Cutaneous squamous cell carcinomas on special locations: perioral, periocular and genital area.

If tumours arise in special locations such as around the eyes, mouth or in the genital area, patients and physicians are challenged by the need for complete removal of the tumour with safety margins and high demands on function and aesthetic aspects. Treatment should be performed by specialized physicians including ophthalmologists, head and neck surgeons, surgical, medical and radiation oncologists. The first-line treatment for most cutaneous malignancies is surgical excision; however, in several situations, such as well-differentiated cutaneous squamous cell carcinomas (cSCC) in the periocular or anal region, radiotherapy is a very reasonable and sometimes treatment of first choice, especially in patients with advanced age. In periocular SCC, radiotherapy with superficial x-ray combined with eye shielding, while in anal SCC, radiotherapy combined with chemotherapy is recommended. However, after failure of local treatment options including surgery and radiotherapy, systemic medications are indicated in order to achieve tumour control or cure. Systemic therapies include immunotherapy, targeted therapy or chemotherapy. Preventive strategies are based on UV protection in facial, and vaccination in HPV associated anogenital SCCs.

Histiocytosis - cutaneous manifestations of hematopoietic neoplasm and non-neoplastic histiocytic proliferations.

Histiocytoses are rare disorders characterized by the accumulation of cells derived from macrophages, dendritic cells or monocytes in various tissues. There is a broad spectrum of disease manifestations with some subtypes commonly showing skin lesions, while in others, the skin is rarely involved. Here, we describe cutaneous manifestations of histiocytoses belonging to the Langerhans group (L group), the group of cutaneous and mucocutaneous histiocytoses (C group) and the group of Rosai-Dorfman disease (RDD) and related histiocytoses (R group) according to the current classification. Characteristic clinical presentations noted were a rust-brown colour or xanthomatous aspect in many cases of histiocytoses. Histological criteria for differentiation are described. Immunohistochemistry shows positivity for S100 and CD1a in Langerhans-cell histiocytoses (LHCH) of the L group, while CD68 positivity with S100 and CD1a negativity are typical in histiocytoses of the C group of cutaneous and mucocutaneous histiocytoses. RDD in the R group shows positivity for S100 and CD68, while CD1a is negative. We further review the pathogenesis of LHCH based on insights on the central role of the mitogen-activated protein (MAPK) kinase pathway. Common mutations in various histiocytic populations of diverse ontogeny and at different stages of differentiation may be responsible for the diverse clinical picture of this neoplastic entity. For histiocytoses of the C group and R group, a reactive origin is discussed with the exception of the disseminated form of juvenile xanthogranuloma. We suggest exploring the role of an origin from skin residing histiocytes for the isolated cutaneous manifestation in some types. With regard to therapeutic options, skin-directed therapies are the first choice in limited disease, while systemic chemotherapy has traditionally been used in extensive disease. In Langerhans-cell histiocytoses and related entities, therapy by BRAF inhibition has led to a breakthrough especially in patients with an activation of the MAPK pathway.

Developments in targeted therapy in melanoma.

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF- and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.