Primary Undifferentiated/Dedifferentiated Cutaneous Melanomas—A Review on Histological, Immunohistochemical, and Molecular Features with Emphasis on Prognosis and Treatment

Abstract

Diagnosing cutaneous melanoma is usually straightforward based on these malignancies’ histopathological and immunohistochemical features. Nevertheless, melanomas can imitate various other neoplasms, sometimes lacking the expression of conventional melanocytic markers and expressing non-melanocytic ones. Furthermore, divergent differentiation is more often encountered in metastatic melanomas and is still poorly described in primary cutaneous melanomas, and little is known about these patients’ prognosis and therapeutic approach. Therefore, we reviewed the literature on undifferentiated/dedifferentiated cutaneous melanomas, and we discuss the histological, immunohistochemical, and molecular profiles of undifferentiated/dedifferentiated cutaneous melanomas to understand these peculiar lesions better and improve their diagnostic algorithm. In addition to this, we also discuss how different genetic mutations may influence prognosis and become potential therapeutic targets.

Cutaneous Melanoma: A Review of Multifactorial Pathogenesis, Immunohistochemistry, and Emerging Biomarkers for Early Detection and Management

“…This lack of specificity can create diagnostic pitfalls by masking the presence of small metastatic melanoma foci amid other S100-expressing structures within lymph nodes [62,63]. Additionally, primary cutaneous, particularly dedifferentiated ones, and metastatic melanomas can, in rare cases, lack S100 expression [17]. In this context, Aisner D.L.…”

“…Genetic testing is particularly useful for the diagnosis of dedifferentiated CMs which lack typical morphological and immunohistochemical features. In such cases, the diagnosis can be established by identifying melanoma-specific mutations [17].…”

“…It is noteworthy that NRAS and BRAF mutations are generally considered to be mutually exclusive, although co-mutations have been observed in rare instances [37]. NRASand NRAS-BRAF-co-mutated melanomas have a less favorable prognosis than BRAF-mutated ones as there are no target therapies for NRAS mutations [17].…”

“…Analyzing NF1 mutation status has some prognostic value even though there are no target therapies for NF1-mutated melanomas, but such cases respond favorably to immunotherapy [42]. Moreover, NF1 analysis can offer important diagnostic information as this mutation is particularly common in dedifferentiated lesions which can be difficult to diagnose otherwise [17].…”

Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment

“…The melanoma markers MLANA (MART-1), TYR, HMB45 (PMEL), SOX10, S100, and the proliferation marker MIB-1, which recognizes the Ki67 antigen, are used to diagnose primary and metastatic melanoma. Using these markers, melanoma can be distinguished from other cancer types such as epithelial tumors, neuroendocrine tumors, sarcomas, lymphomas, and germ cell tumors [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. However, some degree of difficulty remains in distinguishing certain melanoma histotypes from other skin lesions [ 19 ].…”