title: Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy.
abstract: Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. Electronic address: wiesnert@me.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.affiliation: Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Dermatopathologie Friedrichshafen, Friedrichshafen, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Kutzner
authors.affiliation: Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cerroni
authors.affiliation: Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D023281:Genomics; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D018332:Nevus, Epithelioid and Spindle Cell / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009508:Nevus, Pigmented / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D010770:Phosphotransferases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011995:Recombination, Genetic; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D010770:Phosphotransferases; D043222:Ubiquitin Thiolesterase
keywords: BAP1; BRAF; Biomarkers; RAS; Spitz tumours; classification; diagnosis; genetics; genomics; melanocytic tumours; melanoma; molecular biology; pathology; precision oncology; spitzoid neoplasms; targeted therapy