Histopathologic clues for the diagnosisof Wiesner nevus
zalez, MD,b Luis Requena, MD,c and Heinz Kutzner, MDd
d BAP1-associated cancer susceptibility syndrome is aal features, first delineated by Wiesner and colleagues.teria of Wiesner nevus. Wiesner nevus is composed ofifferent degrees of atypia ranging from hyperchromaticmunohistochemically, Wiesner nevus is BAP1 negative49-54.)
pindle cell; human; nevus; proto-oncogene proteins.
Table I. Documented tumor entities associatedwith the BAP1-associated cancer susceptibilitysyndrome
Uveal and cutaneous melanoma
BAP1: BRCA1-associated protein 1BRAF: v-raf murine sarcoma viral oncogene
homolog B1Funding sources: None.Conflicts of interest: None declared.
Accepted for publication October 14, 2013.
2013 by the American Academy of Dermatology, Inc.http://dx.doi.org/10.1016/j.jaad.2013.10.032nevi. Patients may harbor a mixture of Miescher,Unna, and Wiesner nevi within the same anatomicarea. It is our impression, however, that typical
From the Departments of Dermatologya and Pathology,b Hospital
Infanta Cristina, Parla, Madrid; Department of Dermatology of
Fundacion Jimenez Diaz, Madridc; and Dermatopathologie
Reprint requests: Mar Llamas-Velasco, MD, Department of
Dermatology, Hospital Infanta Cristina, C/Avenida 9 de Junio, CP
28981 Parla, Madrid, Spain. E-mail: email@example.com.
Published online December 26, 2013.atients with the BAP1 tumor susceptibilityrome often present with large numbers ofal dome-shaped or pedunculated skin-coloredanocytic nevi without alarming clinical criteria.ause of the BAP1 germline mutation, thesetiple melanocytic nevi often occur in membersll generations of 1 family. It is remarkable thatall of these melanocytic nevi are Wiesner
MesotheliomaRenal cell carcinomaOvarian and breast carcinomaCholangiosarcomaPancreatic carcinomaMeningiomaParagangliomaNeuroendocrine tumorsLung carcinomaClinical features
Wiesner neviMar Llamas-Velasco, MD,a Yosmar Carolina Perez-GonMadrid, Spain, and F
The dermatologic hallmark of a recently describedome-shaped nevus with distinct clinicopathologicHere we describe the leading histopathological crivarious nevomelanocytic populations all showing dnevus cell-like to large atypical epithelioid cells. Imand VE1 positive. ( J Am Acad Dermatol 2014;70:5
Key words: BAP1 protein; B-raf; epithelioid and s
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.Wiesner nevi are characterized by their dome-shaped, smooth-surfaced, skin-colored configura-tion, which differs markedly from typical Spitz nevus549
iagnosed in the pastr Spitzoid melanoma.t to these entities,t show any significantperience, melanocyticvus is much moreional combined Spitzt Wiesner nevus oftenally clonal or evenrious cell variants. An
infiltrate may benal or intraepidermaling, as Wiesner nevusytic proliferation andusually flat without. The bizarre, mostlySpitzoid melanocytes
inverse VE1/BAP1 immuno-
print (Table II).
DISCUSSIONIt is debatable whet
nevus is appropriatewhich might represelignancy. A strong arguis the biological courlesions remaining stablonly 1 case of malignanpre-existent Wiesner nmale member of the fimust be pointed out thnevus may occur withodespite showing theimmunohistochemical
BAP1 Sanger sequencing is feasible with DNA
ly chal Sstaintive
J AM ACAD DERMATOLMARCH 2014
550 Llamas-Velasco et alrepresent 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 inversemost of these tumors were deither as atypical Spitz tumor oHowever, in sharp contrasWiesner nevus usually does nomitotic activity and, in our excombination in Wiesner neasymmetric than in conventnevus. In fact, we suggest thapresents as a morphologicpolyclonal nevus showing vaaccompanying inflammatorypresent. Remarkably, a junctiomelanocytic component is lackis an entirely dermal melanocthe overlying epidermis isany evidence of hyperplasiadiffusely arranged atypicalHistopathologyAt 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 thelesion, sometimes graduallyblending with each other orcolliding. However, the de-scription combined nevusis 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 largeatypical 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 that
d Biallelic loss or inbe associated wit
d Patients with BAPsyndrome have cincluding Wiesnerhistopathologicalatypical intradermmelanocytes that(V600E) but nega
d Multiple Wiesnersuspicion for a BAmaturation, from top to bottom and from left toright, resulting in a chaotic cytologic pattern ofextracted from formalin-fixed paraffin-embeddedspecimens. Comparison of DNA sequences fromlesional versus nonlesional tissue allows differentia-nevus 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 andtion of sporadic WiesWiesner nevus: the syher the description Wiesnerfor a melanocytic tumor,
nt a melanocytic prema-ment for the nevus conceptse of Wiesner nevus, withe over many decades. So far,t melanoma evolving from aevus has been reported in arst founder family.11 And itat sporadic cases of Wiesnerut any syndromal associationsame BAP1-/VE1-positive
profile.12 Moreover, Wiesnerhistochemical 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-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 antibodycan 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. This
ation of BAP1 mayderlying neoplasia.
mor susceptibilitylly banal nevi,i. These arearacterized bypitzoidpositive for VE1
should raiseermline mutation.ner nevus from syndromalndromal nevus shows BAP1
J AM ACAD DERMATOLVOLUME 70, NUMBER 3
Llamas-Velasco et al 551germline 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
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.
Fig 1. A to F, Wiesner nevus. Characteristic inconbiallelic loss of BAP1. Members of the first 2 founand Werner Stieber.)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
8. Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V,
Dubois-dEnghien C, et al. Germline BAP1 mutations
predispose to renal cell carcinomas. Am J Hum Genet 2013;
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.
spicuous dome-shaped nevi in patients withder families. (Courtesy of Thomas Wiesner
J AM ACAD DERMATOLMARCH 2014
552 Llamas-Velasco et al10. 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;
12. Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H,
et al. A distinct subset of atypical Spitz tumors is characterized
Fig 2. A, Wiesner nevus with symmetric silhouettClonal nested populations of melanocytes near rignest of hyperchromatic melanocytes among shewith Spitzoid features. C, Characteristic melanocytample pale amphophilic cytoplasm. D, These atyplymphocytes suggest diagnosis of atypical Spitzoiby BRAF mutation and loss of BAP1 expression. Am J Surg
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:
e and diffuse sheets of atypical melanocytes.ht margin suggest combined nevus. B, Clonaletlike arrangement of atypical melanocyteses with atypical nuclei, hyperchromasia, andical Spitzoid melanocytes with interspersedd tumor. Mitoses are lacking.
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,
MultipleSince childhoodDome-shapedSmall (\1 cm)Skin-colored
Syndromal association None None Syndromal and sporadicMolecular profile BRAF wild-type or BRAF
BRAF wild-typeBAP1 wild-type
BRAF V600EBAP1 biallelic loss
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 focally
positive (30%)Histopathologic pattern Predominantly dermal
Monomorphous cellpopulation, symmetricsilhouette
Junctional and dermalvariants
Combined Spitz always withsymmetric silhouette,with Spitzoid cellpopulation in the center
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...