Dedifferentiated melanomas: Morpho-phenotypic profile, genetic reprogramming and clinical implications

•Dedifferentiated melanomas pose diagnostic interpretative challenges.•Dedifferentiation underlies the phenotypic and genetic plasticity of melanoma.•Melanoma cells can shift through different transcriptional programs of differentiation.•Dedifferentiation is a mechanism of resistance to immunotherap...

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Veröffentlicht in:Cancer treatment reviews Jg. 88; S. 102060
Hauptverfasser: Massi, Daniela, Mihic-Probst, Daniela, Schadendorf, Dirk, Dummer, Reinhard, Mandalà, Mario
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier Ltd 01.08.2020
Schlagworte:
Animals
Cell Dedifferentiation - physiology
Cellular Reprogramming - physiology
Dedifferentiated
Epigenesis, Genetic
Humans
Immunotherapy
MAPK inhibitors
Melanoma
Melanoma - genetics
Melanoma - pathology
Melanoma - therapy
Melanoma, Cutaneous Malignant
Phenotype
Resistance
Skin Neoplasms - genetics
Skin Neoplasms - pathology
Skin Neoplasms - therapy
Resistance
MAPK inhibitors
Phenotype
Dedifferentiated
Immunotherapy
Melanoma
ISSN:0305-7372, 1532-1967, 1532-1967
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Zusammenfassung:•Dedifferentiated melanomas pose diagnostic interpretative challenges.•Dedifferentiation underlies the phenotypic and genetic plasticity of melanoma.•Melanoma cells can shift through different transcriptional programs of differentiation.•Dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy. Phenotypic plasticity of malignant melanoma is a well-known phenomenon. Several translational studies and small case series have reported this clinical and biological entity, particularly in metastatic melanoma, showing frequent aberrant expression of non-melanocytic differentiation markers of different lineages, posing remarkable challenges due to several alternative differential diagnoses including undifferentiated carcinoma and sarcomas. When melanoma loses its typical morpho-phenotype by routinely used diagnostic immunohistochemical markers, it is defined as “dedifferentiated melanoma”. Historically, this process was closely related to diagnostic interpretative difficulties. In recent years, however, dedifferentiation has been increasingly recognized as an important biological phenomenon that demonstrates the phenotypic and genetic plasticity of melanoma, and specifically the non-irreversibility of the multistep cancerogenesis. Furthermore, dedifferentiation emerged as a general hallmark of cancer evolution and a common denominator of cross-resistance to both targeted and immunotherapy. In this review, we summarize the histopathological features, the genetic and epigenetic bases underlying the dedifferentiated phenotype in melanomas and provide additional support that dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy.
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ISSN:0305-7372
1532-1967
1532-1967
DOI:10.1016/j.ctrv.2020.102060