathan, S., Bohl, T. G., and Mason, G. Plasma cell balanitis and vulvitis (of Zoon). A study of 10 cases. J. Reprod. Med. 1994; 39: 939–944.   7. Botros, S. M., Dieterich, M., Sand, P. K., et al. Successful treatment of Zoon’s vulvitis with high potency topical steroid. Int. Urogynecol. J. Pelvic Floor Dysfunct. 2006; 17: 178–179.   8. Heinemann, C., Fischer, T., Barta, U., et al. Plasma cell mucositis with oral and genital involvement – successful treatment with topical cyclosporine. J. Eur. Acad. Dermatol. Venereol. 2006; 20: 739–740.   9. Ee, H. L., Yosipovitch, G., Chan, R., et al. Resolution of vulvitis circumscripta plasmacellularis with topical imiquimod: two case reports. Br. J. Dermatol. 2003; 149: 638–641.

10. Gunter, J. and Golitz, L. Topical misoprostol therapy for plasma cell vulvitis: a case series. J. Low. Genit. Tract Dis. 2005; 9: 176–180. 11. Moreno-Arias, G. A., Camps-Fresneda, A., Llaberia, C., et al. Plasma cell balanitis treated with tacrolimus 0.1%, Br. J. Dermatol. 2005; 153: 1204–1206. 12. Virgili, A., Mantovani, L., Lauriola, M. M., et al. Tacrolimus 0.1% ointment: is it really effective in plasma cell vulvitis? Report of four cases. Dermatology. 2008; 216: 243–246. 13. Burge, S. M., Frith, P. A., Juniper, R. P., et al. Mucosal involvement in systemic and chronic cutaneous lupus erythematosus. Br. J. Dermatol. 1989; 121: 727–741.

Further reading Psoriasis Lowes, M. A., Bowcock, A. M., and Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 2007; 445: 866–873.

Reiter’s syndrome Kataria, R. K. and Brent, L. H. Spondyloarthropathies. Am. Fam. Physician 2004; 69: 2853–2860.

Pityriasis versicolor Gupta, A. K., Kogan, N., and Batra, R. Pityriasis versicolor; a review of pharmacological treatment options. Exp. Opin. Pharmacother. 2005; 6: 165–178.

Plasma cell vulvitis (Zoon’s vulvitis) Scurry, J., Dennerstein, G., Brenan, J., et al. Vulvitis circumscripta plasmacellularis. A clinicopathologic entity? J. Reprod. Med. 1993; 38: 14–18.

Lupus erythematosus Burge, S. M., Frith, P. A., Juniper, R. P., et al. Mucosal involvement in systemic and chronic cutaneous lupus erythematosus. Br. J. Dermatol. 1989; 121: 727–741.

PART: II  Gynecologic Dermatology

CHAPTER 18

Vulvar Dermatoses: the Eczematous Diseases Peter J. Lynch

The eczematous diseases account for a very large proportion of all disorders occurring in the vulvar area. Most of the eczematous diseases are quite symptomatic and this leads to high demand for attention from patients and rapid patient dissatisfaction when the problem is not quickly recognized and appropriately treated. The morphology of the eczematous diseases overlaps with that of the papulosquamous diseases (see Chapter 17). The three ­morphological features that the eczematous diseases share with the papulosquamous diseases include red color, overlying scale, and elevated papules and plaques. However the eczematous diseases do have three distinctive morphologic features that help to separate them from the papulosquamous diseases: (1) the presence of indistinct lesional margination; (2) evidence of epithelial disruption; and, in the special case of pruritic eczematous disease, (3) lichenification. Lesional margination: Margination refers to the transition between normal and diseased tissue. Sharply marginated lesions have an abrupt transition such that one could place a pencil point at the exact border between normal and abnormal tissue. With indistinctly marginated lesions, the transition occurs over a matter of several millimeters. In this case, the margin of the lesions fades imperceptibly into the surrounding normal tissue and it is impossible to mark the exact point of transition. One can also consider the sharpness of margination by visualizing the contour of the lesion as seen in crosssection. A sharply marginated lesion would be quite square-shouldered whereas an indistinctly marginated lesion would demonstrate significantly sloped shoulders. Papulosquamous lesions have sharply marginated borders around the entire circumference of the lesion whereas eczematous lesions are indistinctly marginated over at least a major portion of their circumference. Epithelial disruption: When the epithelial barrier layer is intact it allows no clinically perceptible passage of fluid in either direction

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across it. An intact epithelial barrier layer is found in the papulosquamous disease but it is disrupted in the eczematous diseases. There are five signs, any one or combination of which indicates the presence of epithelial disruption: (1) easily visible linear or angular erosions due to excoriation; (2) barely visible narrow erosions in the form of fine fissures; (3) a wet surface due to “weeping” or “oozing”; (4) crusting, due to the evaporation of surface water leaving dried plasma proteins. The color of crust is yellow (when no blood cells are present) and red, purple, or black (when blood cells are present); and (5) yellow scale, due to minimal fluid flow which colors existing scale rather than building up as crust. Lichenification: When the skin of the palms and soles is chronically traumatized, it undergoes a protective response which we recognize as callus. Chronically traumatized tissue at other sites, due to chronic rubbing, also forms a protective response involving the thickening of the epidermis and the stratum corneum. This response, called lichenification, is characterized by three findings: (1) compacted scale; (2) exaggerated skin markings; and (3) palpable thickening. Lichenification is generally only encountered in the presence of atopic/neurodermatitis and its localized variant, lichen simplex chronicus. Theoretically, the characteristic features described above would allow one to recognize readily the presence of an eczematous disease. Unfortunately, in the anogenital area, the ­ presence of heat and sweat (with resultant maceration) leads to a great deal of background “noise” which can sometimes obscure the true nature of the process. Improvement of the environmental condition, treatment of any associated rubbing or scratching, and/or biopsy may be necessary to differentiate an eczematous disorder from a papulosquamous disorder.

Atopic/neurodermatitis and lichen simplex chronicus Atopic/neurodermatitis and its localized variant lichen simplex chronicus are by far the most important of the conditions found in the eczematous disease category. In fact, this form

of ­ eczematous disease is so important that the entirety of Chapter 16 is devoted to this subject. A clinician faced with vulvar lesions possessing the morphology of an eczematous process (as defined above) that is accompanied by persistent scratching and rubbing is almost certainly dealing with lichen simplex chronicus. In such a situation the material in Chapter 16 should be reviewed as it will allow for confirmation of diagnosis and establishment of an effective therapeutic program.

Contact dermatitis There are two forms of contact dermatitis: irritant and allergic contact dermatitis. The former is due to direct destructive effect by the contactant and is fairly common. The latter is due to a contactantinduced, immunologically mediated reaction and is uncommonly encountered.

Irritant contact dermatitis Epidemiology and clinical manifestations

The exact prevalence of irritant contact dermatitis has not been established but most clinicians would agree that it occurs fairly frequently. This is particularly true when one considers the extremes of age in infancy and the elderly, where “diaper dermatitis” is almost inevitable. For the rest of the population the situation is less clear. Women in early and middle adult life are certainly exposed to many irritants but it is often unclear what role, if any, these are playing in terms of the patient’s presenting symptoms and signs. Irritant contact dermatitis can either arise de novo on normal tissue or may develop as a superimposed phenomenon on some other disorder. Irritant contact dermatitis can be acute or chronic in type1. In acute contact dermatitis, the contactant causing the problem is so damaging that only one or two exposures are enough to create a marked inflammatory response. There is also only a short time period between the point of exposure and the development of the reaction. These two facts make the identification of the contactant quite easy. For patients who withhold history (such as those who are self-destructive and those with obsessive-compulsive behavior),

Contact dermatitis

the diagnosis may be less readily apparent. In the instance of acute irritant contact dermatitis, the involved tissue is quite red and often edematous. Pain is present, scale is minimal, and the surface may be eroded (Figures 18.1 and 18.2). On the other hand, the development of chronic contact dermatitis is due to a less damaging contactant requiring multiple exposures over a longer time frame. In this situation, tissue swelling is minimal and redness, often with dusky or violaceous hues, is less intense (Figure 18.3). Fine cracks and fissures may be noted and the vulva may appear dry and chapped. Some scale is likely to be present. Symptoms are usually those of mild burning or irritation; itching is not usually a prominent feature.

Diagnosis and differential diagnoses

Figure 18.1  Deep redness with erosions (arrows) as a result of acute irritant dermatitis produced by fluorouracil applied to treat genital warts. (Reproduced from P. J. Lynch and L Edwards Genital Dermatology (Fig. 5-11), New York: Churchill Livingstone; 1994.)

Figure 18.2  Harsh disinfectants have produced an exudative, vesicular, and edematous acute irritant ­dermatitis. (Reproduced from P. J. Lynch and L Edwards Genital ­Dermatology (Fig. 5-12), New York: Churchill Livingstone; 1994.)

Nearly all of the other papulosquamous and eczematous diseases have to be considered (Table 18.1). Sometimes it is difficult to separate irritant contact dermatitis from allergic contact dermatitis2. The correct diagnosis depends on obtaining a thorough history of what the patient has been applying to her anogenital area. Unfortunately, patients are often forgetful about what they are using and also may be reticent or ashamed to list everything. For this reason, questions about what products are being used must be asked on multiple occasions. It is also helpful to ask the patient to go through her medicine cabinet and, at the time of the next visit, to bring in every topical agent that is found there.

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Table 18.1  Irritant Contact Dermatitis Diagnosis   Flat, dusky red, chapped, eczematous patches   History of products which overdry or macerate skin   History of excessive hygiene Differential Diagnosis   Candida vulvitis   Allergic contact dermatitis   Atopic/neurodermatitis   Lichen simplex chronicus   Seborrheic dermatitis Therapy   Identify and remove irritants   Low- (1% hydrocortisone) or medium-strength (0.1% triamcinalone) steroid ointments Figure 18.3  The ongoing exposure of skin to urine and feces has produced a chronic irritant dermatitis manifested by dusky redness and edema of the vulva and perianal skin in this incontinent woman.

Histology and laboratory findings

Biopsy is not useful in identifying irritant contact dermatitis, though sometimes it might be warranted to determine if an underlying disorder might also be present. Patch tests are usually not indicated for patients with suspected irritant contact dermatitis but some would argue that, since it is difficult to tell irritant contact dermatitis from allergic contact dermatitis, patch testing should be carried out on all women with therapeutically unresponsive eczematous disease of the vulva. Patch testing is further discussed in the section on allergic contact dermatitis, below. Pathogenesis

In acute irritant contact dermatitis, the irritants are directly cytotoxic to epithelial cells. Most of the strong irritants are physician-ordered or applied medications such as flurouracil, imiquimod, trichloroacetic acid, and podophyllin1.

However, one should never underestimate what products women might apply to the vulva when they are desperate or obsessed. We have seen reactions to bleaches, lye, kerosene, and many other unusual substances. Chronic irritant contact dermatitis arises as a result of relatively minor changes in the environment. Most of these changes have to do with the regulation of water content within the epithelial cells. These cells die when they are either too dry or too wet. In infants and the incontinent elderly, maceration and cell death occur when wet diapers, pads, or clothing are held tightly against the skin such that evaporation cannot easily occur. In this situation the fluid is usually urine, though sweat and fecal contamination may also play a role. A similar problem can occur in women who have chronic vaginal discharge leading to the constant use of panty liners or menstrual pads. On the other hand, in the majority of young and middle-aged women, the problem is one of excess dryness due to unnecessary, inappropriate or overly energetic hygiene. Some women have grown up with the notion that “the area down

Contact dermatitis

there” is “dirty” and must be scrubbed frequently and vigorously. In other instances, women overdo washing because they are worried about real or imagined odor. Water that is too hot, detergents that are too harsh, and toweling that is too brisk are commonly the culprits. But, in addition, “normal” soap and water washing may be carried out too frequently, i.e., more than twice daily.

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Therapy and prognosis

The sine qua non of therapy is the removal of the offending contactant and a return of hygiene habits to normal. Sometimes this is easy but sometimes it is not. For instance, as a part of obsessive-­compulsive behavior a woman may become “addicted’ to a certain ritual and may find it impossible to give it up even when she knows that it is detrimental to her vulvar health. Similarly, sometimes a patient is unwilling to give up her destructive behavior because of secondary gain or because of a feeling of sexual guilt. Topical steroids of mid to high potency (triamcinolone 0.1% or fluocinonide 0.05%) may be used twice daily for a week or two. They are best applied in an ointment vehicle both to retard evaporative water loss and to avoid further irritation due to alcohols, preservatives, and stabilizers found in creams and gels. Lubricants are essential in almost all instances. While the process is acute, products such as petrolatum work well. Later on, a hand cream of the patient’s choice may be acceptable. In instances of maceration, zinc oxide ointment or paste may help to keep the chronic moisture away from the skin.

Allergic contact dermatitis Epidemiology and clinical manifestations

The prevalence of allergic contact dermatitis is difficult to determine. In those clinical settings where patch testing for women with vulvar dermatitis is carried out on a regular basis, about 50% (range 38–78%) of patients have developed one or more positive tests1,3. These patch tests were deemed clinically relevant in about 30% of all women with positive tests1,3,4. However, in clinics where patch testing is carried out infrequently, the percentage of positive patch tests, and hence the purported incidence of allergic contact ­dermatitis,

Figure 18.4  Allergic contact dermatitis of the vulva. The patient intermittently used a topical medication containing neomycin, to which she was allergic.

is much lower. How much lower is difficult to say, but we believe it is less that 5%. At this point, it is not possible to explain this wide discrepancy. The clinical appearance of allergic contact dermatitis is that of bright red, edematous papules and plaques (Figure 18.4). Scale is not prominent and may be absent. Pruritus is marked and excoriations may be present. An element of the itch–scratch cycle (lichen simplex chronicus) often develops, creating a confusing clinical picture. Initial sensitization to an antigen takes 7–10 days but, once sensitization is present, reapplication of the antigen results in an inflammatory reaction within minutes to hours. For this reason, the appearance of allergic contact dermatitis to a new product is delayed for days but reapplication at a later time quickly causes symptoms and signs.

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Diagnosis

when the antigen is removed from the patient’s environment.

  Bright red eczematous plaques

Histology and laboratory testing

Table 18.2  Allergic Contact Dermatitis

  History of topical medication use   Consider patch testing Differential Diagnosis   Candida vulvitis   Irritant contact dermatitis   Atopic/neurodermatitis   Lichen simplex chronicus   Seborrheic dermatitis Therapy   Identify and remove sensitizing products, especially ­topical medications   Mid-potency (triamcinolone 0.1%) steroid ointment

Diagnosis and differential diagnoses

The clinical appearance of allergic contact dermatitis can overlap with that of irritant contact dermatitis2 but brighter red color, presence of edema, lack of a chapped appearance, and prominent itching point more toward an allergic reaction (Table 18.2). Other eczematous diseases such as lichen simplex chronicus and seborrheic dermatitis are also similar in appearance. Even candidiasis and papulosquamous conditions, to include psoriasis and tinea cruris, need to be considered. The diagnosis of allergic contact dermatitis can usually be established on the basis of a history involving the application of “high-risk” products (see below). A suspected diagnosis can be confirmed with patch testing. However, because of the high frequency of positive tests that lack clinical relevance, all the following criteria must be present when a patch test is positive and a diagnosis of allergic contact dermatitis is entertained: the specific antigen causing the positive test must be identified as present in the patient’s environment and resolution of the dermatitis must occur

Biopsy is rarely useful. The histology of allergic contact dermatitis is that of “spongiotic dermatitis” but this finding does not identify the process as specifically that of allergic contact dermatitis. Biopsy can however be useful in ruling out other, noneczematous disorders. Patch testing is very controversial for several reasons. First, a positive patch test does not automatically confirm that the vulvar lesions are those of allergic contact dermatitis. A positive result simply means that the person was previously exposed to that antigen and that allergic sensitization took place. It says very little, if anything, about the relationship of such a reaction and the patient’s current problem. This situation is analogous to that of a patient with a new onset of a cough, in which a positive tuberculosis skin test does not necessarily mean that this new cough is due to tuberculosis. Second, patch testing is not very specific. A large percentage of patients with no skin disease whatsoever have one or more positive patch tests. Third, patch testing is not very sensitive. The number of substances available for use in patch testing is extremely limited ­compared to the hundreds of antigens that are potentially present in the patient’s vulvar environment. Fourth, patch testing cannot realistically be carried out on the vulva and patch testing elsewhere does not mimic the tissue, or the tissue response, of the vulva5. When I think that allergic contact dermatitis may be present, I prefer to test with the actual product suspected of causing the reaction. A small amount of the product is placed on the center of a circular “spot” bandage that is then applied to the patient’s upper inner arm. A piece of tape is applied over the bandage to insure that the product is held in close contact with the skin. The tape and bandage are removed in 48 hours. Redness at the site indicates a positive response. If the patient develops a positive reaction, I test myself as well. If I also react positively, the product is probably acting as an irritant. If I don’t react, the product may be acting as an allergen.

Intertrigo and seborrheic dermatitis Pathogenesis

Allergic contact dermatitis arises as the result of a type 4, cell-mediated immune response. At the time of initial sensitization, an antigen enters the epidermis where it is picked up by a macrophage of the Langerhans cell type. This cell then transports the antigen to the regional lymph nodes. There the antigen is presented to the T-cell system where it induces T-cell activation and proliferation. These activated T cells then move back to the skin, where they create a localized inflammatory reaction. Entry of the antigen into the epidermis is enhanced when the epithelial barrier layer is not intact. For this reason the development of allergic contact dermatitis is most likely to occur when products are applied to already diseased tissue. The products most likely to induce allergic contact dermatitis are medications applied for the treatment of a vulvar disorder3. The most frequent offenders are products such as antibiotics (neomycin, bacitracin, and sulfa-related products) and anesthetics (benzocaine and diphenhydramine). Of these, Vagisil, because it contains benzocaine and because it is so widely used, is perhaps the most common offender1. Other products such as anticandidal agents, estrogens, spermicides, and chemicals used in the preparation of topical agents (preservatives, stabilizers, and fragrances) are much less likely to cause allergic contact dermatitis. Topical steroids have very rarely been reported as offending agents. Some contactants such as latex and seminal fluid cause allergic reactions but these are type 1 in nature and result in urticarial and edematous changes rather than eczematous lesions (see Chapter 25). Although frequently cited by patients and some clinicians, it is unlikely that panty liners, menstrual pads, tampons, underwear, other types of clothing, or the detergents used in laundering are ever responsible for allergic reactions. Reactions that appear to be due to these products are ­generally due to irritant factors such as sweat, urine, or vaginal discharge rather than to the products themselves. Therapy and prognosis

Effective therapy requires the identification and removal of the offending agent from the patient’s vulvar environment. Lists of products containing

the most common antigens responsible for allergic contact dermatitis can be obtained from textbooks and other sources. Offering patients this information will assist them in avoiding unexpected contact with antigens that may not otherwise be apparent from information found on medication labels. Theoretically, additional therapy would not be necessary once the allergen is removed but resolution following removal is a slow process that can be significantly speeded up with the addition of topical steroids, together with lubrication, as described in the therapy section for irritant contact dermatitis, above. Immunological memory lasts a very long time. For this reason, subsequent contact with an allergen will lead to redevelopment of allergic contact dermatitis even after years with no exposure to the offending agent. Moreover, patients can be remarkably sensitive to very small amounts of antigen, requiring great care to insure complete avoidance.

Intertrigo and seborrheic dermatitis The health and function of epithelial cells are constrained by a number of environmental factors. Moisture content, both within and around the cells, is among the most important. When the air around epithelial cells is too dry, water evaporates from the cells. They then shrink, separate, and die (see section on irritant contact dermatitis, above). Likewise, if the air around epithelial cells is too wet, maceration occurs, inflammation is engendered, and cells die. Intertrigo and seborrheic dermatitis arise because of maceration and thus they could be considered as a very mild form of irritant contact dermatitis. Vulvar intertrigo occurs when fluids such as sweat, urine, or vaginal discharge are held in place in the skin folds of the anogenital regions. Not surprisingly, intertrigo occurs most often in those who are obese and those living in hot, humid climates. On examination there is nonelevated redness without scale (Figures 18.5 and 18.6). In the setting of prolonged maceration, inflammation worsens and leads to mild epithelial disruption and some yellow scale formation. Thus, intertrigo can gradually evolve into seborrheic dermatitis. Secondary candidiasis, with small

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Figure 18.5  Seborrheic dermatitis in skin folds. Mild ­seborrhea often shows Pityrosporum ovale on potassium hydroxide examination; severe involvement (shown here) may be an overlap with psoriasis (sebopsoriasis).

Figure 18.6  Seborrheic dermatitis, showing erythema of the vulva and intertriginous areas. This looks very much like psoriasis, but the typical scale is lacking. The patient also had lesions on the face and inframammary area, which were typical of seborrheic dermatitis. If there had also been scaling psoriatic plaques on the knees and elbows, this would have been called “sebopsoriasis.”

papules and pustules, is a frequent complication of both intertrigo and seborrheic dermatitis. Vulvar seborrheic dermatitis is almost entirely confined to infants, where it is usually accompanied by seborrheic dermatitis of the scalp, axillae, and ­retroauricular areas (Figure 18.7). When what looks like severe seborrheic dermatitis occurs in infants, one should consider the possible presence of the Letterer–Siwe type of Langerhans cell histiocytosis, as the appearance of these two conditions can be quite similar. Treatment for intertrigo and seborrheic dermatitis is similar. The key step is to improve the local environment via the use of loose clothing, air

Figure 18.7  Vulvar seborrheic dermatitis is generally a ­pediatric disease, and characterized by red plaques with moist scale. Usually accompanied by “cradle cap” and other skin fold seborrhea, it can resemble psoriasis. (Reproduced from P. J. Lynch and L Edwards Genital Dermatology (Fig. 22-3), New York: Churchill Livingstone; 1994.)

conditioning, frequent drying, avoidance of prolonged sitting, avoidance of vinyl seating surfaces and, where possible, weight loss. Note that the use of hair dryers worsens, rather than helps, the problem. Topical steroids are very helpful. Lowpotency (2.5% hydrocortisone) or mid-potency (triamcinolone 0.1%) products are sufficient. Dermatologists generally treat seborrheic dermatitis of the scalp and upper trunk with antiyeast products based on the premise that the condition is mediated by overgrowth of the yeasts normally found in hair follicles. Whether this approach would be helpful in an anogenital location has not been studied. Recurrences of intertrigo and seborrheic dermatitis are likely and repeated treatment may therefore be necessary.

Candidal vulvitis The primary coverage of candidiasis can be found in Chapter 24. Only the clinical appearance of candidiasis as it occurs on the cutaneous aspects of the anogenital area will be discussed here. On the vestibular portion of the vulva, overgrowth of Candida spp. increases the intensity of the red color that is normally present at that location. Involvement of the labia minora and interlabial folds similarly demonstrates increased redness. In these sites the tissue may also appear somewhat edematous (Figures 18.8 and 18.9).

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Figure 18.9  When Candida affects the surrounding, hair­bearing skin, scale and fissuring of skin folds can be prominent.

Figure 18.8  Candidiasis of the modified mucous membranes of the vulva is associated with redness and edema.

However, involvement of the perianal area, labia majora, genitocrural folds, and upper, inner thighs results in the additional development of red papules and poorly marginated plaques. The papules occur as “satellite” lesions at the periphery of the plaque formation. Characteristically, some of the papules are capped with small pustules (Figure 18.10). Individual and/or grouped pustules can also be found scattered throughout the major area of plaque involvement. In the most severe cases, superficial erosion of the inflamed sites occurs. Overall, the clinical morphology of Candida vulvitis is that of an eczematous process and, as would be expected, itching or burning or both are present. In many instances it will be hard to differentiate candidiasis from other eczematous ­diseases and, in fact, in addition to arising on normal skin, candidiasis can be superimposed on other

Figure 18.10  Candida preferentially affects moist, warm skin folds, and the periphery of the plaques often shows pustules, desquamation, or collarettes, the circles of scale left when fragile pustules break.

eczematous and papulosquamous diseases. Clinical signs pointing towards the presence of candidiasis include the presence of pustules, satellite papules, and fissuring within the gluteal cleft and the interlabial and genitocrural folds. ­Microscopic

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examination with potassium hydroxide (KOH) of a smear taken from an intact pustule may reveal pathognomic hyphae. Most vulvar candidiasis develops concomitantly with vaginal infection. However, vulvar involvement can also occur in the absence of symptomatic vaginitis. Because Candida spp. are frequent asymptomatic inhabitants of both the lower gastrointestinal tract and the vagina, “seeding” on to the vulva can occur from either source. With this in mind, one should never exclude the possibility that a vulvar eruption is due to candidiasis just because there are no vaginal symptoms or signs. Candidal vulvitis is best treated with either topical or oral imidazole or triazole derivatives. These agents are more fully discussed in Chapter 24 and in Appendix 3. All of these “azoles” are about equally effective. Some Candida spp. are more resistant to these agents than is Candida albicans but for vulvar disease (as opposed to vaginal disease) this relative resistance does not seem to interfere with clinical response. Historically, nystatin cream or ointment has been widely used, but most vulvologists believe that it is significantly less efficacious than the “azoles.” If itching and inflammation persist after a few days of “azole” therapy, a low- (hydrocortisone 2.5%) or mid- (triamcinalone 0.1%) potency topical steroid cream or ointment can be added. For various reasons, most dermatologists prefer not to use the prepackaged combination steroid/antifungal agents such as Lotrisone and Mycolog II.

pattern includes the neck, axillae, inframammary folds, and the anogenital skin, to include the vulva. Minute vesicles, occurring within the plaques, can sometimes be found but, because of their fragility, the surface usually takes on an eroded, eczematous appearance (Figures 18.11 and 18.12). Untreated, plaques enlarge centrifugally, sometimes with evidence of clearing in the center. Long-standing lesions located in intertriginous folds may become somewhat vegetative or hypertrophic (Figure 18.13). Itching is minimal but burning or stinging is regularly present. The discomfort, unpleasant appearance, and malodor associated with these lesions regularly interfere with daily activities and interpersonal relationships. The quality of life described by patients is very poor.

Hailey–Hailey disease (familial benign pemphigus)

Histology and laboratory tests

Epidemiology and clinical manifestations This is a rare condition, with a prevalence of about 1 per 100 000 persons. It is inherited as an autosomal-dominant condition but penetrance is highly variable and for this reason a positive family history is not always obtainable. Men and women are affected equally. The severity of the disease ­fluctuates with the temperature and humidity, worsening appreciably in hot, humid weather. The disorder first appears most often in late childhood or early adult life. The usual ­distribution

Differential diagnosis Hailey–Hailey disease can be recognized clinically based on the distinctive distribution pattern and the usual presence of a positive family history (Table 18.3). However, Candida vulvitis, atopic dermatitis, lichen simplex chronicus, seborrheic dermatitis, Darier’s disease, and pemphigus are quite similar in appearance to Hailey–Hailey disease. Candidiasis can be identified by way of its excellent response to anticandidal therapy. Atopic dermatitis, lichen simplex chronicus, and seborrheic dermatitis, in contrast to Hailey–Hailey disease, improve remarkably with steroid therapy. Darier’s disease and pemphigus have a different and distinctive distribution pattern.

The major histological feature is the presence of acantholysis, which is the process whereby epidermal cell adhesion is lost, causing the cells to round up and “float” free from their neighbors within suprabasilar clefts. Uncommonly, there is enough premature keratinization (dyskeratosis) of the cells to suggest the possibility of Darier’s disease. Direct immunofluorescent studies may be necessary to rule out pemphigus. There is another process that histologically (though not clinically) appears almost identical to Hailey–Hailey disease and Darier’s disease. This disorder is variously termed papular acantholytic

Hailey–Hailey disease (familial benign pemphigus) 191

Figure 18.12  The superficial vesicles of Hailey–Hailey typically erode quickly, forming characteristic linear and angular erosions. (Reproduced from P. J. Lynch and L Edwards Genital Dermatology (Fig. 5-14), New York: Churchill Livingstone; 1994.) Figure 18.11  Hailey–Hailey disease of the vulva.

dermatosis, papular acantholytic dyskeratosis, or papular genitocrural acantholysis6,7. It presents as individual, skin-colored, white or slightly red papules that are usually described as “warty” in appearance. Confluence of these lesions to form plaques, such as occurs in Hailey–Hailey and Darier’s disease, does not regularly occur and the distribution does not involve areas outside the anogenital tissue.

Pathogenesis The genetic defect for Hailey–Hailey disease involves mutations in ATP2C1, a gene that plays an important role in calcium transport and, ­subsequently, epidermal cell-to-cell adhesion8. The mutated gene is transmitted in an ­autosomaldominant fashion. Clinical expression of the

Figure 18.13  The chronic maceration, friction, and ­thickening of skin from irritation sometimes eventuate into thickened, white plaques. (Reproduced from P. J. Lynch and L Edwards Genital Dermatology (Fig. 5-15), New York: Churchill Livingstone; 1994.)

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Table 18.3  Hailey–Hailey Disease Diagnosis   Red papules and plaques   Eroded surface with yellow crust   Involvement of multiple intertriginous sites   Family history of similar lesions   Distinctive findings on biopsy Differential Diagnosis   Darier’s disease   Pemphigus Therapy   Decrease heat, sweating, and retained moisture   Oral anticandidal therapy   Oral antibacterial therapy

Bacterial and candidal overgrowth on the diseased skin is regularly present. Treatment of these microbes improves the condition and reduces problems with malodor. We prefer the use of oral, rather than topical, agents as the latter may be locally irritating. Likewise, reduction of inflammation with intramuscular or short-term oral steroids is useful. Good results have also been reported in a few cases with use of the anti-inflammatory calcineurin inhibitor tacrolimus10. Ablative laser therapy, usually with the carbon dioxide laser, seems to work better than might otherwise be expected11. There are scattered case reports describing the beneficial effects of cyclosporine, photodynamic therapy, topical calcipotriene, and surgical excision with grafting. Hailey–Hailey disease is characterized by its chronicity. The best that can be hoped for is clinical clearing followed by recurrent episodes of activity. Several cases of squamous cell carcinoma have been reported in patients with vulvar ­ Hailey–Hailey disease.

  Mid-potency (0.1% triamcinalone) cream   Brief burst of systemic steroids   If insufficient improvement: botulinum toxin, laser therapy

­ isease may require some degree of environmental d insult to the skin, such as sweating, sunburn, or mechanical trauma.

Therapy and prognosis Treatment for this condition is difficult. The first step is to reduce the environmental trauma that is associated with flare-up of the disorder. This can be achieved by reducing friction related to clothing and reducing the amount of heat, and thus sweating, to which the individual is exposed. Sweating in the anogenital area can be usefully reduced with intracutaneously injected botulinum toxin9. Antiperspirants are too irritating to be used on diseased skin, but once the skin has cleared, they may help prevent recurrences. For women with vulvar involvement, care should be taken to treat any vaginal discharge and reduce any urinary incontinence. Avoidance of panty liners and the use of tampons rather than menstrual pads may be helpful.

Darier’s disease (Darier–White disease, keratosis follicularis) Epidemiology and clinical manifestations Darier’s disease is slightly more common than Hailey–Hailey disease, with a prevalence of about 3 per 100 000. The predisposition for the disease is inherited in an autosomal-dominant pattern. The cutaneous lesions first appear in late childhood or early adult life and, initially, consist of brown keratotic papules with overlying scale and yellow crust. With time, the papules coalesce to form hyperkeratotic plaques. The distribution almost always involves the “seborrheic” areas – scalp, forehead, chest, shoulders, and retroauricular folds of the ears. Other intertriginous sites, such as the axillae and anogenital area, are somewhat less commonly involved. The frequency with which vulvar lesions occur is not known but most patients with Darier’s disease are described as having scattered papules involving the flexural folds, to include the genitocrural folds. A few patients have their predominant distribution in intertriginous folds and some of these patients develop sizeable heaped-up, “vegetative,” hyperkeratotic plaques. Oral lesions are fairly

Darier’s disease (Darier–White disease, keratosis follicularis)

common but there is only one report of vaginal involvement. There are a number of reports of so-called localized Darier’s disease limited solely to the anogenital area. However, it is likely that most of these patients have, instead, the entity variously known as papular acantholytic dermatosis, papular acantholytic dyskeratosis, or papular genitocrural acantholysis6,7. These patients usually have fairly mild disease with discrete wart-like papules that do not usually coalesce to form plaques. See Hailey–Hailey disease (above) for an additional discussion of this condition. Most patients experience at least moderate pruritus. A minority describe pain, especially when the hyperkeratotic plaques split, causing open, linear erosions. Bacterial degeneration of soggy keratin in intertriginous folds regularly leads to malodor. Involvement of the hands is very characteristic. Small, skin-colored papules occur on the dorsal hand. Pits and keratotic papules can be found on the palmar surface. Fingernail involvement occurs in nearly all patients, with distal V-shaped notches and ridges or stripes (white or red, or both) running from the posterior nail fold to the distal nail edge. A number of patients with Darier’s disease have been identified with low intelligence, epilepsy, and psychiatric disorders.

Table 18.4  Darier’s Disease Diagnosis Brown-red papules and plaques Scaling and crusted surface Seborrheic distribution: scalp, neck, chest, retroauricular folds Hand lesions: dorsal papules, nail notching, red or white nail stripes Family history of similar lesions Distinctive findings on biopsy Differential Diagnosis Hailey–Hailey disease Candidal vulvitis Atopic/neurodermatitis Lichen simplex chronicus Seborrheic dermatitis Therapy Decreased heat, sweating, and retained moisture Oral anticandidal therapy

Differential diagnosis

Oral antibacterial therapy

Clinically Darier’s disease of the anogenital area can be confused with Hailey–Hailey disease, seborrheic dermatitis, candidiasis, and pemphigus (Table 18.4). The distinct seborrheic distribution pattern, the characteristic hand lesions, and a positive family history usually allow for a correct diagnosis. A good response to anticandidal and steroid therapy identifies candidal vulvitis and the eczematous diseases. Biopsy with direct immunofluorescence may be necessary to rule out pemphigus.

Topical mid-potency (triamcinalone 0.1%) steroid cream

Histology and laboratory findings The characteristic histological changes of Darier’s disease include the presence of acantholysis (separation and rounding-up of individual epidermal cells) and dyskeratosis (premature keratinization resulting in the presence of cells described as “corps ronds” and “grains”). Epidermal thickening,

If necessary, oral retinoids Consider laser therapy

­ yperkeratosis, and papillomatosis are also found. h There are no other specific laboratory tests. Histologically, the features of Darier’s disease may be mimicked quite closely by Grover’s disease and the papular acantholytic dyskeratosis described above.

Pathogenesis The gene defect for Darier’s disease occurs as a mutation of ATP2A2 gene8. This gene plays an important role in intracellular calcium regulation and, when mutated, results in decreased epithelial cell adhesion, acantholysis, and apoptosis of

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e­ pidermal cells. When the skin is not under environmental stress, enough normal gene protein is present to allow epidermal cells to function adequately. But, in the presence of environmental stress, the calcium pump becomes overwhelmed and the epithelial cells fail to function appropriately12. Darier’s disease is inherited in an autosomal-dominant pattern with nearly complete penetrance. However, there are fairly frequent spontaneous mutations accounting for those patients who have no positive family history.

Therapy and prognosis Environmental stress triggers the development of lesions. This situation, and the approach to ameliorate them, is entirely similar to that for Hailey–Hailey disease (see above). Likewise, bacterial and candidal overgrowth occurs frequently. Appropriate measures to treat these problems are, likewise, discussed in the section on Hailey–Hailey disease (above). However, as opposed to Hailey–Hailey disease, oral retinoids (either isotretinoin or acitretin) lead to moderate or even marked improvement in almost all patients13. Unfortunately, side-effects tend to limit the willingness of patients to take these agents on a long-term basis. Topical retinoids have been reported as helpful but they are too irritating to be used in the anogenital area. Anecdotal evidence suggests that topical tacrolimus14, photodynamic therapy15, topical 5-­fluorouracil16 ablative laser therapy, and excision and grafting may be of some use. Darier’s disease is a chronic disorder in which complete clearing rarely occurs, even with retinoid therapy. Development of squamous cell carcinoma has been reported in one woman with vulvar Darier’s disease. Widespread, often serious, cutaneous viral infection with herpes simplex virus or varicella virus seems to occur with more frequency than would be expected17.

  3. Nardelli, A., Degreef, H., and Goossens, A. Contact allergic reactions of the vulva: a 14-year review. Dermatitis 2004; 15: 131–136.   4. Crone, A. M., Stewart, E. J., Wojnarowska, F., et al. Aetiological factors in vulvar dermatitis. J. Eur. Acad. Dermatol. Venereol. 2000; 14: 181–186.   5. Farage, M. and Maibach, H. I. The vulvar epithelium differs from the skin: implications for cutaneous testing to address ­topical vulvar exposures. Contact Dermatitis 2004; 51: 201–209.   6. Saenz, A. M., Cirocco, A., Avendano, M., et al. Papular acantholytic dyskeratosis of the vulva. Pediatr. Dermatol. 2005; 22: 237–239.   7. Bell, H. K., Farrar, C. W., and Curley, R. K. Papular acantholytic dyskeratosis of the vulva. Clin. Exp. Dermatol. 2001; 26: 386–388.   8. Szigeti, R. and Kellermayer, R. Autosomal-dominant calcium ATPase disorders. J. Invest. Dermatol. 2006; 126: 2370–2376.   9. Bansal, C., Omlin, K. J., Hayes, C. M., et al. Novel cutaneous uses for botulinum toxin type A. J. Cosmet. Dermatol. 2006; 5: 268–272. 10. Umar, S. A., Bhattacharjee, P., and Brodell, R. T. Treatment of Hailey–Hailey disease with tacrolimus ointment and clobetasol foam. J. Drugs Dermatol. 2004; 3: 200–203. 11. Collet Villette, A. M., Richard, M. A., Fourquet, F., et al. Treatment of Hailey–Hailey disease with carbon dioxide laser vaporization. Ann. Dermatol. Venereol. 2005; 132: 637–640. 12. Byrne, C. R. The focal nature of Darier’s disease lesions: ­calcium pumps, stress, and mutation? J. Invest. Dermatol. 2006; 126: 702–703. 13. Sehgal, V., Sirvastava, G., and Sardana, K. Isotretinoin – unapproved indications/uses and dosage: a physician’s ­reference. Int. J. Dermatol. 2006; 45: 772–777. 14. Rubegni, P., Poggiali, S., Sbano, P., et al. A case of Darier’s ­disease successfully treated with topical tacrolimus. J. Eur. Acad. Dermatol. Venereol. 2006; 20: 84–87. 15. Exadaktylou, D., Kurwa, H. A., Calonje, E., et al. Treatment of Darier’s disease with photodynamic therapy. Br. J. Dermatol. 2003; 149: 606–610. 16. Yoon, T. Y., Kim, J. W., and Kim, M. K. Successful treatment of Darier disease with topical 5-fluorouracil. Br. J. Dermatol. 2006; 154: 1210–1212. 17. Nikkels, A. F., Beauthier, F., Quatresooz, P., et al. Fatal herpes simplex virus infection in Darier disease under corticotherapy. Eur. J. Dermatol. 2005; 15: 293–297.

Further reading Contact dermatitis Bauer, A., Rodiger, C., Greif, C., et al. Vulvar dermatoses – irritant and allergic contact dermatitis of the vulva. Dermatology. 2005; 210: 143–149. Margesson, L. J. Contact dermatitis of the vulva. Dermatol. Ther. 2004; 17: 20–27.

Hailey–Hailey disease

References   1. Margesson, L. J. Contact dermatitis of the vulva. Dermatol. Ther. 2004; 17: 20–27.   2. Bauer, A., Rodiger, C., Greif, C., et al. Vulvar dermatoses – ­irritant and allergic contact dermatitis of the vulva. ­Dermatology 2005; 210: 143–149.

Szigeti, R. and Kellermayer, R. Autosomal-dominant calcium ATPase disorders. J. Invest. Dermatol. 2006; 126: 2370–2376.

Darier’s disease Sehgal, V. and Srivastava, G. Darier (Darier–White) disease/­keratosis follicularis. Int. J. Dermatol. 2005; 44: 184–192. Szigeti, R. and Kellermayer, R. Autosomal-dominant calcium ATPase disorders. J. Invest. Dermatol. 2006; 126: 2370–2376.

PART: II  Gynecologic Dermatology

CHAPTER 19

Skin-Colored and Red Papules and Nodules Peter J. Lynch Lynette J. Margesson

Skin-Colored Papules And Plaques When the term “skin-colored” is applied to a lesion it reflects the color of the patient’s normal skin. Thus, a brown lesion on a darkly pigmented individual would still be considered as a skin-colored process. Likewise, an erythematous lesion on a normally pink to red mucosal surface would also be a skin-colored lesion. Skin-colored papules and plaques may be smooth or rough-surfaced. Roughness to palpation implies the presence of scale even when such is not visible to the naked eye.

Genital warts (human papillomavirus infection) Epidemiology and clinical manifestations Genital warts are caused by nonenveloped, double-stranded DNAcontaining human papillomaviruses (HPV). The incidence of HPV infection has risen very rapidly in the United Kingdom and somewhat less rapidly in the United States1. The estimated lifetime incidence of visible genital warts in women is about 4%2. The annual incidence of genital warts in the United States, based on private office visit reports, is somewhat less than 1%1. These data reflect only clinically apparent HPV infections. It is estimated that the prevalence of clinically inapparent external genital infections is about 13% in women of all ages and about 22% in 20-year-old women3. Moreover, the cumulative incidence in young sexually active women over a 2–3-year period is greater than 40%3. Prevalence declines fairly rapidly with age, falling to about 10% by age 353. These figures are similar to those reported for HPV infection of the cervix4. Taken together, these data suggest that HPV is the most common of all sexually transmitted infections. From a standpoint of clinical morphology there are four major types of genital warts. Keratotic (common-type) warts are similar to those that occur on the hands and are “square” (5–10 mm in ­diameter and 5–10 mm in height). They have a rough, scaling ­surface, are skin-colored or slightly brown, and occur on the mons pubis, the

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Figure 19.1  Some genital warts show a verrucous, firm surface, as seen in this wart. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-5), Churchill Livingstone.)

upper inner thighs, and other dry regions of the anogenital area (Figure 19.1). Filiform (condylomata acuminata-type) warts are taller (10–20 mm) than they are wide (2–5 mm), are skin-colored or pink, have a “brush-like” filiform tip, and occur in the moist areas of the anogenital area. Flat-topped (papular) warts are wider (5–15 mm) than they are tall (2–5 mm), are smooth-surfaced, and occur anywhere in the anogenital region (Figures 19.2 and 19.3). Their color is highly variable: they may be skin-colored, pink, red, brown, or black (Figure 19.4). This type of wart may enlarge centrifugally or coalesce to form large plaques. Nodular (Buschke–Lowenstein-type) warts are spherical with a cerebriform or mammillated surface. They are skin-colored to pink and are usually smoothsurfaced (Figures 19.5 and 19.6). The first two types of warts have no malignant potential and do not require biopsy whereas the latter two types of warts can have malignant potential and thus may require biopsy.

Diagnosis and differential diagnosis Genital warts can almost always be recognized on a clinical basis but, if there is uncertainty, a biopsy should be performed. Moreover, as indicated

Figure 19.2  The term “condylomata acuminata” refers to genital warts such as these, which exhibit acuminata morphology.

above, biopsy is almost mandatory for the flattopped papular and the nodular types of warts in order to identify any dysplasia that might be ­present. In times past, acetic acid whitening was used to identify genital HPV infection but, as this was neither a sensitive nor specific test, it is no longer recommended. Women with vulvar warts have a high ­likelihood of concomitant cervical HPV ­ infection and, for this reason, visual inspection of the ­cervix coupled with cytology is required. When warts occur at the anal verge, anoscopy, possibly with cytology, is desirable for ­immunocompetent patients and is mandatory for those who are immunosuppressed. The differential diagnoses for genital warts include vestibular papillomatosis, lymphangiectasia, skin tags, and molluscum contagiosum (Table 19.1). All of these are recognizable clinically. Vestibular papillomatosis consists of closely set, uniform-appearing, small, rounded papules occurring in a cobblestone-like pattern. This ­ normal

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Figure 19.4  Hyperpigmented, flat warts, particularly when large, are a morphology especially likely to exhibit changes of intraepithelial neoplasia on biopsy. However, this wart was benign. Figure 19.3  Papular warts in the vestibule and ­perineal body and spiky, acuminata warts on perianal skin ­demonstrate the different morphologies of anogenital warts. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-1), Churchill Livingstone.)

anatomic variant is only found in the vulvar vestibule. Skin tags are pedunculated, soft on palpation, smooth-surfaced, and primarily located on hair-bearing skin. Molluscum contagiosum are skin-colored to white, hemispherical, often umbilicated papules; they are also located primarily on hair-bearing skin.

Histology and laboratory tests Biopsy of genital warts reveals characteristic features of koilocytosis (hyperchromatic nuclei with perinuclear vacuolization) and acanthosis (thickening of the epithelium with elongation of the rete ridges). Note that vacuolated cells are a normal finding in the outer portion of mucosal epithelium and that this normal finding is sometimes overread

by pathologists as indicative of HPV infection. True koilocytosis extends into the mid and lower portions of the epithelium and is accompanied by dense staining of the nuclei. Tests to identify specific HPV types are commercially available5. Proponents of such testing state that identification of high-risk HPV types gives useful prognostic information. However, these tests are expensive and limited in scope. The Centers for Disease Control (CDC) do not recommend the use of DNA testing to determine the HPV type6. HPV cannot be cultured and therefore the only laboratory approach available to identify and type these viruses requires use of primer-­specific polymerase chain reaction (PCR) amplification of viral DNA.

Pathogenesis Genital warts are caused by HPV. These DNA viruses are very small and only contain approximately 8000 base pairs. The DNA is doublestranded and found in the form of a closed circle.

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Table 19.1  Genital Warts (Human Papillomavirus Infection) Diagnosis



Four types of lesions; most are skin-colored and rough surfaced: 1. Keratotic (square shape) 2. Filiform (taller than wide) 3. Flat-topped (wider than tall) 4. Nodular (spherical) Differential Diagnosis Vestibular papillomatosis Molluscum contagiosum Lymphangiectasia Vulvar intraepithelial neoplasia Therapy Medical therapy Podofilox

Figure 19.5  Very large warts are likely to exhibit neoplastic changes. This wart, in an immunosuppressed patient, showed changes of vulvar intraepithelial neoplasia 3.

Imiquimod Podophyllin Bi- or trichloroacetic acid Procedural therapy Cryotherapy Excision Electrosurgery Laser ablation

Figure 19.6  Large, spherical warts should be biopsied to rule out the presence of verrucous squamous cell ­carcinoma (Buschke–Lowenstein tumor). (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-6), Churchill Livingstone.)

HPV DNA is enclosed in an icosahedral protein capsid. Nucleotide sequence is highly variable, resulting in the evolutionary development of more than 100 HPV types. Genital infections are caused by about 30 or 40 of these types. The ­ genital

HPV types are divided into two groups of lowand high-risk viruses based on the predilection to cause epithelial cancers. The most important members of the low-risk group are HPV 6 and 11. These two types account for more than 90% of external genital warts1. The most ­ important members of the high-risk group are HPV 16 and 18. They account for about 70% of cervical carcinomas7 and an even higher proportion of vulvar intraepithelial neoplasia. A dozen or more additional HPV types account for the remainder of HPV-related malignancies7.

Skin-colored papules and plaques

Although DNA for the genital HPV types can be identified by PCR on fingers and inanimate objects such as specula, underwear, and laser plumes, ­ epidemiological studies suggest that almost all genital infections in adults are spread by sexual contact1. The average incubation period from the time of acquisition to the development of visible warts ranges from several weeks to several months. Not surprisingly, other concomitant sexually transmitted diseases are found in about 15% of patients with genital warts8. Studies suggest that condom use might protect against the acquisition of genital warts9. The role played by viral load, hormones, smoking, and male circumcision in the acquisition of HPV infection is controversial3. The situation in children with genital warts is somewhat different. Development as a result of sexual abuse certainly occurs but vertical transmission from an infected vaginal birth canal is quite common, as is horizontal, nonsexual, transmission (Figure 19.7). It is important to recognize that the mode of acquisition in children cannot be determined by the clinical appearance, the anatomic site, or the specific HPV type. A careful and thorough history for the possibility of sexual abuse should always be obtained even though positive evidence for abuse is found in only a minority of such cases10. HPV can only infect epithelial cells. The virus enters the epithelium at the basal layer of the epidermis where initial replication occurs. Additional replication occurs in the suprabasal layers and, eventually, intact virions are shed from the surface as differentiated epithelial cells are sloughed into the environment. In benign infections, the HPV DNA remains in an episomal location and does not become incorporated into the host-cell DNA. The mechanism through which HPV infection results in the development of malignancy is discussed in Chapter 23.

Therapy and prognosis Untreated genital warts tend to resolve with the passage of time. Unfortunately, there are few published data indicating the percentage and rate of resolution. Information regarding the resolution of cervical HPV infections is much better and

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Figure 19.7  Anogenital warts in children raise the­­ ­possibility of sexual abuse, but young children are more often ­infected during delivery through a birth canal with human ­papillomavirus infection or innocuously from a caregiver.

this information will be used as a surrogate for external genital infection. As demonstrated by the marked fall-off in prevalence rates with age, most untreated cervical HPV infections are transient, with approximately 90% resolving within 2 or 3 years11. Infections with low-risk HPV types appear to be cleared more rapidly than those due to high-risk HPV types3,11. Clearance is primarily due to the development of immune reactivity. Innate immune response and humoral immunity presumably play some role but it is cell-mediated immune response that is critical to resolution11. Following clearance, reinfection with the same, or a different, type of HPV is possible. Immunosuppressed individuals, especially those who are human immunodeficiency virus (HIV)-positive, tend to have infections that persist for many years. Women with persistent infections due to high-risk HPV types (mostly HPV 16 and 18) are at increased risk for the development of cervical and vulvar squamous cell carcinoma11.

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In terms of treatment, it is pertinent to ask three questions. First, should sexual partners be examined? The answer is probably no. Acquisition of an asymptomatic infection may have occurred years ago and contact tracing just would not be feasible. And, the contact person may have had latent infection, in which case clinical recognition of the infected partner would not be possible. Second, should genital warts be biopsied? The answer is sometimes. Filiform and small nodular warts are unlikely to show dysplasia and need not be biopsied. Larger nodular warts (Buschke–Lowensteintype) and flat-topped warts of any color have a higher risk of dysplasia and therefore should be sampled. Third, should genital warts be typed? As indicated above, the high cost coupled with the poor sensitivity and specificity of these tests has led the CDC to recommend that typing not be performed6. The CDC discusses the treatment of ­ genital warts in its revised treatment guidelines for ­sexually transmitted disease6. Two statements from this document are worth quoting: ­“Existing data indicate that currently available therapies for genital warts might reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA resulting from treatment impacts future transmission remains unclear” and “No definitive evidence suggests that any of the available treatments are superior to any other and no single treatment is ideal for all patients or all warts”6. In addition to the CDC guidelines, there have been two thorough recent reviews of therapy for genital warts.12,13 Much of what follows is based on the information from these sources. Home-based medical therapy

Patients like this approach for convenience, modesty issues, and self-control of discomfort arising from therapy. Two products are in widespread use. Podofilox 0.5% solution or gel is a cytotoxic agent that is applied twice a day either for 3 days ­followed by 4 days without therapy or by every-other-day application. This product should not be used ­during pregnancy. Cure rates are about 60–70% after 4–8 weeks of therapy. Imiquimod 5% cream is an immunomodulator that is applied once daily

at bedtime. Cure rates are about 50–60% after 16 weeks of therapy. Several factors limit the appeal of these two agents: both cause local ­ irritation, the duration of therapy required is ­ prolonged, cure rates are relatively low, and ­recurrence rates are relatively high. Office-based medical therapy

This approach reduces compliance issues somewhat and allows the clinician to control both the amount of medication used and the duration of therapy. However, there is a high cost in time and money because of the requirement for frequent office visits. Two products are widely used. 25% podophylin in tincture of benzoin, a cytotoxic agent, is applied by the clinician weekly or every other week. It should not be used during pregnancy. Cure rates vary with the duration of therapy but average 50–70% after 2 months of treatment. Recurrences rates are quite high. Bi- or trichloroacetic acid in a concentration of 80–90% is applied by the clinician weekly or every other week. It does not work well on keratinized warts and is associated with erosions surrounding the wart if excess acid contacts normal perilesional skin. Cure rates are similar to those for podophyllin; recurrence rates are quite high. Office-based medical therapy is used less often today than in the past. Office-based destructive therapy

The application of cryotherapy with liquid nitrogen using either a cotton-tipped applicator or a cryospray container is probably the most widely used therapy for genital warts. It is generally carried out every other week. It is moderately painful but local anesthetics are not required. Scarring occurs only rarely. Cure rates of 70–80% are possible after three to four treatments but recurrence rates are quite high. Alternatively, genital warts can be removed by scalpel or scissors excision or they can be destroyed by electrosurgery or carbon dioxide laser ablation. All four of these approaches require the use of a local anesthetic and all may lead to prolonged healing and, potentially, some scarring. The advantage of this approach is that all, or nearly all, of the warts can be destroyed or removed in a single office visit. Unfortunately, recurrence rates are about 25%.

Skin-colored papules and plaques Vaccines

The Food and Drug Administration has recently approved a quadrivalent vaccine for women 9–26 years of age. This vaccine is directed against HPV 6 and 11 (the two types most often associated with genital warts) and HPV 16 and 18 (the two types most often associated with cervical and vulvar carcinoma)14. The impressive results in clinical trials demonstrated that there was a dramatic reduction in the prevention of new infection and some clearance of existing infection. As might be expected, additional information suggests that this vaccine also has high efficacy for the prevention of HPV 16- and 18-related cervical intraepithelial neoplasia (CIN 2 and 3)15. Although this vaccine therapy is probably the most exciting advance ever made for the prevention and therapy of HPV infection, enthusiasm must be tempered by the high cost, unknown duration of effectiveness, and likely resistance to its use by individuals in some groups. A second vaccine, directed only towards HPV 16 and 18, is in development16. For the most part the prognosis of HPV-related disease of the vulva is good. However, there is a risk for the development of both vulvar intraepithelial neoplasia and invasive squamous cell carcinoma, in the approximately 5% of instances where infection has been due to high-risk-type HPV.

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Figure 19.8  Firm, white, shiny, dome-shaped papules ­typical for molluscum contagiosum; this is a sexually transmitted disease in adults, but raises no suspicion when occurring on the vulva of children. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-8), Churchill Livingstone.)

Epidemiology and clinical manifestations Most studies suggest that about 80–90% of all molluscum contagiosum virus (MCV) infections occur in children17,18. However, over the last 30 years there has been an increased incidence in adults, occurring as a result of sexual transmission. The annual incidence of clinically evident molluscum contagiosum is probably around 1–2% in the western world19. Asymptomatic infection must occur with even greater frequency as antibodies to MCV are found in 6–23% of the normal population20,21. The proportion of the population with such antibodies rises with age and may reach 40% by mid-adult life21. Individuals with depressed cell-mediated immunity (especially untreated patients with HIV/acquired immunodeficiency syndrome (AIDS)) are at greater risk of ­developing

molluscum contagiosum22. There may also be an increased risk of MCV infection in those with atopic dermatitis and those who are applying topical steroids or tacrolimus on a regular basis18. The clinical lesions of molluscum contagiosum are smooth-surfaced hemispherical papules averaging 3–10 mm in diameter. These papules are usually skin-colored but they may also be white, pink, or translucent (Figures 19.8 and 19.9). Central umbilication, a highly characteristic feature, is found in about 30–50% of larger lesions but is generally absent in new, small lesions (Figures 19.10 and 19.11). Rarely, giant lesions (up to 2 cm in diameter) develop. Sometimes as a result of trauma, or in the immunologically mediated resolution phase, a molluscum lesion and the perilesional skin become

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Figure 19.9  Mollusca can be white or skin-colored, and mimic pustules and vesicles. The classic central dell can be seen in several lesions on this patient. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-9), Churchill Livingstone.)

Figure 19.10  This solitary molluscum shows the typical central umbilication.

Figure 19.11  The firm, skin-colored to pink papules of molluscum contagiosum are most commonly located on the labia majora. The largest lesions usually demonstrate the pathognomonic central umbillication but this feature is often lacking in the smaller papules.

bright red and tender ­(Figure 19.12). Such lesions simulate furuncles and inflamed cysts. Generally 10–30 lesions are present at any one time18 but, in immunosuppressed individuals, hundreds may be found. In children, most of the lesions are found on the face, trunk, and extremities18. In adults, as a result of sexual transmission, lesions are more commonly located in the anogenital area and on the pubis and upper inner thighs. Lesions are only rarely found on the mucosal aspects of the genitalia.

Diagnosis and differential diagnosis A diagnosis can almost always be established on a clinical basis, especially if umbilication is noted. If necessary, a shave biopsy can be performed or

Figure 19.12  Molluscum contagiosum on the labia majora.

Skin-colored papules and plaques

Skin-colored, pink or white

that contain multiple MCV copies. These inclusion bodies cluster in a crater-like pattern at the surface of the epidermis from which they are shed into the environment. Laboratory tests are not necessary but, in patients with unusually numerous lesions, evidence of immunosuppression should be sought.

Central umbilication

Pathogenesis

Table 19.2  Molluscum Contagiosum Diagnosis Dome-shaped, smooth-surfaced papules 3–10 mm in diameter

Differential Diagnosis Lymphgangiectasia Genital warts, human papillomavirus type Scabies Lichen nitidus Therapy Curettage Cryotherapy Cantharidin Imiquimod

cytological smears, demonstrating the presence of the “molluscum body,” can be obtained from curetted material. The differential diagnoses include lymphangiectasia, scabies, genital warts, and lichen nitidus (Table 19.2). Fluid is present in the vesicles of ­lymphangiectasia. In scabies, the lesions will be located in a characteristic distribution pattern (finger web spaces, areola, and axillary folds), linear burrows may be identified, and mites may be recovered on scrapping of these burrows. Genital warts almost never present as skin-colored smooth­surfaced hemispherical papules and have a characteristic appearance on biopsy. The lesions of lichen ­nitidus are smaller, whiter, and more numerous than are the lesions of molluscum contagiosum.

Histology and laboratory tests MCV can only infect epithelial cells. Infection causes thickening (acanthosis) of the epidermis. The histologically distinctive infected epidermal cells contain intracytoplasmic inclusion bodies

The MCV is a poxvirus (cf. vaccinia, variola) containing double-stranded DNA arrayed in a linear pattern. It is a very large virus consisting of 180 000 base pairs, a size that is roughly 20 times larger than HPV. MCV cannot be cultured in vitro but the genome has been cloned. There are four viral types: MCV 1, 2, 3, and 4. All four types cause identical clinical lesions. The majority of infections in immunocompetent individuals are due to MCV 1. MCV can cause either symptomatic infection, with visible lesions as described above, or asymptomatic latent infection in which no lesions are visible. It is not known whether contagion occurs as a result of asymptomatic infections. The MCV is mostly transmitted by direct skinto-skin contact. This occurs through ordinary play in children and through sexual activity and contact sports in adults. Contagion by way of infected fomites almost surely occurs but the frequency with which this happens is unknown. The incubation period is usually 1–3 months but longer intervals have been reported.

Therapy and prognosis The natural history of molluscum contagiosum is only known for infections occurring in children. In untreated children, individual lesions resolve spontaneously in a month or two. However, new lesions continue to develop such that the total course of the disease lasts for as much as several years23. Spontaneous resolution also occurs in adults but it is not as universal and tends to occur over a longer period of time. Although a humoral immune response with the formation of antibodies occurs, resolution appears to require a robust, cell-mediated immune response. In the absence of such a response (such as in HIV-positive/AIDS patients), lesions spread

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rapidly, huge numbers of lesions develop, and the course of the disease lasts indefinitely. Immunity seems to be relatively long-lasting since recurrence and/or reinfection following complete resolution of molluscum contagiosum is only rarely encountered. Because spontaneous resolution occurs so frequently and because there are no long-term adverse consequences to the presence of molluscum contagiosum, treatment is not required. Nevertheless, the off-putting appearance and potential for contagion generally lead patients to request therapy. There are very few good studies regarding treatment for molluscum contagiosum. A recent Cochrane review identified only five randomized controlled trials and none of these was very helpful in clinical practice24. The therapies most commonly used for molluscum contagiosum are procedural (cryotherapy or curettage) and medical (application of cantharidin or imiquimod). Cryotherapy utilizing liquid nitrogen is cheap, easy to use, and efficient. Unfortunately, it is too painful for use in young children. Curettage, in which a skin curet is used to scrape away the lesion, can be performed without topical anesthesia in adults but not in children. This approach is also relatively inexpensive, easy to use, and fairly efficient. The application of cantharidin with the wooden end of a cotton-tipped applicator causes a blister to form under the papule. In most instances, when the blister roof is sloughed, the molluscum lesion is removed as well. This approach is painless at the time of application but the resultant blisters can be uncomfortable and the slow-healing erosions left after the blisters break may become infected. The application of imiquimod, as described in the section on HPV infection, has the advantage of being carried out at home but the severity of the irritation, the long duration of treatment, and high cost reduce the usefulness of this approach. A recent study compared three of these modalities in the treatment of molluscum contagiosum in children25. More than a single visit was required in 20% of the patients with curettage, 65% for cantharidin, and 45% for imiquimod. Adverse effects were noted in 5% of the patients treated with curettage, 20% treated with cantharidin, and 25%

treated with imiquimod. In my own practice I use cantharidin in children and either cryotherapy or curettage in adults.

Vestibular papillomatosis Vestibular papillae (vestibular papillomatosis) are found in the vulvar vestibule of about one-third of asymptomatic, normal women. These lesions appear as asymptomatic, soft, dome-shaped papules usually arrayed in a “cobblestone-like” pattern. They are quite small, with the base of each lesion having a diameter of about 1–2 mm. The height of the papillae varies from 1 to 8 mm. The color of the papillae matches the adjacent mucosa of the vestibule and therefore vestibular papules are considered to be skin-colored lesions. Since there is considerable color variation of the normal vestibular mucosa, the absolute color of the papillae ranges from very pale pink to bright red. The number of papillae varies from a dozen or so up to hundreds, covering almost the entire surface of the vestibule. The homogeneity of the lesions is striking, with each one appearing similar to its neighbors. Generally they are clustered tightly together but they do retain their separateness rather than becoming truly confluent. Occasionally they are arranged in linear rows (Figure 19.13). Vestibular papules may be considered as analogous to the pearly penile papules found on the corona of the penis. Vestibular papillae are somewhat similar in appearance to genital warts and 30 years ago they were frequently treated as such (Figure 19.14). However, recent molecular studies have demonstrated that HPV DNA is found in these lesions no more frequently than it is found in the vestibules of normal women lacking these lesions. Since vestibular papillae represent normal anatomical variants, they should not be treated.

Sebaceous gland hyperplasia (Fordyce condition) Although only rarely described in published reports26, enlarged ectopic sebaceous glands are fairly often found on the inner aspects of the labia minora. They are asymptomatic, yellow to yellow-white, smooth-surfaced minute papules

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Figure 19.14  Vestibular papillae are often grouped and bilaterally symmetrical; vestibular papillae do not produce itching or pain. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-12), Churchill Livingstone.)

Figure 19.13  Vestibular papillae are sometimes mistaken for genital warts, but, unlike warts, papillae are soft with rounded tips that are discrete to the base. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-13), Churchill Livingstone.)

1–2 mm in diameter (Figure 19.15). The number present varies from a few to as many as several hundred. Similar lesions are found on the penis and on the lips of the mouth. These are variants of the normal anatomy of the vulva and need not be treated.

Skin tags These soft, smooth-surfaced, skin-colored pedunculated papules are discussed in Chapter 23.

Condyloma latum Condylomata lata represent one of the manifestations of secondary syphilis. These lesions occur as 1–2-cm, flat-topped, smooth-surfaced papules and small plaques. Coalescence of neighboring

Figure 19.15  Sebaceous hyperplasia (Fordyce spots) is normally seen in premenopausal women, but, as in this photograph, they are sometimes quite large and mistaken for genital warts or milia. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 1-2), Churchill Livingstone.)

lesions is frequently present. They may be skincolored, pink, white, or brown (Figure 19.16). Usually, multiple lesions are present and they are most often distributed on the genitalia, perigenital skin, or perianal area. The surface of these lesions is teeming with spirochetes and thus there is a high risk for contagion. Syphilis is otherwise covered in Chapter 21.

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Figure 19.17  Fox–Fordyce disease on the vulva and periumbilical area. This intensely itchy disorder involves the apocrine gland-bearing skin and can also affect the axillae and areolae. Figure 19.16  Flat-topped papules of condylomata lata in a woman with secondary syphilis; moist lesions tend to be white, whereas dry ones are more likely to be red or skin-colored. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-3), Churchill Livingstone.)

of topical steroids may reduce the symptom of pruritus.

Miscellaneous disorders Fox–Fordyce disease This is an uncommon condition that involves apocrine gland-related hair follicles. The lesions appear as closely set, smooth-surfaced, small (2–3 mm) papules confined to the axillae and the anogenital region (Figures 19.17 and 19.18). They are most often skin-colored but pink, orange, or brown hues can occur. The condition is most commonly found in African American individuals. Itching is frequently present. The process is hypothesized to be apocrine miliaria in which keratin plugging of an apocrine gland-related follicle leads to the development of a “sweat bubble” just below the surface of the skin. Unfortunately there is no characteristic histologic pattern and there is no documented effective therapy. The application

Ectopic breast tissue occurs along the milk line and thus can occur in the vulva. This condition presents as a skin-colored nodule that is only recognized clinically when there is periodic change in size correlating with a woman’s menstrual cycle. Many cysts and benign tumors appear as skincolored nodules. These are covered with the neoplasms in Chapter 23.

Red Papules And Nodules The disorders considered in this section are ­primarily those due to inflammation. Inflamed cysts and red neoplasms are considered in Chapter 23. In examining patients with the category of “the red papules and nodules” in mind, there are three caveats that must be considered.

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Figure 19.18  Found almost exclusively in black patients, these dome-shaped follicular papules are often pruritic. (Reproduced from P. J. Lynch and L. Edwards Genital ­Dermatology (Fig. 12-3), Churchill Livingstone.)

First, there are many hues of the color red. The spectrum of redness usually varies from a light pink to a bright red but, in addition, violaceous and red-brown hues can occur. Second, in darkskinned patients, the extra melanin in their epidermis can mask the underlying red color. Thus, when presented with what appears to be brown lesions in deeply pigmented patients, consider that inflammation may be present even though it is hidden clinically. Third, the presence of inflammation says nothing about whether the disorder is infectious or not. Many red papules and nodules occur as a result of a sterile inflammatory process.

Hidradenitis suppurativa Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease characterized by recurrent, deep-seated papules, nodules, and abscesses located primarily in the axillary, inframammary, genitocrural, perineal, and perianal regions. In mild cases it is an inflammatory ­folliculopustular disease; in severe cases, sinuses and fistulae develop, as does hypertrophic scarring.

Epidemiology and clinical manifestations HS is relatively common, affecting about 1% of the general population. It occurs more frequently in African Americans than in Caucasians. Femaleto-male ratios range from 2:1 to 5:127. The age of

Figure 19.19  A hallmark of hidradenitis suppurativa is comedones, especially grouped; these comedones ­predispose to follicular retention of keratin.

onset varies from childhood to middle age, with most patients developing their disease in their early 20s27. About 40% of the patients have a positive family history for HS27. Most often the onset is after puberty and the disorder worsens in severity in the second and third decades. Early lesions are solitary, painful inflammatory papules and nodules that persist for weeks or months. These lesions are usually mistaken for furuncles or “boils.” Twin or multiheaded comedones (“blackheads”) are frequently found in the surrounding skin (Figure 19.19). The duration of any individual lesion is usually about 7 days. The average patient with mild to moderate disease develops approximately two new lesions each month. These nodules remain “blind” and initially fail to rupture to the surface, as do true furuncles. Instead, the involved follicle ruptures deep in the skin, causing a massive inflammatory reaction that may encompass adjacent follicles. After a period of time, the inflammatory mass

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Figure 19.20  Sometimes called “inverse acne,” cysts rupture and drain, sometimes producing severe edema, scarring, and chronic drainage. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 8-10), Churchill Livingstone.)

may rupture externally, drain purulent material, and heal with scarring. Lesions may recur at the same site and are particularly likely to do so perimenstrually. Some draining tracts epithelialize, creating chronic sinuses that intermittently drain serous, purulent, or blood-tinged fluid (Figure 19.20). Healing may be accompanied by the formation of webbed bands of thick, deep scars. About 75% of patients have only a few lesions with abscess formation, minor cysts, and pseudocysts, and mild to moderate scarring. About 25% have numerous recurrent abscesses, sinus tract formation, and moderate to severe scarring. Approximately 1% of patients have severe disease with large, confluent, plaque-like areas comprised of inflamed cysts, draining abscesses, sinus tract formation and disfiguring scarring. The axillary, inframammary, and anogenital regions are the most commonly involved sites. In the vulvar area lesions are found on the mons pubis, labia majora, inguinal folds, and genitocrural folds. Lesions can extend through the perineum and on to the upper inner thighs and buttocks. These lesions understandably cause significant pain and dysfunction, leading to much decreased quality of life.

Diagnosis and differential diagnosis The diagnosis of HS is made clinically based on the recurrent nature of the process, lesions confined primarily to the milk line, presence of abnormal comedones, and failure to respond

quickly and completely to antibiotic therapy. The major disease to consider in the differential diagnosis is staphylococcal furunculosis (Table 19.3). Furuncles are few in number, develop at random sites, and respond rapidly and completely to systemic antibiotic therapy. Crohn’s disease must be considered when lesions are present in the anogenital area. Clinical differentiation of these two processes is difficult and the lesions of both diseases may coexist. Biopsy may be helpful in this situation. Other, much less likely considerations include deep fungal infection, mycobacterial infection, lymphogranuloma venereum, granuloma inguinale, and inflamed cysts of various types.

Histology and laboratory tests Biopsy is seldom necessary but if carried out on a relatively early lesion, follicular plugging and perifollicular inflammation will be found around apocrine gland-related hair follicles. Biopsy from later lesions reveals massive destruction of follicles together with widespread, often granulomatous, inflammation. No laboratory tests are necessary but occasionally a complete blood count will show mild anemia and an elevated white blood cell count. Radiograms and/or colonoscopy may be desirable when Crohn’s disease is considered but there are no gastrointestinal symptoms or signs.

Pathogenesis HS is not a primary disease of the apocrine gland but rather it develops in the hair follicle to which the apocrine gland and duct are attached. Within the follicle there is keratin plugging, or anatomic maldevelopment, of the distal follicular outlet. This results in a damming effect with follicular enlargement, and subsequent follicular rupture with eventual dispersion of the follicular contents into the surrounding connective tissue, where a foreign body-type inflammatory reaction develops. Thus, HS is an acneiform process rather than an infectious disease. However, secondary bacterial colonization, or even infection, can develop. The inflammation eventually resolves but when the follicle reforms, the process is likely to start all over again. Eventually, scarring destroys the follicle such that it cannot reform and the process slowly “burns out.”

Red papules and nodules

Table 19.3  Hidradenitis Suppurativa Diagnosis Lesions   Deep-seated, painful papules   Abscess-like “boils”   Fistulae and sinuses   Bridging, webbed scars   Twin or multiheaded blackheads (comedones) Distribution   Axillae   Mammary and inframammary   Labia majora   Genitocrural folds   Perianal and buttocks Differential Diagnosis   Furuncles and carbuncles   Inflamed epidermal cysts   Crohn’s disease   Mycotic and mycobacterial infection Therapy Stage 1 disease   Topical and oral antibiotics   Intralesional steroids   Zinc gluconate   Antiandrogen therapy Stage 2 disease   All of the above plus:   Higher dosing for antibiotics   Dapsone   Surgical unroofing Stage 3 disease   All of the above plus:   Systemic steroids   Tumor necrosis factor-alpha inhibitors   Cyclosporine   Surgical excision

There appear to be several predisposing factors for the development of HS. Nearly half of the patients have a positive family history,27 suggesting that there are genetic aspects. It seems likely that what is actually inherited is the predilection for anatomically malformed apocrine glandrelated follicles. Hormonal factors are reflected in the usual onset at menarche, perimenstrual flares, improvement during pregnancy, and variable association with hirsutism and obesity. Serum hormone levels are usually normal but an abnormal end-organ response to androgenic hormones has been hypothesized. Cigarette smoking worsens the disease, possibly by interfering with wound healing. Some medications, such as lithium, exacerbate the disease.

Therapy and prognosis Determination of therapy depends on the severity of the disease. Three grades of severity have been proposed. The first two grades respond to medical treatment whereas the third stage requires “biologics” and/or surgery. All patients will need good education, support, and constant reassurance. Grading occurs as follows: stage 1 – single or multiple abscesses occur without the development of sinus tracts or significant scarring; stage 2 – recurrent abscesses are present along with sinus tract formation and mild to moderate scarring. Multiple lesions may be present but they are widely separated; and stage 3 – there is diffuse involvement with multiple interconnected abscesses, draining sinus tracts, and severe scarring. Therapy for stage 1

Medical treatment is indicated28 and includes clindamycin 1% lotion twice a day, intralesional triamcinalone (5–10 mg/mL with injection of 0.1–0.5 mL), and oral antibiotics such as tetracycline 250 mg qid, doxycycline 100 mg bid, minocycline 100 mg bid, clindamycin 150 mg qid, or rifampin 300 mg bid29. Since HS is not primarily an infectious disease, these antibiotics are used for their nonsteroidal antiinflammatory properties. Zinc gluconate in a dose of 50 mg/day can be added as adjunctive, preventive therapy. Antiandrogen treatment may be helpful30. This can be achieved by way of oral contraceptives such as Yasmin and, if necessary, spironolactone

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or finasteride can be added. General care involves loose clothing, smoking cessation, weight loss, and avoidance of environmental irritants. Therapy for stage 2

Intralesional triamcinalone can be administered as indicated above. Surgical unroofing or marsupialization should be performed if there are chronic cysts or sinus tracts. Oral antibiotics should be administered as above, but possibly in higher doses, for at least 3 months. Dapsone, used as a nonsteroidal anti-inflammatory agent, can be given in dosages up to 150 mg/day31. Zinc gluconate, antiandrogen therapy, and general measures as described above are appropriate. Oral retinoids such as the tretinoin used for acne are not very helpful. Therapy for stage 3

Medical treatment is intensified through the addition of agents such as prednisone (20–40 mg/day), cyclosporine (4 mg/kg per day), or tumor necrosis factor-alpha inhibitors (etanercept 25 mg subcutaneously twice weekly; infliximab, 5 mg/kg intravenously every 6 weeks)32. However, in most instances, stage 3 disease should be considered to be a surgical disease. Two surgical approaches are possible. Most surgeons prefer to remove all involved tissue from any given area followed by grafting or flap placement33. Alternatively, staged removal with primary closure can be carried out34. This does leave involved tissue at the margins but this can be re-excised subsequently. Healing does not appear to be retarded when disease remains in the surgical margins. Surveys show that patients are extremely pleased with excisional therapy even when their surgeons have reservations about the adequacy and appearance of their results. HS, even with good medical care, is a chronic disease associated with a very poor quality of life. HS often persists for 10–20 years and is accompanied by varying degrees of scarring. Eventually, scar tissue obliterates the follicles involved and, at that point, disease activity slowly resolves. Persistent vulvar edema occurs in many patients and, as is true for other chronic cutaneous inflammatory diseases, development of squamous cell carcinoma is possible35. Approximately 35 such malignancies have been reported.

Bacterial folliculitis Although bacterial folliculitis can occur as a small red papule, nearly all lesions are capped by a pustule. For this reason, this follicular infection is covered in the section on pustules in Chapter 20.

Furuncles and abscesses Furuncles (“boils”) and abscesses arise most commonly as a result of Staphyloccocus aureus infections. These lesions, by definition, are hair follicle-based. The term “folliculitis” is used when the infection is superficial, whereas furunculosis is used when the infection is deep. “Abscess” is the term used when staphylococcal infections (or, in some cases, foreign-body reactions) occur at a site other than a hair follicle. Rarely, in the anogenital area, these two processes develop from other bacteria such as gut-based anaerobes. Furuncles and abscesses have a similar clinical appearance. They present as bright red, smooth-surfaced, tender nodules 2–4 cm in diameter. Early lesions are firm but as neutrophils accumulate, a pustule may form at the summit and/or the whole nodule may become fluctuant. Untreated, the process may break through to the surface and drain purulent material (Figure 19.21). Usually only one or two lesions are present at a single time but lesions may continue to occur consecutively and at random sites over time in the differential diagnosis. Ruptured epidermal cysts have a similar appearance to furuncles. Recognition of these sterile lesions depends on a patient history of a ­preceding noninflammatory lump or cyst. The lesions of HS also look similar to furuncles but these lesions occur only in the milk line, are usually multiple, are sterile or contain organisms other than solely S. aureus on culture, and are resistant to shortterm conventional antibiotic therapy. Small furuncles may heal spontaneously or with the application of topical antibiotics. Large firm lesions should be treated with oral antistaphylococcal agents such as dicloxacillin 250–500 mg qid or cephalexin 250–500 mg qid. If methicillin-resistant S. aureus (MRSA) infection is suspected, alternative agents such as trimethoprim-­sulfamethoxazole, clindamycin, tetracycline, rifampin, or ­vancomycin

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Figure 19.21  This furuncle arose suddenly in a setting of folliculitis, and a culture yielded Staphylococcus aureus.

may be necessary36. Firm lesions do not require ­incision and drainage but fluctuant lesions do. In this situation bacterial cultures and antibiotic sensitivities should be obtained. Antibiotic therapy should be started and can be modified once the results of the sensitivity tests are available. Almost all clinicians suggest the use of warm compresses or soaks, though there is little in the way of evidencebased data to support this recommendation.

Keratosis pilaris Keratosis pilaris represents a common, chronic, sterile form of folliculitis that begins in childhood and persists to mid-adult life37. It arises due to ­keratin plugging of hair follicles. In mild cases, patches of closely set, small (1–2 mm), pink to red follicles are visible. Because of the follicular keratinization, the involved skin feels rough (“sand paper-like”) to palpation. The homogeneity of the papule size and color is distinctive. In some instances, the tip of the follicle is white (Figure 19.22). This represents the follicular plug. This plug is often gouged out by the patient with her fingernail, leaving a shallow red erosion. When the process is more severe, larger, bright red papules, sometimes with a pustular summit, are interspersed among minor lesions. The keratin plugs can cause a damming effect and, in a manner similar to what happens in acne, the follicle enlarges and then ruptures with resultant formation

Figure 19.22  Keratosis pilaris consists of tiny, follicular, monomorphous pink rough papules most often located on the lateral arms, anterior thighs, and buttocks. A small keratin plug in each lesion is sometimes visible and appears white, mimicking a pustule.

of an inflammatory papule. These larger, more inflamed lesions are regularly mistaken for bacterial folliculitis. Keratosis pilaris is differentiated from bacterial folliculitis by the multiplicity of lesions, long course of the process, unresponsiveness to antibiotic therapy, and the characteristic distribution pattern involving the lateral upper arms, anterolateral thighs, and buttocks. There is no effective therapy but some improvement can be obtained with regular use of lubricants and gentle rubbing with a pumice stone.

Urethral caruncle and urethral prolapse Urethral caruncles arise primarily in postmenopausal women and appear as a small (3–10-mm), red, soft, papule at the urethral meatus (Figure 19.23). The lesion may be dome-shaped or pedunculated. Caruncles are usually solitary and asymptomatic. These lesions are clinically fairly distinctive but biopsy may be necessary to rule out other urethral tumors. Microscopic features include vascular dilatation and a mixed inflammatory reaction. Small asymptomatic lesions require no therapy. Topical estrogen application is reputed to improve lesions but in some instances excision or electrosurgical destruction is necessary. Prolapse of the urethral mucosa also results in the development of a red lesion at the urethral meatus. The clinical appearance is somewhat different from that of a caruncle in that the lesion

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Figure 19.24  Diaper granulomas are flat-topped, welldemarcated papules produced by chronic exposure to irritants, most often urine or liquid feces. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 2-22), Churchill Livingstone.)

Figure 19.23  A urethral caruncle is a deep red, lobular protrusion from the urethral meatus that is often seen in postmenopausal women.

is not dome-shaped or pedunculated and instead forms a partial, or full, red elevated ring around the meatus. If edema of this prolapsed tissue is sufficiently great, urination may be difficult. Prolapse occurs primarily in premenarchal girls and postmenopausal women, suggesting that it is related to low estrogen levels. Treatment approaches include manual reduction of the prolapse or ligation, destruction, or excision of the prolapsed tissue.

Erosive papulododular dermatosis This term encompasses several very similar anogenital entities: “granuloma gluteale infantum/ adultorum,” “erosive diaper dermatitis of Jacquet,” “pseudoverrucous papules,” and “diaperarea granuloma38.” It is likely that all of them arise from chronic maceration and irritation occurring as a result of retained sweat, urine and feces. Candida spp. are frequently present but it is not clear whether these yeasts are the cause, or the result, of the underlying problem.

The lesions appear as fairly large (1–3-cm), flattopped nodules that are pink, red, or violaceous in color. Heavily keratinized lesions may even appear white due to the retention of moisture in a waterlogged stratum corneum. Most are round but some may be oval in shape. The surface of the nodules may be smooth, hyperkeratotic, or eroded (Figures 19.24 and 19.25). Some pain may be present but in many instances the lesions are asymptomatic. Lesions are distributed throughout the anogenital area, occurring primarily on flattened, rather than folded or intertriginous, skin. They presumably arise as a result of irritants trapped between the skin surface and diapers or bed sheeting. Treatment requires reduction of maceration and the removal of any other irritants. Application of topical anticandidal agents is generally indicated. The role of topical steroids is controversial. Some reports suggest that the lesions arise in part because of chronic steroid use whereas others suggest that these agents are therapeutically helpful.

Miscellaneous red nodules Cutaneous lesions are found in about 25% of patients with sarcoidosis but there are fewer than 100 reports of this disease involving the ­genitalia and almost all of these have been in men. The scarcity of reports probably relates to oversight

Red papules and nodules 213

Figure 19.26  Sarcoid granuloma. The patient also had cerebral sarcoidosis.

Figure 19.25  Diaper granuloma (granuloma gluteale infantum). These benign reddish-brown granulomatous nodules appear to be a cutaneous response to local inflammation, maceration, and secondary infection, usually with Candida albicans. Biopsy is helpful. Lesions of granuloma gluteale infantum resolve completely and spontaneously within several months of treatment of the inflammation and secondary infection.

in which the vulva is not systematically examined when patients present with cutaneous lesions at other sites. The anogenital lesions of cutaneous sarcoid are quite pleomorphic and include papules, nodules, and plaques. These lesions may be skin-colored, red, brown, or white (Figures 19.26 and 19.27). Diagnosis requires biopsy. Although purely cutaneous forms of sarcoidosis are recognized, true sarcoidosis of the genitalia probably only occurs in individuals with systemic disease.

Figure 19.27  Hyperpigmented, smooth, nodular plaque of sarcoidosis. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 8-6), Churchill Livingstone.)

If no systemic disease can be identified, the lesions may represent misdiagnosed Crohn’s disease or Melkersson–Rosenthal granulomatosis, both of which bear histologic similarity to the granulomas of sarcoidosis.

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Figure 19.28  Endometriosis of the labium majus. There is a small nodule with a dimple on the right side.

Endometriosis of the vulva is an uncommon condition that usually arises secondary to implantation of endometrial fragments following uterine procedures or traumatic births. Lesions are very pleomorphic, varying greatly in size and in color (Figures 19.28 and 19.29). The most characteristic feature is the change in size and symptoms with the menstrual cycle. Diagnosis usually requires biopsy. Treatment is surgical excision. Recurrences are common. All types of cysts present as red nodules and masses when they are inflamed. Cysts are discussed in Chapter 23. Rarely lesions of molluscum contagiosum that are regressing as a result of immunological attack become markedly inflamed and reddened. This subject is discussed under skin-colored papules in this chapter. Red vulvar neoplasms are covered in Chapter 23.

References   1. Lacey, C. J. N., Lowndes, C. M., and Shah, K. V. Chapter 4: Burden and management of non-cancerous HPV-related ­conditions: HPV-6/11 disease. Vaccine. 2006; 24(suppl 3): S3/35–S3/41.

Figure 19.29  Close-up of nodules shown in Figure 19.29, showing cyclic drainage site for blood-tinged fluid when ovulation was not being suppressed.

  2. Fenton, K. A., Korovessis, C., Johnson, A. M., et al. Sexual behavior in Britain: reported sexually transmitted infections and prevalent genital chlamydial trachomatis infection. Lancet. 2001; 358: 1851–1854.   3. Burchell, A. N., Winer, R. L., de Sanjose, S., et al. Chapter 6: Epidemiology and transmission dynamics of genital HPV ­infection. Vaccine. 2006; 24(suppl 3): S352–S361.   4. Dunne, E. F., Unger, E. R., Sternberg, M., et al. Prevalence of HPV infection among females in the United States. J.A.M.A. 2007; 297: 813–819.   5. Chin-Hong, P. V. and Klausner, J. D. Diagnostic tests for HPV infection. Med. Lab. Obstet. 2004; 36: 10–12. 14–16.   6. Workowski, K. A. and Berman, S. M. Sexually transmitted diseases treatment guidelines. Morbid. Mortal. Week. Rep. 2006; 55: 62–67.   7. Clifford, G., Franceshi, S., Diaz, M., et al. Chapter 3: HPV type-distribution in women with and without cervical ­neoplastic diseases. Vaccine. 2006; 24(suppl 3): S3/26–S3/34.   8. Griffiths, V., Cheung, W. H., Carlin, E. M., et al. Incidence of concurrent sexually transmitted infections in patients with genital warts. Int. J. STD AIDS. 2006; 17: 413–414.   9. Manhart, L. E. and Koutsky, L. A. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sex. Transm. Dis. 2002; 29: 725–735. 10. Sinclair, K. A., Woods, C. R., Kirse, D. J., et al. Anogenital and respiratory tract human papillomavirus infections among children: age, gender, and potential transmission through sexual abuse. Pediatrics. 2005; 116: 815–825.

Further reading 11. Moscicki, A. -B., Schiffman, M., Kjaer, S., et al. Chapter 5: Updating the natural history of HPV and anogenital cancer. Vaccine. 2006; 24(suppl 3): S3/42–S3/51. 12. Lacey, C. J. Therapy for genital human papillomavirus-related disease. J. Clin. Virol. 2005; 32(Suppl 1). S82–S0. 13. Scheinfeld, N. and Lehman, D. S. An evidence-based review of medical and surgical treatments of genital warts. Dermatol. Online J. 2006; 12: 5. 14. Garland, S. M., Hernandez-Avila, M., Wheeler, M., et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N. Engl. J. Med. 2007; 356: 1928–1943. 15. The Future II Study Group. Quadrivalent vaccine against ­human papillomavirus to prevent high-grade cervical lesions. N. Engl. J. Med. 2007; 356: 1915–1927. 16. Paavonen, J., Jenkins, D., Bosch, F. X., et al. Efficacy of a prophylactic aduvant bivalent L1 virus-like-particle vaccine against infection with human papilloma-virus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007; 369: 2161–2170. 17. Laxmisha, C., Thappa, D. M., and Jaisankar, T. J. Clinical profile of molluscum contagiosum in children versus adults. Dermatol. Online J. 2003; 9: 1. 18. Dohil, M. A., Lin, P., Lee, J., et al. The epidemiology of molluscum contagiosum in children. J. Am. Acad. Dermatol. 2006; 54: 47–54. 19. Pannell, R. S., Fleming, D. M. and Cross, K. W. The incidence of molluscum contagiosum, scabies and lichen planus. Epidemiol. Infect. 2005; 133: 985–991. 20. Watanabe, T., Nakamura, K., Wakugawa, M., et al. Antibodies to molluscum contagiosum virus in the general population and susceptible patients. Arch. Dermatol. 2000; 136: 1518–1522. 21. Konya, J. and Thompson, C. H. Molluscum contagiosum virus: antibody response in persons with clinical lesions and seroepidemiology in a representative Australian population. J. Infect. Dis. 1999; 179: 701–704. 22. Cribier, B., Scrivener, Y. and Grosshans, E. Molluscum contagiosum: histologic patterns and associated lesions. A study of 578 cases. Am. J. Dermatopathol. 2001; 23: 99–103. 23. Brown, J., Janniger, C. K., Schwartz, R. A., et al. Childhood molluscum contagiosum. Int. J. Dermatol. 2006; 45: 93–99. 24. Van der Wouden, J. C., Menke, J., Gajadin, S., et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst. Rev. 2006; 19. CD004767. 25. Hanna, D., Hatami, A., Powell, J., et al. A prospective randomized trial comparing the efficacy and adverse effects of four recognized treatments of molluscum contagiosum in children. Pediatr. Dermatol. 2006; 23: 574–579. 26. Malliah, R., Gilhooly, P., Lambert, W. C., et al. Sebaceous ­hyperplasia of the vulva: case report and review of the ­literature. J. Low. Genit. Tract Dis. 2006; 10: 55–57. 27. von der Werth, J. M. and Williams, H. C. The natural history of hidradenitis suppurativa. J. Eur. Acad. Dermatol. Venereol. 2000; 14: 389–392. 28. Jemec, G. B. Medical treatment of hidradenitis suppurativa. Exp. Opin. Pharmacother. 2004; 5: 1767–1770. 29. Mendonca, C. O. and Griffiths, C. E. M. Clindamycin and rifampicin combination therapy for hidradenitis suppurativa. Br. J. Dermatol. 2006; 154: 977–978.

30. Joseph, M. A., Jayaseelan, E., Ganapathi, B., et al. Hidradenitis suppurativa treated with finasteride. J. Dermatol. Treat. 2005; 16: 75–78. 31. Kaur, M. R. and Lewis, H. M. Hidradenitis suppurativa treated with dapsone: a case series of five patients. J. Dermatol. Treat. 2006; 17: 211–278. 32. Cusak, C. and Buckley, C. Etanercept: effective in the management of hidradenitis suppurativa. Br. J. Dermatol. 2006; 154: 726–729. 33. Mandal, A. and Watson, J. Experience with different treatment modules in hidradenitis suppurativa: a study of 106 cases. Surgeon. 2005; 3: 23–26. 34. Kagan, R. J., Yakuboff, K. P., Warner, P., et al. Surgical treatment of hidradenitis suppurativa: a 10-year experience. Surgery. 2005; 138: 734–740. 35. Short, K. A., Kalu, G., Mortimer, P. S., et al. Vulval squamous cell carcinoma arising in chronic hidradenitis suppurativa. Clin. Exp. Dermatol. 2005; 30: 481–483. 36. Cohen, P. R. Community-acquired methicillin-resistant Staphylococcus aureus skin infections: a review of epidemiology, clinical features, management and prevention. Int. J. Dermatol. 2007; 46: 1–11. 37. Marquelling, A. L., Gilliam, A. E., Prendiville, J., et al. Keratosis pilaris rubra: a common but underecognized condition. Arch. Dermatol. 2006; 142: 1611–1616. 38. Robson, K. J., Maughan, J. A., Purcell, S. D., et al. Erosive papulonodular dermatosis associated with topical benzocaine: a report of two cases and evidences that granuloma gluteale, pseudoverrucous papules, and Jacquet’s erosive dermatitis are a disease spectrum. J. Am. Acad. Dermatol. 2006; 55: S74–S80.

Further reading Genital warts Ahmed, A. M., Madkan, V. and Tyring, S. K. Human papillomaviruses and genital disease. Dermatol. Clin. 2006; 24: 157–165. Scheinfeld, N. and Lehman, D. S. An evidence-based review of ­medical and surgical treatments of genital warts. Dermatol. Online J. 2006; 12: 5.

Molluscum contagiosum Hanson, D. and Diven, D. G. Molluscum contagiosum. Dermatol. Online J. 2003; 9: 2. Ting, P. T. and Dytoc, M. T. Therapy of external anogenital warts and molluscum contagiosum: a literature review. Dermatol. Ther. 2004; 17: 68–101.

Hidradenitis suppurativa Slade, D. E., Powell, B. W. and Mortimer. P. S. Br. J. Plast. Surg. 2003; 56: 451–461. Lee, R. A., Yoon, A., Kist, J. Hidradenitis suppurativa: an update. Adv. Dermatol. 2007; 23: 289–306.

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PART: II  Gynecologic Dermatology

CHAPTER 20

Pustules, Vesicles, Bullae, and Erosions Libby Edwards

Pustules Folliculitis Folliculitis is an extraordinarily common but medically trivial condition.

Epidemiology and clinical manifestations Folliculitis is defined as inflammation of hair follicles. Therefore, this is a very nonspecific term which can apply to infectious folliculitis produced by bacterial or fungal infection, or to non-infectious from occlusion and friction. Bacterial folliculitis can occur in any population, and there is no predilection for gender, race, or age. Fungal ­folliculitis of anogenital skin is most common in adult men, particularly those with accompanying onychomycosis or tinea pedis. Irritant folliculitis of the vulva, mons, and medial thighs is especially common in women who shave, and in overweight individuals where friction, moisture, and persistent warmth are likely to produce irritant folliculitis. Folliculitis is often an asymptomatic, cosmetic issue, but patients sometimes complain of mild irritation or itching. Folliculitis can be painful, especially in the uncommon case of folliculitis of the ­modified mucous membranes. Folliculitis is manifested by scattered, red dome-shaped and crusted papules, pustules, or small, round erosions that are left as the pustules quickly rupture (Figures 20.1 and 20.2). Folliculitis occurs primarily on dry, keratinized skin, particularly the proximal, medial thighs due to friction, as well as on the buttocks. Folliculitis ­produced by Pseudomonas aeruginosa (hot-tub folliculitis) is manifested by papules that are usually larger and more tender, and pustules are less obvious. These are often prominent in the swimsuit distribution and skin folds. Folliculitis occasionally occurs on the modified mucous membranes, including the labia minora, where lesions often present as small ­papules

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Figure 20.1  Red papules and pustules on the buttocks are a very common manifestation of folliculitis.

Figure 20.2  Discrete red papules, crusts, and pustules are characteristic of folliculitis.

with 1–2 mm superficial round erosions ­ (Figure 20.3). Fungal folliculitis of genital skin occurs within plaques of tinea cruris and ­usually manifests as small nodules or crusts within red, scaling plaques on the proximal, medial thighs (Figure 20.4).

Figure 20.3  Shaving folliculitis is an irritant condition ­produced by short, stiff, sharp hair curling back into the skin.

Figure 20.4  Fungal folliculitis is characterized by papules, pustules, and crusts within an inflamed plaque of tinea cruris.

Differential diagnosis Folliculitis is most often confused with inflamed mollusca contagiosa or insect bites (Figure 20.5). Keratosis pilaris and cutaneous Candida can occasionally mimic folliculitis as well (Table 20.1).

Pustules

Table 20.1  Folliculitis Diagnosis   Clinical appearance Pustules, red papules, crusts   Culture for infectious folliculitis   Confirmed on biopsy or culture if unresponsive Differential Diagnosis   Insect bites   Molluscum contagiosum   Keratosis pilaris Management   Bacterial folliculitis – oral antibiotics according to culture   Fungal folliculitis – fluconzaole 200 mg/day, griseofulvin 500 mg bid, itraconazole 200 mg/day

Figure 20.5  When inflamed, mollusca contagiosa are ­indistinguishable from folliculitis or furunculosis, but ­surrounding typical lesions generally allow for the correct diagnosis.

Laboratory and histology Laboratory abnormalities are limited to cultures revealing the etiology of folliculitis, when it is infectious. A fungal preparation of a pustule roof shows branching hyphae, when the underlying cause is a fungal infection. Histology is generally not performed, but at times a biopsy may be required for diagnosis. A biopsy shows an inflammatory infiltrate that includes neutrophils around the hair follicle, sometimes with rupture of the follicle. Bacterial folliculitis most often shows organisms just under the stratum corneum, although fungal folliculitis shows the dermatophyte within the stratum corneum. Special stains highlight the organisms. Occlusive folliculitis and acneiform folliculitis show no organisms.

  Irritant folliculitis – minimize friction, sweat, stop shaving; chronic anti-inflammatory antibiotics (doxy­ cycline or minocycline 100 mg, clindamycin 150 mg bid)

Pathogenesis As noted above, the pathogenesis depends upon the type of folliculitis. Bacterial folliculitis is almost always produced by Staphylococcus aureus. Occasionally, Pseudomonas aeruginosa causes bacterial folliculitis, usually in patients who have recently used an improperly maintained spa or hot tub. Fungal folliculitis is produced by dermatophytes sometimes self-inoculated from tinea pedis or with fungal folliculitis of the legs spread by shaving. Irritant folliculitis can be produced by friction, occlusion of skin folds, and constant moisture of sweat or urine. Shaving also produces folliculitis when either the tops of hair follicles are irritated by the razor, or when the short, stiff, curly hair curves back into the skin to pierce it.

Management and prognosis The treatment of folliculitis depends upon the cause. Bacterial folliculitis is treated according to cultures. Methicillin-resistant Staphylococcus aureus, even when community-acquired, is

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­ ecoming increasingly prevalent, so that cultures b are frequently indicated. Pseudomonas folliculitis clears whether or not antibiotic therapy is administered as long as the source of the organism is avoided. Patients with significant pain or constitutional symptoms generally benefit from ciprofloxacin or levofloxacin. Fungal folliculitis requires oral therapy since topical medications do not penetrate follicles sufficiently. Options include griseofulvin 500 mg twice daily, terbinafine 250 mg daily, fluconazole 100–200 mg weekly, itraconazole 100 mg daily, or ketoconazole 200 mg daily until clear. Irritant folliculitis generally responds at least partially and slowly to local care to manage friction and moisture. The chronic administration of antibiotics which exert nonspecific anti-inflammatory effects is useful as well. These include doxycycline 100 mg twice daily, clindamycin 150 mg twice daily, and minocycline 100 mg twice daily. Improvement requires several weeks and maximal improvement often requires 2 or 3 months. Recurrence following therapy is common in all forms of folliculitis. When bacterial folliculitis recurs, the patient is likely to be a nasal carrier, and mupirocin ointment can be inserted in the nose two or three times daily for 1 week each month to eliminate this carrier state. Otherwise, intermittent treatment for recurrences is indicated.

Cutaneous candidiasis (see Chapters 18 and 24 for primary discussion) Anogenital candidiasis sometimes exhibits pustules. Although the most prominent skin lesion is that of a red plaque with peripheral desquamation, satellite collarettes are sometimes associated with satellite pustules. The diagnosis is made by the setting, and a positive culture or identification of yeast on a microscopic examination of a pustule roof.

Keratosis pilaris (discussed primarily in Chapter 19) Keratosis pilaris is a common cause of follicular redness and keratin plugs within follicles. This condition is found most often on the lateral upper arms and the buttocks. The keratin plugs

Figure 20.6  Small, monomorphous, rough follicular papules of keratoses pilaris are often red and mimic folliculitis.

often mimic pustules, but at other times ­actually ­produce pustules due to occlusion of the ­ follicle (Figure 20.6). Keratosis pilaris is essentially a normal finding, but patients who do not tolerate the cosmetic aspect are sometimes improved with soaks to soften the keratin plugs and scrubs to remove them. Keratolytics such as lactic acid or salicylic acid have been reported as beneficial, but these are usually too irritating for genital skin.

Mollusca contagiosa (discussed primarily in Chapter 19) Mollusca contagiosa are virally induced skin lesions that, usually, are manifested by skin­colored, dome-shaped papules. However, trauma or a brisk immune response is associated with red lesions as well as, at times, pustules (see Figure 20.5). The diagnosis is made by the typical appearance of nearby mollusca.

VESICLES, BULLAE, AND EROSIONS Both blistering and erosive diseases of mucous membranes and modified mucous membranes ­generally present as erosions. Blisters on this fragile tissue erode as they form, so that the blistering nature is often clinically unrecognized. Neither the patient nor the clinician sees the intact blister except when occurring on dry, keratinized skin. Therefore, these diseases will be discussed together. Vesicles are small blisters that erode into small, round

Vesicular diseases

erosions, and bullae are blisters larger than about 1.5 cm.

221

VESICULAR DISEASES Herpes simplex virus infection Herpes simplex virus (HSV) infection is a very common and nearly always sexually transmitted disease when occurring on anogenital skin. There are two types of HSV, with type 1 usually responsible for orolabial herpes and type 2 most often producing genital disease. Genital HSV infection is a diagnosis which is extraordinarily upsetting to the average patient who perceives this as a condition signifying an unfaithful partner or personal promiscuity. Patients are frequently embarrassed and consider this incurable, but controllable, condition as a lifelong, humiliating sentence. Interestingly, when HSV affects the lips, there is no stigma attached.

Epidemiology and clinical manifestations Genital herpes simplex virus infection occurs most often in younger, sexually active individuals. This is especially common in the adolescent and young adult age group, and it is seen most often in patients who report multiple sexual partners. More people are seropositive for HSV in the United States than Europe, and seropositivity is higher in the western world than in developing countries1. About 17% of people in the United States show exposure to HSV type 2, and about 57.7% to type 12. Clinical disease is present in about 50 million people in the United States3. Previously, acquisition of HSV infection was believed to occur primarily with sexual activity during an active outbreak. Now, asymptomatic shedding has been identified as a major factor in transmission of HSV infection. Shedding can be detected in asymptomatic women with a history of genital HSV infection on about 5% of days when no lesions are present4. In fact, most infections are transmitted during exposure in the absence of lesions. Clinical manifestations vary, with a primary episode classically appearing quite differently from a recurrent outbreak. First-­episode HSV is usually subclinical (or unrecognized), but a true primary first episode typically exhibits widespread vesicles

Figure 20.7  The vesicles of primary herpes simplex virus are diffuse rather than grouped; the central collapse of an otherwise intact vesicle is characteristic of a herpes (simplex or varicella-zoster) blister.

and erosions with only modest grouping of individual lesions (Figures 20.7 and 20.8). These occur on modified mucous membranes of the vulva, on the mucous membranes of the vagina and cervix, and on surrounding dry, keratinized skin. Vaginal and cervical involvement often cause an irritating, purulent vaginal discharge, as well as occasional discharge from the urethra and rectal mucosa. Patients report remarkable pain that sometimes prevents micturition, and swelling is often substantial. Bilateral lymphadenopathy is common, and some patients exhibit fever, myalgias, and headache. A primary outbreak generally requires about 2 weeks for complete evolution of blistering, crusting, and healing. Most patients experience recurrences within the first year, which can be mild and occasional, or as often as two or three episodes per month. The frequency and severity of recurrences are less with infection produced by HSV type 1 than by type 25,6. With the progression of time, episodes usually become less frequent, less severe, and less painful. Most often, the first recognized episode is a recurrence following a subclinical primary infection. Recurrent HSV infection is usually manifested by a prodrome of tingling, itching, or burning. This is quickly followed by red vesicopapules which progress into one or several plaques of clustered vesicles which erode into coalescing erosions (Figures 20.9 and 20.10). Often, this is one small

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Figure 20.9  Recurrent herpes simplex virus infection ­presents as grouped vesicles.

Figure 20.8  When occurring on thin, poorly keratinized skin, primary herpes simplex virus blisters are generally not appreciated, but rather appear as scattered, discrete, round erosions.

plaque. In addition to blisters and round erosions, fissures can occur as a result of an HSV recurrence. Immunosuppressed women sometimes develop typical, ulcerative, chronic HSV infection. Although patients usually describe pain with recurrent HSV lesions, it is usually far less disruptive and painful than a primary outbreak. Headache, fever, and myalgias are uncommon with recurrences. Recurrences usually last a total of about 3–5 days unless they are scrubbed, rubbed, or secondarily infected.

Differential diagnosis Other causes of superficial, small, coalescing red papules and erosions include candidiasis, bullous impetigo, folliculitis, mollusca contagiosa, and very small aphthae (Table 20.2). A fixed drug ­eruption causes recurrent same-site erosions, although

i­ndividual erosions are generally significantly larger than the small coalescing erosions of HSV infection. HSV can be differentiated by cultures, polymerase chain reaction (PCR) technique, or by biopsy. Positive serological tests only report previous exposure, not necessarily current infection.

Laboratory and histology The most significant laboratory abnormality is a positive HSV culture or positive results on PCR for HSV. At times, particularly with a first-episode primary outbreak, patients exhibit leukocytosis. Other laboratory abnormalities include positive serologies for HSV. Negative HSV serology is good evidence that a current eruption does not represent recurrent HSV infection. A biopsy is an excellent means of nearly definitive, rapid diagnosis. Histology reveals ballooning degeneration of keratinocytes, where individual epidermal cells coalesce into very large ­multinucleated cells. This finding is only seen with

Vesicular diseases

Table 20.2  Herpes Simplex Virus Infection Diagnosis   Clinical appearance   Clustered vesicles or erosions (recurrent)   Scattered vesicles and erosions, lymphadeopathy, edema (primary)   Positive culture or polymerase chain reaction for herpes simplex virus (HSV)   Biopsy Differential Diagnosis for Primary HSV   Candidiasis   Molluscum contagiosum   Bullous impetigo   Blistering/erosive contact dermatitis Differential Diagnosis for Recurrent HSV   Fixed drug eruption Figure 20.10  Clustered red papules and blister of ­recurrent herpes simplex virus infection.

  Herpes zoster   Blistering/erosive contact dermatitis

the herpetic blisters of HSV, varicella, or herpes zoster.

Management

Pathogenesis

  Patient education and counseling

HSV infection is produced by DNA doublestranded viruses which are members of the Herpesviridae family. There are two types of HSV: type 1, most often found on the lip; or type 2, most often found on the genitalia. However, the two types are seen increasingly in both areas, possibly due to the prevalence of oral–genital sexual activity. The virus is introduced into the basal layer of the epidermis, either by friction and trauma, or by happenstance of exposure over a break in the epithelium.

  Oral antiviral medication for primary episode within the first 3 days

Therapy and prognosis HSV infection cannot be cured, but it can be controlled very well, and outbreaks can be nearly eliminated with ongoing suppressive oral antiviral therapy. Topical therapy generally produces ­statistically but not clinically significant amelioration of disease. First-episode, primary HSV

  Oral antiviral medication at onset of prodrome for ­recurrent outbreaks or daily suppression

infection is best treated with any of several oral antiviral therapies (Table 20.3). Recurrent HSV infection can be managed several ways, again orally (Table 20.4). First, if patients experience mild or only occasional recurrences, the individual may choose no treatment. Otherwise, patients can take an oral antiviral medication immediately with the onset of the prodrome, often preventing the outbreak. Patients with frequently recurrent outbreaks, those with recurrences not prevented by immediate therapy, and those with a psychological need to eliminate as many symptoms

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Table 20.3  Treatment for Primary Genital Herpes Simplex Virus Infection3

Medication

Dose

Frequency

Duration

Acyclovir

400 mg

3×/day

Until healed, usually 7–10 days

Acyclovir

200 mg

5×/day

Until healed, usually 7–10 days

Famciclovir

250 mg

3×/day

Until healed, usually 7–10 days

Valacyclovir

1g

2×/day

Until healed, usually 7–10 days

Table 20.4  Treatment for Recurrent Genital Herpes Simplex Virus Infection3

Medication

Dose

Frequency

Duration

Acyclovir

400 mg

3×/day

5 days

Acyclovir

800 mg

2×/day

5 days

Acyclovir

800 mg

3×/day

2 days

Famciclovir

125 mg

2×/day

5 days

Famciclovir

1000 mg

2×/day

2 days

Famciclovir

500 mg

Twice

12 hours apart

Valacyclovir

500 mg

2×/day

3 days

Valacyclovir

1g

1×/day

5 days

as possible benefit from daily suppression (Table 20.5). Immunosuppressed patients often require daily suppression to prevent either very frequent outbreaks or chronic HSV erosions and ulcers (Figure 20.11). Unfortunately, immunosuppressed patients have a slight risk for resistant HSV infection that is uncontrolled with currently available antiviral therapies. Foscarnet is sometimes useful in that event. The advent of effective therapy for the acquired immunodeficiency syndrome has significantly decreased the frequency of resistant HSV infection. Reasons for treating and suppressing HSV, in addition to personal patient comfort, include decreasing the risk of transmission of the disease. The risk of transmission of infection to a ­regular partner has been estimated to be about 10% per year when couples only avoid sexual activity during a clinical outbreak7. Interestingly, this study showed that all seroconversions occurred in the female partner, suggesting that women are at higher risk than men. The addition of barrier

protection and suppressive antiviral medication reduces but does not eliminate this risk. In one study, daily valacyclovir and famciclovir decreased shedding to 1.3% and 3.2% of days, respectively, with historical shedding rates at about 5%8. Patient education and support are crucial. The manner of sexual transmission should be discussed. Patients should be advised of the phenomenon of asymptomatic shedding, and the risk of transmissibility in the absence of active lesions. Because the risk of infection can be only minimized but not eliminated, partners must be informed. Women should be made aware that a very unlikely but important primary morbidity of HSV infection is perinatal transmission to a newborn. The majority of neonatal herpes occurs in the presence of a new primary first-episode HSV infection, rather than from a mother with known HSV who has a clinical recurrence at delivery. In addition, the sequelae for the infant are less severe for those with type 1 HSV than type 2.

Vesicular diseases 225

Table 20.5  Schedules for Suppression of Genital Herpes Simplex Virus Infection3

Medication

Dose

Frequency

Acyclovir

400 mg

2×/day

Famciclovir

250 mg

2×/day

Valacyclovir

500 mg

1×/day

Valacyclovir

1g

1×/day

Although the risk of a transmission to a neonate is small, this is a disease with tragic consequences, and the mother and her obstetrician should be aware.

Varicella-zoster virus infection; varicella (chickenpox), herpes zoster virus infection (shingles) An initial infection with the varicella-zoster virus causes varicella (chickenpox), whereas reactivation of the latent virus produces the one-time condition, herpes zoster (shingles).

Epidemiology and clinical manifestations Varicella is a classic childhood viral infection that occurs in nonimmunized individuals. Fortunately, since the relatively recent availability of the varicella vaccine, varicella has become uncommon. Herpes zoster occurs most often in older people as their immune system begins to wane, and the virus migrates from the ganglion, where it has lain dormant, to the skin, producing classic shingles. This occurs earlier in patients who are immunosuppressed for reasons other than age. Although a vaccine is now available for the prevention of herpes zoster, it is not yet widely used9. Patients with varicella experience upper respiratory tract symptoms, fever, and malaise followed by the eruption of single, scattered skin lesions. Lesions begin as pink papules which develop a central vesicle. The anogenital skin is one of the first areas affected. Lesions progress in number, then crust and heal (Figure 20.12). Varicella is often accompanied by a mucopurulent vaginal discharge due to vaginal involvement, particularly in the estrogen-deficient, fragile prepubertal vagina.

Figure 20.11  Herpes simplex virus infection in immunosuppressed patients is often more aggressive, forming nonspecific ulcerations diagnosed by a high index of suspicion and confirmed on culture, polymerase chain reaction, or biopsy of the edge of the ulcer.

Patients with herpes zoster typically describe pain which is burning or aching in quality, followed by red plaques which develop clustered, coalescing vesicles (Figure 20.13). These plaques occur in a dermatomal distribution that is most common on the thorax, with the second most common location being the head and face (Figure 20.14). However, herpes zoster also occurs on the buttocks and thighs, and occasionally on the genitalia, sometimes producing neuropathic pain that extends down the posterior or lateral aspect of the leg. Blisters eventually crust, followed by complete healing in about 3 weeks. Patients who are immunosuppressed by virtue of disease or medication sometimes experience frank, chronic ulcerations. Disseminated herpes zoster is also seen in immunosuppressed patients. This consists of widely scattered discrete vesicles resembling varicella in

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a setting of herpes zoster in a typical dermatomal distribution. The varicella-zoster virus is present in skin lesions of patients with herpes zoster, but usual transmission of this virus is by the respiratory route. However, contact with immunosuppressed patients and pregnant women with no history of varicella or the varicella vaccine should be avoided. Immunosuppressed patients and patients over 55 years of age are at increased risk compared to others for postherpetic neuralgia, long-lasting pain that persists after healing of the blisters of herpes zoster.

226

Differential diagnosis

Figure 20.12  Scattered vesicles showing predilection for anogenital skin are typical of varicella.

Figure 20.13  Coalescing vesicles within a red plaque is the characteristic lesion of herpes zoster, but can be confused with herpes simplex virus infection; unlike herpes simplex virus, herpes zoster does not recur.

Varicella is most often confused with insect bites or folliculitis (Table 20.6). Herpes zoster of anogenital skin most resembles HSV infection, particularly when occurring on the buttocks. A varicella-zoster virus culture or PCR technique can differentiate these two diseases, and plaques extending along a dermatomal distribution are extremely suggestive of herpes zoster rather than herpes simplex. Herpes simplex is a recurrent disease, whereas herpes zoster, in immunocompetent patients, is a one-time phenomenon. Allergic contact dermatitis producing blisters and blistering impetigo are the most common diseases otherwise to be considered in the differential ­diagnosis. These diseases can be differentiated by

Figure 20.14  Red plaques with vesicles scattered along a dermatomal distribution strongly suggest a diagnosis of herpes zoster, although herpes simplex virus infection remains a slight possibility.

Vesicular diseases

the setting, negative culture or PCR, or an inconsistent biopsy, when needed. Other blistering diseases can usually be ruled out by their generalized distribution.

Pathogenesis The varicella-zoster virus causes both varicella and herpes zoster. Herpes zoster occurs when the varicella-zoster virus that lies latent in the ganglia following varicella reactivates and surfaces to produce plaques of blisters along the affected nerve.

Laboratory and histology Other than positive culture and PCR testing, there are no specific accompanying laboratory abnormalities. A biopsy of herpes zoster is specific for a Table 20.6  Herpes Zoster Infection Diagnosis   Clinical presentation   Prodrome of pain along dermatome   Blisters and erosions clustered on red plaques along dermatome   Positive culture, biopsy, or polymerase chain reaction in atypical cases Differential Diagnosis   Herpes simplex virus   Blistering/erosive contact dermatitis   Impetigo Management   Pain control   Oral antivirals if seen within the first 48–72 hours   Management of postherpetic neuralgia if needed

herpes blister, but is indistinguishable from that of varicella or a HSV infection. Reticular degeneration of keratinocytes forms giant multinucleated epithelial cells. Underlying leukocytoclastic vasculitis is sometimes present, but it has no important implications, as systemic vasculitis does not occur.

Therapy and prognosis Patients seen in the first 3 days of illness may benefit from oral antiviral therapy. Topical therapy is not useful for varicella-zoster virus infections. There are distinct benefits if oral medication is begun in the first 24 hours of skin lesions, with the effect being less remarkable as time passes. By 72 hours, therapy produces a statistically but not clinically significant decrease in time to healing of the skin. Standard therapies include valacyclovir 1 g three times daily for 1 week, famciclovir 1 g three times a day, or acyclovir 800 mg five times a day (Table 20.7). For most patients, the primary treatment for herpes zoster is pain control, to include narcotic analgesia. When pain persists after all lesions have healed, the neuropathic pain of postherpetic neuralgia should be addressed. Several systemic medications are used for neuropathic pain, including tricyclic medications, gabapentin, venlafaxine, and pregabalin. Alternatively, patients can be referred to a pain clinic or a neurologist who specializes in neuropathic pain. Topical capsaicin (Zostrix) is available over the counter and is approved for postherpetic ­neuralgia. However, this medication is extremely irritating and should not be applied to anogenital skin. The best management for herpes zoster is prevention with the recently released vaccine, which should be given to elderly patients, those at highest risk for shingles, and postherpetic neuralgia.

Table 20.7  Therapy for Herpes Zoster

Medication

Dose

Frequency

Duration

Acyclovir

800 mg

5×/day

7–10 days

Famciclovir

500 mg

3×/day

7 days

Valacyclovir

1g

3×/day

7 days

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Although herpes zoster occurs only once in immunocompetent patients, immunosuppressed patients may experience more than one episode of herpes zoster, and these patients should be treated at any stage of the disease when they present. Those patients who are ill should be admitted for intravenous antiviral therapy.

Lymphangioma circumscriptum/ lymphangiectasia This finding of ectatic lymphatic vessels that protrude through the dermis and present as blisters can be a primary malformation or secondary to chronic edema, often referred to as lymphangiectasia.

Primary lymphangioma circumscriptum presents as plaques of small, grouped, clear vesicles that are stable, rather than evolving in crops, as occurs with inflammatory blisters. Sometimes, particularly with trauma, these can be red from extravasation of red blood cells into the lymph channels. Lymphangiectasias occurring from chronic edema may be widespread and scattered rather than grouped and localized, and these often arise from skin thickened from edema (Figures 20.15, 20.16). At times, these are accompanied by solid, skin-­colored, firm nodules and verrucous papules (elephantiasis nostra verrucosa). More common causes of edema predisposing to secondary lymphangioma circumscriptum include ­ hidradenitis

Epidemiology and clinical manifestations Primary lymphangioma circumscriptum is a rare malformation occurring with no known ­predisposing factors. Secondary lymphangioma circumscriptum, occurring as a result of chronic edema, is a relatively common occurrence. Although it occurs more often with severe edema, it occasionally occurs in those with even fairly subtle, chronic swelling. Most often, mild disease is asymptomatic. More severe disease can produce irritation and itching, and as thin-walled lymphatic vessels protruding close to the surface erode, chronic lymphatic leakage provides constant moisture and irritation to surrounding skin. This moisture is uncomfortable and the abnormal appearance of the skin can be disfiguring.

Figure 20.15  Lymphangioma circumscriptum is manifested by deep vesicles formed by dilated lymphatic vessels protruding through the epidermis.

Figure 20.16  Secondary lymphangioma circumscriptum (lymphangiectasias) occurs when chronic edema produces obstruction of lymphatic return, allowing bulging lymphatic channels to project through the relatively loose connective tissue of the vulva.

Bullous diseases

s­ uppurativa, Crohn’s disease, radiation therapy, and recurrent cellulitis.

Differential diagnosis Other causes of blistering that should be considered in the differential diagnosis of lymphangioma circumscriptum include HSV infection, bullous impetigo, bullous pemphigoid, allergic contact dermatitis, burns, and other trauma (Table 20.8). The diagnosis is made by the chronic onset and stable nature. A biopsy is useful but does not differentiate between primary lymphangioma circumscriptum and lymphangiectasias secondary to an underlying cause of edema.

Laboratory and histology Ancillary abnormal laboratory findings depend on the underlying cause of lymphangioma circumscriptum. Those with primary disease often have no specific abnormalities, although ultrasound or computed tomography of the vulva and pelvis may show the extent of the almost universal underlying deep component. Histology shows thin-walled lymphatic channels that are dilated and that erupt into the ­epidermis. There is thinning and effacement of Table 20.8  Lymphangioma Circumscriptum Diagnosis   Clinical presentation   Long-standing, firm blisters   Discrete and clustered vesicles in a setting of edema   Biopsy

the epidermis over the distended lymphatic vessels, and downward projection of the epidermis to surround the vessels. The difference between primary and secondary lymphangioma circumscriptum is made on clinical grounds rather than histology.

Pathogenesis The underlying etiology of primary lymphangioma circumscriptum is not known. Secondary lymphangiectasias are produced by edema, scarring, or tumor that obstructs lymphatic vessels, causing distension of the distal portion of the channels.

Therapy and prognosis Many patients do not require therapy for these enlarged lymphatic channels. For those with chronic drainage or symptoms, light electrosurgery or a carbon dioxide laser can cauterize individual lesions, although continual gradual eruption of new lesions is expected. Control of underlying causes of edema, when present, can minimize ongoing evolution of lesions. Definitive removal of lymphangioma circumscriptum and lymphangiectasias is generally not possible. ­ Primary disease is generally associated with a deep component that cannot be removed. Secondary disease is a late complication of edema, and well-established edema is self-perpetuating and chronic. This edema and obstruction of lymphatic return predisposes to cellulitis, which produces more edema and fibrosis, leading to cyclic worsening.

BULLOUS DISEASES

Differential Diagnosis   Herpes simplex virus   Bullous pemphigoid   Impetigo Management   None if asymptomatic   Identification and management of any underlying edema   Light electrosurgery of draining, crusted lesions as they occur

Bullous erythema multiforme (erythema multiforme major, Stevens–Johnson syndrome, toxic epidermal necrolysis) Blistering forms of erythema multiforme are rare hypersensitivity reactions occurring in response to medications or to recurrent HSV infection. Discrete papules with blisters involving less than 10% of the surface area in association with mucous membrane erosions is called Stevens–Johnson syndrome, whereas reactions characterized by generalized sloughing are termed toxic epidermal necrosis.

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230

Figure 20.18  Stevens–Johnson syndrome produces pink papules, with dark centers and, sometimes, blisters, on nonmucous membrane skin.

Figure 20.17  Bullous erythema multiforme of the Stevens– Johnson type appears on mucous membranes as discrete, nonspecific erosions.

Epidemiology and clinical manifestations Blistering forms of erythema multiforme are most common in patients receiving certain medications with a known predisposition to cause allergic reactions, as well as in an occasional patient with recurrent HSV infections. These are more common in women than men, and adults are more often affected than children. Patients with human immunodeficiency virus infection are at greater risk than others. Patients generally present with mucous membrane pain, redness, and blisters that appear clinically as erosions because the fragile blister roofs are short-lived (Figure 20.17). Most patients also exhibit extragenital nonmucous membrane lesions. Milder forms of erythema multiforme major (Stevens–Johnson syndrome) exhibit small erythematous, flat-topped, nonscaling papules with

central necrosis and blistering, forming “target” lesions (Figure 20.18). Stevens–Johnson syndrome covers no more than 10% of the skin surface. More severe disease (toxic epidermal necrolysis) is manifested by widespread redness and skin pain, followed by generalized blistering of at least 30% of the surface skin, and loss of the epidermis; these patients are quite ill (Figure 20.19). Mucous membranes show poorly demarcated, nonspecific erosions, with more severe disease manifested by coalescing erosions and generalized sloughing of the mucosa. Vaginal involvement as well as erosions of the modified mucous membranes of the vulva is expected. The gingiva, inner and external aspect of the lips, tongue, and buccal mucosa are often affected. The conjunctivae are frequently eroded or deeply erythematous, and the nasal mucosa can also be involved. Patients with Stevens–Johnson syndrome are frequently uncomfortable but not ill. More severe disease of toxic epidermal necrolysis is accompanied by fever, hypotension, and increased risk of infection, similar to complications seen in burn patients.

Differential diagnosis Erythema multiforme major is most often mistaken for bullous pemphigoid or pemphigus vulgaris, although these are usually slower in onset (Table 20.9). Staphylococcal scalded-skin syndrome, primarily in children, and widespread bullous ­ impetigo can mimic blistering erythema

Bullous diseases

Table 20.9  Erythema Multiforme Major Diagnosis Clinical presentation   Stevens–Johnson Syndrome   Small erosions on mucous membranes   Red nonscaling papules with central necrosis or blisters on keratinized skin   History of exposure to a known offending medication or recurrent herpes simplex virus Toxic epidermal necrolysis   Widespread, coalescing erosions on mucous membranes   Generalized redness and sloughing on keratinized skin   History of exposure to a known offending medication Differential Diagnosis   Bullous pemphigoid   Pemphigus vulgaris   Staphylococcal scalded-skin syndrome Management   Discontinue underlying etiology Figure 20.19  Blistering erythema multiforme of the toxic epidermal necrolysis type is seen as large denuded or blistering areas.

  Supportive care; infection control, fluids, debridement

multiforme, but mucous membranes are not affected, and biopsies differentiate these diseases.

  Avoidance of future exposures

Laboratory and histology There are no specific laboratory abnormalities, but leukocytosis and eosinophilia are common. The sedimentation rate is increased, and nonspecific findings due to infection and fluid loss often occur with severe disease. Occasionally, patients exhibit neutropenia. Skin biopsies show epidermal necrosis in the face of surprisingly mild inflammation. There is a mononuclear infiltrate in the upper dermis, with exocytosis.

Pathogenesis Erythema multiforme major is a hypersensitivity reaction to medications or to recurrent HSV infection, but the exact mechanisms are poorly

  Burn unit for severe disease

understood. This is a cytotoxic immune reaction directed towards squamous cells of the epithelium that express targeted antigens10. T cells are activated by specific drugs, leading to the production of cytokines. There seems also to be a role for the keratinocytes death receptor Fas and its ligand FasL10,11.

Therapy and prognosis Clearly, the offending medication should be stopped, and HSV infection, when playing a role, should be suppressed to prevent further episodes. However, by the time blistering erythema multiforme has occurred in response to a HSV infection, that particular episode is generally well established and not influenced by antiviral therapy.

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Patients with mild disease can be treated with supportive care, to include control of secondary infections, as well as topical and oral analgesic use. Cool soaks and emollients are often beneficial. Severe disease of the toxic epidermal necrolysis type has a mortality rate of about 25–30%, and should be treated in a burn unit. Careful debridement of necrotic epithelium, infection control, and fluid and electrolyte management are the mainstays of therapy. There is no role for systemic steroids in established blistering. Some believe that patients with early, evolving disease may benefit from 2–3 days of systemic corticosteroids, but this has not been verified. Cyclosporine and intravenous gammaglobulins have been shown in small series possibly to minimize disease, but others have shown no benefit11–15. Blistering of the conjunctiva, the vagina, and the vulva can produce debilitating scarring in some patients16. Careful management of secondary infection and local skin and eye care during the illness can help to prevent scarring and blindness. Specific care of the genitalia includes suppression of menses when possible, to minimize the small risk of vulvovaginal endometriosis, and scrupulous treatment of secondary infections to minimize the risk of scarring. Because vaginal adhesions can obliterate the vaginal canal, care should be taken to insert a vaginal dilator daily until the area has healed.

Fixed drug eruption A fixed drug eruption is an uncommon and peculiar blistering reaction to a medication.

Epidemiology and clinical manifestations Fixed drug eruptions occur in predisposed people who are exposed to any of several medications known to cause this condition. There is no reported predisposition for any gender, race, or age. On extragenital sites, patients experience one or several itchy or tender, characteristically round wheals or blisters. On mucous membranes of the mouth and the vulva, one or more nonspecific round or irregular 5–20-mm erosions are accompanied by irritation and pain (Figure 20.20).

Figure 20.20  A fixed drug eruption presents as a recurring same-site erosion that occurs with each exposure of an offending medication. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 16.3), New York: Churchill Livingstone; 1994.)

Re-exposure to the offending medication produces recurrent same-site lesions. With recurrences, round patches of blue-gray or brown postinflammatory hyperpigmentation appear at the keratinized extragenital sites. These round patches in a setting of past recurrent blisters or wheals are nearly pathognomonic for a fixed medication reaction. Postinflammatory changes on the modified mucous membranes of the vulva and the oral mucosa are generally absent.

Differential diagnosis HSV infection is the major disease to be differentiated from a fixed drug eruption, since recurrent erosions occurring in the same area are characteristic of both diseases. However, HSV infection consists of small round, often coalescing erosions, whereas a fixed drug eruption presents as a larger

Bullous diseases

blister or erosion without morphology suggesting coalescence of smaller lesions (Table 20.10). Blistering erythema multiforme (Stevens–Johnson syndrome, toxic epidermal necrolysis) also resembles a fixed medication reaction. However, this disease displays many more lesions, and affects other mucous membranes, as well as, usually, many keratinized extragenital lesions, including palms and soles. Many medications that produce fixed drug eruptions can also cause erythema multiforme, so overlap is possible.

Table 20.10  Fixed drug eruption Diagnosis   Clinical presentation Nonspecific mucous membrane erosions Keratinized skin with round wheals or blisters that recur in the same site with recurrences and erosions clustered on red plaques Postinflammatory hyperpigmentation of past sites on keratinized skin History of exposure to a known offender

Laboratory and histology

  Biopsy when necessary

There are no specific laboratory findings for a fixed drug eruption. A biopsy of a fixed drug eruption shows necrosis of the epidermis, with a subepidermal blister and liquefaction degeneration of the basal cell layer with pigment incontinence. A mononuclear infiltrate in the upper dermis is common.

Differential Diagnosis

Pathogenesis The cause of a fixed drug eruption is not known. It is presumed to be a hypersensitivity reaction to specific medications but the same-site localization of recurrent lesions is not explained. The clinical and histologic similarity to blistering forms of erythema multiforme suggests similar mechanisms. The medications most likely to produce a fixed drug eruption include the antibiotics: sulfa drugs, tetracyclines, penicillins, NSAIDs metronidazole, and fluoroquinolones. Barbiturates and other anticonvulsants, as well as nonnarcotic analgesics, are known to produce this eruption as well. Phenolphthalein and oral contraceptives are classic causes17.

Therapy and prognosis Therapy consists of local care, to include soaks and the application of bland emollients to the vulva, such as petrolatum (Vaseline petroleum jelly). Pain control as well as the avoidance of irritants and re-exposure of the offending medication is important in the management of these women. Erosions and extragenital wheals and blisters regularly occur with future exposure to the offending medication, and although each exposure may produce additional lesions, old lesions continue to reactivate.

  Herpes simplex virus   Erythema multiforme Management   Local care and pain control   Avoidance of future exposures

Cicatricial pemphigoid (benign mucous membrane pemphigoid) Cicatricial pemphigoid is an autoimmune blistering disease that, as its name suggests, is characterized by significant scarring.

Epidemiology and clinical manifestations Cicatricial pemphigoid is most common in older patients, occurring most often in the 60s, although there are numerous case reports of vulvar cicatricial pemphigoid in childhood18,19. More common in women than men, it shows a predilection for mucous membranes, particularly the mouth and conjunctivae. It also targets the vulva and vagina, as well as the glans penis of men. Patients describe irritation, burning, pain, and dryness. Extragenital blisters of dry, keratinized skin occur in a quarter to a third of individuals. An examination of the vulva shows nonspecific erosions of the modified mucous membranes, with eventual resorption of the labia minora and ­obliteration of the clitoris under a scarred clitoral hood (Figure 20.21). Gradual narrowing of the

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Figure 20.22  Like most other erosive vulvovaginal diseases, cicatricial pemphigoid prominently affects the gingivae with morphologically nonspecific erosions.

Figure 20.21  Cicatricial pemphigoid is characterized by erosions and remarkable scarring, but is indistinguishable clinically from other chronic erosive vulvar disease such as lichen planus or lichen sclerosus.

introitus is common. The eroded vaginal walls sometimes fuse, closing the vagina entirely. Vulvovaginal disease is regularly accompanied by oral disease, particularly redness and erosions of the gingivae and buccal mucosae, but all skin surface can be involved (Figure 20.22). Ocular disease is a major concern in these women, because involvement of the bulbar and palpebral conjunctivae can produce scarring and symblepharon formation, resulting in permanent blindness in some patients. Dry eyes and corneal scarring are frequently problems as well. Extragenital keratinized skin lesions are characterized by tense blisters arising primarily from red plaques and progressing to crusting; these often heal with hypopigmented scarring.

Differential diagnosis Cicatricial pemphigoid can be nearly indistinguishable from pemphigus vulgaris when occurring on mucous membranes and modified mucous

membranes, but the eyes are more prominently affected, and scarring is more evident (Table 20.11). Cicatricial pemphigoid of mucous membranes is sometimes indistinguishable from lichen planus as well. Blistering erythema multiforme (Stevens– Johnson syndrome) can be differentiated from cicatricial pemphigoid by its explosive onset and its association with either recurrent HSV infection or suspicious medication use. A fixed drug eruption can be differentiated by its sudden onset and the history of a characteristic medication as a trigger. Skin biopsies and the history of chronic involvement differentiate all of these diseases.

Laboratory and histology Patients with cicatricial pemphigoid often exhibit circulating immunoglobulin (Ig) G and/or IgA antibodies to components of the basement membrane by indirect immunofluorescent testing. Outside biopsy findings, there are otherwise no abnormal laboratory values beyond nonspecific findings of chronic disease in those patients with severe or widespread disease. Routine histology shows a subepidermal blister with both chronic inflammation and variable numbers of neutrophils and eosinophils. The vaginal mucosa and modified mucous membranes of the vulva often show plasma cells, and old lesions frequently exhibit fibrosis associated with scarring. When positive, direct immunofluorescence testing of perilesional skin showing IgG and C3 (or, less often, IgM or IgA) at the basement

Bullous diseases

Table 20.11  Cicatricial Pemphigoid Diagnosis   Clinical presentation   Older patient   Discrete erosions of mucous membranes   Sometimes, intact blisters of keratinized skin   Chronic nature   Confirmatory routine and direct immunofluorescent biopsy Differential Diagnosis   Erythema multiforme   Pemphigus vulgaris   Fixed drug eruption Management   Local infection control   Oral dapsone   Systemic and topical corticosteroids   Usually, steroid-sparing immunosuppressive medications (azathioprine, cyclophosphamide, methotrexate, etc.)

membrane confirms the diagnosis. Mucous membranes are more likely than nonmucous membrane skin to show this antibody deposition.

Pathogenesis Cicatricial pemphigoid is an autoimmune blistering disease. The circulating autoantibodies are believed to be pathogenic, and directed towards several different antigens located in the epithelial basement membranes, resulting in the detachment of the epidermis from the dermis.

Therapy and prognosis Cicatricial pemphigoid varies from low-grade disease that is somewhat manageable with topical corticosteroids and local care, to widespread disease and the development of blindness despite systemic corticosteroids and concomitant administration of other immunosuppressive medication. Oral dapsone, used for its anti-­inflammatory properties, is first-line therapy for cicatricial

pemphigoid. Often, dapsone is not sufficient for control of this disease. These patients generally require systemic corticosteroids, generally with a concomitant steroid-sparing immunosuppressive agent. Cicatricial pemphigoid is usually managed by dermatologists or rheumatologists who are experienced in the use of these systemic medications. In addition to long-honored, steroid-sparing, modestly effective therapies including methotrexate, azathioprine, cyclophosphamide, and cyclosporine, newer biologic agents such as etanercept and infliximab are being used with anecdotal success20–22. Topical tacrolimus has been reported useful in several patients, but local burning is usually a limiting factor23. Intravenous immunoglobulin therapy has also been reported to be beneficial24. This is an unremitting, chronic disease requiring ongoing therapy and careful local care to minimize pain and scarring. Scarring of anogenital skin can often be impressive, producing vaginal adhesions, urethral strictures, and anal stenosis. Aggressive local care may minimize these sequelae. These patients generally require multidisciplinary management that includes, at least, ophthalmologists, gynecologists, and dermatologists.

Benign familial pemphigus (Hailey–Hailey disease) Benign familial pemphigus is an uncommon, characteristic, autosomal-dominant skin disease that primarily affects skin folds. This disease is discussed primarily in Chapter 18. Benign familial pemphigus exhibits poorly demarcated, red, macerated plaques with small linear and angular erosions and crusts (Figure 20.23). Often, plaques also show white, hyperkeratotic and macerated epithelium. Secondary infection, particularly with Candida, and heavy colonization of normal skin bacteria are common and worsen symptoms and skin disease. First-line therapy of benign familial pemphigus is the control of local exacerbating factors that contribute to friction and moisture. Weight loss, measures to reduce sweating, elimination of surface bacteria with antibiotics, and topical corticosteroids minimize secondary inflammation and erosions. Laser ablation, skin grafts, and botulinum toxin have been beneficial as well.

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Figure 20.23  Hailey–Hailey disease (benign familial pemphigus) shows characteristic intertriginous, coalescing, superficial vesicles that appear as angular or linear erosions within white, fragile papules.

Fissures Fissures consist of splitting of the epithelium from trauma, or as a common, nonspecific response to inflammation. These occur in two primary forms: posterior fourchette fissuring with sexual activity, and fissuring within skin folds such as the interlabial folds, the skin lines on the perineal body, and radial fissures within perianal creases. Posterior fourchette fissures, although sometimes associated with skin disease such as lichen sclerosus, are seen most often in previously asymptomatic, premenopausal women with no other abnormal findings (Figure 20.24). Women report pain at the posterior fourchette with sexual activity, and localized burning that persists for several days. A physical examination shows a fissure that ranges from a fine, red line to a gaping, deep crack. Although logically associated with estrogen deficiency, topical estrogen is rarely useful. Woman-on-top position during sexual activity and generous lubrication minimize splitting. However, in the absence of skin disease or infection, definitive therapy consists of a perineoplasty, where the fissure is excised front-to-back, and vaginal mucosa is advanced to cover the defect. The second form of fissuring presents with complaints of a sensation of “paper cuts.” A physical examination often reveals puffiness of vulvar skin and slightly glazed texture. The fissures can

Figure 20.24  Recurrent tearing at the posterior fourchette with sexual activity is a common event that, although ­sometimes associated with skin disease, is usually idiopathic, requiring surgical intervention.

be obvious, or are sometimes quite subtle, manifested only by deep erythema of skin creases, and only visible with magnification. These often heal overnight, and are therefore missed by the clinician. Skin fold fissures are usually associated with inflammation, either infectious or as a result of skin disease (Figures 20.25 and 20.26). Candida albicans is the classic cause, but bacterial vaginitis (rather than vaginosis) and HSV infection are sometimes associated. Lichen simplex chronicus, contact dermatitis, and lichen sclerosus are the most common dermatoses that produce skin fold fissures. The treatment of these fissures involves addressing the underlying cause. When no etiology is found, a broad-spectrum antibiotic, a topical corticosteroid ointment, and oral candidal suppression often control fissuring.

Bullous impetigo Bullous impetigo is a bacterial infection produced by certain strains of Staphylococcus aureus. The infection occurs in the stratum corneum, and a toxin produces a blister between the stratum corneum and the upper epidermis. This very superficial blister is extremely short-lived, and often manifested by collarettes (edges of the ­desquamated blister roofs) on relatively intact skin. In the unlikely event that the intact blister is seen, it is usually filled with clear, straw-­colored fluid rather than pus. The diagnosis is made by

Bullous diseases 237

Figure 20.26  Sometimes, fissuring of skin folds occurs with lichen sclerosus.

and direct ­ immunofluorescent biopsies do not ­differentiate between the two diseases, so the presence of mucous membrane disease usually separates them. Otherwise, systemic corticosteroids, tetracycline and niacinamide, and topical/local care are used for bullous pemphigoid.

Pemphigus vulgaris

Figure 20.25  Fine fissures within skin folds are most common with infection, especially Candida albicans, but can occur as a result of any underlying inflammation.

culture and response to therapy. Because of the frequency of methicillin-resistant S. aureus, a culture is often required. As in the treatment of folliculitis, recurrence is common and suggests a nasal carrier state. Mupirocin ointment inserted in the nares two or three times a day for 1 week each month is beneficial in controlling recurrences in those patients.

Bullous pemphigoid Bullous pemphigoid is an autoimmune, chronic blistering disease that is very closely associated with cicatricial pemphigoid. Also seen primarily in elderly patients, the primary ­differentiating ­clinical manifestation is the sparing of true mucous membranes. Also, scarring is uncommon. Routine hematoxylin and eosin biopsies

Pemphigus vulgaris is an autoimmune blistering disease that is most common in middle-aged individuals. It prominently affects mucous membranes, including the oral mucosa and vulvovaginal skin (Figure 20.27). Lesions often first appear on mucous membranes as superficial erosions, but flaccid bullae and erosions of hair-bearing skin follow. Although pemphigus vulgaris is generally unassociated with scarring on other skin sites, resorption of vulvar architecture and vaginal synechiae are common. Pemphigus vulgaris of mucous membranes is most often confused with lichen planus, blistering erythema multiforme, and cicatricial pemphigoid. However, the extremely superficial nature of the blister produces flaccid blisters and erosions, and this disease is usually gradual in onset, unlike erythema multiforme. The diagnosis is made by routine and direct immunofluorescence biopsy. Treatment includes local care as well as systemic and topical corticosteroids. Steroid-sparing agents, as are used for cicatricial pemphigoid, are usually required. Although the disease often improves over time, it generally does not completely remit.

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Pustules, Vesicles, Bullae, and Erosions

238

Figure 20.27  Pemphigus vulgaris shows a predilection for mucous membranes, but also affects dry, hair-bearing skin; although primarily a blistering disease, erosions and crusts are prominent due to the thin nature of the blister roof.

Other

Other diseases that are erosive but discussed in more detail elsewhere include lichen planus, the most common cause of chronic noninfectious vulvovaginal erosive disease (Chapter 15). Lichen sclerosus occasionally erodes secondarily, but generally shows typical white, crinkled plaques that indicate the diagnosis. This disease is discussed in detail in Chapter 14. Plasma cell vulvitis is not erosive, but the red, glistening color mimics erosion (Chapter 17).

References   1. Malkin, J. E. Epidemiology of genital herpes simplex virus infection in developed countries. Herpes 2004; 11(Suppl 1): 2A–23A.   2. Xu, F., Sternbery, M. R., Kottiri, B. J., et al. Trends in herpes simplex virus type 2 and type 2 seroprevalence in the United States. J.A.M.A. 2006; 296: 964–973.   3. 2006 STD Treatment Guidelines. From the website of the Centers for Disease Control and Prevention. Available online at: http://www.cdc.gov/std/treatment/default.htm.

  4. Sacks, S. L. Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial. J. Infect. Dis. 2004; 189: 1341–1347.   5. Benedetti, J. K., Corey, L., and Ashley, R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann. Intern. Med. 1994; 121: 847–854.   6. Engleberg, R., Carrell, D., Krantz, E., et al. Natural history of genital herpes simplex virus type 1 infection. Sex. Transm. Dis. 2003; 30: 174–177.   7. Bryson, Y., Dillon, M., Bernstein, D. I., et al. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J. Infect. Dis. 1993; 167: 942–946.   8. Wald, A., Selke, S., Warren, T., et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex. Transm. Dis. 2006; 33: 529–533.   9. Holcomb, K. and Weinbery, J. M. A novel vaccine (Zostavax) to prevent herpes zoster and postherpetic neuralgia. J. Drugs Dermatol. 2006; 5: 863–866. 10. French, L. E. Toxic epidermal necrolysis and Stevens–Johnson syndrome: our current understanding. Allergol. Int. 2006; 55: 9–16. 11. Khalili, B. and Bahna, S. L. Pathogenesis and recent therapeutic trends in Stevens–Johnson syndrome and toxic epidermal necrolysis. Ann. Allergy Asthma Immunol. 2006; 97: 272–280. 12. Trent, J., Halem, M., French, L. E., et al. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin. Cutan. Med. Surg. 2006; 25: 91–93. 13. French, L. E., Trent, J. T., and Kerdel, F. A. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens– Johnson syndrome: our current understanding. Int. Immunopharmacol. 2006; 6: 543–549. 14. Bachot, N., Revuz, J., and Roujeau, J. C. Intravenous immunoglobulin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch. Dermatol. 2003; 139: 33–36. 15. Arevalo, J. M., Lorente, J. A., Gonzalez-Herrada, C., et al. Treatment of toxic epidermal necrolysis with cyclosporine A. J. Trauma 2000; 48: 473–478. 16. Meneux, E., Paniel, B. J., Pouget, F., et al. Vulvovaginal sequelae in toxic epidermal necrolysis. J. Reprod. Med. 1997; 42: 153–156. 17. Sehgal, V. N. and Srivastava, G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int. J. Dermatol. 2006; 45: 897–908. 18. Hoque, S. R. and Patel, M. Childhood cicatricial pemphigoid confined to the vulva. Clin. Exp. Dermatol. 2006; 31: 63–64. 19. Schoeffler, A., Roth, B., Causeret, A., et al. Vulvara cicatricial pemphigoid of childhood. Pediatr. Dermatol. 2004; 21: 51–53. 20. Chang, J. H. and McCluskey, P. J. Ocular cicatricial pemphigoid: manifestations and management. Curr. Allergy Asthma Rep. 2005; 5: 333–338. 21. Canizares, M. J., Smith, D. I., Conners, M. S., et al. Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients. Arch. Dermatol. 2006; 142: 1457–1461. 22. Hoffernan, M. P. and Bentley, D. D. Successful treatment of mucous membrane pemphigoid with infliximab. Arch. ­Dermatol. 2006; 142: 1268–1270. 23. Gunther, C., Wozel, G., Meurer, M., et al. Topical tacrolimus treatment for cicatricial pemphigoid. J. Am. Acad. Dermatol. 2004; 50: 325–326. 24. Ahmed, A. R. Treatment of autoimmune mucocutaneous ­blistering diseases with intravenous immunoglobulin therapy. Exp. Opin. Invest. Drugs 2004; 13: 1019–1032.

Further reading

Further reading Herpes simplex virus infection Beauman, J. G. Genital herpes: a review. Am. Fam. Physician 2005; 72: 1527–1534. Leone, P. Reducing the risk of transmitting genital herpes: advances in understanding and therapy. Curr, Med. Res. Opin. 2005; 21: 1577–1582.

Varicella

Toxic epidermal necrolysis French, L. E. Toxic epidermal necrolysis and Stevens–Johnson ­syndrome: our current understanding. Allergol. Int. 2006; 55: 9–16. Khalili, B. and Bahna, S. L. Pathogenesis and recent therapeutic trends in Stevens–Johnson syndrome and toxic epidermal necrolysis. Ann. Allergy Asthma Immunol. 2006; 97: 272–280. Pereira, F. A., Mudgil, A. V., and Rosmarin, D. M. Toxic epidermal necrolysis. J. Am. Acad. Dermatol. 2007; 56: 181–200.

Fixed drug eruption

Heininger, U. and Seward, J. F. Varicella. Lancet 2006; 368: 1365–1376.

Sehgal, V. N. and Srivastava, G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int. J. Dermatol. 2006; 45: 897–908.

Herpes zoster

Vulvar fissures

Dworkin, R. H., Johnson, R. W., Breuer, J., et al. Recommendations for the management of herpes zoster. Clin. Infect. Dis. 2007; 44(Suppl 1): S1–S26. Niv, D. and Maltsman-Tseikhin, A. Postherpetic neuralgia: the never-ending challenge. Pain Pract. 2005; 3: 327–340. Sederholm, B. and Peterson, D. Zoster vaccine to prevent postherpetic neuralgia. J. Pain Palliat. Care Pharmacother. 2006; 20: 41–42.

Edwards, L. Vulvar fissures: causes and therapy. Dermatol. Ther. 2004; 17: 111–116.

Lymphangioma circumscriptum Roy, K. K., Agarwal, R., Agarwal, S., et al. Recurrent vulval congenital lymphangioma circumscriptum – a case report and literature review. Int. J. Gynecol Cancer. 2006; 16. 930–034.

Cicatricial pemphigoid Goldstein, A. T., Anhalt, G. J., Kligman, D., et al. Mucous membrane pemphigoid of the vulva. Obstet. Gynecol. 2005; 105: 1188–1190. Sacher, C. and Hunzelmann, N. Cicatricial pemphigoid (mucous membrane pemphigoid): current and emerging therapeutic ­approaches. Am. J. Clin. Dermatol. 2005; 6: 93–103.

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PART: Ii  Gynecologic Dermatology

CHAPTER 21

Vulvar Ulcers Peter J. Lynch Ulcers are differentiated from erosions on the basis of depth. Erosions are shallow and are due to absence of the epidermis with no appreciable damage to the underlying dermis. For this reason erosions have a red base or are covered with loosely adherent yellow crust. Ulcers are deep with the defect extending into the dermis. The base of an ulcer contains necrotic tissue, blood-tinged crust, or blueblack adherent eschar. Only vulvar ulcers are discussed in this chapter; erosive vulvar disease is covered in Chapter 20.

Noninfectious Ulcers Aphthous ulcer and complex aphthosis Epidemiology and clinical manifestations Aphthous ulcers (“canker sores”) of the mouth occur in a very large proportion of the normal population. Studies in western societies suggest a point prevalence rate of 1–2% and a lifetime incidence rate of 60%. Risk factors for the development of oral aphthous ulcers include a positive family history, white race, high socioeconomic class, and psychological stress factors. Vitamin and iron deficiency is found fairly frequently but this may be coincidental because replacement of the deficiency does not improve the course of the disease. Lesions first begin to appear in childhood or adolescence. Peak frequency occurs in early adult life and then starts to decrease with age. Most patients tend to have periodic recurrences. Gynecologists and dermatologists generally believe that aphthous ulcers occur only rarely on the vulva. The medical literature seems to support this belief. Even though the first patients with noninfectious vulvar ulcers of this type were reported by Lipschutz as far back as 1913, there are only a handful of such patients described in published reports. Only a single manuscript describes incidence or prevalence rates1. However, our own experience, along with discussion among colleagues, suggests that aphthous ulceration of the vulva occurs with some frequency. The risk factors for development of vulvar ulcers of this type are the same as those described for oral disease and, similarly, recurrences are common.

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Oral aphthous ulcers have been classified into three groups: (1) minor aphthous ulcers – small lesions (< 1.0 cm) that heal without scarring in 7–10 days; (2) major aphthous ulcers – large, deep lesions (> 1.0 cm) that heal, often with scarring, in 10–30 days; and (3) herpetiform aphthous ulcers – multiple, clustered, shallow, small (1–3 mm) ulcers that heal quickly, generally without scarring. Vulvar lesions can be classified similarly, though a larger proportion falls into the category of major aphthous ulcers than is true for the mouth. The term “complex aphthosis” is used when vulvar ulcers occur synchronously or metachronously with oral ulcers. The best data regarding vulvar aphthous ulcers are found in the recent report by Huppert et al.1 These authors described 20 females with idiopathic vulvar ulcers. The mean age of the patients was 14 years (range 10–19 years). Most ulcers were less than 1 cm in diameter but one patient had a 5-cm lesion. Multiple lesions were almost always present, occurring in 17 of 20 patients. The most common site was within the vestibule but ulcers were also occasionally found on the keratinizing epithelial surfaces of labia majora and perineum. (This is in marked distinction to oral aphthae, which are never found on the perioral skin of the face.) Half of their patients reported oral lesions and one-third developed recurrences of their vulvar ulcers. My experience is very similar, though a larger proportion of my patients have had oral lesions and multiple vulvar recurrences. Individual lesions start out as round to oval ulcers but coalescence of neighboring lesions can result in larger ulcers with serpiginous borders (Figures 21.1–21.5). A red rim of erythema (2–3 mm wide) is present and, at the base of the ulcers, there is usually a white coagulum of necrotic tissue. The ulcers are quite painful and healing generally requires 2–3 weeks. Scarring can occur but it seems less severe than would be expected given the size and depth of the lesions. Systemic symptoms and signs such as fever, malaise, headache, gastrointestinal distress, pharyngitis, and myalgia occur in many of these young women with complex aphthosis but these are usually mild, time-limited, and nondebilitating1.

Figure 21.1  This painful ulceration was preceded by fever, sore throat, and myalgias in the 12-year-old daughter of a clinic nurse, who recognized the very typical clinical picture.

Figure 21.2  Although aphthae are more often seen on mucosae or the modified mucosae, they can occur on hair-bearing skin as well.

Diagnosis and differential diagnosis The appearance of these aphthous ulcers is sufficiently distinctive that, in association with a history of recurrence, a clinical diagnosis is possible. Since there are no microscopic or laboratory

Noninfectious ulcers 243

Figure 21.3  Oval, punched-out ulceration on modified mucous membranes is typical for aphthae.

Figure 21.5  Very large aphthae sometimes heal with considerable scarring. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 18-2), New York: Churchill Livingstone; 1994.)

Figure 21.4  Irregular, sharply demarcated aphthous ulcer with a yellow fibrin base in a patient with concomitant oral aphthae. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 18-1), New York: Churchill Livingstone;1994.)

f­ eatures that positively identify the disease, the only way to confirm a clinical diagnosis is to rule out conditions that simulate it (Table 21.1). Genital herpes (herpes simplex virus: HSV) is almost always a consideration but, with the exception of

chronic HSV infection in the immunosuppressed, the lesions of herpes are not as large or deep. However, in some instances, immunofluorescent smears, culture, and biopsy may be necessary to rule out herpetic infection. Primary syphilis (chancre) can be identified by serology and biopsy. Cultures and/or biopsy are appropriate to rule out the anogenital ulcers of Crohn’s disease as well as the lesions of chancroid, granuloma inguinale, and various cutaneous malignancies. As indicated above, complex aphthosis is the term used when vulvar aphthous ulcers occur in association with either a synchronous or metachronous history of oral aphthous ulcers. Patients with complex aphthosis and no related underlying disease are said to have primary complex aphthosis. When patients do have an associated systemic disorder, the term “secondary complex aphthosis” should be used.

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Table 21.1  Aphthous Ulcers and Complex Aphthosis Diagnosis Painful, deep ulcers No undermining of edges Thin red border White coagulum at the ulcer base History of recurrence Differential Diagnosis Herpes simplex virus in the immunosuppressed Crohn’s disease Primary syphilis Therapy Rule out associated disease, especially Behçet’s disease Lidocaine or silver nitrate for pain Topical or intralesional steroids Oral antibiotics as anti-inflammatory agents Consider short-term systemic steroids Consider dapsone, colchicine, thalidomide

conditions include gluten-sensitive ­ enteropathy, lupus erythematosus, cyclic neutropenia, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) infection, the MAGIC syndrome (mucosal and genital ulcers with inflamed cartilage) and the PFAPA syndrome (periodic fever, aphthosis, pharyngitis and adenitis).

Histology and laboratory tests Aphthous ulcers have a rather nonspecific histologic appearance. The earliest lesions demonstrate a predominantly lymphocytic inflammatory infiltrate but later lesions show both a lymphocytic reaction and a central area of intense neutrophilic inflammation with blood vessel destruction and necrosis of the involved tissue. A pathologist encountering this inflammatory pattern will not be able to make a definitive diagnosis of aphthous ulceration but generally can state that such a biopsy is consistent with that diagnosis. Because there are several medical problems that can be associated with complex aphthosis (see above), a complete medical history must be taken. Laboratory tests are then chosen based on a history of specific problems. Letsinger et al. have recently suggested specific steps for laboratory evaluation2.

Pathogenesis Several systemic conditions occur in association with secondary complex aphthosis. Oral and vulvar ulcers are a consistent and characteristic feature of Behçet’s disease and this latter disorder must be considered when patients with complex aphthosis are encountered. However, it should be emphasized that, in Europe and North America, young women with complex aphthosis almost never have, or evolve into, Behçet’s disease. Needless to say, a diagnosis of Behçet’s disease should not be made unless the International Study Group (ISG) and/or O’Duffy diagnostic criteria are strictly met. Aphthous ulcers also occur quite regularly in the setting of inflammatory bowel disease. For that reason patients should be queried regarding the symptoms and signs of associated Crohn’s disease and ulcerative colitis. Other rarely associated

The cause of aphthous ulceration is not known. Based on the high frequency of a positive family history, genetic factors are probably important. It has been hypothesized that inheritance involves the predisposition to develop a more brisk than normal cell-mediated immune response to one or another unrecognized antigen. Although the nature of the antigen(s) has not been identified, there is some evidence to suggest that microbial proteins, by way of molecular mimicry, initiate an autoreactive (autoimmune) response. In any event, activation of the cell-mediated immune response results in the generation of many inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-2. Both the activated immune cells and the cytokines they release are presumably cytotoxic to epithelial cells and possibly also to fibroblasts. Risk factors for the development of

Noninfectious ulcers

aphthous ulceration are discussed above. Specific triggers to the development of individual attacks include local tissue trauma (pathergy), psychological stress, and possibly acidic and salty foods.

Therapy and prognosis Letsinger et al. have developed a widely accepted therapeutic ladder that starts with topical agents (local anesthetics, local steroids, and tacrolimus) and progresses to systemic therapy with oral colchicine, dapsone, a combination of these two agents and, if necessary, thalidomide2. However, as indicated in their manuscript, only about 5% of patients respond satisfactorily to topical agents alone. On the other hand, with systemic therapy, 88% of their patients achieved 50% or greater improvement2. I have found that topical anesthetics such as 5% lidocaine ointment and EMLA are of limited use. For the reduction of pain in small lesions I prefer the application of silver nitrate using standard silver nitrate sticks3. Clobetasol 0.05% ointment and gel are only modestly effective anti-inflammatory agents. Intralesional injection with triamcinolone in a concentration of 10 mg/mL works much better but such therapy is painful and requires an office visit for each recurrence. My initial treatment of choice is a brief “burst” of oral prednisone in a dose of 40 mg q a.m. for 7 days. Oral antibiotics, used for their anti­inflammatory properties, such as doxycycline 100 mg bid or minocycline 100 mg bid, can be started at the same time and may be continued indefinitely in an attempt to prevent the recurrence of additional lesions. Colchicine, 0.06 mg bid to tid, dapsone 100–150 mg/day, and pentoxyphylline 400 mg tid are useful alternatives to antibiotics4,5. Thalidomide and other tumor necrosis factoralpha inhibitors are remarkably effective6,7 but adverse side-effects, high cost, and relatively short history of their use limit this approach to patients who have failed more conventional therapy. The prognosis for women with idiopathic (primary) complex aphthosis involving the vulva is unclear. The medical literature on Behçet’s disease states that patients may have oral and genital lesions (complex aphthosis) for several years prior to the development of systemic symptoms and signs. In the series reported by Letsinger et al.,

15% of patients with complex aphthosis referred to their group met established criteria for the diagnosis of Behçet’s disease2. However, no information was provided in that paper as to whether the complex aphthosis preceded the Behçet’s disease or, if so, by how long. Importantly, none of the 20 patients studied by Huppert et al. had or developed Behçet’s disease when followed over a rather short mean period of 14 months1. Finally, based on my own experience and on discussion with other vulvologists, I believe that progression to Behçet’s disease is extremely unlikely in women of European or North American background. Thus, when the standard diagnostic criteria for Behçet’s disease are not met, I feel that it is inappropriate to suggest that patients have, or are likely to develop, Behçet’s disease (see also discussion in the section on Behçet’s disease, below).

Behçet’s disease Behçet’s disease is seen with some frequency in the Eastern Mediterranean and Asia. The prevalence in Turkey varies from village to village but can be as high as 370 per 100 000. Conversely, it is an extremely rare disease in the United Kingdom and North America, where the prevalence is estimated at about 0.3 per 100 000. Several sets of criteria for the diagnosis of Behçet’s disease are available. Physicians in most countries use the diagnostic criteria developed by the ISG in 1990. These criteria can be summarized as requiring the presence of recurrent oral ulcerations plus any two of the following: (1) recurrent genital ulceration; (2) eye lesions (anterior or posterior uveitis, cells in the vitreous or retinal vasculitis); (3) skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules in postadolescent patients); and (4) a positive pathergy test. Women with complex aphthosis (see above) already have recurring oral and vulvar ulcers and thus need only one other criterion before they meet the ISG diagnostic guidelines for Behçet’s disease. Unfortunately, in western societies, the skin lesions listed in the ISG criteria are quite common as “stand-alone” conditions and they also occur with appreciable frequency in patients with

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i­ nflammatory bowel disease, lupus ­erythematosus, and other autoimmune disease. For this reason, many women in the United States, continental Europe, and the United Kingdom meet the ISG criteria for Behçet’s, but do not develop the severe ocular or central nervous system disease that characterizes eastern patients with Behçet’s disease. For this reason, one must be extremely cautious about telling a woman with complex aphthosis and mild skin or eye findings that she has, or is likely to develop, Behçet’s disease. The therapy of the oral and genital ulcers in patients with Behçet’s disease is the same as is discussed above for complex aphthosis.

Crohn’s disease Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) is quite common in North ­America and Europe, with a prevalence of around 400 per 100 000 persons. Crohn’s disease occurs somewhat less frequently than ulcerative colitis. It has an annual incidence rate of about 8 per 100 000 and a prevalence of about 150–175 per 100 0008. However, cutaneous lesions are found more often in Crohn’s disease, occurring in about 2–3% of such patients9. Patients with ulcerative colitis can develop perianal fistulae but other types of anogenital involvement are rare, if they occur at all. For the purposes of this section, discussion will be restricted to Crohn’s disease. Extraintestinal involvement of the skin in patients with Crohn’s disease occurs with some frequency. These mucocutaneous lesions can be divided into two categories: histologically specific involvement and histologically nonspecific involvement. Histologically specific lesions demonstrate the same microscopic granulomatous features as are found in the intestine. Nonspecific lesions, such as aphthous ulcers, pyoderma gangrenosum, and erythema nodosum, lack this granulomatous histology. Note that the development of either type of skin lesion is not related to the extent or severity of the intestinal disease. In fact, skin lesions often precede the appearance of any intestinal symptoms or signs. Among the nonspecific lesions, aphthous ulcers are discussed earlier in this chapter; erythema nodosum does not involve the vulva,

and pyoderma gangrenosum rarely does so. Thus, these conditions will not be further discussed.

Epidemiology and clinical manifestations Although histologically specific mucocutaneous lesions of Crohn’s disease can occur anywhere on the body, most occur in the anogenital area. Ploysangam et al., in the largest available review, identified 80 children who had cutaneous Crohn’s disease10. Of these, 45 had genital involvement, with ulcers and genital swelling accounting for most of the lesions (Figures 21.6 and 21.7). Twothirds of patients with genital involvement were female. In most instances the Crohn’s disease appeared prior to the skin lesions but in 20% the skin lesions occurred first. In the 10 years since

Figure 21.6  The classic deep, linear “knife cut” ulcerations of Crohn’s disease in skin folds were accompanied by undiagnosed associated intestinal disease. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 18-5), New York: Churchill Livingstone; 1994.)

Figure 21.7  Chronic edema of Crohn’s disease often results in lymphedema and firm fibrotic nodules.

Noninfectious ulcers

this report, only about 15 additional patients with vulvar involvement have been published. The most common anogenital lesion in women is vulvar edema; the swelling can be either unilateral or bilateral. It may be inflamed (erythematous) or noninflamed (skin-colored) (Figures 21.8 and 21.9). Since biopsies have only rarely been performed it is not possible to say what proportion of these cases had granulomatous involvement and what proportion had nonspecific edema due to passive congestion. However it is interesting that isolated granulomatous swelling of the vulva, occurring in the absence of significant gastrointestinal symptoms and signs, has been reported under several titles, including vulvitis granulomatosa, idiopathic granulomatous vulvitis, and Melkersson–­Rosenthal disease. It is likely

that some of these patients have, or will develop, Crohn’s disease (see also Chapter 25)11,12. Perianal disease, primarily due to the presence of fistulae, occurs in about 10–15% of patients with Crohn’s disease (Figure 21.10)13. The likelihood

Figure 21.9  Edema producing firm, coalescing papules and pedunculated nodules in this woman with Crohn’s disease is a nonspecific finding also found in some patients with hidradenitis, lymphatic obstruction from surgery, or other causes of chronic lymphedema.

Figure 21.8  Crohn’s disease can also be manifested by enlargement of the labia by diffuse granulomatous thickening, as well as ulcerated outlets to sinus tracts, as seen on the buttock in this photograph.

Figure 21.10  Both the draining fistulae and the thickened perianal tags are characteristic of Crohn’s disease.

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Figure 21.12  Chronic ulcerations of any kind, including this one of Crohn’s disease, have a slight potential for malignant transformation and should be followed carefully. Table 21.2  Crohn’s Disease Diagnosis Vulvar edema Perianal fistulae Figure 21.11  Although fairly uncommon, these linear ulcers that mimic lacerations are nearly pathognomonic for ulcerative Crohn’s disease.

Draining abscesses Elongated, “knife cut” ulcers

of developing fistulae is much higher for those patients whose intestinal disease occurs in the colon and rectum rather than in the small intestine. The fistulae may extend into either the anal canal or the rectum. Fistulae may also extend from the vagina to the vulva. Abscesses may develop anywhere in the anogenital region. In some instances they occur over unrecognized fistulae and in others they occur as noncontiguous (“metastatic”) foci of Crohn’s disease. Elongated ulcers of the “knife cut” type sometimes develop in creased areas such as the interlabial and genitocrural folds (Figures 21.6, 21.11 and 21.12). These ulcers are highly characteristic for Crohn’s disease and otherwise are found only in the rarely encountered condition of granuloma inguinale.

History of gastrointestinal tract symptoms and signs

Diagnosis and differential diagnosis

Intralesional steroid injections

A clinical diagnosis of vulvar Crohn’s disease can be established if characteristic elongated, linear “knife cut” ulcers occur in association with typical intestinal symptoms and signs (Table 21.2). Other types of lesions, especially when they occur in the absence of recognized intestinal disease, require biopsy for identification.

Tumor necrosis factor-alpha inhibitors

Biopsy Differential Diagnosis Aphthous ulcer Hidradenitis suppurativa Granuloma inguinale Therapy Treat gastrointestinal tract disease Incision and drainage for abscesses Surgical repair for fistulae

Hidradenitis suppurativa (HS) causes abscesses, ulcers, and draining sinuses that look very much like Crohn’s disease. The presence of inflammatory lesions in other sites along the milk line generally allows for recognition of HS but separating

Noninfectious ulcers

the two diseases is much more difficult when lesions of HS are confined to the anogenital area. Confusion can even occur histologically when the early severe folliculitis pattern develops into granulomatous inflammation. The vulvar labial edema seen in Melkersson– Rosenthal syndrome (see Chapter 25) is clinically and histologically similar to that occurring in Crohn’s disease and, in the absence of typical intestinal symptoms and signs, correct identification of these two conditions may be difficult. It is possible that a subset of Melkersson–Rosenthal patients actually have Crohn’s disease. Histologically the granulomas of cutaneous sarcoidosis are similar to those seen in Crohn’s disease. However the clinical appearance is dissimilar (see Chapter 19). Granuloma inguinale can present with “knife cut” linear ulcers but the histology is distinctive.

Histology and laboratory tests The histologic changes found in biopsies of mucocutaneous Crohn’s disease are similar to those that occur in the gastrointestinal tract. The findings include epithelial thickening overlying noncaseating, granulomatous inflammatory foci. The granulomatous reaction may occur in association with blood vessels resulting in the development of granulomatous vasculitis and/or perivasculitis. Although long-standing intestinal disease may be associated with complete blood count abnormalities due to gastrointestinal bleeding, anemia, and nutritional deficiencies, no specific laboratory tests are needed in the evaluation of vulvar lesions in patients with Crohn’s disease.

Pathogenesis Even though only about 10% of patients have a positive family history for Crohn’s disease, genetic factors are important in the development of this condition. Loci on seven different chromosomes confer some degree of susceptibility for the disorder. Specifically, mutations in the nod 2 gene are found in about one-third of patients14. The protein made by this gene participates in both the recognition of bacteria and the subsequent immune response to these microbes. For this reason, Crohn’s disease may occur as a genetically dysfunctional, overly brisk immunoinflammatory

response to the presence of intestinal bacteria. It is not known how or why noncontiguous (“metastatic”) lesions arise in the skin.

Therapy and prognosis As indicated above, active intestinal disease may or may not be present at the time the skin lesions are recognized. If intestinal disease is present, treatment for the skin lesions is first directed toward achieving control of the intestinal involvement. Historically, this has been achieved through the systemic administration of diverse medications such as sulfasalazine, metronidazole, corticosteroids, azathioprine, thalidomide, or 6-mercaptopurine. More recently, biological agents that act as tumor necrosis factor-alpha inhibitors have come to the forefront as safe, effective medications. Of these, infliximab has been best studied and demonstrates a beneficial response in at least 65% of patients with closure of fistulae occurring in about half of the patients15. Other types of skin lesion, including aphthous ulcers and pyoderma gangrenosum, respond to this drug at an even better rate16. Local therapy for anogenital lesions of Crohn’s disease include incision and draining of abscesses, intralesional triamcinolone injection, with a solution of 10 mg/mL, for ulcers and nonhealing abscesses, and surgery for sinuses and fistulae. Crohn’s disease of the anogenital region is a chronic process and, as indicated above, control of the intestinal component of the disorder does not always result in clearing of the skin lesions. As is true in almost all chronic inflammatory anogenital diseases, the development of squamous cell carcinoma in the anogenital area is an uncommon, but definite, possibility17.

Excoriation and factitial disease Ulcers of the vulva can be caused by external trauma. There are five settings in which this occurs: (1) excoriations (“gouging”) by the fingernails in response to intense pruritus; (2) severe reactions to caustic medications; (3) recognized, but unwitting, destructive therapy by patients; (4) self-mutilation as a part of psychiatric disease such as overwhelming sexual guilt or obsessive-compulsive disorder;

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Figure 21.14  This woman produced irregular ulcerations by “digging out” mollusca contagiosa.

Figure 21.13  Intense pruritus produces not only rubbing, but scratching that sometimes produces excoriations, the resulting linear, irregular erosions, and ulcerations.

and (5) genital mutilation as a cultural or religious process. There are two good clues for the recognition of these externally caused ulcers. First, the shape of the ulcers is angular or linear rather than the round or oval configuration found in nontraumatic ulcers occurring as part of a medical disease. Second, the base of the ulcer may be surprisingly “clean,” lacking necrotic debris, crust, and eschar formation. First, about 95% of small (1–2-cm) angular and linear traumatic ulcers of the vulva occur as a result of chronic scratching and gouging of the skin (Figures 21.13 and 21.14). This situation nearly always occurs in the setting of lichen simplex chronicus. Patients usually acknowledge that they are scratching but indicate that they just cannot stop scratching no matter how hard they try. In addition, the patient may scratch while sleeping, leaving the individual unaware of how it is occurring. In such a situation, history obtained from a bed partner and/or the morning presence of blood flecks on the bed linens or under the patient’s fingernails will lead to the identification of the cause.

The treatment of this “itch–scratch cycle” is covered in Chapter 16. Second, about 1% of the time the ulcers are induced either by the patient or by the clinician through the use of potentially caustic therapy for vulvar disease. Such ulcers can occur after the use of 5-fluorouracil, bi- and trichloroacetic acid, podophyllin, or imiquimod. This subject is covered under irritant contact dermatitis in Chapter 18. In a similar fashion, ulcers can develop at the site of genital piercings due to trauma or infection. Third, in another 1% of the patients, vulvar ulcers arise because of a patient’s misguided efforts at hygiene. We have seen ulcerative reactions from steel wool, stiff brushes, bleach, lye, and other caustic “cleansers” used by patients anxious to clean what they have been taught is “the dirty area down there.” Likewise, patients will sometimes use excessive hygiene in a futile attempt to treat a real or imagined vulvar disorder. This is particularly likely to happen if the patient believes, usually incorrectly, that she has a “bad odor” coming from the anogenital region. Fourth, psychiatrically disturbed patients may mutilate their genitalia over sexual guilt, paranoid feelings about something unnatural happening in the genital area, or as part of severe obsessive-compulsive disorder. Diagnosis may be difficult since patients with this type of vulvar ulceration usually deny any knowledge of how it is occurring. Similarly, genital “cutting” by women seems to be occurring with increasing frequency. This problem was vividly portrayed in a recent movie, The Piano Teacher.

Infectious ulcers

inflammatory bowel disease. Fewer than a dozen cases involving the vulva have been reported18. Nicorandil is an oral medication used in the treatment of ischemic heart disease in the United Kingdom and continental Europe. Oral and perianal ulceration can occur in a small percentage of patients taking this agent19. Genital ulcers have been reported in a few patients receiving foscarnet, but it is not clear whether the ulcers were due to the medication or to the viral infections for which the medication was being used.

Infectious ulcers Primary syphilis Primary syphilis (“chancre”) consists of one or several ulcerating lesions of mucocutaneous tissue. Secondary syphilis is a nonulcerating, generalized eruption consisting of papules and plaques. The main discussion of syphilis is presented in this chapter, while brief descriptions of secondary syphilis can be found in Chapters 17 and 19. Figure 21.15  The overhanging, red borders of this ulceration are typical for pyoderma gangrenosum.

Fifth, in certain cultural and religious rituals, young women are coerced into infibulation and female circumcision. Breakdown of the suturing, sexual trauma, or the development of infection can lead to the development of vulvar ulceration.

Miscellaneous noninfectious ulcers Erosions occur with many of the vulvar dermatoses but ulcerated dermatoses are seen less often. The most frequent conditions associated with secondary ulceration are HS (Chapter 19) and various forms of vulvar neoplasms (Chapter 23). Pyoderma gangrenosum is a primary cutaneous ulcer that forms as the result of intense neutrophilic destruction of dermal connective tissue and blood vessels. Classically, the ulcer is deep, with overhanging, violaceous edges (Figure 21.15). The base is usually covered with a dark eschar. The cause is unknown but about one-third of patients have

Epidemiology and clinical manifestations Syphilis is a global problem but the epidemiological information discussed in this chapter is limited to western societies, primarily that of the United States. The latest information available from the Centers for Disease Control and Prevention (CDC) contains data only through 200520. The rate of primary and secondary syphilis infections in the United States reached a nadir in 2000 but has been rising steadily since then. Over 90% of this increase has occurred in men who have sex with men. The rate of primary and secondary syphilis for men is now 5.1 per 100 000. The overall rate for women is much lower and has remained fairly stable over the last 10 years. However, the incidence in women overall did rise about 12% in 2005 to 0.9 per 100 000. The rate of infection is appreciably higher, and is also rising, in African American women. Ordinarily, the first clinical sign of infection due to syphilis is the development of a chancre at the site of treponemal inoculation. The chancre begins as a small papule which rapidly breaks down to form an ulcer that averages 1–2 cm in diameter. Usually only a single ulcer is present but

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Table 21.3  Primary Syphilis Diagnosis Painless, clean ulcer No undermining of edges Firm, “button-like” feel on palpation Lymphadenopathy Treponemal and nontreponemal serologies Biopsy Differential Diagnosis Herpes simplex virus, especially in the immunosuppressed Aphthous ulceration Chancroid Crohn’s disease Therapy 2.4 million units of intramuscular benzathine penicillin

Figure 21.16  This chancre, an ulcer of primary syphilis, is indistinguishable visually from an aphthous ulcer and several other causes of ulcers. Although the firm borders and relatively painless nature suggest syphilis, ulcers are best diagnosed not by morphology, but by setting and ­confirmatory testing.

two or three ulcers may be found in about ­ onethird of patients. The base of the ulcer is red and “clean” with no overlying crust or eschar (Figure 21.16). On palpation, the base of the ulcer feels firm and is sometimes described as being “buttonlike.” The margins of the ulcer may have a narrow rim of erythema; the edges of the ulcer are not undermined. Mild discomfort may be described but, in nearly all instances, the chancre is surprisingly painless. Lymphadenopathy is often present and may be either unilateral or bilateral. The most common site for the development of a chancre in women is stated to be the labia majora but it is not known how many unrecognized chancres occur on the cervix or in the vagina and anus.

Diagnosis and differential diagnosis The presence of a noninflamed, clean, firm painless ulcer is almost pathognomonic for syphilis (Table 21.3). Nevertheless, laboratory confirmation is mandatory (see below under histology and laboratory tests). Genital herpes should be considered, though such lesions are less deep, more painful, and lack a firm base on palpation. Aphthous ulcers are also similar, though they too are quite painful and lack a firm base. Chancroid tends to form a “dirty” ulcer with necrotic tissue and crusting at the base. In addition the ulcer is painful and the base is soft. Patients with granuloma inguinale and Crohn’s disease may present with genital ulcers but the clinical features and biopsy findings are quite different from that of primary syphilis.

Histology and laboratory tests Biopsy is indicated if an ulcer, suspected to be that of primary syphilis, is associated with a negative serology. The histological findings in primary

Infectious ulcers

syphilis are distinctive because of the large number of perivascular and interstitial plasma cells. With this clue, silver stains can then be used to identify the presence of the spirochetes that cause the disease. Historically the most important laboratory test for primary syphilis was the dark-field examination, where a drop of plasma, squeezed from the chancre, was spread on a slide and was examined histologically for the presence of spirochetes. In well-trained hands this was an excellent test but today most technicians do not have the requisite skill or experience to perform it. Serological tests for syphilis should be obtained in any instance where syphilis is even remotely possible. Generally both a nontreponemal screening test and a treponemal confirming test are ordered. In the United States, the two most commonly used nontreponemal screening tests are the rapid plasma reagin (RPR) test and the Venereal Disease Research Laboratory (VDRL) test. Both of these are widely available, are inexpensive, and the antibody response can be titered. The ability to obtain a titer is very important in terms of following the activity of syphilis and its response to therapy. However, these screening tests have several limitations. Most often they do not become positive until shortly after the chancre appears and they are associated with both false-negative reactivity (especially in HIV-infected individuals due to the prozone phenomenon) and false-positive reactivity (e.g., patients with parasitic disease, autoimmune disease). Because of these difficulties with screening tests, the more specific treponemal tests are also obtained. In the United States the tests most widely used are the fluorescent treponemal antibody absorbed (FTA-ABS) test, the Treponema pallidum particle agglutination (TPPA) test, and the T. pallidum hemagglutination assay (TPHA). These tests are more sensitive and specific than the nontreponemal tests but are also more costly and time-consuming. Moreover, antibody titers cannot be obtained. All three of these tests may eventually be replaced by the enzyme immunosorbent assay (EIA) as it can be automated, is titratable, and has excellent specificity. Currently it is being used in association with the TPPA test in order to assure sufficient sensitivity21.

Examination of the spinal fluid is usually not recommended in patients with primary syphilis.

Pathogenesis Syphilis is caused by infection with the spirochete Treponema pallidum. This organism cannot be cultured in vitro but can be grown in animals. These spirochetes are found on the surface of moist lesions in syphilis. Person-to-person contagion occurs by way of close contact with infected tissue. The spirochetes can enter through intact tissue but passage is facilitated through “microbreaks” created during frictional trauma associated with sexual activity. The level of contagion is extremely high, with about 30–50% of exposed persons becoming infected after a single contact. The presence of HIV infection appears to enhance the likelihood of acquiring syphilis. The likelihood of infection is reduced through male circumcision22. Very shortly after inoculation, the spirochetes travel to the regional lymph nodes and thus systemic infection has already taken place before the chancre appears. The chancre appears on average about 3 weeks after an infection but there is wide variability in the incubation period, with a range of 2–12 weeks. In the absence of treatment, spontaneous healing of the ulcer takes place in 4–6 weeks.

Therapy and prognosis In the United States the most widely used guidelines for the treatment of syphilis are those published by the CDC23. These guidelines were recently revised and were made available in August 2006. Similar guidelines are available in the United Kingdom but these were last published in 2002. The treatment suggested below is based on the recommendations of the CDC. The treatment of choice for primary and secondary syphilis is an intramuscular injection of 2.4 million units of benzathine penicillin given as a single, one-time dose. Care must be taken to be sure that Bicillin L-A, rather than Bicillin C-R, is used as the latter contains a mixture of benzathine penicillin and short-acting procaine penicillin. This product is not approved for use in syphilis. If the patient is allergic to penicillin, doxycycline (100 mg orally bid for 14 days), or ceftriaxone

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(1 g intramuscularly for 10 days) can be used. ­Azithromycin was originally thought to be effective in a single 2-g oral dose but there have been recent reports of treatment failure and use of this agent is currently not recommended. Patients who are pregnant may be treated with the same single intramuscular dose of 2.4 million units of benzathine penicillin. However, if a pregnant woman is allergic to penicillin, it is recommended that she be desensitized and then treated with penicillin. Some experts recommend that a second 2.4 million unit dose be administered a week later for women who are pregnant and for all patients who are HIV-positive. Antibody titers as determined in the RPR or VDRL tests should be followed. A fourfold drop in titer suggests that an appropriate response to therapy has occurred. Patients with syphilis should be reported to the appropriate authorities. Management of sex partners goes beyond the scope of this chapter but is covered in the CDC guidelines23. Patients with primary syphilis who are treated in accordance with the above recommendations recover completely. Their nontreponemal serology titers gradually fall until the test becomes negative. Their treponemal tests are very likely to remain positive indefinitely. Untreated patients progress to secondary syphilis and are at eventual risk for tertiary syphilis.

Miscellaneous genital ulcers Genital ulcers have been reported in fewer than 30 cases of patients with Epstein–Barr virus infection and in only a few patients with cytomegalovirus infection24,25. Almost all of these ulcers have occurred in children or young women, many of whom were not sexually active. The age of these patients and the clinical similarity of their ulcers to those of aphthous ulcers suggest the possibility that this is a manifestation of genital aphthosis1. Serologic testing is not always conclusive. Sometimes immunoglobulin M antibodies are present, suggesting an association with a primary infection, but at other times serologies only indicate the presence of a preceding infection. At this point, it is probably not possible to conclude whether the association is coincidental or causal1 (see Chapter 26).

Orogenital ulcers can occur in patients with HIV/ AIDS but in most instances these appear to be aphthous ulcers rather than ulcers caused directly by HIV infection. Infection with HSV results in the appearance of shallow erosions rather than ulcers (see Chapter 20). However, in immunosuppressed patients, notably those with HIV/AIDS, the lesions often become true ulcers that persist for long periods of time. Diagnosis is usually based on viral culture but immunofluorescent smears and biopsies can also be used. This type of herpetic infection was a major problem before the use of highly active antiretroviral (HAART) therapy, but is seen much less often today. Treatment usually requires antiretroviral, as well as antiherpetic, therapy. Chancroid is a vanishingly rare disease in western societies. Thirteen cases were reported in the United States in 2005. Most patients will have acquired their infection in Africa, Asia, or Latin America. Chancroid is caused by the bacterium Haemophilus ducreyi, a fastidious anerobic organism that requires special media for growth. After a short incubation of only a few days, a papule or pustule appears at the site of inoculation. This lesion quickly breaks down to form a painful ulcer with undermined edges. The base of the ulcer usually contains purulent necrotic tissue and yellow crust. Lymphadenopathy, often unilateral, is a characteristic feature. Involved nodes may enlarge massively and in many instances become fluctuant. These nodes (“buboes”) may break down, resulting in draining sinuses. The diagnosis is made clinically on the basis of a painful, “dirty” ulcer with massive lymphadenopathy (Figure 21.17). However a diagnosis should not be established until primary syphilis and HSV infection are ruled out. A clinical diagnosis can be confirmed by culture but appropriate media are not likely to be available. The CDC recommends treatment with azithromycin (1 g orally in a single dose), ceftriaxone (250 mg intramuscularly in a single dose), ciprofloxacin (500 mg orally bid for 3 days), or erythromycin (500 mg orally tid) for 7 days. Granuloma inguinale is also rarely seen in the western world but it is endemic in some tropical and developing countries. It is cause by infection with the bacterium Klebsiella granulomatis,

References

References

Figure 21.17  Painful superficial ulcerations are typical and nonspecific for chancroid, which more often produces shaggy, undermined borders rather than these welldemarcated ulcers, again demonstrating the nonspecific morphology for ulcers in general.

a Gram-negative organism that is very difficult to grow in culture. The disease begins with a painless ulcer that expands centrifugally. The base of the ulcer is covered with granulation tissue that bleeds easily following mild trauma. Multiple ulcers can develop and when they do, they often involve the folds of the anogenital region appearing as linear, “knife cut” ulcers rather similar to those seen in Crohn’s disease. Clinically palpable lymph nodes are only rarely present. Diagnosis is established by tissue smears or biopsies which demonstrate clustered intracytoplasmic bacteria in the form of “Donovan bodies.” The CDC recommends treatment with azithromycin (1 g orally weekly), ciprofloxacin (750 mg orally bid), erythromycin (500 mg orally qid), or trimethoprim-sulfamethoxazole (one double-strength tablet bid). All of these treatments should be continued for at least 3 weeks. If healing has not occurred by that time, treatment is continued until all of the lesions have resolved.

  1. Huppert, J. S., Geerber, M. A., Deitch, H. R., et al. Vulvar ulcers in young females: a manifestation of aphthosis. J. Pediatr. Adolesc. Gynecol. 2006; 19: 195–204.   2. Letsinger, J. A., McCarty, M. A., and Jorizzo, J. L. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J. Am. Acad. Dermatol. 2005; 52: 500–508.   3. Alidaee, M. R., Taheri, A., Mansoori, P., et al. Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Br. J. Dermatol. 2005; 153: 521–525.   4. Yurdakul, S., Mat, C., Tuzan, Y., et al. A double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum. 2001; 44: 2686–2692.   5. Sharquie, K. E., Najim, R. A., and Abu-Raghif, A. R. Dapsone in Behçet’s disease: a double-blind, placebo-controlled crossover study. J. Dermatol. 2002; 29: 267–279.   6. Shek, L. P. and Lim, D. L. Thalidomide in Behçet’s disease. Biomed. Pharmacother. 2002; 56: 31–35.   7. Scheinfeld, N. The medical uses and side effects of etanercept with a focus on cutaneous disease. J. Drugs Dermatol. 2004; 3: 653–659.   8. Loftus, C. G., Loftus, E.V. Jr, Harmsen, W.S., et al. Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmstead County, Minnesota, 1940–2000. Inflamm Bowel Dis. 2006; Dec 19 2007; 13: 254–261.   9. Tomm, A., May, D., Almus, E., et al. Cutaneous manifestations in inflammatory bowel disease. Z. Gastroenterol. 2001; 39: 137–144. 10. Ploysangam, T., Heubi, J. E., Eisen, D., et al. Cutaneous Crohn’s disease in children. J. Am. Acad. Dermatol. 1997; 36: 697–704. 11. Rowan, D. M. and Jones, R. W. Idiopathic granulomatous vulvitis. Australas. J. Dermatol. 2004; 45: 181–183. 12. Gunthert, A. R., Hinney, B., Nelselhut, K., et al. Vulvitis granulomatosa and unilateral hypertrophy of the vulva related to Crohn’s disease: a case report. Am. J. Obstet. Gynecol. 2004; 191: 1719–1720. 13. Lapidus, A. Crohn’s disease in Stockholm county during 1990–2001: an epidemiological update.World J. Gastroenterol. 2006; 12: 75–81. 14. Bamias, G., Nyce, M. R., De La Rue, S. A., et al. New concepts in the pathophysiology of inflammatory bowel disease. Ann. Intern. Med. 2005; 143: 895–904. 15. Bressler, B. and Sands, B. E. Review article: Medical therapy for fistulizing Crohn’s disease. Aliment. Pharmacol. Ther. 2006; 24: 1283–1293. 16. Kaufman, I., Caspi, D., Yeshurun, D., et al. The effect of infliximab on extraintestinal manifestations of Crohn’s disease. Rheumatol. Int. 2005; 25: 406–410. 17. Fox, L. P., Pasternaak, F. R., Geyer, A. S., et al. Perineal squamous cell cancer in a patient with fistulizing and ulcerating Crohn’s disease. Clin. Exp. Dermatol. 2005; 30: 718–719. 18. Sau, M. and Hill, N. C. W. Pyoderma gangrenosum of the vulva. Br. J. Obstet. Gynaecol. 2001; 108: 1197–1198. 19. Cooke, N. S., Tolland, J. P., and Dolan, O. M. Nicorandilassociated perianal ulceration: a case series of 10 patients. Br. J. Dermatol. 2006; 154: 199–200. 20. STD Surveillance 2005: syphilis. Available online at: http://www.cdc.gov/std/stats/syphilis.htm. Accessed on January 28, 2007. 21. Manavi, K., Young, H., and McMillan, A. The sensitivity of syphilis assays in detecting different stages of early syphilis. Int. J. STS AIDS 2006; 17: 768–771.

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Vulvar Ulcers 22. Weiss, H. A. Male circumcision as a preventative measure against HIV and other sexually transmitted disease. Curr. Opin. Infect. Dis. 2007; 20: 66–72. 23. Workowski, K. A. and Berman, S. M. Sexually transmitted diseases treatment guidelines, 2006. Morbid. Mortal. Week. Rep. 2006; 55: 22–35. 24. Halvorsen, J. A., Brevig, T., Aas, T., et al. Genital ulcers as initial manifestations of Epstein–Barr virus infection: two new cases and a review of the literature. Acta. Dermatol. Venereol. 2006; 86: 439–442. 25. Hancox, J. G., Shetty, A. K., Sangueza, O. P., et al. Perineal ulcers in an infant: an unusual presentation of postnatal cytomegalovirus infection. J. Am. Acad. Dermatol. 2006; 54: 536–539.

Further reading Aphthous ulcer and complex aphthosis Jurge, S., Kuffer, R., Scully, C., et al. Recurrent aphthous stomatitis. Oral Dis. 2006; 12: 1–21. Letsinger, J. A., McCarty, M. A., and Jorizzo, J. L. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J. Am. Acad. Dermatol. 2005; 52: 500–508.

Behçet’s disease Krause, I., Weinberger, A. Behçet’s disease. Curr. Opin. Rneumatol. 2008; 20: 82–87.

Crohn’s disease Feller, E. R., Ribaudo, S., and Jackson, N. D. Gynecologic aspects of Crohn’s disease. Am. Fam. Physician 2001; 64: 1725–1728. Kamm, M. A. Review article: biological drugs in Crohn’s disease. Aliment. Pharmacol. Ther. 2006; 24(Suppl 3): 80–89. Ruocco, E., Cuomo, A., Salerno, R., et al. Crohn’s disease and its mucocutaneous involvement. Skinmed. 2007; 6: 179–185.

Excoriation and factitial ulceration Van Moffaert, M. The spectrum of dermatological self-mutilation and self destruction including dermatitis artefacta and neurotic excoriations. In: Koo, J. Y. M. and Lee, C. S. (eds) Psychocutaneous Medicine, pp. 169–189. Marcel Decker, New York, 2003.

Primary syphilis French, P. Syphilis. Br. Med. J. 2007; 334: 143–147.

PART: Ii  Gynecologic Dermatology

CHAPTER 22

Disorders of Pigmentation Libby Edwards

Pigmentary alterations of vulvar skin have more varied causes than those of other skin surfaces. Both inflammatory diseases and tumors may present with hypopigmentation or hyperpigmentation when occurring on mucous membranes or modified mucous membrane skin.

Hypopigmentation Vitiligo Vitiligo is a relatively common autoimmune disease of melanocytes, manifested by loss of pigment.

Epidemiology and clinical manifestations Vitiligo is either most common or most recognized in darkly complexioned patients, particularly African Americans and those of Middle East extraction. This occurs in approximately 1% of patients1. The hallmark of vitiligo is its clinical appearance. The presenting complaint is generally one of cosmetic unacceptability, although most patients are only minimally bothered by vitiligo of the genitalia. Itching and pain are absent. Vitiligo presents as well-demarcated, depigmented (totally white as compared to only light) patches (Figure 22.1). Vitiligo of the vulva usually affects keratinized, hair-bearing skin, the perineum, and perianal skin. Extragenital vitiligo is usually, but not always, present. A general skin examination most often shows similar patches over the extensor surfaces of joints, including the dorsal hands and fingers, wrists, knees, and elbows. Vitiligo is often perioroficial, occurring around the mouth, eyes, and nares. Vitiligo exhibits the Koebner phenomenon, in which areas of irritation or trauma are preferentially affected, partially accounting for this distribution (Figure 22.2).

Diagnosis and differential diagnosis Vitiligo superficially resembles other white diseases, especially lichen sclerosus (Table 22.1). Lichen simplex chronicus in areas of moist modified mucous membranes is sometimes white as well. However, lichen simplex

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Table 22.1  Vitiligo Diagnosis Clinical appearance   Acquired depigmented, well-demarcated patches Differential Diagnosis Postinflammatory hypopigmentation Lichen sclerosus Figure 22.1  Vitiligo is characterized by asymptomatic, well-demarcated white patches with no surface change of scale, thickening, or crusting.

Management Reassurance; therapy not usually successful Topical corticosteroids twice daily may be useful Tacrolimus or pimecrolimus twice daily can be tried

chronicus and lichen sclerosus show surface texture change, whereas vitiligo shows color change only. Like vitiligo, postinflammatory hypopigmentation consists of light patches without texture change or thickening, but postinflammatory hypopigmentation is not white, only lighter in color than surrounding skin, and it is usually less well demarcated. Occasionally, inflammation, as a result of the Koebner phenomenon, precipitates vitiligo, so that depigmentation occurs in the area of active or past inflammatory disease (see Figure 22.2).

Laboratory findings and histology No laboratory findings regularly occur in patients with vitiligo. However, patients with vitiligo are more likely to exhibit laboratory manifestations of hypothyroidism, so thyroid function tests should be measured. Patients sometimes also show signs of inflammatory eye disease, and an ophthalmologic examination is recommended by some. A biopsy is rarely performed to make the diagnosis of vitiligo. However, routine histology generally shows normal skin, although the borders of lesions occasionally reveal a mild lymphocytic infiltrate. Silver stains show an absence of melanocytes. Figure 22.2  Because vitiligo preferentially affects irritated or inflamed skin, vitiligo in the setting of other skin disease such as lichen sclerosus or lichen simplex chronicus (LSC) is relatively common, as seen here in this patient with lichenified LSC and vitiligo. The diagnosis is more obvious when extragenital vitiligo is present as well.

Pathogenesis Vitiligo is disease that may be multifactorial, including an autoimmune factor, characterized by antibodies against melanocytes as well as cellular immunity1,2. Environmental factors and metabolic abnormalities

Hypopigmentation

leading to damage to melanocytes, particularly in the setting of oxidative stress, and possible neurologic abnormalities may also play roles3,4.

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Therapy and prognosis There is no predictably beneficial treatment for vitiligo. Other than reassurance and education, vitiligo of the genitalia is generally not treated. Occasionally, vitiligo improves with topical corticosteroid therapy, but this is most likely in children, and the experience of this author suggests that genital vitiligo is more difficult to treat successfully with topical corticosteroids than other areas5. There are reports of both benefit and no efficacy with the calcineurin inhibitors tacrolimus and pimecrolimus, although this is irritating to many patients6,7. Topical calcipotriene has been reported as useful in small series8. Although ultraviolet light treatments have been reported as beneficial for vitiligo, this therapy is usually avoided on genital skin because of the risk of squamous cell carcinoma9. The 308-nm excimer laser has been reported useful as well10. Finally, skin grafts sometimes prompt repigmentation of vitiligo.

Postinflammatory hypopigmentation Postinflammatory hypopigmentation consists of lightening of the skin due to inflammation or injury. This is more common and more obvious in darkly pigmented races. Postinflammatory hypopigmentation consists of light patches of skin in the distribution of the inflammation or injury, and the degree of pigment loss is often proportional to the degree of injury (Figure 22.3). For example, cryotherapy can produce very white and permanent loss of pigment, whereas eczema most often results in poorly demarcated, transient mild lightening of the skin. The diagnosis is made by the setting and clinical morphology. The treatment consists of eliminating the underlying cause of the hypopigmentation.

Lichen sclerosus (lichen sclerosus Et atrophicus, hypoplastic dystrophy): see Chapter 14 Lichen sclerosus is a well-recognized dermatosis characterized by white plaques and showing a predilection for the vulva. Probably multifactorial in

Figure 22.3  This patient with recently treated lichen simplex chronicus exhibits poorly demarcated hypopigmentation in the previously affected areas.

origin with autoimmune mechanisms prominent, lichen sclerosus superficially resembles vitiligo. Classic lichen sclerosus presents as well-demarcated, white plaques encompassing the vulva, perineal body, and perianal skin (Figure 22.4). However, most patients describe itching and pain, and there is crinkling or thickening of the skin, unlike the asymptomatic white patches of vitiligo. Treatment consists of a potent topical corticosteroid and careful follow-up because of the slight increased risk for secondary squamous cell carcinoma.

Hyperkeratosis Any form of hyperkeratosis appears white on hydrated skin, just as normally thickened and relatively keratotic skin on the palms and soles is white with prolonged water exposure. Therefore, lichen simplex chronicus, lichen planus, warts, vulvar intraepithelial neoplasia 3 (VIN 3), and squamous cell carcinoma all appear white on mucous

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Figure 22.4  The crinkled texture of this white skin and the patient’s complaint of itching indicate a diagnosis of lichen sclerosus.

Figure 22.6  The genital warts seen in the vestibule and the vulvar intraepithelial neoplasia located in the interlabial folds are hyperkeratotic lesions that appear white due to the natural hydration of mucous membranes and skin folds.

Figure 22.5  This hyperkeratotic, macerated lichen simplex chronicus appears white because it is hydrated by sweat; after the patient had been in stirrups for a few minutes, the white color disappeared.

­ embranes and modified mucous membranes, m and in skin folds (Figures 22.5 and 22.6).

Hyperpigmentation Vulvar melanosis/vulvar lentiginosis Vulvar melanosis is patchy hyperpigmentation that must be differentiated from melanoma.

Epidemiology and clinical manifestations The frequency of vulvar melanosis is not known. This condition can occur with no apparent underlying cause, or it can be associated with lichen sclerosus11.

Vulvar melanosis presents without symptoms. Most often, the pigmented area is noted by a physician, a partner, or during self-examination. Vulvar melanosis ranges from bland, patchy tan hyperpigmentation on the modified mucous membranes to wild, irregular, coalescing patches of variegate pigmentation consisting of brown color, blue and black discoloration (Figures 22.7–22.9). Vulvar melanosis spares the keratinized, dry skin, perianal skin, and the vagina.

Diagnosis and differential diagnosis The most important disease to be differentiated from vulvar melanosis is superficial spreading melanoma12 (Table 22.2). On most skin surfaces, superficial spreading melanoma occurs as a solitary lesion, sometimes with satellite macules and patches representing in-transit metastasis. However, multifocal melanoma is more likely on the vulva than on other skin surfaces. Pigmented VIN 3 (squamous cell carcinoma in situ) can be nearly

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Figure 22.9  Sometimes, vulvar melanosis can present with wild, irregular hyperpigmentation; most patients with melanosis require a biopsy to rule out a malignant or premalignant process.

Table 22.2  Vulvar Lentiginosis/Melanosis Diagnosis

Figure 22.7  Vulvar melanosis can present as tan, poorly demarcated patches without texture change or symptoms.

Clinical presentation  Irregular macular hyperpigmentation of modified ­mucous membranes Biopsy Differential Diagnosis Melanoma Postinflammatory hyperpigmentation Management Reassurance

identical to vulvar melanosis. Postinflammatory hyperpigmentation can be differentiated by its uniform, symmetrical appearance.

Laboratory manifestations and histology There are no accompanying laboratory abnormalities. A biopsy shows lentiginous elongation of the rete ridges in otherwise unremarkable skin.

Pathogenesis Figure 22.8  Often, dark, irregular, and poorly demarcated patches of vulvar melanosis raise the suspicion of melanoma.

A significant proportion of women with vulvar melanosis have preceding lichen sclerosus, so that vulvar melanosis occurs as a postinflammatory

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change. However, histology shows ­ lentiginosis rather than typical postinflammatory change. Otherwise, the cause is unknown.

Therapy and prognosis There is no effective medical treatment for vulvar melanosis, and most patients should be given reassurance alone. Destructive or excisional therapy may be effective. This is a cosmetic issue only, and excision of the affected area is not needed as long as biopsies are bland. Patients with vulvar melanosis appear to have no increased risk of melanoma or squamous cell carcinoma in situ. However, vulvar melanosis is associated with lichen sclerosus, and there may be a small association of melanoma with lichen sclerosus. Also, one case of genital melanosis associated with melanoma of the urinary bladder has been reported. So, although malignant transformation is theoretical only, there are few data, and regular follow-up with a high index of suspicion, particularly in women with lichen sclerosus and vulvar melanosis, is a reasonable approach.

Postinflammatory hyperpigmentation Postinflammatory hyperpigmentation is a wellknown phenomenon consisting of hyperpigmentation corresponding to areas of past or ongoing inflammation. In general, postinflammatory changes are relatively uncommon on the modified mucous membranes of the vulva, occurring most often on the hair-bearing labia majora, crural crease and proximal, medial thighs. Interestingly, women are often unaware of the existence of the precipitating inflammatory process.

Epidemiology and clinical manifestations Postinflammatory hyperpigmentation occurs in all age groups, but it is most common in patients with naturally dark complexion, including Hispanic patients and those of African background. Patients generally come to the attention of the clinician because of the appearance. As long as the underlying cause of inflammation has resolved, patients do not experience itching or pain. Some patients present with concomitant ongoing skin disease as well as postinflammatory

Figure 22.10  This woman with lichen simplex chronicus exhibits hyperpigmentation both as a postinflammatory change and due to ongoing inflammation from rubbing.

hyperpigmentation, and their symptoms correspond to the nature of the underlying dermatosis (Figure 22.10). Postinflammatory hyperpigmentation is manifested by tan or brown patches, ranging from uniform, poorly demarcated tan discoloration to irregular and deeply pigmented skin. The postinflammatory change is in the distribution of the preceding insult. Postinflammatory hyperpigmentation is more likely to be irregular and striking when occurring on modified mucous membranes.

Diagnosis and differential diagnosis Postinflammatory hyperpigmentation can mimic physiologic hyperpigmentation and vulvar melanosis. VIN is sometimes hyperpigmented, resembling postinflammatory change. Very occasionally, unusually irregular postinflammatory ­hyperpigmentation must be differentiated from ­ superficial spreading malignant melanoma. Acanthosis nigricans

Hyperpigmentation

s­ ometimes resembles postinflammatory hyperpigmentation occurring following skin fold dermatitis.

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Laboratory abnormalities and histology There are no accompanying laboratory abnormalities, except those that may be associated with the underlying inflammatory process.

Pathogenesis Inflammation of any kind can stimulate production of melanin. Inflammation which causes disruption of the basement membrane allows melanin from the melanocytes within the basal cell layer to be released into the dermis, producing especially deep hyperpigmentation. Therefore, postinflammatory change occurs most often and is darker in those diseases that disrupt the basement membrane, such as lichen sclerosus, lichen planus, fixed drug eruption, lupus erythematosus, and blistering erythema multiforme. Trauma, as occurs with destructive therapies for genital warts, results in postinflammatory hyperpigmentation at times.

Therapy and prognosis Once any underlying skin disease is controlled, postinflammatory hyperpigmentation is of cosmetic importance only. As long as malignant disease is ruled out clinically or histologically, no therapy is required, and the dark color fades over time. For those patients especially bothered by the appearance, hydroquinone 4% cream applied twice daily hastens the resolution on nonmucous membrane skin. Otherwise, excellent management of underlying inflammatory disease often allows postinflammatory hyperpigmentation to resolve gradually.

Physiologic hyperpigmentation Although common and subtle, physiologic hyperpigmentation can occasionally present with very dark patches that concern either the patient or clinician. Marked physiologic anogenital hyperpigmentation occurs primarily in women of naturally dark skin color, including those of African ancestry and Hispanics. In addition, natural pigmentation

Figure 22.11  Physiologic hyperpigmentation is symmetrical and asymptomatic, and it is most remarkable in women with naturally darker complexions.

in some areas is accentuated by hormones, as in pregnant women or in neonates who are under the influence of maternal hormones. Physiologic hyperpigmentation is asymptomatic, producing neither itching nor pain. The pattern of physiologic hyperpigmentation is characteristic, with poorly demarcated, symmetrical brown patches most striking on the labia minora and perianal skin (Figure 22.11). Postinflammatory hyperpigmentation and acanthosis nigricans are the skin conditions most likely to be confused with physiologic hyperpigmentation. There are no abnormal laboratory findings, and histology simply shows increased melanin in the basal cell layer of the epidermis. This is a natural phenomenon, and there is no therapy.

Acanthosis nigricans Acanthosis nigricans is most common on the neck and in the axillae of patients, who are normally dark-complected and overweight, although this can occur in any skin fold and in more genetically fair people.13 Acanthosis nigricans does not produce itching or pain, but this condition sometimes causes significant embarrassment because of its resemblance to dirty skin. Acanthosis nigricans presents as poorly demarcated brown plaques found in the skin folds (Figure 22.12). With careful examination, the skin appears thickened and papillomatous or velvety, sometimes mimicking lichenification (Figure 22.13). In rare instances, this condition can be found in areas

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Figure 22.12  Acanthosis nigricans consists of poorly demarcated hyperpigmentation within skin folds and on other areas of friction, such as the surface of the labia majora.

Acanthosis nigricans is associated with insulin resistance13. When found in patients with diabetes, or in obese patients, this is considered a benign condition. However, slender patients with acanthosis nigricans and those with acanthosis nigricans in unusual areas should be evaluated for other endocrinologic conditions14. Any accompanying laboratory abnormalities are those associated with diabetes or other endocrine dysfunction. A biopsy shows papillomatosis of the epidermis without acanthosis or increased melanin or melanocytes. There is no therapy for acanthosis nigricans other than weight loss and correction of any underlying endocrine disease.

References

Figure 22.13  A careful examination of acanthosis nigricans shows apparent thickening of the skin, either with velvety, fine, linear folds of the skin or a closely set papillomatous texture.

other than skin folds, such as extensor surfaces of the fingers. Acanthosis nigricans can be confused with physiologic hyperpigmentation or lichen simplex chronicus in some patients.

  1. Oyarbide-Valencia, K., van den Boorn, J. G., Denman, C. J., et al. Therapeutic implications of autoimmune vitiligo T cells. Autoimmun. Rev. 2006; 5: 486–492.   2. Trcka, J. and Kunz, M. Functional genome and proteome ­analysis of cutaneous autoimmune diseases. Curr. Pharm. Des. 2006; 12: 3787–3798.   3. Manga, P., Sheyn, D., Yang, F., et al. A role for tyrosinase-related proteins 1 in 4-tert-butylphenol-induced toxicity and melanocytes: implications for vitiligo. Am. J. Pathol. 2006; 169: 1652–1662.   4. Dell’anna, M. L. and Picardo, M. A review and new hypothesis for non-immunological pathogenic mechanisms in vitiligo. ­Pigment Cell Res. 2006; 19: 406–411.   5. Kwinter, J., Pelletier, J., Khambalia, A., et al. High-potency steroid use in children with vitiligo: a retrospective study. J. Am. Acad. Dermatol. 2007; 56: 236–241.   6. Coskun, B., Saral, Y., and Turgut, D. Topical 0.05% clobetasol propionate versus 1% pimecrolimus ointment in vitiligo. Eur. J. Dermatol. 2005; 16: 319–320.   7. Dawid, M., Veensalu, M., Grassberger, M., et al. Efficacy and safety of pimecrolimus cream 1% in adult patients with vitiligo: results of a randomized, double-blind, vehicle-controlled study. J. Dtsch Dermatol. Ges. 2006; 4: 942–946.   8. Kumaran, M. S., Kaur, I., and Kumar, B. Effect of topical ­calcipotriol, betamethasone dipropionate, and their combination in the treatment of localized vitiligo. J. Eur. Acad. ­Dermatol. Venereol. 2006; 20: 269–273.   9. Nicolaidou, E., Antoniou, C., and Stratigos, A. J. Efficacy, ­predictors of response, and long-term follow-up in patients with vitiligo treated with narrowband UVB phototherapy. J. Am. Acad. Dermatol. 2007; 56: 274–278. 10. Hadi, S., Tinio, P., Al-Ghaithi, K., et al. Treatment of vitiligo using the 308-nm excimer laser. Photomed. Laser Surg. 2006; 24: 354–357. 11. El Shabrawi-Caelen, L., Soyer, H. P., Schaeppi, H., et al. Genital lentigines and molested nevi with superimposed lichen sclerosus: a diagnostic challenge. J. Am. Acad. Dermatol. 2004; 50: 690–694. 12. Quatresooz, P. and Pierard, G. E. [Anatomo-clinical confrontation. Vulvar melanosis.] Rev. Med. Liege 2004; 59: 731–733.

Further reading 13. Maitra, S. K. and Rowland Payne, C. M. The obesity syndrome and acanthosis nigricans. Acanthosis nigricans is a common cosmetic problem providing epidemiological clues to the obesity syndrome, the insulin-resistance syndrome, the thrifty metabolism, dyslipidaemia, hypertension and diabetes mellitus type II. J. Cosmet. Dermatol. 2004; 3: 202–210. 14. Krause, W. Skin diseases in consequence of endocrine alterations. Aging Male 2006; 9: 81–95.

Further reading Vitiligo Sehgal, V. N. and Srivastava, G. Vitiligo treatment options: an evolving scenario. J. Dermatol. Treat. 2006; 17: 262–275.

Vulvar melanosis Estrada, R. and Kaufman, R. Benign vulvar melanosis. J. Reprod. Med. 1993; 38: 5–8.

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PART: II  Gynecologic Dermatology

CHAPTER 23

Vulvar Neoplasms and Cysts Peter J. Lynch

The vulva is an anatomically complicated site. It includes: (1) keratinizing skin with associated hair follicles, eccrine glands,and apocrine glands; (2) nonkeratinizing, nonhair-bearing mucous membrane; and (3) components of tissue related to the embryonic urogenital tracts. As a result, a splendid panoply of cysts and neoplasms can arise in this area.

Cysts Epidermoid cysts Epidermoid cysts are the most common cysts that occur in the anogenital area. They are lined with stratified squamous epithelium and are filled with the keratin end product of keratinocyte differentiation. Sebum is not present and thus the old term “sebaceous cyst” is a misnomer and its use should be discontinued. In undisturbed cysts, the keratin within the cyst forms a solid white mass but, in inflamed cysts, the keratin is degraded by neutrophils to form a foul-smelling, yellow-white liquid. Epidermoid cysts form by one of two mechanisms: traumatic inclusion of epithelial fragments or blockage of a pilosebaceous unit. Inclusion-type cysts generally arise during surgical procedures in which fragments of epithelium are unwittingly implanted under the epithelial surface. There, these epithelial fragments round up and the keratinocytes begin making keratin which is released into a central cavity. This mechanism accounts for essentially all the epidermoid cysts encountered within the vagina and most of these occurring in the vulvar vestibule. On the other hand, epidermoid cysts found lateral to Hart’s line (on the labia minora, on the labia majora, and on other hair-bearing portions of the anogenital region) arise from pilosebaceous units. Those with a visible opening (a “blackhead” or tiny pit) on the surface develop due to blockage of the follicular outlet with subsequent production of keratin within the closed space of the follicle. Those without a visible opening are more likely to

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268

Figure 23.1  The diagnosis of epidermal cyst was confirmed by extrusion of the typical odiferous, cheesy keratin contents, but recurrence is expected without removal of the sac wall.

have developed from a remnant of an anatomically malformed follicle that lacks an opening to the ­surface. The size of epidermoid cysts varies from 1 to 2 mm (so-called milia) to several centimeters (Figures 23.1 and 23.2). One or several cysts may be present. Multiple, grouped cysts are particularly common on the labia majora (Figure 23.3). Cysts arising close to the surface appear white or yellow-white due to the visibility of the keratin contents that can be seen through stretched overlying epithelium (Figure 23.4). Deeper lesions are skin-colored. The sharp boundary and firmness of the cyst wall can often be appreciated on palpation. Epidermoid cysts, unless inflamed, are asymptomatic. As an epidermoid cyst enlarges, the wall may be thinned to the point that rupture occurs. When this happens, the contents of the cyst spill into the surrounding dermis where they incite a foreignbody inflammatory reaction. The resulting bright red, painful nodules may be mistaken for furuncles (“boils”). Noninflamed small cysts are best left untreated. Larger or symptomatic cysts can be incised with manual extrusion of the cyst contents. Unfortuna­ tely cysts treated in this way frequently recur. However, excision of the entire cyst can subsequently be performed while the recurring cyst is still very small.

Figure 23.2  Vestigial follicles on the labia minora allow for folliculitis and epidermal cysts in some patients. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-6), New York: Churchill Livingstone; 1994.)

Bartholin cysts Bartholin glands are situated bilaterally, posterior and lateral to the vagina. The ducts from these glands open into the vestibule at approximately 5:00 and 7:00 in relation to the vaginal introitus. These glands secrete a mucus-like material that plays a role in lubrication during sexual activity. Cysts form within the ducts of Bartholin glands, presumably as a result of ductal obstruction. Small cysts (< 1 cm) are extremely common. They are painless and may be palpable but may not be visible. Larger cysts (1–5 cm) may be associated with discomfort and may interfere with penile intromission. A characteristic diagnostic feature is the fact that the labium minus crosses over the midline of the cyst (Figure 23.5). Bartholin cysts may become inflamed and painful. The historical presumption was that the

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Figure 23.4  Typical firm, well-demarcated, asymptomatic nodules of epidermal cysts can be found anywhere on the vulva, and the range from skin-colored to yellow-white can be appreciated in this patient.

Figure 23.3  Epidermal cysts sometimes present as ­multiple lesions; these typical yellowish, skin-colored, and white nodules are primarily on the labia minora. (Reproduced from P. J. Lynch and L. Edwards Genital ­Dermatology (Fig. 10-7), New York: Churchill Livingstone; 1994.)

inflammation was due to infection, especially that of gonorrhea. Today it seems likely that, in most cases, the thinned wall of an enlarging cyst ruptures and releases cyst contents into the surrounding tissue, thereby causing a foreign-body inflammatory reaction. Rarely, Bartholin cysts develop in postmenopausal women as a result of malignant transformation1. Immediate treatment is that of incision and drainage. Asymptomatic cysts should be left untreated. Inflamed cysts can be incised and drained, with a sample of purulent material being sent for bacterial culture. Empirical antibiotic therapy may be carried out until the results of the cultures are known. Incised cysts frequently reform, which may then require more extensive surgery such as marsupialization or incision with insertion of a Word catheter1.

Figure 23.5  Bartholin gland duct cysts are recognized by the presence of a nodule of variable size within the posterior vestibule, with the labium minus transecting the cyst. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-9), New York: Churchill Livingstone; 1994.)

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Figure 23.7  This mucinous cyst is yellow, although some are skin-colored or blue. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-10), New York: Churchill Livingstone; 1994.) Figure 23.6  This location in the anterior labium majus is typical of a cyst of the canal of Nuck.

Cysts of the canal of Nuck (female hydrocele) In women, a diverticulum of peritoneal membrane follows the round ligament and extends through the inguinal ring and into inguinal canal. This peritoneal membrane forms the canal of Nuck in women and is analogous to the processus vaginalis testis in men. Occasionally the canal of Nuck fails to close completely during postembryonic development, in which case it may fill with serous fluid, forming a cyst (female hydrocele). This type of cyst presents clinically as a skin-­colored, asymptomatic mass in the inguinal canal or labium majus (Figure 23.6). No treatment is necessary but surgical removal can be carried out if the patient views the cyst as troublesome.

Mesonephric and paramesonephric duct cysts The mesonephric (wolffian) ducts in women form vestigial tissue during fetal development. The paramesonephric (müllerian) ducts form the

vagina and uterus. Later in the development of the vagina, the glandular müllerian epithelium is replaced by stratified squamous epithelium. Occasionally, remnants of these ducts undergo cystic dilation. The cysts may be formed from either mesonephric or paramesonephric tissue and are often termed Gartner’s cysts. They usually occur as small (< 1 cm) asymptomatic lesions in the vagina but occasionally they are much larger. Less often, mesonephric tissue forms similar small, asymptomatic cysts in the vulva. These cysts require no treatment but larger lesions may be excised.

Mucinous cysts Mucinous cysts occur quite commonly in the vulvar vestibule. They arise, presumably as a result of outlet blockage, from the numerous minor vestibular glands that occur in that location. Their size is variable (2–15 mm), as is the color, which may be translucent, skin-colored, light blue, or yellow (Figures 23.7 and 23.8). These lesions are asymptomatic and require no therapy.

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Figure 23.9  This nevus is small, well marginated, and regular, with no concern for melanoma.

Figure 23.8  The translucent nature of this nodule suggests the correct diagnosis of a mucinous cyst. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-11), New York: Churchill Livingstone; 1994.)

Pilonidal cysts (pilonidal sinus) Pilonidal “cysts” appear as persistent, painful, inflammatory papules and nodules. Most occur at the upper end of the gluteal cleft in the ­sacrococcygeal area but there are a few reports of lesions occurring in the vulva, especially in the ­ periclitoral area. It is believed that these lesions arise either as a result of a ruptured, hair­containing dermoid cyst or as a direct reaction to “ingrown” hairs. A chronic draining sinus may connect the inflammatory focus with the surface of the skin. Therapy is difficult and requires surgical removal of the entire inflamed area along with the draining sinus tract. Inadequate excision is quickly followed by recurrence.

Benign Neoplasms Melanocytic nevi (moles) The word nevus derives from the Latin naevus meaning a mark on the skin. As such, there are many forms of nevi, such as vascular nevi, ­collagen

nevi, and pigmented nevi. For the purposes of this section, the term “nevus” will refer only to pigmented nevi made up of melanocytic “nevus” cells.

Epidemiology and clinical manifestations Several studies have looked at the prevalence of nevi on the vulva but the diagnosis was made on a clinical basis. Only one study included biopsies to determine the underlying nature of the pigmented lesions2. In that study most of the pigmented lesions turned out to be lentigines rather than nevi. Lentigines are discussed in Chapter 22. Nevi occurred in 2.3% of patients. All of these patients were Caucasian; no nevi occurred in the small number of Asian or African American women who were examined. One of the nevi showed some atypical features but the other six were histologically benign. Nevi may appear as flat macules or raised papules. Typical, normal nevi are brown to black, evenly pigmented, sharply marginated, and 2–10 mm in diameter (Figures 23.9–23.13). Occasionally, nevi that are papular may appear tan or skin-colored because of their sparse melanin production. Nevi may be located on either the mucosal or hair-bearing regions of the vulva. Patients with darkly pigmented skin tend to have darker nevi, but note that dark color alone says nothing about malignant potential. Nevi may be present

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272

Figure 23.10  Nevi are relatively common on the modified mucous membranes of the vulva and should be differentiated from pigmented warts and vulvar intraepithelial neoplasia 3. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 12-5), Churchill Livingstone.)

Figure 23.11  A typical soft, small, regular nevus on the mons. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 12-6), Churchill Livingstone.)

at birth and, in general, these tend to be larger, darker lesions (Figure 23.14). Acquired nevi begin to develop in childhood and may increase in number during early adult life. After mid-adult life, the number of nevi gradually decreases. Some clinicians believe that the examination of nevi with magnification (such as is carried out with dermoscopy or vulvoscopy) allows for ­better discrimination of benign versus dysplastic or malignant lesions. This approach is currently unproven and adds cost and inconvenience.

Diagnosis and differential diagnosis Most elevated pigmented nevi are easily recognized as such (Table 23.1). They differ from seborrheic keratoses in that the latter lesions have a

Figure 23.12  Multiple nevi in this sun-protected area are unusual, and the mildly dysplastic large nevus with slightly fuzzy borders also indicated that this woman should be followed with regular and careful whole-body examinations.

rough, scaling surface. Small, flat nevi are identical in appearance to lentigines. Melanomas have a history of enlargement and the pigment may be more variegated. Skin-colored papular nevi are similar in appearance to fibroepithelial polyps. Other pigmented lesions to be considered include pigmented warts and the pigmented lesions of vulvar intraepithelial neoplasia (VIN). In all of these situations, biopsy will allow for correct diagnosis. Clinical findings that suggest histological atypia or even the presence of a melanoma include asymmetrical configuration, irregular or indistinct borders, uneven pigmentation (especially with red and white hues), and diameter larger than about 7 mm. A history of change in a pigmented lesion is also useful but women are only rarely aware of change

Benign neoplasms

Table 23.1  Melanocytic Nevi Diagnosis Brown to black color Smooth-surfaced Flat macules or elevated papules Biopsy Differential Diagnosis Lentigines Melanoma Seborrheic keratoses Figure 23.13  Although small, the very irregular pigmentation and borders suggest a small atypical nevus or melanoma, but the biopsy showed a benign nevus.

Pigmented warts Pigmented vulvar intraepithelial neoplasia Therapy None needed Excisional biopsy if diagnosis is uncertain

in pigmented lesions in the seldom-inspected tissue of the vulva.

Histology and laboratory tests Biopsy, preferably with complete excision, can confirm a clinical diagnosis and can of course rule out melanoma and the other pigmented lesions ­ considered in the differential ­ diagnosis. ­Histological examination allows for sorting benign nevi into the three categories of junctional, compound, and dermal nevi, but this information is clinically of little use. There is appreciable controversy as to whether or not genital nevi, especially those on the vulva, have the same histological appearance as do benign nevi found elsewhere. There are however three subsets of nevi that can have unusual or atypical features. This subject is discussed in the section below on atypical nevi. Figure 23.14  Congenital nevi are generally much larger than acquired lesions; although the light brown color resembles a café-au-lait spot, it is a palpable lesion rather than a flat patch.

Pathogenesis Nevus cells are rounded-up, nondendritic, ­pigment-producing cells that are derived from melanocytes. A clonal population of nevus cells

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can form clusters (“nests”) in the epidermis (junctional nevi), nests in the dermis (dermal nevi), or in nests located both in the epidermis and the dermis (compound nevi). Nevi may be present at birth or may be acquired. Nevi begin to develop in childhood but the number increases appreciably in the second and third decades. After mid-adult age, nevi regress and slowly decrease in number. On average a light-skinned person will have 15–50 nevi by age 30. Factors increasing the likelihood of acquiring nevi include light skin pigmentation, a positive family history for nevi, and sunlight exposure.

Therapy and prognosis Dermatologists generally believe that benignappearing nevi need not be removed. Excisional biopsies are thus carried out only when clinically atypical features, as previously discussed, are present. Gynecologists, on the other hand, generally favor excisional biopsies for all nevi occurring on the vulva. A decision in most instances will be based on the clinician’s level of experience dealing with pigmented lesions. However, given the ­controversy mentioned above about the atypical histology of some vulvar nevi, it is probably best to err on the side of removal. Melanoma risk increases if there is a positive family history of melanoma, if there are a very large number (> 100) of total body nevi, and if there are many clinically atypical nevi. These factors can be given some weight when making a decision about removal of vulvar nevi.

Skin tags and fibroepithelial polyps Skin tags, also known as acrochordons, are extremely common. Approximately half of all adults have them. They occur more frequently in obese individuals and are somewhat more ­common in women than in men. Typical locations for skin tags are the axillae, neck, groin, and anogenital area. Small lesions are soft, skin-colored or tan, pedunculated papules (Figure 23.15). Most are about 2 mm in diameter at the base and 4–10 mm tall. Larger nodules are termed “fibroepithelial polyps”; some of these may be several centimeters in size (Figure 23.16). Fibroepithelial polyps have particular predilection for the labia majora, upper inner thighs,

Figure 23.15  A soft, skin-colored, pedunculated papule within skin folds that is typical for a skin tag, or acrochordon.

and buttocks. The histology is similar in both types, with a normal epidermis enclosing loose connective tissue and dilated capillaries. Fat cells are found in the larger fibroepithelial polyps and account for the very soft feel of these lesions on palpation. Skin tags are associated with increased risks for insulin and lipid abnormalities and, not surprisingly then, also with diabetes. Perianal skin tags are found more often than would be expected with Crohn’s disease. At one time it was believed that skin tags were an indicator pointing to the presence of intestinal polyps but this is no longer thought to be true. Skin tags are always benign. Treatment may be indicated if they become irritated or infarcted. Removal can be carried out with scissor excision, with or without local anesthesia, depending on size. Alternatively, they can be destroyed with electrosurgery or cryotherapy. Electrosurgery usually requires local anesthesia and cryotherapy is most easily handled by grasping the lesion with forceps and then freezing the forceps until the lesion frosts

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Figure 23.17  The flat-topped keratotic nature of these brown lesions is classic for seborrheic keratoses.

Figure 23.16  Very large skin tags are called fibroepithelial polyps.

over. Patients can remove their own lesions by tying a thread tightly around the base. The tags then undergo necrosis and fall off in 7–10 days.

Seborrheic keratoses Seborrheic keratoses occur as sharply marginated, square-shouldered, pigmented papules 3–20 mm in diameter. Height from the skin surface ranges from 2 to 10 mm. The surface is usually rough to palpation and scale is often visible (Figures 23.17 and 23.18). Note that both of these attributes may be less apparent when seborrheic keratoses develop in moist areas. Most of the lesions are brown but the color varies from light tan to dark black. Seborrheic keratoses only arise on hair-bearing skin and are most commonly located on the trunk and upper extremities. Their prevalence increases with age, rising from about 10% in the third decade to 90% in the eighth decade. In the anogenital area,

Figure 23.18  The keratotic nature of the surface of seborrheic keratoses is often less obvious on occluded anogenital skin, but the monomorphous cobblestoned surface is characteristic.

seborrheic keratoses may be found on the mons pubis, thighs, buttocks, genitocrural folds, and labia majora. Examination with magnification (dermoscopy or vulvoscopy) may reveal the typical small pits that characterize seborrheic keratoses3. The differential diagnosis for seborrheic keratosis includes warts, VIN, nevi, and melanoma. When the surface of a seborrheic keratosis is scraped with a blade, scale becomes apparent. This is a helpful diagnostic clue since scale is not apparent when nevi and melanomas are scraped. Differentiation from warts and VIN may be difficult. Seborrheic keratoses usually occur as solitary lesions in the anogenital region, whereas warts and VIN are most often multifocal (Figure 23.19).

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­ emonstrating the presence of HPV DNA are d actually misdiagnosed warts. Clinically typical seborrheic keratoses are benign lesions and no therapy is necessary. Lesions that are inflamed or otherwise troubling to the patient are best treated with cryotherapy7.

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Hemangiomas Vascular anomalies are classified as either vascular malformations or vascular tumors. Only the latter are commonly encountered in the anogenital area and these occur almost only in infants. The ­ preferred term, “hemangiomas of infancy,” includes lesions previously described as capillary, cavernous, and strawberry hemangiomas.

Epidemiology and clinical manifestations

Figure 23.19  Multiple seborrheic keratoses can occur, but should suggest a diagnosis of pigmented genital warts or vulvar intraepithelial neoplasia 3, which can be indistinguishable.

Shave removal for biopsy should be carried out in most instances where there is diagnostic question but if melanoma is a strong consideration, excisional biopsy is preferred. Biopsies from lesions mistakenly considered to be seborrheic keratoses in nongenital areas reveal the presence of melanoma in about 0.5% of specimens4. Seborrheic keratoses probably arise as clonal proliferations of epithelial cells. A significant proportion of the cells demonstrate mutations5. Cell markers for proliferation and inhibitors of apoptosis are also regularly present6. For some time questions have been asked about what, if any, role human papillomavirus (HPV) infection plays in the etiology of seborrheic keratoses. This controversy currently remains unresolved, though most clinicians believe that lesions of this type

Approximately 2% of infants are born with ­hemangiomas and up to 10% will have developed ­hemangiomas by the end of the first year of life. They occur more commonly in light-skinned infants and in those born prematurely. Hemangiomas occur four to five times more frequently in girls than in boys. Involvement of the anogenital area occurs more often than would be expected if the distribution of hemangiomas occurred randomly. Anogenital hemangiomas develop from a red patch but by the time most are recognized they are smooth-surfaced, soft, red nodules varying in diameter from 1 to 10 cm. Less often the lesion appears as a flat, elevated plaque (Figures 23.20 and 23.21). When superficial vessels make up the bulk of the lesion, the color is bright red but when deeper vessels are the ones primarily involved, the color takes on a violaceous or blue hue. Usually only a solitary lesion is present but, in the condition known as hemangiomatosis, multiple lesions are noted. Hemangiomas tend to enlarge slowly over a few months, at which point they stabilize in size. Spontaneous regression, sometimes with scarring, is highly likely by age 5–8 years.

Diagnosis and differential diagnosis The diagnosis is based on clinical findings. Biopsy is contraindicated as bleeding at the time of biopsy can be quite troublesome. There are very

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Figure 23.20  Sharply marginated, red hemangioma encompassing the vulva of an infant; the friction of skin folds on this thickened skin is likely to produce nonhealing painful erosions and bleeding. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 22-4), Churchill Livingstone.)

few lesions that can be confused with infantile hemangiomas, though the red lesions described in Chapter 19 along with amelanotic melanoma could be considered (Table 23.2).

Histology and laboratory examination Histologically there is a marked proliferation of small blood vessels which possess small lumens and rounded-up endothelial cells. Numerous mast cells can be found within the connective tissue stroma. Laboratory tests are not usually necessary. Platelet sequestration and destruction (the Kasabach–Merritt phenomenon) were previously thought to be associated with infantile hemangiomas but it is now thought that this only occurs in the very uncommon neoplasms, kaposiform

Figure 23.21  The bright-red, well-demarcated, superficial component of this hemangioma anterior to the clitoral hood is easily visible; the deeper involvement of the clitoral hood itself is manifested primarily by more diffuse, subtle enlargement of the clitoral hood.

hemangioendothelioma, and tufted angiomas, and therefore platelet studies are not necessary. Infants with lumbosacral hemangiomas may require imaging studies because of an increased risk for associated spinal cord and genitourinary abnormalities.

Pathogenesis Hemangiomas of infancy arise as a developmental abnormality during the first trimester of pregnancy. The mechanism through which this occurs is incompletely understood.

Therapy and prognosis Usually no therapy is necessary. Unfortunately hemangiomas occurring in the anogenital area ulcerate fairly frequently. These ulcerated lesions may be painful and may be accompanied by bleeding or infection. Topical antibiotics such as

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Table 23.2  Hemangiomas Diagnosis Occurrence in newborn and neonates Red to violaceous color Smooth-surfaced Flat patches becoming papules and nodules Differential Diagnosis Pyogenic granulomas Amelanotic melanoma Biopsy is contraindicated

Figure 23.22  Multiple angiokeratomas are common, red to purple, and most often found on the labia majora.

Therapy Usually no therapy is indicated Topical antibiotics if ulcerated Large hemangiomas occasionally require intralesional steroids, systemic steroids, or laser ablation

bacitracin or mupirocin are recommended for all ulcerated lesions. Systemic antibiotics should be used if there is evidence of sepsis. These ulcerated hemangiomas respond to a varying degree when treated with pulsed-dye laser therapy or intralesional corticosteroid injection. In desperate situations, oral steroids may be used. Most hemangiomas resolve spontaneously, though a subset of those present at the time of birth are noninvoluting.

Angiokeratomas Angiokeratomas occur as age-related, minute varices on the scrotum of men and the vulva of women. In contrast to scrotal lesions, angiokeratomas in women are fewer in number (usually 1–10), larger in size (3–6 mm), and darker (violaceous to blue) in color (Figures 23.22 and 23.23). The lesions appear in adult life. Histologically there is dilation of superficial capillaries overlaid by a slightly thickened epidermis, demonstrating elongation of the rete ridges to partially surround the dilated vessels. In a simplistic manner, these

Figure 23.23  Angiokeratomas are sometimes solitary, large, and so dark purple as to appear nearly black; these lesions sometimes mimic nodular melanoma.

lesions can be thought of as tiny varices. They are asymptomatic and, unless there is frequent bleeding secondary to trauma, no treatment is needed. Symptomatic lesions can be excised or can be destroyed using electrosurgery.

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Figure 23.25  Often presenting as confluent, skin-colored nodules, syringomas occasionally produce pruritus.

Figure 23.24  Syringomas are generally multiple, and may be skin-colored or white.

Syringomas Syringomas are benign adnexal neoplasms of sweat gland and sweat duct origin. Historically, it was believed that they were derived from eccrine tissue but more recent data suggest that an apocrine origin is possible. They are very common on the infraorbital region of the face and women are affected more frequently than men. Less often, syringomas are more widely disseminated. Onset is insidious in most instances but an eruptive variety is associated with a fairly rapid appearance of successive crops of new lesions. There appears to be a genetic aspect as many familial cases have been reported. Syringomas occasionally develop on the vulva, though this is an uncommon finding. Fewer than 50 cases have been reported in the literature and in one older series from a vulvar disease clinic, vulvar syringomas were found in only one of 1100 consecutive patients examined. Almost all ­vulvar

syringomas are found on the labia majora where they appear as clustered papules 5–20 mm in diameter. The papules are sloped-shouldered and smooth-surfaced. Most are skin-colored but white, yellow, and brown hues have been reported (Figures 23.24 and 23.25). Onset is usually in late childhood or early adult life. Pruritus occurs in a considerable proportion of the patients and in some cases it can be severe, leading to superimposed lichen simplex chronicus. Once present, lesions persist indefinitely. Because syringomas occur more commonly in women and are likely to appear first at or around puberty, the possibility that they are under hormonal influence has been considered. However studies on hormone receptors have reported widely varying results. A clinical diagnosis can be confirmed with biopsy where a characteristic histologic pattern of dilated ductal structures can be found in the upper portion of a somewhat sclerotic dermis. These are benign lesions and are best left untreated. Pruritus can usually be handled as

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280

Figure 23.26  Hidradenoma papilliferum often presents with a smooth-surfaced nodule. This patient was asymptomatic.

described in Chapter 16. Destruction of the lesions with carbon dioxide laser ablation also leads to cessation of pruritus. An excellent review article describing 18 new cases of vulvar syringomas is available8.

Hidradenoma papilliferum Hidradenoma papilliferum is an uncommon sweat gland tumor that is almost solely restricted to the anogenital area in middle-aged women. Most are located on the vulva, especially the labium majus, but perianal lesions are also found. The tumor presents as a small, smooth-surfaced, skin-­colored to slightly red nodule 0.5–2.0 cm in diameter (Figures 23.26 and 23.27). Most are asymptomatic but may be painful if ulceration occurs. Histologically this neoplasm is an adenoma composed of cystic and glandular structures. These microscopic changes are somewhat similar to papillary adenomas found in the nipple and to the mammary-like glands found in the anogenital area. Hidradenoma is nearly always benign and treatment is local excision. A related sweat gland-derived lesion, ­ syringocystadenoma papilliferum, occurs mainly on the face and scalp, but a few lesions have been reported on the vulva.

Neurofibromas Neurofibromas of the vulva may occur as a component of generalized neurofibromatosis or, less often, as sporadic, solitary neoplasms. In either

Figure 23.27  A small hidradenoma is seen at the right side of the vulva, which also shows unrelated background agglutination of vulvar agglutination.

setting, they appear as asymptomatic, ­ skin­colored to tan, smooth-surfaced, soft nodules ­(Figure 23.28). They are most often located on the labia majora or around the clitoris. Small lesions are hemispherical whereas large lesions may be pedunculated. In many instances they cannot be clinically differentiated from fibroepithelial polyps. Neurofibromas can be excised if they are troublesome to the patient.

Lipomas Lipomas are common neoplasms of fatty tissue. Most often they are found on the trunk and extremities but rarely one will be encountered on the labium majus or in the periclitoral area. They usually present as asymptomatic, slope-­shouldered, skin-colored, smooth-surfaced, soft masses several centimeters in diameter (Figure 23.29). Several of the reports of large vulvar lipomas describe them

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Figure 23.28  This skin-colored, asymptomatic nodule exhibited the typical extremely soft texture of a neurofibroma, which was confirmed on histology in this patient without neurofibromatosis. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-12), Churchill Livingstone.)

Figure 23.30  This firm, pink nodule on the labium majus was found on histology to be a granular cell tumor. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-13), Churchill Livingstone.)

when they do occur, are clinically identical to their benign counterparts. Excision is the treatment of choice. Recurrence rates are low for lesions that are histologically benign. Recently, a prepubertal variant, with a higher recurrence rate, has been described9.

Granular cell tumors

Figure 23.29  This diffuse, deep swelling was far softer than a cyst, and represented an asymptomatic lipoma.

as being pedunculated. Treatment is not necessary, though rapidly growing or very firm lesions warrant biopsy to rule out liposarcoma.

Fibromas Vulvar fibromas are not often encountered. Two clinical types are recognized. The first is a slopeshouldered, smooth-surfaced, skin-colored, firm nodule. The second is a pedunculated, smoothsurfaced, skin-colored lesion that, except for being appreciably firmer on palpation, resembles a fibroepithelial polyp. Both types are found in adult women. Nearly all are benign but ­fibrosarcomas,

Granular cell tumors, formerly called granular cell myoblastoma, are uncommon neoplasms that can involve the skin and subcutaneous tissue. They derive from neural tissue, most likely that of Schwann cell origin. The most common site of involvement is the tongue and other aspects of the oral cavity. However, as many as 15% of the tumors occur in the vulva. Somewhat fewer than 100 vulvar cases have been reported. Most ­vulvar lesions ­ present as asymptomatic, fairly firm, smooth-surfaced, skin-colored nodules 1–5 cm in diameter (see Figure 23.30). Once present, they enlarge slowly. Most are solitary but in about 10% of instances multiple lesions will be present. Granular cell tumors appear to be more common in African Americans. Age at diagnosis is usually between 35 and 60 years. Histologically these tumors are characterized by nests of fairly large cells with small nuclei and a notably granular cytoplasm. Often the microscopic margins of the tumor are poorly defined. The ­ literature suggests that overall only 2% of

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these neoplasms are malignant 10. Clinical risk factors for malignancy include larger size, advanced age at diagnosis, and history of recurrence after excision. Those that are malignant are associated with rapid growth, early metastases, and a high fatality rate. Treatment of benign lesions requires wide local resection but even when margins are reported as clear, there is a risk of recurrence.

Langerhans cell histiocytosis Langerhans cell histiocytosis is most often found on the vulva as part of multiorgan involvement in patients with widespread mucosal, cutaneous, and systemic disease. The frequency with which this occurs is not known but at least 50 such cases have been reported. This is probably an ­underestimate in that it does not include anogenital involvement in infants with the Letterer–Siwe variant of this disease. Much less commonly, vulvar involvement may be confined solely to the genital tissue. Only about a dozen such cases have been reported11. The clinical presentation in both forms is similar and consists of erythematous papules and plaques, often associated with fissures and small ulcers. Rarely, a solitary, larger, ulcerated nodule may be present. Involvement may be unilateral or bilateral. The average age at diagnosis for those with primary genital involvement is around 45–50 years, with a range of 35–85 years12. Langerhans histiocytosis occurs as a clonal proliferation of a subset of activated histiocytes that are CD1a-, S100-, and human leukocyte antigen (HLA)-DR positive. This clonality suggests that the disorder can behave as a true malignancy though the outcome in individual cases is hard to predict. Some, but not all, of the cases with primary vulvar involvement have developed systemic disease. Recurrence often follows resection. Treatment of this condition lies outside the scope of this book.

Miscellaneous benign neoplasms of the vulva Lymphangiomas occur with some frequency in the vulva. These lesions are covered in Chapter 20. Verruciform xanthoma, in which a proliferation

of non-Langerhans cell dendritic macrophages become lipid-filled, usually involves the oral cavity but has rarely been reported on the vulva. Other benign neoplasms, such as sebaceous adenoma, pyogenic granuloma, leiomyoma, angiomyxoma, and angiomyofibroblastoma, have been reported as occurring in vulvar tissue but they are encountered too infrequently to warrant further discussion here.

Premalignant And Malignant Neoplasms Vulvar intraepithelial neoplasia In 1986, the International Society for the Study of Vulvovaginal Disease (ISSVD) attempted to standardize the nomenclature of VIN by ­ replacing previously used terms such as “Bowen’s disease,” “bowenoid papulosis,” and “carcinoma in situ” with “vulvar intraepithelial neoplasia.” In addition, by analogy with cervical intraepithelial neoplasia (CIN), the ISSVD classified VIN as VIN 1, 2, and 3. A differentiated form of VIN was recognized and placed within the VIN 3 category. The World Health Organization currently uses a classification somewhat similar to this. However, dissatisfaction with this approach led the ISSVD to revise the classification in 2004, as follows: VIN, usual type a. VIN, warty type b. VIN, basaloid type c. VIN, mixed (warty/basaloid) type VIN, differentiated type This classification, together with the rationale for the revision, may be found in Appendix A.

Epidemiology and clinical manifestations Thirty years ago VIN was considered to be an uncommon disorder, occurring mainly in older women as a unifocal lesion. Since then there has been an astounding 400% increase in reported cases13. The demographics have shifted in other ways as well. Presently most of the VIN is being reported in women under the age of 40 and it is presenting as multifocal rather than unifocal disease. The lesions of VIN are remarkably diverse in appearance (Figures 23.31–23.36). The most

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Figure 23.33  When occurring on dry, keratinized skin, vulvar intraepithelial neoplasia (Bowen’s disease) can be keratotic, rough, and scaly. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 6-17), Churchill Livingstone.)

Figure 23.31  Vulvar intraepithelial neoplasia manifested by an irregular red surface with white, keratotic, flat-topped papules in an immunosuppressed kidney transplant patient with human papillomavirus infection. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 22-4), Churchill Livingstone.)

Figure 23.34  Erythematous and hyperpigmented, moist plaque of perianal intraepithelial neoplasia (Bowen’s disease) arising in a patient with lichen sclerosus. (­Reproduced from P. J. Lynch and L. Edwards Genital ­Dermatology (Fig. 6-18), Churchill Livingstone.)

Figure 23.32  This red variety of vulvar intraepithelial neoplasia in a background of lichen sclerosus appears nearly erosive.

c­ ommon presentation is that of sharply marginated flat-topped papules and plaques, 2 cm or less in diameter. One to as many as 20 lesions may be present. In about 20% of patients, confluent growth leads to much larger lesions and,

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284

Figure 23.36  Although an initial biopsy diagnosed this tumor as seborrheic keratosis, the inconsistent clinical picture prompted a second biopsy which was interpreted as vulvar intraepithelial neoplasia 3. Figure 23.35  Extensive, erythematous and hyperpigmented plaque and papules of multifocal vulvar intraepithelial neoplasia (bowenoid papulosis). (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 6-20), Churchill Livingstone.)

­ ncommonly, to almost total involvement of the u vulvar tissue. Infrequently, nodular lesions are encountered. Color is highly variable. White, brown-black, pink, and red hues are found most frequently but mixtures of these colors occur approximately 20% of the time. The surface of the lesions may be scaling, crusted, or eroded. More often than not, the lesions of VIN appear de novo and occur on a background of normalappearing tissue but in a significant minority of instances they are superimposed on lichenified skin or on other skin lesions, notably those of lichen sclerosus and lichen planus. Symptoms of pruritus, and less often, pain, occur in about twothirds of patients. Any aspect of the anogenital area, from the vestibule to perivulvar and perianal skin, may be involved.

Diagnosis and differential diagnosis The lesions of VIN cannot be recognized with certainty based on clinical examination. Because of their disparate appearance they may resemble genital warts, seborrheic keratoses, psoriasis, lichen simplex chronicus, lichen sclerosus, and lichen planus. Biopsy will be necessary to identify these conditions separately.

Histology and laboratory tests As the classification of VIN described above suggests, the microscopic appearance of VIN occurs in several subsets. In all of the ­subsets there is epithelial thickening (acanthosis) with overlying hyperkeratosis and parakeratosis. VIN, warty type is seen most commonly and is characterized in addition by papillomatosis (spiking undulation of the epithelial surface, many atypical mitoses, upper ­epithelial koilocytosis, and some degree of abnormal keratinization). VIN, basaloid type occurs less frequently and is characterized by replacement of the usual epithelial cells with small, rounded-up

Premalignant and malignant neoplasms

basal-type cells. The epithelial surface is flatter, there is little or no koilocytosis, and there is no abnormal keratinization. These two types exist both independently and, less often, coexist with each other. Together they account for about 80% of VIN cases. VIN, differentiated type (also called “simplex type”) accounts for about 20% of cases. It is characterized by abnormal ­ differentiation of keratinocytes in the lower portions of the epithelium at the basal or adjacent suprabasal layer. These changes are particularly notable at the base of the rete ridges. Only modest cellular atypia is found.

these HPV-related lesions demonstrate the warty and basaloid types of VIN. Women with this type of VIN also commonly have multicentric intraepithelial neoplasia, with about 50% demonstrating CIN, vaginal intraepithelial neoplasia, or anal intraepithelial neoplasia17. The risk of anal intraepithelial neoplasia rises appreciably in patients who are human immunodeficiency virus (HIV)-positive. Smoking is also a risk factor for the development of HPV-related VIN. The mechanism of carcinogenesis is related to the integration of high-risk-type HPV DNA into the human genome. When this occurs, there is a marked increase in production of the early HPV viral proteins, E6 and E7. These proteins bind to, and degrade, the important tumor suppressor proteins produced by the p53 and Rb genes. This loss of tumor suppression function leads to a major decrease in DNA repair which in turn allows for the accumulation of other cancerrelated mutations. The E7 protein may also have a mutator effect on other genes by way of inducing chromosome instability and, in addition, may act as a tumor promoter through the stimulation of epithelial cell proliferation. Finally, the E6 protein may stimulate telomerase activity which then prevents normal cell senescence. The second group of patients has lesions that lack any association with HPV infection. The lesions in these women histologically demonstrate the differentiated type of VIN16. Patients in this group tend to be older women with unifocal disease. Moreover a very high percentage of this type of VIN occurs in association with vulvar lichen sclerosus and, less frequently, with vulvar lichen planus. The mechanism for neoplastic transformation in these lesions is not well worked out but appears to be associated with mutations in the p53 and CDKN2A genes18.

Pathogenesis

Therapy and prognosis

From an etiological standpoint, two groups of VIN can be identified. High-risk-type HPV is found in about 75% of VIN specimens14. In 80–90% of these HPV-positive lesions, HPV 16 is identified15. HPV 18, 33, 35, and 52 are present much less often 16. HPV DNA is mostly found in young women who present with multifocal disease. Histologically,

The prognosis of VIN is not known with certainty. Spontaneous regression can occur but estimates for the frequency with which this happens vary from 1.2% (in an average of about 10 months)19 to 11.6% (in an average of 9.5 months)20. Spontaneous regression appears to occur only in the HPVrelated type of VIN and, among these patients,

Table 23.3  Vulvar Intraepithelial Neoplasia (VIN) Diagnosis Red, brown, and white color Flat-topped papules and plaques Surface scale, crust, or ulceration Biopsy is necessary Differential Diagnosis Genital warts Seborrheic keratoses Vulvar dermatoses: psoriasis, lichen sclerosus, lichen ­planus, lichen simplex chronicus. Biopsy is necessary to differentiate among these Therapy One-year observation for women less than 30 years old Wide local excision for localized disease Skinning vulvectomy for generalized disease Electrosurgical destruction, laser ablation, and topical therapy with imiquimod are less desirable

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regression rates are higher for young women and decrease significantly after age 3020. Overall progression of VIN to squamous cell carcinoma (SCC) in untreated patients has been reported in from as few as 9% of patients19 to as high as 88% of patients20. Progression to SCC in treated patients has been reported in 3.8%20, 6.5%19, and 20%17 of patients. The variable rates described here probably relate to the composition of the reported series and the length of follow-up. Progression occurs less often and more slowly in patients with HPV-related VIN than it does in differentiated VIN. In fact, the situation in differentiated VIN is quite dire, such that one study reported that occult invasive SCC was found in about 75% of patients at the time undifferentiated VIN was first diagnosed21. With this much variability in reported data, it is perhaps not surprising that there is considerable difference of opinion regarding the approach to therapy. “Watchful waiting” for spontaneous regression is probably only justified in young women (ages 25–30) with HPV-related VIN and, even then, the period of observation should be limited to only about 1 year. All other patients should be treated. Surgical excision with 0.5–1.0-cm margins is the gold standard for treatment of area-­limited VIN. Unfortunately recurrence rates are quite high, averaging about 40%22, though this figure does decrease appreciably when ­ surgical margins are clear19,20. When multifocal disease covers a large area, a skinning vulvectomy may used but here, too, recurrence rates are very high19. Laser ablation and various forms of electrosurgical destruction are also used but, due to the depth of tissue that needs to be treated, these are accompanied by appreciable postoperative discomfort and prolonged healing. Moreover, recurrence rates with these destructive modalities are similar to those for excision22. Medical therapy with 5% imiquimod cream appears to work very well23 but there are insufficient data to recommend this approach at this time.

Invasive squamous cell carcinoma Invasive SCC occurs in only about 2–3/100 000 women per year and accounts for about 5% of genital cancers in women. The incidence of SCC

Figure 23.37  Infiltrated, irregular plaques of invasive squamous cell carcinoma, showing ulceration as well as surrounding hyperpigmented discrete flat-topped papules, indicating an underlying etiology of human papillomavirus.

has risen 20% over a 25-year period but this rate of increase is much less than the 400% increase noted for VIN13. During this same period the average age at diagnosis of SCC has decreased comparably to the decrease that has also occurred for VIN. SCC usually develops in the setting of VIN. The most common presentation is that of scaling or crusted plaques and nodules; ulceration is frequently found (Figures 23.37–23.39). The color is variable and is similar to that described above for VIN. Most lesions are 1–4 cm at the time of diagnosis but occasionally much larger lesions are encountered. Rarely, it arises without a precursor lesion from normal-appearing tissue as an exophytic nodule. Pruritus is present in a majority of

Premalignant and malignant neoplasms

patients and ulcerated lesions may be painful. The main risk factor associated with the development of SCC is the presence of lichen sclerosus, lichen planus, or any one of other inflammatory vulvar diseases. Other risk factors include a past history of CIN, HIV/acquired immunodeficiency syndrome (AIDS), and other forms of immunosuppression. As opposed to cervical SCC, which arises almost entirely via an HPV-related pathway, vulvar SCC develops by way of two pathways: one HPV-related and the other not HPV-related24. The HPV-related pathway accounts for about 20% of cases and is the form of SCC that most often occurs in young women with precursor lesions of warty or ­basaloid VIN25. Approximately 80% of SCC occurs through the HPV-negative pathway. This is the type of SCC found in older women, where it is usually ­accompanied by differentiated-type VIN and is quite likely to be associated with lichen sclerosus or lichen planus26,27. The mechanisms through which oncogenesis occurs in both pathways are the same as described above for the pathogenesis of VIN. Information regarding staging, therapy, and prognosis can be found in standard textbooks of gynecology and oncology. Figure 23.38  Invasive squamous cell carcinoma of the left posterior labium minus, arising in a setting of classic lichen sclerosus.

Figure 23.39  Massive metastasizing squamous cell carcinoma in a young woman.

Verrucous carcinoma Verrucous carcinoma is a nonaggressive subtype of SCC. It can occur on mucous membranes as well as skin. Lesions occurring in the anogenital area are sometimes termed giant condyloma ­acuminata of Buschke and Lowenstein. Lesions on the vulva have a markedly “warty” appearance in that they are exophytic lesions, 2–10 cm in diameter, arising from normal-appearing skin (Figure 23.40). The surface is cauliflower-like with multiple, closely set, rounded projections. Scale and/or crust may be noted. Rarely ulceration is present. Regional lymph nodes are occasionally enlarged. When small biopsies are taken, the histological appearance is strikingly similar to that of a large genital wart and the diagnosis of malignancy may be missed. Larger excisional biopsies reveal massive epithelial acanthosis with exaggerated papillomatosis. Cellular atypia and mitotic figures are either absent or only minimally present. The characteristic feature is the rounded, acanthotic rete

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be HPV infection. However recent studies using molecular techniques have, for the most part, failed to identify HPV DNA in the tumor. The treatment of choice is wide local excision. Local recurrence develops in 20% of the patients but metastases and death from the neoplasm rarely, if ever, occur.

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Basal cell carcinoma

Figure 23.40  Verrucous carcinoma manifested by a large plaque of coalescing verrucous nodules.

ridges which appear to be pushing into the dermis. In true verrucous carcinoma, the basement membrane is intact and thus there is no invasion. However, when multiple sections are cut, foci of microscopic invasion can sometimes be found. Some authors believe that this represents the coexistence of verrucous and SCC of the vulva. But arguing against this point of view is the observation that lesions with, and lesions without, microscopic invasion have a similar, benign outcome. Even enlarged lymph nodes, which are associated with metastases in other forms of cancer, are benign in that, when biopsied, the histologic picture is only that of profound inflammatory changes. The cause of verrucous carcinoma is unknown, but neither VIN nor diseases such as lichen sclerosus or lichen planus are found in the tissue surrounding the neoplasm. Because the histology is so similar to that of genital warts there has been a lingering belief that the cause of the tumor might

Basal cell carcinoma (BCC) is the most common cancer occurring in humans. Approximately a million cases per year are diagnosed in the United States. Nearly all BCCs occur on sun-exposed skin. A small percentage of cases develop on nonsun-exposed skin and about 300 cases of BCC ­involving the vulva have been reported. This is probably an underestimate of the true incidence, as there is one recent series of 63 patients28. BCCs account for about 3% of vulvar cancers. The mean age at diagnosis is about 70 but tumors have been noted in women in their 30s. Tumors are almost always solitary and the labium majus is the site that is usually involved. BCC occurring on the vulva are much more variable in morphology than those arising in sundamaged skin. Papules, nodules, and plaques have been described (Figures 23.41 and 23.42). These may be skin-colored, red, or brown and the surface may be scaling, crusted, or eroded. The average size is about 2 cm but, occasionally, extremely large lesions are encountered. Symptoms most often include awareness of a mass and pruritus. When the lesion is ulcerated, pain and bleeding may be present (Figure 23.43). The cause is not known but ultraviolet light clearly does not play a role in BCC occurring at a vulvar location. Chronic irritation, prior radiation therapy, immune deficiency, and genetic predisposition (as occurs in Gorlin’s syndrome) have been suggested as predisposing factors. BCCs occurring elsewhere are generally associated with defects in the sonic hedgehog signaling pathway and mutations in the tumor suppressor gene, p53. The treatment of choice is wide local excision. The clinical margination of vulvar BCC is often indistinct and thus the surgical margins may be microscopically involved. Thus, re-excision may

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Figure 23.41  The translucent quality of these skin-colored and pigmented papules was a clue to the correct diagnosis of basal cell carcinomas. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 19-1), Churchill Livingstone.)

Figure 23.43  Nonspecific, poorly demarcated, erosive plaque that revealed a basal cell carcinoma on biopsy.

Extramammary Paget’s disease Epidemiology and clinical manifestations Figure 23.42  This basal cell carcinoma on the sun-protected skin of the buttock showed the classic translucent texture and rolled borders.

be necessary. Several histological patterns have been reported and some of these (morpheaform, infiltrating, basosquamous, adenocystic, and perineural infiltrating types) are associated with recurrence. Mohs-type surgery, with microscopic control, might be considered for recurrent tumors. The overall prognosis is very good but about 10 cases with metastases have been reported. This seems excessive in comparison to the number of metastases reported for BCC arising in sunexposed skin but it may simply reflect the older age of the patients and larger size of lesions at the time of diagnosis.

Extramammary Paget’s disease (EMPD) is an uncommon neoplasm that arises only in apocrine gland-bearing skin. Women are affected three to four times more often than men and two-thirds of all EMPDs occur on the vulva. Perianal involvement may be present either in association with vulvar EMPD or as a sole site of involvement. Perineal and groin lesions are found much less often. EMPD accounts for 1–3% of all vulvar malignancies. It is more common in older white women. The median age is 70, with a general range from 50 to 80. It has only rarely been reported in women younger than 40 years. The lesions of EMP are very nonspecific in appearance (Figures 23.44–23.49). The most common presentation is that of fairly well-­marginated red patches and plaques. The surface of these lesions demonstrates mixed areas of scale, crust, and erosion. More advanced lesions often have

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Figure 23.44  This plaque of extramammary Paget’s disease is asymmetric and red with a white, macerated surface.

Figure 23.46  Recalcitrant inflammatory skin disease should be biopsied to rule out a malignancy; a biopsy showed extramammary Paget’s disease despite morphology consistent with lichenified lichen simplex chronicus.

Figure 23.45  This red plaque of extramammary Paget’s disease is nonspecific and could be confused with several inflammatory diseases, including erosive lichen planus or secondarily infected lichen simplex chronicus.

white islands of tissues scattered throughout widely eroded areas. A rare hypopigmented form of the disease has been reported. The labia majora are the major site of involvement. One or several lesions may be found and these may be unilateral or bilateral. Rarely, multicentric disease with axillary or breast involvement may be noted. The diameter of the lesion can be as small as 2 cm but the entire vulva, mons pubis, perineum, and perianal skin may be affected. Seventy-five percent of patients describe moderate to severe itching. Awareness of a lesion or mass is also commonly reported. A minority of patients present with pain or “discharge” arising from an eroded surface. On average, symptoms will have been present for 2 years or more. Usually multiple physicians will have been consulted and failure to respond to topical steroids and/or anticandidal agents is a helpful clue to diagnosis.

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Figure 23.48  Paget’s disease can appear as irregular ­inflammatory plaques. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 6-26), Churchill Livingstone.)

Figure 23.47  Red, exudative plaques of extramammary Paget’s disease can occur on both modified mucous membranes and keratinized skin. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 6-24), Churchill Livingstone.)

Diagnosis and differential diagnosis The diagnosis is established by biopsy. In the most common scenario, EMPD is not suspected and a “blind” biopsy is submitted from a patient with vulvar disease that has failed to respond to local treatment. EMPD clinically can mimic the ­appearance of psoriasis, lichen simplex chronicus, intertrigo, contact dermatitis, intraepithelial neoplasia, Hailey–Hailey disease, lichen sclerosus, and lichen planus (Table 23.4).

Histology and laboratory examination The histology of EMPD is distinctive. Large cells with pale cytoplasm and large nuclei are found singly and in nests within the epidermis. Cellular atypia and mitotic figures are usually

Figure 23.49  This inflamed plaque of extramammary Paget’s disease exhibits the classic islands of white, hyperkeratotic epithelium.

fairly ­ prominent. These cells often extend into the ­epithelial portions of hair follicles and sweat glands. In most instances vulvar EMPD is entirely intraepithelial but some cases show microinvasion, deep invasion or, in 5–15% of vulvar cases, underlying invasive adenocarcinoma of sweat gland-related type.

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Table 23.4  Extramammary Paget’s Disease Diagnosis Red patches and plaques Islands of white tissue Eczematous or eroded surface Often multifocal Biopsy is necessary Differential Diagnosis Candidiasis All forms of eczematous disease Vulvar dermatoses, especially psoriasis Vulvar intraepithelial neoplasia Therapy Wide local excision Check for invasion and underlying carcinoma Check for breast, urological, and gastrointestinal malignancy Lymph node examination only if invasive Expect recurrences Recurrences can be treated with excision, laser ablation, photodynamic therapy, and electrosurgical destruction

Since this disease occurs in elderly patients it is not surprising that they may have other malignancies as well as EMPD. Nevertheless, there is a higher than expected likelihood (10–20%) of finding breast, urological, and gastrointestinal ­malignancy. For this reason, appropriate tests to search for these neoplasms should be carried out in all patients with EMPD.

Pathogenesis Although the cause of EMPD is unknown, two pathophysiologic pathways have been suggested. In the primary form of the disease, the neoplasm arises from within the epithelium. Most likely the cell of origin is the Toker cell, which is a cell that is found in the normal nipple, accessory nipples occurring along the milk line, and in anogenital tissue30. These Toker cells stain for mucin and express CK 7 just as do the clear cells in EMPD. They overlie the lactiferous ducts in nipples and are found at the ductal outlets of the mammarylike glands of the vulva30. Toker cells also appear to be responsible for the hypopigmented lesions of clear cell papulosis and, possibly, the hypopigmented forms of EMPD31. In the secondary form of EMPD, the atypical cells appear to travel to the epidermis from an underlying adnexal, genitourinary, or gastrointestinal adenocarcinoma. This would represent a pathway similar to that responsible for almost all Paget’s disease of the breast.

Therapy and prognosis In EMPD, the pale cells are positive for mucin with conventional mucin stains such as periodic acid–Schiff (PAS) and alcian blue. These cells are also positive when immunostained for ­carcinoembryonic antigen and low-molecular-weight keratins such as CK7. The cells are regularly estrogen- and progesterone-receptornegative. Androgen receptors are found in about half of the lesions as is HER-2 oncogene-related protein29. In most instances, additional special stains are required to rule out melanoma and pagetoid intraepithelial neoplasia. Melanoma is S-100-positive and PAS-negative, whereas intraepithelial neoplasia of the squamous cell type is both S-100- and PAS-negative.

The prognosis for patients with primary EMPD, whose disease is confined to the epidermis (in situ neoplasia) or who have minimally invasive (< 1 mm) disease, is excellent. They do not develop node involvement or distant metastases, do not die of their Paget’s disease, and have a lifespan similar to normal individuals of similar age32. Patients who have primary disease with invasion deeper than 1 mm have a much poorer outcome. They do develop node metastases and, depending on the depth of the invasion, have a 0–35% 5-year survival32. The prognosis for patients with associated breast, urologic, or gastrointestinal adenocarcinoma is that of their associated tumor. The treatment of choice is wide local excision, though vulvectomy may be necessary in those

Premalignant and malignant neoplasms

with very widespread disease. If only intraepithelial involvement or microinvasive disease is present histologically, no node dissection is necessary32. If invasion beyond 1 mm is present, either sentinel node dissection or general node dissection is usually warranted. Positive histologic margins are commonly found even when the margins at surgery are set several centimeters outside clinically visible disease. Recurrence rates are extremely high (20–40%) even when clinical and histologic margins (as determined by intraoperative frozen sections) appear to be clear. Mohs micrographic surgery offers only a modest reduction in these recurrence rates. This problem with recurrence is presumably the result of two things: first, microscopic involvement is regularly present at the periphery of lesions even in the absence of overlying visible clinical disease and, second, EMPD is multifocal with unconnected islands of microscopic disease occurring at some distance beyond clinically visible lesions. Fortunately, the prognosis for life is independent of recurrence and is, instead, related to the level of invasion. Probably the best approach is to remove visible disease with narrow margins in order to preserve tissue and reduce recovery times. Recurrences can then be re-excised as they develop. Other treatment, such as photodynamic therapy, radiotherapy, laser therapy, and topical chemotherapy with imiquimod, works well for eradication of visible disease though, as is true for surgery, recurrence rates are very high33. More importantly, when these modalities are used for initial therapy, there is no tissue available to determine whether invasion has occurred or whether there is underlying adenocarcinoma. Probably the best place for these nonsurgical approaches is in the treatment of recurrent disease as these subsequent recurrences are uncommonly associated with invasive disease or underlying carcinoma.

Atypical nevi In a prospective study, 300 consecutive women attending a reproductive endocrinology clinic were examined for vulvar nevi. Seven patients (2%), all white women, had such lesions and of these, only one was histologically atypical2. This is similar to

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Figure 23.50  These atypical (dysplastic) nevi are large with blurred borders.

Figure 23.51  Women with atypical nevi often have more nevi than the average person, both atypical and benign. These women need regular general skin examinations.

the results of a 1987 study in which 5% of 59 vulvar nevi were histologically atypical. Three types of atypical nevi can be recognized histologically and each type is associated with a fairly characteristic clinical phenotype. First, “classical” atypical nevi, usually termed “dysplastic nevi,” occur in a widespread distribution pattern in 5–10% of the white population. Most are solitary, sporadic nevi but multiple lesions and familial patterns are commonly encountered (Figures 23.50 and 23.51) These dysplastic nevi are flat or only minimally elevated, are somewhat asymmetrical in shape, have slightly blurred ­margination, display color variegation (mixes of tan, brown, red, and white hues) and are larger (5–15 mm) than common nevi. Histologically,

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there is ­melanocyte proliferation, both singly and in nests, at the dermal–epidermal border. These nests often bridge adjacent, elongated rete ridges. A few of the melanocytes demonstrate mild cellular atypia. In the dermis there is fibroplasia of the papillary dermis and a band-like lymphocytic inflammatory infiltrate. Such dysplastic nevi are markers of an individual’s susceptibility for the development of melanoma but the individual lesions rarely develop into melanomas. Perhaps because sunlight plays a role in their development, atypical nevi of this dysplastic type appear to be underrepresented in the vulva. Second, “atypical nevi of the genital type” (also termed “milk line nevi” and “flexural nevi”) have been reported as occurring in a small proportion of vulvar nevi34. These lesions occur in young women (age 20–35) and may be located on either mucosal or nonmucosal aspects of the vulva. They are elevated, often polypoid, evenly pigmented, light brown papules generally lacking the clinical dysplastic features described in the paragraph above (Figure 23.52). Histologically there is a junctional component with horizontal confluence of enlarged nests of nevus cells. Within the nests, the nevus cells are larger and less adhesive than is true in common nevi but mitotic figures are not usually present. Focal areas of upward (“pagetoid”) melanocyte spread are noted. There is little or no lentiginous elongation of the rete ridges. Cytologic atypia may be present, and although these nevi have some unusual microscopic features, they are completely benign and carry no risk for the subsequent development of melanoma. Third, atypical nevi have been described in the setting of vulvar lichen sclerosus. Those occurring in older patients with lichen sclerosus are histologically benign, whereas those occurring in children and young women are clinically and histologically atypical35. The usual presentation is that of a child who has suddenly developed an irregularly shaped, flat or slightly elevated, dark black lesion arising against the white backdrop of lichen sclerosus. These nevi are microscopically similar to the so-called “persistent nevi” that have regrown after previous removal35. The histologic features include confluent junctional nests, lentiginous melanocytic hyperplasia, focal pagetoid

Figure 23.52  This atypical nevus of the genital type is elevated and appears benign clinically, but may histologically exhibit signs of atypia.

upward spread of melanocytes, papillary dermal fibrosis, and an underlying ­ dermal lymphocytic inflammatory response. The meaning of these nevi is not clear. Melanoma is reported to develop with greater than expected frequency in young girls with lichen sclerosus but some, though not all, of the reported lesions may have been these atypical nevi rather than true melanomas35,36.

Melanoma Melanomas occurring in the vulva are quite different from those occurring on sun-exposed skin. The contrasts include: (1) a decreasing, as opposed to increasing, incidence; (2) occurrence at an older age; (3) more frequent presentation as an amelanotic lesion; (4) utilization of a pathogenetic pathway unrelated to ultraviolet light exposure; (5) a more frequent presentation as a lentiginous (acral/ mucosal) histological subtype; (6) less common association with a contiguous nevus; (7) a predilection to occur on mucous membrane or glabrous skin; and (8) an outcome carrying an appreciably poorer prognosis.

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Figure 23.53  The asymmetry, irregular borders, variegate color, and large diameter (the ABCDs of melanoma morphology) suggest the correct diagnosis of melanoma.

Epidemiology and clinical manifestations Melanoma is stated to be the second most common vulvar malignancy but it only accounts for about 3–5% of such neoplasms. The annual incidence of vulvar melanoma is approximately 0.1 per 100 000 persons. The incidence is stable or decreasing with time, in marked contradistinction to the rapidly rising incidence in melanoma on sun-exposed skin37,38. Vulvar melanoma represents about 3% of all melanomas in women and since the vulva accounts for about 1–2% of the skin surface, it would appear that vulvar tissue may be predisposed to the development of these neoplasms. It occurs primarily in white women and the usual age at onset is between 50 and 80. Notably, a few cases have been reported in children with lichen sclerosus 36. Melanomas in nongenital tissue are asymptomatic, presumably because they are usually discovered when they are small lesions. However, most women with vulvar melanomas are probably unaware of small lesions and do not seek medical attention until they are aware of a mass or other symptoms develop. For this reason a large ­ proportion of patients with vulvar ­ melanomas complain of ­pruritus, pain, discharge, or bleeding. There is appreciable heterogeneity in the appearance of vulvar melanomas (Figures 23.53– 23.57). Most present as pigmented, elevated, polypoid nodules but some are flat, darkly pigmented patches. Three physical findings occur more often with vulvar melanomas than with those at other sites: ulceration, decreased pigment (amelanotic

Figure 23.54  Fungating, black, nodular melanoma of the vulva with amelanotic pink, polypoid component. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 12-9), Churchill Livingstone.)

Figure 23.55  This mucosal melanoma is deeply pigmented; the irregular nodules on the labium minus denote an ­advanced lesion with a poor prognosis.

melanoma), and multifocal lesions (possibly representing satellitosis). The average diameter in the longest axis is 1.5–2.5 cm. Two-thirds of the lesions are found on the clitoris, labia minora, and inner aspect of the labia majora. An explanation for the predilection to occur on mucous membrane and glabrous skin, especially the clitoris, is not available.

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296

Figure 23.56  This nodular melanoma demonstrates not only the pigmented nature of melanoma, but also an amelanotic portion, which is more common on the vulva than on other parts of the body.

Diagnosis and differential diagnosis Figure 23.57  Although this lesion is extraordinarily dark, it is totally flat and proved to be a melanoma in situ with an excellent prognosis.

The correct diagnosis is usually suspected clinically when the lesion is darkly pigmented but melanomas with a lesser degree of pigment can easily be missed. The differential diagnoses include ­lentiginosis, benign nevi, seborrheic keratosis, Paget’s disease, and VIN (Table 23.5). Biopsy rules out these conditions and confirms the diagnosis of melanoma.

site and consequent delayed recognition. Detailed discussion of the microscopic appearance of vulvar melanoma falls outside the scope of this textbook.

Histology and laboratory examination

Pathogenesis

Three histologic types of melanoma occur in the vulva. The commonest, in most series at least, is that of mucosal lentiginous melanoma. This type of tumor is analogous to acral lentiginous melanoma. The second most frequent type is nodular melanoma followed by superficial spreading melanoma37,39. This is just the reverse order for ­melanomas found on sun-exposed skin. The mean depth of invasion at the time of diagnosis is 2–3 mm, which is appreciably deeper than the mean depth of melanoma found on other cutaneous sites38,39. This is likely related to the location at a “hidden”

The major factor determining the presence of melanoma at cutaneous sites is a history of sun exposure, especially sunburn in childhood. This is obviously not the explanation for vulvar melanoma. But, other factors important in the pathogenesis of cutaneous melanomas, such as family history of dysplastic nevi or melanoma, personal presence of dysplastic nevi, and immunosuppression, may also be risk factors for vulvar melanoma. Many melanomas occurring on hair-bearing skin appear to derive from a previously existing

Premalignant and malignant neoplasms

Table 23.5  Melanoma Diagnosis Darkly pigmented patches, plaques, or nodules Surface is smooth or ulcerated Amelanotic types are pink to red Patients are usually elderly Biopsy is necessary Differential Diagnosis Lentigenes Nevi Pigmented seborrheic keratoses, vulvar intraepithelial neoplasia Therapy Excision with 1–2-cm margins Sentinel node biopsy

nevus. Such contiguous nevi are not found with those vulvar melanomas that arise in glabrous ­tissue but may be present in anogenital melanomas arising on hair-bearing skin37. There has been a recent impressive increase in understanding of the molecular events leading to melanoma. Specifically, mutations in BRAF, N-RAS, PTEN, CDKN2A, MC1R and several other genes have been identified as present in most melanomas40. Interestingly, BRAF is often mutated in melanomas occurring on sun-exposed skin but is rarely mutated in acral lentiginous melanomas of the palms and soles. Since this latter type of melanoma is analogous to the most common form of vulvar melanoma41, one might expect a lack of BRAF mutations in vulvar melanomas as well. If this should prove to be true, it might help explain the many differences between vulvar mucosal melanomas and those arising as a result of ultraviolet light damage. A special situation exists in which melanoma develops in children with vulvar lichen planus36. It is known the SCC of the non-HPV type ­develops

with greater than expected frequency in older women with vulvar lichen sclerosus. One might expect that there could be an increased frequency in other malignancies as well. And, in fact, it does appear that superimposed melanoma occurs with increased frequency in young girls (but not in adult women) with lichen sclerosus. As discussed in the section above, something about lichen sclerosus in children seems to provide a fertile ground for the development of atypical nevi as well as melanoma.

Therapy and prognosis The prognosis for vulvar melanoma is appreciably poorer than for melanoma at other sites: the 5-year survival rate for vulvar melanoma is 25–50% versus 75–85% for cutaneous types38,39. However, as is true for melanoma at all other sites, the prognosis is primarily dependent on the depth of invasion and node status. The depth of invasion is best measured by the Breslow technique, where the average depth of melanoma is about 1.0 mm for cutaneous lesions and nearly 3.0 mm for vulvar lesions39. When thin vulvar melanomas are found, the 5-year survival rates improve but ­generally still do not match that of cutaneous lesions of the same depth42. As regards node status, in a large Swedish study, the 5-year survival rate was about 65% without nodal involvement and about 25% with nodal involvement37. Prognosis can also be determined through the use of various staging techniques. These lie outside the scope of this chapter but are reviewed elsewhere38. Historically, extensive surgery with radical vulvectomy and lymphadenectomy was carried out for almost all patients. Recent studies have shown that equally good survival rates can be obtained with relatively narrow-margin (1–2 cm) local excision. Unfortunately, recurrence rates remain high regardless of the margin size. Lymphadenectomy does not improve survival rates and thus the frequency with which this procedure is undertaken has markedly decreased. However, there is a trend today to perform sentinel node biopsy, primarily to determine node status and thus prognosis. Additional material on therapy can be found in other recent reports37,38,39,42

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Miscellaneous rare malignancies Many very rare neoplasms can involve the vulva. Most of these have been reported only as individual cases and thus do not warrant inclusion in this chapter. Some of them, to include Bartholin’s gland carcinoma, sarcoma, dermatofibroma protuberans, Kaposi’s sarcoma, adenosquamous carcinoma, lymphoma, and Merkel cell tumor, are covered in an authoritative review article43.

References   1. Marzano, D. A. and Haefner, H. K. The Bartholin gland cyst: past, present and future. J. Lowe. Genital Tract Dis. 2004; 8: 195–204.   2. Rock, B., Hood, A. F., and Rock, J. A. Prospective study of vulvar nevi. J. Am. Acad. Dermatol. 1990; 22: 104–106.   3. de Giorgi, V., Masi, D., Salvini, C., et al. Pigmented seborrheic keratoses of the vulva clinically mimicking a malignant melanoma: a clinical, dermoscopic–pathologic case study. Clin. Exp. Dermatol. 2005; 30: 17–19.   4. Izikson, L., Sober, A. J., Mihm, M. C., et al. Prevalance of melanoma clinically resembling seborrheic keratosis: analysis of 9204 cases. Arch. Dermatol. 2002; 138: 1562–1566.   5. Hafner, C., van Oers, J. M. M., Hartman, A., et al. High ­frequency of FGFR3 mutations in adenoid seborrheic keratoses. J. Invest. Dermatol. 2006; 126: 2404–2407.   6. Bowen, A. R., Hanks, A. N., Murphy, K. J., et al. Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias. Am. J. Dermatopathol. 2004; 26: 177–181.   7. Herron, M. D., Bowen, A. R., and Krueger, G. G. Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int. J. Dermatol. 2004; 43: 300–302.   8. Huang, Y. -H., Chuang, Y. -H., Kuo, T. -T., et al. Vulvar syringoma: a clinicopathologic and immunohistologic study of 18 patients and the results of treatment. J. Am. Acad. Dermatol. 2003; 48: 735–739.   9. Iwassa, Y. and Fletcher, C. D. Distinctive prepubertal vulval fibroma: a hitherto unrecognized mesenchymal tumor of prepubertal girls: analysis of 11 cases. Am. J. Surg. Pathol. 2004; 28: 1601–1608. 10. Levavi, H., Sabah, G., Kaplan, B., et al. Granular cell tumor of the vulva. Six new cases. Arch. Gynecol. Obstet. 2006; 273: 246–249. 11. Venizelos, I. D., Mandala, E., Tatsiou, Z. A., et al. Primary Langerhans cell histiocytosis of the vulva. Int. J. Gynecol. Pathol. 2006; 25: 48–51. 12. Santillan, A., Montero, A. J., Kavanagh, J. J., et al. Vulvar Langerhans cell histiocytosis: a case report and review of the literature. Gynecol. Oncol. 2003; 91: 241–246. 13. Judson, P. L., Haberman, E. B., Baxter, N. N., et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet. Gynecol. 2006; 107: 1018–1022. 14. Ueda, Y., Enomoto, T., Miyatake, T., et al. Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa. Am. J. Clin. Pathol. 2004; 122: 266–274. 15. Hillemanns, P. and Wang, X. Integration of HPV-16 and H­PV-18 DNA in vulvar intraepithelial neoplasia. Gynecol. Oncol. 2006; 100: 276–282.

16. Bonvicini, F., Venturoli, S., Ambretti, S., et al. Presence and type of oncogenic human papillomavirus in classic and in differentiated vulvar intraepithelial neoplasia and keratinizing vulvar squamous cell carcinoma. J. Med. Virol. 2005; 77: 102–106. 17. Zawislak, A. A., Price, J. H., Dobbs, S. P., et al. The management of vulval intraepithelial neoplasia in Northern Ireland. Int. J. Gynecol. Cancer. 2006; 16: 780–785. 18. Soufir, N., Queille, S., Liboutet, M., et al. Inactivation of the CDKN2A and the p53 tumor suppressor genes in external genital carcinomas and their precursors. Br. J. Dermatol. 2007; 156: 448–453. 19. van Seters, M., van Beurden, M. and de Craen, A. J. Is the ­natural history of vulvar intraepithelial neoplasia based on enough evidence? A systematic review of 3322 published ­patients. Gynecol. Oncol. 2005; 97: 645–651. 20. Jones, R. W., Rowan, D. M. and Stewart, A. W. Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women. Obstet. Gynecol. 2005; 106: 1319–1326. 21. Scurry, J., Campion, M., Scurry, B., et al. Pathologic audit of 164 consecutive cases of vulvar intraepithelial neoplasia. Int. J. Gynecol. Pathol. 2006; 25: 176–181. 22. Hillemanns, P., Wang, X., Staehle, S., et al. Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO2 laser vaporization, photodynamic therapy, excision and vulvectomy. Gynecol. Oncol. 2006; 100: 271–275. 23. Le, T., Hicks, W., Menard, C., et al. Preliminary results of 5% imiquimod cream in the primary treatment of vulva intraepithelial neoplasia grade 2/3. Am. J. Obstet. Gynecol. 2006; 194: 377–380. 24. van der Avoort, I. A., Shirango, H., Hoevenaars, B. M., et al. Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways. Int. J. Gynecol. Pathol. 2006; 25: 22–29. 25. Al-Ghamdi, A., Freedman, D., Miller, D., et al. Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases. Gynecol. Oncol. 2002; 84: 91–94. 26. Derrick, E. K., Ridley, C.M., Kobza-Black, A., et-al. A clinical study of 23 cases of female anogenital carcinoma. Br. J. Dermatol. 200; 143: 1217–1223. 27. Chieso-Vottero, A., Dvoretsky, P. M. and Hart, W. R. Histopathologic study of this vulvar squamous cell carcinomas and ­associated cutaneous lesions: a correlative study of 48 tumors in 44 patients with analysis of adjacent vulvar intraepithelial neoplasia types and lichen sclerosus. Am. J. Surg. Pathol. 2006; 30: 310–318. 28. de Giorgi, V., Salvini, C., Massi, D., et al. Vulvar basal cell carcinoma: retrospective study and review of the literature. Gynecol. Oncol. 2005; 97: 192–194. 29. Liegl, B., Horn, L. C. and Moinfar, F. Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease. Mod. Pathol. 2005; 18: 1283–1288. 30. Willman, J. H., Golitz, L. E., and Fitzpatrick, J. E. Vulvar clear cells of Toker. Precursors of extramammary Paget’s disease. Am. J. Dermatopathol. 2005; 27: 185–188. 31. Chen, Y. H., Wong, T. W., and Lee, J. Y. Depigmented genital extramammary Paget’s disease: a possible histogenetic link to Toker’s clear cells and clear cell papulosis, J. Cutan. Pathol. 2001; 28: 105–108. 32. Tsutsumida, A., Yamamoto, Y., Minakawa, H., et al. Indications for lymph node dissection in the treatment of extramammary Paget’s disease. Dermatol. Surg. 2003; 29: 21–24. 33. Shepherd, V., Davidson, E. J., and Davies-Humphreys, J. Extramammary Paget’s disease. Br. J. Obstet. Gynaecol. 2005; 112: 273–279. 34. Gleason, B. C., Hirsch, M. S., Nucci, M. R., et al. Atypical genital nevi. A clinicopathologic analysis of 56 cases. Am. J. Surg. Pathol. 2008; 32: 51–57.

Further reading 35. Carlson, J. A., Mu, X. C., Slomski, A., et al. Melanocytic proliferations associated with lichen sclerosus. Arch. Dermatol. 2002; 138: 77–87. 36. Rosamilia, L. L., Schwartz, J. L., Lowe, L., et al. Vulvar melanoma in a 10-year old girl in association with lichen sclerosus. J. Am. Acad. Dermatol. 2006; 54: S52–S53. 37. Ragnarsson-Olding, B. K., Kanter-Lewensohn, L. R., Lagerlof, B., et al. Malignant melanoma of the vulva in a nationwide, 25year study of 219 Swedish females. Cancer. 1999; 86: 1273–1284. 38. Irvin, Jr W. P. , Legallo, R. L., Stoler, M. H., et al. Vulvar melanoma: a retrospective analysis and literature review. Gynecol. Oncol. 2001; 83: 457–465. 39. Wechter, M. E., Gruber, S. B., Haefner, H. K., et al. Vulvar melanoma: a report of 20 cases and review of the literature. J. Am. Acad. Dermatol. 2004; 50: 554–562. 40. Miller, A. J. and Mihm, M. C. Melanoma. N. Engl. J. Med. 2006; 355: 51–65. 41. Saldanha, G., Potter, L., Daforno, P., et al. Cutaneous melanoma subtypes show different BRAF and NRAS mutation frequencies. Clin. Cancer Res. 2006; 12: 4405–4499. 42. Verschraegen, C. F., Benjapibal, M., Supakarapongkul, W., et al. Vulvar melanoma at the M.D. Anderson Cancer Center: 25 years later. Int. J. Gynecol. Cancer. 2001; 11: 359–364. 43. Finan, M. A. and Barre, G. Bartholin’s gland tumor, malignant melanoma and other rare tumors of the vulva. Best Pract. Res. Clin. Obstet. Gynecol. 2003; 17: 609–633.

Granular cell tumors Levavi, H., Sabah, G., Kaplan, B., et al. Granular cell tumor of the vulva: six new cases, Arch. Gynecol. Obstet. 2006; 273: 246–249.

Vulvar intraepithelial neoplasia Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer, Clin. Sci. 2006; 110: 525–541. Jones, R. W., Rowan, D. M. and Stewart, A. W. Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women, Obstet. Gynecol. 2005; 106: 1319–1326.

Extramammary Paget’s disease MacLean, A. B., Makwana, M., Ellis, P. E., et al. The management of Paget’s disease of the vulva. J. Obstet. Gynaecol. 2004; 24: 124–128. Hatta, N., Yamada, M., Hirano, T., et al. Extramammary Paget’s disease: treatment, prognostic factors, and outcome in 76 ­patients. Br. J. Dermatol. 2008; 158: 313–318.

Atypical nevi Elder, D. E. Precursors to melanoma and their mimics: nevi of special sites. Mod. Pathol. 2006; 19: S4–S20.

Melanoma

Further reading General Finan, M. A. and Barre, G. Bartholin’s gland carcinoma, malignant melanoma and other rare tumors of the vulva, Best Pract. Res. Clin. Obstet. Gynecol. 2003; 17: 609–633.

Hemangiomas Bruckner, A. L. and Frieden, I. J. Infantile hemangiomas, J. Am. Acad. Dermatol. 2006; 55: 671–682.

Markovic, S. N., Erickson, L. A., Rao, R. D., et al. Malignant melanoma in the 21st century, part 1: Epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin. Proc. 2007; 82: 364–380. Miller, A. J. and Mihm, M. C. Melanoma., N. Engl. J. Med. 2006;

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PART: II  Gynecologic Dermatology

CHAPTER 24

Vaginitis Libby Edwards Vaginitis and vaginosis refer to vaginal infections, skin diseases involving the vagina, or a disruption of the normal vaginal flora. Common and nonspecific symptoms include vaginal discharge, odor, introital itching, or irritation. Vaginosis refers to vaginal disease unassociated with inflammation as characterized by redness and a wet mount showing an increase in white blood cells. Vaginitis is associated with clinical and wet-mount changes of inflammation. Although Candida albicans is the most common cause of acute vaginitis, and it is credited with most chronic vulvovaginal symptoms, noninfectious conditions are more likely causes in a setting of chronic, recalcitrant symptoms. The evaluation of a vaginal discharge and symptoms of vaginitis requires a wet mount and, at times, a culture. A pH is often useful. The diagnosis is not made on the basis of symptoms and the gross appearance of vaginal secretions, as these are not specific. In addition to the identification of organisms, attention to the presence of white blood cells, lactobacilli, and immature (parabasal) epithelial cells can add clues to the diagnosis. A pH, where a piece of pH paper is dipped into vaginal secretions pooled in the speculum, or touched against the vaginal wall (far from the cervix with its alkaline mucus), also adds information. A high pH is an indirect measurement for the absence of lactobacilli. Lactobacilli are absent – and therefore the pH of vaginal fluid is high – in the setting of low estrogen, inflammation of any cause, and bacterial vaginosis.

Candida vulvovaginitis The most common, well-recognized, and overdiagnosed infectious vaginitis is that of Candida vulvovaginitis.

Epidemiology and clinical manifestations About 75% of women experience vaginal candidiasis at some point in their life1. Candida vaginitis is more common with antibiotic ­therapy, diabetes, human immunodeficiency viral infection, and pregnancy. Although Candida vulvitis occurs at any age in a ­setting of

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Figure 24.1  Candida vaginitis usually produces redness and puffiness of the modified mucous membranes of the vulva.

obesity and incontinence, vaginal Candida does not generally occur in the absence of estrogen. Therefore, premenarchal girls almost never develop vaginal yeast, and postmenopausal women not on estrogen replacement are usually spared vaginal yeast also2. Most women describe introital itching as an early sign of Candida vulvovaginitis. Those women with more marked vulvar involvement experience interlabial and skin fold fissures and excoriations that produce burning, stinging, and dyspareunia (Figures 24.1 and 24.2). Classically, Candida vaginitis is manifested by dry, cottage cheese-like vaginal secretions, but very often secretions are nearly normal clinically. The vaginal epithelium ranges from normal to red. Introital erythema is usual, but vulvar involvement sometimes produces redness and puffiness of the modified mucous membranes. Vaginitis produced by non-albicans Candida lacks significant vulvar abnormalities beyond

Figure 24.2  Candida vaginitis is associated at times with more marked Candida vulvitis, characterized by erythema extending beyond the modified mucous membranes, sometimes with satellite papules, pustules, and desquamation.

introital redness in more severe disease. Vaginal secretions of women with non-albicans Candida are clinically normal.

Diagnosis and differential diagnosis The differential diagnosis of C. albicans includes all other causes of vaginitis (Table 24.1) as well as red vulvar plaques, including psoriasis, lichen simplex chronicus, seborrheic dermatitis, irritant contact dermatitis, and tinea cruris. Non-albicans Candida, particularly C. glabrata, is most often confused with vestibulodynia (vulvar vestibulitis syndrome) or generalized vulvodynia (Table 24.2). Trichomoniasis and desquamative inflammatory vaginitis (DIV) superficially resemble Candida vaginitis, but vaginal secretions are most often grossly purulent with those diseases.

Candida vulvovaginitis

Table 24.1  Candida albicans and C. tropicalis Vaginitis

Table 24.2  Non-albicans Candida Vaginitis

Diagnosis

Diagnosis

Pruritus in setting of vestibular erythema, sometimes vulvar edema

Introital burning, irritation, very often asymptomatic

Often clumped, white vaginal secretions Wet mount showing mycelia and budding yeast

No discharge Wet mount showing budding yeast without mycelia Confirmed by culture in order to type

May be confirmed by culture when atypical, recurrent, or resistant

Differential Diagnosis

Differential Diagnosis

All other causes of vaginitis, most often desquamative inflammatory vaginitis

All other causes of vaginitis; statistically most often ­Trichomonas, bacterial vaginosis

Vestibulodynia (vulvar vestibulitis)

Physiologic discharge

Management

Vulvodynia/vestibulodynia (vulvar vestibulitis) Management

A standard trial of any therapy for Candida albicans can be given, but expect nonresponse and re-evaluate for response to therapy. Then:

Topical

Topical

Any azole cream or tablet/suppository inserted into ­vagina according to package insert (miconazole, ­clotrimazole, terconazole, tioconoazole, butconazole)

Boric acid capsulesa 600 mg, inserted in vagina at bedtime; if tolerated, twice daily for 2–4 weeks. When more comfortable, if cure not effected, three times a week to suppress

Nystatin ointment/tablets bid for 1 week

Nystatin ointment/tablets bid for 2–4 weeks; may require ongoing suppressive dosing

Orala Fluconazole Orala150 mg once Itraconazoleb 200 mg once, or daily from 2 to 7 days Terbinafineb 500 mg daily for 1 week Ketoconazoleb,c 200 mg daily for 5 days aMedication

interactions can occur with azoles, particularly ketoconazole.

Flucytosine 500 mg capsules, #14 dissolved in 45 grams of hydrophilic base, 6.4 g inserted daily until gone Amphotericina 50 mg compounded vaginal suppositories inserted qd for 2 weeks Amphotericin/flucytosinea inserted daily

bNot approved by the Food and Drug Administration for vaginal candidiasis. cKetoconazole

has been associated with idiosyncratic hepatotoxicity.

Pathogenesis Yeast vaginitis is most often produced by C. albicans, but non-albicans Candida infections are increasingly common. These include C. tropicalis, C. glabrata, Saccharomyces cerevisiae, C. parapsilosis, C. krusei, as well as other Candida species. C. albicans and C. tropicalis produce mycelia and invade the upper layers of the epithelium, provoking an inflammatory response. Other non­albicans Candida species do not exhibit mycelia, are characterized by budding yeast which attach to

Systemic Any oral antifungal can be tried, including in ­combination with topical therapy. Several new ­antifungal medications show greater in vitro effects against non-albicans Candida species, but none has cleared a patient in this author’s office In extraordinary circumstances, intravenous ­amphotericin B can be used and sometimes cures ­infection aNot approved by the Food and Drug Administration for vaginal ­candidiasis.

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Figure 24.3  A wet mount of Candida albicans and C. tropicalis shows branching hyphae and budding yeast.

the surface epithelium, and incite inflammation. C. tropicalis closely resembles C. albicans in morphology and response to therapy, and for practical purposes does not require differentiation from this common yeast.

Laboratory abnormalities and histology There are no laboratory abnormalities except for cultures which show the offending organisms, and microscopic preparations showing hyphae, pseudohyphae, and budding yeast in the vaginal fluid of women with most infections (Figures 24.3 and 24.4). About 15% of yeast infections show only budding yeast that represent non-albicans Candida. Biopsies show hyphae and pseudohyphae invading upper layers of the epidermis in the case of C. albicans and C. tropicalis. Neutrophils are frequently noted within the epidermis, particularly the upper epidermis.

Management and prognosis Vaginitis produced by C. albicans and C. ­tropicalis can be cleared with any of a large group of oral or topical medications. Patients with fairly ­remarkable inflammatory changes of the skin of the vulva may benefit from oral medication such as fluconazole 150 mg to avoid immediate burning sideeffects of topical azole cream preparations. This author supplements oral fluconazole with very soothing nystatin ointment applied three or four times a day for women with more than ­ introital

Figure 24.4  Non-albicans yeast infections produce only budding yeast, best seen with the 40× objective. These “bowling pins” are characteristic of Candida glabrata.

vulvar ­ involvement. In addition to ­ fluconazole, ­itraconazole and ketoconazole are oral medications that have been used for vulvovaginal candidiasis. Terbinafine is a medication available orally and topically and shown to have some anticandidal effect, but it appears somewhat less effective and it does not have US Food and Drug Agency approval for candidiasis3. Although the treatment of C. albicans is quite easy, with all standard therapies being effective in immunocompetent patients, several issues complicate therapy and predispose to ongoing symptoms. First, recurrent candidiasis is a problem in a significant minority of patients. These patients benefit from chronic suppression with weekly fluconazole 150 mg for several months, which often breaks the cycle4. The use of lactobacillus supplementation has not been shown to be beneficial in the prevention of recurrent yeast infections5. Second, many women have a concomitant process such as lichen simplex chronicus, accounting for much of the symptoms of itching. Third, non-albicans Candida vaginitis can sometimes be extremely resistant to treatment, with patients often responding poorly to azoles. C. krusei is routinely resistant to fluconazole. C. glabrata, the most common species of non-albicans Candida, is often resistant to azoles. Medications that have been used for non-­albicans Candida include boric acid, nystatin, ­flucytosine,

Bacterial vaginosis

and amphotericin6–8. Sometimes, the use of ­combination or prolonged therapy is required, and sometimes patients never clear, but ongoing twice- or thrice-weekly dosing allows patients to be comfortable despite lack of cure. Fourth, resistant C. albicans is certainly recognized in immunosuppressed patients with Candida vaginitis.

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Bacterial vaginosis (nonspecific vaginitis, haemophilus vaginitis, gardnerella vaginalis vaginitis, anaerobic vaginitis) Bacterial vaginosis is an imbalance of the vaginal flora that results in a vaginal discharge and odor.

Epidemiology and clinical manifestations Bacterial vaginosis occurs primarily in premenopausal sexually active women. It is common, occurring in 29% of women between the ages of 14 and 49 years9. Patients present with a complaint of increased vaginal secretions and odor. Most report a fishy odor that is most pronounced after exposure to alkaline semen. Occasionally, women experience introital itching or irritation. The vulva is nearly normal to inspection without increased redness of the modified mucous membranes of the vulva or of the vagina. Vaginal secretions are classically white and increased in volume. When potassium hydroxide is added to a microscope slide with a drop of vaginal secretions, a distinct fishy odor is released (positive whiff test). A microscopic examination of a wet mount of secretions shows no increase in white blood cells (hence the term “vaginosis” rather than “vaginitis” to indicate the noninflammatory nature of bacterial vaginosis). A wet mount also shows mature epithelial cells and “clue” cells. Clue cells are epithelial cells that are stippled with bacteria so that the cells appear granular, and the borders of the cells are ragged and indistinct due to adherent bacteria (Figure 24.5). Lactobacilli are absent, so the vaginal pH is more alkaline, greater than 4.5. The guidelines from the Centers for Disease Control dictate that the diagnosis of bacterial vaginosis is made by the presence of at least three of the following: white, homogeneous, noninflammatory vaginal secretions; the presence of clue cells; a pH of vaginal secretions of greater than

Figure 24.5  A predominance of clue cells, where cells are stippled with bacteria so that the borders are ragged, is pathognomonic of bacterial vaginosis. This diagnosis also requires an absence of lactobacilli and an absence of inflammatory cells.

4.5; and a fishy odor of secretions in the presence of an alkali such as potassium hydroxide9a.

Diagnosis and differential diagnosis Patients sometimes confuse any other cause of vaginitis, particularly Trichomonas or Candida, with bacterial vaginosis (Table 24.3). However, the criteria of clue cells, fishy odor, and lack of neutrophils for bacterial vaginosis do not show overlap with any other causes of vaginitis. Bacterial vaginitis also presents with an increased volume and high pH of secretions, and two possible forms of vaginosis, cytolytic vaginosis and lactobacillus vaginosis, also cause an increase in vaginal secretions, but exhibit increased lactobacilli and an acid pH.

Pathogenesis Bacterial vaginosis is associated with a shift in the population of normal vaginal flora. Lactobacilli, those bacteria normally present that produce hydrogen peroxide, are decreased, with a corresponding dramatic increase in Mobiluncus spp., Gardnerella vaginalis, Mycoplasma hominis, anaerobic Gramnegative bacilli of Prevotella genera, Porphyromonas, Bacteroides, and Peptostreptococcus spp. This population releases amines in the presence of a base (such as ­potassium ­hydroxide or semen), producing the characteristic fishy odor. The underlying cause of this imbalance of normal bacterial flora is not known. This is not

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Table 24.3  Bacterial Vaginosis Diagnosis Vaginal discharge pH greater than 5 Microscopic examination showing: Clue cells Absent lactobacilli No increase in white blood cells F ishy odor of secretions in the presence of an alkaline substance Differential Diagnosis All other causes of vaginitis Management (Center for Disease Control guidelines 2006) Metronidazole 500 mg bid for 7 days Metronidazole .075% gel 5 g daily for 5 days Clindamycin cream 2% 5 g daily for 7 days Clindamycin 300 mg po bid for 7 days Clindamycin 100 g ovules hs for 3 days

a sexually transmitted disease, and treatment of the partner is not useful. However, sexual activity appears to be a factor, and any condition that decreases lactobacilli appears to predispose to this condition.

Laboratory abnormalities and histology There are no laboratory abnormalities outside the abnormal wet mount and pH value. Cultures notoriously tend to be false-positive, since the involved bacteria are often part of normal vaginal flora. There are other rapid diagnostic tests available, such as the Affirm VPIII microbial identification test. Biopsies are not performed for this condition.

Management and prognosis Bacterial vaginosis can be treated in a number of ways. Oral and topical metronidazole and clindamycin are standard therapies.

Generally, clearing bacterial vaginosis is relatively easy. However, recurrent disease develops in about 30% of patients. Those patients who experience recurrent disease can be treated for a more prolonged period of time, sometimes minimizing recurrence10. Treatment of partners does not prevent recurrence. Bacterial vaginosis has no medical ramifications for the patient herself other than annoyance. However, the presence of bacterial vaginosis during pregnancy predisposes to premature labor.

Trichomonas Trichomonas is a sexually transmitted parasitic vaginitis which causes a copious discharge and, usually, intense irritation and itching.

Epidemiology and clinical manifestations Trichomonas vaginitis occurs only in sexually active patients. Like other sexually transmitted diseases, it is found most often in patients with multiple sexual partners, and it has been called the most common sexually transmitted infection. Generally, patients describe introital irritation and itching, sometimes with associated burning. Mild disease may produce no symptoms. An examination of the vulva shows erythema and edema of the modified mucous membranes, particularly the vestibule. Likewise, the vaginal epithelium shows erythema, and vaginal secretions are classically frothy and yellow/green. The cervix in particular shows redness, and classically this is perceived as a “strawberry cervix,” because the surface of the cervix is covered with monomorphous, equidistant small deep-red papules. The diagnosis is made by the wet mount or, sometimes, culture. The wet mount shows nonspecific findings of increased neutrophils and immature epithelial cells, and pathognomonic small (about the size of a lymphocyte) oval flagellate organisms can be seen rapidly swimming through the secretions. The organisms are extremely sensitive to cold and desiccation, so the secretions should be examined immediately. Polymerase chain reaction technique can be used for diagnosis as well.

Bacterial vaginitis

Diagnosis and differential diagnosis The differential diagnosis of Trichomonas includes all causes of vaginitis, particularly inflammatory vaginitis (Table 24.4). DIV, atrophic vaginitis, and bacterial vaginitis with their associated redness and purulent secretions commonly mimic Trichomonas vaginitis. Occasionally, severe Candida vaginitis also exhibits deep erythema and inflammatory cells in vaginal fluid. Milder forms of Trichomonas certainly occur, and can be confused with other forms of vaginitis.

Laboratory abnormalities and histology

Table 24.4  Trichomonas Vaginitis Diagnosis Introital itching and burning, but sometimes ­asymptomatic Vulvar erythema and edema are common Grossly purulent vaginal secretions with a pH greater than 5 Microscopic examination showing: Large numbers of neutrophils Mobile, flagellate trichomonads

Other than the abnormal wet mount described above and cultures showing T. vaginalis, there are no laboratory abnormalities. Biopsies are not performed for this entity.

Absent lactobacilli

Pathogenesis

All other causes of vaginitis, particularly inflammatory vaginitis of desquamative inflammatory vaginitis, bacterial vaginitis, and atrophic vaginitis

Trichomonas vaginitis results from the sexual transmission of the organism T. vaginalis. This one-cell flagellate organism prompts a marked inflammatory response.

Management and prognosis Trichomoniasis is treated with the 5-nitroimidazole medications, most often metronidazole or tinidazole. Because the organism is harbored in the relatively inaccessible paraurethral and Bartholin glands, topical therapy does not provide adequate clearing, so that oral medication is required. Low-level resistance of Trichomonas is common and can be treated with higher or more prolonged dosing11. Those patients with rare high-level drug-resistant Trichomonas or allergy to the 5-nitroimidazole medications may respond to furazolidone, and topical paromomycin in a hdydrophilic cream may control disease in the vagina, but can be extremely irritating. In addition, an allergist can be consulted to institute a desensitization protocol for metronidazole. Trichomonas is associated with higher transmission rates for human immunodeficiency virus infection. Also, the presence of trichomoniasis is associated with premature rupture of membranes, premature delivery, and low birth weight, but treatment of the infection does not ­necessarily prevent

Sometimes, culture or polymerase chain reaction Differential Diagnosis

Management Metronidazole 2 g once, or 500 mg bid for 7 days Tinidazole 2 g once

these complications. Treatment does, however, prevent neonatal genital and respiratory infection, and metronidazole is a pregnancy category B medication.

Bacterial vaginitis Although less common than bacterial vaginosis, bacterial vaginitis produces symptoms of irritation, itching, and clinical inflammation12.

Epidemiology and clinical manifestations Bacterial vaginitis occurs in all age groups. Prepubertal girls and postmenopausal women not on estrogen replacement are at risk because of thin, fragile epithelium that is easily eroded with minor trauma. Other risk factors include a foreign body (from retained toilet paper or tampon, to hairpins, sticks, or toys) or a primary erosive vaginal dermatosis, such as lichen planus. In addition,

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Figure 24.7  A wet mount of vaginal fluid of a woman with bacterial vaginitis shows immature epithelial cells, absent lactobacilli, and multiple neutrophils.

Diagnosis and differential diagnosis

Figure 24.6  The inflammatory vaginal secretions of bacterial vaginitis often irritate or infect the modified mucous membranes of the vulva, producing redness and edema.

a significant proportion of otherwise healthy premenopausal women sometimes develop bacterial vaginitis, especially that associated with group B streptococcus (GBS). Although almost always a colonizer, GBS on occasion causes symptomatic vaginitis or otherwise induces inflammation13,14. Patients usually present with descriptions of vulvovaginal irritation, burning, dyspareunia and, less often, itching. Often, they also complain of discharge. The vulva, often only the vestibule, is erythematous, as is the vaginal epithelium. Occasionally, the entire vulva shows redness, scale, and even crusting (Figure 24.6). Yellow, occasionally green, vaginal secretions are sometimes visible at the introitus. Microscopically, a wet mount shows a dramatic increase in neutrophils, immature epithelial cells, and a lack of lactobacilli (Figure 24.7). Sometimes organisms are visible, particularly chains of cocci. There are no constitutional symptoms or signs; there is no fever, abdominal pain, or malaise.

The differential diagnosis includes all causes of vaginitis, but especially those inflammatory ­vaginitides such as atrophic vaginitis, Trichomonas vaginitis, and DIV, all of which produce identical symptoms and clinically and microscopically purulent vaginal secretions (Table 24.5). The increased volume of secretions suggests a diagnosis of bacterial vaginosis or a physiologic discharge. As usual, Candida should also be eliminated as a potential cause.

Pathogenesis Bacterial vaginitis is an inflammatory response to a specific organism. This is not generally a sexually transmitted disease, and there are several organisms which produce bacterial vaginitis. The most common bacteria are GBS, alpha-hemolytic streptococcus, Staphylococcus aureus, and Escherichia coli.12–16 A positive culture for an organism does not make the diagnosis. Because of the wellknown mixed vaginal flora, any disruption in this population sometimes allows cultures that yield coincidental organisms that are not pathogens, or are not producing symptoms.15 Therefore, associated inflammation as well as a complete response to antibiotic therapy are required to confirm this diagnosis and the pathogenesis. In a prepubertal girl, the most common pathogen is alpha-hemolytic streptococcus, often associated with perianal streptococcal dermatitis

Cytolytic vaginosis

Table 24.5  Bacterial Vaginitis Diagnosis Introital itching and burning, dyspareunia Vestibular erythema and edema Grossly purulent vaginal secretions with a pH greater than 5 Microscopic examination showing: Large numbers of neutrophils Increase in parabasal cells Absent lactobacilli Culture showing organism Complete and prompt response to therapy

antibiotic therapy should be prompt. However, those with underlying issues such as atrophic vaginitis or erosive vaginitis of lichen planus usually remain symptomatic until the underlying factors are corrected. The antibiotic therapy depends upon the organism. GBS can be treated with penicillin V potassium, amoxicillin, ampicillin, and clindamycin, as well as other antibiotics. Topical clindamycin can be very useful. Unfortunately, GBS tends to recur almost immediately after cessation of therapy. If symptoms recur, many women benefit from more prolonged therapy, sometimes as long as several months. Most women with GBS vaginitis do not have specific underlying factors or triggers, so that additional therapy is not ­usually required.

Differential Diagnosis All other causes of vaginitis, particularly ­inflammatory vaginitis of desquamative inflammatory vaginitis, ­Trichomonas vaginitis, and atrophic vaginitis Management Oral or topical antibiotic according to culture. Group B streptococcal vaginitis may require prolonged therapy due to its usual tendency to recur immediately upon ­cessation of antibiotic.

(see p. 331). Otherwise, the most common cause is GBS, but, again, this should not be confused with colonization. Bacterial vaginitis often occurs in a setting of a foreign body, estrogen deficiency, or an erosive vaginitis such as lichen planus.

Laboratory abnormalities and histology The only laboratory abnormalities are cultures revealing the causative organism, and a wet mount showing abundant neutrophils, immature epithelial cells, and absent lactobacilli. The underlying organism is sometimes seen on Gram stain. A biopsy is not performed.

Management and prognosis The treatment of bacterial vaginitis consists of antibiotic therapy directed to the specific organism, and elimination of any underlying ­ predisposing condition, such as atrophic vaginitis. Response to

Lactobacillus vaginosis Lactobacillus vaginosis is a controversial condition consisting of an overgrowth of lactobacilli. First described by Horowitz et al., there have been no confirmatory studies17. Patients present with signs and symptoms similar to that of vulvovaginal candidiasis, including itching, irritation, and a cottage-cheese discharge. Wet mounts and cultures show no inflammation or yeast, but rather long filaments previously and erroneously termed “leptothrix,” which instead represent lactobacilli that have attached end to end (Figure 24.8). This condition has been postulated to occur as a result of overtreatment for yeast, and it clears with antibiotics, including doxycycline, Augmentin, and ciprofloxacin.

Cytolytic vaginosis Another controversial vaginosis produced by lactobacilli is cytolytic vaginosis. Reported by Cibley and Cibley in 1991, there have been several corroborative reports18,18a. A recent report of 2947 smears showed 54 that met the criteria of cytolygic vaginosis18. Symptoms include itching, irritation, and discharge, and microscopic findings of vaginal secretions reveal an increase in lactobacilli as well as an increase in “naked nuclei” – epithelial cells stripped of cytoplasm. This finding is best seen under phase microscopy. Management

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Figure 24.8  Lactobacillosis is characterized by a wet mount showing multiple elongated lactobacilli in the absence of signs of inflammation, including no increase in white blood cells or immature epithelial cells.

Figure 24.9  A wet mount of the atrophic vagina generally yields only scant cells, and these are immature. Lactobacilli are absent.

consists of the intermittent or chronic use of baking soda douches to akalinize the vagina.

Most often, an atrophic vagina is asymptomatic, or produces only symptoms of dryness or irritation with intercourse. However, many women with atrophic vaginitis describe irritation, dyspareunia, burning, and/or a sensation of rawness and extreme dryness. Some women complain of a purulent vaginal discharge and odor. An atrophic vagina simply appears pale, dry, and smooth, lacking normal rugae. Atrophic vaginitis is recognized by red epithelium, ­varying degrees of dryness, and a grossly purulent ­vaginal discharge. Some women have a rectocele or cystocele that bulges the thinned and fragile vaginal wall, so that friction produces ­ superficial erosions resulting in secondary inflammation. Other women experience vulvar fissures and ­erosions as a result of sexual activity in the setting of thin, poorly lubricated vulvovaginal skin. Microscopically, the vaginal secretions of an atrophic vagina simply show parabasal cells and a marked decrease in bacteria, particularly lactobacilli (Figure 24.9). However, the vaginal secretions of atrophic vaginitis are identical to those of DIV, lichen planus and bacterial vaginitis, showing immature epithelial cells (basal cells and parabasal cells), an increase in white blood cells, and a lack of lactobacilli (Figure 24.10). Some women exhibit increased background bacteria due to secondary infection. Yeast is almost never seen, nor is bacterial vaginosis.

Atrophic vaginitis Atrophic vaginitis has become far more common during the last few years, since the safety and efficacy of systemic estrogen therapy have been seriously questioned and its use has decreased. An atrophic vagina differs from atrophic vaginitis, in that atrophic vaginitis is characterized by inflammation, not simply by thinning and dryness.

Epidemiology and clinical manifestations Atrophic vaginitis occurs in women who are estrogen-deficient. Most often, this represents women who are several years postmenopausal and not using estrogen replacement therapy of any kind. However, pregnancy, especially followed by breastfeeding, produces an atrophic vagina as well. Prepubertal girls have very low estrogen levels and resulting atrophic vaginas. Mildly atrophic vaginas can occur with some oral contraceptives, and data suggest that some women have abnormalities of estrogen receptors, resulting in mildly atrophic changes even in the face of normal estrogen levels. Vaginal atrophy on the basis of low estrogen is worst in women who are not sexually active, since sexual activity tends to prevent an atrophic vagina.

Atrophic vaginitis

Table 24.6  Atrophic Vaginitis Diagnosis Setting of low or absent estrogen Symptoms of introital irritation, dryness, and dyspareunia Vaginal redness Grossly purulent vaginal secretions with a pH greater than 5 Microscopic examination showing: Figure 24.10  Atrophic vaginitis is manifested on a wet mount with an abundance of inflammatory cells, multiple immature epithelial cells, and absent lactobacilli. This wet mount is indistinguishable from those of bacterial vaginitis and desquamative inflammatory vaginitis, and differention among these diseases is made by setting, culture, and response to therapy.

Large numbers of neutrophils Increase in parabasal cells Absent lactobacilli Negative culture or lack of response to antibiotic Complete and prompt response to therapy

Diagnosis and differential diagnosis The differential diagnosis of atrophic vaginitis includes DIV, bacterial vaginitis, and Trichomonas vaginitis, all of which are characterized by redness, microscopically and grossly purulent vaginal secretions, immature epithelial cells, and a lack of lactobacilli (Table 24.6).

Pathogenesis Underlying the thinning and dryness of an ­atrophic vagina is a lack of estrogen, which occurs at parturition, with breastfeeding, and following natural or surgical menopause. The inflammation can occur as a result of superficial erosions from sexual activity, or a cystocele or rectocele, and, sometimes, superimposed secondary infection.

Laboratory abnormalities and histology Laboratory abnormalities are limited to low ­levels of estrogen and the wet mounts noted above. Biopsies are not performed, but histology shows extreme thinning of the vaginal epithelium to three or four cell layers, with a lack of maturation and flattening of the squamous epithelium. Acute and chronic inflammation and spongiosis may occur.

Differential Diagnosis All other causes of vaginitis, particularly inflammatory vaginitis of desquamative inflammatory vaginitis, erosive lichen planus, T­ richomonas vaginitis, and bacterial vaginitis Management Estradiol or conjugated estrogen cream, 1 g in vagina three nights a week, or Estradiol vaginal tablet, one in vagina three nights a week, or Estradiol vaginal ring inserted every 3 months by patient or clinician, or Systemic replacement by oral or patch can be used

Therapy and prognosis The response to treatment of atrophic vaginitis is prompt and rewarding. This can be achieved topically with 1 g estradiol (the less irritating) or conjugated estrogen cream inserted three nights a week. Those who experience irritation or burning with creams can be treated with estradiol vaginal tablets three nights a week, or an extended-release estradiol ring (Estring), although insertion can be uncomfortable until the underlying process is controlled.

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Systemic estrogen replacement therapy is also beneficial, but slower, and is accompanied by both benefits and risks of systemic therapy. When estrogen is replaced, the risk of vaginal candidiasis increases significantly, particularly in the first month or two of therapy. This can be prevented with weekly fluconazole 150 mg, or the patient can be advised of this possibility so that she can either be evaluated or self-treat immediately at the onset of introital itching. Clearly, if estrogen is stopped, vaginal atrophy recurs. However, inflammation may not recur without a precipitating event, and some patients remain comfortable with estrogen, or with intermittent dosing. Most women who are sexually active are more comfortable with ongoing topical estrogen therapy.

Desquamative inflammatory vaginitis DIV is a presumably noninfectious but inflammatory disorder of the vaginal epithelium. It is characterized by vaginal redness and purulent vaginal secretions in the setting of negative cultures. This condition may either exist on a spectrum of mild to severe, or it possibly represents several similar diseases.

Epidemiology and clinical manifestations This is an uncomfortable but benign condition that occurs in all postpubertal age groups, and is often recognized in premenopausal women. The incidence of DIV has been said to be rare, but those who specifically evaluate symptomatic patients for this condition find it to be relatively common, especially in a mild form. It has been recognized most often in white patients, and there are no known associations with other diseases19. DIV is characterized by introital irritation, burning, and soreness, with associated superficial dyspareunia. Occasionally, women describe itching. On examination, the vestibule is usually red, and more severe cases are accompanied by redness and puffiness of all of the modified mucous membranes (Figure 24.11). The modified mucous membranes sometimes appear glazed or dull, and fissuring of skin folds is relatively common.

Figure 24.11  Edema and erythema of the modified mucous membranes are characteristic of desquamative inflammatory vaginitis.

The vaginal epithelium is also red, sometimes with multiple, monomorphous, bright-red 1–2 mm macules or papules similar to those classically found on a “strawberry” cervix in a setting of trichomoniasis (Figures 24.12 and 24.13). Vaginal secretions are usually yellow or yellow-green, and often copious. Vaginal secretions show an alkaline pH, greater than 5. Microscopically, a wet mount shows multiple neutrophils. There are large numbers of immature epithelial cells as well, and no lactobacilli (Figure 24.14). Often, cocci are present. Candidiasis in this setting of inflammatory vaginitis is uncommon.

Pathogenesis The cause of DIV is unknown. Some clinicians theorize that it is not a specific disease, but rather a common clinical picture found with any erosive mucosal dermatosis affecting the vagina, particularly lichen planus.

Desquamative inflammatory vaginitis 313

Figure 24.14  The wet mount of desquamative inflammatory vaginitis is indistinguishable from that of atrophic vaginitis and bacterial vaginitis, showing multiple white blood cells, immature epithelial cells, and no lactobacilli.

Figure 24.12  This diffuse redness of the vaginal ­epithelium, with yellowish vaginal secretions, is typical of desquamative inflammatory vaginitis.

Figure 24.13  At times, small, monomorphous red macules on the vaginal wall are seen in women with desquamative inflammatory vaginitis.

Diagnosis and differential diagnosis The clinical presentation of DIV is indistinguishable from that of atrophic vaginitis and bacterial vaginitis, both of which present with vaginal and vestibular erythema and grossly

and ­ microscopically purulent vaginal secretions (Table 24.7). These are differentiated by a history consistent with low estrogen or an abnormal bacterial culture, followed by response to therapy. Any erosive skin disease that can involve the muc­ ous membranes, including cicatricial pemphigoid, pemphigus vulgaris, and, most often, lichen planus, can resemble DIV. These diseases also produce erythema of the vestibule and vagina, as well as inflammatory vaginal secretions. However, these diseases generally produce specific erosions, and nearly always involve other mucous membranes such as the mouth, perianal skin, or eyes. Trichomonas produces a clinical picture identical to DIV except for the presence of Trichomonas within vaginal fluid. To the casual observer, all other forms of vaginitis enter the differential diagnosis, but the lack of inflammation and presence of yeast or clue cells on wet mount should easily differentiate these diseases.

Laboratory manifestations and histology There are no laboratory abnormalities associated with DIV except for the characteristic wet mount showing an increase in white blood cells, immature epithelial cells, and an absence of lactobacilli. These patients may have an increased prevalence of cultures positive for GBS, although they do not respond to oral antibiotics, suggesting no causal relationship19.

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Table 24.7  Desquamative Inflammatory Vaginitis Diagnosis Introital irritation and dyspareunia, often vulvar fissuring with sexual activity Erythema of vestibule Vaginal erythema, sometimes small red macules Grossly purulent vaginal secretions with a pH greater than 5 Microscopic examination showing: Large numbers of neutrophils Increase in parabasal cells Absent lactobacilli Negative culture or lack of response to oral antibiotic Adequate estrogen Differential Diagnosis All other causes of vaginitis, particularly inflammatory vaginitis of atrophic vaginitis, Trichomonas vaginitis, ­erosive lichen planus, and bacterial vaginitis Management Clindamycin cream 2% inserted nightly for 2–4 weeks, then used intermittently or in an ongoing, suppressive dose tapered to the least frequent dosing required for control Hydrocortisone acetate rectal suppositories 25 mg per vaginam nightly, tapering frequency when possible. Higher potency can be used, including 500 mg ­com­pounded suppository, or ultrapotent ointment such as clobetasol Clindamycin cream and topical corticosteroid inserted together nightly, and tapered when possible Cover with fluconzaole 150 mg weekly to prevent yeast, especially with antibiotic/corticosteroid combination

There have been few biopsies performed of DIV. This author performed biopsies of 11 patients who met criteria for DIV. This showed two patterns of inflammation: mild to moderate lichenoid inflammation without specific changes of lichen planus, and spongiosis with a mixed inflammatory infiltrate with lymphocytes, eosinophils, and plasma

cells. There were no specific findings on direct immunofluorescence20.

Therapy and prognosis DIV, as an inflammatory but not infectious disease, responds to the anti-inflammatory effects of antibiotics and to corticosteroids. First-line therapy for DIV is intravaginal clindamycin cream 2%21. Approximately 5 g is inserted nightly. In this setting, clindamycin is effective primarily for its anti-inflammatory effects rather than its antimicrobial effects. Because clindamycin is not treating infection in this disease, the time to improvement is generally several weeks. In addition, relapse is common when the medication is discontinued. Some patients benefit from weekly fluconazole to eliminate the risk of secondary candidiasis during initiation of therapy. This author treats patients for 1 month, with re-evaluation in the office at that time. Patients are instructed to discontinue vaginal cream 3–4 days prior to the visit to avoid the presence of cream in vaginal secretions which can obscure findings. Those patients who respond well can decrease frequency of insertion of clindamycin cream, with gradual tapering to the least frequent dosing that controls the signs and symptoms of the disease. An occasional patient can discontinue medication altogether with rare to no recurrences. Some patients do not experience clearing of vaginal secretions with clindamycin cream. Second-line therapy consists of an intravaginal topical corticosteroid. There are no corticosteroid ­preparations approved by the Food and Drug Administration for vaginal use. Formulations that can be tried off-label include hydrocortisone acetate rectal suppositories 25 mg inserted into the vagina nightly, a compounded hydrocortisone 500 mg suppository, or even the use of any corticosteroid ointment inserted with an applicator. This author often uses clobetasol ointment initially, because this is the most potent topical corticosteroid available, and serves as a rapid indicator of corticosteroid-responsiveness in these patients. Frequency of application is tapered when possible to avoid significant systemic absorption, which is much greater in the vagina than on the vulva. Again, fluconazole 150 mg weekly minimizes the

Discharge and odor

risk of candidiasis in this artificially immunosuppressed environment. Patients who do not respond to topical corticosteroids can be treated with a combination of clindamycin cream and a corticosteroid ointment daily. There are no medically significant sequelae of DIV. Unlike lichen planus and cicatricial pemphigoid, there is no scarring, and no risk of secondary squamous cell carcinoma. The sequelae are psychological, with chronic pain and dyspareunia taking their own toll on patients.

Inflammatory vaginitis on the basis of specific mucosal erosive dermatoses (see chapter 20) Any dermatosis which affects mucous membranes, particularly erosive and blistering diseases, can cause an inflammatory vaginitis. Signs and symptoms are identical to DIV, except that the vagina is more likely to show specific erosions, and vulvar and oral lesions are usual. Occasionally, nonmucous membrane disease is also evident. Those rare patients with autoimmune blistering disorders are more likely to show intact extragenital blisters, whereas lichen planus usually shows no associated skin lesions. Diseases that cause erosive vaginitis include lichen planus, by far the most common cause, as well as cicatricial pemphigoid and pemphigus vulgaris (Figure 24.15). Sudden onset of vaginal erosions includes erythema multiforme, a fixed drug eruption, and pemphigus vulgaris. Estrogen deficiency and bacterial vaginitis can be identical but are differentiated by the setting and negative cultures. Finally, DIV can resemble erosive vaginitis, but specific erosions are not seen, rather than just diffuse redness. The diagnosis is made by the identification of lesions that are characteristic of lichen planus, ­ cicatricial pemphigoid, or pemphigus vulgaris. Often, a routine biopsy from the edge of an ­ erosion shows characteristic findings of one of these ­ diseases. Cicatricial pemphigoid and ­pemphigus vulgaris can often be confirmed by characteristic direct immunofluorescence findings in perilesional skin.

315

Figure 24.15  Those erosive diseases that affect the vaginitis generally produce true erosions that are often discrete, rather than diffuse redness, as is seen in this woman with lichen planus.

The treatment and prognosis of these diseases depend upon the etiology. The specific diseases can be found in Chapter 15 (lichen planus) and Chapter 20 (pustules, vesicles, bullae and erosions).

Physiologic discharge Heavy discharge, sometimes associated with the patient’s perception of odor, in the absence of objective clinical abnormalities is a relatively common complaint. Generally there is no associated itching, irritation, or dyspareunia. The physical examination is either normal or shows copious but otherwise normal vaginal secretions. Odor is unremarkable, and wet mounts are normal, showing no yeast, no clue cells, mature squamous epithelial cells, and normal vaginal flora. Cultures are normal. As this is not a disease, there is no satisfactory treatment. Some patients are reassured by explanations, but others are disbelieving and continue to search for an infectious cause.

Discharge and odor Some women complain of discharge and odor in the absence of bacterial vaginosis, and in the absence of abnormal odor or discharge detected in the office. This can be a manifestation of body dysmorphic disorder, and the patient is tearful, perceives that others are offended by odor, and

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she cannot be reassured. This is a psychological disorder rather than an infectious condition or a dermatosis. Other women have odor, and sometimes even wetness, of skin origin. The use of antiperspirants and deodorants can be useful.

Vestibulodynia (vulvar vestibulitis) Vestibulodynia does not represent vaginitis or vaginosis, but rather a pain syndrome often misdiagnosed by both patients and clinicians as vaginitis. The introital burning and symptoms of irritation are mistaken for vaginal candidiasis or bacterial vaginosis, because of the frequency of these infections and ease of treatment. However, wet mounts showing no yeast (or confirmatory cultures in patients with apparent yeast who do not respond to therapy) or clue cells rule out those diagnoses. Also, atrophic vaginitis and DIV are superficially indistinguishable if only a vulvar examination is performed. The absence of immature epithelial cells and increased white cells on a microscopic examination of vaginal fluid rule out DIV and atrophic vaginitis.

References   1. Pirotta, M. V. and Garland, S.M. Genital Candida species detected in samples from women in Melbourne, Australia, before and after treatment with antibiotics. J. Clin. Microbiol. 2006; 44: 3213–3217.   2. Banerjee, K., Curtis, E., de San Lazaro, G., et al. Low prevalence of genital candidiasis in children. Eur. J. Clin. Microbiol. Infect. Dis. 2004; 23: 696–698.   3. Ferahbas, A., Koc, A. N., Uksal, U., et al. Terbinafine versus Easter cause all and fluconazole and the treatment of vulvovaginal candidiasis. Am. J. Ther. 2006; 13: 332–336.   4. Sobel, J. D., Wiesenfeld, H. C., Martens, M., et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N. Engl. J. Med. 2004; 351: 876–883.   5. Falagas, M. E., Betsi, G. I., and Athanasiou, S. Probiotics for prevention of recurrent vulvovaginal candidiasis: a review. J. Antimicrob. Chemother. 2006; 58: 1266–1272.   6. Phillips, A. J. Treatment of nonalbicans Candida vaginitis with amphotericin B vaginal suppositories. Am. J. Obstet. Gynecol. 2005; 192: 2009–2012.   7. Ray, D., Goswami, R., Banerjee, J., et al. Prevalence of Candida glabrata and its response to boric acid vaginal suppositories in comparison with oral fluconazole in patients with diabetes and vulvovaginal candidiasis. Diabetes Care 2007; 30: 312–317.   8. Sobel, J. D., Chaim, W., Nagappan, V., et al. Treatment of vaginitis caused by Candida glabrata: use of topical boric acid and flucytosine. Am. J. Obstet. Gynecol. 2003; 189: 1297–1300.   9. Allsworth, J. E. and Peipert, J. F. Prevalence of bacterial vaginosis: 2001–2004 National Health and Nutrition Examination Survey data. Obstet. Gynecol. 2007; 109: 114–120.

9a. STD Treatment Guidelines, from the website of the Centers for Disease Control and Prevention. Online. Available: http://www. cdc.gov/std/treatment/default.htm. 10. Sobel, J. D., Ferris, D., Schwebke, D. J., et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am. J. Obstet. Gynecol. 2006; 194: 1283–1289. 11. Dunne, R. L., Dunn, L. A., Upcroft, P., et al. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis. Cell Res. 2003; 13: 239–249. 12. Donders, G. G.G., Vereecken, A., Bosmans, E., et al. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. Br. J. Obstet. Gynaecol. 2002; 109: 34–43. 13. Clark, L. R. and Atendido, M. Group B streptococcus vaginitis in post pubertal adolescent girls. J. Adolesc. Health 2005; 36: 437–440. 14. Honig, E., Mouton, J. W., and van der Meijden, W. I. Can group B streptococci cause symptomatic vaginitis? Infect. Dis. Obstet. Gynecol. 1999; 7: 206–209. 15. Shaw, C., Mason, M., and Scoular, A. Group B streptococcus carriage and vulvovaginal symptoms: causal or casual? A case-controlled study in a GUM clinic population. Sex. Transm. Infect. 2003; 79: 246–248. 16. Sobel, J. D., Funaro, D., and Kaplan, E. L. Recurrent group A streptococcal vulvovaginitis in adult women: family epidemiology. Clin. Infect. Dis. 2007; 44: e43–e45. 17. Horowitz, B. J., Mardh, P. A., Nagy, E., et al. Vaginal lactobacillosis. Am. J. Obstet. Gynecol. 1994; 170: 857–861. 18. Demirezen, S. Cytolytic vaginosis: examination of 2947 vaginal smears. Cent. Eur. J. Public Health 2003; 11: 23–24. 18a. Cibley, L. J. Cytolytic vaginosis. Obstet. Gynecol. 1991; 165: 1245–1249. 19. Newbern, E. C., Foxman, B., Leaman, D., et al. Desquamative inflammatory vaginitis: an exploratory case-control study. Ann. Epidemiol. 2002; 12: 346–352. 20. Murphy, R. and Edwards, L. Desquamative inflammatory vaginitis: What is it? J. Reprod. Med. 2008; 53: 124–128. 21. Sobel, J. D. Desquamative inflammatory vaginitis: a new subgroup of purulent vaginitis responsive to topical 2% clindamycin cream. Am. J. Obstet. Gynecol. 1994; 171: 15–20.

Further reading ACOG Committee on Practice Bulletins – Gynecology. ACOG Practice Bulletin Clinical management guidelines for obstetriciangynecologists. Obstet. Gynecol. 2006; 107: 1195–1206. Edwards, L. The diagnosis and treatment of infectious vaginitis. Dermatol. Ther. 2004; 17: 102–110. Nyirjesy, P., Peyton, C., Weitz, M. V., et al. Causes of chronic vaginitis. Analysis of a prospective database of affected women. Obstet. Gynecol. 2006; 108: 1185–1191.

Candida vaginitis Ringdahl, E. N. Recurrent vulvovaginal candidiasis. Mol. Med. 2006; 103: 165–168. Spence, D. Candidiasis (vulvovaginal), Clin. Evid. 2004; 12: 2493–2511.

Trichomonas vaginitis Nanda, N., Michel, R. G., Krudgelashvili, G., et al. Trichomoniasis and its treatment. Exp. Rev. Anti Infect. Ther. 2006; 4: 125–135.

PART: II  Gynecologic Dermatology

CHAPTER 25

Vulvar Edema Peter J. Lynch

Edema represents the abnormal presence of fluid deep in the skin and/ or in the subcutaneous tissue. The fluid responsible for edema is either plasma (“angioedema”) or lymph (“lymphedema”). Angioedema occurs as a result of capillary dilation and excess plasma leakage into the surrounding tissue. This generally occurs as part of an acute inflammatory process and, at least in the early stages of the process, it may be transient and episodic. Lymphedema develops when there is interference with the removal of tissue fluid due to absence, destruction, or blockage of lymph flow. When angioedema due to inflammation becomes chronic, lymphatic vessel destruction occurs and there is a gradual developing blend of both angioedema and lymphedema. The clinical manifestations for these two types of edema are very similar. However at the acute end of the spectrum the edema is softer on palpation (“pitting edema”) and more transient in course. At the chronic end of the spectrum, the edema is firmer, sometimes almost to the point where it will not “pit” with fingertip pressure. Otherwise, the appearance of the two forms of edema is remarkably similar and consists of variably sized, skin-colored to slightly red, poorly marginated, smooth-surfaced, slope-shouldered areas of skin swelling. Edema is generally skin-colored rather than red because the depth and amount of fluid obscure any red color that would otherwise be visible due to the vascular dilation that is an inherent part of the pathophysiology. Edema generally develops in sites where there is loose, distensible skin and thus frequently involves the lips, eyelids, and genitalia. Edema is usually asymptomatic, although when distension of the skin occurs acutely, some pain may be noted. If the edema is the result of an allergic process, some itching may be present.

Acute vulvar edema Acute angioedema develops over minutes to hours and lasts one to several days. Resolution is accompanied by a complete return to ­normalappearing skin. Many instances of acute angioedema are due to allergic reactions (medication reactions, contact allergy, etc.) but others

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are not (e.g., hereditary angioedema, edema due to use of angiotensin-converting enzyme inhibitors).

Allergic vulvar edema Angioedema of the vulva regularly occurs as a part of generalized allergic reactions but these patients will not present with the primary complaint of vulvar swelling. Less often, women will develop acute edema localized only to the vulva (Figure 25.1). These patients generally develop their vulvar swelling as a result of an allergic contact reaction. Two such antigens, latex and semen, are of particular importance because they are mediated by immunoglobulin (Ig) E reactions and thus may have the potential to develop anaphylaxis. Patients with reactions to either of these antigens appear to be atopic more frequently than would otherwise be expected.

Latex allergy occurs in about 1% of the general population and up to 4% of health care workers1. This would suggest that there is a large pool of women potentially susceptible to reactions from condoms, diaphragms, and gloved examining fingers. Exact data are lacking regarding the frequency with which vulvar problems arise secondary to latex reactions but the identification of three positive skin test reactions in a group of 92 women investigated for the presence of vulvar contact allergy suggests that this may be a commonly overlooked diagnosis2. Approximately 80 women have been reported to develop reactions to their male partner’s semen3. But this probably underestimates the real prevalence of this condition based on the finding of two positive skin test reactions among 92 women with suspected vulvar allergic reactions2. Many patients develop vulvar edema due to lubricants, spermicides, and medications as part of allergic contact dermatitis. These patients experience a type 4, T-cell-mediated reaction rather than a type 1, IgE-mediated reaction. Thus they develop a much greater degree of inflammation than those with classical IgE-mediated allergic reactions and generally present with an eczematous morphology. Such problems are covered in Chapter 18. Treatment of acute allergic vulvar edema may require the use of systemic antihistamines such as loratidine, hydroxyzine, or diphenhydramine. Prevention of recurrence depends on identifying and removing the cause.

Nonallergic acute vulvar edema Acute vulvar edema also occurs in the setting of multiple vulvovaginal infections, notably that due to candidiasis (Figure 25.2). The development of acute vulvar edema in a patient who has concomitant malaise, fever, and chills may be the earliest sign of impending necrotizing fasciitis and thus represents a medical emergency4.

Chronic vulvar edema Figure 25.1  Remarkable acute allergic edema which ­resolved spontaneously over 2 weeks. (Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 10-14), Churchill Livingstone.)

Chronic vulvar edema can represent a problem as to causation and always represents a problem with therapy. There are several important complications of chronic vulvar lymphedema. ­ Infection in the

Chronic vulvar edema

involved area occurs with appreciable ­ frequency. This is probably due to the fact that the chronic lymphatic blockage seen in lymphedema interferes with the trafficking of Langerhans cells and lymphocytes that are important in immune response. Acquired lymphangioma (lymphangiectasia) arises as an uncommon complication of chronic vulvar edema. Angiosarcoma can develop at sites of chronic lymphedema occurring at nongenital sites. So far this appears not to have been observed in chronic vulvar lymphedema. The primary approach to treatment of chronic lymphedema is the attempt to reduce the amount of fluid present through compression. Compression garments for the vulva are available but they are uncomfortable and difficult to put on and take off. As a result patient compliance with their use is quite poor. Lymphedema at nongenital sites can be reduced through massage. Presumably this would work for vulvar lymphedema but, not ­surprisingly,

there appears to be nothing published about massage for chronic vulvar edema. Antibiotic therapy is used for instances where there is a recurrent infectious component and, of course, treatment of any underlying infection or inflammatory disease is mandatory. Specific types of chronic vulvar edema are described in the following paragraphs.

Vulvar, pelvic, and inguinal surgery Any surgery involving the vulva will destroy some of the lymphatic vessels that drain the labia but this is not usually accompanied by chronic edema. However, since lymph flows from the vulva through the inguinal nodes, removal of more than a few superficial and/or deep inguinal nodes regularly leads to long-standing, and often severe, labial edema. Likewise, lymph flow from the inguinal nodes passes through the iliac vessels and nodes. Thus pelvic surgery that leads to destruction of iliac lymphatic vessels or removal of iliac nodes has the potential to cause chronic vulvar edema (Figure 25.3). However, in the pelvis there are many cross-connecting lymphatic vessels and thus blockage sufficient to cause significant vulvar edema is relatively infrequently encountered. The development of lymphedema appears to be enhanced when radiation therapy is used in conjunction with surgery.

Recurring cellulitis

Figure 25.2  This edema in a nursing-home patient was multifactorial, produced by irritant contact dermatitis to urine, secondary skin fold candidiasis, and stasis changes from sitting for long periods.

As indicated above, sites of lymphedema develop infection with appreciable frequency. For this reason, lymphedema can be considered as a locus minoris resistentiae. With each episode of infection there is further lymphatic damage and subsequent worsening of the lymphedema. These recurrent episodes occur spontaneously and no cut or other form of trauma is required for initiation. Some redness of the lymphedematous tissue occurs during the acute episode but sometimes it is surprisingly minimal. The episodes may or may not be accompanied by low-grade fever and malaise. This recurring cellulitis (erysipelas) appears always to be a streptococcal, rather than staphylococcal, infection. Unfortunately the presence of infection can be difficult to prove as there is no reliable way of obtaining bacterial cultures. On the other hand, this cellulitis responds well

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to standard antibiotic therapy and this response helps to confirm the diagnosis. As a result of infection, further lymphatic damage occurs and, thus, with each episode of infection the edema worsens. Because of this deleterious effect, most clinicians believe in the use of prophylactic antibiotic therapy5. This can be accomplished with oral cephalosporins or penicillin. The use of intramuscular benzathine-penicillin once or twice monthly is also quite effective. Clinically troublesome bacterial resistance does not seem to develop as a result of this treatment.

Inflammatory bowel disease (IBD) Crohn’s disease and, to a lesser degree, ulcerative colitis can affect the vulva in two ways: direct fistulous extension from the bowel to the vulva and through the development of discrete, separate granulomas6. Chronic vulvar lymphedema can occur with either form of disease and can even occur in the absence of any visible vulvar

Figure 25.3  Any cause of obstruction of deep lymphatic return can produce chronic vulvar edema, including surgery, malignancy, and radiation therapy.

i­ nvolvement when the IBD occurs in the colon and rectum (Figure 25.4). Biopsy of the vulvar edema may or may not reveal granulomatous changes. In most of the reported cases, the IBD appeared prior to vulvar edema and specific vulvar lesions but this may be an artifact since patients who present with vulvar edema, lacking symptoms and signs of gastrointestinal symptoms, are unlikely to receive a thorough gastrointestinal evaluation (see the section on Crohn’s disease in Chapter 21).

Hidradenitis suppurativa Hidradenitis suppurativa (HS) represents a noninfectious, acne-like inflammation of apocrine gland-related follicles. Rupture of these inflamed follicles results in leakage of follicular contents into the adjacent dermis where a prominent inflammatory reaction develops. Since these follicles occur primarily in the milk line, vulvar involvement is

Figure 25.4  A 24-year-old woman with severe cutaneous and intestinal Crohn’s disease experienced edema on the basis of direct, diffuse granulomatous change throughout her vulva; the perianal fistulae provide the diagnosis of Crohn’s as the cause of this edema.

Chronic vulvar edema

commonly found. Chronic lymphedema frequently accompanies vulvar HS. It occurs as a result of scarring secondary to inflammatory destruction of vulvar lymphatic vessels (Figures 25.5 and 25.6). Ordinarily HS as a cause of vulvar edema is easy to recognize because of the characteristic clinical lesions, additional involvement of the axillae and breasts, and the presence of characteristic “twin” comedones. However, some cases are localized to the anogenital area, in which case differentiation from Crohn’s disease, even with biopsy, can be difficult (see the section on HS in Chapter 19).

Melkersson–rosenthal syndrome Melkersson–Rosenthal syndrome (orofacial granulomatosis) was first described more than 100 years ago. The full syndrome consists of facial nerve palsy, fissured tongue, and lip swelling with varying degrees of granulomatous inflammation on biopsy. Lip involvement without the other two features has been termed “Miescher’s cheilitis granulomatosa.” Similar granulomatous changes at other sites of

Figure 25.5  Severe scarring of hidradenitis suppurativa has produced edema in this woman.

soft tissue such as the periorbital and genital areas have also been identified. Literature review indicates that fewer than 20 cases involving the vulva have been reported but clinical experience suggests that it occurs much more commonly. Vulvar involvement begins as noninflammatory, asymptomatic swelling of one or both labia majora7. Biopsy of well-established lesions reveals granulomatous changes that are very similar to those seen in Crohn’s disease and sarcoidosis. This has led to the hypothesis that Melkersson–Rosenthal syndrome is simply a precursor to the development of either sarcoidosis or Crohn’s disease. However, the majority of the patients, even when followed over long periods of time, do not appear to develop either disorder. The best initial treatment appears to be the intralesional administration of

Figure 25.6  Diffuse, severe inflammation of nearly ­confluent draining nodules of hidradenitis suppurativa ­contributed to this patient’s edema, which gradually ­worsened as fibrosis advanced.

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steroids. Other forms of therapy include systemic steroids and other systemic nonsteroidal antiinflammatory agents8.

and may be more likely to occur in women who experience pre-eclampsia.

Miscellaneous conditions

References

In Third World countries the most common cause of genital edema in men is filariasis due to infection with Wuchereria bancrofti but, interestingly, this infection rarely causes chronic vulvar lymphedema. In the past, chronic genital lymphedema was prominently associated with the two sexually transmitted diseases, lymphogranuloma venereum and granuloma inguinale9. These diseases are rarely encountered in the western world and thus will be a most unlikely cause of vulvar edema for the readers of this book. Sarcoidosis can presumably cause chronic vulvar edema (cf. the Melkersson–Rosenthal syndrome discussed above) since biopsies of chronic vulvar edema are sometimes reported as demonstrating sarcoidal epithelioid granulomas. However in most of the cases in which sarcoid was considered, there was a disclaimer that, alternatively, the granulomas could have been those of Crohn’s disease. Primary congenital lymphedema (Milroy’s disease) causes massive edema of the legs. The genitalia are only rarely involved and men are affected more often than are women. A few cases of vulvar edema have been reported in women with the ovarian hyperstimulation syndrome. A recent report describes the development of vulvar edema as the result of chronic bicycle seat trauma. Vulvar edema can also occur in the course of pregnancy

  1. Bousquet, J., Flahault, A., Vandenplass, O., et al. Natural rubber latex allergy among health care workers: a systematic review of the literature. Allergy Clin. Immunol. 2006; 118: 447–454.   2. Nardelli, A., Degreef, H., and Goossens, A. Contact allergic reactions of the vulva: a 14-year review. Dermatitis 2004; 15: 131–136.   3. Weidinger, S., Ring, J., and Kohn, F. M. IgE-mediated allergy against human seminal plasma. Chem. Immunol. Allergy 2005; 88: 128–138.   4. Cabrera, H., Skoczdopole, L., Marini, M., et al. Necrotizing gangrene of the genitalia and perineum. Int. J. Dermatol. 2002; 41: 847–851.   5. Vignes, S. and Dupuy, A. Recurrence of lymphedema-­associated cellulitis (erysipelas) under prophylactic antibiotherapy: a retro­ spective cohort study. J. Eur. Acad. Dermatol. Venereol. 2006; 20: 818–822.   6. Feller, E. R., Ribaudo, S., and Jackson, N. D. Gynecologic aspects of Crohn’s disease. Am. Fam. Physician 2001; 64: 1725–1728.   7. Sbano, P., Rubegni, P., Risulo, M., et al. A case of idiopathic granulomatous cheilitis and vulvitis. Int. J. Dermatol. 2007; 46: 720–721.   8. Sciubba, J. J. and Said-Al-Naief, N. Orofacila granulomatosis: presentation, pathology and management of 13 cases. J. Oral Pathol. Med. 2003; 32: 576–585.   9. Gupta, S., Ajith, C., Kanwar, A. J., et al. Genital elephantiasis and sexually transmitted infections – revisited. Int. J. STD AIDS 2006; 17: 157–165.

Further reading Cueni, L. N. and Detmar, M. New insights into the molecular ­control of the lymphatic vascular system and its role in disease. J. Invest. Dermatol. 2006; 126: 2167–2177.

PART: iI  Gynecologic Dermatology

CHAPTER 26

Pediatric Vulvar Disorders Lynette J. Margesson

Introduction Vulvar conditions in children include a wide spectrum from congenital malformations through infections, dermatoses, and tumors. Nondermatologic disorders are quite familiar to specialized gynecologists and pediatricians, and a full discussion of these conditions is beyond the scope of this text. Many of the conditions discussed in this chapter also occur in adults and generally the major discussion of these disorders will occur elsewhere in this book. To reduce unnecessary overlap, only capsule discussions will be found here.

Congenital vulvar abnormalities Female genital tract developmental abnormalities are rare. They may involve only the external genitalia or the whole reproductive tract (Tables 26.1 and 26.2).

Ambiguous external genitalia At birth the external genital organs in these conditions are not clearly male or female, thus the sexual ambiguity. Eighty percent of ambiguous genitalia are due to female pseudohermaphroditism with androgenization of the female fetus. Such infants present with an enlarged phallus alone or associated with some degree of labioscrotal fusion because of a recessive congenital enzymatic defect of adrenal steroid biosynthesis. The most common cause is a 21-hydroxylase deficiency resulting in overproduction of cortisol and androgen that virilizes the fetal female external genitalia. Rarely this can be caused by an 11-hydroxylase deficiency. Exogenous hormones from a maternal androgen-producing tumor or maternal ingestion of androgen can also produce virilization of a female fetus. Male pseudohermaphroditism is far less common and represents only 15% of cases of ambiguous genitalia. In these infants there is a partial or complete block in the masculinization process during development due to a lack of gonadotropins, an enzyme defect in testosterone biosynthesis, or a defect in the androgen-dependent ­target

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Table 26.1  Ambiguous External Genitalia

Table 26.2  Abnormalities of External Genitalia

Clinical Presentation Clitoromegaly or variable phallus formation with ventral opening; variable labial formation with opening or scrotal sac formation

Diagnosis

Etiology

Disorder

Clinical Presentation

Female   pseudoher-­ maphroditism Congenital adrenal ­hyperplasia

Enzyme deficiencies (recessive) 21-­Hydroxylase deficiency 11-­Hydroxylase deficiency (rare)

Labial ­hypertrophy

Long labia minora

Surgery

Hymenal ­abnormalities

Variable hymenal openings or com-­ plete closure

Surgery

Hemangiomas

Red to purple vascular mac-­ ules, nodules or plaques with or without erosions or ulcers

Reassurance; laser destruc-­ tion if extensive or ulcerated

Congenital nevi

Small to large pigmented mac-­ ules or plaques

Biopsy if atypical; close observation as indicated

Exogenous hormones

Male pseudo-­ hermaphro-­ ditism

Maternal androgen­producing tumor Exogenous androgen exposure Lack of ­ onadotropin g Enzyme defect in testosterone synthesis Target tissue androgen ­receptor defect

tissue response (e.g., androgen receptor defect or 5α-­reductase deficiency). Clinically these children present with varying degrees of phallus formation, scrotal sac formation, and with varying genital openings (Figures 26.1 and 26.2)1–3.

Congenital labial hypertrophy This relatively common developmental abnormality is typically noted at puberty. Labial hypertrophy is defined as a maximum distance of 4 cm from the base of the labium minus to the edge. Rarely it may develop as a result of lymph stasis or chronic physical pulling of the labia. Patients complain of difficulties with hygiene or local irritation with physical activity and sexual ­intercourse. The problem may be unilateral or bilateral (Figure 26.3). Treatment is surgical reduction.

Treatment

Labial adhesions Superficial fusion of the labia minora occurs in 1–3% of prepubertal girls. It starts posteriorly and usually involves the posterior two-thirds of the labia minora. Only rarely is there almost complete labial agglutination .This is an acquired condition seen mostly in children 2–3 years of age4. The cause is unknown, but local irritation, poor hygiene, genital trauma, and lack of estrogen may all play a role5. The result is inflammation and adherence of skin surfaces on either side of the labia, giving the vulva a flat appearance. Localized posterior fusion is often minor and asymptomatic. Although this condition resolves spontaneously with pubertal estrogenization, extensive fusion leaving only a pinhole opening can result in urine retention, urinary infection, genital irritation, and burning. The first line of therapy is topical estrogen cream, used two or three times a day with gentle traction for 2–3 weeks if needed6. If extensive, surgery may be required1,7–10.

Hymenal abnormalities The thin membrane of connective tissue over the entrance of the vagina normally has a round or crescentic opening. There can be several

Congenital vulvar abnormalities 325

A

B

Figure 26.1A  Clitoromegaly with posterior labial fusion in congenital adrenal hyperplasia. An example of female ­pseudohermaphroditism. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and ­Treatment. Mosby, St Louis, 1998.) Figure 26.1B  Female pseudohermaphroditism. Eleven-year-old girl with increasing facial hirsutism, thick genital hair, ­normal vagina, and clitoromegaly as a result of a 21-hydroxylase deficiency. (Courtesy of Dr. G. D. Oliver, Hospital for   Sick Children, University of Toronto, Toronto, Canada.)(Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin ­Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

­ icroperforations, giving a cribriform or fenesm trated hymen or no opening at all (imperforate hymen). With only partial opening of the hymen at the time of menarche, secretions can be trapped, ­resulting in infection. An imperforate hymen presents as primary amenorrhea and there will be lower abdominal discomfort with progressive cyclical lower abdominal pain (Figures 26.4 and 26.5). ­Treatment is surgical4,11,12.

Hemangiomas Hemangiomata are the most common vascular lesions, affecting 5% of newborns with a predominance in females (a male-to-female ratio of

1:3). These benign tumors are characterized by endothelial cell hyperproliferation and they form pink to reddish papules or plaques anywhere on the body. They usually start within a few days of birth with a flat red patch that gradually enlarges. The proliferative phase of rapid growth lasts about 8–9 months, then the lesion stabilizes for a time. Involution starts at about 2 years of age, and most of these lesions flatten into a ­ whitish scar by the age of 9 years. Symptoms depend on size: large tumors can create considerable discomfort with ulcers, erosions, and bleeding (Figures 26.6 and 26.7). Treatment depends on the degree of involvement, and asymptomatic lesions

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A

B

Figure 26.2A  Male pseudohermaphroditism resulting from partial androgen insensitivity. Ambiguous genitalia in an XY child raised as a girl. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.) Figure 26.2B  Ambiguous genitalia in an XY child with partial androgen insensitivity. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

may be left to resolve on their own. Corticosteroids may be used for problematic hemangiomata, intralesionally for small lesions and systemically for large ones. Hemangiomata that bleed or ulcerate may respond well to early laser treatment. For severe cases, co-management with a pediatric dermatologist is recommended13–18.

Melanocytic nevi Congenital melanocytic nevi (“moles”) are not common on the vulvar area. These melanocytic hamartomata may present at birth, when they can show varying degrees of pigmentation. Flat tan-colored macules or papules with varying degrees of pigmentation often grow and darken as the patient ages. Giant nevi present at birth (Figure 26.8) are more likely to undergo malignant transformation. Most nevi have little risk

of malignant change, although rare cases of vulvar malignant melanoma have been reported in prepubertal girls. There are 13 documented cases in patients less than 16 years old. Five of these cases were associated with lichen sclerosus19–21. Treatment is observation with biopsy of suspicious lesions.

Vulvar dermatoses Many childhood vulvar problems are associated with estrogen depletion (Table 26.3). Estrogen is an important factor in vulvar skin reactions to irritants and infection. Estrogen is present and effective during the first 3 months of life and then again 2–3 years before menarche. In the interval, the vulva is relatively estrogen-deficient. In this state, the labia minora and the vulvar epithelia are

Vulvar dermatoses 327

Figure 26.4  Septate hymen. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. ­Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby,

Figure 26.3  An elongated left labium minus. (Courtesy of Dr P. Bryson, Kingston General Hospital, Queen’s University, Kingston, Canada.) (Reproduced from B. K. Fisher and   L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and

thin with a visible capillary network. The result is a weakened barrier function and the tissue is more susceptible to irritants but resistant to Candida. The ­estrogenized vulva is resilient and pink with plump labia minora and well-moisturized vulvar introital epithelium. This results in resistance to chemical and physical irritants but increased susceptibility to Candida.

Contact dermatitis Contact dermatitis is an inflammation resulting from an external agent that acts either as an irritant or an allergen, producing an erythematous rash that may be acute (blistering, itching, ­oozing), subacute (chapping and cracking), or chronic (thickening of the skin with varying degrees of scaling). Primary irritant contact dermatitis is due to prolonged or repeated exposure to an irritating product such as soap, detergent, or urine. There

is no immune reactivity. The problem is the caustic or physically irritating effect of the substance. Allergic contact dermatitis is caused by a specific allergy (type IV delayed hypersensitivity reaction) to even a small amount of a chemical substance such as a perfume, benzocaine, neomycin, or poison ivy. Irritation is the commonest cause of vulvar contact dermatitis, particularly in atopic patients. Diapers, poor hygiene habits, overzealous cleansing with caustic soaps or “wipes,” irritating creams – all can cause trouble22.

Diaper dermatitis This term means any dermatitis in the diaper area, usually due to repeated contact irritation from urine, feces, and friction. This is the commonest skin condition in infancy, with a prevalence of 7–35%. Babies aged 7–12 months are most commonly affected. The skin is pink to red, with shiny or chapped areas of friction. Typically the convex surfaces of the mons pubis, the labia majora, and the buttocks are irritated, but the skin folds are usually spared (Figure 26.9). Children with atopic dermatitis or a tendency

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A

B

Figure 26.5A  Imperforate hymen in a 13-year-old adolescent who presented with an acute abdomen. (Courtesy of   Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and   L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.) Figure 26.5B  The patient’s imperforate hymen is incised and the old blood is released. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

to ­ psoriasis are more susceptible. With time, a mixed pattern develops due to secondary infection with bacteria and Candida. The skin in the folds and on the convex surfaces may become red, chapped, and raw with scattered satellite pustules or desquamating papules and, if severe, open ulcers may develop. Treatment is to remove the irritants and change the diapers more frequently and, when possible, to leave the infant without a diaper. Superabsorbent disposable diapers are best to reduce irritation. Routine cleansing should be with bare or vinyl-gloved hands in plain water with a soapless cleanser (Cetaphil, unscented Dove bar or superfatted soap) followed by a thorough rinse, then 1% hydrocortisone ­ ointment. An imidazole cream (clotrimazole) is added for secondary yeast. For diaper changes away from home, cleansing with plain water or light mineral

oil on a soft tissue or cotton ball is permitted23–29. “Baby wipes” are best avoided.

Irritant dermatitis Repeated exposure to caustic or physically irritating products, usually soap, cleanser, or “wipe,” may result in erythema, itching, and burning of the labia and perineum. Children who have this problem often have a background history of atopic dermatitis, making their skin more sensitive and more easily irritated. Most vulvar contact dermatitis in children is due to irritants. Poor genital hygiene habits (especially fecal smearing of the vulva), excess exposure to soaps, shampoos, and wet bathing suits can all irritate. A thorough ­history is important to pinpoint the important ­factors. The irritants must be identified, stopped, and a topical hydrocortisone ointment prescribed.

Vulvar dermatoses 329

A

B

Figure 26.6A  Rapidly growing capillary hemangioma on the perineum in a 1-month-old baby. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.) Figure 26.6B  Capillary hemangioma. Eroded ulcerated perineum 10 days after the second pulsed-dye laser treatment. The first pulsed-dye treatment was at 1 month of age, the second at 2 months of age. After laser treatment, the ulcers resolved in 3 weeks. The interval between Figures 26.6 A and B was 6 weeks. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

Allergic contact dermatitis This is not an uncommon problem in children. It occurs in up to 20% of cases of dermatitis but is seldom seen on the vulva. Typically, allergic contact dermatitis increases with age and it should be sought in any child with any persistent eczematous lesions. The commonest allergens are nickel, neomycin, thimerosal, fragrance, or wool ­alcohols. There may be an acute blistering eruption or a more chronic picture with erythema and scaling. Other sites may be involved if the allergen has been applied elsewhere. Patch testing may confirm the diagnosis. The condition improves over 2–3 weeks after the allergen is stopped. For severe reactions, a topical corticosteroid ointment such as triamcinolone 0.1% might be needed. If there is blistering, systemic prednisone could be used starting at 1 mg/kg daily for 4–5 days, then decreasing over 10 days30–34.

Seborrheic dermatitis This condition produces erythema and greasy, yellowish scaling around the vulva and the labiocrural fold. In the first 3 months of life, it is often

associated with a greasy dandruff-type rash in the scalp, around the ears, down the central part of the face, and in the axillae. The irritation is due to the immune reaction to Malassezia, a species of lipophilic yeast that thrives in areas rich in sebaceous glands that have been activated before birth by maternal or placental hormones. Treatment is with gentle soapless cleansing and topical imidazole, such as clotrimazole cream with 1% hydrocortisone added35,36.

Psoriasis Psoriasis is a common, hereditary, red, scaly rash of the skin. In infants, it may present as a chronic, sometimes itchy, diaper dermatitis with bright red, sharply outlined plaques around the mons pubis and labia majora through the perineum and often up into the gluteal cleft with varying degrees of fissuring. In young infants it often presents as a diaper dermatitis that is resistant to therapy. The white scales typical of psoriasis are not present in body folds, but may occur on elbows, knees, or scalp. A history of psoriasis in other family members helps to make a diagnosis37–39.

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Figure 26.8  Giant pigmented nevus of the vulva, thighs, and buttocks in a baby with an eroded diaper rash. (Repro-­ duced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

a day intermittently for psoriasis and atopic dermatitis (see below)40–42. Figure 26.7  Extensive capillary hemangioma of abdomen,   vulva, and right leg in a 2-month-old with Klippel– ­Trenaunay–Weber syndrome. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

Treatment involves avoiding trauma such as irritating soaps and lotions, and keeping the area cool and dry. Cleanse with a bland product such as Cetaphil cleanser, unscented Dove bar, or superfatted soap. A low-potency steroid ointment (hydrocortisone 2.5%, desonide 0.05%) may be used twice a day initially, tapering to 1% ­hydrocortisone ­ointment with response. In more severe cases, mid- or even high-potency topical corticosteroids may be necessary for 1–2 weeks followed by longterm management with intermittent use of lowdose hydrocortisone. For concurrent secondary infection antiyeast topical clotrimazole and antibacterial mupirocin ointment may be needed. The topical calcineurin inhibitors can be useful as steroid-sparing agents: pimecrolimus 1% cream for milder psoriasis and tacrolimus 0.03% and 0.1% ointment for more severe. These can be used twice

Atopic dermatitis This eruption consists of a dry itchy rash that occurs in patients who usually have a personal or family history of one or more atopic conditions: asthma, allergic rhinitis (“hayfever”), or eczema. Infants with atopic dermatitis present with chapped red skin over the cheeks and extensor surfaces of the extremities. Older children show involvement of the antecubital fossae and behind the knees. Although the typical rash is not common on the vulva, children with a background history of atopic dermatitis have much more easily irritated skin and may present with an irritant dermatitis or diaper dermatitis. Management combines avoidance of harsh, irritating soaps and cleansers; treatment of any secondary infection; and the application of a mild corticosteroid ointment, as for diaper dermatitis or a topical calcineurin inhibitor, pimecrolimus cream or tacrolimus ointment, as a steroid sparer as for psoriasis43,44. These can be used safely short-term and intermittently in children over 2 years old. Long-term safety has not been established and is controversial45–47.

Vulvar dermatosis 331

Table 26.3  Pediatric Vulvar Dermatoses

Clinical Presentation

Etiology

Diaper ­dermatitis

Red, shiny to chapped skin on friction areas, spare skin folds

Moisture from urine and feces; candida may be present

Irritant ­dermatitis

Inflamed red chapped skin on friction areas

Allergic contact dermatitis

Condition

Other Areas/ Factors

Diagnosis

Treatment

Tendency to eczema or psoriasis

Clinical ­pattern; culture for ­secondary   infection

Stop irritants; improve ­hygiene,1%   hydrocortisne­ ointment with imidazole cream

Detergents, soaps, baby wipes, etc.

Other skin areas where irritant used

Clinical   pattern; family with psoriasis   or atopy

Stop irritants, hydrocortisone ointment

Red itchy rash at sites of allergen contact

Allergen: neo-­ mycin, benzo-­ caine, perfume

Other skin areas where allergen used

Careful history, patch test

Stop allergen, triamcinolone   0.1% ointment

Seborrheic ­dermatitis

Greasy, red­orange skin   rash in folds

Malassezia globosa

Scalp, face, ­behind ears, other body folds; note ­secondary ­infection

Clinical pattern

Hydrocortisone 1% plus   imidazole cream

Psoriasis

Patchy to diffuse red rash,   including folds

Familial defect in skin, worsened with friction and moisture

Scalp, ears, elbows, knees, other body folds, gluteal cleft; nail pits

Clinical ­pattern plus family ­history

Hydrocortisone 2.5% ointment; brief treatments with more potent topical steroids; treat secondary infection

Atopic ­dermatitis

Patchy, red, chapped rash on labial and gluteal surfaces

Familial with ­ istory ­eczema, h hay fever, asthma

Itchy red rashes on face, ­extensor areas in babies; ante-­ cubital fossae, behind knees in older children

Clinical pattern; note family ­history of atopy

Stop irritants; corticosteroid ointment of low to mid potency

Lichen sclerosus

White papules and plaques in ‘figure of eight’ pattern, vulvar and perianal; purpura

Autoimmune

Other area of skin in 20%

Clinical pattern; biopsy

Potent to super-­ potent steroid for 6–12 weeks then maintenance 2–3 times per week; close follow-up; condition chronic

Dermatoses

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Table 26.3  Pediatric Vulvar Dermatoses—cont’d.

Condition

Clinical Presentation

Etiology

Vitiligo

White groin skin

Autoimmune

Impetigo

Superficial ­erosions and peeling red areas

Staphylococcus aureus, some-­ times Streptococcus pyogenes

Streptococcal infection

Acute, burning, red, eroded peri-­ anal or vulvar rash

Streptococcus pyogenes

Herpes simplex

Acute onset of burning with groups of vesicles and pustules, ero-­ sions; recurrent

Herpes simplex virus (HSV)

Molluscum

Itchy,   skin-­colored, ­umbilicated   papules isolated and in groups

Genital warts

Other Areas/ Factors

Diagnosis

Treatment

In folds of skin, face, hands, elbows, knees

Clinical pattern; biopsy

Mild topical   ­steroid; ­observation

May be   localized,   primary,   secondary, or generalized

Culture positive for organism

Dicloxacillin, cephalosporin, erythromycin

Culture for ­streptococci

Penicillin

Primary or secondary

Culture for HSV

Valacyclovir, ­famciclovir

Molluscum ­contagiosum

Other lesions scattered on body

Clinical; smear

Local destruction or removal (e.g. cryotherapy)

Warty papules or cauliflower-like clusters

Human ­papilloma   virus (HPV)

May have warts on hands, etc.

Clinical

Observation   only or local destruction

Candida

Itchy, burning rash, erythema-­ tous, swollen patches with satellite pustules

Candida albicans

Often ­associated   with diaper dermatitis

KOH; culture

Topical imidazole cream

Tinea

Annular, red rash around edges of genitalia

Trichophyton rubrum or   T. mentagrophytes

Scaling fourth– fifth toewebs in parent or sibling with tinea

KOH; culture

Topical imidazole or terbinafine cream

Infections Bacterial

Viral

Fungal

Vulvar dermatosis 333

Table 26.3  Pediatric Vulvar Dermatoses—cont’d.

Condition

Clinical Presentation

Etiology

Other Areas/ Factors

Diagnosis

Treatment

Infestations Scabies

Scattered, very itchy papules and nodules; look for tracks

Sarcoptes scabiei

Tracks in finger web; other family member itchy

Scrapings of tracks for KOH

Permethrin 5% cream; 6% ­precipitated ­sulfur in petrola-­ tum for infants

Pinworms

Nocturnal scratching with perianal and vulvar itching

Enterobius vermicularis

Other siblings itchy

Examine ­Cellophane   tape applied   to perianal area for eggs

Oral mebenda-­ zole, pyrantel pamoate

Foreign Body Vaginitis

Red, itchy,   sore vulva with discharge

Foreign body; peanut, tissue

None

Locate foreign body

Remove for-­ eign body, treat ­secondary ­infection

Sexual Abuse

Red, sore   vulva with or without discharge; ­lacerations or distortion of introitus or anus

Typically male with access   to child, not   necessarily father

May have bruises in acute cases, chronic cases may ­develop psychologic problems

Requires   investigative team if suspected by physician

Remove offender from household or remove child from situation; counseling

Linear IgA disease

Large, tense bullae in circular plaques around the groin

Autoimmune

Perioral; may be generalized

Biopsy for histology  and immuno­ fluorescence

Avlosulfone

Erythema ­multiforme

Blisters and   erosions

Hypersensitivity to infection (e.g., HSV) or drugs (e.g., sulfa)

Mucous mem-­ branes, mouth, eye; may be generalized

Clinical pattern; biopsy

Minor disease – no treatment; major blistering – early use of cyclosporine

Sharply margin-­ ated, vesicular, pustular, or eroded rash   in the groin

Zinc deficiency

Perioral, nose, eyes, flexural areas; hair   loss, irritability; diarrhea

Serum zinc levels

Oral zinc

Bullous Diseases

Miscellaneous Acrodermatitis enteropathica

(Continued)

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Table 26.3  Pediatric Vulvar Dermatoses—cont’d.

Condition

Clinical Presentation

Etiology

Other Areas/ Factors

Langerhans cell histiocytosis

Greasy, yellowish, scaly papules in the diaper area and buttock; sometimes ulcers, purpura

Excess   proliferation of histiocytes

In infants, brown, crusted areas, scalp, ears, perioral; fever, anemia, etc.; erosive papules with vulvar ulcers; associated dia-­ betes insipidus

Labial adhesions

Variable fusion of labia minora

Local ­inflammation

None

Figure 26.9  Extensive diaper dermatitis on the mons, ­convex surfaces of the labia majora, and thighs with erythema, scaling, and crusting in a 6-month-old baby girl. Note sparing of the folds, secondary Candida, and satellite pustules in the mons area.

Lichen sclerosus This is a common chronic cutaneous disease of the genitalia resulting in marked hypopigmentation, skin thinning, and scarring (Figures 26.10 and 26.11). Some 10–15% of cases develop in childhood, as early as 1–2 years of age, but ­average age of onset

Diagnosis

Treatment Chemotherapy

Clinical

Topical estrogen

is 5 years. The commonest symptoms are itching and soreness but dysuria can occur, and pain on defecation may present as recalcitrant ­constipation48. Ten percent of cases are ­asymptomatic. Typical lesions are small white papules that coalesce into plaques of parchment-like skin. Lesions of the vulva, perineum, and perianal area may be patchy or form a white “figure-of-eight” pattern. With time, there is atrophy with loss of labia, scarring, and loss of the clitoris. Scratching causes purpura, erosions, excoriations, and even bleeding that can be confused with sexual abuse, although these two conditions are not mutually exclusive49–51. The symptoms of lichen sclerosus may improve at puberty but the disorder does not spontaneously resolve52. Treatment is with topical steroids53–55. Because of the risk for developing squamous cell carcinoma, patients should be followed at regular intervals, indefinitely. Squamous cell carcinoma is a risk in adult patients.

Vitiligo This is an acquired loss of pigmentation on an autoimmune basis that often starts in ­childhood, although it may occur at any age. Irregularly shaped patches of hypopigmentation present around orifices (eyes, nose, mouth, vagina) and over the extensor areas of the body, often at sites of trauma such as the backs of the hands, knees, and body folds. There is no surface skin change,

Infections 335

Figure 26.10  Hypopigmentation in lichen sclerosus. (Cour-­ tesy of Dr B. Krafchik, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

just color loss. For involvement of the vulvar area, generally no treatment is recommended38,56.

Infections Impetigo Staphylococcus aureus infection may occur anywhere on the body. It may involve the vulva and perineum in a young child, producing fragile blisters that rapidly evolve into red, round, desquamating erosions. Associated streptococcal infection may produce honey-colored crusts that may be dry or soft and wet. Treatment with oral antibiotics is recommended: dicloxacillin, a cephalosporin, or erythromycin. For localized lesions, topical mupirocin or retapamulin ointment can be used57,58,58a.

Streptococcal infection Streptococcus (group A ß-hemolytic streptococcus) can cause a vulvitis and/or a perianal dermatitis in children 6 months to 10 years of age. Classically, there is a burning, bright red rash that forms a red ring around the perianal area and may be associated with perianal fissures and painful defecation. Less commonly in the vulvar area the onset can be acute

Figure 26.11  Lichen sclerosus. Scarring and mild purpura (mistaken for sexual abuse). (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis

with a painful red swollen vulva and vagina plus a thin mucoid discharge. Diagnosis is confirmed by skin culture. Treatment is with oral penicillin or erythromycin and topical mupirocin or retapamulin ointment. This can be mistaken for chronic yeast, eczema, psoriasis, pinworms, or abuse59–61a.

Herpes simplex virus (HSV) Although herpes simplex infections are usually found in sexually active adolescents or adults, they can sometimes present in infancy or childhood. HSV is usually acquired innocently from an infected caregiver but the possibility of sexual abuse must be excluded. In primary disease there are multiple, often rather widespread, small vesicles or pustules with surrounding erythema and swelling (Figure 26.12). These rapidly break, leaving tender erosions that may last for up to 2 weeks. Recurrence is common. Recurrent lesions are much less extensive, have fewer vesicles, and demonstrate much more of a grouped appearance. They also have a shorter duration with less swelling. If herpes is suspected, a culture for HSV should be obtained. In some countries polymerase chain reaction testing for HSV (more sensitive than ­culture) is now available. Type-specific HSV

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Figure 26.12  Primary herpes simplex on the perineum   and buttocks with groups of vesicles. (Reproduced from   B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

s­ erology can be very helpful to support the diagnosis. In primary infection early serology will be negative with seroconversion after 3 months (allowing for a 5% false-negative result). If the genital lesion is due to HSV type I, there is less chance of recurrence; HSV type II has a recurrence rate of up to 95%. Treatment is with acyclovir, valacyclovir or famciclovir. In children with eczema, herpes simplex can spread all over the body in a serious infection termed “eczema herpeticum”62–64.

Molluscum contagiosum This common poxvirus infection of the skin presents with discrete, firm, 1–3 mm flesh-colored, umbilicated papules anywhere on the body (Figure 26.13). It spreads in children and young adults by autoinoculation or through fomites. A few initial papules are easily spread by scratching. It is often seen on the vulva as part of a more extensive eruption. Diagnosis is usually clinical but a direct smear of the whitish material from one of these lesions can confirm the diagnosis. Molluscum contagiosum resolves spontaneously in 6–12 months in young children, so treatment is optional. However concerns about contagion usually do lead to treatment with modalities such as liquid nitrogen, curettage, or keratolytics65–67.

Figure 26.13  Molluscum contagiosum. Multiple domeshaped pink papules.

Genital warts Genital warts are caused by human papillomavirus (HPV). The most common serotypes are 6 and 11 and these types are associated with low oncogenic risk. Even as the incidence of condylomata has increased in adults, there has been an increased prevalence of this condition in children. Oral or laryngeal lesions may be transmitted to infants through an infected birth canal. Transmission of the virus is usually from infected caregivers or, rarely, as a result of autoinoculation from warts on the patient’s hand. HPV is the most common sexually transmitted disease in the United States. Because 30–40% of cases in children have been associated with abuse, this must always be ruled out (see below). These children should be referred to the local experts in sexual abuse screening68. Pinheadsized papules that grow into filiform papules or plaques are usually found symmetrically on opposing skin surfaces. The lesions can be small or large, skin-colored to reddish, and may grow into confluent, cauliflower-like clusters. The commonest site is perianal. ­Diagnosis is based on the clinical picture. No treatment for HPV guarantees a cure. In young children, treatment may be simple observation. Treatment is undertaken if there are symptoms of itching, burning, spread, ­disfiguring lesions, or

Infections 337

Figure 26.14  Epstein–Barr virus infection. A painful punched-out, red-rimmed vulvar ulcer in a 15-year-old girl.

bleeding. Treatment with caustic agents, as is usually recommended for adults, is not usually appropriate. If treatment is needed, electrodesiccation or laser surgery under general anesthesia should be considered. Imiquimod is currently being studied for use in children69–72. Adoption of the new polyvalent vaccine directed at serotypes 6, 11, 16, and 18 has the potential to reduce the incidence of this problem significantly.

Epstein–barr virus Epstein–Barr virus may occasionally cause vulvar ulcers in teenagers and young adults. The illness has an inconsistent prodrome of fever, fatigue, sore throat, oral ulcers, and swollen cervical glands. Deep, painful, punched-out ulcerations appear on the labia minora. Lesions are solitary or multiple, with erythema surrounding an irregular grayish ulcer base with a serous or purulent exudate (Figure 26.14). The differential diagnosis includes herpes simplex, aphthosis, syphilis, human immunodeficiency virus, and Behçet’s disease. Diagnosis is made by serology when immunoglobulin (Ig) M antiviral capsid antigen for Epstein–Barr virus is present. These antibodies may not be detectable until 1–2 weeks after the onset of infection. The MonoSpot test may be negative73,74. Treatment is symptomatic. The lesions resolve in 2 weeks75,76.

Candida The majority of candidal infections in girls under 2 years old are from Candida albicans. The development of candidiasis is usually associated with the

Figure 26.15  Candidal infection. A 3-month-old infant with red swollen labia majora studded with red papules and pustules of Candida, with satellite pustules.

development of diaper dermatitis. C. albicans is an estrogen-dependent condition so it is not often seen past “diaper age” unless risk factors such as diabetes and oral systemic antibiotics are present. Look for Candida infection with diaper dermatitis, other chronically moist rashes, or with any vulvar dermatitis not responding to topical steroid therapy. Candida vulvitis presents with redness, swelling, and pruritus. Satellite pustules (Figure 26.15) or dried collarette scales and fissures are common. Diagnosis is made by culture or potassium hydroxide examination showing the budding yeast and/or pseudohyphae. Topical imidazole cream, miconazole, or clotrimazole represents the usual treatment. If vaginitis is also present (rare at this age), oral fluconazole is indicated.

Tinea This superficial dermatophyte infection is not common in infancy or childhood. This disorder, often called “ringworm,” involves the upper inner thighs but may occur on other areas of the body as well. It presents as an annular or circular red rash that clears in the center to leave a ring-like pattern. It may be missed, masked by the use of topical steroids, and can present an atypical appearance with a bland ill-defined pink to red patchy rash

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or a rapidly spreading rash. Diagnosis is made by culture or with a potassium hydroxide examination showing the typical fungal hyphae. Treatment is with a topical imidazole or terbinafine cream77. Oral terbinafine may rarely be required.

Infestations Scabies This highly contagious skin infestation is caused by the mite, Sarcoptes scabiei. It is spread among children and young adults by skin-to-skin contact and also by fomites. Patients describe intense itching that is worse at night. It typically involves body creases, finger webs, wrists, axillary and groin folds. Tiny linear tracks may be visible in finger webs or groin areas, but excoriated and sometimes crusted papules are typical. In infants, there may be nodules on the mons pubis, thighs, buttocks, axillae, and even the head and scalp. For diagnosis, a scraping for examination under oil or potassium hydroxide must be taken from papules or tracks. Treatment for children aged 2 months or more is with topical 5% permethrin cream. For younger infants, 6% precipitated sulfur in a petrolatum base can be applied twice a day for 2 days. All members of a household and those in contact with the child must be treated to avoid reinfestation by this very contagious mite78–80.

Pinworms Infestation by Enterobius vermicularis results in nocturnal itching as the worms migrate out on to the perianal skin to lay eggs. Clinically there may be little rash, but scratching may result in chronic skin changes from the perianal area to the vulva. Diagnosis is made with Cellophane tape applied to the perianal skin in the morning to collect the eggs, which are identified in a potassium hydroxide preparation. The whole family needs treatment with oral mebendazole or pyrantel pamoate, with one retreatment 1–2 weeks later.

Vaginitis due to a foreign body Foreign bodies inserted into the vagina may cause chronic vaginal discharge with an irritant contact dermatitis of the vulva. The whole vaginal area

Figure 26.16  Foreign body. A 6-year-old girl who ­presented with scratching, pain, bleeding, and vaginal discharge showed an intact red hymenal ring with toilet tissue just inside the opening. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

may be swollen with varying degrees of burning, itching, and soreness. The discharge is often purulent, blood-tinged, and foul-smelling. Treatment of this secondary infection without removal of the foreign object is insufficient. The most common cause is toilet tissue (Figure 26.16), but peanuts or other small items may be found. In young adults, forgotten tampons can cause copious malodorous discharge with secondary infection. Treatment is removal of the foreign body81.

Sexual abuse Sexual abuse refers to the involvement of a dependent, developing, immature child or adolescent in sexual activities by an older person for their own sexual stimulation or for gratification of others, as in pornography and prostitution. Sexual abuse

Bullous diseases

involves the misuse of power and the betrayal of the child’s trust by an older person. Activities involve oral–genital, genital–genital, and anogenital contact, including exhibitionism, sexual kissing, fondling, masturbation, and digital or object penetration of the vagina and anus. Being aware that sexual abuse is a common problem should alert the physician to consider this when examining children who present with an infection (condyloma acuminata, herpes simplex, gonorrhea, or other sexually transmitted diseases) or with trauma that includes scratches, bruising, hematomas, lacerations, or fissures (Figure 26.17), scars, and gaping of the anus or introitus82. The diagnosis of sexual abuse is complex. Skin conditions may mimic abuse. These include lichen sclerosus that can present with pain, ulcers, purpura, and scarring. Tumors such as ulcerated hemangiomata or epidermal nevi of the vulva masquerading as genital warts can present an appearance similar to “sexual abuse.” Other mimics of sexual abuse include a vaginal foreign body with pain and a foul discharge, blistering conditions like bullous pemphigoid with painful erosions, trauma from a fall on to the crossbar of a bicycle, vulvar and Crohn’s disease with pain, swelling, and ulcers. A very rare case of vulvitis plasmocellularis circumscripta was diagnosed as abuse83–86. Then there are the diseases that could be either or both, such as vulvar contact dermatitis, HSV, or HPV. Major long-term problems occur with sexually abused children and their families. Obtaining an appropriate history requires interview techniques used by specially trained personnel. Children who have been abused are often withdrawn or may even act out. Sometimes they are very anxious to please. Examination of these children involves specific local protocols. Total physical examination is necessary plus cultures for all sexually transmitted infections when indicated. The hymen is usually annular or crescentic in normal children. A variety of notches and bumps is quite normal. After trauma there can be a variety of different hymeneal changes. Healed transections of the hymen between 4 and 8 o’clock (Figure 26.18), and sometimes partial hymenal loss, may be seen.

339

Figure 26.17  Perineal laceration through the hymen and posterior fossa with hematoma formation and ­surrounding bruising in a raped child. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. ­Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby,

Most young girls who have been abused will have no signs of physical injury as the abuse may not involve penetration and even when penetration has occurred, traumatic lesions may have healed. If there is any question, children should be referred to the proper authorities. Treatment is best managed by a specialized team.

Bullous diseases Linear IgA disease Linear IgA disease of children is also referred to as chronic bullous disease of childhood. This condition presents as tense bullae and erosions forming an annular pattern around the vulva and perianal areas. Often these are grouped in dense clusters with varying degrees of erosions and scarring. The condition can become generalized87,88.

Erythema multiforme Erythema multiforme is a cutaneous hypersensitivity phenomenon due to infections (herpes simplex, Streptococcus, and Mycoplasma in children) and sometimes drugs (sulfonamides, penicillin, or phenytoin). In the mild form, there are few or no

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symptoms, and crops of iris or target-like lesions (Figure 26.19) erupt anywhere on the body, classically on hands, feet, elbows, knees, and perineum. These disappear gradually over 2–4 weeks and no treatment may be needed. A more severe form (Stevens–Johnson syndrome) presents with extensive blistering that can start in the mouth, around the eyes, and in the perianal area. There is painful erythema and erosion with blistering (Figure 26.20), which can become generalized with fever and malaise. Treatment is to identify and manage the underlying condition. Local care may include soaks, bandaging, and antibiotics. If the condition is diagnosed within 72 hours, some authorities recommend systemic corticosteroids or cyclosporine

A

but the use of these agents remains controversial. A rare, serious, variant is toxic epidermal necrolysis (TEN). This is usually due to a medication reaction. Lesions first develop in the body folds of the groin and around the neck, with a full-­thickness desquamation. Because this disease can be life threatening, aggressive early therapy in a specialized burn unit is warranted. Long-term consequences may include vaginal stenosis or vulvar adenosis89–93.

Miscellaneous Acrodermatitis enteropathica This is a rare disorder. It may be caused by a hereditary (autosomal-recessive) failure of zinc absorption or an acquired zinc-deficient diet due to

B

Figure 26.18A  Sexual abuse. A 5-year-old girl with a typical keyhole deformity of the hymenal ring at the 6 o’clock posi-­ tion resulting from penetration, laceration, and scarring. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.) Figure 26.18B  Sexual abuse. Same child as in Figure 26.18A (supine position) 2 years later with a healed scar at 6 o’clock. (Courtesy of Dr. G. D. Oliver, Hospital for Sick Children, University of Toronto, Toronto, Canada.) (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

Miscellaneous

inadequate intake or malabsorption. The acquired form can be seen with zinc-deficient breast milk, inadequate zinc in parenteral nutrition, or malabsorption accompanying cystic fibrosis, Crohn’s disease, or any protracted colitis. The clinical triad

consists of: (1) acral dermatitis (scaling, redness, and irritation) with (2) diarrhea and (3) alopecia. Infants present with diarrhea and persistent “diaper rash” that will not heal (Figure 26.21). A variable degree of anorexia, alopecia, and irritability is associated. A low serum zinc level, low zinc absorption test using zinc radioisotopes, and the clinical picture make the diagnosis. Management is with oral zinc gluconate94–96.

Langerhans cell histiocytosis

Figure 26.19  Erythema multiforme. Iris or target lesions   on the buttock. (Reproduced from B. K. Fisher and   L. J. ­Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

A

This neoplastic proliferation of the epidermal Langerhans cells can result in a spectrum of disease in children or young adults. In infants, it is often confused with a seborrheic dermatitis or chronic diaper dermatitis. Brown crusty papules can involve the diaper area (Figure 26.22) and ­buttock, as well as the scalp, behind the ears, and even around the mouth. In older children there may be extensive hemorrhagic papules on the labia minora and majora, sometimes forming ­confluent sheets and/or well-defined ulcers. Diagnosis is by histopathological examination. Management depends on the case and may include prednisone and/or chemotherapy. Co-management with a pediatric oncologist is suggested97,98.

B

Figure 26.20A  Erythema multiforme. Painful erythema and erosion of the perianal skin extending to the vulva. (Repro-­ duced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.) Figure 26.20B  Erythema multiforme. Same child as in Figure 26.20A, showing blistering and erosion of the lips and face. (Reproduced from B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

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342

Figure 26.21  Acrodermatitis enteropathica. Well­demarcated scaling plaque of the whole diaper area   with erosion and perianal bleeding. (Reproduced from   B. K. Fisher and L. J. Margesson (eds) Genital Skin Disorders: Diagnosis and Treatment. Mosby, St Louis, 1998.)

Crohn’s disease Crohn’s disease is a chronic granulomatous inflammatory disease of the gastrointestinal tract. It usually affects adults 20–40 years of age. About 2% of patients develop this condition under age 10 and an additional 30% develop it between 10 and 19 years of age. Fewer than 25 cases have been reported in children. Childhood cases more frequently involve the genitals and about 17 cases of genital Crohn’s disease have been reported in girls. Not uncommonly the genital involvement precedes the onset of the gastrointestinal disease. Only about 50% of the children present with the classic triad of diarrhea, weight loss, and abdominal pain. The majority complain of atypical abdominal pain. Children usually have soreness and discomfort in the vulvar, perineal, and perianal areas. Not uncommonly there are tender vulvar, perineal and perianal ulcers, fissures (including the classic “knife cut” type), and perianal skin tags. Vulvar swelling can be seen (unilateral or bilateral). Nongenital oral signs include oral aphthae, swelling, cheilitis, and gingival hyperplasia. On the skin there can be abscesses, and red papules and plaques and reactive rashes include erythema nodosum, erythema multiforme,

Figure 26.22  Langerhans cell histiocytosis. A baby with extensive erythematous papules on the lower abdomen, vulva, and inner thighs with petechiae and erosion in   the inguinal crease. (Reproduced from B. K. Fisher and   L. J. ­Margesson (eds) Genital Skin Disorders: Diagnosis and

epidermolysis bullosa acquisita, and vasculitis (Figure 26.23). Systemically there may be weight loss, growth failure, anemia, and even arthritis. The diagnosis is made with a biopsy and it can show a granulomatous infiltrate. Management should be coordinated with a pediatric gastroenterologist99–102.

Aphthae Vulvar aphthae, unlike oral aphthae are uncommonly found in children. The cause is unknown. Most are idiopathic and are unassociated with any underlying disease. However, a small percentage is associated with other conditions such as inflammatory bowel disease and infections such as human immunodeficiency virus and paratyphoid. Other rare associations include drugs, hematologic disorders, Behçet’s disease and unusual syndromes such as mouth ulcers, genital ulcers, inflamed cartilage (MAGIC syndrome); and fever, aphthosis, pharyngitis, and adenitis (FAPA) syndrome. Complex aphthosis is the term for recurrent oral and genital ulcers. Children can present with or without a history of oral canker sores. Clinically there is a sudden onset of single or multiple punched-out or painful ulcers that may last 1–3 weeks. Pain and dysuria are the most common presenting symptoms.

References 343

Figure 26.25  Aphthous ulcer. This 17-year-old had severe recurrent vulvar aphthous ulcers with a perforated left labium minus and an active ulcer on the perineum  (Courtesy of Dr. Hope Haefner).

Figure 26.23  Crohn’s disease. This 16-year-old had Crohn’s disease and a fistula from bowel to right labium minus (Courtesy of Dr. Hope Haefner).

The majority of lesions occur on the labia minora or vulvar trigone but the perineum and perianal areas may be involved. The ulcers can be shallow or punched-out and can look herpetiform. The majority of patients also have fever, malaise, headache, and gastrointestinal symptoms. About 50% will have upper respiratory symptoms such as cough and sore throat and about one-third will have oral aphthae103,104. Diagnosis is by exclusion. Cultures and biopsies are noncontributory. In ­nonsexually active teenagers presenting with painful vulvar ulcers, consider HSV, idiopathic aphthae, Epstein–Barr virus, fixed drug eruption, and erythema multiforme. These vulvar aphthae can be recurrent. A brief course of oral prednisone is the most effective treatment. Topical corticosteroid ointments can be helpful. Long-term treatment may involve the use of dapsone, colchicine, or the combination104–107 (Figures 26.24 and 26.25).

References

Figure 26.24  Crohn’s disease and aphthous ulcers. This baby has vulvar Crohn’s disease with aphthous ulcers, perianal tags, and diffuse involvement of the labia majora (Courtesy of Dr. Hope Haefner).

  1. Hewitt, J., Pelisse, M., and Paniel, B. J. Congenital malformations of the vulva. In Hewitt, J., Pelisse, M., and Paniel, B. J. (eds) Diseases of the Vulva, pp 64–71. McGraw-Hill, London, 1991.   2. Margesson, L. J. Congenital malformations of the vulva. In Fisher, B. K. and Margesson, L. J. (eds) Genital Skin Disorders: Diagnosis and Treatment, pp.108–114.Mosby, St. Louis, 1998.   3. Ridley, C. M. and Neill, S. M. Embryology and congenital abnormalities of the vulva. In Ridley, C. M. and Neill, S. M. (eds) The Vulva, 2nd edn, pp. 1–36. Blackwell Scientific, ­Oxford, 1999.

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Pediatric Vulvar Disorders   4. Heard, M. J. and Malinak, L. R. Developmental anomalies of the vulva and vagina. In Kaufman, R. H., Faro, S. and Brown, D. (eds) Benign Diseases of the Vulva and Vagina, 5th edn, pp. 21–45. Elsevier Mosby, Philadelphia, 2005.   5. Kumar, R. K., Sonika, A., Charu, C., et al. Labial adhesions in pubertal girls. Arch. Gynecol. Obstet. 2006; 273: 243–245.   6. Leung, A. K., Robson, W. L., Kao, C. P., et al. Treatment of labial fusion with topical estrogen therapy. Clin. Pediatr. (Phila.) 2005; 44: 245–247.   7. Bacon, J. L. Prepubertal labial adhesions: evaluation of a referral population. Am. J. Obstet. Gynecol. 2002; 187: 327–331.   8. Capraro, V. J. and Greenberg, H. Adhesions of the labia ­minora. A study of 50 patients. Obstet. Gynecol. 1972; 39: 65–69.   9. Jenkinson, S. D. and MacKinnon, A. E. Spontaneous separation of fused labia minora in prepubertal girls. Br. Med. J. (Clin. Res. Ed.) 1984; 289: 160–161. 10. Nurzia, M. J., Eickhorst, K. M., Ankem, M. K., et al. The surgical treatment of labial adhesions in pre-pubertal girls. J. Pediatr. Adolesc. Gynecol. 2003; 16: 21–23. 11. Anania, C. and Malinak, L. R. Developmental anomalies of the vulva and vagina. In Kaufman, R. H. and Faro, S. (eds) Benign Diseases of the Vulva and Vagina, 4th edn, pp. 23–46. Mosby, St. Louis, 1994. 12. Pokorny, S. F. Pediatric vulvovaginitis. In Kaufman, R. H. and Faro, S. (eds) Benign Diseases of the Vulva and Vagina. 4th edn, pp. 47–61. Mosby,St. Louis, 1994. 13. Astner, S. and Anderson, R. R. Treating vascular lesions. ­Dermatol.Ther. 2005; 18: 267–281. 14. Drolet, B. A., Esterly, N. B., and Frieden, I. J. Hemangiomas in children. N. Engl. J. Med. 1999; 341: 173–181. 15. Gampper, T. J. and Morgan, R. F. Vascular anomalies: hemangiomas. Plast. Reconstr. Surg. 2002; 110: 572–585. 16. Miller, T. and Frieden, I. J. Hemangiomas: new insights and classification. Pediatr. Ann. 2005; 34: 179–187. 17. Powell, J. L., Zwirek, S. J., and Sankey, H. Z. Hemangioma of the cervix managed with the Nd:YAG laser. Obstet. Gynecol. 1991; 78: 962–964. 18. Richards, K. A. and Garden, J. M. The pulsed dye laser for ­cutaneous vascular and nonvascular lesions. Semin. Cutan. Med. Surg. 2000; 19: 276–286. 19. Hassanein, A. M., Mrstik, M. E., Hardt, N. S., et al. Malignant melanoma associated with lichen sclerosus in the vulva of a 10-year-old. Pediatr. Dermatol. 2004; 21: 473–476. 20. Rosamilia, L. L., Schwartz, J. L., Lowe, L., et al. Vulvar ­melanoma in a 10-year-old girl in association with lichen ­sclerosus. J. Am. Acad. Dermatol. 2006; 54(Suppl): S52–S53. 21. Wechter, M. E., Gruber, S. B., Haefner, H. K., et al. Vulvar melanoma: a report of 20 cases and review of the literature. J. Am. Acad. Dermatol. 2004; 50: 554–562. 22. Margesson, L. J. Contact dermatitis of the vulva. Dermatol. Ther. 2004; 17: 20–27. 23. Atherton, D. J. The aetiology and management of irritant diaper dermatitis. J. Eur. Acad. Dermatol. Venereol. 2001; 15(Suppl 1): 1–4. 24. Atherton, D. J. A review of the pathophysiology, prevention and treatment of irritant diaper dermatitis. Curr. Med. Res. Opin. 2004; 20: 645–649. 25. Boiko, S. Treatment of diaper dermatitis. Dermatol. Clin. 1999; 17: 235–240. 26. Gupta, A. K. and Skinner, A. R. Management of diaper dermatitis. Int. J. Dermatol. 2004; 43: 830–834. 27. Hayakawa, R. and Matsunaga, K. Common conditions and factors associated with diaper dermatitis. Pediatrician 1987; 14(Suppl 1): 18–20. 28. Singalavanija, S. and Frieden, I. J. Diaper dermatitis. Pediatr. Rev. 1995; 16: 142–147.

29. Sires, U. I. and Mallory, S. B. Diaper dermatitis. How to treat and prevent. Postgrad. Med. 1995; 98: 79–84, 86. 30. Clayton, T. H., Wilkinson, S. M., Rawcliffe, C., et al. Allergic contact dermatitis in children: should pattern of dermatitis determine referral? A retrospective study of 500 children tested between 1995 and 2004 in one U.K. centre. Br. J. Dermatol. 2006; 154: 114–117. 31. Fernandez Vozmediano, J. M. and Armario Hita, J. C. Allergic contact dermatitis in children. J. Eur. Acad. Dermatol. ­Venereol. 2005; 19: 42–46. 32. Lynch, P. J. and Edwards. L. Red plaques with erythematous features. In Lynch, P. J. and Edwards, L. (eds) Genital Dermatology, pp. 27–55. Churchill Livingstone, New York, 1994. 33. Marren, P., Wojnarowska, F., and Powell, S. Allergic contact dermatitis and vulvar dermatoses. Br. J. Dermatol. 1992; 126: 52–56. 34. Seidenari, S., Giusti, F., Pepe, P., et al. Contact sensitization in 1094 children undergoing patch testing over a 7-year period. Pediatr. Dermatol. 2005; 22: 1–5. 35. Heng, M. C., Henderson, C. L., Barker, D. C., et al. Correlation of Pityosporum ovale density with clinical severity of seborrheic dermatitis as assessed by a simplified technique. J. Am. Acad. Dermatol. 1990; 23: 82–86. 36. Skinner, R. B., Jr., Noah, P. W., Zanolli, M. D., et al. The pathogenic role of microbes in seborrheic dermatitis. Arch. Dermatol. 1986; 122: 16–17. 37. Farber, E. M. and Nall, L. Childhood psoriasis. Cutis 1999; 64: 309–314. 38. Janniger, C. K., Schwartz, R. A., Musumeci, M. L., et al. Infantile psoriasis. Cutis 2005; 76: 173–177. 39. Rogers, M. Childhood psoriasis. Curr. Opin. Pediatr. 2002; 14: 404–409. 40. Carroll, C. L. and Fleischer, A. B., Jr. Tacrolimus ointment: the treatment of atopic dermatitis and other inflammatory cutaneous disease. Exp. Opin. Pharmacother. 2004; 5: 2127–2137. 41. Gisondi, P., Ellis, C. N., and Girolomoni, G. Pimecrolimus in dermatology: atopic dermatitis and beyond. Int. J. Clin. Pract. 2005; 59: 969–974. 42. Steele, J. A., Choi, C., and Kwong, P. C. Topical tacrolimus in the treatment of inverse psoriasis in children. J. Am. Acad. Dermatol. 2005; 53: 713–716. 43. Boerio, M., Brooker, J., Freese, L., et al. Pediatric dermatology: that itchy scaly rash. Nurs. Clin. North Am. 2000; 35: 147–157. 44. Wuthrich, B. Clinical aspects, epidemiology, and prognosis of atopic dermatitis. Ann. Allergy Asthma Immunol. 1999; 83: 464–470. 45. Beck, L A. The efficacy and safety of tacrolimus ointment: a clinical review. J. Am. Acad. Dermatol. 2005; 53(Suppl 2): S165–S170. 46. Breuer, K., Werfel, T., and Kapp, A. Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. Am. J. Clin. Dermatol. 2005; 6: 65–77. 47. Hultsch, T., Kapp, A., and Spergel, J. Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Dermatology 2005; 211: 174–187. 48. Maronn, M. L., and Esterly, N. B. Constipation as a feature of anogenital lichen sclerosus in children. Pediatrics 2005; 115: e230–e232. 49. McLelland, J. Lichen sclerosus in children. J. Obstet. Gynaecol. 2004; 24: 733–735. 50. Powell, J. and Wojnarowska, F. Childhood vulval lichen sclerosus and sexual abuse are not mutually exclusive diagnoses. Br. Med. J. 2000; 320: 311. 51. Powell, J. and Wojnarowska, F. Childhood vulvar lichen sclerosus: an increasingly common problem. J. Am. Acad. Dermatol. 2001; 44: 803–806.

References 52. Powell, J, and Wojnarowska, F. Childhood vulvar lichen sclerosus. The course after puberty. J. Reprod. Med. 2002; 47: 706–709. 53. Fischer, G. and Rogers, M. Treatment of childhood vulvar lichen sclerosus with potent topical corticosteroid. Pediatr. Dermatol. 1997; 14: 235–238. 54. Meffert, J. J., Davis, B. M., and Grimwood, R. E. Lichen sclerosus. J. Am. Acad. Dermatol. 1995; 32: 393–416. 55. Ridley, C. M. Genital lichen sclerosus (lichen sclerosus et atrophicus) in childhood and adolescence. J.R. Soc. Med. 1993; 86: 69–75. 56. Halder, R. M. Childhood vitiligo. Clin. Dermatol. 1997; 15: 899–906. 57. Darmstadt, G. L. and Lane, A. T. Impetigo: an overview. ­Pediatr. Dermatol. 1994; 11: 293–303. 58. Hogan, P. Paediatric dermatology. Impetigo. Aust. Fam. Physician. 1998; 27: 735–736. 58a. Oranje, A. P., Chosidow, O., Sacchidanand, S., et al; Toc100224 Study Team. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study. Dermatology. 2007; 215: 331–340. 59. Herbst, R. A. Perineal streptococcal dermatitis/disease. Am. J. Clin. Dermatol. 2003; 4: 555–560. 60. Kokx, N. P., Comstock, J. A., and Facklam, R. R. Streptococcal perianal disease in children. Pediatrics 1987; 80: 659–663. 61. Krol, A. L. Perianal streptococcal dermatitis. Pediatr. Dermatol. 1990; 7: 97–100. 61a. Jones, R. N., Fritsche, T. R., Sader, H. S., et al. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected restraint gram-positive cocci. Antimicrob. Agents Chemother. 2006; 50: 2583–2586. 62. Annunziato, P. W. and Gershon, A. Herpes simplex virus infections. Pediatr. Rev. 1996; 17: 415–423. 63. Hornor, G. Ano-genital herpes in children. J. Pediatr. Health Care. 2006; 20: 106–114. 64. Whitley, R. J. Herpes simplex virus infection. Semin. Pediatr. Infect. Dis. 2002; 13: 6–11. 65. Dohil, M. A., Lin, P., Lee, J., et al. The epidemiology of ­molluscum contagiosum in children. J. Am. Acad. Dermatol. 2006; 54: 47–54. 66. Smith, K. J., Yeager, J., and Skelton, H. Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum. Int. J. Dermatol. 1999; 38: 664–672. 67. van der Wouden, J. C., Menke, J., Gajadin, S., et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev 2006; (2): CD004767. 68. Hornor, G. Ano-genital warts in children: sexual abuse or not? J. Pediatr. Health Care 2004; 18: 165–170. 69. Armstrong, D. K. and Handley, J. M. Anogenital warts in prepubertal children: pathogenesis, HPV typing and management. Int. J. STD AIDS 1997; 8: 78–81. 70. Fiorillo, L. Therapy of pediatric genital diseases. Dermatol. Ther. 2004; 17: 117–128. 71. Moscicki, A. B. Human papillomavirus infection in adolescents. Pediatr. Clin. North Am. 1999; 46: 783–807. 72. Obalek, S., Jablonska, S., and Orth, G. Anogenital warts in children. Clin. Dermatol. 1997; 15: 369–376. 73. Sisson, B. A. and Glick, L. Genital ulceration as a presenting manifestation of infectious mononucleosis. J. Pediatr. Adolesc. Gynecol. 1998; 11: 185–187. 74. Taylor, S., Drake, S. M., Dedicoat, M., et al. Genital ulcers ­associated with acute Epstein–Barr virus infection. Sex. Transm. Infect. 1998; 74: 296–297. 75. Cheng, S. X., Chapman, M. S., Margesson, L. J., et al. Genital ulcers caused by Epstein–Barr virus. J. Am. Acad. Dermatol. 2004; 51: 824–826.

76. Lorenzo, C. V. and Robertson, W. S. Genital ulcerations as presenting symptom of infectious mononucleosis. J. Am. Board Fam. Pract. 2005; 18: 67–68. 77. Rudy, S. J. Superficial fungal infections in children and adolescents. Nurse Pract. Forum. 1999; 10: 56–66. 78. Chosidow, O. Scabies and pediculosis. Lancet 2000; 355: 819–S26. 79. Karthikeyan, K. Treatment of scabies: newer perspectives. Postgrad. Med. J. 2005; 81: 7–11. 80. Peterson, C. M. and Eichenfield, L. F. Scabies. Pediatr. Ann. 1996; 25: 97–100. 81. Pokorny, S. F. Long-term intravaginal presence of foreign ­bodies in children. A preliminary study. J. Reprod. Med. 1994; 39: 931–935. 82. Kaufman, R. H. and Faro, S. Traumatic lesions of the vulva and vagina. In Kaufman, R. H. and Faro, S. (eds) Benign ­Diseases of the Vulva and Vagina. 4th edn. pp. 389–399. Mosby, St. Louis, 1994. 83. Al-Khenaizan, S., Almuneef, M., and Kentab, O. Lichen sclerosus mistaken for child sexual abuse. Int. J. Dermatol. 2005; 44: 317–320. 84. Albers, S. E., Taylor, G., Huyer, D., et al. Vulvitis circumscripta plasmacellularis mimicking child abuse. J. Am. Acad. Dermatol. 2000; 42: 1078–1080. 85. Harth, W. and Linse, R. Dermatological symptoms and sexual abuse: a review and case reports. J. Eur. Acad. Dermatol. Venereol. 2000; 14: 489–494. 86. Porzionato, A., Alaggio, R., and Aprile, A. Perianal and vulvar Crohn’s disease presenting as suspected abuse. Forensic Sci. Int. 2005; 155: 24–27. 87. Kulthanan, K., Akaraphanth, R., Piamphongsant, T., et al. Linear IgA bullous dermatosis of childhood: a long-term study. J. Med. Assoc. Thai 1999; 82: 707–712. 88. Rabinowitz, L. G. and Esterly, N. B. Inflammatory bullous diseases in children. Dermatol. Clin. 1993; 11: 565–581. 89. Pereira, F. A., Mudgil, A. V., and Rosmarin, D. M. Toxic ­epidermal necrolysis. J. Am. Acad. Dermatol. 2007; 56: 181–200. 90. Sheridan, R. L., Schulz, J. T., Ryan, C. M., et al. Long-term consequences of toxic epidermal necrolysis in children. Pediatrics. 2002; 109: 74–78. 91. Arevalo, J. M., Lorente, J. A., Gonzalez-Herrada, C., et al. Treatment of toxic epidermal necrolysis with cyclosporin A. J. Trauma. 2000; 48: 473–478. 92. Martin Mateos, M. A., Roldan, R. A., and Munoz-Lopez, F. Erythema multiforme: a review of twenty cases. Allergol. Immunopathol. (Madr.) 1998; 26: 283–287. 93. Weston, W. L. What is erythema multiforme? Pediatr. Ann. 1996; 25: 106–109. 94. Kumar, S., Sehgal, V. N., and Sharma, R. C. Acrodermatitis enteropathica. J. Dermatol. 1997; 24: 135–136. 95. Perafan-Riveros, C., Franca, L. F., Alves, A. C., et al. Acrodermatitis enteropathica: case report and review of the literature. Pediatr. Dermatol. 2002; 19: 426–431. 96. Piela, Z., Szuber, M., Mach, B., et al. Zinc deficiency in exclusively breast-fed infants. Cutis. 1998; 61: 197–200. 97. Howarth, D. M., Gilchrist, G. S., Mullan, B. P., et al. Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 1999; 85: 2278–2290. 98. Huang, F. and Arceci, R. The histiocytoses of infancy. Semin. Perinatol. 1999; 23: 319–331. 99. Diefenbach, K. A. and Breuer, C. K. Pediatric inflammatory bowel disease. World J. Gastroenterol. 2006; 12: 3204– 3212. 100. Dinulos, J. G., Darmstadt, G. L., Len, M. K., et al. Infantile Crohn disease presenting with diarrhea and pyoderma ­gangrenosum. Pediatr. Dermatol. 2006; 23: 43–48.

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Pediatric Vulvar Disorders 101. Feller, E. R., Ribaudo, S., and Jackson, N. D. Gynecologic aspects of Crohn’s disease. Am. Fam. Physcian 2001; 64: 1725–1728. 102. Ploysangam, T., Heubi, J. E., Eisen, D., et al. Cutaneous Crohn’s disease in children. J. Am. Acad. Dermatol. 1997; 36: 697–704. 103. Deitch, H. R., Huppert, J., and Hillard, P. J. Unusual vulvar ulcerations in young adolescent females. J. Pediatr. Adolesc. Gynecol. 2004; 17: 13–16. 104. Huppert, J. S., Gerber, M. A., Deitch, H. R., et al. Vulvar ­ulcers in young females: a manifestation of aphthosis. J. Pediatr. Adolesc. Gynecol. 2006; 19: 195–204.

105. Letsinger, J. A., McCarty, M. A., and Jorizzo, J. L. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J. Am. Acad. Dermatol. 2005; 52: 500–508. 106. McCarty, M. A., Garton, R. A., and Jorizzo, J. L. Complex aphthosis and Behcet’s disease. Dermatol. Clin. 2003; 21: 41–48, vi. 107. Rogers, R. S., Complex aphthosis. Adv. Exp. Med. Biol. 2003; 528: 311–316.

PART: II  Gynecologic Dermatology

CHAPTER 27

Vulvodynia Libby Edwards

Vulvodynia is defined as chronic burning, stinging, irritation, soreness, rawness, stabbing, or other painful sensations of the vulva in the absence of any clinical or laboratory abnormalities that could account for the discomfort. Itching is not a typical symptom.

Epidemiology and clinical manifestations Vulvodynia is an extremely common condition. Several surveys report that approximately 10–16% of women have experienced unexplained chronic vulvar pain at some point in their life, and about 4–7% of women experienced unexplained discomfort at the time of surveys1–3. Vulvodynia occurs in Caucasians and African women at similar rates, and may be increased in women of Hispanic background1. The incidence in Asians is unknown. It generally occurs after the teenage years. Patients typically present with pain with intercourse. Most women report that any touch or pressure to the vulva, including tight clothes, wiping, tampon insertion, and sexual activity, produces pain. Some women have pain only with touch, whereas others have pain that is only worsened by touch, or an occasional patient experiences pain that is completely independent of touch or pressure. Pain ranges from mild, annoying discomfort to severe pain that precludes activities of daily living, including exercising, sexual activity, and sometimes even sitting. Most patients believe that chronic yeast infections or bacterial vaginosis are the cause of their burning. Although these infections may have occurred, they are nearly always coincidental, and patients rarely report that symptoms completely remit, even briefly, with treatment. As a result, some women are convinced that they have resistant infections, and believe that they may have a compromised immune system. By definition, the physical examination of women with vulvodynia shows no specific cause for pain. Mild erythema is sometimes present, and patients usually indicate the vulvar vestibule as the area of greatest discomfort. Many women, however, experience pain that extends beyond the vestibule at least at times, and some patients

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report discomfort involving the labia majora and even the perineum and perianal skin. Pressing on the vulva with a cotton-tipped applicator usually elicits pain in the vestibule, sometimes with discomfort that extends beyond that area. An occasional person reports no pain with cotton-tipped applicator pressure despite background, constant vulvar burning or pain. Often, women with vulvodynia exhibit coincidental abnormalities such as Candida albicans, irritant contact dermatitis, bacterial vaginosis, or other abnormalities, but these are insufficiently severe to produce the degree of discomfort. When these factors are corrected, and the discomfort remains, a diagnosis of vulvodynia is confirmed. Vulvodynia has been classified into different subsets depending upon location of pain and the presence of spontaneous pain (unprovoked) versus pain only to touch or irritants (provoked). The significance of these subsets lies in the possibility of different etiologies for different patterns; the importance of standardizing terminology so that research evaluates like populations; and the fact that surgical therapy is only appropriate for very localized forms of vulvodynia. The International Society for the Study of Vulvovaginal Disease has clarified and redefined the classification and terminology of vulvar pain vulvodynia and subsets4. This new classification divides causes of pain into that produced by specific disorders and vulvodynia, and further divides vulvodynia according to location and the presence or absence of pain with touch, friction, pressure, urine, or other usually nonpainful stimuli (Box 27.1). From a practical standpoint, patients with vulvodynia most often fall into one of two major patterns. First, and most common, is that of vestibulodynia (formerly called vulvar vestibulitis, vulvar vestibulitis syndrome, vestibular adenitis, and infection of the minor vestibular glands). These patients tend to be premenopausal and report pain with touch in the vestibule, including sexual activity, constricting clothing, tampon use, and bicycle-riding. Nonspecific erythema within the vestibule is sometimes present (Figure 27.1). The other primary pattern is that of generalized vulvodynia, where discomfort is either generalized or migratory, and generally reported to be

B o x 2 7 . 1  T e r m i n o l o g y a n d Classification of Vulvar Pain A. Specific disorders (skin disease, infection, tumors, neurologic diseases) B. Vulvodynia Generalized or migratory in location Provoked by touch or other stimulation Spontaneous Mixed (both provoked and spontaneous) Strictly localized at all times to same area Provoked by touch or other stimulation (vestibulodynia, clitorodynia) Spontaneous Mixed (both provoked and spontaneous) Adapted from: Moyal-Barracco, M. and Lynch, P. J. 2003 ISSVD ­terminology and classification of vulvodynia: a historical perspective. J. Reprod. Med. 2004; 49: 772–777.

Figure 27.1  Vestibulodynia (vulvar vestibulitis) is characterized by pain to touch in the vestibule, sometimes associated with redness that is often localized to the ostia of vestibular glands just external to the hymeneal caruncles.

i­ ndependent of touch. Unfortunately, few studies carefully characterize patients with vulvodynia sufficiently to validate the separation of two or more subsets, and this author and others do not find these to be easily separable subsets5,6. Most patients exhibit symptoms that exist on a spectrum, with considerable overlap, suggesting that vestibulodynia and generalized vulvodynia are variants of the same process. Often, patients report comorbid conditions, including interstitial cystitis, chronic constipation or irritable bowel syndrome, fibromyalgia, headaches, temporomandibular joint syndrome,

Pathogenesis

low-back pain, depression, anxiety, premenstrual syndrome, sleep disorders, multiple medication “allergies,” and low energy levels7.

Diagnosis and differential diagnosis The differential diagnosis of vulvodynia includes any cause of vulvovaginal pain. Vulvar pain can occur with infection, skin disease, and several specific neurologic diseases, such as pudendal neuralgia or postherpetic neuralgia. These causative conditions are usually easily identified with a history and a careful physical examination. Most common infections are unlikely causes of chronic pain; bacterial vaginosis more often produces ­ discharge and odor, whereas C. albicans usually causes itching. However, more subtle or unusual presentations of infection in skin disease must be ruled out. Bacterial vaginitis (streptococcal or staphylococcal) and non-albicans Candida infection (such as C. glabrata or C. krusei) are occasional causes of vulvovaginal pain. Specific skin diseases that produce erosions or ulcerations cause pain; most common are lichen planus, and secondarily scratched or eroded lichen sclerosus and lichen simplex chronicus. More subtle are dermatoses of the vaginal epithelium, which result in irritating vaginal secretions that produce an irritant contact dermatitis of the vestibule. These dermatoses include desquamative inflammatory vaginitis as well as erosive dermatoses such as lichen planus and the much less common cicatricial pemphigoid and pemphigus vulgaris. Specific neuropathic pain syndromes mimic vulvodynia: diabetic neuropathy, postherpetic neuralgia (which occurs following herpes zoster virus infection rather than herpes simplex virus infection); and pudendal neuralgia8. At times, nerve root compression from a protruding disk, or central nervous system diseases such as multiple sclerosis, cause pain, but these are generally not localized to the vulva. The diagnosis of vulvodynia can be made largely by history, with the majority of women selfreporting chronic burning or irritation ultimately receiving a diagnosis of vulvodynia9. However, in order to avoid missing the occasional patient with an easily correctable cause of pain, these conditions must be ruled in or out by a careful

physical examination, routine vaginal cultures, and the careful evaluation of a wet amount of vaginal secretions for both infectious organisms and inflammation. Neuropathic pain syndromes can be more difficult to rule out, although a history and physical examination to include a local neurologic examination usually help to identify specific, definable neurologic causes of pain. Even when abnormalities are identified and corrected, factors such as C. albicans, irritant contact dermatitis, and mild vaginal inflammation are often found to be merely coincidental and not causative.

Laboratory findings and histology There are no relevant accompanying laboratory abnormalities in patients with vulvodynia, although vaginal cultures frequently yield coincidental trivial infection or colonization. A biopsy of affected vulvar skin typically shows a ­nonspecific, mild, chronic perivascular inflammatory infiltrate, frequently with accompanying mild acanthosis and hyperkeratosis. This represents normal histology of the vulva.

Pathogenesis The pathogenesis of vulvodynia appears to be multifactorial. Vulvodynia is a symptom rather than a disease, so that different factors may operate in different patients. Factors include neurologic abnormalities, pelvic floor dysfunction, irritant contact dermatitis, inadequate estrogen effects, and psychosexual factors (Box 27.2). Most vulvologists believe the most likely underlying factor in vulvodynia is that of a neuropathic genital pain syndrome not diagnosable as a specific neuropathy10. Most likely, some patients experience vulvodynia as a result of peripheral neuropathy11,12, whereas others may have vulvar pain as a result of complex regional pain syndrome (reflex sympathetic dystrophy) or from an injury or other insult that triggers the pain13. Still others may experience discomfort as a result of a central nervous system processing disorder, where normal touch is perceived centrally as a painful sensation14,15. This could help to explain many of the comorbid conditions commonly reported by women with vulvodynia.

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Box 27.2   Vulvodynia Diagnosis History Burning, stinging, rawness, irritation, pain, stabbing, tearing Negative history for specific neuropathic disease, including diabetic neuropathy or postherpetic neuralgia

B o x 2 7 . 3  T h e r a p y o f V u l v o d y n i a – An Algorithm Nonspecific – but important – therapy Patient education on vulvodynia, with written materials; join the National Vulvodynia Association Counseling Avoidance of irritants and unnecessary topical agents Lidocaine jelly 2%/ointment 5%

Clinical examination showing normal skin or macular erythema

Amitriptyline/gabapentin/venlafaxine/duloxetine/ pregabalin

Negative wet mount and vaginal culture

Pelvic floor therapy

Differential Diagnosis

Surgery (for vestibulodynia only, if not controlled by medical therapy)

Infection (especially non-albicans Candida, bacterial vaginitis, herpes simplex virus infection) Erosive dermatoses (lichen planus, excoriated lichen simplex chronicus, lichen sclerosus) Atrophic vaginitis Desquamative inflammatory vaginitis and associated noninfectious inflammatory vaginitis Neurologic diseases: postherpetic neuralgia, diabetic neuropathy, multiple sclerosus

The pelvic floor plays an etiologic role in vulvodynia. Surface electromyography of most women with vulvodynia shows increased resting tension and irritability of pelvic floor muscles, but overall weakness16. Exercises or physical therapy that normalize these pelvic floor muscles gradually, but remarkably, improve symptoms in most women17. Often, an important factor producing vulvar irritation is the multiple treatments empirically used, including topical treatments for infection and skin disease, as well as rigorous washing and drying techniques. Destructive therapies for warts and malignancy sometimes precipitate pain. Several studies have shown a decrease in estrogen receptors of the vulva in women with vulvodynia, and estrogen deficiency may result in an increase in local nerve density18. Also, some clinicians informally describe good results with the use of topical estrogens, even in premenopausal women with normal wet mounts. This suggests a role for insufficient estrogen effect in some patients. Nearly all women with vulvodynia report depression and psychosexual dysfunction7,19,20. Some clinicians believe that vulvodynia is a psychosexual symptom21, whereas most vulvologists

believe that vulvodynia has specific, although variable and often unknown, physiologic bases, with depression and psychosexual dysfunction as one underlying, and nearly always exacerbating, factor. Most clinicians believe that psychological factors play a striking role in some patients and a minor role in others.

Therapy and prognosis The treatment of vulvodynia requires time, communication, medication for neuropathic pain, and counseling (Box 27.3). Many patients benefit from pelvic floor exercises and physical therapy, and an occasional patient requires surgery to excise a painful area. The vulvodynia guideline, written by experienced vulvologists of many disciplines, describes currently available therapies22. A mainstay in the therapy of vulvodynia is patient education and counseling. Although common, the existence of vulvodynia is not widely appreciated, and a referral to the National Vulvodynia Association (www.NVA.org) for support and further information is invaluable. Patient handouts are crucial, because vulvodynia is a disease that is unfamiliar to most women; written information helps women to feel that this is a real disease and that they are not alone. Daily nonspecific local care is very useful for some women, including minimizing irritants and the use of nonallergenic topical anesthetics such as lidocaine (Xylocaine) jelly 2% as needed for pain, and applied liberally about 20 minutes before sexual activity.

Pelvic floor therapy

Specific topical therapy Lidocaine ointment 5% applied liberally in the vestibule and occluded overnight with a cotton ball has reported useful in one report, and the reporting group believes that the addition of estradiol cream to the lidocaine ointment produces better results23. Compounded amitriptyline and baclofen cream is used by some, as is topical nitroglycerin22.

Specific oral therapy A mainstay in the specific management of vulvodynia is oral medication for neuropathic pain. These oral medications are often difficult to take, producing side-effects such as drowsiness, dizziness, dry eyes and mouth, and weight gain, and the benefit is delayed. However, those women who can tolerate them often experience a dramatic improvement. There are no adequate, doubleblind, placebo-controlled trials evaluating the following medications in the treatment of vulvodynia. In general, there also are no open trials or series of significant number to provide conclusions; these are anecdotal. Tricyclic medications such as amitriptyline and desipramine are first-line therapy and often useful for those who can tolerate them24,25. These medications are begun at a low dose such as 5–10 mg an hour or two before bedtime, and gradually increased up to 150 mg, until the patient is comfortable, or until there are limiting side-effects, whichever occurs first. Second-line therapy is gabapentin (Neurontin), beginning at 100 mg each day and increasing up to 3200 mg in three divided doses, until the patient is comfortable, or until there are limiting sideeffects26. Venlafaxine (Effexor) and duloxetine (Cymbalta) are newer-generation ­antidepressants which exhibit a norepinephrine reuptake inhibitor effect, known to be beneficial for neuropathic pain. Venlafaxine is begun at a dose of 37.5 mg XR (extended-release) and increasing up to 150 mg XR. The most prominent side-effects are nausea, drowsiness, insomnia, dizziness, and dry mouth. Abrupt withdrawal sometimes produces malaise and nausea. Duloxetine is started at 20 mg once daily and increased up to 60 mg.

Side-effects include nausea, dry mouth, constipation, decreased appetite, insomnia, and fatigue. Finally, most recently, pregabalin (Lyrica) has become available and is approved by the Food and Drug Administration for diabetic neuropathy and postherpetic neuralgia. Again, there are no clinical trials evaluating the effect of pregabalin on vulvodynia, but, anecdotally, this author has had several patients improve remarkably using this medication. Patients begin at 50 or 75 mg, and increase to as high as 300 mg twice daily if needed. Side-effects include drowsiness, fatigue, and leg edema. Historically, opioid analgesia has been of little benefit for patients with vulvodynia.

Intralesional therapy Currently, the role of intralesional therapy for vulvodynia is limited. An occasional patient presents with such localized discomfort as to represent a trigger point. Triamcinolone acetonide 10 mg/mL (Kenalog 10) injected into this painful area in a volume of about 0.1–0.3 mL sometimes effects significant alleviation of discomfort. In the event of improvement, many patients benefit from a second injection 3–6 weeks later, as the effect of the corticosteroid dissipates over about 1 month. Interferon-alpha injected locally into the vestibule of patients with vestibulodynia was reported to be useful in the past, but over time has not proved to be useful. Botulinum toxin A (Botox) has been used in many pain syndromes, and there are several early reports of use in vulvodynia27.

Pelvic floor therapy Those patients who are not adequately controlled with medication for neuropathic pain should have their pelvic floor evaluated. There are two common methods of addressing the pelvic floor. The most widely available is physical therapy, where internal massage and release of spasm as well as exercises relax and strengthen the pelvic floor28. There are no trials looking at formal physical therapy, but, anecdotally, many vulvologists report physical therapy as an enormous benefit in many of their patients. An alternative approach is surface electromyography to assess the degree of pelvic muscle

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dysfunction, followed by, if indicated, home exercises. These exercises, which are performed with a sensor in place to allow biofeedback, also eliminate irritability while strengthening pelvic floor muscles. Clinical trials suggest that 80–95% of women with vulvodynia who have a pelvic floor profile of high resting tension, irritability, and overall weakness improve very significantly as the pelvic floor normalizes29.

Surgical treatment Women with vestibulodynia, vulvar pain that is strictly limited to the vestibule and that occurs primarily with touch, usually benefit from surgery. A vestibulectomy has been shown in many independent trials to produce about an 85–93% marked improvement or cure rate in patients who are good candidates for this treatment30–32. This surgery should be performed by an experienced surgeon, and there is a slight risk of worsening pain. Before the patient is anesthetized, the area of the pain is mapped, using pressure with a cotton-tipped applicator. This area is then excised to include the hymeneal caruncles: the vaginal mucosa is undermined and advanced to cover the defect. The surgical area then naturally retracts into the vagina, leaving a normal-appearing vulva. Only the loss of hymeneal caruncles, generally not noticed even by an examining gynecologist, shows the effects of surgery. Those women who experience pain following surgery are likely to have symptoms in areas of the vestibule not excised at surgery. To avoid this possibility, many surgeons elect to remove even nonpainful portions of the vestibule. Otherwise, the most common cause of failure of a vestibulectomy is a patient whose pain either extended beyond the vestibule, or who had significant background burning. Specifically, carbon dioxide laser surgery is not helpful and should be avoided. It has served as a trigger for the development and worsening of pain.

Counseling Counseling, both individual and with a partner, as well as sex therapy are usually extraordinarily important in the successful management of vulvodynia. Studies show that, like other chronic pain

conditions, vulvodynia is associated with depression, and the nature of this pain introduces the added stresses associated with the disruption of sexual activity and intimacy in general. Whereas a minority of clinicians believe that vulvodynia is entirely produced by psychosexual dysfunction, most feel that psychological factors are significant in this multifactorial complex. Attention to this aspect is required to maximize the patient’s quality of life and hasten improvement, whether or not underlying psychosexual dysfunction causes vulvodynia or vulvodynia produces psychosexual dysfunction. Counseling is important to re-establish physical intimacy and to help re-establish libido33,34. Of patients whose symptoms are controlled with medication, nearly half, in one study, were able to discontinue medication after a year23. However, patients should be advised that there is no definitive cure for vulvodynia. The goals are control of vulvar burning and discomfort with reasonable therapy, so that pain is uncommon, and sexual activity is comfortable, and alleviation of the psychological symptoms of fear, isolation, and loss of intimacy.

References   1. Harlow, B. L. and Stewart, E. G. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J. Am. Med. Womens Assoc. 2003; 58: 82–88.   2. Arnold, L. D., Bachmann, G. A., Rosen, R., et al. Assessment of vulvodynia symptoms in a sample of US women: a prevalence survey with a nested case control study. Am. J. Obstet. Gynecol. 2007; 196: 128el–128.e6.   3. Lavy, R. J., Hynan, L. S., and Haley, R. W. Prevalence of vulvar pain in an urban, minority population. J. Reprod. Med. 2007; 52: 59–62.   4. Moyal-Barracco, M. and Lynch, P. J. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J. Reprod. Med. 2004; 49: 772–777.   5. Edwards, L. Subsets of vulvodynia: overlapping characteristics. J. Reprod. Med. 2004; 49: 883–887.   6. Masheb, R. M. and Lozano, C. On the reliability and validity of physician ratings for vulvodynia and the discriminant validity of its subtypes. Pain Med. 2004; 5: 349–358.   7. Arnold, L. D., Bachmann, G. A., Rosen, R., et al. Vulvodynia: characteristics and associations with comorbidities and quality of life. Obstet. Gynecol. 2006; 107: 617–624.   8. Beco, J., Climov, D., and Bex, M. Pudendal nerve decompresson in perineology: a case series. BMC Surg. 2004; 4: 15.   9. Reed, B. D., Haefner, H. K., Harlow, S. D., et al. Reliability and validity of self-reported symptoms for predicting vulvodynia. Obstet. Gynecol. 2006; 108: 906–913.

Further reading 10. Wesselmann, U., Burnett, A. L., and Heinberg, L. J. The ­urogenital and rectal pain syndromes. Pain. 1997; 73: 269–294. 11. Tympanidis, P., Casula, M. A., Yiangou, Y., et al. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur. J. Pain. 2004; 8: 129–133. 12. Tympanidis, P., Terenghi, G., and Dowd, P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br. J. Dermatol. 2003; 148: 1021–1027. 13. Tschanz, C., Salomon, D., Skaria, A., et al. Vulvodynia after CO2 laser treatment of the female genital mucosa. Dermatology 2001; 202: 371–372. 14. Foster, D. C., Dworkin, R. H., and Wood, R. W. Effects of intradermal foot and forearm capsaicin injectons in normal and vulvodynia-afflicted women. Pain 2005; 117: 128–136. 15. Giesecke, J., Reed, B. D., Haefner, H. K., et al. Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity. Obstet. Gynecol. 2004; 104: 126–133. 16. Reissing, E. D., Brown, C., Lord, M. J., et al. Pelvic floor muscle functioning in women with vulvar vestibulitis syndrome. J. Psychosom. Obstet. Gynaecol. 2005; 26: 107–113. 17. McKay, E., Kaufman, R. H., Doctor, U., et al. Treating vulvar vestibulitis with electromyographic biofeedback of pelvic floor musculature. J. Reprod. Med. 2001; 46: 337–342. 18. Ting, A. Y., Blacklock, A. D., and Smith, P. G. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol. Reprod. 2004; 71: 397–404. 19. Jantos, M., Burns, N. R. and Vulvodynia. Development of a psychosexual profile. J. Reprod. Med. 2007; 52: 63–71. 20. Wylie, K., Hallam-Jones, R., and Harrington, C. Psychological difficulties within a group of patients with vulvodynia. Psychosom. Obstet. Gynaecol. 2004; 25: 257–265. 21. Mascherpa, F., Bogliatto, F., Lynch, P. J., et al. Vulvodynia as a possible somatization disorder. More than just an opinion. J. Reprod. Med. 2007; 52: 107–110. 22. Haefner, H. K., Collins, M. E., Davis, G. D., et al. The vulvodynia guideline. J. Low. Genit Tract Dis. 2005; 9: 40–51. 23. Zolnoun, D. A., Hartmann, K. E., and Steege, J. F. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet. Gynecol. 2003; 102: 84–87. 24. McKay, M. Dysesthetic (“essential”) vulvodynia. Treatment with amitriptyline. J. Reprod. Med. 1993; 38: 9–13. 25. Reed, B. D., Caron, A. M., Gorenflo, D. W., et al. Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J. Low. Genit. Tract Dis. 2006; 10: 245–251. 26. Scheinfeld, N. The role of gabapentin in treating diseases with cutaneous manifestations and pain. Int. J. Dermatol. 2003; 42: 491–495.

27. Yoon, H., Chung, W. S., and Shim, B. S. Botulinum toxin A for the management of vulvodynia. Int. J. Impot. Res. 2007; 19: 84–87. 28. Hartmann, D., Strauhal, M. J., and Nelson, C. A. Treatment of women in the United States with localized, provoked vulvodynia: practice survey of women’s health physical therapists. J. Reprod. Med. 2007; 52: 48–52. 29. Danielsson, I., Torstensson, T., Brodda-Jansen, G., et al. EMG biofeedback versus topical lidocaine gel: a randomized study for the treatment of women with vulvar vestibulitis. Acta Obstet. Gynecol. Scand. 2006; 85: 1360–1367. 30. Goldstein, A. T., Klingman, D., Christopher, K., et al. Surgical treatment of vulvar vestibulitis syndrome: outcome assessment derived from a postoperative questionnaire. J. Sex Med. 2006; 3: 923–931. 31. Lavy, Y., Lev-Sagie, A., Hamani, Y., et al. Modified vulvar vesti­ bulectomy: simple and effective surgery for the treatment of vulvar vestibulitis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2005; 120: 91–95. 32. Gaunt, G., Good, A., and Stanhope, C. R. Vestibulectomy for vulvar vestibulitis. J. Reprod. Med. 2003; 48: 591–595. 33. Munday, P., Buchan, A., Ravenhill, G., et al. A qualitative study of women with vulvodynia: II. Response to a multidisciplinary approach to management. J. Reprod. Med. 2007; 52: 19–22. 34. Slowinski, J. Multimodal sex therapy for the treatment of vulvodynia: a clinician’s view. Sex Marital Ther. 2001; 27: 607–613.

Further reading Brachmann, G. A., Rosen, R., Pinn, V. W., et al. Vulvodynia: a stateof-the-art consensus on definitions, diagnosis and management. J. Reprod. Med. 2006; 51: 447–456. Edwards, L. New concept in vulvodynia. Am. J. Obstet. Gynecol. 2003; 189(3 suppl): S24–S30. Haefner, H. K., Collins, M. E., Davis, G. C., et al. The vulvodynia guideline. J. Low. Genit. Tract Dis. 2005; 9: 40–51. Lotery, H. E., McClure, N., Galask, R. P. Vulvodynia. Lancet 2004; 363: 1058–1060. Reed, B. D. Vulvodynia: diagnosis and management. Am. Fam. Physicians 2006; 73: 1231–1238. Smart, O. C. MacLean, A. B. Vulvodynia. Curr. Opin. Obstet. ­Gynecol. 2003; 15: 497–500.

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Appendices

Appendix 1

International Society for the Study of Vulvovaginal Disease Classification of Vulvar Disease Peter J. Lynch

Women with disorders of the vulva are cared for by clinicians trained in several different disciplines and each of these specialties has historically used its own terminology and classification for vulvar diseases. Furthermore, within each specialty, the terminology varied from country to country. This variability in nomenclature led to marked confusion and tremendous communication difficulties. Partly for this reason, the International Society for the Study of Vulvar Disease (ISSVD) was formed 35 years ago. The membership of this organization included a multinational assembly of gynecologists, dermatologists, pathologists, and others involved in the care of women with vulvar and vaginal disease. The ISSVD founding documents stated that one of the organization’s major goals was to develop and promulgate uniform terminology and classification that would be acceptable to all specialists from all countries. The initial classifications were established in the mid-1970s and revisions have subsequently been published from time to time. The history of these efforts is reviewed in three recent manuscripts that contain the current ISSVD classifications for vulvar pain, vulvar squamous cell intraepithelial neoplasia, and the vulvar dermatoses1–3. These classifications, and the terminology contained therein, are summarized in this appendix. However, we wish to emphasize that, in order to understand fully the rationale used in their formulation, it is important that the additional explanatory material contained in the original articles be reviewed.

Vulvar pain Vulvar pain can be divided into two categories: (1) pain secondary to a specific, identifiable, underlying disorder; and (2) “idiopathic” pain associated with no recognizable underlying disease. This second category of idiopathic pain was originally termed “the burning vulva syndrome”

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Table A1.1  International Society for the Study of Vulvar Disease (ISSVD) Terminology and Classification of Vulvar Pain (2003)

A. Vulvar Pain Related to a Specific Disorder 1. Infectious (e.g., candidiasis, herpes, etc.) 2. Inflammatory (e.g., lichen planus, immunobullous disorders, etc.) 3. Neoplastic (e.g., Paget’s disease, squamous cell carcinoma, etc.) 4. Neurologic (e.g., herpes neuralgia, spinal nerve compression, etc.) A. Vulvodynia 1.  Generalized (a) Provoked (sexual, nonsexual, or both) (b) Unprovoked (c) Mixed (provoked and unprovoked) 2.  Localized (vestibulodynia, clitorodynia, hemivulvodynia, etc.) (a) Provoked (sexual, nonsexual, or both) (b) Unprovoked (c) Mixed (provoked and unprovoked) Definitions and notes “Vulvodynia” is defined as vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder. Specifically, a peripheral neuropathy (e.g., related to herpes zoster or herpes simplex) should be excluded based on the lack of associated symptoms such as sphincter dysfunction, weakness in the lower limbs, or sensory changes such as hypoesthesia or anesthesia involving the area of discomfort. Vulvodynia is represented under the term “vulvar pain syndrome” in the classification of the International Society for the Study of Pain. “Relevant” takes into account the following considerations: (1) diffuse and periductal vestibular erythema (i.e., bilateral, usually symmetrical, erythema localized around the openings of Bartholin’s glands, and minute epithelial depressions) is a normal finding, and is therefore not responsible for vulvar discomfort; and (2) disorders such as genital warts, nevi, and cysts, may be present on the vulva but not be relevant (i.e., not necessarily responsible for vulvar discomfort). “Generalized” specifies involvement of the whole vulva and “localized” specifies involvement of a portion of the vulva such as the vestibule (vestibulodynia), the clitoris (clitorodynia), and the hemivulva (hemivulvodynia). “Unprovoked” means that the discomfort occurs spontaneously without a specific physical trigger; “provoked” means that the discomfort is triggered by physical contact. Such contact may be sexual, nonsexual, or both. Examples include intromission, clothing pressure, tampon insertion, cotton tip applicator pressure, and fingertip pressure. “Vestibulitis” has been deleted from the ISSVD terminology because the presence of inflammation, as implied by the suffix “-itis”, has not so far been documented. The term “vestibulitis” is now replaced by “provoked vestibulodynia,” defined as discomfort on intromission (introital dyspareunia), clothing pressure, tampon insertion, cotton tip applicator pressure, and fingertip pressure. Adapted with permission of the publisher from Moyal-Barracco, M., Lynch, P. J. 2003. ISSVD terminology and classification of vulvodynia: a historical perspective. J. Reprod. Med. 2004; 49: 772–777.

but was subsequently renamed “vulvodynia,” a term coined by Marilynne McKay, a previous editor of this book. More recently “vulvar dysesthesia” briefly replaced it but now, once again, “vulvodynia” has become the nomenclature of choice. In the mid-1980s, Eduard Friedrich and others identified a separate subset of patients with idiopathic vulvar pain. The pain these patients experienced was confined to the vulvar vestibule and was accompanied by entrance dyspareunia. On examination, varying degrees of vestibular redness were found. Such patients were said to have “vulvar vestibulitis.” Subsequently it has been shown that the redness was not due to inflammation and was instead just part of the normal spectrum of vulvar color. As a result, the ISSVD recommended

e­ limination of the term ­“vestibulitis” and replaced it with “vestibulodynia.” The current terminology and classification of vulvar pain (Table A1.1) were formulated in 2003 and continue in use today. They remain quite well accepted, though some members of the ISSVD now believe that there are few, if any, differences between localized and generalized vulvodynia and, for that reason, classification into these two categories may be unnecessary.

Vulvar squamous cell intraepithelial neoplasia A major effort has been made by the ISSVD to delete terms such as “carcinoma in situ,” ­“erythroplasia of Queyrat,” “Bowen’s disease,” and “bowenoid

Vulvar dermatoses

Table A1.2  Squamous cell Vulvar Intraepithelial ­Neoplasia (VIN): International Society for the Study   of Vulvar Disease (ISSVD) 2004 Modified Terminology VIN, usual type (a) VIN, warty type (b) VIN, basaloid type (c) VIN, mixed (warty/basaloid) type VIN, differentiated type Note: The occasional example of VIN that cannot be classified into either of the above VIN categories (usual or differentiated type) may be classified as VIN, unclassified type. The rare VIN of pagetoid type may be classified as such or placed in this category. Adapted with permission of the publisher from Sideri, M., Jones, R. W., Wilkinson, E. J., et al. Squamous vulvar intraepithelial neoplasia. 2004 modified terminology, ISSVD vulvar oncology subcommittee. J. Reproductive Med. 2005; 50: 807–810.

papulosis” as descriptors for ­squamous cell vulvar intraepithelial neoplasia (VIN). By analogy with cervical intraepithelial neoplasia (CIN), the ISSVD, in 1986, divided VIN into three categories: VIN 1, VIN 2, and VIN 3. However, it is now known that there are significant differences between VIN and CIN and thus use of this analogous classification may be inappropriate. First, in contrast to CIN, there is no evidence that VIN 1 is an obligate precursor for the development of malignancy. Second, squamous cell carcinoma of the cervix has only a single cause, human papillomavirus (HPV) infection, whereas VIN contains two subsets, one HPVrelated and the other not HPV-related. Third, the course of CIN is uniform, whereas the course for VIN is highly variable, depending on whether or not it is HPV- related. With these observations in mind, in 2004, the ISSVD membership approved the Oncology Committee’s report recommending significant modification to the earlier classification. This revised classification (Table A1.2) has several changes. First, it deletes “VIN 1.” Second, the histological changes previously identified as VIN 1 are now referred to as “HPV effect.” Third, VIN 2 and VIN 3 are grouped together and labeled simply as “VIN.” Fourth, VIN is divided into “VIN, usual type” and “VIN, differentiated type.” These two subtypes differ in several important ways. “VIN, usual type” is usually HPV-related, is often multifocal, progresses slowly, and tends to occur in younger women. On the other hand, “VIN, differentiated type” is not

HPV-related, is usually unifocal, progresses rapidly, is superimposed on an underlying inflammatory disorder, and tends to occur in older women.

Vulvar dermatoses Thirty years ago the ISSVD grouped the noninfectious, nonneoplastic “white” lesions previously termed leukoplakia, leukoplastic vulvitis, leukokeratosis, hyperplastic vulvitis, and kraurosis vulvae into a single category termed “the vulvar dystrophies.” This terminology served an important purpose in that it removed the connotation that these disorders were always precursors to malignancy and it also reduced the number of vulvectomies used to treat them. The term “dystrophy,” however, was not popular with everyone primarily because it had no real clinical or histological meaning. Subsequently, in 1987, these disorders were recategorized as “nonneoplastic epithelial disorders.” Although this nomenclature remained in place for 20 years, it came under increasing criticism, especially from dermatologists and dermatopathologists. With these concerns in mind, a multinational ISSVD committee (comprised of two gynecologists, two dermatologists, and a pathologist) was appointed in 2003 with instructions to review and, possibly recommend, revision of the classification. The committee recognized that most of the conditions contained within the ­ nonneoplastic epithelial disorders represented well-recognized dermatological diseases. For this reason, the ­committee ­recommended that the title of the category be changed from “nonneoplastic epithelial disorders” to that of “vulvar dermatoses.” In debating which diseases were to be classified within the vulvar dermatoses, the committee initially considered simply listing the standard dermatologic names of the disorders. However, it was quickly realized that consensus could not be reached over which diseases, and which of their variable names, should be included. Moreover, they concluded that such a listing would not be helpful for ­ nondermatologists when faced with a condition they did not recognize. The committee then considered basing the classification on etiology or pathogenesis but felt that knowledge in these areas was incomplete and was likely to

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Table A1.3  2006 International Society for the Study of Vulvar Disease (ISSVD) Classification of Vulvar Derma­ toses: Pathological Subsets and their Clinical Correlates Spongiotic Pattern Atopic dermatitis Allergic contact dermatitis Irritant contact dermatitis Acanthotic Pattern (Formerly, Squamous Cell Hyperplasia) Psoriasis Lichen simplex chronicus Primary (idiopathic) Secondary (superimposed on lichen sclerosus, lichen planus, or other vulvar disease) Lichenoid Pattern Lichen sclerosus Lichen planus Dermal Homogenization/Sclerosis Pattern Lichen sclerosus Vesiculobullous Pattern Pemphigoid, cicatricial type Linear immunoglobulin A disease Acantholytic Pattern Hailey–Hailey disease Darier’s disease Papular genitocrural acantholysis Granulomatous Pattern Crohn’s disease Melkersson–Rosenthal syndrome Vasculopathic Pattern

advance too rapidly to allow for a durable classification. Moreover, once again, they recognized that such a classification would not help clinicians identify a condition that was unfamiliar to them. Eventually it became apparent that a classification based on lesion morphology would represent a better approach. Unfortunately using clinical morphology proved to be unworkable given the multitude of disease names used by various specialists residing in different countries. In addition, most diseases can present with varying types of morphology, making such a classification very cumbersome. The committee eventually settled, instead, on using histological morphology (with pathological subsets and their clinical correlates) as the basis for classification. This decision was largely based on the recognition that histologic terminology is quite standardized from one country to another and the fact that it is accepted by physicians regardless of their different specialty backgrounds. One might wonder how such a classification could be helpful to a clinician encountering an unrecognized disease. To answer this question, the committee stated that, in such a situation, the clinician would undoubtedly perform a biopsy. The pathologist would then either render a specific diagnosis (in which case the problem was solved) or, if that were not possible, would identify the histological pattern that was present and recommend that clinicopathologic correlation be used to arrive at a specific diagnosis. At that point, the clinician could then use the new histological classification with its clinical correlates. The classification (Table A1.3) based on this approach was approved by the ISSVD membership in 2006.

Aphthous ulcers Behçet’s disease Plasma cell vulvitis Note: The histological patterns we have included in the classification are generally well accepted and widely used by pathologists. Nevertheless, we judged that, for clinicians, better clarity and more usefulness could be achieved if simplified definitions and guidelines for use of the histological patterns were to accompany the classification. The definitions we formulated for the histological patterns are largely based on the widely used, and highly respected, dermatopathology textbooks of Weedon and McKee. Please see the complete original manuscript for these definitions3. We also considered including definitions of the clinical entities contained within the histological patterns but elected not to do so, reasoning that such definitions are readily available to clinicians in standard textbooks of dermatology and vulvology. Adapted with permission of the publisher from Lynch, P. J., Moyal­Barracco, M., Bogliatto, F., et al . 2006 ISSVD classification of vulvar dermatoses: pathological subsets and their clinical correlates. J. Reprod. Med. 2007; 52: 3–9.

References 1. Moyal-Barracco, M. and Lynch, P. J. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J. Reprod. Med. 2004; 49: 772–777. 2. Sideri, M., Jones, R. W., Wilkinson, E. J., et al. Squamous vulvar intraepithelial neoplasia. 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J. Reprod. Med. 2005; 50: 807–810. 3. Lynch, P. J., Moyal-Barracco, M., Bogliatto, F., et al. 2006 ISSVD classification of vulvar dermatoses: pathological subsets and their clinical correlates. J. Reprod. Med. 2007; 52: 3–9.

Appendices

Appendix 2

Evaluation of Vulvovaginal Disease Libby Edwards

The evaluation of chronic vulvovaginal disease differs somewhat from that of skin disease appearing on other skin surfaces. An understanding of several general principles of the diagnosis and evaluation of skin disease or symptoms of vulvovaginal skin allows for better care (Table A2.1). Normal variants often mimic skin disease. There is wide variation in the shape, size, and symmetry of the labia minora. Some women have very small labia minora, whereas other women have large, redundant labia minora, sometimes asymmetric, and sometimes extending well below the labia majora. The origin of the labia minora is sometimes bifid, originating both from the clitoral frenulum and the edge of the clitoral hood or the medial labium majus (Figure A2.1). Most asymptomatic premenopausal women exhibit erythema of modified mucous membranes, and redness is more marked in lightcomplexioned women. This normal erythema of modified mucous membranes is often misinterpreted by the patient and the examiner as inflammation (Figure A2.2). Vulvar papillomatosis is sometimes mistaken for genital warts. These tubular projections are characterized by rounded tips and symmetrical distribution. Clusters of lesions show papillae that are discrete to the base, whereas genital warts produced by papillomavirus infections are fused at the base. Vulvar papillomatosis classically occurs in the vestibule, but can be seen on any surface of the modified mucous membranes (Figures A2.3–A2.5). The ostia of the vestibular glands appear primarily just external to the hymeneal caruncles, but they are sometimes seen in other areas of the vulva (Figure A2.6). These ostia range from a few to many, and they are generally symmetrical. Fordyce spots consist of enlarged sebaceous glands manifested by lobular, hypopigmented to yellowish papules which are most often noted on the medial aspect of the labia minora, but can occur on any aspect of the modified mucous membranes of the vulva except for the vestibule (Figure A2.7). While Fordyce spots vary in size and number, these are normal findings in the premenopausal woman, and they do not cause symptoms.

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Evaluation of Vulvovaginal Disease

Table A2.1  Issues in the Evaluation of Women with Chronic Vulvovaginal Symptoms Normal variants can be confusing Subtle abnormalities sometimes cause marked symptoms Vulvovaginal symptoms are often multifactorial Iatrogenic disease is common Morphologic appearance of diseases tends to be ­nonspecific Many inflammatory diseases produce scarring

Figure A2.2  The labia minora are frequently asymmetrical, and the origin can be bifid.

Figure A2.1  Erythema of the modified mucous membranes of the vulva is not necessarily a sign of inflammation.

Very subtle vulvovaginal abnormalities occasionally produce striking symptoms, so the vulva and vagina should be examined carefully, with the patient in stirrups under a good light. Subtle findings may require minor magnification for adequate evaluation, but colposcopy of the vulva is not required. Trivial abnormalities should not be automatically discounted, but rather treated,

Figure A2.3  Vestibular papillomatosis is a normal finding consisting of discrete tubular or dome-shaped papules that are bilaterally symmetrical.

since they may or may not be responsible for symptoms. Skin disease on the vulva and in other skin folds differs morphologically from the classic appearance of those diseases on dry, keratinized skin.

Making a diagnosis 363

Figure A2.4  Often, vulvar papillomatosis consists of very closely set monomorphous papules that produce a cobblestoned surface, sometimes confused with diffuse human papillomavirus infection.

Figure A2.6  The ostia of vestibular glands are occasionally obvious, appearing as red or skin-colored pits.

Figure A2.5  Vulvar papillae are found not only in the vestibule, but sometimes on the labia minora as well.

Figure A2.7  Fordyce spots, ectopic sebaceous glands, are sometimes quite prominent and lobular, mimicking genital warts or cysts.

Both inflammatory diseases and erosive diseases often exhibit nonspecific inflammation clinically and histologically. For example, although psoriasis classically appears as sharply marginated red plaques with heavy, silvery scale, vulvar psoriasis usually manifests as moist, red plaques with inapparent or fine scale, and individual plaques are often poorly demarcated. Ulcers generally exhibit nonspecific morphology, so that an ulcer that displays a classic appearance for a disease may well actually be produced by an unrelated process. Not only is the morphologic appearance of skin disease on the vulva atypical compared to

other skin surfaces, but also erosive and intensely inflammatory diseases often produce scarring and resorption of normal architecture. Agglutination of the labia minora and adhesions of the clitoral hood to the clitoris are characteristic of lichen sclerosus, lichen planus, cicatricial pemphigoid, and pemphigus vulgaris (Figure A2.8). Even a single, short-lived episode of blistering erythema multiforme (Stevens–Johnson syndrome, toxic epidermal necrolysis) can produce loss of labia minora. Any chronic inflammation, including psoriasis, occasionally causes resorption of vulvar architecture1.

Appendix

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364

Figure A2.8  Scarring and patchy hyperpigmentation of the vulva are nonspecific findings that can be seen with a number of diseases, including lichen planus, lichen sclerosus, and cicatricial pemphigoid. In the absence of specific, active lesions of the genitalia or mouth, this patient was never diagnosed.

Figure A2.9  Lichen simplex chronicus, secondary staphylococcal skin infection, and contact dermatitis to benzocaine, demonstrate the common occurrence of ­multifactorial disease.

Quite often, chronic vulvar symptoms are produced by more than one abnormality. For example, psoriasis and lichen simplex chronicus are often accompanied by vulvovaginal candidiasis, and lichen simplex chronicus is frequently superimposed on lichen sclerosus, contact dermatitis, or psoriasis (Figure A2.9). Many women with chronic vulvovaginal symptoms compensate by washing frequently, using antibacterial soaps, and treating symptoms with over-the-counter medications. These activities sometimes produce secondary irritant or allergic contact dermatitis2. Vulvar symptoms cannot be evaluated adequately without an examination of the vaginal epithelium and a microscopic evaluation of vaginal secretions. Some skin diseases occur in the vagina, particularly lichen planus and desquamative inflammatory vaginitis. These conditions can produce vulvar or introital symptoms via

an irritant contact dermatitis from the purulent vaginal secretions characteristic of inflammatory and erosive vaginal skin diseases. The wet mount should be examined for signs of atrophic vaginitis, inflammatory vaginal secretions consistent with vaginal dermatoses, and both typical and unusual infections, including non-albicans Candida infection and bacterial vaginitis (in addition to bacterial vaginosis). Wet mounts and fungal preparations are performed with minor individual variations in technique. One easy method is to touch the cotton end of a cotton-tipped applicator into the pool of secretions in the cul-de-sac under the cervix, or any other area where secretions have collected. The applicator should not be rubbed against vaginal walls. A small drop of vaginal fluid is placed on two glass slides, and a drop of saline is added to one, and a drop of 10% potassium hydroxide

Making a diagnosis 365

Figure A2.10a  This vulva shows nonspecific findings of scarring and irregular hyperkeratosis. Figure A2.10b   An examination of the mouth revealed the pathognomonic lacy, white lesions of lichen planus, allowing   for diagnosis.

is placed on the other. A cover slip is then placed over the secretion/saline and secretion/potassium hydroxide mixtures. They are examined first under 10× power, evaluating the fungal preparation for hyphae/pseudohyphae, and the saline preparation for the presence of white blood cells, immature epithelial cells, clue cells, and hyphae/pseudohyphae. The wet mount is then examined under 40× to evaluate for budding yeast and the nature and numbers of bacteria. In the setting of chronic symptoms, a routine vaginal culture helps to eliminate subtle, resistant infections such as C. glabrata and C. krusei, which occasionally cause or exacerbate vulvovaginal symptoms, but often prove to be coincidental and unimportant.

Making a diagnosis Because the presentation of skin disease on modified mucous membranes is often nonspecific, and because multifactorial processes are usual, making

a definitive diagnosis can be difficult. An examination of other skin surfaces and the oral mucosa can be helpful. The same disease that presents nonspecifically on the vulva can exhibit very specific and even pathognomonic lesions when occurring in the mouth or on extragenital sites (Figure A2.10). For those patients with an unknown diagnosis, a biopsy is sometimes useful. Only specific lesions should be sampled, because a biopsy of nonspecific erythema often yields a nonspecific histologic description rather than a diagnosis. When present, white epithelium or the edge of an erosion that includes both normal skin and a transition to the eroded area is a good site to sample. This author chooses the lesion to be sampled, then anesthetizes with 1% lidocaine with epinephrine buffered with sodium bicarbonate, with or without preceding topical anesthesia according to patient preference (Figure A2.11). A 10-minute wait for the onset of the vasoconstrictive effects of the epinephrine before obtaining the biopsy minimizes bleeding and hematoma formation.

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Figure A2.12  Because grasping the thin, fragile skin of the vulva, especially when inflamed, crushes the tissue, stabilizing the tissue with a suture allows for a less traumatic biopsy while allowing careful control of the depth and diameter of the sample.

Figure A2.11  When topical anesthesia is used before definitive anesthesia with intralesional lidocaine, it must be applied very heavily for at least 30 minutes. Table A2.2  Vulvar Biopsy Options Shave Biopsy Preferred Erosions Blisters Punch Biopsy Preferred Possible malignancy, especially melanoma Indurated lesions Hyperkeratotic lesions Excisional Biopsy For removal rather than sampling only

The vulva can be biopsied by punch, shave, or excision (Table A2.2). The choice of biopsy technique depends upon the location of the lesion, the nature of the lesion, and personal preference of the surgeon. Because a biopsy that does not extend to fat minimizes bleeding on mucous membranes and modified mucous membranes, a relatively

Figure A2.13 a, b  A punch biopsy confers the factor of depth, both allowing for visualization of deep aspects of the skin disease and increasing the complications of bleeding and slower healing; the punch should be buried to the hub to ensure sampling to fat.

Further reading

deep shave biopsy is one good technique for many skin lesions. The thin, slippery nature of vulvar skin makes traditional shave techniques difficult, but the skin can be stabilized by tethering with suture rather than grasping with forceps, which crushes tissue (Figure A2.12). Thicker, keratinized skin that requires biopsy can be sampled with either shave or punch biopsy technique, and pigmented lesions that could conceivably represent a melanoma are best sampled by punch or excision to ensure histologic visualization of the base of the lesion (Figure A2.13). Patients with erosive and blistering disease who have a nondiagnostic initial biopsy sometimes benefit from a direct immunofluorescence (DIF) biopsy of perilesional skin. In the case of an immunobullous disease, such as cicatricial pemphigoid or pemphigus vulgaris, a DIF biopsy usually shows characteristic or diagnostic changes indicated by the location of antibody deposition. Samples intended for DIF should be submitted in a special transport medium, such as Michele’s solution, rather than the formalin used for routine biopsies. Biopsy specimens of skin disease should be submitted to a dermatopathologist or a gynecologic

pathologist with a special interest in ­inflammatory skin disease. The specimen should be accompanied by a differential diagnosis to help guide the pathologist. Relatively often, a specific diagnosis cannot be made. Once infection and tumor have been ruled out, most diseases can be managed with patient education, careful supportive care, and topical corticosteroids. Follow-up visits sometimes yield new genital or extragenital lesions that allow for a definitive diagnosis.

References 1. Albert, S., Neill, S., Derrick, E. K., et al. Psoriasis associated with vulval scarring. Clin. Exp. Dermatol. 2004; 29: 354–356. 2. Kugler K, Brinkmeier, T, Frosch PJ, et al. [Anogenital dermatoses – allergenic and irritative causitive factors. Analysis of IVDK data and review of the literature.] J. Dtsch Dermatol. Ges. 2005; 3: 979–986.

Further reading Edwards, L. Dermatologic therapy of chronic genital disease. Dermatol. Ther. 2004; 17: 1–7.Pathogenesis

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Appendix 3

Principles of Therapeutics for Vulvovaginal Disease Libby Edwards

The management of women with chronic vulvovaginal symptoms requires a multifaceted approach. Generally, gynecologists are accustomed to curing their patients, and women expect their gynecologist to cure their problems. However, chronic vulvovaginal symptoms are most often produced by chronic dermatoses or pain syndromes which are not treated quickly or definitively. More often, their symptoms are controlled or improved, sometimes using more than one intervention. Some of the more common causes of management failures include unreasonable expectations, undertreatment either by potency or duration, and inattention to secondary factors.

Nonspecific measures There are several nonspecific measures that are important in achieving the best outcome for women with chronic vulvovaginal symptoms (Table A3.1). Inattention to these can prevent the success of otherwise correct and reasonable specific management.

Patient education Women with chronic vulvovaginal symptoms require education regarding the nature of their condition, therapy, expectations as to rapidity of improvement, and expectations as to duration of therapy Table A3.1  Nonspecific Measures Patient education Address depression, anxiety, psychosexual dysfunction Decrease irritants Control secondary infections Replace estrogen when deficient Re-evaluate flares

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required. Patients should be taught about their disease, causes, and the options for therapy. Most often, the conditions producing chronic vulvovaginal symptoms are unfamiliar to patients, so that written information can be crucial to understanding and successful management. Patient handouts on the more common diseases are found in Appendix 4. Part of patient education is reassurance regarding sexual transmission, infertility, risk of malignancy, absence of human immunodeficiency virus (HIV), or other dangerous accompanying diseases.

Attention to psychosexual issues An overriding factor in the management of chronic vulvovaginal symptoms is the usual anxiety and depression of patients, and the resulting psychosexual issues. In general, chronic pain or itching produces anxiety and depression and is worsened by this psychological dysfunction. Chronic vulvovaginal symptoms are especially anxietyprovoking due to patient concerns about potential issues of sexually transmitted disease, fertility, and malignancy. Self-esteem, sexual functioning, and intimate relationships suffer and compound symptoms. Inattention to the psychosexual aspects of vulvovaginal disease prevents optimal response to therapy. In addition to reassurance, antidepressant therapy, and psychological counseling, couple counseling to include sex therapy is often crucial in producing maximal improvement.

Avoidance of irritants The local environment of anogenital skin produces unique issues. Chronic symptoms are usually multifactorial. Prolonged moisture from sweat, urine, and normal and abnormal vaginal secretions, friction of skin folds, and heat combine to increase the risk of intermittent trivial but annoying infections, heavy colonization of normal organisms, and irritant contact dermatitis. The clinician should evaluate for any contributing factors both on the vulva and within the vagina. Specifically, irritant contact dermatitis from overwashing, an atrophic vagina from estrogen deficiency, and secondary infections should be evaluated for and addressed. A handout

which specifically lists irritating ­activities to avoid can be extremely useful for patients who may find a drastic change in habits psychologically difficult (Table A3.2). Many women have focused on their vulvovaginal symptoms, arranging their lives, activities, diet, and choice of clothing all in the context of their genital symptoms. Therefore, minimizing daily care often helps to relieve anxiety as well. For a woman with isolated vulvovaginal symptoms, the choice of detergent and fabric softener is unimportant. Double-rinsing underwear serves no purpose. The color and the fabric of panties are unimportant unless the patient finds that particular types of underwear are uncomfortable. Low-yeast diets, avoidance of sugar, and eating or douching with yogurt or lactobacilli provide no substantiated benefits. Not only do overuse of medications and hygiene measures by patients worsen symptoms, but clinician-prescribed therapies frequently cause or exacerbate symptoms. For example, antibiotics or corticosteroids can precipitate yeast, and creams contain alcohols and preservatives that can sting with application and produce an irritant dermatitis. Therefore, ointments are generally preferred over creams. When reasonable, oral therapy is favored over topical medication in order to avoid these problems. Patients who require vaginal corticosteroids, vaginal estrogen, or antibiotics, and particularly those who receive a combination of these agents, are at a high risk for secondary candidiasis. These patients benefit from initial preventive Table A3.2  Common Irritants Too frequent washing Soaps Panty liners Topical medications   Benzocaine   Antifungal medications   Any cream Hair dryers Fingernails Personal lubricants (KY)

Nonspecific measures

­ edication, most often in the form of weekly flum conazole 150 mg. Patients who have flares of their symptoms should be re-evaluated. Often, the flare is produced by a new problem, and a telephone diagnosis is substandard care.

First aid for acute symptoms and flares Patients with severe itching or burning due to inflammation, redness, erosion, ulceration, excoriation, or infection often need immediate first aid for comfort while awaiting effects of specific therapy (Table A3.3). In addition to reassurance and patient education, there are nonspecific measures that can improve symptoms in the short term. The first item to address is the possibility of an intercurrent infection. Women should not receive empiric therapy, but only treatment for confirmed infection. Patients should be cultured if the index of suspicion is high, but microscopic confirmation is lacking. Tepid or cool tap-water soaks are often helpful for itching and pain. These can be achieved in a bathtub with a temperature that is comfortable, soaking for 10–15 minutes two or three times a day. For those women unable to use tub soaks, a sitz bath in a shallow pan can be used. A less satisfactory alternative is the application of wet towels to the area. Women with fissures, erosions, or ulcers may experience stinging when water first touches the skin. However, this is usually short-lived, and the soaks provide some degree of comfort. As the cells of the epidermis are hydrated and swell, fissures and cracks close temporarily, decreasing the sensation of irritation. Soaks are short-term therapy only, because the chronic use of frequent soaks dissolves natural oils and overall dries the

Table A3.3  First Aid Soaks Emollients Ice Topical anesthetics Nighttime sedation

skin, as well as producing maceration in normally moist areas. Following soaks, the skin should be patted dry gently, and the moisture sealed in immediately with the application of a bland emollient such as petrolatum (Vaseline petroleum jelly). Although historically avoided by gynecologists, there are several studies that incidentally exhibit the benefit of petrolatum on pain and irritation in the course of evaluating the effects of testosterone1. Petrolatum is a cost-effective emollient that contains no irritants, allergens, preservatives, or stabilizers. Women who are incontinent or have diarrhea often benefit from a barrier paste that protects surrounding skin. Although messy, zinc oxide paste or Desitin applied liberally and regularly protects the skin from alkaline urine and, especially, liquid feces. Itching and pain are also improved by cold. Ice packs, or crushed ice wrapped in a soft towel and applied to the vulva, frequently provide short-term comfort. Ice should not be applied directly to the vulva because of risk of frostbite. Topical anesthetics are useful in some patients. Benzocaine (Vagisil) is an extremely effective anesthetic, but it is a highly allergenic agent, and it is often compounded with irritants such as resorcinol, which exacerbate inflammatory skin disease. Prescription lidocaine jelly 2% is soothing and variably effective. Lidocaine ointment 5% is more potent and equally safe, but it frequently produces burning with application. Prescription lidocaine cream 4% (ElaMax) or Emla (lidocaine with prilocaine) are more potent, but cause redness and burning in most patients. Pramoxine is found in some over-the-counter anesthetics (Summer’s Eve Anti-itch gel), and it is quite safe but less effective. There are no nonspecific anti-itch oral medications. Although antihistamines are often prescribed for itching of any cause, these only improve histamine-mediated itching such as urticaria, but not, for example, candidiasis, lichen sclerosus, or lichen simplex chronicus. However, nighttime sedation provides relief from itching by producing sleep, and sedation that causes sleep without scratching ultimately decreases the inflammation perpetuated by nights of rubbing and scratching.

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Therefore, nighttime diphenhydramine (Benadryl) and hydroxyzine hydrochloride (Atarax) are reasonable nighttime therapies. However, these induce light sleep, and many patients scratch while asleep. Better still are amitriptyline (Elavil) or doxepin (Sinequan) because these tricyclic antihistamines, originally developed for depression, induce deeper sleep and have a longer half-life, reducing nighttime scratching and rubbing. The antidepressant side-effects are also welcome.

Table A3.4  Corticosteroid Side-Effects Secondary infection   Candidiasis   Enlarging warts Steroid dermatitis/rosacea Atrophy/striae Epidermal cysts Systemic absorption (from vagina only)

Principles of topical therapy Topical therapy is often a mainstay of treating skin disease, since topical medications can be applied directly to the affected organ without significant concerns of interaction with other medications or systemic adverse reactions. However, topical therapies often produce superimposed irritant or allergic contact dermatitis, and, less often, maceration if overused on moist or thickened skin. As noted above, ointments are preferred over creams, because ointments contain fewer irritants and allergens in the form of alcohols, preservatives, and stabilizers, and, when possible, antifungal therapy and antibiotics should be administered orally to avoid these pitfalls.

Specific medications Corticosteroids (cortisones, steroids, glucocorticoids) Corticosteroids exert several effects. First, and best known, are the anti-inflammatory effects. Second, corticosteroids exert immunosuppressive effects, serving as a mechanism of action for the treatment of disease as well as a factor in increasing risk of infection. Third, chronic corticosteroids thin the skin, most often viewed as an adverse reaction, but used to advantage in patients with thickened skin of psoriasis, lichen simplex chronicus, and some women with lichen sclerosus. Topical corticosteroids

Most clinicians have been taught that potent topical corticosteroids should not be applied to skin folds, including anogenital skin. However, we now know that the modified mucous membranes of the vulva are relatively steroid-resistant, and respond

best to an ultrapotent preparation such as clobetasol propionate (Temovate), betamethasone dipropionate in optimized vehicle (Diprolene), halobetasol propionate (Ultravate), and difluorasone diacetate (Psorcon). Not only are these potent corticosteroids the treatment of choice for lichen sclerosus, but these are becoming first-line therapies for any steroid-responsive dermatoses on mucous membrane or modified mucous membrane skin. However, the hair-bearing labia majora, crural crease, proximal, medial thighs, and perianal skin are quite sensitive to the adverse reactions of topical corticosteroids (Table A3.4). These areas are most often treated with lower-potency medications such as triamcinolone acetonide or desonide (Table A3.5). Only extremely tiny amounts of corticosteroid ointment are applied to the affected skin; little is required for improvement and this avoids inadvertent spread of medication to areas prone to sideeffects. A pea-sized amount more than covers the entire vulva and perianal area. Only the smallest commercial size, which normally lasts several months, should be prescribed, with no refills. See patient handout in Appendix 4. In addition, patients should be shown with a mirror exactly where to apply medication as well as how much medication to apply (Figure A3.1). Alternatively, a photograph can be taken, with the areas to be treated indicated on the photograph with a marker. Patients using daily potent topical corticosteroid ointments should be evaluated monthly for benefits and side-effects until the skin disease is controlled. Then, the potency can be decreased

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Table A3.5  Stoughton Potency Scale   for Topical Corticosteroids Ultrapotent Clobetasol dipropionate (Temovate, Embelline, Cormax) Halobetasol (Ultravate) Betamethasone dipropionate in optimized vehicle   (Diprolene) Difluorasone diacetate (Psorcon, Apexicon) High Fluocinonide (Lidex) Halcinonide (Halog)

Figure A3.1  Patients are very surprised when they are shown the very small amount of topical steroid required to treat the vulva.

Betamethasone dipropionate (Diprosone) Medium Triamcinolone acetonide (Kenalog, Aristocort) Betamethasone valerate (Valisone) Low Hydrocortisone Desonide (Tridesilon) Hydrocortisone butyrate (Westcort)

either by decreasing the frequency of application or by changing to a lower-potency preparation. Thrice-weekly application of an ultrapotent corticosteroid is generally safe long-term, and patients no longer require monthly follow-up to assess for adverse reactions. A common mistake in prescribing topical corticosteroids is that of discontinuing medication prematurely in a misguided effort to avoid sideeffects. Many steroid-responsive dermatoses itch, with scratching serving as a major perpetuating factor. If medication is discontinued before the skin is normal, low-grade itching and resulting scratching prevent ultimate healing. Therefore, the corticosteroid should be continued until the skin is as normal as possible, and the frequency tapered to the least frequent dosing required to control the disease.

There are no corticosteroids formulated for the vagina. Therefore, corticosteroid preparations used off-label include hydrocortisone acetate rectal suppositories 25 mg, compounded hydrocortisone acetate suppository 500 mg, or the use of a preparation intended for the skin, such as clobetasol ointment, inserted into the vagina nightly with an applicator, understanding that the degree of systemic absorption is not known. Patients using this medication should be followed carefully and the frequency of insertion tapered from nightly use as soon as possible. The use of an intravaginal corticosteroid is associated with a high risk of secondary vaginal candidiasis, but either a weekly fluconazole 150 mg tablet or a topical antifungal medication inserted regularly suppresses yeast until the underlying disease process is controlled. Intralesional therapy

Because the skin is easily visible and accessible, intralesional therapy is sometimes an excellent delivery mode when topical therapy is inadequate (Figure A3.2). Intralesional corticosteroids are used in two situations. The first is when there is localized, deep or recalcitrant inflammation with inadequate penetration by a topical steroid, particularly an inflamed cyst of hidradenitis suppurativa. The second is when the goal is to thin an area of thickened skin, such as very localized lichenification or a thickened scar.

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Figure A3.2  Intralesional corticosteroids are sometimes very useful; triamcinolone in a concentration of 3.3 mg/mL is being injected directly into a red plaque of plasma cell vulvitis, eliminating the necessity and potential adverse reactions of topical corticosteroids for this very localized problem.

When used for anti-inflammatory effects, a c­ ommon preparation is triamcinolone ­ acetonide 10 mg/mL (Kenalog 10) diluted with injectable saline to about 3.3 mg/mL (a ratio of about one part triamcinolone and two parts saline). An average cyst is treated with about 0.2–0.4 mL injected with a 30-gauge needle. Generally, within 24 hours the painful inflamed cyst is much more comfortable. When reducing thickened skin or scar, the triamcinolone acetonide 10 mg/mL is used undiluted, and is again infiltrated with a 30-gauge needle in very small, often unmeasurable amounts. The steroid is gradually absorbed from the skin, providing continuous release over about 1 month, so the patient does not need to continue a topical corticosteroid on that skin for the next several weeks. The treated, thickened areas should be re-evaluated in 4–6 weeks to determine if retreatment is needed. Injecting too much medication or inadvertently treating the surrounding skin produces atrophy and hypopigmentation. Systemic corticosteroids

Although most patients are treated satisfactorily with topical corticosteroids, patients with significant erosive disease or severe inflammatory disease often benefit from initial systemic corticosteroid therapy to induce healing so that topical

medication can be used more comfortably and effectively. Short-term oral or intramuscular corticosteroids are usually quite well tolerated. Prednisone is the most common preparation used. A dose pack, with an automatic tapering schedule, is neither required nor useful, delivering a subtherapeutic dose for much of the duration of therapy. A dose of 40–60 mg each morning generally produces good results. Patients should be evaluated after 7–10 days to determine whether discontinuation or transition to alternate-day dosing is possible. A topical corticosteroid serves to prevent rebound when the systemic preparation is discontinued. Possible short-term side-effects include sleeplessness, anxiety, increased appetite, and dependent edema occurring after several days. After 5–7 days, immune suppression occurs. Patients treated for less than 2 weeks do not require tapering to avoid complications of adrenal suppression. Alternatively, patients can be treated with intramuscular triamcinolone acetonide, which allows the clinician to control most precisely the dosing and provides a systemic automatic tapering over about 1 month. This is especially useful for patients with chronic itching from lichen simplex chronicus/eczema, when administered at 60–80 mg intramuscularly.

Calcineurin inhibitors Tacrolimus (Protopic) and pimecrolimus (Elidel) are closely related topical nonsteroidal antiinflammatory medications approved by the Food and Drug Administration (FDA) for eczema. As topical immune suppressants, these have also shown some benefit in other inflammatory diseases, including lichen planus, psoriasis, and lichen sclerosus. Tacrolimus is only available as an ointment, and pimecrolimus only as a cream. Tacrolimus, in particular, tends to produce burning with application, limiting its usefulness. The effect is moderate and benefit requires several weeks. Recently, the FDA has labeled these medications as posing a possible risk for malignancy. This is primarily because, when used systemically as an antirejection medication for transplant patients, oral tacrolimus is associated with an increased late risk for skin cancers and lymphoma. This is a recognized side-effect of chronic use of most

Specific medications

immunosuppressive medications. Fortunately, there is only trivial systemic absorption of tacrolimus and pimecrolimus, so most clinicians do not believe that this is a reasonable risk. However, both lichen sclerosus and lichen planus are associated with an increased risk of squamous cell carcinoma, and the prescribing clinician is at risk for malpractice if a woman treated with one of these medications develops a malignancy after the use of these medications.

Antifungal therapy Because candidiasis often produces genital itching, antifungal medications are among the treatments most used for vulvovaginal symptoms. Most antifungal therapies for the use in vulvovaginal disease are from the azole class, because of the excellent coverage for Candida albicans as well as the dermatophytes that produce tinea cruris. Topical antifungal therapy

The irritant properties of preservatives and stabilizers in vaginal creams tend to sting very inflamed skin, but most topical azole medications are unavailable in ointment vehicles. Azole vaginal tablets and suppositories are comfortable, but do not treat the vulva. The most soothing topical medication for yeast is a polyene, nystatin ointment (also available as vaginal tablets), but an applicator is not provided with this medication and it must be obtained separately. All azoles and nystatin are very effective for Candida albicans and C. tropicalis. Non-albicans Candida infections are often resistant to therapy, including terconazole and butoconazole, which are said to be more effective for these non-­albicans infections on the basis of in vitro studies. There are no clinical trials verifying these claims, and this author has not found any azoles more effective than others in treating non-albicans yeast infections. The choice of medication depends upon price, convenience, and avoidance of creams in very inflamed skin. Nystatin, boric acid compounded as 600 mg capsules to be inserted in the vagina once or twice a day, compounded flucyosine cream, gentian violet, and compounded amphotericin vaginal suppositories are the medications used for resistant non-albicans Candida.

Topical terbinafine (Lamisil) is only available in a cream base and there is no formulation for vaginal administration. It provides fairly good coverage for cutaneous candidiasis and excellent coverage for dermatophytes. Systemic antifungal therapy

Fluconazole is the only medication with indication approval for vulvovaginal candidiasis, as a one-time dose of 150 mg. Other azoles are certainly effective, but with fluconazole now available as an inexpensive generic, this medication is a cost-effective, convenient, and practical firstline therapy. Potential medication interactions are somewhat limiting, and women with very prominent vulvar involvement may require either more than one dose or supplementation with a topical medication for the skin. Headache and dysgeusia are occasional side-effects. Women with documented frequently recurrent candidiasis benefit from weekly fluconazole for several months to interrupt this cycle. Fluconazole is also used as weekly dosing when women at risk for yeast are on antibiotics.

Antibiotic therapy Antibiotics are used for both their anti-inflammatory effects as well as their antimicrobial effects. By far the most common antibiotics used for vulvovaginal disease are metronidazole (bacterial vaginosis and Trichomonas), clindamycin (bacterial vaginosis, group B streptococcal disease, and desquamative inflammatory vaginitis), and the penicillins (group B streptococcal disease). Topical antibiotic therapy

Topical metronidazole gel (Metrogel) and clindamycin cream (Cleocin) are used for bacterial vaginosis, and clindamycin cream is also beneficial for elimination of group B streptococcal disease (Table A3.6). Topical clindamycin is the treatment of choice for desquamative inflammatory vaginitis, a presumably noninfectious inflammatory dermatosis of the vagina. When used for its antiinflammatory effects, chronic or recurrent use is often necessary and several weeks are generally required for benefit. Relapse is common, since control rather than cure is effected. Reports of

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Table A3.6  Topical Antibiotics for Vulvovaginal Disease For Infection Metronidazole gel Clindamycin vaginal cream/ovules For Inflammation Clindamycin vaginal cream/ovules

benefit have studied primarily clindamycin cream, which is well tolerated, but vaginal tablets are available as well. Antibiotics predispose to yeast in some patients, and these women benefit from weekly fluconazole to prevent secondary candidiasis. There are rare reports of Clostridium difficile infections with the use of intravaginal topical clindamycin. Topical antibiotics, such as mupirocin, neomycin/polymyxin B (Neosporin), and bacitracin are of limited value for the treatment of vulvar infections, and simply add the possibility of an irritant or allergen. Therefore, conditions such as folliculitis, furunculosis, and impetigo should be cultured and treated orally according to the identified organism and sensitivities, particularly with the large number of community-acquired methicillin­resistant staphylococcal organisms producing infections. Systemic antibiotic therapy

Patients with very symptomatic vulvovaginal infec­ tions and vulvar irritation often benefit from oral antibiotic therapy to avoid irritant reactions to topical therapy. Oral metronidazole is the treatment of choice for trichomoniasis, and it is also effective for bacterial vaginosis, as is oral clindamycin. Bacterial vaginitis is treated according to culture results.

Estrogen Now that postmenopausal women are no longer regularly treated with systemic estrogen, atrophic vaginas are a common cause of symptoms, both as a primary factor, as well as an exacerbating issue. Fortunately, local estrogen replacement is extremely and quickly effective and usually well tolerated.

Estradiol cream 0.01% (Estrace) is arguably the most soothing topical estrogen cream. Conjugated equine estrogen (Premarin) cream is less expensive, but sometimes more irritating in women with significant pre-existing symptoms or skin disease. Both are prescribed as 1 g intravaginally three times a week. Thrice-weekly dosing provides little systemic exposure but normalizes the vaginal epithelium within 2–3 weeks. Some patients experience irritation with any estrogen cream. These patients can be treated with estradiol vaginal tablets (Vagifem) three times a week. There is essentially no irritation with this product. A third alternative is an inert, flexible ring that releases estradiol in therapeutic concentrations over a 3-month period. Patients who, for one reason or another, are unable to use these preparations can be treated with estradiol compounded in a petrolatum base, which is generally very well tolerated. The use of vaginal estrogen increases the risk of candidiasis. Some believe that initial, partial estrogenization is especially likely to precipitate ­vulvovaginal candidiasis. Weekly fluconazole ­admin­istered for the first month for the presence eliminates this risk.

Psychoactive medications Medications that affect the central nervous system are indispensable in the treatment of women with chronic vulvovaginal symptoms. These are used for three main purposes. The first function of psychotropic medication is that of nighttime sedation, primarily in patients with itching, as discussed above under “first aid.” The second use of psychoactive medication is for depression, which is nearly universally present in individuals with chronic itching or pain. This is especially true for women with vulvovaginal symptoms, because of the issues with sexual function, and concerns about malignancy and fertility. The best choices of antidepressants are those most familiar to the clinician. These medications should be accompanied by a referral for counseling.

Reference

A third primary purpose of psychotropic medication is the alleviation of discomfort of pain ­syndromes (vulvodynia, anodynia). The medications used for this purpose are primarily tricyclic antidepressants (amitriptyline, desipramine), gabapentin (Neurontin), venlafaxine (Effexor), duloxetine (Cymbalta), and pregabalin (Lyrica). The use of these medications is discussed ­primarily in ­Chapter 27. The treatment of vulvovaginal disease requires more than simply writing the prescription. Most patients with chronic symptoms require several

concomitant medications used in sufficient doses and duration for the best possible management of symptoms. Patient education, follow-up of flares, and adjustments of types and dosing of medications as symptoms change are all important, as is a setting of support and psychotherapy.

Reference   1. Sideri, M., Origoni, M., Spinaci, L., et al. Topical testosterone in the treatment of vulvar lichen sclerosis. Int. J. Gynaecol. ­Obstet. 1994; 46: 53–56.

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Appendix 4

Patient Information Libby Edwards

Handouts can be extraordinarily important for women with chronic vulvovaginal symptoms. Most patients believe that all vulvovaginal symptoms are due to yeast infection, bacterial vaginosis, or sexually transmitted diseases, and they are unfamiliar with other conditions. This appendix contains handouts on the more common causes of chronic symptoms, as well as information on the use of topical corticosteroids and amitriptyline, and a handout on avoiding vulvar irritants. These are designed to be photocopied for your patients’ use.

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Desquamative inflammatory vaginitis (div) DIV is a vaginitis that is irritating but not dangerous in any way. DIV is not an infection or sexually transmitted disease, but it is produced by inflammation of the vagina of unknown cause. Women with DIV report yellow or green vaginal discharge, with irritation and redness at the opening of the vagina. Most women experience pain with intercourse. An examination shows no abnormalities except for redness of the vagina and yellow-green vaginal discharge, and cultures as well as office testing shows no infection. First-line therapy is clindamycin (Cleocin) cream in the vagina nightly. Even though DIV is not an infection, this antibiotic cream is usually effective. Clindamycin has a side-effect of decreasing even inflammation that is not infectious (for example, clindamycin has been used for years for acne, another inflammatory skin disease that is not an infection). Sometimes, a corticosteroid (steroid, cortisone) suppository or ointment is used for this as well. DIV is not usually cured with treatment, but symptoms go away on therapy. Most women either need to use clindamycin once or twice a week to remain comfortable, or wait until symptoms return and retreat nightly. Occasionally, after the inflammation is gone, women still report feelings of irritation, and some of their symptoms are caused by vulvodynia.

Group B streptococcus in the vagina

Group B streptococcus in the vagina Group B streptococcus is a bacterium that lives normally in the vagina of many women, along with many other bacteria, including lactobacilli. Group B streptococcus is only medically important in the last stages of pregnancy, since babies can develop streptococcal infections as they pass through a birth canal with group B streptococcus. Group B streptococcus is a different strep than the bacterium that causes strep throat or “flesheating strep.” It is not a sexually transmitted disease, and only causes significant illness in newborns. This is not a health hazard in any other way. In the past few years, some physicians have observed that group B streptococcus is sometimes associated with symptoms of vulvar and vaginal irritation. Therefore, many physicians who care for women with chronic vulvovaginal irritation, burning, or itching prescribe an antibiotic for women found to have vaginal group B streptococcus on a vaginal culture. Usually, there is no improvement in symptoms, because the strep was coincidental and unrelated. However, an occasional woman experiences clearing of symptoms. When the antibiotic is discontinued, group B streptococcus usually recurs quickly. So, women who improve substantially with an antibiotic are frequently treated for several weeks or months in order to suppress the streptococcus long enough for the skin to recover. For those women whose symptoms are not relieved with an antibiotic, further treatment is unnecessary and unhelpful.

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Lichen planus Lichen planus is a skin disease that sometimes affects the vulva, vagina, and inside of the mouth. Lichen planus can appear either as white skin or as superficial sores. The vulvar areas that are white are usually itchy, whereas those areas with sores are usually sore and painful. Often, women have both white skin and sores, with itching and soreness. The cause of lichen planus is believed to be an overactive immune system (autoimmune disease). The immune system is that part of the body that fights off infections. Lichen planus is one of several skin diseases that occur when the immune system becomes overactive and mistakenly attacks skin. Lichen planus cannot be cured, but medications improve the skin and provide comfort. Treatments for lichen planus fool the immune system so that it doesn’t attack the skin. Although some medications, especially oral cortisone (prednisone), depress the entire immune system a great deal and allow the skin to heal, this amount of immune suppression is dangerous when used for a long time. Therefore, prednisone is used only briefly – if at all – to help heal skin. Then, we try to control lichen planus with topical corticosteroid (steroid, cortisone) creams or ointments, or other medications that do not suppress the immune system to a dangerous degree. While there are still open sores, minor infections sometimes occur. For this reason, patients should call their doctor if symptoms suddenly worsen. When corticosteroid ointments do not improve the skin enough, other treatments can be added. These include topical or oral cyclosporine, topical tacrolimus (Protopic), methotrexate, azathioprine, etanercept, and other medications that partially suppress the immune system. There is no one medication that always clears lichen planus, so different treatments may be tried to find one that is useful. Untreated or severe lichen planus of the vulva and vagina often produces scarring. When lichen planus occurs in the vagina, the vaginal walls can scar together and close the vagina so that intercourse is no longer possible. Therefore, in addition to using medication in the vagina, women with lichen planus of the vagina should either have regular intercourse or insert a vaginal dilator on a daily basis to prevent scarring. Often, multiple visits and several different medications are required to control lichen planus. Although the treatment of itchy areas is usually easy, sores and painful skin are more difficult to treat. However, most women become much more comfortable.

Lichen sclerosus

Lichen sclerosus Lichen sclerosus is a skin disease that occurs more often on the vulva than any other area of the body. The cause is unknown. However, many physicians believe that it occurs when the immune system, that part of your body that fights off infection, becomes overactive and attacks the skin. Lichen sclerosus usually causes itching, and in later stages, easy bruising, tearing, and pain. Skin affected by lichen sclerosus is usually white, and sometimes there is a fine, crinkled texture. When untreated, lichen sclerosus often causes scarring, and the opening of the vagina can narrow. About 1 out of 30 women with untreated vulvar lichen sclerosus develops a skin cancer in the area. Usually, lichen sclerosus does not affect other areas of skin, but about 1 woman in 10 has a few scattered white spots in other areas. Lichen sclerosus on these other areas almost never itches or causes symptoms in any way. In the past, lichen sclerosus was treated with testosterone ointment, which was not very useful for most women. Fortunately, more recent research shows that a very-high-potency cortisone (steroid, corticosteroid) ointment usually returns the skin to its original color and texture, although it does not reverse scarring. The usual medications are clobetasol propionate, difluorasone diacetate, betamethasone dipropionate in optimized vehicle, or halobetasol, used once or twice a day. Over-the-counter hydrocortisone is not nearly strong enough to clear lichen sclerosus. Most women need 3–5 months of daily strong corticosteroid treatment. Women are generally examined every month while using this medicine daily, because sometimes the skin can thin from too much corticosteroid. After the skin has returned to a normal texture, women use the cortisone about three times a week to prevent return of lichen sclerosus. There is a slight increase of trivial skin infections during the first few weeks until the skin returns to normal. Also, the medication can irritate the skin of some patients. Therefore, brief setbacks are common during the first month or two. Ultimately, women with lichen sclerosus do extremely well. After the lichen sclerosus is controlled, visits should be made with a health care provider every 6 months. This is to examine for return of lichen sclerosus or for signs of side-effects from the cortisone. Also, the health care provider needs to ensure that scarring is not occurring, and that there are no early signs of cancer. With regular check-ups and use of a topical steroid, these should not become problems.

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Lichen simplex chronicus (atopic dermatitis, eczema) Lichen simplex chronicus (LSC), atopic dermatitis, eczema, neurodermatitis, and dermatitis are different names for the same problem. LSC is an itchy skin rash that occurs in people who have sensitive skin. Normal mild irritations of daily living such as soap, water, perspiration, stress, and rubbing from clothes cause irritation. Although some people feel irritation as soreness, people with LSC feel irritation as an itch. Rubbing and scratching usually feel good, but these cause more irritation and make the skin itch even more, until the rubbing and scratching cause the skin to turn red and thick – the rash of lichen simplex chronicus. Because people with LSC have sensitive skin that itches easily, there is no cure for LSC. However, avoiding irritations and using corticosteroid ointments usually control the problem. Treatment includes: 1. A very important part of the treatment is careful skin care to avoid irritation. Washing the skin is irritating because soap and water dissolve the natural oils in the skin and make tiny, invisible but ­irritating cracks. Therefore, hot water and harsh soaps should be avoided. Soap and feminine hygiene products are not needed; clear water once daily is all that is needed to clean the skin. Rough fabric and tight clothes can increase itching. Overheating also makes itching worse, and sweat can be very irritating, so staying cool and wearing loose, light fabrics may help your itching. Panty liners are irritating for many women as well. You should avoid douches, perfumes, deodorants, and medications other than those prescribed by your health care provider because of the possibility of allergy or irritation. 2. Corticosteroid (steroid, cortisone) ointments are extremely important in the treatment of LSC. These medications help to soothe irritation and inflammation as well as to help the itch. Corticosteroids are applied very sparingly – a pea-sized amount, and more does not work better than less. Apply the ointment only to the areas of scaling, redness, or itching. Use the medicine until the skin feels normal to the touch, and often it can then be discontinued. If you stop using the medicine as soon as itching is better, but not completely clear, itching usually comes back. 3. Medication at night to sleep without scratching is important. As long as the skin is being scratched or rubbed, it will not heal. You may be scratching in your sleep, or waking with itching. Nighttime medication with an antihistamine such as Benadryl (diphenhydramine), Atarax (hydroxyzine), or amitriptyline (Elavil) can help you sleep without scratching. When the itching stops, this medication can be discontinued. 4. Sometimes, when there is weeping or crusting of the skin or a vaginal discharge, infection is present, so that antibiotics or medication for yeast are important in some patients until the itching is controlled. The treatment of eczema is a lot of work. It is important to follow these instructions carefully until the itching has disappeared, and then gradually decrease the frequency of corticosteroid use and nighttime medication. Don’t be discouraged if stress or a new irritation makes you start itching again. The next time you will know how to control it.

Physiologic (normal) vaginal discharge

Physiologic (normal) vaginal discharge Normal vaginal fluid is sometimes called a “physiologic vaginal discharge.” Normal vaginal secretions are formed by mucus, dead skin cells shed from the surface of the vagina and cervix, white blood cells, and many different normal bacteria, as well as other proteins and fluid. Physiologic (normal) vaginal discharge is white and thin or creamy, often with odor. This discharge can be slight or heavy. Before puberty and after menopause, estrogen levels are low, so the vagina is fairly dry and there is little vaginal fluid. When hormone levels increase, the skin of the vagina becomes healthier, stronger, and thicker, and the volume of secretions increases. Besides normal estrogen levels, infections and skin problems in the vagina also change the amount, color, or texture of vaginal secretions. The volume and color of vaginal secretions vary by the time of the menstrual cycle, by the time of the woman’s life, hormone use, and possibly other recent therapies such as antibiotics. A sudden increase in vaginal secretions is sometimes associated with an infection (most often, bacterial vaginosis). Your health care provider can rule out infection or skin disease causing a change in your discharge with a vaginal culture and by looking for abnormalities with a microscope. Often, an increase in vaginal secretions is not caused by disease, but simply by a change in your body. When there is no infection or skin disease causing a discharge, the discharge is called a physiologic vaginal discharge. Although not dangerous, and rarely a cause of irritation or itching, this can be annoying. Unfortunately, because there is no disease causing the discharge, there is no good treatment. The use of medication for yeast or bacterial vaginosis does not help a physiologic discharge.

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Vulvodynia and vestibulodynia (vulvar vestibulitis syndrome) Vulvodynia and vestibulodynia are common problems, defined as feelings of vulvar or vaginal burning, rawness, stinging, stabbing, tearing, aching, or irritation that have been present for at least 6 months, when an examination is normal. There is no infection, skin disease, or specific nerve problem causing the symptoms. Burning or other pain that moves from one place to another or is all over is called generalized vulvodynia. Pain that is felt only at the opening to the vagina and hurts when the area is touched is called vestibulodynia (previously called vulvar vestibulitis syndrome). Many women have a combination of both of these. Sometimes, when a woman with burning or irritation is examined, the doctor finds a common problem like a yeast infection, low estrogen, or irritation from overwashing. If the discomfort doesn’t go away when the problem is fixed, the diagnosis of vulvodynia or vestibulodynia is made. There is no test for vulvodynia/vestibulodynia. Women with burning, irritation, or pain who have vulvar and vaginal skin that looks normal, cultures that rule out infection, and vaginal secretions that look normal under the microscope have vulvodynia/vestibulodynia. Many women with vulvodynia have some redness and feeling of swelling of the skin. Although vulvodynia/vestibulodynia is not generally cured, the pain can generally be controlled with a combination of medication by mouth, creams, and exercises. Treatment is slow, and sometimes several different therapies have to be tried. Occasionally, the pain and burning simply go away. Vestibulodynia/vulvodynia is most likely caused by a combination of a nerve abnormality (neuritis, neuralgia), pelvic floor muscle weakness and irritability, irritation from previous treatments and overwashing, and anxiety/depression. Some women have other pain syndromes, such as headaches, irritable bowel syndrome, interstitial cystitis, fibromyalgia, and temporomandibular joint syndrome. Treatment for vulvodynia/vestibulodynia often helps these other pain syndromes as well. Vestibulodynia/vulvodynia is not associated with cancer, sexually transmitted disease, or any kind of infection that is passed back and forth between sexual partners. There is no relationship of vulvodynia/vestibulodynia to acquired immunodeficiency syndrome (AIDS). Vestibulodynia/vulvodynia does not affect fertility or the ability to carry pregnancy to term and have a normal delivery. Vestibulodynia/vulvodynia is not an early sign of any disease that affects overall health. There is no good evidence that this problem is a psychosomatic disease, but vulvodynia/vestibulodynia certainly causes tremendous emotional stress, and stress worsens the symptoms of any disease. Also, the anxiety and depression of vulvar pain, the psychological injury to a woman’s self-esteem and her sexual identity, and the damage to the relationship with a sexual partner can be devastating. The management of vestibulodynia addresses the several different causes of vestibulodynia, so treatment generally involves several different therapies at the same time. First, you should stop all things that may be irritating the skin. Avoid soap, panty liners, creams for infections, any medications with benzocaine or diphenhydramine to numb the skin, and most commercial vaginal lubricants (KY jelly). Lidocaine jelly 2% is a mild and safe numbing jelly that can be used both any time you are burning, and for 15–30 minutes before sexual activity to help avoid some of the pain. Second, medication for neuropathic pain is a first-line therapy. These include medications that were originally developed for depression, but have been found to have specific benefits for neuropathic pain. These are amitriptyline (Elavil), desipramine, venlafaxine (Effexor), and duloxetine (Cymbalta). Other well-known antidepressants have no independent effects on pain. Medications developed for seizures are used for neuropathic pain also. Those most often used are gabapentin (Neurontin) and pregabalin (Lyrica). Third, most women benefit from therapy to strengthen pelvic floor muscles. This can be done with physical therapy or with a fairly well-studied (but not widely available) schedule of home biofeedback exercises.

Vulvodynia and vestibulodynia (vulvar vestibulitis syndrome)

Fourth, there are a number of topical therapies used in some women, depending upon many factors, including the location of pain, age, and response to other treatments. These include the regular nighttime use of lidocaine ointment 5%, estrogen, nitroglycerin, and amitriptyline/baclofen combination ointment. A few clinicians have used more experimental treatments, including Botox (botulinum toxin), acupuncture, and hypnosis. A low-oxalate diet with calcium citrate with meals is occasionally used. Women with vestibulodynia have another option for treatment. The painful area can be surgically removed, and this is the single best treatment for vestibulodynia. However, success of this surgery, called a vestibulectomy, is dependent upon the location of the pain. Many clinicians find that women who have been treated with oral medications and pelvic floor therapy have better success with surgery. Last, but not least, is counseling and sex therapy. Even though the cause of vestibulodynia/vulvodynia is not primarily psychological, the pain and burning interfere with sex and intimacy. Most women experience feelings of depression, anger, anxiety, guilt, loss of self-esteem, loss of sexual desire, and loss of feelings of femininity and sexuality. Their partners are often experiencing many of the same emotions. As women avoid sexual activity, many also avoid other kinds of physical contact (such as holding hands and kissing) because of fear that touching of any kind might progress to painful or unwanted sexual activity. Soon, many women feel isolated and lonely, both physically and emotionally. Also, the pain sometimes interferes with choice of clothing, diet, and activities such as exercise, sitting for long periods, thus impacting all areas of life. Couple counseling can be crucial to the successful treatment of vulvodynia/vestibulodynia and to help the woman and her partner survive this difficult problem. Additional information and regular newsletters can be obtained by joining the National Vulvodynia Association (www.NVA.org). Information from this organization helps women to realize that they are not alone, and that this is a common problem and an active area for research.

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Amitriptyline (elavil) Amitryptyline was originally developed as an antidepressant, but experience has shown that it has an independent effect on neuropathic pain, and it is an excellent medication for sleep. Although it is a good antidepressant, the major side-effect of drowsiness makes newer medications easier for the treatment of depression. Amitriptyline is also used for its potent antihistamine effects, and it is especially used for patients with nighttime itching. When used for itching, the proper dose is whatever amount, usually about 20–30 mg (but sometimes higher), which produces deep sleep without long-lasting morning drowsiness. When used for pain, an ultimate dose of 125–150 mg is often required for comfort. You should start your amitriptyline at an extremely low dose so that your body can adjust to it, without being “hung over” the next day. You should start with a 10-mg tablet – the smallest available size – and increase your dose as tolerated by a half or whole tablet each evening. Usually, amitriptyline is best taken an hour or two before bedtime, because the effect of drowsiness lasts about 10 hours. You should increase your dose until you are comfortable or until you reach 150 mg, whichever occurs first. When your prescription is finished, call your doctor’s office for a more potent tablet, so you are not taking several pills each night. Amitriptyline is available in 10-mg, 25-mg, 50-mg, 75-mg, 100-mg, and 150-mg size tablets.

Side-effects Although some people have very few side-effects with amitriptyline, others have aggravating problems. Fortunately, if the dose is started very low, your body usually adjusts to the medication and you will be able to increase the dose to an effective amount. Sleepiness is a common side-effect, so you should take your medication an hour or two before bedtime. If you have problems feeling groggy in the morning, try taking your medication earlier in the evening. Also, you may need to increase your medication more slowly. Although some people can increase their medication by 5 mg each night, other people can only increase their medication once a week. If sleepiness is still a problem, call your doctor’s office, since you may need a change in medication. Dry eyes and mouth are a common effect seen with all antihistamines, including amitriptyline. Usually, this effect is minor and eventually goes away. Sucking on sour apple or lemon sugar-free hard candy and using artificial tears can be helpful. Some people experience an increase in appetite, especially for sweets. In order to prevent weight gain, count calories until you know that an increased appetite is not a side-effect for you. If you find that an increased appetite or weight gain is a significant problem for you, call your doctor’s office. Constipation is common, especially in patients who already have problems with constipation. Be sure to eat high-fiber foods, like cereal with 10–14 grams of fiber per serving, and drink plenty of water at the same time to control this side-effect if it occurs. A rapid heart rate or jitteriness is not common, but sometimes occurs.

Topical corticosteroids (cortisones, steroids)

Topical corticosteroids (cortisones, steroids) Corticosteroid creams and ointments, also called cortisones and steroids, are medications that treat skin diseases by decreasing inflammation and suppressing the immune system in the area applied. These medications are usually effective and quite safe if they are used carefully. Topical corticosteroids are used for eczema, psoriasis, lichen sclerosus, and several other skin problems. Generally, topical corticosteroids do not cure skin problems, but they control or help to control them. This means that chronic or intermittent use of medication is often required to keep you comfortable. Topical corticosteroids usually produce at least some improvement within a week. Discontinuing them too soon, however, allows the skin problem to return. There are several side-effects from overuse of corticosteroids. One of the more common effects is thinning of the skin. This first appears as unusually smooth or shiny skin, and if the medication is not discontinued or applied less often, stretch marks may appear eventually. Other side-effects are the appearance of tiny, visible, broken blood vessels and small cysts. When medication is inserted into the vagina with an applicator, some of the medication can be absorbed into the blood stream, and the same side-effects as happen with cortisone (prednisone) pills can occur. These include weight gain, thinning of the skin in other areas, a decreased immune system, high blood pressure, diabetes, swelling of the legs, and weakening of muscles. For these reasons, the frequency of insertion into the vagina is decreased as soon as symptoms improve. Because of the side-effects, caregivers do not give automatic refills on the very-high-potency corticosteriods. Most often, you will need to return to the office for re-evaluation of your skin both for benefits and for side-effects before refills are given. Sometimes, when you have been seen many times and are comfortable with both the benefits and side-effects on your skin, refills will be provided. Generally, there are more problems from discontinuing the cortisone too soon than in using too much topical corticosteriods. The long-term use of corticosteriods is often necessary, and, with proper monitoring, they are safe.

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Tips for vulvar skin care Often, women try so hard to clean themselves and avoid infection that they mistakenly do things that worsen itching and irritation. Here are some suggestions to help relieve symptoms and prevent further irritation. Although most women can use soaps, panty liners, and feminine hygiene products, women with sensitive skin, itching, or irritation have to be more careful. After your symptoms are under control, you can try to restart any habits that are important to you. • Wash the vulva no more often than once a day, using water only; do not use a washcloth, but only soft finger tips • Avoid soap, douches, powders, over-the-counter medications (especially Vagisil or benzocaine) on this area • If any prescribed topical medications produce burning, stop using them and call your health care provider • Do not use panty liners, especially the brand Always • With periods, use tampons rather than pads if possible • Prevent constipation by adding fiber to your diet; an easy solution is one or two large helpings of a very-high-fiber cereal with 8–14 grams of fiber per serving, and drink at least one large glass of fluid at the same time. If necessary, use a psyllium product such as Metamucil with several large glasses of fluid daily • Sometimes cold can help burning or itching. Ice, frozen peas, or a frozen blue gel pack (lunch box size) wrapped in a soft towel can relieve symptoms. But be careful not to overdo this, since frostbite is a real possibility • Use a lubricant with sexual activity. Women with vaginal symptoms tend to be dry. Astroglide, Slippery Stuff (www.slipperystuff.com), and vegetable oil (not K-Y) are good choices for a lubricant • Try applying a lot of topical anesthestic (Xylocaine, lidocaine – not Vagisil) 30 minutes before sexual activity if sexual activity is painful for you • Contraceptive creams or spermicides and latex condoms can be irritating Let us know of any tips you have learned that we can pass on to our other patients!

Index A ABCB4 gene 58 abscess 210–11 acantholysis 190 acanthosis 53 acanthosis nigricans 263–4 and insulin resistance 264 Accutane see isotretinoin acetylsalicylic acid see aspirin aciclovir see acyclovir acitretin see retinoic acid acne conglobata 84 acneiform eruption in pregnancy 76 acne, inverse 208 acne neonatorum 84 acne rosacea, premenstrual 15 acne vulgaris 6–7 management 84 antibiotics 84 systemic drugs 84–5 in pregnancy 83–5 premenstrual 14 acquired immune deficiency syndrome see HIV acrochordons see skin tags acrodermatitis enteropathica in children 333, 340–1, 342 in pregnancy 95 acute fatty liver of pregnancy 62 acyclovir erythema multiforme 91 herpes simplex virus 114, 116, 224, 225 herpes zoster 227 adalimumab, psoriasis 82, 172 adenosquamous carcinoma 298 AIDS see HIV alefacept, psoriasis 82, 172 allergic contact dermatitis 185–7 in children 331 clinical manifestations 185 diagnosis/differential diagnosis 186 epidemiology 185 histology and laboratory testing 186 management and prognosis 187 pathogenesis 187 vulvar 360 allergic vulvar edema 318

alopecia areata, pemphigoid (herpes) gestationis and 41 ambiguous external genitalia 323–4 amitriptyline 388 side effects 388 vulvodynia 347 amoxicillin, in bacterial vaginitis 309 amphotericin, Candida vulvovaginitis 303, 305 ampicillin, in bacterial vaginitis 309 anaerobic vaginitis see bacterial vaginosis angioedema 317 angiokeratoma 278 antiandrogens acne 84 hidradenitis suppurativa 209 antibiotics acne 84 allergy 187 hidradenitis suppurativa 209 vulvovaginal disease 375–6 see also individual drugs anti-BPAg1 autoantibodies 42 anti-BPAg2 autoantibodies 43 anticardiolipin antibodies, in SLE 101 antifungals in vulvovaginal disease 375 antileucoproteinase in impetigo herpetiformis 83 antiphospholipid antibodies in SLE 101 antiphospholipid syndrome 102–3 anus 129 aphthous ulcer 241–5, 360 in children 342–3 clinical manifestations 241–2 diagnosis/differential diagnosis 242–4 epidemiology 241–2 laboratory findings and histology 244 management and prognosis 245 oral 242 pathogenesis 244–5 apocrine glands in pregnancy 29 arthritis 172 aspirin antiphospholipid syndrome 102 connective tissue disease 100 atopic dermatitis 158, 182, 384 in children 330–1 vulvar 360 atopic eczema 158 premenstrual 15, 16

Index 392

atopic eruption of pregnancy 32, 33, 65–72, 74 clinical and diagnostic features 66–71 etiology 66 history 65–6 management 68–71 prognosis 68 P-type variant see prurigo of pregnancy ATP2A2 gene 193 ATP2C1 gene 191 atrophic vaginitis 310–12 clinical manifestations 310–11 diagnosis/differential diagnosis 311 epidemiology 310–11 laboratory findings and histology 311 pathogenesis 311 therapy and prognosis 311–12 atrophie blanche 103 atypical nevi 293–4 of genital type 294 autoimmune estrogen dermatitis 21 autoimmune progesterone dermatitis 16–21 challenge following chemical oophorectomy 20 clinical manifestations 16–17 history 16 intramuscular/oral progesterone challenge 20 mechanism of sensitization 17–18 pregnancy 18 progesterone intradermal tests 19–20 progesterone sensitivity 18–19 treatment 20–1 azathioprine cicatricial pemphigoid 235 connective tissue disease 100 Crohn’s disease 249 lichen planus 155 lupus erythematosus 179 pemphigus 87 psoriasis 82 azithromycin, in syphilis 254

B bacitracin allergy 187 baclofen, in vulvodynia 347 bacterial folliculitis 210 bacterial vaginitis 307–9 clinical manifestations 307–8 diagnosis/differential diagnosis 308 epidemiology 307–8 laboratory findings and histology 309 management and prognosis 309 pathogenesis 308–9 bacterial vaginosis 305–6, 344 clinical manifestations 305

bacterial vaginosis (Continued) diagnosis/differential diagnosis 305 epidemiology 305 laboratory findings and histology 306 management and prognosis 306 pathogenesis 305–6 Bacteroides spp. 305 balanitis circinata 172 Bartholin cysts 268–9 Bartholin duct openings 128 Bartholin’s gland carcinoma 298 basal cell carcinoma 288–9 basal cell epithelioma 91 Behçet’s disease 245–6, 360 differential diagnosis 244 benign mucous membrane pemphigoid see cicatricial pemphigoid benzathine penicillin, in syphilis 253 benzocaine allergy 187 lichen planus 153 benzoyl peroxide, in acne 84 betamethasone dipropionate 373 lichen sclerosus 140 betamethasone valerate 373 bichloroacetic acid, in genital warts 198, 200 bile duct obstruction 62 biopsy, vulvar 366 blackheads 14 Borrelia bergdorferi 139 botulinum toxin, in Hailey-Hailey disease 192 Bowen’s disease see VIN3 breast ectopic tissue 206 nipple eczema 70, 71 Tanner stages of development 5 breastfeeding cyclophosphamide 87 dapsone 89 bullae 220–1 bullous diseases 229–38 in children 333, 339 see also individual conditions bullous erythema multiforme 229–32 clinical manifestations 230 differential diagnosis 230–1 epidemiology 230 laboratory findings and histology 231 management and prognosis 231–2 pathogenesis 231 bullous impetigo 230, 236–7 bullous pemphigoid 42, 237 differential diagnosis 44 immunopathology 45

Index burning vulva syndrome 357 Buschke-Lowenstein tumor 198 butoconazole, in Candida vulvovaginitis 303

C calcineurin inhibitors vulvovaginal disease 374–5 see also individual drugs calcipotriene in psoriasis 172 calcipotriol, in psoriasis 81 calcium, in impetigo herpetiformis 83 Candida albicans 304, 337, 344, 375 in children 332, 337 diaper granuloma 212, 213 fissures 236 vaginitis 301, 303 vulvitis 188–90 Candida glabrata 302, 345 Candida krusei 303, 345 Candida parapsilosis 303 Candida tropicalis 303, 304, 375 Candida vulvovaginitis 301–5 clinical manifestations 301–2 diagnosis/differential diagnosis 302–3 epidemiology 301–2 laboratory findings and histology 304 management and prognosis 304–5 pathogenesis 303–4 candidiasis 157 cutaneous 220 canker sores see aphthous ulcer cantharidin, in molluscum contagiosum 203, 204 capsaicin, in herpes zoster 227 ceftriaxone, in syphilis 253–4 cellulitis, recurring 319–20 cetirizine, in polymorphic eruption of pregnancy 54, 70 chancre see syphilis chancroid 254, 255 chickenpox see varicella-zoster virus chloasma see melasma chloroquine lupus erythematosus 179 porphyria cutanea tarda 90 chlorphenamine maleate, in polymorphic eruption of pregnancy 54 chlorpheniramine, in polymorphic eruption of pregnancy 70 cholestyramine, in porphyria cutanea tarda 90 choriocarcinoma 40 cicatricial pemphigoid 136, 150, 233–5 clinical manifestations 233 differential diagnosis 234 epidemiology 233

cicatricial pemphigoid (Continued) laboratory findings and histology 234–5 management and prognosis 235 pathogenesis 235 cidofovir, in genital warts 118 ciprofloxacin, in folliculitis 220 climacteric see menopause clindamycin acne 84 bacterial vaginitis 309 bacterial vaginosis 306 desquamative inflammatory vaginitis 314, 380 erythrasma 175 folliculitis 219, 220 furuncles 210 hidradenitis suppurativa 209 vulvovaginal disease 376 cliteromegaly 325, 363 clitoris 126–7 cloaca 123–4 clobetasol propionate 373 aphthous ulcer 245 lichen planus 154 lichen sclerosus 139 lichen simplex chronicus 165 plasma cell vulvitis 178 clobetasone butyrate, in polymorphic eruption of pregnancy 54 clofazimine, in leprosy 118 clotrimazole, in Candida vulvovaginitis 303 coal tar ointment, in psoriasis 81 coccidiomycosis 86 colchicine, in aphthous ulcer 244, 245 collarettes 189, 236 comedones acne 14, 84 hidradenitis suppurativa 207 complex aphthosis 242, 244 see also aphthous ulcer condyloma acuminata see genital warts condyloma latum 205, 206 congenital vulvar abnormalities 323–6 ambiguous external genitalia 323–4 hemangioma 325–6 hymenal abnormalities 324–5 labial adhesions 324 labial hypertrophy 324 melanocytic nevi 325–6 connective tissue diseases in pregnancy 99–106 see also individual conditions contact dermatitis 34, 182–7 allergic see allergic contact dermatitis in children 327

393

Index 394

contact dermatitis (Continued) irritant see irritant contact dermatitis coratadine, in polymorphic eruption of pregnancy 54, 70 corps ronds 193 corpus luteum 9 corticosteroids aphthous ulcer 244 atopic eruption of pregnancy 68–9 bullous pemphigoid 237 cicatricial pemphigoid 235 Crohn’s disease 249 impetigo herpetiformis 83 lichen planus 382 lichen simplex chronicus 165 lupus erythematosus 179 plasma cell vulvitis 178 psoriasis 81 pyoderma gangrenosum 94–5 topical 389 vitiligo 258, 259 vulvovaginal disease 372–4 see also individual drugs Corynebacterium minutissimum 175 Crohn’s disease 213, 246–9, 360 in children 342 clinical manifestations 246–8 diagnosis/differential diagnosis 248–9 epidemiology 246–8 laboratory tests and histology 249 management and prognosis 249 pathogenesis 249 vulvar edema 320 cryotherapy genital warts 200 molluscum contagiosum 203, 204 curettage, in molluscum contagiosum 203, 204 cutaneous candidiasis 220 cutaneous neonatal lupus 101–2 cutaneous T-cell lymphoma 93 cyclophosphamide breastfeeding 87 cicatricial pemphigoid 235 connective tissue disease 100 lichen planus 155 lupus erythematosus 179 pemphigus 87 teratogenicity 87 cyclosporine bullous erythema multiforme 232 hidradenitis suppurativa 210 lichen planus 155 psoriasis 81, 82 pyoderma gangrenosum 94–5

cysts 214, 267–71 Bartholin 268–9 of canal of Nuck 270 epidermoid 267–8 mesonephric and paramesonephric duct 270 mucinous 270–1 pilonidal 271 cytolytic vaginosis 309–10 cytomegalovirus 254

D dapsone aphthous ulcer 244, 245 breastfeeding 89 cicatricial pemphigoid 235 dermatitis herpetiformis 88 hidradenitis suppurativa 210 leprosy 118 pemphigoid gestationis 46 Darier’s disease 192–4, 360 clinical manifestations 192–3 differential diagnosis 193 epidemiology 192–3 histology and laboratory findings 193 management and prognosis 194 pathogenesis 193–4 Darier-White disease see Darier’s disease deferoxamine, in porphyria cutanea tarda 90 dehydroepiandrosterone 6 dermatitis herpetiformis autoimmune progesterone dermatitis 18 immunopathology 45 management 88–9 in pregnancy 88–9 premenstrual 15 dermatitis multiformis gestationis see pemphigoid gestationis dermatofibroma protruberans 298 dermatomyositis 103–4 dermatoses of pregnancy 31–6, 62 vulvar 359–60 eczematous 181–94 paediatric 326–35 papulosquamous 167–80 see also individual conditions desipramine, in vulvodynia 347 desmoglein 388 desonide 373 desquamative inflammatory vaginitis 312–15, 380 clinical manifestations 312, 313 diagnosis/differential diagnosis 313 epidemiology 312

Index desquamative inflammatory vaginitis (Continued) laboratory findings and histology 313–14 pathogenesis 312 therapy and prognosis 314–15 diaper dermatitis 182, 184, 212, 327–8, 331, 334 diaper granuloma 213 diethylstilbestrol, in papular dermatitis of pregnancy 75 difluorasone diacetate 373 lichen planus 154 lichen sclerosus 140 diphenhydramine allergy 187 lichen planus 153 lichen simplex chronicus 166 dithranol, in psoriasis 81 Donovan bodies 255 doxycycline aphthous ulcer 245 folliculitis 219, 220 hidradenitis suppurativa 209 syphilis 253 drug eruption 34 drug icterus 62 duloxetine, in vulvodynia 347 dyskeratosis 190 dysplastic nevi 293–4

E eccrine glands in pregnancy 29 ectopic breast tissue 206 eczema 16, 17, 384 autoimmune progesterone dermatitis 17 exacerbation in pregnancy 66, 67 hand 71 nipple 70, 71 pompholyx 71 efalizumab, psoriasis 82, 172 Ehlers-Danlos syndrome 104–6 elafin, in impetigo herpetiformis 83 elephantiasis nostra verrucosa 228 endometriosis, vulvar 214 Enterobius vermicularis 338 enterovirus 111 fetal/neonatal consequences 110 maternal infection 108 epidermal barrier layer 164–5 epidermoid cysts 267–8 Epidermophyton floccosum 174 Epstein-Barr virus 254 in children 337 erosions 220–1 erosive papulododular dermatosis 212 erythema annulare centrifugum 16

erythema infectiosum see parvovirus B19 erythema multiforme 16, 32, 150 autoimmune progesterone dermatitis 17 in children 333, 339–40, 341 major see bullous erythema multiforme in pregnancy 90–1 premenstrual 15 erythema nodosum 34 in pregnancy 85–6 underlying conditions 85 erythrasma 175 erythromycin acne 84 erythrasma 175 hidradenitis suppurativa 85 Escherichia coli 308 estradiol, in atrophic vaginitis 311 estrogens 13 autoimmune dermatitis 21 deficiency 142 vulvovaginal disease 376 etanercept cicatricial pemphigoid 235 hidradenitis suppurativa 210 lichen planus 155 psoriasis 172 etretinate, teratogenicity 84 excoriation 249–51

F factitious disease 249–51 famciclovir herpes simplex virus 114, 116, 224, 225 herpes zoster 227 familial benign pemphigus see Hailey-Hailey disease female hydrocele 270 fibroepithelial polyps 274–5 fibroma 281 fifth disease see parvovirus B19 filariasis 322 finasteride, in hidradenitis suppurativa 209 fissures 236 fixed drug eruption 150, 232–3 clinical manifestations 232 differential diagnosis 232–3 epidemiology 232 laboratory findings and histology 233 management and prognosis 233 pathogenesis 233 flexural nevi 294 fluocinonide 373 lichen simplex chronicus 165

395

Index 396

fluconazole Candida vulvovaginitis 303, 304 desquamative inflammatory vaginitis 314 folliculitis 219, 220 lichen planus 154 pityriasis versicolor 176 tinea cruris 174 vulvovaginal disease 375 flucytosine, in Candida vulvovaginitis 303 fluocinonide, in irritant contact dermatitis 185 5-fluorouracil in allergy 184 Darier’s disease 194 folliculitis 217–20 bacterial 210, 217 clinical manifestations 217–18 differential diagnosis 218–19 epidemiology 217–18 fungal 217 HIV-related 112 hot-tub 217, 219 laboratory findings and histology 219 management and prognosis 219–20 pathogenesis 219 shaving 218 fondaparinux, in connective tissue disease 100 Fordyce spots 127, 205, 361, 363 foreign body vaginitis 333, 338 fossa navicularis 128 Fox-Fordyce disease 205–6 in pregnancy 29 Friedrich, Eduard 358 fungal folliculitis 217 furuncles 210–11 fusidic acid, in polymorphic eruption of pregnancy 54, 70 Futcher lines 24, 26

G gabapentin, in vulvodynia 347 Gardnerella vaginalis 305 vaginitis see bacterial vaginosis Gartner’s cysts 270 genital herpes 113–14 clinical features 113–14 diagnosis and treatment 114 epidemiology 113 management in pregnancy 116–17 see also herpes simplex virus genital warts 112, 117–18, 195–201, 260 Buschke-Lowenstein-type 196 in children 332, 336–7 clinical manifestations 195–6

genital warts (Continued) diagnosis/differential diagnosis 196–7 epidemiology 195–6 filiform 196 flat-topped 196 histology and laboratory tests 197 keratotic 195–6 management and prognosis 199–201 pathogenesis 197–9 vaccines 201 gold connective tissue disease 100 pemphigus 87 gonadotrophin-releasing hormone 4 Gorlin’s syndrome 91, 288 goserelin, in pemphigoid gestationis 46 Gottron papules 104 grains 193 granular cell tumors 281–2 granuloma inguinale 254–5, 322 Graves disease 41 griseofulvin folliculitis 219, 220 pityriasis versicolor 176 tinea cruris 174 group B streptococcus 308, 381 growth spurt, pubertal 4, 5

H HAART therapy 111 Haemophilus ducreyi 254 Haemophilus vaginitis see bacterial vaginosis Hailey-Hailey disease 190–2, 235–6, 360 clinical manifestations 190 differential diagnosis 190 epidemiology 190 histology and laboratory tests 190–1 management and prognosis 192 pathogenesis 191–2 halcinonide 373 halobetasol propionate 373 lichen planus 154 lichen sclerosus 140 hand eczema 71 Hart’s line 127 Hashimoto thyroiditis 41 hemangioma 276–8 in children 329, 330 clinical manifestations 276, 277 congenital 325–6 diagnosis/differential diagnosis 276–7 epidemiology 276 histology and laboratory examination 277

Index hemangioma (Continued) management and prognosis 277–8 pathogenesis 277 hemorrhoids in pregnancy 28 heparin, in connective tissue disease 100 herald patch 176 herpes circinatus bullosus see pemphigoid gestationis herpes gestationis see pemphigoid gestationis herpes simplex virus 113–17, 221–5 in children 332, 335–6 clinical manifestations 221–2 differential diagnosis 222 epidemiology 221–2 genital herpes 113–14 history 117 laboratory findings and histology 222–3 management 223–5 in pregnancy 116–17 neonatal herpes 114–15 pathogenesis 223 prevention 117 prognosis 223–5 vertical transmission 115–16 herpes zoster see varicella-zoster virus hidradenitis suppurativa 207–10 clinical manifestations 207–8 diagnosis/differential diagnosis 208 epidemiology 207–8 histology and laboratory tests 208 management and prognosis 209–10 pathogenesis 208–9 in pregnancy 29, 85 vulvar edema 320–1 hidradenoma papilliferum 280 hirsutism in pregnancy 24, 26–7 HIV 111–13 folliculitis 112 genital conditions 112 genital warts 199 Kaposi’s sarcoma 112 varicella-zoster virus 112 hormonal changes menopause 10–12 menstrual cycle 7–9 pregnancy 9–11 puberty 4–7 hormone replacement therapy 11–12 hot-tub folliculitis 217, 219 human immunodeficiency virus see HIV human leukocyte antigen 49 lichen sclerosus 137 human papillomavirus see genital warts hydatidiform mole 40

hydrocortisone 373 desquamative inflammatory vaginitis 314 intertrigo 188 seborrheic dermatitis 188 hydrocortisone butyrate 373 polymorphic eruption of pregnancy 54 hydrops fetalis 111 hydroquinone, in postinflammatory hyperpigmentation 263 hydroxychloroquine connective tissue disease 100 lichen planus 155 lupus erythematosus 179 hydroxyurea, in psoriasis 82 hydroxyzine lichen simplex chronicus 166 polymorphic eruption of pregnancy 54, 70 hymen abnormalities 324–5, 327 imperforate 328 hyperbilirubinemic states 62 hyperemesis gravidarum 62 hyperkeratosis 53, 259–60 hyperpigmentation 260–6 in pregnancy 23–4, 25, 26 hypoparathyroidism, and reduced vitamin D absorption 83 hypopigmentation 257–60 hypoplastic dystrophy see lichen sclerosus hypothalamic-pituitary axis 3–4

I ichthyosis 112 imiquimod allergy 184 genital warts 198, 200 molluscum contagiosum 203, 204 immune system in pregnancy 29–30 immunosuppressants, in pemphigus 87 impetigo 332, 335 impetigo herpetiformis 32 in pregnancy 82–3 infectious diseases in pregnancy 107–19 inflammatory bowel disease, and vulvar edema 320 inflammatory vaginitis 315 infliximab cicatricial pemphigoid 235 connective tissue disease 100 Crohn’s disease 249 hidradenitis suppurativa 210 lichen planus 155 psoriasis 172 insect bites 34

397

Index 398

interferon-alpha, in vulvodynia 347 interlabial sulcus 126 International Society for the Study of Vulvovaginal Disease 357–60 intertrigo 187–8 intrahepatic cholestasis of pregnancy 32, 33, 57–63 clinical features 58–9, 60, 61 differential diagnosis 59, 62 etiology 58 fetal risks 57, 60–1 history 5708 laboratory findings 58–9 management 59, 61–2 inverse acne 208 irritant contact dermatitis 182–5, 344 in children 328, 331 clinical manifestations 182–3 diagnosis and differential diagnosis 183 epidemiology 182–3 histology and laboratory findings 184 management and prognosis 185 pathogenesis 184–5 vulvar 360 irritants, avoidance of 370–1 isotretinoin acne 84 Darier’s disease 194 lupus erythematosus 179 teratogenicity 84 itraconazole Candida vulvovaginitis 303, 304 folliculitis 219, 220 tinea cruris 174

J jaundice 58–9 jock itch see tinea cruris

K Kaposi’s sarcoma 112, 298 Kasabach-Merritt phenomenon 277 keratosis follicularis see Darier’s disease keratosis pilaris 211, 220 ketoconazole Candida vulvovaginitis 303 folliculitis 220 pityriasis versicolor 176 tinea cruris 174 Klebsiella granulomatis 254–5 Koebner phenomenon 51, 139, 168, 257 koilocytosis 197

L labial adhesions 324 in children 334 labial fusion 11, 12 labial hypertrophy 324, 327 labia majora 125–6 labia minora 126 lactic acid, in keratosis pilaris 220 lactobacillus vaginosis 309 Langerhans cell histiocytosis 282 in children 334, 341–2 Letterer-Siwe type 188, 282 latex allergy 318 leflunomide, in connective tissue disease 100 leprosy in pregnancy 118 leptothrix 309 lesional margination 181 levofloxacin, in folliculitis 220 lichenification 134, 160, 182 lichen planus 147–56, 382 clinical manifestations 147–50 diagnosis/differential diagnosis 150–2 epidemiology 147–50 laboratory findings and histology 152–3 management and prognosis 153–6 morphologic variants 147 pathogenesis 153 premenstrual 15 vulvar 360, 365 lichen sclerosus 133–45, 157, 259, 260, 383 in children 331, 334, 335 clinical manifestations 133–5 compliance 144 diagnosis/differential diagnosis 135–6 epidemiology 133–5 estrogen deficiency 142 hyperkeratotic lesions 143–4 laboratory findings and histology 136–7 management and prognosis 139–42 pathogenesis 137–9 prepubertal girls 142 skin erosion 142–3 vulvar 360 lichen simplex chronicus 158–66, 269, 384 clinical manifestations 158–9 diagnosis/differential diagnosis 161–2 epidemiology 158–9 examination 159–61 histology and laboratory tests 162–3 management and prognosis 163–6 nighttime scratching 166 pathogenesis 163 vulvar 182, 360, 364

Index lidocaine aphthous ulcer 244, 245 vulvodynia 347 linea alba, pigmentation in pregnancy 23, 24 linear IgA bullous dermatosis 45 linear IgA disease 360 in children 333, 339 in pregnancy 89 linear IgM dermatosis of pregnancy 32 lipoma 280–1 livedo reticularis 102 low-molecular-weight heparin, in antiphospholipid syndrome 102 lupus erythematosus 178–9 neonatal lupus syndromes 101–2 premenstrual 15 systemic 99–101, 105 lupus pernio 93, 94 lupus vasculitis 101 luteinizing hormone levels in puberty 5 lymphangiectasia 196, 228–9, 319 lymphangioma 282 lymphangioma circumscriptum 228–9 clinical manifestations 228–9 differential diagnosis 229 epidemiology 228–9 laboratory findings and histology 229 management and prognosis 229 pathogenesis 229 lymphedema 317 primary congenital 322 lymphogranuloma venereum 322 lymphoma 298

M MAGIC syndrome 244 Malassezia furfur 176 margination 181 Markel cell tumor 298 melanocytic nevi 91–2, 271–4 clinical manifestations 271–2 congenital 325–6 diagnosis/differential diagnosis 272–3 epidemiology 271–2 laboratory tests and histology 273 management and prognosis 274 pathogenesis 273–4 melanoma 92–3, 294–7 clinical manifestations 295–6 diagnosis/differential diagnosis 296 epidemiology 295 laboratory findings and histology 296 management 93, 297

melanoma (Continued) pathogenesis 296–7 in pregnancy 93 prognosis 297 timing of pregnancy 93 melanonychia 27 melanosis see vulvar melanosis melasma 10, 24, 27 Melkersson-Rosenthal granulomatosis 213, 249, 360 vulvar edema 321–2 menarche 4 menopause 4 hormonal changes 10–12 menstrual cycle 7–9 follicular phase 7, 8 luteal phase 8 oocyte release 7–8 skin changes 8–9 6-mercaptopurine, in Crohn’s disease 249 mesonephric duct cysts 270 methotrexate cicatricial pemphigoid 235 connective tissue disease 100 lichen planus 155 pemphigus 87 psoriasis 82, 172 metronidazole bacterial vaginosis 306 Crohn’s disease 249 Trichomonas vaginitis 307 vulvovaginal disease 375–6 miconazole, in Candida vulvovaginitis 303 milaria 34 milia 268 milk line nevi 294 Milroy’s disease 322 minocycline aphthous ulcer 245 folliculitis 219, 220 hidradenitis suppurativa 209 Mobiluncus spp. 305 molluscum contagiosum 112, 196, 197, 201–4, 214, 220 in children 332, 336 clinical manifestations 201–2 diagnosis/differential diagnosis 202–3 epidemiology 201–2 histology and laboratory tests 203 management and prognosis 203–4 pathogenesis 203 mons pubis 125 Montgomery’s tubercules 29 mucinous cysts 270–1 mupirocin, in polymorphic eruption of pregnancy 54, 70

399

Index 400

mycophenolate mofetil connective tissue disease 100 lichen planus 155 Mycoplasma hominis 305 Mycoplasma pneumoniae 91 mycosis fungoides 93

N nails melanonychia 27 onycholysis 27 in pregnancy 27 neomycin allergy 187 neonatal herpes 114–15 neonatal lupus syndromes 101–2 neoplasms benign 271–82 angiokeratomas 278 fibroma 281 granular cell tumors 281–2 hemangiomas 276–8 hidradenoma papilliferum 280 Langerhans cell histiocytosis 282 lipoma 280–1 melanocytic nevi 271–4 neurofibroma 280 seborrheic keratoses 275–6 skin tags and fibroepithelial polyps 274–5 syringomas 279–80 premalignant/malignant 282–98 atypial nevi 283–4 basal cell carcinoma 288–9 extramammary Paget’s disease 289–93 invasive squamous cell carcinoma 286–7 melanoma see melanoma verrucous carcinoma 287–8 vulvar intraepithelial neoplasia see VIN neurodermatitis 158, 182 neurofibroma 280 neurofibromatosis in pregnancy 95–6 nevi atypical 293–4 dysplastic 293–4 flexural 294 melanocytic 325–6 milk line 294 nevoid telangectasia syndrome, in pregnancy 29 niacinamide, in bullous pemphigoid 237 nicorandil allergy 251 nipple eczema 70, 71 pigmentation in pregnancy 23, 25 nitroglycerin, in vulvodynia 347

nonallergic vulvar edema 318 nonspecific vaginitis see bacterial vaginosis non-steroidal anti-inflammatory drugs see NSAIDs NSAIDs, in connective tissue disease 100 nystatin, Candida vulvovaginitis 303, 304

O odor 315–16 onycholysis 27 oral contraceptive pill, and melasma 24 ovarian hyperstimulation syndrome 322

P paediatric vulvar disorders bullous diseases 333 congenital abnormalities 323–6 dermatoses 326–35 infections 332 infestations 333 sexual abuse 333 Paget’s disease, extramammary 289–93 clinical manifestations 289–91 diagnosis/differential diagnosis 291 epidemiology 289–90 laboratory findings and histology 291–2 management and prognosis 292–3 pathogenesis 292 palmar erythema in pregnancy 29, 100 papular acantholytic dermatosis 190–1 papular acantholytic dyskeratosis 191 papular dermatitis of pregnancy 32, 75–6 papular genitocrural acantholysis 191, 360 papules red 207–14 skin-colored 195–207 see also individual conditions parakeratosis 53 paramesonephric duct cysts 270 parvovirus B19, 111 fetal/neonatal consequences 109–10 maternal infection 108 patient education 369–70 patient information 379–90 pelvic floor therapy 347–8 pemphigoid bullous 42, 44, 45, 237 cicatricial 136, 150, 233–5 vulvar 360 pemphigoid gestationis 31, 32, 33, 37–47 associated autoimmune disease 41 choriocarcinoma 40 clinical features 37

Index pemphigoid gestationis (Continued) differential diagnosis 43, 44 fetal and neonatal disease 40–1 histopathology 41 historical terminology 37 hydatidiform mole 40 immunogenetics 42 immunopathogenesis 42–3 immunopathology 41–2, 45 natural history 38–40 onset of disease 38 premenstrual 15 rash 38 treatment 43–6 pemphigoid gravidarum see pemphigoid gestationis pemphigus 86–8 fetal prognosis 86 immunopathology 45 management 87–8 mortality/morbidity 88 neonatal 88 pemphigus antibody titer 87 pemphigus foliaceus 86 pemphigus hystericus see pemphigoid gestationis pemphigus pruriginosus see pemphigoid gestationis pemphigus vulgaris 86, 87, 136, 150, 237–8 Penelope phenomenon 159 penicillamine, in connective tissue disease 100 penicillin, in polymorphic eruption of pregnancy 54, 70 penicillin V, in bacterial vaginitis 309 pentoxyphylline, in aphthous ulcer 245 Peptostreptococcus spp. 305 perimenstrual dermatoses 14–16 exacerbation of existing dermatoses 15–16 premenstrual syndrome 14–15 perineal body 128 pernicious anemia 41 petrolatum fixed drug eruption 233 irritant contact dermatitis 185 photodynamic therapy, Darier’s disease 194 physiologic hyperpigmentation 263 pigmentary demarcation lines 24, 26 pigmentation disorders 257–65 hyperpigmentation 260–6 hypopigmentation 257–60 see also individual conditions pilonidal cysts 271 pimecrolimus lichen planus 155 lichen sclerosus 140 lichen simplex chronicus 165 psoriasis 172 vitiligo 258, 259

pimecrolimus (Continued) vulvaginal disease 374–5 pinworms 333, 338 pityriasis rosea 34, 176 pityriasis versicolor 175–6 Pityrosporum ovale 77, 112, 188 placenta 9–10 plaques, skin-colored 106–207 plasma cell vulvitis 150, 176–8 clinical manifestations 177 differential diagnosis 177 epidemiology 177 laboratory manifestations and histology 178 management and prognosis 178 pathogenesis 178 plasmapheresis, in pemphigoid gestationis 45–6 podofilox, genital warts 198, 200 podophyllin allergy 184 genital warts 118, 198, 200 polycystic ovary syndrome 6, 26 polymorphic eruption of pregnancy 31, 32, 33, 49–55 clinical features 50–3 differential diagnosis 44, 53 etiology 49–50 histopathology 53 history 49 immunofluorescence 53 management 54 prognosis 44, 53–4 polymyositis 103–4 polyps, fibroepithelial 274–5 pompholyx 16 premenstrual 15 pompholyx eczema 71 porphyria cutanea tarda 89–90 management 90 in pregnancy 89 Porphyromonas spp. 305 posterior fourchette 128 postinflammatory hyperpigmentation 262–3 clinical manifestations 262 diagnosis/differential diagnosis 262–3 epidemiology 262 laboratory findings and histology 263 management and prognosis 263 pathogenesis 263 postinflammatory hypopigmentation 259 prednisolone atopic eruption of pregnancy 69 lichen simplex chronicus 165 papular dermatitis of pregnancy 75 pemphigoid gestationis 44–5 polymorphic eruption of pregnancy 69

401

Index 402

prednisone aphthous ulcer 245 connective tissue disease 100 hidradenitis suppurativa 210 lichen simplex chronicus 165 pemphigus 87 Stevens-Johnson syndrome 91 pre-eclampsia 62 pregabalin, in vulvodynia 347 pregnancy autoimmune progesterone dermatitis 18 connective tissue diseases 99–106 eccrine/apocrine gland activity 29 effects on skin disorders 79–98 acne vulgaris 83–5 acrodermatitis enteropathica 95 dermatitis herpetiformis 88–9 erythema multiforme 90–1 erythema nodosum 85–6 hidradenitis suppurativa 85 impetigo herpetiformis 82–3 linear IgA disease 89 neoplasia 91–3 neurofibroma 95–6 pemphigus 86–8 porphyria cutanea tarda 89–90 psoriasis 79–82 pyoderma gangrenosum 94–5 sarcoidosis 93–4 hair and nail changes 24, 26–7 hormonal changes 9–10 immune system changes 29–30 infectious diseases 107–19 skin changes 10, 23–6 hyperpigmentation 23–4 melasma 10, 24, 27 striae distensae 23, 24, 25, 27 vascular changes 28–9 pregnancy dermatoses 31–6, 62 algorithmic approach 34, 35 differential diagnosis 33 history 31–4 premenstrual syndrome 14–15 prepuce 126 Prevotella spp. 305 progesterone 14 autoimmune dermatitis 16–21 intradermal tests 19–20 intramuscular and oral challenge 20 promethazine, polymorphic eruption of pregnancy 54, 70 prurigo annularis 32 prurigo gestationis 31, 32, 73 prurigo of pregnancy 31, 32, 73–5 pruritic folliculitis of pregnancy 31, 32, 76–7

pruritic urticarial papules and plaques of pregnancy see polymorphic eruption of pregnancy pruritus in pregnancy 34, 35 vulvar see pruritus vulvae pruritus gravidarum 32 pruritus vulvae 147–8 premenstrual 15 pseudohermaphroditism 323–4, 325, 326 Pseudomonas aeruginosa 217, 219 pseudoxanthoma elasticum 104 in pregnancy 105, 106 psoriasis 79–82, 157 in children 329–30, 331 course of disease 82 erythrodermic 79, 168 generalized pustular (of von Zumbusch) 80, 81 guttate 79, 80, 168, 169 and HIV 112 inverse 168 management 81 palmoplantar pustulosis 80 plaque-type 79, 80 in pregnancy 81 premenstrual 15 pustular 79, 168 scalp 80 systemic therapy 82 vulgaris 168 vulvar 167–72, 360 psychosexual issues 370 puberty growth spurt 4, 5 hormonal changes 4–7 pustules 217–20 see also individual conditions PUVA therapy psoriasis 81–2 teratogenicity 93 pyoderma faciale 84 pyoderma gangrenosum 94–5, 251 pyogenic granuloma, in pregnancy 28 pyridoxine, in pemphigoid gestationis 46

Q quinicrine, in lupus erythematosus 179

R rash of pemphigoid gestationis 38 toxemic of pregnancy 32 see also individual conditions

Index Raynaud’s phenomenon 103 Reiter’s syndrome 169, 172–3 restriction fragment length polymorphism 42 retinoic acid Darier’s disease 194 lupus erythematosus 179 psoriasis 82, 172 teratogenicity 84 retinoids Darier’s disease 194 impetigo herpetiformis 83 lichen planus 155 psoriasis 81 teratogenicity 83 rheumatoid arthritis, in pregnancy 99, 100, 105 rifampin furuncles 210 hidradenitis suppurativa 209 leprosy 118 ritodrine, in pemphigoid gestationis 46 Roaccutane see isotretinoin rosacea fulminans 84 rubella 110–11 fetal/neonatal consequences 109 maternal infection 108

S Saccharomyces cerevisiae 303 salicylic acid keratosis pilaris 220 teratogenicity 83 salicylism 83 sarcoidosis 212–13 in pregnancy 93–4 vulvar edema 322 sarcoma 298 scabies 34, 59, 62 in children 333, 338 scleroderma 103 in pregnancy 105 sebaceous gland hyperplasia see Fordyce spots sebopsoriasis 188 seborrheic dermatitis 112, 170, 187–8 in children 329, 331 seborrheic keratoses 275–6 semen allergy 318 sex hormone-binding globulin 6 sex hormones 13–14 sexual abuse 333, 338–9, 340 shingles see varicella-zoster virus silver nitrate, in aphthous ulcer 244 Sjögren’s syndrome 101 Skene duct openings 128

skin menopause-related changes 11–12 menstrual cycle-related changes 8–9 pregnancy-related changes 10 skin-colored papules/plaques 195–207 skin tags 196, 205, 274–5 slapped-cheek syndrome see parvovirus B19 spider nevi in pregnancy 29 squamous cell carcinoma 91 invasive 286–7 in situ see VIN staphylococcal scalded skin syndrome 230 Staphylococcus aureus 112, 210, 219, 308 impetigo 335 steroids see corticosteroids Stevens-Johnson syndrome 90, 91, 150, 230 see also bullous erythema multiforme stomatitis 16 strawberry cervix 306, 312 streptococcal infection 335 stretch marks 23, 24, 25 striae distensae 23, 24, 25, 27 striae gravidarum 10 sulfapyridine, in dermatitis herpetiformis 88 sulfasalazine connective tissue disease 100 Crohn’s disease 249 surgery, and vulvar edema 319 syphilis, primary 251–4 clinical manifestations 251–2 diagnosis/differential diagnosis 252 epidemiology 251–2 histology and laboratory tests 252–3 management and prognosis 253–4 pathogenesis 253 syringoma 279–80 systemic lupus erythematosus 99–101, 105

T tacrolimus cicatricial pemphigoid 235 connective tissue disease 100 Darier’s disease 194 Hailey-Hailey disease 192 lichen planus 154–5, 382 lichen sclerosus 140 lichen simplex chronicus 165 psoriasis 172 vitiligo 258, 259 vulvaginal disease 374–5 Tanner stages of breast development 5 telogen effluvium 26

403

Index 404

terbinafine Candida vulvovaginitis 303, 304 folliculitis 220 pityriasis versicolor 176 tinea cruris 174 terconazole, in Candida vulvovaginitis 303 testosterone, in lichen sclerosus 139 tetracycline acne 84 bullous pemphigoid 237 furuncles 210 hidradenitis suppurativa 85, 209 thalidomide aphthous ulcer 244, 245 Crohn’s disease 249 lupus erythematosus 179 thyrotoxicosis 41 tinea cruris 157, 170, 173–5 clinical manifestations 173 differential diagnosis 173 epidemiology 173 laboratory abnormalities and histology 173–4 management and prognosis 174–5 pathogenesis 174 tinea infections 112 in children 332, 337–8 tinea versicolor 175–6 tinidazole, in Trichomonas vaginitis 307 tioconazole, in Candida vulvovaginitis 303 topical anesthesia, vulva 366 toxemic rash of pregnancy 32 toxic epidermal necrolysis see bullous erythema multiforme Treponema pallidum 253 tretinoin, in lichen sclerosus 143 triamcinolone acetonide 373 intertrigo 188 irritant contact dermatitis 185 lichen sclerosus 143 lichen simplex chronicus 165 seborrheic dermatitis 188 trichloroacetic acid allergy 184 genital warts 198, 200 Trichomonas vaginitis 306–7 clinical manifestations 306 diagnosis/differential diagnosis 307 epidemiology 306 laboratory findings and histology 307 management and prognosis 307 pathogenesis 307 Trichophyton mentagrophytes 174 in children 332

Trichophyton rubrum 174 in children 332 trimethoprim-sulfamethoxazole, treatment of furuncles 210

U ulcers aphthous 241–5, 343, 360 knife cut 247, 248 vulvar 241–56 ultraviolet B see UVB irradiation urea, in atopic eruption of pregnancy 68 urethra 128 prolapse 211–12 urethral caruncle 211–12 ursodeoxycholic acid, intrahepatic cholestasis of pregnancy 59, 62 urticaria 34 autoimmune progesterone dermatitis 17 premenstrual 15 UVB irradiation polymorphic eruption of pregnancy 54, 70 psoriasis 81–2

V vaccine for human papillomavirus 201 vaginal discharge, normal 315, 385 vaginitis 301–16 atrophic vaginitis 310–12 bacterial 307–9 Candida vulvovaginitis 301–5 cytolytic vaginosis 309–20 desquamative inflammatory 312–15 foreign body 333, 338 inflammatory 315 lactobacillus vaginosis 309 Trichomonas 306–7 vaginosis, bacterial 305–6 Vagisil allergy 187 valacyclovir herpes simplex virus 114, 116, 224, 225 herpes zoster 227 vancomycin, in treatment of furuncles 210 varicella-zoster virus 107–10, 225–8 clinical manifestations 225–6 differential diagnosis 226–7 epidemiology 225–6 fetal/neonatal consequences 109 and HIV 112, 113 laboratory findings and histology 227 management and prognosis 227–8

Index varicella-zoster virus (Continued) maternal infection 108 pathogenesis 227 vascular changes in pregnancy 28–9 venlafaxine, in vulvodynia 347 verruciform xanthoma 282 verrucous carcinoma 287–8 vesicles 220–1 vesicular diseases 221–9 see also individual conditions vestibular papillae 127–8 vestibular papillomatosis 196, 204–5 vestibule 127–8 vestibulodynia 316, 344, 358, 386–7 see also vulvodynia VIN 157, 179–80, 282–6 clinical manifestations 282–4 diagnosis/differential diagnosis 284 epidemiology 282–4 laboratory tests and histology 284–5 management and prognosis 285–6 pathogenesis 285 viral exanthems 107–11 enteroviruses 111 parvovirus B19, 111 rubella 110–11 varicella-zoster virus 107–10 viral hepatitis 62 vitamin D impetigo herpetiformis 83 reduced absorption 83 vitiligo 257–9 in children 332, 334–5 clinical manifestations 257, 258 diagnosis/differential diagnosis 257–8 epidemiology 257 laboratory findings and histology 258 management and prognosis 259 pathogenesis 258–9 Voigt lines 24, 26 vulva anatomy 123–31 anus 129 Bartholin duct openings 128 biopsy 366 blood supply 129–30 clitoris 126–7 embryology 123–4 erythema 362 fossa navicularis 128 hyperkeratosis 365 hyperpigmentation 364 interlabial sulcus 126 labia majora 125–6

vulva (Continued) labia minora 126 mons pubis 125 muscles 131 nerve supply 130–1 normal 124–5 pain 357–8 perineal body 128 posterior fourchette 128 prepuce 126 scarring 364 Skene duct openings 128 topical anesthesia 366 urethra 128 vestibule 127–8 vulvar dermatoses 359–60 in children 326–35 eczematous 181–94 papulosquamous 167–80 see also individual conditions vulvar dystrophy 359–60 vulvar edema 317–22 acute 317–18 chronic 318–22 vulvar intraepithelial neoplasia see VIN vulvar melanosis 136, 260–2 clinical manifestations 260, 261 diagnosis/differential diagnosis 260–2 epidemiology 260 laboratory findings and histology 261 management and prognosis 262 pathogenesis 261–2 in pregnancy 23, 26 vulvar papillae 363 vulvar papillomatosis 361, 362, 363 vulvar pruritus 157–8 vulvar skin care 390 vulvar squamous cell intraepithelial neoplasia 358–9 vulvar ulcers 241–56 infectious 251–5 non-infectious 241–51 see also individual conditions vulvar varicosities, in pregnancy 28 vulvitis candidal 188–90 plasma cell 360 plasma cell see plasma cell vulvitis vulvitis plasmacellularis see plasma cell vulvitis vulvodynia 343–9, 358, 386–7 clinical manifestations 343–5 diagnosis/differential diagnosis 345 epidemiology 343–5 laboratory findings and histology 345 management and prognosis 346–8

405

Index 406

vulvodynia (Continued) counseling 348 intralesional therapy 347 oral therapy 347 pelvic floor therapy 347–8 surgical treatment 348 topical therapy 347 pathogenesis 345–6 vulvovaginal disease diagnosis 365–7 evaluation 361–7 International Society for the Study of Vulvovaginal Disease Classification 357–60 patient education 369–70 patient information 379–90 psychosexual issues 370 therapy 369–77 antibiotics 375–6 antifungals 375 calcineurin inhibitors 374–5 corticosteroids 372–4

vulvovaginal disease (Continued) estrogens 376 first-aid measures 371–2 irritant avoidance 370–1 psychoactive medication 376–7 vulvo-vaginal-gingival syndrome 148

W warfarin, in connective tissue disease 100 whiteheads 14 Wuchereria bancrofti 322

Z zinc gluconate, in hidradenitis suppurativa 209, 210 zinc oxide irritant contact dermatitis 185 porphyria cutanea tarda 90 zinc supplements in acrodermatitis enteropathica 95 Zoon’s vulvitis see plasma cell vulvitis