Primary cutaneous CD8+ positive aggressive epidermotropic T- cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19 – 89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double positive or double negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or MF. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Adipophilin is a monoclonal antibody against a protein on the surface of intracellular lipid droplets, and it was recently shown to be expressed in sebocytes and sebaceous lesions. This study examines adipophilin expression in various sebaceous lesions and other cutaneous tumors with a clear cell histology that may mimic sebaceous differentiation. A total of 117 cutaneous clear cell lesions including 16 sebaceous adenomas, 25 sebaceous carcinomas, 8 basal cell carcinomas, 12 squamous cell carcinomas, 6 xanthomas, 10 xanthelasmas, 10 xanthogranulomas, 4 balloon cell nevi, 5 trichilemmomas, 8 clear cell hidradenomas, and 13 metastatic renal cell carcinomas were examined using immunohistochemistry for the expression of adipophilin. Of these 117 lesions, 42 (36%) were from the periocular region. Adipophilin was expressed in 16 of 16 (100%) sebaceous adenomas, 23 of 25 (92%) sebaceous carcinomas, 10 of 10 (100%) xanthelasmas, 9 of 10 (90%) xanthogranulomas, 6 of 6 (100%) xanthomas, and 9 of 13 (62.5%) metastatic renal cell carcinomas. The characteristic staining pattern differed between sebaceous and non-sebaceous tumors with the former showing a membranous vesicular pattern and the latter being more granular. Adipophilin expression was not seen in any of the other lesions with clear cell histology, basal cell carcinomas, or squamous cell carcinomas, including cases that had focal clear cell differentiation. Adipophilin can be valuable in an immunohistochemical panel when evaluating cutaneous lesions with clear cell histology as it identifies intracytoplasmic lipid vesicles in sebaceous and xanthomatous lesions. In periocular lesions, it is effective in helping to exclude basal cell carcinoma and squamous cell carcinoma when sebaceous carcinoma is under consideration. Adipophilin expression is not as useful for the differential diagnosis that includes metastatic renal cell carcinoma, a rare but important, diagnostic differential. The pattern of adipophilin reactivity is important to observe as membranous vesicular staining is suggestive of intracellular lipids whereas granular cytoplasmic reactivity is not. Modern Pathology (2010) 23, 567-573; doi:10.1038/modpathol.2010.1; published online 29 January 2010Keywords: adipophilin; sebaceous tumors; differential diagnosis Sebaceous carcinoma is a relatively uncommon tumor comprising 0.05% of all cutaneous malignancies, but is the second or third most common malignant eyelid tumor in most series accounting for 2-4% of periocular tumors. 1 Local recurrence complicates 6-29% of periocular sebaceous cell carcinomas. [2][3][4][5] Regional or distal metastases affect 14-25% of patients with an associated 5-year mortality ranging from 30 to 67% according to different reports. 2,4 Owing to its variable clinical appearance, sebaceous carcinoma mimics both benign processes, such as chalazions and blepharitis, and other malignant

The role of immunohistochemistry in the assessment of KIT status in melanomas, especially acral lentiginous/mucosal, is not well established. Although the reported prevalence of KIT mutations in acral lentiginous/ mucosal melanomas is relatively low, detection of mutations in KIT can have profound therapeutic implications. We evaluated the efficacy of immunohistochemistry to predict mutations in KIT. One hundred seventy-three tumors, comprising primary and metastatic melanomas (141 acral lentiginous/mucosal, 5 nodular, 4 lentigo maligna, 3 superficial spreading, 2 uveal, 1 melanoma of soft parts, 8 metastases from unclassified primaries, and 9 metastases from unknown primaries) were studied. Immunohistochemical expression of KIT using an anti-CD117 antibody and KIT mutational analysis by gene sequencing of exons 11, 13, and 17 were performed. Eighty-one percent of acral lentiginous/mucosal melanomas, primary and metastatic, showed KIT expression by at least 5% of the tumor cells. The overall frequency of activating KIT gene mutations in acral lentiginous/ mucosal melanomas was 15% (14 out of 91 cases), being the L576P mutation in exon 11 the most frequently detected (4 of 14 cases). Cases showing less than 10% positive tumor cells were negative for KIT mutations. Eighty-two percent (12 of 14) of cases positive for KIT mutation showed KIT expression in more than 50% of the cells. An association between immunohistochemical expression of KIT and mutation status was found (P= 0.007). Immunohistochemical expression of KIT in less than 10% of the cells of the invasive component of acral lentiginous/mucosal melanomas appears to be a strong negative predictor of KIT mutation and therefore can potentially be used to triage cases for additional KIT genotyping.

Monoclonal antibodies against the immune checkpoint programmed cell death receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed tremendous promise in the treatment of advanced solid tumors and hematologic malignancies. Reports of serious autoimmune dermatologic toxicities from immune checkpoint blockade therapy, however, are emerging. We report our experience with five patients who presented with pruritic vesicles and blisters on the skin while treated with anti-PD-1 antibody immunotherapy with either nivolumab or pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae with immunohistochemical study for type IV collagen labeling the floor of the blister cavity and direct immunofluorescence studies (in three of the four patients tested) decorated linear IgG and C3 immune deposits on the blister roof, diagnostic of bullous pemphigoid. One patient developed bullous erythema multiforme. All patients had partial or complete resolution of skin lesions following treatment with systemic corticosteroid and cessation of checkpoint blockade. Recognition and treatment of rare immune-related bullous dermatologic toxicities will become increasingly important as more patients are treated with effective and newer immune checkpoint blockade therapy.

The management of melanoma has evolved due to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent event in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600 mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma ( 30-40%). In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = −2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas.

Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm with variable clinical presentation. Although a distinct vascular tumour, cAS shares many overlapping histopathological features with other vasoformative and epithelioid tumours or 'mimickers'. cAS shows aggressive behaviour and carries a grave prognosis, thus early diagnosis is of paramount importance to achieve the best possible outcomes. Recently, several genetic studies were conducted leading to the identification of novel molecular targets in the treatment of cAS. Herein, we present a comprehensive review of cAS with discussion of its clinical, histopathological and molecular aspects, the differential diagnosis, as well as current therapies including ongoing clinical trials.

p63, a recently identified homologue of the p53 gene, has been reported to be essential in the development of epithelia and is mainly expressed by basal and myoepithelial cells. The purpose of this study was to investigate the pattern of p63 expression in cutaneous adnexal neoplasms and to assess its possible value in the differential diagnosis of primary cutaneous neoplasms vs adenocarcinomas metastatic to the skin. Immunohistochemical analysis for p63 was performed on formalin-fixed, paraffin-embedded archival tissue from 20 benign adnexal tumors, 10 malignant adnexal tumors and 14 adenocarcinomas metastatic to the skin. The expression of p63 was evaluated in epidermal cells, skin appendages and metastatic tumor cells. p63 was consistently expressed in the basal and suprabasal cells of epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands. Out of 20 benign adnexal tumors, 13 (65%) showed strong (score 3) p63 expression; the remaining seven (35%) cases had score 2. All primary cutaneous carcinomas, including adenocarcinomas, expressed p63. In contrast, none of the metastatic adenocarcinomas to the skin was positive for p63 (Po0.001). Based on our findings, analysis of p63 expression may help in the differential diagnosis of primary vs metastatic cutaneous adenocarcinomas.