- Email: [email protected]
Histopathologic clues for the diagnosis of Wiesner nevus
DERMATOPATHOLOGY
Histopathologic clues for the diagnosis of Wiesner nevus Mar Llamas-Velasco, MD,a Yosmar Carolina Perez-G onzalez, MD,b Luis Requena, MD,c and Heinz Kutzner, MDd Madrid, Spain, and Friedrichshafen, Germany The dermatologic hallmark of a recently described BAP1-associated cancer susceptibility syndrome is a dome-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 of various nevomelanocytic populations all showing different degrees of atypia ranging from hyperchromatic nevus cell-like to large atypical epithelioid cells. Immunohistochemically, Wiesner nevus is BAP1 negative and 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.
iesner et al1 recently delineated clinical and molecular criteria of a distinct melanocytic tumor (Wiesner nevus), which is the most reliable marker lesion of a novel cancer susceptibility syndrome.2,3 This syndrome is associated with biallelic loss or inactivation of BAP1 in chromosome 3p21.1,4 As this melanocytic tumor is the cutaneous hallmark of a cancer susceptibility syndrome (Table I) encompassing cutaneous and uveal melanoma, mesothelioma, renal cell carcinoma, and probably several other neoplastic entities,5-9 it is paramount for dermatopathologists to be well acquainted with the clinicopathological features of the diagnostically challenging Wiesner nevus.
W
REPORT Clinical features Patients with the BAP1 tumor susceptibility syndrome often present with large numbers of banal dome-shaped or pedunculated skin-colored melanocytic nevi without alarming clinical criteria. Because of the BAP1 germline mutation, these multiple melanocytic nevi often occur in members of all generations of 1 family. It is remarkable that not all of these melanocytic nevi are Wiesner nevi. Patients may harbor a mixture of Miescher, Unna, and Wiesner nevi within the same anatomic area. It is our impression, however, that typical From the Departments of Dermatologya and Pathology,b Hospital Infanta Cristina, Parla, Madrid; Department of Dermatology of Fundaci on Jimenez Diaz, Madridc; and Dermatopathologie Friedrichshafen.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 14, 2013.
Abbreviations used: BAP1: BRAF:
BRCA1-associated protein 1 v-raf murine sarcoma viral oncogene homolog B1
Wiesner nevi are characterized by their domeshaped, smooth-surfaced, skin-colored configuration, which differs markedly from typical Spitz nevus (Fig 1). Table I. Documented tumor entities associated with the BAP1-associated cancer susceptibility syndrome Wiesner nevi Uveal and cutaneous melanoma Mesothelioma Renal cell carcinoma Ovarian and breast carcinoma Cholangiosarcoma Pancreatic carcinoma Meningioma Paraganglioma Neuroendocrine tumors Lung carcinoma Multiple myeloma Leiomyosarcoma Myeloproliferative disease
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 protected]. Published online December 26, 2013. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.10.032
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different cell clones, which seems to defy the rules Histopathology of melanocytic tumor biology, giving rise to multiple At scanning magnification, Wiesner nevus shows speculations. the silhouette and shape of a symmetric banal dermal melanocytic nevus (Fig 1). At medium power, it becomes obvious that the lesion harbors various Immunohistochemistry melanocytic populations in an irregular nested or It has recently been shown that immunohistosheetlike array, diffusely distributed throughout the chemical staining with the monoclonal VE1 antibody lesion, sometimes gradually can be used as a surrogate for blending with each other or molecular detection of actiCAPSULE SUMMARY colliding. However, the devating V600E point mutation scription ‘‘combined nevus’’ in exon 15 of the BRAF Biallelic loss or inactivation of BAP1 may is inaccurate for this peculiar gene.10 In contrast to Spitz be associated with underlying neoplasia. melanocytic nevus because nevus cells, the large epithePatients with BAP1 tumor susceptibility there are no regular or banal lioid melanocytes in Wiesner syndrome have clinically banal nevi, melanocytes. The leading nevus harbor the V600E including Wiesner nevi. These are cell type in Wiesner nevus is mutation and therefore stain histopathologically characterized by a large epithelioid melanopositively with the VE1 antiatypical intradermal Spitzoid cyte with ample pale cytobody. Conversely, Spitz nemelanocytes that stain positive for VE1 plasm and an atypical vus cells stain positive with (V600E) but negative for BAP1. nucleus. All melanocytes in the BAP1 antibody, whereas Wiesner nevus show atypia Multiple Wiesner nevi should raise melanocytes in Wiesner neranging from small nevuslike suspicion for a BAP1 germline mutation. vus are BAP1 negative. This cells with slight nuclear inverse VE1/BAP1 immunohyperchromasia to large histochemical staining proatypical epithelioid cells with bizarre nuclei reminisfile is quite helpful for the histopathologic cent of atypical Spitz tumor or Spitzoid melanoma. differential diagnosis between Wiesner nevus and Therefore, a morphologic description of ‘‘atypical intradermal variants of dermal Spitz nevus, as it Spitzoid, clonal, and sheetlike pattern’’ appears more represents a reliable immunohistochemical fingerappropriate (Figs 2 and 3). It is not surprising that print (Table II). most of these tumors were diagnosed in the past either as atypical Spitz tumor or Spitzoid melanoma. However, in sharp contrast to these entities, DISCUSSION Wiesner nevus usually does not show any significant It is debatable whether the description ‘‘Wiesner mitotic activity and, in our experience, melanocytic nevus’’ is appropriate for a melanocytic tumor, combination in Wiesner nevus is much more which might represent a melanocytic premaasymmetric than in conventional combined Spitz lignancy. A strong argument for the nevus concept nevus. In fact, we suggest that Wiesner nevus often is the biological course of Wiesner nevus, with presents as a morphologically clonal or even lesions remaining stable over many decades. So far, polyclonal nevus showing various cell variants. An only 1 case of malignant melanoma evolving from a accompanying inflammatory infiltrate may be pre-existent Wiesner nevus has been reported in a present. Remarkably, a junctional or intraepidermal male member of the first founder family.11 And it melanocytic component is lacking, as Wiesner nevus must be pointed out that sporadic cases of Wiesner is an entirely dermal melanocytic proliferation and nevus may occur without any syndromal association the overlying epidermis is usually flat without despite showing the same BAP1-/VE1-positive any evidence of hyperplasia. The bizarre, mostly immunohistochemical profile.12 Moreover, Wiesner diffusely arranged atypical Spitzoid melanocytes nevus often presents together with banal Unna or represent the hallmark of Wiesner nevus, as their Miescher nevi in the same patient. Ancillary molecsheetlike or nested arrangement dominates the ular studies are necessary to differentiate syndromal entire tumor scene. Quite remarkably, there is no from sporadic variants of Wiesner nevus. BRAF and maturation from the surface toward the base of the BAP1 Sanger sequencing is feasible with DNA lesion in Wiesner nevus; a finding that is in sharp extracted from formalin-fixed paraffin-embedded contrast to most variants of Spitz nevus. In fact, specimens. Comparison of DNA sequences from Wiesner nevus may be an example of inverse lesional versus nonlesional tissue allows differentiamaturation, from top to bottom and from left to tion of sporadic Wiesner nevus from syndromal right, resulting in a chaotic cytologic pattern of Wiesner nevus: the syndromal nevus shows BAP1 d
d
d
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Fig 1. A to F, Wiesner nevus. Characteristic inconspicuous dome-shaped nevi in patients with biallelic loss of BAP1. Members of the first 2 founder families. (Courtesy of Thomas Wiesner and Werner Stieber.)
germline mutation in the adjacent skin, whereas the sporadic variant exhibits the wild type.13 The histopathological diagnosis can be straightforward, based on the findings of an entirely intradermal, markedly atypical, Spitzoid-dominated, sheetlike and/or clonally arranged, melanocytic population, lacking mitotic activity and typical melanocytic maturation toward the base of the lesion. The BAP1-negative/VE1-positive immunophenotype is helpful for differentiating Wiesner nevus from Spitz nevus and its variants, which show 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.
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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, Clonal nest of hyperchromatic melanocytes among sheetlike arrangement of atypical melanocytes with Spitzoid features. C, Characteristic melanocytes with atypical nuclei, hyperchromasia, and ample pale amphophilic cytoplasm. D, These atypical Spitzoid melanocytes with interspersed lymphocytes suggest diagnosis of atypical Spitzoid tumor. Mitoses are lacking. 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.
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Fig 3. A, Wiesner nevus, sectioned in center. Note heterogeneous sheets of melanocytes with clonal hyperchromatic subpopulations in the center and at right margin. Top section shows clearly that there is no maturation of melanocytes toward base of lesion. Clonally aggregated melanocytes in a chaotic arrangement. B, Nested arrangement of atypical melanocytes with pleomorphism and hyperchromasia. Mitoses are lacking. C, Populations of atypical melanocytes intermingled with a sparse lymphocytic infiltrate. D, Nested atypical melanocytes among sheetlike arrangement of atypical Spitzoid melanocytes. No mitotic activity. E, Paradigmatic pattern of Wiesner nevus. Note that all melanocytes are atypical. There is no maturation of melanocytes. The blending of various clonal populations of atypical melanocytes suggests a combined nevus. There are no mitoses. F, Immunohistochemical profile of Wiesner 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, Santa Cruz Biotechnology, Heidelberg, Germany) applied at a dilution 1:1000 with pH 9.0 antigen retrieval, and VE1 (clone VE1, mouse, DCS, Hamburg, Germany) applied at a dilution 1:100 with 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
Clinical
Solitary or multiple Often acquired Dome-shaped Small (\1 cm) Skin-colored
Syndromal association Molecular profile
None BRAF wild-type or BRAF V600E BAP1 wild-type VE1 negative or positive BAP1 positive p16 Positive p21 Negative
Immunohistochemical profile p16/p21 Profile
Histopathologic pattern
Predominantly dermal Monomorphous cell population, symmetric silhouette
Maturation
Present
Mitoses
None or few
Inflammatory infiltrate Cytology
Absent Round small cells with uniform nuclei
Pleomorphism, hyperchromatism Multicolor FISH
Absent Diploid; no gains/losses of copy numbers
FISH, Fluorescence in situ hybridization.
Spitz nevus
Solitary Often acquired Several shapes Several sizes (\2.5 cm) Several skin-color tones, often brownish None BRAF wild-type BAP1 wild-type VE1 negative BAP1 positive p16 Strongly positive (100%) p21 Positive (80%) Junctional and dermal variants Combined Spitz always with symmetric silhouette, with Spitzoid cell population in the center Present
Few, mostly at the junctional component Occasionally Spindle and/or epithelioid cells
Moderate, within the Spitzoid spectrum Diploid; tetraploid profile in some cases
Wiesner nevus
Multiple Since childhood Dome-shaped Small (\1 cm) Skin-colored Syndromal and sporadic BRAF V600E BAP1 biallelic loss VE1 positive BAP1 negative p16 Strongly positive (100%) p21 Scarce or focally positive (30%) Predominantly dermal proliferation Often combined but mostly with asymmetric pattern, similar to clonal or polyclonal nevus Missing, because of mostly asymmetricecombined, clonal, or polyclonal pattern Very scarce (\3 per section) Often Predominantly epithelioid cells with ample cytoplasm Marked morphologic plasticity: largeepithelioid, smallepithelioid, small-banal nevus cell types Marked, often suggesting atypical Spitzoid tumor Polyploid plus aneuploid profile (unbalanced gains of copy numbers)
Histopathologic clues for the diagnosis of Wiesner nevus Mar Llamas-Velasco, MD,a Yosmar Carolina Perez-G onzalez, MD,b Luis Requena, MD,c and Heinz Kutzner, MDd Madrid, Spain, and Friedrichshafen, Germany The dermatologic hallmark of a recently described BAP1-associated cancer susceptibility syndrome is a dome-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 of various nevomelanocytic populations all showing different degrees of atypia ranging from hyperchromatic nevus cell-like to large atypical epithelioid cells. Immunohistochemically, Wiesner nevus is BAP1 negative and 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.
iesner et al1 recently delineated clinical and molecular criteria of a distinct melanocytic tumor (Wiesner nevus), which is the most reliable marker lesion of a novel cancer susceptibility syndrome.2,3 This syndrome is associated with biallelic loss or inactivation of BAP1 in chromosome 3p21.1,4 As this melanocytic tumor is the cutaneous hallmark of a cancer susceptibility syndrome (Table I) encompassing cutaneous and uveal melanoma, mesothelioma, renal cell carcinoma, and probably several other neoplastic entities,5-9 it is paramount for dermatopathologists to be well acquainted with the clinicopathological features of the diagnostically challenging Wiesner nevus.
W
REPORT Clinical features Patients with the BAP1 tumor susceptibility syndrome often present with large numbers of banal dome-shaped or pedunculated skin-colored melanocytic nevi without alarming clinical criteria. Because of the BAP1 germline mutation, these multiple melanocytic nevi often occur in members of all generations of 1 family. It is remarkable that not all of these melanocytic nevi are Wiesner nevi. Patients may harbor a mixture of Miescher, Unna, and Wiesner nevi within the same anatomic area. It is our impression, however, that typical From the Departments of Dermatologya and Pathology,b Hospital Infanta Cristina, Parla, Madrid; Department of Dermatology of Fundaci on Jimenez Diaz, Madridc; and Dermatopathologie Friedrichshafen.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 14, 2013.
Abbreviations used: BAP1: BRAF:
BRCA1-associated protein 1 v-raf murine sarcoma viral oncogene homolog B1
Wiesner nevi are characterized by their domeshaped, smooth-surfaced, skin-colored configuration, which differs markedly from typical Spitz nevus (Fig 1). Table I. Documented tumor entities associated with the BAP1-associated cancer susceptibility syndrome Wiesner nevi Uveal and cutaneous melanoma Mesothelioma Renal cell carcinoma Ovarian and breast carcinoma Cholangiosarcoma Pancreatic carcinoma Meningioma Paraganglioma Neuroendocrine tumors Lung carcinoma Multiple myeloma Leiomyosarcoma Myeloproliferative disease
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 protected]. Published online December 26, 2013. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.10.032
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different cell clones, which seems to defy the rules Histopathology of melanocytic tumor biology, giving rise to multiple At scanning magnification, Wiesner nevus shows speculations. the silhouette and shape of a symmetric banal dermal melanocytic nevus (Fig 1). At medium power, it becomes obvious that the lesion harbors various Immunohistochemistry melanocytic populations in an irregular nested or It has recently been shown that immunohistosheetlike array, diffusely distributed throughout the chemical staining with the monoclonal VE1 antibody lesion, sometimes gradually can be used as a surrogate for blending with each other or molecular detection of actiCAPSULE SUMMARY colliding. However, the devating V600E point mutation scription ‘‘combined nevus’’ in exon 15 of the BRAF Biallelic loss or inactivation of BAP1 may is inaccurate for this peculiar gene.10 In contrast to Spitz be associated with underlying neoplasia. melanocytic nevus because nevus cells, the large epithePatients with BAP1 tumor susceptibility there are no regular or banal lioid melanocytes in Wiesner syndrome have clinically banal nevi, melanocytes. The leading nevus harbor the V600E including Wiesner nevi. These are cell type in Wiesner nevus is mutation and therefore stain histopathologically characterized by a large epithelioid melanopositively with the VE1 antiatypical intradermal Spitzoid cyte with ample pale cytobody. Conversely, Spitz nemelanocytes that stain positive for VE1 plasm and an atypical vus cells stain positive with (V600E) but negative for BAP1. nucleus. All melanocytes in the BAP1 antibody, whereas Wiesner nevus show atypia Multiple Wiesner nevi should raise melanocytes in Wiesner neranging from small nevuslike suspicion for a BAP1 germline mutation. vus are BAP1 negative. This cells with slight nuclear inverse VE1/BAP1 immunohyperchromasia to large histochemical staining proatypical epithelioid cells with bizarre nuclei reminisfile is quite helpful for the histopathologic cent of atypical Spitz tumor or Spitzoid melanoma. differential diagnosis between Wiesner nevus and Therefore, a morphologic description of ‘‘atypical intradermal variants of dermal Spitz nevus, as it Spitzoid, clonal, and sheetlike pattern’’ appears more represents a reliable immunohistochemical fingerappropriate (Figs 2 and 3). It is not surprising that print (Table II). most of these tumors were diagnosed in the past either as atypical Spitz tumor or Spitzoid melanoma. However, in sharp contrast to these entities, DISCUSSION Wiesner nevus usually does not show any significant It is debatable whether the description ‘‘Wiesner mitotic activity and, in our experience, melanocytic nevus’’ is appropriate for a melanocytic tumor, combination in Wiesner nevus is much more which might represent a melanocytic premaasymmetric than in conventional combined Spitz lignancy. A strong argument for the nevus concept nevus. In fact, we suggest that Wiesner nevus often is the biological course of Wiesner nevus, with presents as a morphologically clonal or even lesions remaining stable over many decades. So far, polyclonal nevus showing various cell variants. An only 1 case of malignant melanoma evolving from a accompanying inflammatory infiltrate may be pre-existent Wiesner nevus has been reported in a present. Remarkably, a junctional or intraepidermal male member of the first founder family.11 And it melanocytic component is lacking, as Wiesner nevus must be pointed out that sporadic cases of Wiesner is an entirely dermal melanocytic proliferation and nevus may occur without any syndromal association the overlying epidermis is usually flat without despite showing the same BAP1-/VE1-positive any evidence of hyperplasia. The bizarre, mostly immunohistochemical profile.12 Moreover, Wiesner diffusely arranged atypical Spitzoid melanocytes nevus often presents together with banal Unna or represent the hallmark of Wiesner nevus, as their Miescher nevi in the same patient. Ancillary molecsheetlike or nested arrangement dominates the ular studies are necessary to differentiate syndromal entire tumor scene. Quite remarkably, there is no from sporadic variants of Wiesner nevus. BRAF and maturation from the surface toward the base of the BAP1 Sanger sequencing is feasible with DNA lesion in Wiesner nevus; a finding that is in sharp extracted from formalin-fixed paraffin-embedded contrast to most variants of Spitz nevus. In fact, specimens. Comparison of DNA sequences from Wiesner nevus may be an example of inverse lesional versus nonlesional tissue allows differentiamaturation, from top to bottom and from left to tion of sporadic Wiesner nevus from syndromal right, resulting in a chaotic cytologic pattern of Wiesner nevus: the syndromal nevus shows BAP1 d
d
d
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Fig 1. A to F, Wiesner nevus. Characteristic inconspicuous dome-shaped nevi in patients with biallelic loss of BAP1. Members of the first 2 founder families. (Courtesy of Thomas Wiesner and Werner Stieber.)
germline mutation in the adjacent skin, whereas the sporadic variant exhibits the wild type.13 The histopathological diagnosis can be straightforward, based on the findings of an entirely intradermal, markedly atypical, Spitzoid-dominated, sheetlike and/or clonally arranged, melanocytic population, lacking mitotic activity and typical melanocytic maturation toward the base of the lesion. The BAP1-negative/VE1-positive immunophenotype is helpful for differentiating Wiesner nevus from Spitz nevus and its variants, which show 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.
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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, Clonal nest of hyperchromatic melanocytes among sheetlike arrangement of atypical melanocytes with Spitzoid features. C, Characteristic melanocytes with atypical nuclei, hyperchromasia, and ample pale amphophilic cytoplasm. D, These atypical Spitzoid melanocytes with interspersed lymphocytes suggest diagnosis of atypical Spitzoid tumor. Mitoses are lacking. 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.
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Fig 3. A, Wiesner nevus, sectioned in center. Note heterogeneous sheets of melanocytes with clonal hyperchromatic subpopulations in the center and at right margin. Top section shows clearly that there is no maturation of melanocytes toward base of lesion. Clonally aggregated melanocytes in a chaotic arrangement. B, Nested arrangement of atypical melanocytes with pleomorphism and hyperchromasia. Mitoses are lacking. C, Populations of atypical melanocytes intermingled with a sparse lymphocytic infiltrate. D, Nested atypical melanocytes among sheetlike arrangement of atypical Spitzoid melanocytes. No mitotic activity. E, Paradigmatic pattern of Wiesner nevus. Note that all melanocytes are atypical. There is no maturation of melanocytes. The blending of various clonal populations of atypical melanocytes suggests a combined nevus. There are no mitoses. F, Immunohistochemical profile of Wiesner 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, Santa Cruz Biotechnology, Heidelberg, Germany) applied at a dilution 1:1000 with pH 9.0 antigen retrieval, and VE1 (clone VE1, mouse, DCS, Hamburg, Germany) applied at a dilution 1:100 with 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
Clinical
Solitary or multiple Often acquired Dome-shaped Small (\1 cm) Skin-colored
Syndromal association Molecular profile
None BRAF wild-type or BRAF V600E BAP1 wild-type VE1 negative or positive BAP1 positive p16 Positive p21 Negative
Immunohistochemical profile p16/p21 Profile
Histopathologic pattern
Predominantly dermal Monomorphous cell population, symmetric silhouette
Maturation
Present
Mitoses
None or few
Inflammatory infiltrate Cytology
Absent Round small cells with uniform nuclei
Pleomorphism, hyperchromatism Multicolor FISH
Absent Diploid; no gains/losses of copy numbers
FISH, Fluorescence in situ hybridization.
Spitz nevus
Solitary Often acquired Several shapes Several sizes (\2.5 cm) Several skin-color tones, often brownish None BRAF wild-type BAP1 wild-type VE1 negative BAP1 positive p16 Strongly positive (100%) p21 Positive (80%) Junctional and dermal variants Combined Spitz always with symmetric silhouette, with Spitzoid cell population in the center Present
Few, mostly at the junctional component Occasionally Spindle and/or epithelioid cells
Moderate, within the Spitzoid spectrum Diploid; tetraploid profile in some cases
Wiesner nevus
Multiple Since childhood Dome-shaped Small (\1 cm) Skin-colored Syndromal and sporadic BRAF V600E BAP1 biallelic loss VE1 positive BAP1 negative p16 Strongly positive (100%) p21 Scarce or focally positive (30%) Predominantly dermal proliferation Often combined but mostly with asymmetric pattern, similar to clonal or polyclonal nevus Missing, because of mostly asymmetricecombined, clonal, or polyclonal pattern Very scarce (\3 per section) Often Predominantly epithelioid cells with ample cytoplasm Marked morphologic plasticity: largeepithelioid, smallepithelioid, small-banal nevus cell types Marked, often suggesting atypical Spitzoid tumor Polyploid plus aneuploid profile (unbalanced gains of copy numbers)