DERMATOPATHOLOGY

Histopathologic clues for the diagnosisof Wiesner nevus

Mar Llamas-Velasco, MD,a Yosmar Carolina P�erez-G�onzalez, MD,b Luis Requena, MD,c and Heinz Kutzner, MDd

Madrid, Spain, and Friedrichshafen, Germany

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The dermatologic hallmark of a recently described BAP1-associated cancer susceptibility syndrome is adome-shaped nevus with distinct clinicopathological features, first delineated by Wiesner and colleagues.Here we describe the leading histopathological criteria of Wiesner nevus. Wiesner nevus is composed ofvarious nevomelanocytic populations all showing different degrees of atypia ranging from hyperchromaticnevus cell-like to large atypical epithelioid cells. Immunohistochemically, Wiesner nevus is BAP1 negativeand VE1 positive. ( J Am Acad Dermatol 2014;70:549-54.)

Key words: BAP1 protein; B-raf; epithelioid and spindle cell; human; nevus; proto-oncogene proteins.

Table I. Documented tumor entities associatedwith the BAP1-associated cancer susceptibilitysyndrome

Wiesner nevi

Uveal and cutaneous melanomaMesotheliomaRenal cell carcinomaOvarian and breast carcinomaCholangiosarcomaPancreatic carcinomaMeningiomaParagangliomaNeuroendocrine tumorsLung carcinomaMultiple myelomaLeiomyosarcomaMyeloproliferative disease

Abbreviations used:

BAP1: BRCA1-associated protein 1BRAF: v-raf murine sarcoma viral oncogene

homolog B1

Wiesner et al1 recently delineated clinicaland molecular criteria of a distinctmelanocytic tumor (Wiesner nevus),

which is the most reliable marker lesion of a novelcancer susceptibility syndrome.2,3 This syndrome isassociated with biallelic loss or inactivation of BAP1in chromosome 3p21.1,4 As this melanocytic tumor isthe cutaneous hallmark of a cancer susceptibilitysyndrome (Table I) encompassing cutaneousand uveal melanoma, mesothelioma, renal cellcarcinoma, and probably several other neoplasticentities,5-9 it is paramount for dermatopathologists tobe well acquainted with the clinicopathologicalfeatures of the diagnostically challenging Wiesnernevus.

REPORTClinical features

Patients with the BAP1 tumor susceptibilitysyndrome often present with large numbers ofbanal dome-shaped or pedunculated skin-coloredmelanocytic nevi without alarming clinical criteria.Because of the BAP1 germline mutation, thesemultiple melanocytic nevi often occur in membersof all generations of 1 family. It is remarkable thatnot all of these melanocytic nevi are Wiesnernevi. Patients may harbor a mixture of Miescher,Unna, and Wiesner nevi within the same anatomicarea. It is our impression, however, that typical

the Departments of Dermatologya and Pathology,b Hospital

fanta Cristina, Parla, Madrid; Department of Dermatology of

ndaci�on Jimenez Diaz, Madridc; and Dermatopathologie

iedrichshafen.d

ing sources: None.

licts of interest: None declared.

pted for publication October 14, 2013.

Wiesner nevi are characterized by their dome-shaped, smooth-surfaced, skin-colored configura-tion, which differs markedly from typical Spitz nevus(Fig 1).

Reprint requests: Mar Llamas-Velasco, MD, Department of

Dermatology, Hospital Infanta Cristina, C/Avenida 9 de Junio, CP

28981 Parla, Madrid, Spain. E-mail: mar.llamasvelasco@gmail.com.

Published online December 26, 2013.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.10.032

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HistopathologyAt scanning magnification, Wiesner nevus shows

the silhouette and shape of a symmetric banal dermalmelanocytic nevus (Fig 1). At medium power, itbecomes obvious that the lesion harbors variousmelanocytic populations in an irregular nested orsheetlike array, diffusely distributed throughout the

CAPSULE SUMMARY

d Biallelic loss or inactivation of BAP1 maybe associated with underlying neoplasia.

d Patients with BAP1 tumor susceptibilitysyndrome have clinically banal nevi,including Wiesner nevi. These arehistopathologically characterized byatypical intradermal Spitzoidmelanocytes that stain positive for VE1(V600E) but negative for BAP1.

d Multiple Wiesner nevi should raisesuspicion for a BAP1 germline mutation.

lesion, sometimes graduallyblending with each other orcolliding. However, the de-scription ‘‘combined nevus’’is inaccurate for this peculiarmelanocytic nevus becausethere are no regular or banalmelanocytes. The leadingcell type in Wiesner nevus isa large epithelioid melano-cyte with ample pale cyto-plasm and an atypicalnucleus. All melanocytes inWiesner nevus show atypiaranging from small nevuslikecells with slight nuclearhyperchromasia to large

atypical epithelioid cells with bizarre nuclei reminis-cent of atypical Spitz tumor or Spitzoid melanoma.Therefore, a morphologic description of ‘‘atypicalSpitzoid, clonal, and sheetlike pattern’’ appears moreappropriate (Figs 2 and 3). It is not surprising thatmost of these tumors were diagnosed in the pasteither as atypical Spitz tumor or Spitzoid melanoma.However, in sharp contrast to these entities,Wiesner nevus usually does not show any significantmitotic activity and, in our experience, melanocyticcombination in Wiesner nevus is much moreasymmetric than in conventional combined Spitznevus. In fact, we suggest that Wiesner nevus oftenpresents as a morphologically clonal or evenpolyclonal nevus showing various cell variants. Anaccompanying inflammatory infiltrate may bepresent. Remarkably, a junctional or intraepidermalmelanocytic component is lacking, as Wiesner nevusis an entirely dermal melanocytic proliferation andthe overlying epidermis is usually flat withoutany evidence of hyperplasia. The bizarre, mostlydiffusely arranged atypical Spitzoid melanocytesrepresent the hallmark of Wiesner nevus, as theirsheetlike or nested arrangement dominates theentire tumor scene. Quite remarkably, there is nomaturation from the surface toward the base of thelesion in Wiesner nevus; a finding that is in sharpcontrast to most variants of Spitz nevus. In fact,Wiesner nevus may be an example of inversematuration, from top to bottom and from left toright, resulting in a chaotic cytologic pattern of

different cell clones, which seems to defy the rulesof melanocytic tumor biology, giving rise to multiplespeculations.

ImmunohistochemistryIt has recently been shown that immunohisto-

chemical staining with the monoclonal VE1 antibody

can be used as a surrogate formolecular detection of acti-vating V600E point mutationin exon 15 of the BRAFgene.10 In contrast to Spitznevus cells, the large epithe-lioid melanocytes in Wiesnernevus harbor the V600Emutation and therefore stainpositively with the VE1 anti-body. Conversely, Spitz ne-vus cells stain positive withthe BAP1 antibody, whereasmelanocytes in Wiesner ne-vus are BAP1 negative. Thisinverse VE1/BAP1 immuno-histochemical staining pro-

file is quite helpful for the histopathologicdifferential diagnosis between Wiesner nevus andintradermal variants of dermal Spitz nevus, as itrepresents a reliable immunohistochemical finger-print (Table II).

DISCUSSIONIt is debatable whether the description ‘‘Wiesner

nevus’’ is appropriate for a melanocytic tumor,which might represent a melanocytic prema-lignancy. A strong argument for the nevus conceptis the biological course of Wiesner nevus, withlesions remaining stable over many decades. So far,only 1 case of malignant melanoma evolving from apre-existent Wiesner nevus has been reported in amale member of the first founder family.11 And itmust be pointed out that sporadic cases of Wiesnernevus may occur without any syndromal associationdespite showing the same BAP1-/VE1-positiveimmunohistochemical profile.12 Moreover, Wiesnernevus often presents together with banal Unna orMiescher nevi in the same patient. Ancillary molec-ular studies are necessary to differentiate syndromalfrom sporadic variants of Wiesner nevus. BRAF andBAP1 Sanger sequencing is feasible with DNAextracted from formalin-fixed paraffin-embeddedspecimens. Comparison of DNA sequences fromlesional versus nonlesional tissue allows differentia-tion of sporadic Wiesner nevus from syndromalWiesner nevus: the syndromal nevus shows BAP1

Fig 1. A to F, Wiesner nevus. Characteristic inconspicuous dome-shaped nevi in patients withbiallelic loss of BAP1. Members of the first 2 founder families. (Courtesy of Thomas Wiesnerand Werner Stieber.)

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germline mutation in the adjacent skin, whereas thesporadic variant exhibits the wild type.13

The histopathological diagnosis can be straight-forward, based on the findings of an entirely intra-dermal, markedly atypical, Spitzoid-dominated,sheetlike and/or clonally arranged, melanocyticpopulation, lacking mitotic activity and typicalmelanocytic maturation toward the base of thelesion. The BAP1-negative/VE1-positive immuno-phenotype is helpful for differentiating Wiesnernevus from Spitz nevus and its variants, whichshow an inverse immunophenotype.12,14

REFERENCES

1. Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P,

et al. Germline mutations in BAP1 predispose to melanocytic

tumors. Nat Genet 2011;43:1018-21.

2. Goldstein AM. Germline BAP1 mutations and tumor

susceptibility. Nat Genet 2011;43:925-6.

3. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G.

BAP1 and cancer. Nat Rev Cancer 2013;13:153-9.

4. Cheung M, Talarchek J, Schindeler K, Saraiva E, Penney LS,

Ludman M, et al. Further evidence for germline BAP1

mutations predisposing to melanoma and malignant

mesothelioma. Cancer Genet 2013;206:206-10.

5. Dey A, Seshasayee D, Noubade R, French DM, Liu J,

Chaurushiya MS, et al. Loss of the tumor suppressor BAP1

causes myeloid transformation. Science 2012;337:1541-6.

6. Murali R, Wiesner T, Scolyer RA. Tumors associated with BAP1

mutations. Pathology 2013;45:116-26.

7. Henderson DW, Reid G, Kao SC, van Zandwijk N, Klebe S.

Challenges and controversies in the diagnosis of malignant

mesothelioma, part 2: malignant mesothelioma subtypes,

pleural synovial sarcoma, molecular and prognostic aspects

of mesothelioma, BAP1, aquaporin-1 and microRNA. J Clin

Pathol 2013;92:974-80.

8. Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V,

Dubois-d’Enghien C, et al. Germline BAP1 mutations

predispose to renal cell carcinomas. Am J Hum Genet 2013;

92:974-80.

9. Ribeiro C, Campelos S, Moura CS, Machado JC, Justino A,

Parente B. Well-differentiated papillary mesothelioma:

clustering in a Portuguese family with a germline BAP1

mutation. Ann Oncol 2013;24:2147-50.

Fig 2. A, Wiesner nevus with symmetric silhouette and diffuse sheets of atypical melanocytes.Clonal nested populations of melanocytes near right margin suggest combined nevus. B, Clonalnest of hyperchromatic melanocytes among sheetlike arrangement of atypical melanocyteswith Spitzoid features. C, Characteristic melanocytes with atypical nuclei, hyperchromasia, andample pale amphophilic cytoplasm. D, These atypical Spitzoid melanocytes with interspersedlymphocytes suggest diagnosis of atypical Spitzoid tumor. Mitoses are lacking.

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10. Long GV, Wilmott JS, Capper D, Preusser M, Zhang YE,

Thompson JF, et al. Immunohistochemistry is highly sensitive

and specific for the detection of V600E BRAF mutation in

melanoma. Am J Surg Pathol 2013;37:61-5.

11. Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, et al.

Toward an improved definition of the tumor spectrum

associated with BAP1 germline mutations. J Clin Oncol 2012;

30:e337-40.

12. Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H,

et al. A distinct subset of atypical Spitz tumors is characterized

by BRAF mutation and loss of BAP1 expression. Am J Surg

Pathol 2012;36:818-30.

13. Busam KJ, Wanna M, Wiesner T. Multiple epithelioid Spitz nevi

or tumors with loss of BAP1 expression: a clue to a hereditary

tumor syndrome. JAMA Dermatol 2013;149:335-9.

14. Busam KJ, Sung J, Wiesner T, von Deimling A, Jungbluth A.

Combined BRAF(V600E)-positive melanocytic lesions with

large epithelioid cells lacking BAP1 expression and

conventional nevomelanocytes. Am J Surg Pathol 2013;37:

193-9.

Fig 3. A, Wiesner nevus, sectioned in center. Note heterogeneous sheets of melanocytes withclonal hyperchromatic subpopulations in the center and at right margin. Top section showsclearly that there is no maturation of melanocytes toward base of lesion. Clonally aggregatedmelanocytes in a chaotic arrangement. B, Nested arrangement of atypical melanocytes withpleomorphism and hyperchromasia. Mitoses are lacking. C, Populations of atypicalmelanocytes intermingled with a sparse lymphocytic infiltrate. D, Nested atypical melanocytesamong sheetlike arrangement of atypical Spitzoid melanocytes. No mitotic activity.E, Paradigmatic pattern of Wiesner nevus. Note that all melanocytes are atypical. There is nomaturation of melanocytes. The blending of various clonal populations of atypical melanocytessuggests a combined nevus. There are no mitoses. F, Immunohistochemical profile ofWiesner nevus with negative staining for BAP1 (top) and positive staining for VE1 (bottom).Spitz nevus exhibits an inverse staining pattern with positivity for BAP1 and negativity for VE1.Peroxidase-antiperoxidase techniques were performed by using BAP1 (clone C4, mouse, SantaCruz Biotechnology, Heidelberg, Germany) applied at a dilution 1:1000 with pH 9.0 antigenretrieval, and VE1 (clone VE1, mouse, DCS, Hamburg, Germany) applied at a dilution 1:100with pH 9.0 antigen retrieval.

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Table II. Major clinical, molecular, and histopathological differences among intradermal nevus, Spitz nevus,and Wiesner nevus

Intradermal nevus Spitz nevus Wiesner nevus

Clinical Solitary or multipleOften acquiredDome-shapedSmall (\1 cm)Skin-colored

SolitaryOften acquiredSeveral shapesSeveral sizes (\2.5 cm)Several skin-color tones,often brownish

MultipleSince childhoodDome-shapedSmall (\1 cm)Skin-colored

Syndromal association None None Syndromal and sporadicMolecular profile BRAF wild-type or BRAF

V600EBAP1 wild-type

BRAF wild-typeBAP1 wild-type

BRAF V600EBAP1 biallelic loss

Immunohistochemicalprofile

VE1 negative or positiveBAP1 positive

VE1 negativeBAP1 positive

VE1 positiveBAP1 negative

p16/p21 Profile p16 Positivep21 Negative

p16 Strongly positive (100%)p21 Positive (80%)

p16 Strongly positive (100%)p21 Scarce or focallypositive (30%)

Histopathologic pattern Predominantly dermalMonomorphous cellpopulation, symmetricsilhouette

Junctional and dermalvariants

Combined Spitz always withsymmetric silhouette,with Spitzoid cellpopulation in the center

Predominantly dermalproliferation

Often combined but mostlywith asymmetric pattern,similar to clonal orpolyclonal nevus

Maturation Present Present Missing, because of mostlyasymmetricecombined,clonal, or polyclonalpattern

Mitoses None or few Few, mostly at thejunctional component

Very scarce (\3 per section)

Inflammatory infiltrate Absent Occasionally OftenCytology Round small cells with

uniform nucleiSpindle and/orepithelioid cells

Predominantly epithelioidcells with amplecytoplasm

Marked morphologicplasticity: large-epithelioid, small-epithelioid, small-banalnevus cell types

Pleomorphism,hyperchromatism

Absent Moderate, within theSpitzoid spectrum

Marked, often suggestingatypical Spitzoid tumor

Multicolor FISH Diploid; no gains/losses ofcopy numbers

Diploid; tetraploid profile insome cases

Polyploid plus aneuploidprofile (unbalanced gainsof copy numbers)

FISH, Fluorescence in situ hybridization.

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