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Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term “primary cutaneous CD4+ small/medium T-cell lymphoma” was modified to “primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder” because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

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In the WHO classification, subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a distinct type of T-cell

Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected patients developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of the BAP1 gene. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histologic similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with neuroendocrine features. MCC pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. The two aetiologies share similar clinical, histopathological and prognostic characteristics. MCC presents with a solitary cutaneous or subcutaneous nodule, most frequently in sun-exposed areas. In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. Confirmation of diagnosis relies on analyses of histological features and immunological marker expression profiles of the lesion. At primary diagnosis, loco-regional metastases are already present in ~30% of patients. Excision of the tumour is the first-line therapy; if not feasible, radiotherapy can often effectively control the disease. Chemotherapy was the only alternative in advanced-stage or refractory MCC until several clinical trials demonstrated the efficacy of immune-checkpoint inhibitors.

Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas.

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.