The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma

Ingrid Ferreira, Alastair Droop, Olivia Edwards, Kim Wong, Victoria Harle, Omar Habeeb, Deepa Gharpuray-Pandit, Joseph Houghton, Katharina Wiedemeyer, Thomas Mentzel, Steven Billings, Jennifer S Ko, Laszlo Füzesi, Kathleen Mulholland, Ivana Kuzmic Prusac, Bernadette Liegl-Atzwanger, Nicolas de Saint Aubain, Helen Caldwell, Laura Riva, Louise van der WeydenMark J Arends, Thomas Brenn, David J Adams

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42–86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4–80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months; range: 8–36 months), two died from their disease, and three developed metastases. Next-generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

Original languageEnglish
Pages (from-to)2009–2019
Number of pages11
JournalModern Pathology
Issue number11
Early online date21 Jun 2021
Publication statusPublished - Nov 2021
Externally publishedYes


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