Identification No. 889-207

Answers to Self-Assessment examination of theAmerican Academy of Dermatology

July 1989 issue of the JOURNAL OF THE AMERfCAN ACADEMY

OF DERMATOLOGY

DISCUSSION OF QUESTIONS 1·12

Case presented by Jeff Dover. MD. and Sewon Kang. MD.Boston, Mass.

Ne~s spilus is a pigmented lesion that consists ofa cafe-au-Iait spot and macular and/or papulardarker speckles of melanocytic or nevomelanocyticproliferation (or both). The speckles of an individuallesion may be flat, raised, or both. Confusion overnomenclature exists as cases that fit clinically andpathologically into the category of nevus spilus havebeen called speckled lentiginous nevus and zoster­iform lentiginous nevus. Another disease confusedwith nevus spilus is segmental lentiginosis, wherecircumscribed pigmented macules are closelygrouped over normal skin. One rare type of clinicalpresentation for epithelioid cell-spindle cell nevi isgrouped (agminated) macules, papules, or noduleson a cafe-au-lait spot or a nevus spilus.

Nevus spilus is either present at birth or occurs inearly childhood. There is no sex predilection. Thesize may vary from less than 1 em to more than 10em. It is found most commonly on the trunk and ex­tremities, although it can occur anywhere, except formucosal surfaces. A giant nevus spilus may occurthat is segmental or zosteriform; in one case the le­sion was divided along the upper and lower eyelids.

Wood's lamp examinations of a nevus spilus inpatients with the skin types I through IV will makethe lesion accentuated compared with normal skinbecause most of the pigment is found in the epider­mis. Wood's lamp examination is not interpretablein patients with skin types V and VI.

Histopathologic examination shows increasednumbers of melanocytes and occasional nevus cellspresent in the macular background area ofthe nevusspilus. The flat speckles contain lentiginous melano­cytic hyperplasia. The raised speckles are usuallycollections of nevus cells in the epidermis or dermis(or both); however, rarely they are composed of ep-

ithelioid cell-spindle cell nevi. Melanin macroglob­ules are seen in nevi spill, as well as in other condi­tions, including normal skin, tinea versicolor, lesionsof neurofibromatosis, and, rarely, lesions of Al­bright's syndrome. Ephelides do not contain melaninmacroglobules.

The prevalence of nevus spilus in normal adultswas 2.3% in a study by Kopf et al., which did notdiffer significantly from its prevalence in patientswith malignant melanoma reported by the same au­thors. Because a few cases of melanoma arising innevus spilus have been reported, and because nevuscells may be present in this lesions, some believe thatnevus spilus may carry an increased risk for malig­nant change. However, there are insufficient data tomake any conclusions. As with other pigmentedmelanocytic lesions, follow-up should be individual­ized with biopsy performed in any suspicious areas.There is no evidence that relatives of patients withnevus spilus have a higher incidence of melanoma.Because nevus spilus has been observed in relativesof patients with neurofibromatosis, an associationbetween the two must be considered.

Segmental lentiginosis can be confused with ne­vus spilus, although in segmental lentiginosis thebackground of the pigment macules is normal skinrather than a cafe-au-lait spot. It is rare, affects bothse~es equally, .and usually is present at birth or earlychildhood as hght brown macules, 2 to 10 mm in di­ameter in a segmental and sometimes zosteriformdistribution. Histologicexamination shows that eachmacule represents a lentiginous proliferation ofmelanocytes along elongated rete ridges akin to len­tigo simplex without collection of nevus cells andwithout cellular inflammation. No malignant po­tential has been ascribed to segmentallentiginosis.

For this series the recommended choices are: 1, C;2, a, b, c; 3, c; 4, d, e; 5, a; 6, e; 7, a, d; 8, a; 9, c; 10,d; 11, a; 12, b.

Rita Berman, MD, Sewon Kang, MD.Michael Imber, MD, and

Jeffrey Dover, MD. Boston. Massachusetts

163

164 Self-Assessment examination answers

REFERENCES

Jackson R. The lines of Blaschko: a review and reconsider­ation. Br J Dermatol 1976;95:349.

Kopf AW, Levine LJ, Rigel DS, et al. Prevalence ofcongenitalnevus-like nevi, nevi spili, and cafe-au-Iait spots. Arch Der­matoI1985;121:766-9.

Kopf AW, Levine LJ, Rigel DS, et al. Congenital nevus-likenevi, nevi spiti, and cafe-au-lait spots in patients with malig­nant melanoma. J Dermatol Surg OncoI1985;11:275-80.

Matsudo H, Reed WB, Homme D, et al. Zosteriform lcntigi­nous nevus. Arch DermatoI1973;107:902-5.

Mosher DB, Fitzpatrick TH, Ortonne J, et al. Disorders of me­lanocytes. In: Fitzpatrick TB, Eisen AZ, WoIff K, et aI, eds.Dermatology in general medicine. New York: McGraw-Hill,1987;794-946.

Nguyen KQ, Pierson DL, Rodman OG. Mosaic speckled len­tiginous nevi. Cutis 1982;30:65-8.

Pritchett RM, Pritchett PS. Zosteriform speckled lentiginousnevus with giant melanosomes. Cutis 1982;30:329-34.

Rhodes AR. Neoplasms: benign neoplasias, hyperplasias anddysplasias of melanocytes. In: Fitzpatrick TB, Eisen AZ,Wolff K, et aI., eds. Dermatology in general medicine. NewYork: McGraw-Hill, 1987:877-946.

Ruth WK, Shelburne JD, Jegasothy BV. Zosteriform lentigi­nous nevus. Arch DermatoI1980;1l6:478.

Sato S, Kato H, Hidano A. Divided nevus spilus and dividedform of spotted grouped pigmented nevus. J Cutan Pathol1977;6:507-12.

DISCUSSION OF QUESTIONS 13-24

Case presented by Sharon Littzi. MD, and Arthur J. Sober,MD, Boston, Mass.

A German medical professor, Erwin Balz, teach­ing in Tokyo in 1885, noted a bluish spot on the but­tocks of many Japanese children. Thinking theywere characteristic ofthe Mongolian race, he namedthem mongolian spots. Today we know that mon­golian spots (congenital dermal melanocytosis) arefound in approximately 96% of blacks, in a slightlysmaller percentage of Orientals, in more than 45%of Hispanics, and in approximately 9.5% of whites.These lesions are present at birth and usually disap­pear within the first 5 years of life, although somepersist into adulthood. In one study of approximately10,000 Japanese men, about 4% had persistentmongolian spots. In this study persistent lesions weremostly solitary, but occasionally two or three spotswere found on one person. Approximately 85% ofthe lesions were 3 cm or less, but there were a fewlarger than 10 em. Persistent mongolian spots werefound most frequently on the buttocks, followed bythe sacrococcygeal region and back, and less fre­quently on the shoulder region. Typical regressingmongolian spots are found most frequently on the

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Dermatology

sacrococcygeal area, followed by the buttocks, back,and shoulders.

Histopathologic examination shows that mongo­lian spots have spindle-shaped melanin-producingmelanocytes dispersed within the reticular dermis.Melanophages are absent. It is believed that thesemelanocytes arise from the neural crest during fetaldevelopment and are retained in the reticular dennisduring their migration to the epidermis. Otherexamples of dermal melanocytoses include blue ne­vus and nevus ofOta where malignant forms ofeachhave been rarely described and nevus of Ito. Malig­nant degeneration of mongolian spots has not beenreported. The pathologic changes in Becker's nevusare mainly epidermal and adnexal.

Why typical mongolian spots faded whereas a fewof these lesions persist has been examined. In 1967it was found that the melanocytes in congenitalmongolian spots have a filamentous sheath aroundthem. Melanocytes in persistent mongolian spotsretain their filamentous sheaths, whereas regressingmongolian spots have melanocytes with reducedsheaths and disintegrated plasma membranes dis­charging melanin granules into the dermis. The re­gression may begin before birth, as these destroyedmelanocytes have been found in fetuses. It has alsobeen postulated that the persistence of these mon­golian spots might be due to the presence of dermalmelanocytes around blood vessels.

The blue-gray hue 01mongolian spots is due to theTyndall phenomenon, whereby longer wavelengthsof visible light (e.g., red, orange, yellow) are ab­sorbed by the reticular dermal melanocytes, whereasthe shorter wavelengths (e.g., blue, indigo, violet) arereflected. The amount of melanin in dermal mel­anocytes, the number of melanocytes, and theirdepth in the dermis are all factors that influence thecolor of a mongolian spot.

In skin types I and IV, hyperpigmentation fromdermal melanocytes or melanophages do not be­come enhanced when viewed with a Wood's lamp,although melanin pigmentation found in the epider­mis is markedly accentuated. Wood's lamp exami­nations in patients with skin types V and VI are notinterpretable.

For this series, the recommended choices are: 13,e; 14, a; 15, d; 16, c; 17, d; 18, a, c; 19, b; 20, c; 21,d; 22, b; 23, d; 24, c.

Rita Berman, MD. Ernesto Gonzalez, MD, andMichael Imber, MD, Boston, Massachusetts

Volume 21Number 1July 1989

REFERENCESCordova A. The Mongolian spot: a study of ethnic differ­

ences and a literature review. Clinical Pediatr1981;20:714-9.

Hidano A. Persistent Mongolian spot in the adult. ArchDermatol 1971;103:680-1.

Inoue A. Studies on nevus ofOta. Jpn J DermatoI1967;(SeriesB)77:130-8.

Jacobs AH, Walton RG. The incidence of birthmarks in theneonate. Pediatrics 1976;58:218-22.

Kikuchi I. What is a Mongolian spot? Int J Dermatol1982;21:131-3.

Kikuchi I, Inoue S. Circumscribed dermal melanocytosis (Mon­golian spot). In: Fitzpatrick TB, Kukita A, Fujio M, et al.,eds. Biology and diseases of dermal pigmentation. Tokyo:University of Tokyo Press, 1981:83-94.

Moroaka K. On the Mongolian spot in the Japanese. Acta AnatJpn 1931;3:1371-1490.

Mosher DB, Fitzpatrick TB, Ortonne J, et al. Disorders of pig­mentation. In: Fitzpatrick TB, Eisen AZ, Wolff KW, et al.,eds. Dermatology in general medicine. New York: McGraw­Hill, 1987:794-876.

Okawa Y, Yokota R, Yamaguchi A. On the extracellularsheath of dermal melanocytes in nevus fuseoceruleus aero­miodeltoideus (Ito) and Mongolian spot. An ultrastructuralstudy. J Invest DermatoI1979;73:224-30.

DISCUSSION OF QUESTIONS 25-36

This case is representative of the protean clinicalpicture of epidermolysis bullosa acquisita and therecent advances developed to diagnose this entityand understand its pathogenesis. Originally de­scribed by Elliot in 1895 as a nonhereditary form ofa cutaneous disease clinically resembling hereditarydystrophic epidermolysis bullosa, the disease did nothave definite, albeit limited, diagnostic criteria es­tablished unti1l97L Criteria included adult onset;no family history of the disease or hereditary epi­dermolysis bullosa; clinical presentation resemblingdystrophic epidermolysis bullosa with mechanobul­lous lesions, atrophic scarring, milia, and nail dys­trophy; and the exclusion of other bullous diseases.Clinical experience since, however, showed thatthese exclusionary criteria, although helpful, werenot sufficiently discriminating to identify the widespectrum of clinical manifestations of epidermolysisbullosa acquista. Although the "typical" cases ofthisdisease closely resemble noninflammatory mecha­nobullous diseases such as the hereditary form ofepidermolysis bullosa and porphyria cutanea tarda,the inflammatory stages of epidermolysis bullosaacquisita can mimic clinically and histologically(with a cell-rich inflammatory infiltrate) the pem­phigoid group of disorders. Other bullous diseases

Self-Assessment examination answers 165

that need to be ruled out are bullous lupus erythe­matosus, erythema multiforme, and dermatitis her­petiformis. In some of these the history, porphyrinlevels, and serologic studies are enough to rule themout whereas others, primarily bullous pemphigoid,require immunohistologic studies, such as direct andindirect immunofluo,rescence techniques, to excludethem.

Several subsequent reports showed, however, thatthe direct and indirect immunofluorescence tech­niques available at the time were not able to differ­entiate these overlapping diseases. The eventualdemonstration, by immunoelectron microscopy, thatthe ultrastructural localization of the immune de­posits in patients with epidermolysis bullosa ac­quisita was below the lamina densa of the basementmembrane whereas the immunoreactants in bullouspemphigoid were deposited within the lamina lucidaof the dermoepidermal junction provided an impor­tant additional factor to distinguish these two enti­ties. This observation showed that these autoim­mune bullous disorders have autoantibodies directedagainst two distinct, naturally existing antigens inthe basement membrane zone ofthe skin: the bullouspemphigoid antigen in the epidermal side and theepidermolysis bullosa acquisita antigen in the der­mal side.

Between 20% and 50% of patients with epider­molysis bullosa acquisita have circulating antibodiesin their serum directed against the cutaneous base­ment membrane zone that will produce a linearstaining pattern with indirect immunofluorescenceidentical to the pemphigoid group of disorders.When normal human skin used as the substrate forthis technique is chemically split by incubation withhypertonic sodium chloride solution, indirect immu­nofluorescence can discriminate between the bullouspemphigoid antigen located in the epidermal side ofthe split and the epidermolysis bullosa acquisita an­tigen located in the dermal side. This modified indi­rect immunofluorescent technique, developed byGammon and his colleagues, is simple, cheaper, andmore accessible than immunoelectron microscopyand has become an additional criterion for the diag­nosis of epidermolysis bullosa acquisita.

Immunoblotting also has become another methodto confirm the diagnosis of epidermolysis bullosa ac­quisita. As reported by Woodley and colleagues, thistechnique uses serum from patients with epidermo­lysis bullosa acquisita that will react with proteins

166 Self-Assessment examination answers

extracted from the dermoepidermalbasement mem­brane zone of normal persons. These proteins areseparated and transferred to paper by electrophore­sis and identified by radiolabeled or peroxidase­labeled reagents. The circulating antibodies in pa­tients with epidermolysis bullosa acquisita will reactagainst a polypeptide in normal skin with subunitmolecular weights of 290 and 145 kD whereas theantibodies in the serum of patients with bullouspemphigoid will react against a different proteinwith a molecular weight of 220 kD. Recently, thisepidermolysis bullosa acquista antigen present in thedermoepidermalbasement membranezonehas beencharacterized as a type VII procollagen distinctfrom the type IV collagen and laminin also presentin this location.

The fact that epidermolysis bullosa acquisita hasbeen reported in association with other autoimmuneand lymphoreticular disorders gives credence to itsproposed autoimmune pathogenesis. Some diseasesreported include systemic lupus erythematosus, in­flammatory bowel disease, multiple endocrinopathysyndrome, rheumatoid arthritis, chronic thyroiditis,diabetes mellitus, and chronic lymphocytic leuke­mia.

Epidermolysis bullosa acquisita has been notori­ously unresponsive to therapy such as topic and oralcorticosteroids, dapsone, azathioprine, gold, meth­otrexate, retinoids, and phenytoin. Plasmapheresiswas reported to be effective in a case reported fromJapan but these results have not been confirmed.Recently, Connolly et al. reported a patient withepidermolysis bullosa acquisita treated successfullywith cyclosporine. A more recent report by Crow etal. confirmed this response although they observed

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Dermatology

that the autoantibodies to the antigen did not disap­pear during treatment.

For this series, the recommended choices are: 25,c,d, e; 26,d,e; 27, b,d,e;28,d;29,c; 30, b; 3I,a;32, b, c; 33, b, c; 34, a, d; 35, e; 36, d.Ernesto Gonzalez, MD, and Michael Imber, MD,

Boston, Massachusetts, andSharon Raimer, MD, Galveston, Texas

REFERENCES

Caughman SW. Epidermolysis bullosa acquisita [Edito­rial]. Arch Dermatol 1986;112:159-61.

Connolly SM, Sander HM. Treatment ofepidermolysis bullosaacquisita with cyclosporine. J AM ACAD DERMATOL1987;16:890.

Crow LL, Finkle JP, Gammon WR, et al. Clearing of epider­molysis bullosa acquisita with cyclosporine. J AM ACADDERMATOL 1988;19:937-41.

Elliot GT. Two cases ofepidermolysis bullosa acquisita. 1 CutanGenitourin Dis 1895;13:10-8.

Furue M, Iwata M, Yoon H, et al. Epidermolysis bullosaacquisita: clinical response to plasma exchange therapy andcirculating anti-basement membrane zone antibody titer.JAM ACAD DERMATOL 1986;14:873-8.

Gammon WR, Briggaman RA, Inman AO, et al. Differenti­ating anti-lamina lucida and anti-sublamina densa anti­BMZ antibodies by direct immunofluorescence on 1.0M so­dium chloride--separated skin. J Invest Dermatol 1984;82:139-44.

Gammon WR, Briggaman RA, Woodley DT, et al. Epider­molysis bullosa acquisita-a pemphigoid-like disease. J AMACAD DERMATOL 1984;11:820-32.

Roenigk HH, Ryan JG, Bergfeld WF. Epidermolysis bullosaacquisita: report of three cases and review of all publishedcases. Arch DermatolI971;103:1-1O.

Woodley DT. Epidermolysis bullosa acquisita. Prog Dermatol1988;22:1-13.

Woodley DT, Briggaman RA, O'Keefe El, et al. Identificationof the skin basement membrane autoantigen in epidermoly­sis bullosa acquisita. N Engl J Moo 1984;310:1007-13.