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Uncommon Variants of Melanoma and Collision Scenarios
20 Uncommon Variants of Melanoma and Collision Scenarios Klaus J. Busam and Richard A. Scolyer
OUTLINE Histopathologic Findings and Differential Diagnosis, 235 Balloon Cell/Clear Cell Melanoma, 235 Deep Penetrating Nevus-Like (Plexiform) Melanoma, 235 Primary Dermal Melanoma, 235 Follicular Melanoma, 236 Rhabdoid Melanoma, 236 Sarcomatoid Melanoma, 236 Signet Ring Cell Melanoma, 236 Small Cell Melanoma, 236 Undifferentiated Melanoma, 236
Verrucous (Papillomatous Keratotic Variant of) Melanoma, 237 Melanoma Associated With Pseudoepitheliomatous Epidermal Hyperplasia, 237 Melanoma With Pseudovascular Changes, 238 Melanoma With Epithelial Features, 238 Spindle Cell Melanoma, 238 Polypoid Melanoma, 241 Collision Scenarios, 241 Melanoma Colliding With a Basal Cell Carcinoma, 241 Melanoma Colliding With a Squamous Proliferation, 241
The purpose of this chapter is to present unusual morphologic variants of primary cutaneous melanomas, which are not the subject of specific chapters elsewhere in the book. The main value of mentioning and describing these variants is for the practicing pathologist to be aware of the morphologic spectrum of melanomas. Since there is no known clinical significance or associated molecular signature to the variants described herein, we simply present the microscopic findings and discuss the differential diagnosis.
and display a plexiform growth pattern.2 There may be, as in a deep penetrating nevus (DPN), a deeply extending pigmented tumor component (Fig. 20.2). The diagnosis is particularly challenging when a DPN-like melanoma arises in association with a melanocytic nevus, thereby simulating a combined nevus. DPN-like melanoma can be distinguished from a DPN by its asymmetric silhouette and/or expansile growth, a higher degree and more uniform (as opposed to random scattered) nuclear atypia and higher number of mitoses, including mitoses near the base of the lesion. The presence of associated features of melanoma in situ also facilitates the diagnosis of melanoma. Ancillary studies may also help, as DPN-like melanomas may be associated with molecular aberrations typical of melanoma.
HISTOPATHOLOGIC FINDINGS AND DIFFERENTIAL DIAGNOSIS Balloon Cell/Clear Cell Melanoma This variant of melanoma is characterized by distinct cytoplasmic changes: on hematoxylin and eosin (H&E)–stained sections the cytoplasm is not pink (eosinophilic), but “clear.”1 Sometimes it may be foamy. Often the cytoplasm is enlarged and abundant. Balloon cell changes are most often associated with superficial spreading or nodular melanomas. Although in some melanomas all or nearly all tumor cells display balloon cell features (Fig. 20.1), often those features are focal and part of a melanoma with otherwise conventional cytology. If a tumor displays nearly exclusively balloon cell features and pagetoid spread is present, it may need to be distinguished from other pagetoid cutaneous clear cell neoplasms, such as sebaceous carcinoma or clear cell sweat gland neoplasms. Nodular balloon cell melanomas may be confused with metastatic renal cell carcinoma or histiocytic tumors, such as a xanthoma.
Deep Penetrating Nevus-Like (Plexiform) Melanoma This variant of melanoma shows some similarity to and may be confused with a deep penetrating nevus. The tumors are typically heavily pigmented
Primary Dermal Melanoma Primary dermal melanoma is listed herein as an unusual form of melanoma. However, it lacks distinctive cytologic features and is in our opinion best regarded as a variant of primary nodular melanoma. By definition, there is a dermal nodule of melanoma with no associated precursor lesion (melanoma in situ or melanocytic nevus) (Fig. 20.3).3 Accordingly, the main diagnostic challenge is correct staging. Is the dermal melanoma nodule a primary or a metastatic tumor? The initial series of primary dermal melanomas reported a lower Ki-67 labeling index compared with conventional nodular melanomas and suggested a more favorable clinical course. However, this has not been independently validated, and the difference in observed outcomes may have been biased by the selection of tumors with a low proliferative index. Current evidence suggests that primary dermal melanomas are genomically heterogeneous, some carry NRAS and others carry BRAF mutations, whereas some lack both BRAF and NRAS mutations. Some tumors may be associated with gene rearrangements and fusions.
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Keywords melanoma balloon cell small cell folliculotropic primary dermal melanoma rhabdoid osetosarcomatous rhabdomyosarcomatous basomelanocytic squamomelanocytic
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A
(Fig. 20.5). The term rhabdoid refers to cytologic similarity to rhabdoid tumor, a term originally coined by Haas et al. in 1981 to describe an aggressive childhood renal tumor.5 Tumors with similar features have in the meantime been reported to occur at many other sites (extrarenal rhabdoid tumors). Rhabdoid melanoma was first reported by Bittesini et al. in 1992.6 This phenotype is usually seen in metastatic tumors but can also be found in primary tumors.7 The tumors are usually amelanotic. If there is associated melanoma in situ, the diagnosis is usually straightforward. Otherwise clinical correlation and immunostains may be necessary to distinguish primary nodular melanoma with rhabdoid features from a primary soft tissue or cutaneous metastasis or other malignant neoplasms with rhabdoid features, such as malignant rhabdoid tumor of childhood, malignant peripheral neuroectodermal tumor, or rhabdomyosarcoma.
Sarcomatoid Melanoma
B Fig. 20.1 Balloon Cell Melanoma. (A) An invasive melanoma nodule with pale/clear cell features. (B) Intraepidermal melanocytes displaying a pagetoid growth pattern. The dermal tumor cells are characterized by abundant pale cytoplasm.
Follicular Melanoma Follicular or folliculotropic melanoma is a variant of melanoma in which the in situ component is predominantly located within folliculosebaceous structures (Fig. 20.4).4 Melanoma in situ exclusively confined to a follicle (follicular melanoma) is exceedingly rare. More often, there is prominent follicular involvement (folliculotropic melanoma), but a portion of the melanoma in situ tends also to involve adjacent epidermis. Most follicular and folliculotropic melanomas occur in the head and neck region. Associated invasive melanoma is usually found in the perifollicular stroma. Follicular melanomas pose a problem for precise measurement of tumor thickness. Using the granular cell layer of the overlying epidermis as starting point for measuring tumor thickness would often result in an overestimate of tumor thickness. For follicular melanomas, we recommend using the center of the follicle or the epithelial border of the pilar canal closest to the most peripheral invasive melanoma cell as an estimate of tumor thickness. Primary follicular melanoma with no significant in situ component adjacent to the follicle must be distinguished from a folliculotropic melanoma metastasis.
Rhabdoid Melanoma In this variant of melanoma, the tumor cells display “rhabdoid” features characterized by epithelioid cell features and eccentric nuclei with a single prominent nucleolus as well as intracytoplasmic hyaline inclusions
A melanoma can simulate and be confused with a sarcoma. The spectrum of sarcomatoid features is broad and ranges from an appearance simulating an atypical fibroxanthoma (AFX)8 or pleomorphic dermal-based sarcoma to a melanoma with osteocartilaginous or rhabdomyosarcomatous differentiation (Fig. 20.6).9,10 Diagnostic pitfalls are usually related to partial biopsies in which the sarcomatoid component dominates or nodular tumors with no associated in situ component. Immunohistochemical studies usually permit a definitive diagnosis. However, caution is needed in reviewing the results of immunohistochemistry. For example, some lesions of AFX may stain for microphthalmia-associated transcription factor (MITF) or Melan-A. On the other hand, some melanomas may be positive for smooth muscle actin (SMA) and even desmin. Thus the diagnosis of a sarcomatoid melanoma requires taking into account a number of features (superficial skin tumor, possible presence of melanoma in situ, at least focal presence of expression of S100, Sox10 and/or other differentiation antigens supporting melanocytic differentiation). Melanoma with osteocartilaginous differentiation (Fig. 20.7),11 which tends to be more common at acral sites, must be distinguished from osteosarcoma and melanoma invading bone with reactive osseous metaplasia.
Signet Ring Cell Melanoma Signet ring cell changes are rare in primary melanomas. They are most likely seen in metastatic lesions. However, focal signet ring cell and pseudoglandular features may be found in a rare, usually advanced primary melanoma.
Small Cell Melanoma Melanoma may present with small cell features simulating a primitive small round cell sarcoma, lymphoma, or neuroendocrine carcinoma.12,13 The tumors are usually amelanotic. Mitotic figures and apoptotic bodies are common (Fig. 20.8). Nuclear molding may be seen. A diagnostic error is unlikely if there is associated melanoma in situ, but there is potential for confusion with epidermotropic Merkel cell carcinoma. Intradermal (nodular) small cell melanomas require immunohistochemical studies for diagnosis and distinction from sarcoma or neuroendocrine carcinoma. A nodular melanoma with “melanoblastic” small round cell features may develop in a large congenital nevus and needs to be distinguished from proliferative nodules (see Chapters 3 and 21).
Undifferentiated Melanoma Undifferentiated melanoma refers to a tumor that is a melanoma but does not display differentiating features by light microscopy (e.g., melanin pigment, nested growth) or by immunohistochemistry.14 The tumor cells are negative not only for Melan-A, gp100, and tyrosinase
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A B
C D Fig. 20.2 Deep Penetrating Melanoma. (A) Silhouette of a melanoma with an exophytic superficial portion and a deep penetrating pigmented invasive tumor. (B) The tumor is composed of pigmented spindle and epithelioid melanocytes admixed with melanophages. (C) Focal lymphatic invasion is present in this case. (D) Sheet-like infiltration by pigmented melanoma cells in the superficial subcutis.
but also fail to label or only minimally label S100 protein or Sox 10. Clinical correlation and mutation analysis are essential for the correct diagnosis. Sometimes a subsequent metastasis may express S100 protein or Sox10. Usually undifferentiated melanoma is a metastatic tumor. For example, if a patient has a known prior melanoma and an undifferentiated malignant neoplasm is found in the regional node draining the site of the primary melanoma, detection of the same mutation profile in the primary and metastatic tumor can help to establish a diagnosis of metastatic melanoma. On rare occasion, a primary melanoma may also have an undifferentiated immunophenotype; the diagnosis then becomes apparent with a subsequent metastasis and mutation analysis.
Verrucous (Papillomatous Keratotic Variant of) Melanoma Verrucous melanoma is characterized by melanoma-associated verrucous epidermal hyperplasia (Fig. 20.9).15,16 Its main diagnostic pitfall is clinical: because of the verrucous silhouette, the lesion is often thought to be a wart or seborrheic keratosis and is treated accordingly. A small superficial shave biopsy with prominent papillomatous epidermal hyperplasia and
hyperkeratosis may not capture the melanocytic neoplasm and thus support the assumption of a wart, thereby delaying recognition of the correct diagnosis and treatment. It may also be challenging for the pathologist to diagnose the melanoma, if, for example, a small biopsy sample submitted to rule out a wart shows mainly wart-like epidermal features and only focally an atypical melanocytic proliferation. Verrucous melanoma is also relevant as a challenge for assessing Breslow thickness. Extensive papillomatous growth may make it difficult to precisely measure the thickness of a superficially invasive melanoma.
Melanoma Associated With Pseudoepitheliomatous Epidermal Hyperplasia Sometimes melanoma is associated with florid pseudoepitheliomatous epidermal hyperplasia with or without adjacent ulceration (Fig. 20.10). The presence of prominent epidermal changes may make the clinical recognition more difficult (e.g., the presence of a scale crust may lead to confusion with a keratosis or carcinoma), and lead to potential confusion with a collision scenario of squamous cell carcinoma and melanoma. Furthermore, a pathologist focusing on the epidermal changes may consider a squamous cell carcinoma and fail to recognize the
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A
B Fig. 20.3 Primary Dermal Melanoma. (A) Silhouette of an intradermal tumor nodule with superficial dermal fibrosis. There is no associated melanocytic nevus or in situ melanoma. (B) Melanoma cells display nuclear atypia and are associated with stromal fibrosis and inflammation.
melanoma if, for example, a superficial biopsy sample contains mainly the epithelial proliferation.
Melanoma With Pseudovascular Changes Just like melanocytic nevi, the tumor cells within an invasive melanoma may become discohesive and, with histopathologic processing, give rise to pseudovascular spaces, which may lead to confusion with angiosarcoma (Fig. 20.11). Immunohistochemical studies can readily determine the line of differentiation and distinguish melanoma from sarcoma.
Melanoma With Epithelial Features In some melanomas, the tumor cells may display features simulating a carcinoma by growing in cords or strands or by forming duct-like structures (Fig. 20.12). This may lead to diagnostic confusion with a myoepithelial carcinoma or adenocarcinoma. A panel of immunomarkers is usually necessary, since melanoma may on occasion show aberrant expression of cytokeratins (usually focal and weak) and myoepithelial carcinomas commonly express S100 and Sox10 (occasionally strong and diffuse). Therefore coexpression of melanocyte differentiation antigens (e.g., gp100, tyrosinase, Melan-A/MART1) is very helpful in supporting a diagnosis of melanoma. Melanoma may also display epithelial features by aberrantly expressing cytokeratins. However, this is usually seen in undifferentiated metastatic tumors and is rarely a problem with primary melanomas.
B Fig. 20.4 Folliculotropic Melanoma. (A) Melanoma cells prominently populating a hair follicle. They also involve adjacent epidermis. (B) Multiple follicles are involved by melanoma in situ. Isolated microinvasive tumor cells are seen in the perifollicular stroma.
Spindle Cell Melanoma Spindle cell melanoma refers to invasive melanomas in which the tumor is predominantly or exclusively composed of spindle cells. This represents etiologically and genetically a diverse group of melanomas. Spindle cell features may be seen in the invasive component of various melanomas (lentigo maligna, acral, superficial spreading, nodular). Pure solid spindle cell melanomas are mentioned here separately to emphasize their heterogeneous composition as well as the related differential diagnosis. Primary cutaneous spindle cell melanomas must be distinguished from miscellaneous sarcomas, in particular pleomorphic dermal sarcoma. Although many desmoplastic and/or neurotropic melanomas are composed of spindle cells, they are not synonymous with spindle cell melanoma. A spindle cell melanoma is desmoplastic only if a significant part of its invasive tumor cell population is associated with and dispersed in a dense fibrous stroma. Likewise a spindle cell melanoma is neurotropic
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Fig. 20.6 Melanoma with rhadomyosarcomatous differentiation.
A
A
B Fig. 20.5 Rhabdoid Melanoma. (A) Ulcerated large tumor nodule. (B) The tumor cells are epithelioid in appearance, with eccentric nuclei and intracytoplasmic hyaline inclusions.
B Fig. 20.7 Melanoma With Osteocartilaginous Differentiation. (A) Acral melanoma with area displaying osteosarcomatous features. (B) The melanoma also displayed focal chrondroid features. (Courtesy of Dr. A Lazar).
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A
A
B Fig. 20.8 Melanoma With Small Cell Features. (A) Subtle melanoma in situ involving squamous mucosa overlying an invasive tumor component that lacks melanin pigment and has minimal cytoplasm. (B) The tumor cells have a blue-cell appearance. Focal nuclear molding is seen. Mitoses and apoptotic bodies are present.
Fig. 20.10 Melanoma With Florid Epidermal Hyperplasia. (A) Ulcerated polypoid nodular melanoma with prominent pseudoepitheliomatous epidermal hyperplasia adjacent to the ulcer. At the right side of the B polyp the epidermal hyperplasia has seborrheic keratosis-like features. (B) Pseudoepitheliomatous epidermal hyperplasia overlying invasive spindle melanoma.
Fig. 20.9 Verrucous/Papillomatous Melanoma. Superficial spreading melanoma associated with papillomatous exophytic growth. Expanded dermis within papillomatous projections is filled with tumor cells. Fig. 20.11 Melanoma With Pseudovascular Changes. Tumor cells are separated forming pseudovascular spaces. Pseudovascular change may also occur in nevi.
CHAPTER 20 Uncommon Variants of Melanoma and Collision Scenarios
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B
A
Fig. 20.12 Melanoma With Epithelial-like Features. (A) This ulcerated acral melanoma displays predominantly solid spindle cell features but also focal carcinoma-like features. The epithelial-like tumor cells in myxoid stroma were negative for cytokeratins but expressed Sox10 and Melan-A. (B) Juxtaposition of solid spindle cell melanoma and a subpopulation of tumor cells displaying epithelioid features forming cord-like structures in a myxoid stroma.
only when its tumor cells prominently surround and/or infiltrate nerves, especially at the periphery of the tumor away from the main tumor mass.
Polypoid Melanoma Any type of melanoma may display a polypoid silhouette (see Fig. 20.10). The main diagnostic pitfall related to a polypoid silhouette is clinical. If a tumor is amelanotic, it may be mistaken for a skin tag. The histopathologic diagnosis of a polypoid melanoma is usually not difficult, since many of these are advanced melanomas with high-risk features. However, precise assessment of Breslow thickness may sometimes be difficult with polypoid tumors.
COLLISION SCENARIOS A melanocytic proliferation—including a melanocytic nevus, primary melanoma, or metastatic melanoma—may on occasion collide with another neoplasm, including mesenchymal and epithelial lesions,17-24 and thereby provide a diagnostic challenge. Failure to recognize a collision scenario may lead to erroneous interpretation of a biphenotypic neoplasm and/or errors in tumor staging.
Melanoma Colliding With a Basal Cell Carcinoma Basal cell carcinoma may collide not only with a melanocytic nevus (Fig. 20.13) but also with a melanoma. The most common collision scenario of a melanoma and basal cell carcinoma is that of melanoma in situ and basal cell carcinoma. Intratumoral melanoma cells may be seen on H&E-stained sections or by immunohistochemistry. If the basal cell carcinoma nodule is connected to the epidermis, intratumoral melanoma cells are prognostically not equivalent to melanoma cells present in dermal stroma. We believe that intratumoral melanoma is best regarded as colonization of a basal cell carcinoma by melanoma in situ. However, primary invasive melanoma may also collide with a basal cell carcinoma (Fig. 20.14), but the diagnosis of invasive melanoma should be based on documentation of melanoma in the dermal stroma.
Fig. 20.13 Basal cell carcinoma colliding with a melanocytic nevus.
Lastly, metastatic melanoma may spread to the site of a basal cell carcinoma, be located adjacent to carcinoma, and colonize some of the tumor nodules (Fig. 20.15).
Melanoma Colliding With a Squamous Proliferation Melanoma in situ and/or invasive melanoma may also collide with a spectrum of squamous proliferations, including verruca, seborrheic keratosis, actinic keratosis, and squamous cell carcinoma. Melanoma may be located adjacent to or surround the squamous lesion. Often it grows into and colonizes the epithelial proliferation. When in situ melanoma collides with and populates the tumor area of an acanthoma, adnexal tumor with squamous features, or squamous cell carcinoma (Fig. 20.16) and extends within the invasive carcinoma deeper to the level of the adjacent nonneoplastic epidermis, this should not, for prognostic purposes, be equated with stromal invasion.
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Fig. 20.14 Primary Melanoma Colliding With a Basal Cell Carcinoma. A basal cell carcinoma found at the same site as a melanoma.
B A
C B Fig. 20.15 Metastatic Melanoma Colliding With a Basal Cell Carcinoma. (A) Shave biopsy of a collision of basal cell carcinoma (most of it is located on the right side of the biopsy) and melanoma (most of it is found on the left side). (B) Juxtaposition of melanoma and basal cell carcinoma. The latter is pigmented and associated with melanophages.
Fig. 20.16 Melanoma In Situ Colliding With a Squamous Cell Carcinoma. (A) Silhouette of the tumor. The first impression is that of a squamous cell carcinoma. However, there are pigmented nests in the superficial portion of the tumor. (B) The tumor is flanked by melanoma in situ characterized by a proliferation of predominantly solitary units of atypical melanocytes at the dermoepidermal junction (arrows). (C) Nests of pigmented melanocytes are seen within the lesion admixed with the squamous cell carcinoma.
CHAPTER 20 Uncommon Variants of Melanoma and Collision Scenarios
REFERENCES 1. Kao GF, Helwig EB, Graham JH. Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations. Cancer. 1992;69:2942–2952. 2. Magro CM, et al. Deep penetrating nevus-like borderline tumors: a unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics. Eur J Dermatol. 2014;24:594–602. 3. Cassarino DS, et al. Primary dermal melanoma: distinct immunohistochemical findings and clinical outcome compared with nodular and metastatic melanoma. Arch Dermatol. 2008;144:49–56. 4. Hantschke M, Mentzel T, Kutzner H. Follicular malignant melanoma: a variant of melanoma to be distinguished from lentigo maligna melanoma. Am J Dermatopathol. 2004;26:359–363. 5. Haas JE, et al. Ultra-structure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol. 1981;12:646–657. 6. Bittesini L, Dei Tos AP, Fletcher CD. Metastatic malignant melanoma showing a rhabdoid phenotype: further evidence of a non-specific histological pattern. Histopathology. 1992;20:167–170. 7. Borek BT, et al. Primary malignant melanoma with rhabdoid features: a histologic and immunocytochemical study of three cases. Am J Dermatopathol. 1998;20:123–127. 8. Sangüeza M, Zelger B. Melanoma simulating atypical fibroxanthoma. Am J Dermatopathol. 2007;29:551–554. 9. Cachia AR, Kedziora AM. Subungual malignant melanoma with cartilaginous differentiation. Am J Dermatopathol. 1999;21:165–169. 10. Gharpuray-Pandit D, et al. Rhabdomyoblastic differentiation in malignant melanoma in adults: report of 2 cases. Int J Surg Pathol. 2007;15:20–25. 11. Ali AM, Wang WL, Lazar AJ. Primary chondro-osseous melanoma(chondrosarcomatous and osteosarcomatous melanoma). J Cutan Pathol. 2017 Oct 25;[Epub ahead of print]. 12. Hanson IM, et al. A study of eleven cutaneous malignant melanomas in adults with small-cell morphology: emphasis on diagnostic difficulties and unusual features. Histopathology. 2002;40:187–195. 13. Eyden B, Pandit D, Banerjee SS. Malignant melanoma with neuroendocrine differentiation: clinical, histological,
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immunohistochemical and ultrastructural features of three cases. Histopathology. 2005;47:402–409. 14. Agaimy A, et al. Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker. Am J Surg Pathol. 2016;40:181–191. 15. Clark WH Jr. A classification of malignant melanoma in man correlated with histogenesis and biologic behaviour. In: Montagna W, ed. Advances in Biology of the Skin, The Pigmentary System. New York: Pergamon Press; 1967:621–647. 16. Kuehnl-Petzoldt C, Berger H, Wiebelt H. Verrucous-keratotic variations of malignant melanoma: a clinicopathological study. Am J Dermatopathol. 1982;4(5):403–410. 17. Specchio F, et al. Photoletter to the editor: collision tumor of melanoma and atypical fibroxanthoma of the scalp. J Dermatol Case Rep. 2014;8:84–85. 18. Erickson LA, et al. Malignant basomelanocytic tumor manifesting as metastatic melanoma. Am J Surg Pathol. 2004;28:1393–1396. 19. Busam KJ, Halpern A, Marghoob AA. Malignant melanoma metastatic to a basal cell carcinoma simulating the pattern of a basomelanocytic tumor. Am J Surg Pathol. 2006;30:133–136. 20. Rodriguez J, et al. Combined high-grade basal cell carcinoma and malignant melanoma of the skin (“malignant basomelanocytic tumor”): report of two cases and review of the literature. Am J Dermatopathol. 2005;27:314–318. 21. Goeser M, DiMaio DJ. A colonization of basal cell carcinoma by malignant melanoma in situ resembling a malignant basomelanocytic tumor. Am J Dermatopathol. 2014;36:e179–e182. 22. Amin SM, et al. Combined cutaneous tumors with a melanoma component: a clinical, histologic, and molecular study. J Am Acad Dermatol. 2015;73:451–460. 23. Scruggs JM, et al. Cutaneous collision cancers: a report of two squamomelanocytic malignancies and review of the literature. Dermatol Surg. 2011;37:1679–1683. 24. Leonard N, Wilson N, Calonje JE. Squamomelanocytic tumor: an unusual and distinctive entity of uncertain biological potential. Am J Dermatopathol. 2009;31:495–498.
OUTLINE Histopathologic Findings and Differential Diagnosis, 235 Balloon Cell/Clear Cell Melanoma, 235 Deep Penetrating Nevus-Like (Plexiform) Melanoma, 235 Primary Dermal Melanoma, 235 Follicular Melanoma, 236 Rhabdoid Melanoma, 236 Sarcomatoid Melanoma, 236 Signet Ring Cell Melanoma, 236 Small Cell Melanoma, 236 Undifferentiated Melanoma, 236
Verrucous (Papillomatous Keratotic Variant of) Melanoma, 237 Melanoma Associated With Pseudoepitheliomatous Epidermal Hyperplasia, 237 Melanoma With Pseudovascular Changes, 238 Melanoma With Epithelial Features, 238 Spindle Cell Melanoma, 238 Polypoid Melanoma, 241 Collision Scenarios, 241 Melanoma Colliding With a Basal Cell Carcinoma, 241 Melanoma Colliding With a Squamous Proliferation, 241
The purpose of this chapter is to present unusual morphologic variants of primary cutaneous melanomas, which are not the subject of specific chapters elsewhere in the book. The main value of mentioning and describing these variants is for the practicing pathologist to be aware of the morphologic spectrum of melanomas. Since there is no known clinical significance or associated molecular signature to the variants described herein, we simply present the microscopic findings and discuss the differential diagnosis.
and display a plexiform growth pattern.2 There may be, as in a deep penetrating nevus (DPN), a deeply extending pigmented tumor component (Fig. 20.2). The diagnosis is particularly challenging when a DPN-like melanoma arises in association with a melanocytic nevus, thereby simulating a combined nevus. DPN-like melanoma can be distinguished from a DPN by its asymmetric silhouette and/or expansile growth, a higher degree and more uniform (as opposed to random scattered) nuclear atypia and higher number of mitoses, including mitoses near the base of the lesion. The presence of associated features of melanoma in situ also facilitates the diagnosis of melanoma. Ancillary studies may also help, as DPN-like melanomas may be associated with molecular aberrations typical of melanoma.
HISTOPATHOLOGIC FINDINGS AND DIFFERENTIAL DIAGNOSIS Balloon Cell/Clear Cell Melanoma This variant of melanoma is characterized by distinct cytoplasmic changes: on hematoxylin and eosin (H&E)–stained sections the cytoplasm is not pink (eosinophilic), but “clear.”1 Sometimes it may be foamy. Often the cytoplasm is enlarged and abundant. Balloon cell changes are most often associated with superficial spreading or nodular melanomas. Although in some melanomas all or nearly all tumor cells display balloon cell features (Fig. 20.1), often those features are focal and part of a melanoma with otherwise conventional cytology. If a tumor displays nearly exclusively balloon cell features and pagetoid spread is present, it may need to be distinguished from other pagetoid cutaneous clear cell neoplasms, such as sebaceous carcinoma or clear cell sweat gland neoplasms. Nodular balloon cell melanomas may be confused with metastatic renal cell carcinoma or histiocytic tumors, such as a xanthoma.
Deep Penetrating Nevus-Like (Plexiform) Melanoma This variant of melanoma shows some similarity to and may be confused with a deep penetrating nevus. The tumors are typically heavily pigmented
Primary Dermal Melanoma Primary dermal melanoma is listed herein as an unusual form of melanoma. However, it lacks distinctive cytologic features and is in our opinion best regarded as a variant of primary nodular melanoma. By definition, there is a dermal nodule of melanoma with no associated precursor lesion (melanoma in situ or melanocytic nevus) (Fig. 20.3).3 Accordingly, the main diagnostic challenge is correct staging. Is the dermal melanoma nodule a primary or a metastatic tumor? The initial series of primary dermal melanomas reported a lower Ki-67 labeling index compared with conventional nodular melanomas and suggested a more favorable clinical course. However, this has not been independently validated, and the difference in observed outcomes may have been biased by the selection of tumors with a low proliferative index. Current evidence suggests that primary dermal melanomas are genomically heterogeneous, some carry NRAS and others carry BRAF mutations, whereas some lack both BRAF and NRAS mutations. Some tumors may be associated with gene rearrangements and fusions.
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CHAPTER 20 Uncommon Variants of Melanoma and Collision Scenarios
Keywords melanoma balloon cell small cell folliculotropic primary dermal melanoma rhabdoid osetosarcomatous rhabdomyosarcomatous basomelanocytic squamomelanocytic
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(Fig. 20.5). The term rhabdoid refers to cytologic similarity to rhabdoid tumor, a term originally coined by Haas et al. in 1981 to describe an aggressive childhood renal tumor.5 Tumors with similar features have in the meantime been reported to occur at many other sites (extrarenal rhabdoid tumors). Rhabdoid melanoma was first reported by Bittesini et al. in 1992.6 This phenotype is usually seen in metastatic tumors but can also be found in primary tumors.7 The tumors are usually amelanotic. If there is associated melanoma in situ, the diagnosis is usually straightforward. Otherwise clinical correlation and immunostains may be necessary to distinguish primary nodular melanoma with rhabdoid features from a primary soft tissue or cutaneous metastasis or other malignant neoplasms with rhabdoid features, such as malignant rhabdoid tumor of childhood, malignant peripheral neuroectodermal tumor, or rhabdomyosarcoma.
Sarcomatoid Melanoma
B Fig. 20.1 Balloon Cell Melanoma. (A) An invasive melanoma nodule with pale/clear cell features. (B) Intraepidermal melanocytes displaying a pagetoid growth pattern. The dermal tumor cells are characterized by abundant pale cytoplasm.
Follicular Melanoma Follicular or folliculotropic melanoma is a variant of melanoma in which the in situ component is predominantly located within folliculosebaceous structures (Fig. 20.4).4 Melanoma in situ exclusively confined to a follicle (follicular melanoma) is exceedingly rare. More often, there is prominent follicular involvement (folliculotropic melanoma), but a portion of the melanoma in situ tends also to involve adjacent epidermis. Most follicular and folliculotropic melanomas occur in the head and neck region. Associated invasive melanoma is usually found in the perifollicular stroma. Follicular melanomas pose a problem for precise measurement of tumor thickness. Using the granular cell layer of the overlying epidermis as starting point for measuring tumor thickness would often result in an overestimate of tumor thickness. For follicular melanomas, we recommend using the center of the follicle or the epithelial border of the pilar canal closest to the most peripheral invasive melanoma cell as an estimate of tumor thickness. Primary follicular melanoma with no significant in situ component adjacent to the follicle must be distinguished from a folliculotropic melanoma metastasis.
Rhabdoid Melanoma In this variant of melanoma, the tumor cells display “rhabdoid” features characterized by epithelioid cell features and eccentric nuclei with a single prominent nucleolus as well as intracytoplasmic hyaline inclusions
A melanoma can simulate and be confused with a sarcoma. The spectrum of sarcomatoid features is broad and ranges from an appearance simulating an atypical fibroxanthoma (AFX)8 or pleomorphic dermal-based sarcoma to a melanoma with osteocartilaginous or rhabdomyosarcomatous differentiation (Fig. 20.6).9,10 Diagnostic pitfalls are usually related to partial biopsies in which the sarcomatoid component dominates or nodular tumors with no associated in situ component. Immunohistochemical studies usually permit a definitive diagnosis. However, caution is needed in reviewing the results of immunohistochemistry. For example, some lesions of AFX may stain for microphthalmia-associated transcription factor (MITF) or Melan-A. On the other hand, some melanomas may be positive for smooth muscle actin (SMA) and even desmin. Thus the diagnosis of a sarcomatoid melanoma requires taking into account a number of features (superficial skin tumor, possible presence of melanoma in situ, at least focal presence of expression of S100, Sox10 and/or other differentiation antigens supporting melanocytic differentiation). Melanoma with osteocartilaginous differentiation (Fig. 20.7),11 which tends to be more common at acral sites, must be distinguished from osteosarcoma and melanoma invading bone with reactive osseous metaplasia.
Signet Ring Cell Melanoma Signet ring cell changes are rare in primary melanomas. They are most likely seen in metastatic lesions. However, focal signet ring cell and pseudoglandular features may be found in a rare, usually advanced primary melanoma.
Small Cell Melanoma Melanoma may present with small cell features simulating a primitive small round cell sarcoma, lymphoma, or neuroendocrine carcinoma.12,13 The tumors are usually amelanotic. Mitotic figures and apoptotic bodies are common (Fig. 20.8). Nuclear molding may be seen. A diagnostic error is unlikely if there is associated melanoma in situ, but there is potential for confusion with epidermotropic Merkel cell carcinoma. Intradermal (nodular) small cell melanomas require immunohistochemical studies for diagnosis and distinction from sarcoma or neuroendocrine carcinoma. A nodular melanoma with “melanoblastic” small round cell features may develop in a large congenital nevus and needs to be distinguished from proliferative nodules (see Chapters 3 and 21).
Undifferentiated Melanoma Undifferentiated melanoma refers to a tumor that is a melanoma but does not display differentiating features by light microscopy (e.g., melanin pigment, nested growth) or by immunohistochemistry.14 The tumor cells are negative not only for Melan-A, gp100, and tyrosinase
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A B
C D Fig. 20.2 Deep Penetrating Melanoma. (A) Silhouette of a melanoma with an exophytic superficial portion and a deep penetrating pigmented invasive tumor. (B) The tumor is composed of pigmented spindle and epithelioid melanocytes admixed with melanophages. (C) Focal lymphatic invasion is present in this case. (D) Sheet-like infiltration by pigmented melanoma cells in the superficial subcutis.
but also fail to label or only minimally label S100 protein or Sox 10. Clinical correlation and mutation analysis are essential for the correct diagnosis. Sometimes a subsequent metastasis may express S100 protein or Sox10. Usually undifferentiated melanoma is a metastatic tumor. For example, if a patient has a known prior melanoma and an undifferentiated malignant neoplasm is found in the regional node draining the site of the primary melanoma, detection of the same mutation profile in the primary and metastatic tumor can help to establish a diagnosis of metastatic melanoma. On rare occasion, a primary melanoma may also have an undifferentiated immunophenotype; the diagnosis then becomes apparent with a subsequent metastasis and mutation analysis.
Verrucous (Papillomatous Keratotic Variant of) Melanoma Verrucous melanoma is characterized by melanoma-associated verrucous epidermal hyperplasia (Fig. 20.9).15,16 Its main diagnostic pitfall is clinical: because of the verrucous silhouette, the lesion is often thought to be a wart or seborrheic keratosis and is treated accordingly. A small superficial shave biopsy with prominent papillomatous epidermal hyperplasia and
hyperkeratosis may not capture the melanocytic neoplasm and thus support the assumption of a wart, thereby delaying recognition of the correct diagnosis and treatment. It may also be challenging for the pathologist to diagnose the melanoma, if, for example, a small biopsy sample submitted to rule out a wart shows mainly wart-like epidermal features and only focally an atypical melanocytic proliferation. Verrucous melanoma is also relevant as a challenge for assessing Breslow thickness. Extensive papillomatous growth may make it difficult to precisely measure the thickness of a superficially invasive melanoma.
Melanoma Associated With Pseudoepitheliomatous Epidermal Hyperplasia Sometimes melanoma is associated with florid pseudoepitheliomatous epidermal hyperplasia with or without adjacent ulceration (Fig. 20.10). The presence of prominent epidermal changes may make the clinical recognition more difficult (e.g., the presence of a scale crust may lead to confusion with a keratosis or carcinoma), and lead to potential confusion with a collision scenario of squamous cell carcinoma and melanoma. Furthermore, a pathologist focusing on the epidermal changes may consider a squamous cell carcinoma and fail to recognize the
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A
A
B Fig. 20.3 Primary Dermal Melanoma. (A) Silhouette of an intradermal tumor nodule with superficial dermal fibrosis. There is no associated melanocytic nevus or in situ melanoma. (B) Melanoma cells display nuclear atypia and are associated with stromal fibrosis and inflammation.
melanoma if, for example, a superficial biopsy sample contains mainly the epithelial proliferation.
Melanoma With Pseudovascular Changes Just like melanocytic nevi, the tumor cells within an invasive melanoma may become discohesive and, with histopathologic processing, give rise to pseudovascular spaces, which may lead to confusion with angiosarcoma (Fig. 20.11). Immunohistochemical studies can readily determine the line of differentiation and distinguish melanoma from sarcoma.
Melanoma With Epithelial Features In some melanomas, the tumor cells may display features simulating a carcinoma by growing in cords or strands or by forming duct-like structures (Fig. 20.12). This may lead to diagnostic confusion with a myoepithelial carcinoma or adenocarcinoma. A panel of immunomarkers is usually necessary, since melanoma may on occasion show aberrant expression of cytokeratins (usually focal and weak) and myoepithelial carcinomas commonly express S100 and Sox10 (occasionally strong and diffuse). Therefore coexpression of melanocyte differentiation antigens (e.g., gp100, tyrosinase, Melan-A/MART1) is very helpful in supporting a diagnosis of melanoma. Melanoma may also display epithelial features by aberrantly expressing cytokeratins. However, this is usually seen in undifferentiated metastatic tumors and is rarely a problem with primary melanomas.
B Fig. 20.4 Folliculotropic Melanoma. (A) Melanoma cells prominently populating a hair follicle. They also involve adjacent epidermis. (B) Multiple follicles are involved by melanoma in situ. Isolated microinvasive tumor cells are seen in the perifollicular stroma.
Spindle Cell Melanoma Spindle cell melanoma refers to invasive melanomas in which the tumor is predominantly or exclusively composed of spindle cells. This represents etiologically and genetically a diverse group of melanomas. Spindle cell features may be seen in the invasive component of various melanomas (lentigo maligna, acral, superficial spreading, nodular). Pure solid spindle cell melanomas are mentioned here separately to emphasize their heterogeneous composition as well as the related differential diagnosis. Primary cutaneous spindle cell melanomas must be distinguished from miscellaneous sarcomas, in particular pleomorphic dermal sarcoma. Although many desmoplastic and/or neurotropic melanomas are composed of spindle cells, they are not synonymous with spindle cell melanoma. A spindle cell melanoma is desmoplastic only if a significant part of its invasive tumor cell population is associated with and dispersed in a dense fibrous stroma. Likewise a spindle cell melanoma is neurotropic
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Fig. 20.6 Melanoma with rhadomyosarcomatous differentiation.
A
A
B Fig. 20.5 Rhabdoid Melanoma. (A) Ulcerated large tumor nodule. (B) The tumor cells are epithelioid in appearance, with eccentric nuclei and intracytoplasmic hyaline inclusions.
B Fig. 20.7 Melanoma With Osteocartilaginous Differentiation. (A) Acral melanoma with area displaying osteosarcomatous features. (B) The melanoma also displayed focal chrondroid features. (Courtesy of Dr. A Lazar).
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A
A
B Fig. 20.8 Melanoma With Small Cell Features. (A) Subtle melanoma in situ involving squamous mucosa overlying an invasive tumor component that lacks melanin pigment and has minimal cytoplasm. (B) The tumor cells have a blue-cell appearance. Focal nuclear molding is seen. Mitoses and apoptotic bodies are present.
Fig. 20.10 Melanoma With Florid Epidermal Hyperplasia. (A) Ulcerated polypoid nodular melanoma with prominent pseudoepitheliomatous epidermal hyperplasia adjacent to the ulcer. At the right side of the B polyp the epidermal hyperplasia has seborrheic keratosis-like features. (B) Pseudoepitheliomatous epidermal hyperplasia overlying invasive spindle melanoma.
Fig. 20.9 Verrucous/Papillomatous Melanoma. Superficial spreading melanoma associated with papillomatous exophytic growth. Expanded dermis within papillomatous projections is filled with tumor cells. Fig. 20.11 Melanoma With Pseudovascular Changes. Tumor cells are separated forming pseudovascular spaces. Pseudovascular change may also occur in nevi.
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B
A
Fig. 20.12 Melanoma With Epithelial-like Features. (A) This ulcerated acral melanoma displays predominantly solid spindle cell features but also focal carcinoma-like features. The epithelial-like tumor cells in myxoid stroma were negative for cytokeratins but expressed Sox10 and Melan-A. (B) Juxtaposition of solid spindle cell melanoma and a subpopulation of tumor cells displaying epithelioid features forming cord-like structures in a myxoid stroma.
only when its tumor cells prominently surround and/or infiltrate nerves, especially at the periphery of the tumor away from the main tumor mass.
Polypoid Melanoma Any type of melanoma may display a polypoid silhouette (see Fig. 20.10). The main diagnostic pitfall related to a polypoid silhouette is clinical. If a tumor is amelanotic, it may be mistaken for a skin tag. The histopathologic diagnosis of a polypoid melanoma is usually not difficult, since many of these are advanced melanomas with high-risk features. However, precise assessment of Breslow thickness may sometimes be difficult with polypoid tumors.
COLLISION SCENARIOS A melanocytic proliferation—including a melanocytic nevus, primary melanoma, or metastatic melanoma—may on occasion collide with another neoplasm, including mesenchymal and epithelial lesions,17-24 and thereby provide a diagnostic challenge. Failure to recognize a collision scenario may lead to erroneous interpretation of a biphenotypic neoplasm and/or errors in tumor staging.
Melanoma Colliding With a Basal Cell Carcinoma Basal cell carcinoma may collide not only with a melanocytic nevus (Fig. 20.13) but also with a melanoma. The most common collision scenario of a melanoma and basal cell carcinoma is that of melanoma in situ and basal cell carcinoma. Intratumoral melanoma cells may be seen on H&E-stained sections or by immunohistochemistry. If the basal cell carcinoma nodule is connected to the epidermis, intratumoral melanoma cells are prognostically not equivalent to melanoma cells present in dermal stroma. We believe that intratumoral melanoma is best regarded as colonization of a basal cell carcinoma by melanoma in situ. However, primary invasive melanoma may also collide with a basal cell carcinoma (Fig. 20.14), but the diagnosis of invasive melanoma should be based on documentation of melanoma in the dermal stroma.
Fig. 20.13 Basal cell carcinoma colliding with a melanocytic nevus.
Lastly, metastatic melanoma may spread to the site of a basal cell carcinoma, be located adjacent to carcinoma, and colonize some of the tumor nodules (Fig. 20.15).
Melanoma Colliding With a Squamous Proliferation Melanoma in situ and/or invasive melanoma may also collide with a spectrum of squamous proliferations, including verruca, seborrheic keratosis, actinic keratosis, and squamous cell carcinoma. Melanoma may be located adjacent to or surround the squamous lesion. Often it grows into and colonizes the epithelial proliferation. When in situ melanoma collides with and populates the tumor area of an acanthoma, adnexal tumor with squamous features, or squamous cell carcinoma (Fig. 20.16) and extends within the invasive carcinoma deeper to the level of the adjacent nonneoplastic epidermis, this should not, for prognostic purposes, be equated with stromal invasion.
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A
Fig. 20.14 Primary Melanoma Colliding With a Basal Cell Carcinoma. A basal cell carcinoma found at the same site as a melanoma.
B A
C B Fig. 20.15 Metastatic Melanoma Colliding With a Basal Cell Carcinoma. (A) Shave biopsy of a collision of basal cell carcinoma (most of it is located on the right side of the biopsy) and melanoma (most of it is found on the left side). (B) Juxtaposition of melanoma and basal cell carcinoma. The latter is pigmented and associated with melanophages.
Fig. 20.16 Melanoma In Situ Colliding With a Squamous Cell Carcinoma. (A) Silhouette of the tumor. The first impression is that of a squamous cell carcinoma. However, there are pigmented nests in the superficial portion of the tumor. (B) The tumor is flanked by melanoma in situ characterized by a proliferation of predominantly solitary units of atypical melanocytes at the dermoepidermal junction (arrows). (C) Nests of pigmented melanocytes are seen within the lesion admixed with the squamous cell carcinoma.
CHAPTER 20 Uncommon Variants of Melanoma and Collision Scenarios
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