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Michael T Tetzlaff,1 Carlos A Torres-Cabala,1,2 Penvadee Pattanaprichakul,1,3 Ronald P Rapini,2 Victor G Prieto,1,2 Jonathan L Curry1,21Department of Pathology, Section of Dermatopathology, 2Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Dermatology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, ThailandAbstract: Melanoma is a lethal skin disease with a mostly predictable clinical course according to a known constellation of clinical and pathologic features. The distinction of melanoma from benign melanocytic nevus is typically unequivocol; however, there is a subset of tumors known for its diagnostic challenges, development of late metastases, and difficulties in treatment. Several melanocytic tissue biomarkers are available that can facilitate the histopathologic interpretation of melanoma as well as provide insight into the biologic potential and mutational status of this disease. This review describes the clinical application of some of these established and emerging tissue biomarkers available to assess melanocytic differentiation, vascular invasion, mitotic capacity, and mutation status. The selected tissue biomarkers in this review include MiTF, Sox10, D2-40, PHH3, H3KT (anti-H3K79me3T80ph), anti-BRAFV600E, and anti-BAP-1.Keywords: immunohistochemistry, melanocytic differentiation, histone marks, BRAFV600E

Abstract: Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and clinical significance in patients with ALM. Thus, we assessed protein expression of BCL2, MCL1, BIM, and BRAF V600E by immunohistochemistry in 32 melanoma samples from White and Hispanic populations, including ALM and non-ALM (NALM). BCL2, MCL1, and BIM were expressed in both ALM and NALM tumors, and no significant differences in expression of any of these proteins were detected between the groups, in our relatively small cohort. There were no significant associations between protein expression and BRAF V600E status, overall survival, or ethnicity. In summary, ALM and NALM demonstrate frequent expressions of apoptosis-related proteins BCL2, MCL1, and BIM. Our findings suggest that patients with melanoma, including ALM, may be potential candidates for apoptosis-directed therapies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to Yap S127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P = .007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P = .016), deeper invasion (P < .001), and more frequently metastasized to lymph nodes (P < .001) and distant organs (P < .001). Patients with nuclear YAP melanomas had poorer disease-free survival (P < .001) and overall survival (P < .001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI, 1.032-9.961; P = .044). Proliferative ability was decreased in siYapB16F1 (P < .001) and siYapB16F10 (P = .001) cells and increased in Yap S127A B16F1 (P = .003) and Yap S127A B16F10 (P = .002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P < .001) and siYapB16F10 (P < .001) cells and S retention in Yap S127A B16F1 cells (P = .008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P = .001; siYapB16F10, P < .001), whereas nuclear YAP promoted it (Yap S127A B16F, P < .001; Yap S127A B16F1, P = .017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P = .003) and B16F10 (P < .001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P < .001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases., Competing Interests: Conflicts of Interest and Source of Funding: A.L.F. receives research funding from Seattle Genetics, is an inventor of technology for which Mayo Clinic holds an unlicensed patent, and has intellectual property licensed to Zeno Pharmaceuticals. A.A.G. is an investigator for StemLine Therapeutics, Innate Pharma, and Dren Bio. He is also consultant for Kyowa Kirin and BluePrints Medicine. For the remaining authors none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Background: Changes in immunophenotype in mycosis fungoides (MF) are rarely reported, making this phenomenon a diagnostic challenge with unclear significance for the disease's biological behavior. This study examines a large series of MF patients who exhibited a phenotype switch (PS) and analyzes their clinical and histopathologic characteristics., Design: Institutional files were searched for MF cases exhibiting PS between 2010 and 2020. Clinical, follow-up, and histopathological data were collected., Results: Forty-two biopsies from 32 patients (13 women and 19 men, median age 67.5) showed PS. Eight patients (25 %) experienced multiple PS during their disease course. The median time for PS was 22 months from the initial diagnosis. In 5 cases tested, identical TCR clone peaks were detected in the immunophenotypically distinct lesions. Median follow-up was 14.5 months. Among deceased patients, median time from MF diagnosis to PS was 20.6 months, while among the patients who were still alive, median time was 44.1 months., Conclusion: MF biopsies can show PS during the course of the disease and may indicate a change in clinical behavior. 28.1 % of patients displayed more than one PS, further indicating high plasticity of MF cells. No obvious association was found between PS and therapy initiation or response. Features that appeared to portend a worse clinical course were earlier PS in the course of the disease and PS from CD4-/CD8-to CD8 + , and CD8 + to CD4-/CD8-. Awareness of this phenomenon is crucial to avoid misdiagnosing phenotypically distinct lymphomas as second primaries and to alert clinicians about potential changes in the disease's clinical course., Competing Interests: Declaration of competing interest No relevant conflicts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Melanoma is the leading cause of death from cutaneous malignancy. While targeted therapy and immunotherapy with checkpoint inhibitors have significantly decreased the mortality rate of this disease, advanced melanoma remains a therapeutic challenge. Here, we confirmed that interferon-gamma (IFN-γ)-induced PD-L1 expression in melanoma cell lines. This increased expression was down-regulated by the reduction in phosphorylated STAT3 signaling via MET tyrosine kinase inhibitor treatment. Furthermore, immunoprecipitation and confocal immunofluorescence microscopy analysis reveals MET and PD-L1 protein-protein interaction and colocalization on the cell surface membrane of melanoma cells. Together, these findings demonstrate that the IFN-γ-induced PD-L1 expression in melanoma cells is negatively regulated by MET inhibition through the JAK/STAT3 signaling pathway and establish the colocalization and interaction between an RTK and a checkpoint protein in melanoma cells.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma 1 . We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate 2 . The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial 1 , provide further confirmation of the efficacy and safety of this new immunotherapy regimen., (© 2022. The Author(s).)

Background: Staging systems for cutaneous squamous cell carcinoma (cSCC) produce inconsistent risk stratification., Objective: The aim of this study was to identify further prognostic parameters for better stratification., Methods: We retrospectively analysed the prognostic significance of clinicopathologic parameters of 230 patients who underwent primary excision of invasive cSCC of the head and neck (n = 115) and non-head and non-neck (n = 115) locations. In addition to known high-risk features, we analysed tumour nest shape, invasion pattern, lymphoid response pattern and tumour budding., Results: On multivariable analysis, lymphovascular invasion (LVI) and high tumour budding predicted worse disease-specific survival, and ulceration, LVI and high tumour budding predicted worse overall survival. Only ulceration was independently associated with risk of nodal metastasis., Conclusion: High tumour budding, LVI and ulceration are independently associated with poor outcome in cSCC and may be used to refine cSCC prognostic stratification, which is crucial to optimize clinical decision and to identify patients who are more likely to benefit from more aggressive interventions or clinical trials., (© 2022 European Academy of Dermatology and Venereology.)

An infusion of checkpoint blockade immunotherapy (CBI) has revolutionized cancer treatments for some patients, but the majority of patients experience disappointing responses. Because adaptive immune responses are mounted by the concentrated assembly of antigens, immune cells, and mediators in the secluded and protective environment of draining lymph nodes (dLNs), we hypothesize that lymphatic delivery of CBI (αCTLA-4 and αPD-1) to tumor dLNs (tdLNs) improves anti-tumor responses over intravenous (i.v.) administration, and that vaccination against tumor associated antigen (TAA) further enhances these responses. Mono- and combination CBI were administered i.v. or through image-guided intradermal (i.d.) injection to reach tdLNs in vaccinated and unvaccinated animals bearing either primary or orthotopically metastasizing B16F10 melanoma. Vaccination and boost against TAA, Melan-A, was accomplished with virus-like particles (VLP) directed to tdLNs followed by VLP boost after CBI administration. Lymphatic delivery of CBIs reduced primary tumor size and metastatic tumor burden, alleviated the pro-tumorigenic immune environment, and improved survival over systemic administration of CBIs. Animals receiving CBIs lymphatically exhibited significantly enhanced survival over those receiving therapies administered partially or completely through systemic routes. By combining vaccination and CBI for effective T-cell priming in the protected environment of dLNs, anti-tumor responses may be improved.

Tumor heterogeneity is a relevant hallmark of melanoma due to the high mutation burden and immunogenicity commonly encountered. Heterogeneity at the histologic level frequently corresponds to heterogeneity at the molecular level. A better understanding of this feature of malignancy can help refine the development of predictive biomarkers and to define more effective targeted therapies. Here, we describe a case of melanoma displaying a dual phenotype: a DPN-like/plexiform portion in conjunction with a conventional epithelioid morphology. Molecular studies revealed shared BRAF and PTEN mutations in both components but a CTNNB1 mutation was exclusively found in the DPN-like area of the tumor, consistent with the distinct morphology observed. There was considerable heterogeneity in sequence variants identified in the two regions. Gene expression analysis highlighted differentially regulated genes between the two histologies, including a relevant cluster of genes in the receptor tyrosine kinase (RTK) family and related signaling pathways upregulated in the DPN-like/plexiform area., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Introduction: Balamuthia mandrillaris, a free-living amoeba, causes an uncommon infection that is characterized by cutaneous and neurological involvement, which carries a poor prognosis., Methods: This is a retrospective observational study including patients with clinical suspicion of cutaneous balamuthiasis, their skin biopsies, and/or a positive direct immunofluorescence test. The data were collected from the Dermatology and Pathology service of the Hospital Cayetano Heredia and the Instituto Tropical Alexander von Humboldt, Lima, Peru, from January 1985 to June 2007. We identified 60 biopsies from 35 patients, from which clinical data were available in 30., Results: Twenty-two (73%) patients had centrofacial lesions, mostly located on the nose. The classical lesion was an asymptomatic, erythematous, or violaceous infiltrated plaque. Twenty-two (73%) patients had neurologic involvement. Fifty (83%) biopsies showed granulomatous dermatitis and 75% showed ill-defined tuberculoid granulomas without caseous necrosis. Multinucleated giant cells were observed in 52 (87%) biopsies. Trophozoite forms were identified in the biopsies of 25 (71%) patients. Direct immunofluorescence was positive in 25 (71%) patients., Conclusion: B. mandrillaris is a pathogen that is capable of inducing a characteristic skin lesion with a reaction pattern of ill-defined tuberculoid granulomas and many giant cells., Competing Interests: None disclosed., (© 2021 Published by Elsevier Inc on behalf of the American Academy of Dermatology, Inc.)

Mucosal melanomas (MMs) are rare and aggressive tumors that arise from melanocytes in the mucosal tissues that line the respiratory, gastrointestinal, and urogenital tracts. Most MMs occur during the 6th and 7th decades of life. MMs may be asymptomatic but may also cause bleeding, pain, and itching, depending on the site of origin. Because of their asymptomatic or oligosymptomatic nature and the difficulty of visualizing them in some cases, they are often advanced tumors at patient presentation. MM staging varies depending on the site of the primary tumor. A simplified staging system allows classification of clinically localized disease as stage I, regional nodal involvement as stage II, and distant metastasis as stage III. MM differs genetically from its cutaneous counterparts. Common drivers in cutaneous melanoma such as B-raf proto-oncogene serine/threonine kinase ( BRAF ) have a lower mutation rate in MM, whereas mutations of other genes including the KIT proto-oncogene, receptor tyrosine kinase ( KIT ) and splicing factor 3b subunit 1 gene ( SF3B1 ) are more common in MM. Complete resection is the best curative option. However, surgical intervention with wide local excision and negative margins may be difficult to attain because of the local anatomy and the extent of disease. In addition, despite aggressive surgical resection, most patients develop local recurrence and metastatic disease. Recent advances in the treatment of melanoma include immunotherapy and targeted therapy. Unfortunately, MMs have a relatively poor prognosis, with an overall 5-year survival rate of 25%. Online supplemental material is available for this article. © RSNA, 2021.

Currently there is no highly specific and sensitive marker to identify breast cancer-the most common malignancy in women. Breast cancer can be categorized as estrogen receptor (ER)/progesterone receptor (PR)-positive luminal, human epidermal growth factor receptor 2 (HER2)-positive, or triple-negative breast cancer (TNBC) types based on the expression of ER, PR, and HER2. Although GATA3 is the most widely used tumor marker at present to determine the breast origin, which has been shown to be an excellent marker for ER-positive and low-grade breast cancer, but it does not work well for TNBC with sensitivity as low as <20% in metaplastic breast carcinoma. In the current study, through TCGA data mining we identified trichorhinophalangeal syndrome type 1 (TRPS1) as a specific gene for breast carcinoma across 31 solid tumor types. Moreover, high mRNA level of TRPS1 was found in all four subtypes of breast carcinoma including ER/PR-positive luminal A and B types, HER2-positive type, and basal-type/TNBC. We then analyzed TRPS1 expression in 479 cases of various types of breast cancer using immunochemistry staining, and found that TRPS1 and GATA3 had comparable positive expression in ER-positive (98% vs. 95%) and HER2-positive (87% vs. 88%) breast carcinomas. However, TRPS1 which was highly expressed in TNBC, was significantly higher than GATA3 expression in metaplastic (86% vs. 21%) and nonmetaplastic (86% vs. 51%) TNBC. In addition, TRPS1 expression was evaluated in 1234 cases of solid tumor from different organs. In contrast to the high expression of GATA3 in urothelial carcinoma, TRPS1 showed no or little expression in urothelial carcinomas or in other tumor types including lung adenocarcinoma, pancreatic adenocarcinoma, colon and gastric adenocarcinoma, renal cell carcinoma, melanoma, and ovarian carcinoma. These findings suggest that TRPS1 is a highly sensitive and specific marker for breast carcinoma and can be used as a great diagnostic tool, especially for TNBC.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

The dramatic recent advances in therapy of melanoma require a more personalized and precise diagnostic approach to aid in clinical decisions. Tissue-based biomarkers in pathology have diagnostic, prognostic and predictive relevance. Herein we review the most commonly used pathology-based biomarkers in melanoma. Most of these biomarkers are evaluated through immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) performed on formalin fixed paraffin embedded tissue (FFPE), and are widely available in clinical pathology laboratories. We describe the utility of MART1/Ki67, p16, PRAME, markers of lymphovascular invasion (D2-40, CD31, D2-40/MITF, CD31/SOX-10), BRAF V600E, NRAS, KIT, BAP1, ALK, NTRK, PD-L1, TERT, PTEN, iNOS, and MMR proteins (MLH1, MSH2, MSH6, PMS2) in the evaluation of melanoma specimens. Correct interpretation and awareness of the significance of these biomarkers is crucial for pathologists, dermatologists, and oncologists who take care of melanoma patients., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Cutaneous squamous cell carcinoma (cSCC) is the second most common cause of nonmelanoma skin cancers. Although it has a relatively low mortality rate, it may be locally destructive and potentially metastasize. Tumor thickness of the primary lesion is one important parameter associated with biologic behavior. Such measurement is currently performed in different ways depending on the anatomic location and subspecialty (eg, skin vs. head and neck vs. gynecologic pathology). Furthermore, the new The American Joint Committee on Cancer eighth edition has changed the previously recommended method of measurement of cSCC of head and neck from a modified Breslow thickness to measuring from the granular layer of adjacent, normal-appearing skin to the deepest invasive tumor cell. This study evaluated the clinical significance on patient outcome by measuring tumor thickness using 4 common, currently available methods (measurement from: A. uninvolved dermoepidermal junction; B. top of granular cell layer of the epidermis overlying the tumor, that is, similar to Breslow thickness; C. dermoepidermal junction with in situ cSCC; D. top of granular layer of uninvolved skin) in 85 specimens from nongenital areas of 78 patients with cSCC. Thirty-five percent of them were from the head and neck area. Measurements were performed in millimeters using the digital ruler of image analysis software (Olympus cellSens Standard) on whole-slide scanned images. Associations between recurrence-free survival (RFS) and each method were assessed. When thickness was considered as a continuous measure, there was no statistically significant association between any of the 4 measurement techniques and RFS. When using the currently recommended 6.0-mm cutoff, methods B and C were significantly associated with RFS. Similarly, when optimal cutoff values were selected, all 4 methods were significantly associated with RFS in univariable analysis. However, in a multivariable model that included the techniques and location of lesion, only method B, using the optimal cutoff value of 8.7 mm, was independently associated with RFS. In summary, in our series of cSCC, measurement of thickness using a Breslow method (method B) was significantly associated with RFS using the optimal cutoff and the currently recommended 6.0 mm in univariable analyses and the optimal cutoff in a multivariable assessment. Therefore, our data indicate that measurement of tumor thickness in a manner similar to Breslow thickness may be used to help predict recurrence in patients with cSCC.

Background: Cancer patients receiving antibodies abrogating immune checkpoint pathways may develop a diverse array of immune-related adverse events (irAEs), of which lichenoid dermatitis (LD) is the most common. The mechanism driving the emergence of these irAEs remain understudied, underscoring a critical need to determine the unique gene expression profiles and immune composition in LD-irAE., Methods: LD-irAE (n = 3) and benign lichenoid keratosis (BLK) control (n = 3) were profiled with NanoString nCounter PanCancer Immune Profiling Panel interrogating the mRNA levels of 770 genes. Immunohistochemical (IHC) studies (n = 14 samples) for CD14, CD16, T-Bet, Gata-3, and FoxP3 were further evaluated using Aperio digital image analysis., Results: The LD-irAE showed downregulation of 93 mRNA transcripts (P < 0.05) and upregulation of 74 mRNA transcripts (P < 0.04) including toll-like receptor (TLR) 2 and TLR4 (P < 0.05). CD14 + and CD16 + monocytes quantified by IHC (H-score) were higher in LD-irAE than in the BLK control (P < 0.05). The immune composition of LD-irAE exhibited higher numbers of T-Bet + (Th1) cells compared with Gata-3 + (Th2) cells (P = 0.016) and lower numbers of FoxP3 (T regulatory) cells (P = 0.008)., Conclusions: LD-irAE exhibited activation of CD14/TLR innate immune response with increased CD14 + and CD16 + monocytes compared with BLK control. CD14/TLR signaling may drive the development of LD-irAE., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Spitzoid neoplasms pose diagnostic difficulties because their morphology is not consistently predictive of their biological potential. Recent advances in the molecular characterization of these tumours provides a framework by which they can now begin to be categorized. In particular, spitzoid lesions with ALK rearrangement have been specifically associated with a characteristic plexiform growth pattern of intersecting fascicles of amelanotic spindled melanocytes. We report the case of an 87-year-old man with a 3-cm nodule on his mid-upper back comprised of an intradermal proliferation of fusiform amelanotic melanocytes arranged in intersecting fascicles with occasional peritumoral clefts. Immunohistochemical studies demonstrated diffuse, strong expression of SOX10 and S100 by the tumour cells and diffuse, weak-to-moderate cytoplasmic positivity for anaplastic lymphoma kinase (ALK), suggestive of ALK rearrangement. Fluorescence in situ hybridization revealed no ALK rearrangements but instead revealed at least three intact ALK signals in 36% of the tumour cells, confirming ALK copy number gain. To our knowledge, this is the first reported case of a plexiform spitzoid neoplasm exhibiting ALK copy number gain instead of ALK rearrangement. This case suggests that ALK copy number gain is a novel mechanism of ALK activation but with the same characteristic histopathological growth pattern seen among ALK-rearranged spitzoid neoplasms., (© 2018 British Association of Dermatologists.)

Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy. At the University of Texas MD Anderson Cancer Center, a total of 81 advanced melanoma patients were treated on the Ipilimumab Expanded Access Program from 2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor tissue. Associations between these biomarkers and progression-free survival (PFS) and OS were analyzed with univariate and multivariate Cox proportional-hazards models. There was a significant correlation between high CTLA-4 protein expression levels in tumor cells and risk of death (P=0.02) and decreased PFS (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes correlated with poor OS (P=0.023). In multivariate analysis, patients with high CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test, P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt expression in pretreatment tumor cells in melanoma patients were associated with poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in pretreatment tumor samples provides useful biomarkers that may enable improved patient selection for ipilimumab therapy. Prospective clinical studies are warranted to investigate the predictive value of these biomarkers.

Primary cutaneous γ/δ T-cell lymphoma (PCGDTCL) accounts for <1% of all primary cutaneous lymphomas. These rare diseases are believed to originate from γ/δ lymphocytes. Clinical presentation may vary, but its clinical behavior is regarded as aggressive and long-term survival is anecdotal. This study describes the case of a 60-year-old man with multiple, rapidly progressing skin plaques on his head, arms, torso, buttocks, and legs. The histopathological changes seen in the skin biopsy were extraordinarily subtle with mild epidermal hyperplasia and a very sparse lymphoid infiltrate involving epidermis and superficial dermis. Immunohistochemical studies revealed the atypical intraepidermal hyperchromatic cells to be mostly positive for CD3 and CD7 and negative for both CD4 and CD8. The intraepidermal atypical lymphocytes were positive for TCR gamma, and negative for betaF1 and CD56. The clinical, morphologic, and immunohistochemical findings supported the diagnosis of PCGDTCL. This case illustrates a case of epidermotropic variant of PCGDTCL that, albeit a bland histopathological presentation, was associated with an aggressive clinical behavior.

Background: Indeterminate dendritic cell tumor is an extremely rare neoplastic proliferation of dendritic cells that share immunophenotypic features of Langerhans cells and macrophages but lack Birbeck granules and Langerin expression., Methods: We report a 55-year-old female presenting with a leonine facies and generalized multiple confluent papules, nodules and plaques on neck, upper trunk, arms and thighs. Laboratory evaluations were performed including skin biopsies, peripheral blood flow cytometry and positron emission tomography-computed tomography., Results: The lesional skin biopsy showed a dense dermal and perifollicular infiltrate composed of histiocytoid cells with nuclear grooves lacking dendritic processes in a background of lymphocytes. Eosinophils were absent. The histiocytoid cells were CD68+CD1a+Langerin- and only focally S100+. Special stains including GMS, Gram and Fite were all negative for infectious organisms. Although an initial diagnosis suggesting Langerhans cell histiocytosis was proposed due to CD1a positivity, a diagnosis of indeterminate dendritic cell tumor was finally rendered based on the histopathological findings and the lack of expression of Langerin., Conclusion: This case illustrates the variegated clinical presentation of indeterminate cell tumor and the necessity of appropriate immunohistochemical workup for its diagnosis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Atypical fibroxanthoma (AFX) is a dermal mesenchymal neoplasm arising in sun-damaged skin, primarily of the head and neck region of older men. Conservative excision cures most. However, varying degrees of subcutaneous involvement can lead to a more aggressive course and rare metastases. Thus, AFX involving the subcutis are termed pleomorphic dermal sarcomas or other monikers by some to recognize the more threatening natural history. We reviewed cases of "metastatic AFX" from our institution and from the files of a consultative dermatopathology practice. Nine of 152 patients with AFX were identified at a single institution (2000-2011). Two additional patients were identified from the files of a consultative practice. Clinical, radiological, and pathological features were reviewed and cases with histologically verified metastases identified. Median age was 67 (range, 45-91) years, all male, and involving the head and neck region. Two cases had no documented involvement of the subcutis, and 2 cases had only superficial subcutis involvement. Median time to metastases was 13 (range, 8-49) months. Three patients developed solitary regional lymph node metastases while 8 had widespread metastases. Five patients developed local recurrence within 8 months, and all 5 developed widespread metastasis. With median follow-up of 26 (range, 10-145) months, 6 died of disease (median, 19 months; range, 10-35 months), 4 were alive and well, and 1 was alive with disease. AFX has very rare metastatic potential, even those without or with minimal subcutis involvement, and can lead to mortality. Most metastasis and local recurrence occurred within 1 year of presentation. Solitary regional metastases were associated with better outcomes than those with multiple distant metastases. Patients with repeated local recurrences portended more aggressive disease including development of distant metastases.

The management of melanoma has evolved owing 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 events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations 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.

Background: Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye., Case Presentation: A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma., Conclusion: Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma.