Life-threatening blood loss from scratching provokedby pruritus in the bulky perineal nevocytoma variant

of giant congenital melanocytic nevus in a child

Jing Feng, BS,a Aisha Sethi, MD,a Miguel Reyes-Mugica, MD,b and Richard Antaya, MDa,c

New Haven, Connecticut

We describe a 3-year-old girl with intractable, debilitating pruritus associated with a giant congenitalmelanocytic nevus, resulting in life-threatening anemia from extensive bleeding skin excoriations. Multipleconventional oral and topical antipruritic medications failed to provide relief, but the patient wassuccessfully treated with the selective serotonin 5-hydroxytryptamine type 3 inhibitor ondansetron,suggesting a serotonin-related mechanism to her pruritus. ( J Am Acad Dermatol 2005;53:S139-42.)

Giant congenital melanocytic nevi (GCMN)are pigmented skin lesions occurring inapproximately 1 in 20,000 newborns.1

Besides the obvious cosmetic disfigurement, thesepatients have an increased lifetime risk of malignantmelanoma2 and neural crest proliferations within thespectrum of neurocutaneous melanosis.3 Thus far,no reports of GCMN causing pruritus have beendocumented to our knowledge. We describe anunusual case of a 3-year-old girl with intractablepruritus in her GCMN, who continuously bled fromher excoriations.

CASE REPORTA 3-year-old, African American girl with a history

of intractable, localized pruritus in her bathing-trunkGCMN was hospitalized for acute respiratory distressand high-output heart failure secondary to severeanemia (hemoglobin, 3.1 g/dL; hematocrit, 10.7%).She had undergone 4 partial surgical reductions ofthe nevus in her genital/perineal area and back, all ofwhich were successful without extensive scarringor keloid formation.

Supported by Stiefel Laboratories.

From the Departments of Dermatology,a Pathology,b and Pedia-

trics,c Yale University School of Medicine.

Funding sources: None.

Conflicts of interest: None identified.

Reprints not available from the authors.

Correspondence to: Richard Antaya, MD, Department of

Dermatology, Yale University School of Medicine, PO Box

208059, New Haven, CT 06520-8059. E-mail: Richard.

Antaya@yale.edu.

0190-9622/$30.00

ª 2005 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2004.12.040

The patient’s past medical history was significantfor a hospitalization 7 months before caused bysevere anemia (hemoglobin, 5.7 g/dL; hematocrit,18.9%), with guaiac-positive stools and active bleed-ing from perianal ulcerations in the area of the nevus.She was transfused, and iron supplementation wasstarted at that time.

Physical examination revealed a poorly nourishedchild with markedly increased work of breathing,bilateral pulmonary crackles, and anasarca. Nohepatosplenomegaly was detected. A GCMN ina bathing-trunk distribution extended from herlower abdomen and back to her upper thighs,completely covering her perineum and buttocks,with numerous terminal hairs distributed through-out. Most notably, the labia were grossly hypertro-phic and edematous. The clitoral hood measured5 cm 3 4 cm 3 2 cm and had a verrucous andpapillated surface (Fig 1). Erosions and shallowulcerations oozing blood were found on her labia,perianal region, and inner buttocks. Her diapercontained bright red blood mixed with liquid stool.Although the patient had a family history of atopicdermatitis, minimal clinical features suggesting ac-tive atopic or other types of dermatitis were seen onexamination.

Workup for the anemia included a peripheralblood smear showing microcytic, hypochromic redblood cells. Iron studies were consistent with irondeficiency anemia. A colonoscopy showed normalmucosa without evidence of bleeding. A coagulop-athy workup was also negative.

The patient was intubated 4 hours after presenta-tion and was repeatedly transfused. Over the next4 days, she continued to scratch and bleed fromthe superficial erosions in the GCMN, saturating herdiapers with blood. It became clear that the anemia

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was secondary to blood loss from her externalwounds in the nevus secondary to scratching.

Between the 2 hospitalizations, the patient hadbeen seen in the emergency department numeroustimes with uncontrolled bleeding from excoriationsof her perineal and perianal region. These woundshad been attributed to constant scratching of herGCMN because of intractable pruritus, which be-came progressively worse, impairing the patient’sability to walk. During this period, the followingtreatments were tried, all without beneficial effect.Oral medications included doxepin, hydroxyzine,and diphenhydramine. Topical treatments includeddoxepin cream, calamine, camphor, menthol, mu-pirocin, ketoconazole, iLEX skin barrier, zinc oxide,hydrogel, hydrocortisone, anesthetics, and emol-lients. The pruritus worsened and the patient’s labiaenlarged and became hypertrophic (Fig 2).

During the second hospitalization, the patient’sperineal wounds were managed with hydrocolloiddressings, barrier cream, iLEX, and Vaseline. Oraldoxepin, hydroxyzine, diphenhydramine, and anal-gesics plus topical antipruritics, antifungals, andanesthetics failed to relieve the pruritus. Despitehand restraints, the patient awoke at night, using herfeet and inner thighs to scratch.

At this time, a trial of ondansetron 0.6 mg orallytwice daily was started on hospital day 7, to whichthe patient responded with mild improvement of herpruritus. She was discharged on ondansetron; upon6-week follow-up the patient’s pruritus was signifi-cantly improved, her wounds were healing, andfurther reduction surgeries were scheduled.

ANATOMIC PATHOLOGYSpecimens derived from the surgical reductions

of this lesion featured the characteristic histologicappearance of a GCMN. In the initially resected skin,the epidermis showed mild hyperkeratosis and

Fig 1. Clitoral hood measuring 5 cm 3 4 cm 3 2 cm, andshowing verrucous and papillated surface with ulceration.

moderate hyperpigmentation of the basal layer.The dermis revealed a diffuse proliferation of nevuselements arranged in nests with prominent melanindeposits and extensive formation of Wegner-Meissnerelike bodies (lames foliacees), recapitulat-ing the neural crest derivation and ability to undergoneuroid differentiation of these nevus cells. Thisproliferation extended very deeply into the dermisand subcutaneous tissues, where the melanocytesexhibited the characteristic spindle morphology(Fig 3, A). These features have been previously re-cognized as prominent in massive nevomelanocyticlesions involving the perineal area, representing thenevus variant named bulky perineal nevocytoma.4

In view of the intractable pruritus, immunohisto-chemical labeling of mast cells was carried out withthe use of antibodies to detect CD117 (c-kit) andshowed a moderately increased number of CD117-positive cells uniformly distributed at all levels of thenevus involvement (Fig 3, B). Biopsies from thevulva and clitoral hood showed an intradermal nevuswith hyperkeratosis, papillomatosis and acanthosis,and ruled out the presence of mastocytoma andhuman papillomavirus infection.

DISCUSSIONPruritus is thought to be mediated peripherally

by unmyelinated C fibers (distinct from those

Fig 2. Comparison of patient’s perineal region (A) 2 yearsbefore and (B) during hospitalization, showing remark-able hypertrophy and growth of the clitoral hood.

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responsible for pain), which may be stimulated bychemical mediators such as histamine5 and seroto-nin.6 Histamine causes severe pruritus if appliedsuperficially to damaged skin or injected intrader-mally,7 and its effect may be potentiated by prosta-glandins and neuropeptides.8 Serotonin acting onthe C fibers via 5-hydroxytryptamine type 3 (5-HT3)receptors also induces pruritus, and elevated plasmalevels are found in pruritus associated with uremia,polycythemia vera, and cholestasis.9

The centrally mediated mechanism of pruritus isincompletely understood. Endogenous opioids reg-ulate itch and pain through the central nervoussystem. The mechanism is thought to involve themu receptor,10 the same receptor activated bymorphine. Opioids may also act peripherally byreleasing histamine after intradermal injection.11

Opioid antagonists such as naltrexone have beensuccessfully used to treat pruritus associated withopioid pharmacotherapy10 and cholestasis.12-14

Thus far, no associations of GCMN and pruritushave been made in the literature to our knowledge,and the mechanism of GCMN-induced pruritus inour case is unclear. Although there were moderatelyincreased numbers of mast cells within the nevus ofour patient, histamine appears to have been anunlikely mediator since all antihistamines failed toprovide relief. It was also unlikely that postoperativescarring contributed to the pruritus since the patient’sitch began long before any reduction surgeries andwas present in all regions of the GCMN. It has beenproposed that a local intermittent stimulation ofafferent sensory nerve fibers produces itch, whilea prolonged stimulation results in inhibition ofpruritus by inhibitory neuronal pathways withinthe spinal cord.15 In our case, local intermittentirritation from ingrown hairs within the nevus mayhave initiated the itch. It is also possible thatdysregulation from the central inhibitory circuitresulted in persistent pruritus. Further, in this bulkyperineal nevocytoma variant of GCMN showingextensive neuroid differentiation, local growth cyto-kines responsible for the lesion’s massive dimen-sions may sensitize superficial unmyelinated C fibersso that the perception of pruritus is increased.However, we know of no data in the literature thatsupport this hypothesis, and no reports of associa-tions between melanocyte growth factor and pruri-tus have been made to date.

Our case was diagnostically and therapeuticallychallenging. The severity and repeated episodes ofthe patient’s anemia prompted a thorough gastroin-testinal and hematologic workup, which only re-vealed iron deficiency. In due course, it becameapparent that the bleeding was caused by external

wounds and erosions, resulting from pruritus asso-ciated with the nevus. The patient’s pruritus wasprimarily localized to the perineal region, but shereportedly had pruritus in her back, which improvedafter multiple GCMN reduction surgeries. This sup-ports our hypothesis that an element within thenevus perpetuates the itch. Perhaps the skin near theperineum is more sensitive than that on the back,thus responding less effectively to the surgicalexcisions. The patient’s iron-depleted state mayhave also contributed to the itch since iron deficiencyanemia has been reported to cause pruritus.16,17 Thepathogenesis of this association, while unclear, isthought to be attributable to alterations in iron-dependent enzyme functions. Pruritus related toiron deficiency anemia should respond well to ironsupplementation, but in our patient the prurituspersisted.

New therapies were urgently needed to managethe patient’s intractable pruritus. Selective serotonin5-HT3 inhibitors such as ondansetron have beenshown to relieve itching associated with uremia,polycythemia vera, and cholestasis, possibly throughblocking of the effect of serotonin acting onthe C fibers responsible for pruritus.14,18,19 One

Fig 3. A, Photomicrograph showing the congenital ap-pearance of the nevus, with deep dermal involvement.Inset shows the aggregates of nevus cells reminiscent ofWegner-Meissner bodies. B, Immunohistochemical stainfor CD117 reveals scattered mast cells within the nevus.(Original magnifications: A, 348; inset, 3120; B, 3240.)

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case reported successful use of ondansetron intreating idiopathic intractable palmoplantar pruri-tus.15 Commonly used for nausea and vomiting,ondansetron can be safely administered to children.It is generally well tolerated, the most common sideeffects being headache, constipation, drowsinessand elevated transaminases. Our patient showedsustained, dramatic improvement after treatmentwith ondansetron, suggesting a serotonin-relatedmechanism to the pruritus in her GCMN. Thepossible link between 5-HT3 inhibition and in-creased numbers of mast cells in our patient remainsunknown since human mast cells are not able tosynthesize serotonin, although this mediator ispresent in rodent mast cells.

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