Contributed by Umberto Maccio, M.D., M.Sc., M.B.A.

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• Adult / resting melanocytes (J Cutan Pathol 1989;16:49)
• Dermal component of benign nevi (Semin Diagn Pathol 2022;39:239)
• Desmoplastic melanoma (J Eur Acad Dermatol Venereol 2021;35:1290)
• Undifferentiated / dedifferentiated melanoma (Am J Surg Pathol 2016;40:181)
• Adrenal cortical carcinoma (Medicine (Baltimore) 2017;96:e8956)
• Atypical fibroxanthoma (only one case reported to be positive) (J Cutan Pathol 2011;38:954, Am J Dermatopathol 2021;43:e218)
• Granular cell tumor (Am J Dermatopathol 2007;29:22)
• Epithelioid sarcoma (Am J Surg Pathol 1997;21:130)
• Angiolipoma (World J Gastroenterol 2007;13:467)
• Clear cell renal cell carcinoma (Cancers (Basel) 2020;12:602)
• Low grade oncocytic tumor of the kidney (LOT) (Virchows Arch 2022;480:999)
• Subependymal giant cell astrocytoma (SEGA) (Mod Pathol 1997;10:313)
• Non-small cell lung cancer (NSCLC, positive in < 1% of cases) (Diagn Pathol 2018;13:68)
• Metaplastic breast carcinoma and ductal carcinoma, no special type (NST) with melanotic pattern (focal positive only in isolated cases) (Mod Pathol 1997;10:592, Am J Clin Pathol 1989;92:491)
• Mammary Paget disease (positive only in isolated cases) (J Am Acad Dermatol 2011;65:247)
• Malignant lymphoma (positive only in one isolated case) (Arch Pathol Lab Med 1991;115:826)
• Malignant peripheral nerve sheath tumor (other than melanotic) (Histopathology 2018;73:969)
• Alveolar soft part sarcoma (only one isolated case with focal positivity) (Am J Clin Pathol 1990;93:32, Am J Surg Pathol 2017;41:622)
• Epithelioid fibrous histiocytoma (Diagnostics (Basel) 2020;10:233)
• Myoepithelioma / myoepithelial carcinoma (Diagnostics (Basel) 2020;10:233)
• Cutaneous carcinomas (squamous cell, basal cell and Merkel cells) (Diagnostics (Basel) 2020;10:233)
• Pheochromocytoma (chief cells can be positive in 33% of cases) (Arch Pathol Lab Med 1992;116:151)
• Uterine leiomyosarcoma (can be focally positive in 36% of cases) (Am J Surg Pathol 2007;31:95)

Which statement about HMB45 is correct?

1. HMB45 can be used as marker alone to diagnose a melanoma in metastatic setting
2. HMB45 combined with other makers (e.g., S100) can be helpful in diagnosing melanoma
3. In nonneoplastic tissues, HMB45 expression is limited only to fetal or neonatal melanocytes
4. Melanocytic lesion with HMB45+ dermal component is always consistent with melanoma

B. HMB45 combined with other makers (e.g., S100) can be helpful in diagnosing melanoma. HMB45 is a relatively specific marker but should be combined with other markers for diagnosing a melanoma. Answer D is incorrect because other melanocytic lesions (e.g., blue nevi) can be positive for HMB45. Answer A is incorrect because HMB45 alone is neither sensitive nor specific for melanoma (i.e., melanomas can be negative for HMB45 and other tumors such as PEComas can be positive for HMB45). Answer C is incorrect because HMB45 can be also expressed in reactive melanocytes (e.g., in case of inflammatory skin disorders).

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Reference: HMB45

A renal tumor shows a mixed morphology with mature adipose tissue, epithelioid cells and thick walled vessels. Immunohistochemistry for HMB45 is shown in figure above. SMA is also positive, whereas AE1 / AE3, PAX8 and CAIX are negative (not shown). Which is the most likely diagnosis?

1. Adrenal cortical carcinoma
2. Angiomyolipoma
3. Clear cell renal cell carcinoma
4. Metastatic melanoma

B. Angiomyolipoma. The morphology is consistent with a tumor with 3 components without atypia, mitotic activity or necrosis, which in this anatomic location is suggestive of angiomyolipoma. Immunohistochemistry for HMB45 is positive, which combined with the immunohistochemical profile provided above is diagnostic for angiomyolipoma. Answer D is incorrect because the morphology described is not typical for melanoma and HMB45 alone is not specific for melanoma as it can be expressed in other tumors. Answer C is incorrect because although some renal cell carcinomas (e.g., TFE and TFEB rearranged renal cell carcinoma) can express HMB45, clear cell carcinomas are typically negative for HMB45 and express PAX8 and CAIX. Answer A is incorrect because adrenal cortical carcinomas are typically negative for HMB45, although they express MelanA.

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Reference: HMB45

Which of the following tumors is typically positive for HMB45?

1. Angiolipoma
2. Desmoplastic melanoma
3. Oncocytoma
4. TFE rearranged renal cell carcinoma

D. TFE rearranged renal cell carcinoma. Rearrangements of genes of the MiT family (MITF, TFE, TFEB) lead typically to overexpression of premelanosome protein gp100, resulting in positivity for HMB45. Answer B is incorrect because desmoplastic melanomas are most commonly negative for HMB45. Answer C is incorrect because HMB45 is typically negative in oncocytic tumors of the kidney. Answer A is incorrect because HMB45 is typically positive in angiomyolipoma but not in angiolipoma.

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Reference: HMB45