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The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Acral lentiginous melanoma (ALM) is a rare tumor that occurs on non-sun exposed skin areas of the hands and feet. Reports suggest that ALM exhibits poor prognosis, although mechanisms driving this remain poorly understood. Alterations in TERT and the Wnt/β-catenin (Wnt) pathway have been suggested to correlate with prognosis of ALM. Thus, immunohistochemical expression of β-catenin and LEF1 along with TERT amplification by FISH was investigated in 34 primary ALMs, 20 metastatic ALMs, 10 primary non-ALMs, and 15 acral nevi. Foot/toe was the most common primary tumor location (85%) for ALM. TERT amplification was detected in 6 of 28 (21.4%) primary ALM, 2 of 8 (25%) primary non-ALM, and 8 of 18 (44.4%) metastatic ALM, the latter showing significantly higher frequency compared with primary melanomas (P = 0.043). Most metastatic ALMs positive for TERT amplification lacked BRAF V600E (87.5%). Cytoplasmic and nonnuclear expression of β-catenin was variably detected in all cases. Metastatic ALM revealed lower expression of β-catenin compared with primary ALM (P = 0.017). No differences in LEF1 expression were detected among the groups; however, acral nevi showed decreased labeling with dermal descent, in contrast to melanoma. No molecular-genetic alteration correlated with prognosis. TERT amplification by FISH is a frequent finding in primary ALM and appears to increase in metastatic tumors, suggesting a role in tumor progression to metastasis. Although TERT amplification has been reported to be infrequent in primary non-ALM, it showed comparable frequency with ALM in our series. Our immunohistochemical findings are not fully supportive of activation of either canonical or noncanonical Wnt cascades in ALM. TERT amplification by FISH and LEF1 immunohistochemistry may help in the differential diagnosis between primary ALM and acral nevus. TERT amplification appears to be a promising target for therapy in patients with metastatic ALM.

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma–specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus–negative subgroup. Combining SDom with CD3+ or CD8+ T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3+ or CD8+ T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3+ or CD8+ T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3+ or CD8+ had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.

Cutaneous melanoma causes most of the skin cancer deaths in the USA. Melanoma is the fifth most common cancer among men and the sixth most common cancer among women. The incidence of melanoma has risen sharply over the past three decades. In this review, which is informed by our extensive experience at a large cancer centre, we outline the key differences between the tumour, node and metastases staging criteria for cutaneous melanoma in the seventh and eighth editions of the AJCC Cancer Staging Manual. We also offer advice on how to assess the histophenotypic parameters that are relevant for staging, with a special focus on avoiding potential pitfalls, and how to report all the prognostically and therapeutically relevant histophenotypic parameters. Correct assessment and reporting of these clinically relevant histophenotypic parameters is of outmost importance for practising pathologists because these parameters help treating clinicians select the most appropriate personalised treatment for patients in this era of promising targeted and immunotherapies.

Basal cell carcinomas (BCCs) are epithelial tumors originating from basal layer of the epidermis or follicular infundibulum on sun-exposed skin of adult patients. BCCs in the pediatric population is rare and is almost exclusively seen in association with xeroderma pigmentosum or basal cell nevus syndrome (Gorlin-Goltz syndrome). BCCs can be classified into five principal clinical types: nodular/ulcerative, infiltrative, multifocal/superficial, pigmented and fibroepithelioma of Pinkus. These clinical types generally reflect their respective histopathologic growth patterns, although considerable overlap may occur, not only among the histologic variants, but also with other cutaneous basaloid neoplasms.

Small-molecule inhibitors (nibs) have revolutionized cancer therapy with the emergence of clinically efficacious treatment for advanced-stage malignancies. Fibroblast growth factor receptor (FGFR) inhibitors have shown therapeutic efficacy in malignancies with molecular-genetic alterations in the FGFR/fibroblast growth factor pathway. In a phase 1 clinical trial, erdafitinib, a pan FGFR inhibitor, was well tolerated with a manageable toxicity profile. Hyperphosphatemia was a frequent adverse event in patients treated with erdafitinib; however, no serious complications were observed with this therapy. Here, we report the development of calcinosis cutis dermatologic toxicity in a patient with hyperphosphatemia while treated with a novel selective FGFR inhibitor, INCB 54828-101. Awareness of this form of dermatologic toxicity from an FGFR inhibitor will be important for close monitoring of serum levels of phosphate, FGF23, vitamin D, and calcitriol, the management of adverse serum chemistry with chelators, and treatment decisions to either reduce dose or withhold FGFR inhibitor.

Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor (n = 5, 100%, intratumor: n = 2, 40%, intertumor: n = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions (n = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy.

Checkpoint inhibitors (CPIs) restore the function of effector immunocytes to target and destroy cancer cells. Immune-related adverse events (irAEs) are a consequence of immune reactivation, with unpredictable inflammatory response, loss of self-tolerance, and development of autoimmunity. Adverse events from CPIs that present as dermatologic toxicities have diverse clinical and histopathologic features. CPI-associated dermatologic toxicities may exhibit histopathologic features of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid-like reactions. Suprabasal acantholytic dermatologic toxicities associated with CPIs are particularly rare but represent an emerging histopathologic pattern and include lichenoid dermatitis with suprabasal acantholysis/vesicle formation to Grover disease (transient acantholytic dermatosis). Here, we report two patients who developed suprabasal acantholytic dermatologic toxicities during CPI therapy. One patient exhibited a CPI-associated autoimmune blistering disease with paraneoplastic pemphigus (PNP)-like features restricted to histopathology and immunofluorescence, while the other patient had Grover-like lesions. A review of the literature revealed a spectrum of suprabasal acantholytic dermatologic toxicities associated CPIs that may present as lichenoid dermatitis with acantholysis/vesicle formation, Grover-like eruptions, and lesions with PNP-like features restricted to histopathology and immunofluorescence. It is important for clinicians and pathologists to recognize the types of dermatologic toxicities associated with CPIs to direct appropriate therapeutic strategies.

Primary cutaneous Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy in which lymphovascular invasion (LVI) correlates with more aggressive phenotype. The prognostic significance of LVI detected by D2-40 immunohistochemistry (IHC) in MCC remains controversial. We aimed to determine how LVI detected by D2-40 IHC compares with LVI detected by hematoxylin and eosin (HE) staining in predicting MCC metastasis. Clinical and histopathologic features of MCCs diagnosed and treated in 2002 to 2015 were assembled and included 58 MCC tumors from 58 patients. HE-stained tissue sections and D2-40 IHC studies were reviewed. When LVI was present, the location (peritumoral or intratumoral) and the size of the largest invaded vessel were recorded. LVI findings by HE staining and D2-40 IHC were compared with each other and with histologic features and clinical outcomes. HE staining showed LVI in 37 of 58 cases; D2-40 IHC confirmed LVI in 30 of these cases but failed to confirm LVI in 7. D2-40 IHC also detected 14 cases of LVI not identified on HE staining. Histologically, D2-40-detected LVI was associated with infiltrative growth pattern and nonbrisk lymphoid infiltrate (P = .005 and P = .055, respectively). There was a statistically significant difference between the frequency of detection of peritumoral LVI by HE in comparison to D2-40 IHC (P = .0009). MCCs in which D2-40 IHC-detected both intratumoral and peritumoral LVI were typically larger than MCCs without (mean, 24.5 mm versus 17.3 mm; P = .03) and more frequently metastasized (87% versus 51%; P = .03). D2-40 IHC detection of both intratumoral and peritumoral LVI is associated with metastasis.

Background Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein, which regulates cell proliferation and facilitates intracellular transport of albumin bound particles including chemotherapeutic agents such as Nab-paclitaxel/ABI-007. Therefore the presence of SPARC may achieve higher intra-tumoral drug concentration with lower dosage and thus reduce systemic side-effects. Several trials of ABI-007, in melanoma, show promising clinical activity. Design Fifty-four cases of dermal based neoplasms were retrieved including 24 angiosarcomas (AS), 10 hemangiomas, 9 nodular melanomas, 4 Kaposi sarcomas (KS), 3 leiomyosarcomas (LMS), 3 atypical fibroxanthomas (AFX) and 1 spindle cell squamous cell carcinoma (SSCC). SPARC immunohistochemistry (IHC) was performed with a mouse monoclonal antibody. Results SPARC expression was detected in a majority of AS (17/24), melanomas (8/9), AFX (3/3), LMS (3/3) and KS (4/4) with some expression in hemangiomas (3/10), while being negative in SSCC (0/1); and was significantly associated with tumor group (p = 0.017). Although a significant difference in overall survival was observed between SPARC expression groups (positive vs. negative) for all patients, there was no significant difference noted among angiosarcoma patients. Conclusion We have confirmed the presence of SPARC expression in melanoma, KS, LMS and AS and also detected it for the first time in AFX. Since paclitaxel has shown some effectiveness in AS, melanoma and KS, ABI-007 could also be beneficial in these patients.

LL-37 is a naturally occurring 37-amino-acid peptide that is part of the innate immune system in human skin. Preclinical studies have showed that intra-tumoral injections of LL-37 stimulate the innate immune system by activation of plasmacytoid dendritic cells, which mediate tumor destruction. LL-37 intra-tumoral injections have been utilized in a phase 1 clinical trial for melanoma patients with cutaneous metastases. We report dermatologic toxicity in a 63-year-old woman with stage IIIC melanoma of the right calf and inguinal lymph nodes. She was previously treated with nivolumab and combination chemotherapy (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL-37 injections upon progression of both prior regimens. She received a total of 8 weekly LL-37 injections, with interval clinical shrinkage of injected lesions. However, approximately 45 days after initiation of this therapy, she presented with multiple verrucous papules and a vesiculo-bullous lesion on the trunk and extremities. Clinically, most of these lesions were thought to be either squamous cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total 12 skin biopsies showed similar histopathologic features, with a prominent lichenoid inflammatory infiltrate admixed with eosinophils and an overlying atypical squamous epithelial proliferation with verrucous and keratoacanthoma-like features and varying degrees of keratinocytic atypia. Interestingly, a majority of the lesions did not show spongiosis (11/12). All lesions resolved within 2 months of cessation of LL-37 injection therapy. This case highlights adverse dermatological manifestations of LL-37 therapy, similar to the consequences of other novel therapies.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed significant therapeutic benefit in patients with clinically advanced solid malignancies, including melanoma. However, immune-related adverse events (irAE) are common, and novel dermatologic toxicities continue to emerge as more patients are treated with immunotherapy. Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. This case expands the dermatologic toxicity profile of immune checkpoint blockade, as recognition of such toxicities is critical to optimal patient management.

Background Immune checkpoint therapy has dramatically changed the landscape of cancer therapy, providing an efficacious and durable therapeutic option for patients with advanced-stage disease. However, dermatologic toxicities are a well-recognized side effect in patients receiving this therapy. A spectrum of immune related adverse events (irAEs) involving the skin can occur and include immunobullous disorders, lichenoid dermatitis, and vitiligo. Granulomatous/sarcoid-like lesions are now being recognized with the current class of checkpoint inhibitors (CPIs) that involve the dermis, the subcutaneous tissue (panniculitis), and lymph nodes. Case presentation We report 3 patients who developed granulomatous/sarcoid-like lesions while being treated with immune checkpoint therapy for advanced-stage melanoma, and we provide a comprehensive review of the literature in which similar cases are described. To date, 26 patients (including the 3 from this report) have been described with a median age of 57 years who developed granulomatous/sarcoid-like lesions associated with CPIs (median onset 6 months), of which 77% of patients had melanoma as primary tumor. To manage this adverse side effect, therapy was withheld in 38% of patients and 44% of the patients were treated with systemic steroids and 8% patients with localized therapy (one patient with intralesional triamcinolone). 96% of patients demonstrated either resolution or improvement of granulomatous/sarcoid-like lesions associated with CPIs irrespective of medical intervention. Therapeutic response, stable disease, or remission of primary malignancy was observed in 71% of reported patients who developed granulomatous/sarcoid-like lesions associated with CPIs over a median follow-up of 11.5 months since initiation of treatment. Conclusions The development of granulomatous/sarcoid-like lesions associated with CPIs is a recognized manifestation with the current class of immune checkpoint therapy that may clinically and radiographically mimic disease recurrence. Awareness of this type of toxicity is important for appropriate management and possible measurement of therapeutic response in a subset of patients who manifest this type of immune-mediated reaction.

Mycosis fungoides with large-cell transformation is historically associated with a poor prognosis. Pediatric cases of mycosis fungoides with large-cell transformation are rare, with only three other cases reported in the literature. We present the first case of a child with almost complete remission of his mycosis fungoides with large-cell transformation shortly after administration of psoralen plus ultraviolet A, interferon-alfa, and localized radiation.

Digital pathology has become an integral part of pathology education in recent years, particularly during the COVID-19 pandemic, for its potential utility as a teaching tool that augments the traditional 1-to-1 sign-out experience. Herein, we evaluate the utility of whole slide imaging (WSI) in reducing diagnostic errors in pigmented cutaneous lesions by pathology fellows without subspecialty training in dermatopathology. Ten cases of 4 pigmented cutaneous lesions commonly encountered by general pathologists were selected. Corresponding whole slide images were distributed to our fellows, along with two sets of online surveys, each composed of 10 multiple-choice questions with 4 answers. Identical cases were used for both surveys to minimize variability in trainees' scores depending on the perceived level of difficulty, with the second set being distributed after random shuffling. Brief image-based teaching slides as self-assessment tool were provided to trainees between each survey. Pre- and post-self-assessment scores were analyzed. 61% (17/28) and 39% (11/28) of fellows completed the first and second surveys, respectively. The mean score in the first survey was 5.2/10. The mean score in the second survey following self-assessment increased to 7.2/10. 64% (7/11) of trainees showed an improvement in their scores, with 1 trainee improving his/her score by 8 points. No fellow scored less post-self-assessment than on the initial assessment. The difference in individual scores between two surveys was statistically significant (p = 0.003). Our study demonstrates the utility of WSI-based self-assessment learning as a source of improving diagnostic skills of pathology trainees in a short period of time.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.

Chronic myelomonocytic leukemia (CMML) is a hematopoietic stem cell neoplasm exhibiting both myelodysplastic and myeloproliferative features. Cutaneous involvement by CMML is critical to recognize as it typically is a harbinger of disease progression and an increased incidence of transformation to acute myeloid leukemia. Cutaneous lesions of CMML exhibit heterogeneous histopathologic features that can be challenging to recognize as CMML. We describe a 67-year-old man with a 3-year history of CMML who had been managed on single-agent azacitidine with stable disease before developing splenomegaly and acute onset skin lesions. Examination of these skin lesions revealed a dense infiltrate of histiocytic cells morphologically resembling Langerhans type cells (lacking frank histopathologic atypia), and with the immunophenotype of an indeterminate cell histiocytosis (S100+ CD1a+ and langerin-). Given the history of CMML, next-generation sequencing studies were performed on the skin biopsy. These revealed a KRAS (p.G12R) mutation identical to that seen in the CMML 3 years prior, establishing a clonal relationship between the 2 processes. This case expands the spectrum for and underscores the protean nature of cutaneous involvement by CMML and underscores the importance of heightened vigilance when evaluating skin lesions of CMML patients.

The histopathologic spectrum of Spitzoid neoplasms includes Spitz nevi, atypical Spitz tumors, and Spitzoid melanomas. Advances in molecular genetics have evolved to the point that Spitzoid lesions can now be reasonably classified according to their distinctive molecular-genetic alterations: Spitzoid lesions with (1) 11p amplification and/or HRAS mutations; (2) isolated loss of 6q23 by fluorescence in situ hybridization (FISH); (3) homozygous deletion of 9p21 by FISH; (4) BAP1 loss and BRAFV600 E mutation; (5) translocations involving any of a number of different oncogenic kinase drivers, including ROS1, ALK, NTRK1, NTRK3, MET, BRAF, and RET; and (6) TERT promoter mutations.

Purpose: Primary vulvar melanoma (PVM) is the second most common vulvar malignancy. Despite their distinct anatomic site and unique molecular–genetic alterations, PVMs are staged according to the American Joint Committee on Cancer (AJCC) guidelines for primary cutaneous melanomas (PCM). However, whether parameters derived for PCM also apply to PVM remain a critical yet largely unexplored clinical question. The objective of this study was to determine the parameters predictive of survival in PVM. Experimental Design: We retrospectively reviewed 100 patients with PVM and determined associations between clinical and histopathologic parameters and disease-specific survival (DSS) and overall survival (OS). Results: Univariate Cox regression analysis demonstrated older age (>56 years), greater tumor thickness, higher dermal mitotic rate, ulceration, lymphovascular invasion, perineural invasion, microscopic satellitosis, and absence of precursor nevus associated with decreased OS. Furthermore, age, midline, and/or multifocal involvement, greater tumor thickness, higher dermal mitotic rate, ulceration, lack of regression, lymphovascular invasion, perineural invasion, and microscopic satellitosis associated with decreased DSS. Multivariate analysis demonstrated tumor thickness, dermal mitotic rate, lymphovascular invasion, microscopic satellitosis, and absence of precursor nevus independently predicted shorter OS. Only tumor thickness and increased dermal mitotic rate (≥2/mm2) independently predicted reduced DSS. In comparison with the AJCC T-category, a novel, bivariate T-category based only on tumor thickness and dermal mitotic rate robustly predicted OS and DSS in our patient cohort. Conclusions: In the largest single institutional study of PVM, we demonstrate a combination of tumor thickness and mitotic rate comprise a simple but robust T-category to direct staging and prognosis. Clin Cancer Res; 23(8); 2093–104. ©2016 AACR.

Immunotherapy targeting the programmed cell death 1 (PD-1) receptor has demonstrated tremendous promise in the treatment of advanced solid tumors. Dermatologic toxicities, however, are an emerging consequence of this therapy and have been clearly associated with immune checkpoint blockade antibodies. Distinctive clinical and histologic subtypes of dermatologic toxicity secondary to immunotherapy are emerging and include rare autoimmune bullous reactions (eg, bullous pemphigoid) and lichenoid eruptions. We report three patients who developed lichenoid dermatitis while receiving anti-PD-1 antibody therapy. The mean time to onset of lichenoid dermatologic toxicity was 42 days (range: 1-75 days) from initiation of anti-PD-1 antibody therapy. Lesions most frequently presented on the extremities and trunk as pustules, papules, and plaques. The face was not commonly involved. Of the five skin biopsies examined, all demonstrated dense band-like lymphocytic infiltrate, hyperkeratosis, hypergranulosis, saw-tooth rete ridge pattern, and dyskeratosis. Acanthosis was a feature in all of the skin biopsies, and in one, epidermal hyperplasia was prominent. In several skin biopsies, histologic features supporting a lichenoid drug eruption were present, including parakeratosis, spongiosis, periadnexal/perivascular inflammation, and eosinophils. Furthermore, the histologic features varied in skin biopsy specimens taken from the same patient at different sites, supporting a drug reaction. All patients' skin lesions improved with use of steroids: two were treated with topical steroids and one with systemic steroids. Recognition of the histopathologic patterns of dermatologic toxicities resulting from immune checkpoint blockade therapy will become increasingly important for ensuring appropriate management of dermatologic toxicities and optimal patient care.

Capsular nevi (CN) are clusters of benign melanocytes situated in the capsule of lymph nodes and occur in up to 20% of lympadenectomy specimens. The molecular profile of CN in relation to prognostic parameters in patients with primary cutaneous melanoma (PCM) has not been previously investigated. We assessed BRAF V600E mutation by immunohistochemistry (IHC) in the CN of sentinel lymph nodes (SLN) in PCM patients and correlated the findings with demographic characteristics, PCM histopathologic and molecular features, and clinical outcome parameters. Seventy-eight cases of CN involving SLN of PCM patients were evaluated for BRAF V600E mutation by IHC. The results were correlated with patient demographics, PCM histopathologic and molecular features, and outcome measures. Thirty-six (46%) of 78 CN cases expressed BRAF V600E mutation by IHC. Nineteen (53%) of those BRAF-positive CN cases were from patients with at least American Joint Committee on Cancer stage II melanoma, whereas 62% of BRAF-negative CN cases (26/42) were from patients with stage I melanoma (P = .013). Twelve (33%) of the 36 BRAF-positive CN cases had metastatic melanoma involving lymph nodes, compared with 14% (6/42) of BRAF-negative CN cases (P = .061). CN mutation status was not associated with patient demographics, histopathologic or molecular features of the PCM, or survival outcomes. A high percentage of CN identified in the SLN of patients with PCM harbor BRAF V600E mutation. Positive mutation was associated with adverse clinicopathological parameters, specifically increased tumor stage and lymph node metastasis. These findings suggest that BRAF V600E mutation in CN of SLN may be useful as an adverse predictive biomarker in patients with melanoma.

Melanoma remains one of the most aggressive forms of cutaneous malignancies. While its diagnosis based on histologic parameters is usually straight forward in most cases, distinguishing a melanoma from a melanocytic nevus can be challenging in some instances, especially when there are overlapping clinical and histopathologic features. Occasionally, melanomas can histologically mimic other tumors and even demonstration of melanocytic origin can be challenging. Thus, several ancillary tests may be employed to arrive at the correct diagnosis. The objective of this review is to summarize these tests, including the well-established and commonly used ones such as immunohistochemistry, with specific emphasis on emerging techniques such as comparative genomic hybridization, fluorescence in situ hybridization and imaging mass spectrometry.

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care

Coccidioidomycosis is the major systemic mycoses, considered to be 1 of the most infectious fungal diseases. In symptomatic patients, the most common manifestation is pulmonary disease, but many other organs can be affected. Disseminated disease occurs in 1%-5% of all patients affected by coccidioidomycosis and can affect any organ, with the skin, central nervous system, and musculoskeletal system being reported as the most prevalent. Here, we report a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats. He was treated with various antibiotics for possible upper respiratory tract infection without symptomatic improvement. Computed tomography of the chest revealed numerous subcentimeter noncalcified pulmonary nodules scattered throughout both lungs with extensive mediastinal and bilateral hilar lymphadenopathy. The patient was referred to our hospital for further evaluation of suspected metastatic lung disease. Physical examination revealed an erythematous 1.2 cm nodule on his left medial eyebrow. Skin biopsy of the lesion revealed prominent squamous epithelial hyperplasia with basal keratinocytic atypia and associated mixed inflammatory infiltrate and scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells. Special stain Periodic acid-Schiff tissue culture studies confirmed these to be Coccidioides immitis. After appropriate treatment with antifungal therapy for 5.5 months, his symptoms have improved with complete disappearance of lung nodules and a partially cavitated (1.1 × 1.1 cm) lesion in the left upper lung confirmed by follow-up chest computed tomography. With this report, the authors highlight disseminated coccidioidomycosis, a great mimicker of metastatic lung disease, which was diagnosed by skin biopsy, to ensure its prompt recognition and appropriate antifungal therapy.

Background Chimeric antigen receptor T-cell (CART) therapy can significantly improve outcomes for patients with certain hematologic malignancies. The most notable drawbacks of CART are cytokine release syndrome and CART-related encephalopathy syndrome. Gastrointestinal adverse events (GI-AEs) have not yet been reported in association with CART. Herein, we describe the incidence and clinical features of GI-AEs observed after CART. Materials and methods We report a case series of patients with hematologic malignancies who received CART, in a clinical trial or as the standard of care, and subsequently suffered from GI-AEs between 2012 and 2018. Results In our cohort, 37 of 132 (28%) patients experienced GI-AEs. All 37 experienced diarrhea with a median onset of 7 days (interquartile range, 4 to 25 d) after CART infusion. The median age of these patients was 58 years. Most had diffuse large B-cell lymphoma (51%). Seventeen patients experienced cytokine release syndrome, and 9 experienced CART-related encephalopathy syndrome. The interleukin-6 antagonist was required in 15 patients. Overall, 49% of patients had grade 1 diarrhea, 32% had grade 2, and 15% had grade 3. Other gastrointestinal symptoms in these patients were abdominal pain (41%), nausea and vomiting (49%), fever (8%), bloody stools (3%), and abdominal distension (5%). The median duration of symptoms was 6 days (interquartile range, 3 to 9 d). In 32 patients who underwent imaging, 8 (25%) had findings suggestive of gastrointestinal tract inflammation. Nine (24%) patients experienced GI-AE recurrence after initial improvement. The symptoms were attributed to an alternative cause in 17 (13%) cases and to CART in 20 (15%) cases. One patient developed CART-related refractory colitis that eventually responded to antibiotics for pneumonia. Conclusion CART-related GI-AEs occur in 15% of patients treated with CART. These symptoms are typically mild and self-limiting, requiring only symptomatic treatment. Nevertheless, CART may, in rare cases, lead to refractory colitis.

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.

Most of metastatic tumors to the skin are from primary tumors of the breast, lung, or from melanoma; metastases to the skin from primary carcinomas at other sites are rare. Cutaneous metastases of visceral carcinomas most often occur in patients with advanced disease, and are associated with a poor prognosis. We report 6 cases of nonmammary, nonpulmonary carcinoma metastatic to the skin. Most patients were elderly with advanced disease at the time of diagnosis of skin metastasis. The primary tumor sites included the thyroid, esophagus, biliary tract, ovary, and prostate. Awareness of these rare cases of metastasis to the skin will help pathologists and clinicians make the correct diagnosis.

Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KIT gene (24%) were most common followed by NRAS (19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.

Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21, 14%) and the tumor-associated immune infiltrate (15/21, 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2, range, 543&ndash, 2115, ) than in those who died (median, 611 cells/mm2, range, 481&ndash, 908, p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

Cutaneous immune-related adverse events (irAEs) are a known consequence of immune checkpoint inhibitor (ICI) therapy and may exhibit a spectrum of morphologic features both clinically and histologically. Lichenoid dermatitis associated with ICI therapy (LD-ICI) is the most frequently encountered histopathologic type of irAE biopsied by dermatologists. There is frequent clinical and histologic overlap between irAEs and several reactive and neoplastic dermatologic disorders; thus, clinical information is essential. LD-ICI with histologic, immunohistochemical, and molecular features typical of mycosis fungoides (MF) are unique. Here, we report a patient who developed LD-ICI with MF-like morphologic features with monoclonal T-cell receptor gene rearrangement on consecutive biopsies during ICI therapy. The development of monoclonal LD-ICI is important for clinicians and pathologists to recognize in patients receiving ICI therapy.

Purpose: In patients with cutaneous melanoma, metastasis in a nonsentinel lymph node (non-SLN) is a strong independent adverse prognostic factor. However, patients with a tumor-involved SLN no longer routinely undergo completion lymph node dissection (CLND). We hypothesized that SLN tumor burden may predict non-SLN tumor burden. Experimental Design: We compared tumor burden parameters between SLN and non-SLN in patients with cutaneous melanoma who underwent SLN biopsy with a positive SLN during 2003 to 2008 at The University of Texas MD Anderson Cancer Center. Results: We identified 336 eligible patients with a positive SLN. Of these, 308 (92%) underwent CLND, and 35 (10%) had non-SLN metastasis. The median follow-up time was 6.0 years. For patients with maximum diameter of tumor in the SLN ≤2.0 mm, >2.0–5.0 mm, and >5.0 mm, non-SLN metastasis was detected in 5 of 200 patients (3%), 10 of 63 patients (16%), and 20 of 57 patients (35%), and the mean maximum diameters of the non-SLN tumor deposits were 0.09, 1.56, and 2.71 mm, respectively (P < 0.0001). The percentage of patients with both subcapsular and intraparenchymal non-SLN tumor was higher for patients with SLN tumor in both locations than for patients with SLN tumor in only one location (P < 0.0001). Extranodal extension in a non-SLN was more common in patients with extranodal extension in an SLN (P = 0.003). Conclusions: In patients with cutaneous melanoma who undergo CLND, SLN tumor burden predicts non-SLN tumor burden. SLN tumor burden parameters provide accurate prognostic stratification independent of non-SLN status and should be considered for incorporation into future staging systems and integrated risk models.

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.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.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). CD14LD-irAE exhibited activation of CD14/TLR innate immune response with increased CD14

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted-, and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium-caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large-caliber deep dermal blood vessel in an en-face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra-operative frozen section evaluation, leading to false-negative margins and is therefore, a diagnostic pitfall.

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by strong and uniform expression of CD30. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate has been approved by the U.S. FDA for relapsed/refractory systemic ALCL and achieves improved outcomes. We report a 44-year-old African-American man who presented with lymphadenopathy, lip and chest nodules diagnosed as CD30+, ALK-negative ALCL. The patient was treated with BV upon recurrence. While on treatment, the patient developed new-onset nodules on the chest and back. Skin biopsy showed a diffuse dermal infiltrate of medium-to-large atypical lymphocytes with frequent mitosis and scattered eosinophils. Immunohistochemically, the atypical cells displayed the same immunophenotype as previous specimens (CD3+, CD4-/CD8-, CD56-, ALK- and TCR γ-), except for lack of CD30 expression which was attributed to BV treatment effect. The diagnosis was thought to be consistent with ALK-negative ALCL and the patient was continued on BV along with total skin electron beam radiation and the lesions cleared. The patient relapsed 2 months later with extensive disease and expired. In summary, this is the first report in the literature of loss of CD30 expression in ALCL after BV therapy. Awareness of this may prevent a mistaken diagnosis of a CD30-negative secondary T-cell lymphoma.

Disseminated histoplasmosis most commonly occurs in immunosuppressed individuals and involves the skin in approximately 6% of patients. Cutaneous histoplasmosis with an intraepithelial-predominant distribution has not been described. A 47-year-old man was admitted to our institution with fever and vancomycin-resistant enterococcal bacteremia. He had been diagnosed with T-cell prolymphocytic leukemia 4 years earlier and had undergone matched-unrelated-donor stem cell transplant 2 years earlier; on admission, he had relapsed disease. His medical history was significant for disseminated histoplasmosis 6 months before admission, controlled with multiple antifungal regimens. During this final hospitalization, the patient developed multiple 2-5 mm erythematous papules, a hemorrhagic crust across the chest, shoulders, forearms, dorsal aspect of the fingers, abdomen and thighs. Skin biopsy revealed clusters of oval yeast forms mostly confined to the cytoplasm of keratinocytes and within the stratum corneum; scattered organisms were present in the underlying superficial dermis without any significant associated inflammatory infiltrate. Special stains and immunohistochemical studies confirmed these to be Histoplasma organisms. We highlight this previously unrecognized pattern of cutaneous histoplasmosis to ensure its prompt recognition and appropriate antifungal therapy.

Sebaceous carcinoma (SC) is a rare but aggressive malignancy with frequent recurrence and metastases. Surgery is the mainstay of therapy, but effective systemic therapies are lacking because the molecular alterations driving SC remain poorly understood. To identify these, we performed whole-exome next-generation sequencing of 409 cancer-associated genes on 27 SCs (18 primary/locally recurrent ocular, 5 paired metastatic ocular, and 4 primary extraocular) from 20 patients. In ocular SC, we identified 139 non-synonymous somatic mutations (median/lesion 3; range 0-23). Twenty-five of 139 mutations (18%) occurred in potentially clinically actionable genes in 6 of 16 patients. The most common mutations were mutations in TP53 (n = 9), RB1 (n = 6), PIK3CA (n = 2), PTEN (n = 2), ERBB2 (n = 2), and NF1 (n = 2). TP53 and RB1 mutations were restricted to ocular SC and correlated with aberrant TP53 and RB protein expression. Systematic pathway analyses demonstrated convergence of these mutations to activation of the PI3K signalling cascade, and PI3K pathway activation was confirmed in tumours with PTEN and/or PIK3CA mutations. Considerable inter-tumoural heterogeneity was observed between paired primary and metastatic ocular SCs. In primary extraocular SC, we identified 77 non-synonymous somatic mutations (median/lesion 22.5; range 3-29). This overall higher mutational load was attributed to a microsatellite instability phenotype in three of four patients and somatically acquired mutations in mismatch repair genes in two of four patients. Eighteen of 77 mutations (23%) were in potentially clinically actionable genes in three of four patients, including BTK, FGFR2, PDGFRB, HRAS, and NF1 mutations. Identification of potentially clinically actionable mutations in 9 of 20 SC patients (45%) underscores the importance of next-generation sequencing to expand the spectrum of genotype-matched targeted therapies. Frequent activation of PI3K signalling pathways provides a strong rationale for application of mTOR inhibitors in the management of this disease. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas, and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.

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.

Although sequencing provides the gold standard for identifying colorectal carcinoma with BRAF V600E mutation, immunohistochemistry (IHC) with the recently developed mouse monoclonal antibody VE1 for BRAF V600E protein has shown promise as a more widely available and rapid method. However, we identified anecdotal discordance between VE1 IHC and sequencing results and therefore analyzed VE1 staining by two different IHC methods (Leica Bond and Ventana BenchMark) in whole tissue sections from 480 colorectal carcinomas (323 BRAF wild-type, 142 BRAF V600E mutation, and 15 BRAF non-V600E mutation). We also compared the results with melanomas and papillary thyroid carcinomas (PTC). With the Bond method, among 142 BRAF V600E-mutated colorectal carcinomas, 77 (54%) had diffuse VE1 staining and 48 (33%) had heterogeneous staining, but 17 (12%) were negative. Among 323 BRAF wild-type colorectal carcinomas, 196 (61%) were negative, but 127 (39%) had staining, including 7 with diffuse staining. When positivity was defined as staining in ≥20% of tumor cells, VE1 IHC had sensitivity of 75% and specificity of 93% for BRAF V600E mutation. With the Ventana method, among 57 BRAF V600E-mutated colorectal carcinomas, 36 (63%) had diffuse VE1 staining, whereas 6 (11%) had no or weak (

Melanoma is the most common tumor to metastasize to the gastrointestinal tract, commonly affecting the small intestine, colon, and anorectum. Primary mucosal melanoma can arise in any gastrointestinal site, most frequently affecting anorectal mucosa. Melanoma involving the gastric mucosa, specifically, is exceedingly rare and carries a poor prognosis with a median survival of 5 months. The presence of atypical melanocytes exclusively within gastric epithelium has not been previously described. We report a case of a 52-year-old man with widespread BRAFV600E mutant metastatic melanoma who was referred to our institution for immune checkpoint antibody-blockade therapy. The patient had previously been treated with BRAF inhibitors, and despite initial response to therapy, developed resistance leading to disease progression and multiorgan involvement including the liver, spleen, and axial skeleton. Immune checkpoint antibody blockade with ipilimumab and pembrolizumab has been shown to induce significant tumor regression in patients with melanoma by upregulating T-cell activity and removing the natural check on the host immune response. After his first dose of combination therapy, the patient underwent an upper gastrointestinal tract endoscopy for severe nausea and was found to have 2 pigmented lesions within the gastric body, one of which was biopsied. The biopsy showed gastric body-fundic type mucosa with melanophages and scattered atypical intraepithelial melanocytes within the lamina propria, which were strongly positive for S100, HMB45, SOX10, and MITF. A Fontana-Masson silver stain was performed for confirmation. The finding of predominantly atypical intraepithelial melanocytes associated with melanin pigment was interpreted as metastatic melanoma to the stomach with some regression in response to immune checkpoint blockade therapy.

Background: Anorectal melanoma (AM) is generally staged using criteria developed and validated for cutaneous melanoma (CM), primarily due to its rarity and the lack of a specific staging system, despite limited evidence to support this. In an attempt to risk-stratify AM patients (pts), we analyzed the performance of the AJCC 8th edition CM staging system and a system recently developed for vulvar melanoma (VM) in a retrospective cohort. Methods: Demographics, clinicopathologic factors, and follow-up information were collected for 160 AM pts treated at our institution. The pts were grouped based on their clinical stage at presentation (localized to anorectum [L], regional metastases [R], distant metastases [D]). For further risk stratification, L pts were grouped according to the following systems: (i) AJCC 8th edition CM T-categories (T1a to T4b, 8 tiers); (ii) AJCC 8th edition CM stage (I vs. II, 2 tiers); (iii) the tumor thickness (TT) system (thin [T1], intermediate [T2-T3], thick [T4], 3 tiers); and TM system previously derived for VM (T1: TT≤ 2.0mm and mitotic rate (MR) 2.0mm and MR Results: The cohort (n=160) included 67 L, 55 R and 38 D pts. With median follow-up of 1.63 years (y), the median DSS was 1.75y for all pts. DSS progressively decreased according to stage at presentation (L: 2.39y; R: 1.81y and D: 1.25y). By UV analysis, clinical stage at presentation correlated with DSS (R: p=0.05, HR=1.52; D: p Conclusion: Clinical stage at presentation and T-categorization of L pts based on modifications of the 8th edition AJCC CM staging criteria (stage and TT system) appear to be potentially informative tools to stratify risk in AM pts. Citation Format: Priyadharsini Nagarajan, JIn Piao, Jing Ning, Laura E. Noordenbos, Jonathan L. Curry, Carlos A. Torres-Cabala, A. Hafeez Diwan, Phyu P. Aung, Doina Ivan, Merrick I. Ross, Richard E. Royal, Jennifer A. Wargo, Wei-Lien Wang, Rashmi Samdani, Alexander J. Lazar, Asif Rashid, Michael A. Davies, Victor G. Prieto, Jeffrey E. Gershenwald, Michael T. Tetzlaff. Prognostic model for disease-specific survival in anorectal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A11.

Dermatologic toxicities are the most common immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI). First-line treatment for grade 3 or 4 skin irAEs is high-dose corticosteroids, which have their own side effects. Prolonged treatment with corticosteroids may abrogate antitumor ICI activity. The cellular causes of these dermatologic toxicities, which can manifest as a variety of clinical presentations, remain unclear. Beyond steroids, recommended treatment options are limited. We report a case of psoriasiform dermatologic toxicity, induced by inhibition of PD-1 with the mAb pembrolizumab, which resolved after treatment with systemic interleukin IL17A blockade. Introduction of IL17A blockade did not alter the patient's melanoma response to pembrolizumab. This case suggests a possible pathogenic role of Th17 cells the irAE of the skin in this metastatic melanoma patient.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX, DIPK2A, NELFB, and TEF. However, when primary AMs (PALM + NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.

Myeloid sarcoma is a rare extramedullary hematologic malignancy. Accurate and timely diagnosis may be challenging because myeloid sarcoma is known to mimic solid tumors, including hepatobiliary, nasopharyngeal, and breast carcinomas. We report a case of myeloid sarcoma that developed in the primary tumor lymphatic drainage field of a previously treated intermediate-thickness cutaneous melanoma, clinically and radiographically mimicking an in-transit metastasis, in a patient with myelodysplastic syndrome. The diagnosis of myeloid sarcoma was achieved after surgical excision of the mass and pathological examination that included extensive immunohistochemical studies. Awareness of such an unusual clinical presentation can help reduce diagnostic delay and ensure that adequate tissue is obtained for pathological examination and ancillary studies that are critical for accurate diagnosis and appropriate patient management.

Ocular adnexal sebaceous carcinoma (OASC) is an aggressive malignancy that frequently recurs locally and metastasizes. Surgical extirpation may produce significant aesthetic morbidity, and effective systemic therapies for locally advanced or metastatic disease are largely ineffective. Immune checkpoint inhibitors have shown efficacy in the management of several solid tumors where tumor cell PD-L1 expression correlates with improved response. To determine whether OASC might be amenable to immune checkpoint blockade, we performed comprehensive immune profiling for CD3, CD8, PD-1, FOXP3, and PD-L1 in 24 patients with primary OASC. The composition, distribution and density of the tumor associated immune infiltrate were quantified by automated image analysis and correlated with measures of clinical outcome. Tumor cells in 12 OASCs (50%) expressed PD-L1. Higher densities of CD3+ (p = 0.01), CD8+ (p = 0.006), and PD-1+ (p = 0.024) tumor-associated T cells were associated with higher T category (≥T3a per the 7th edition of the American Joint Committee on Cancer staging manual). Higher tumor cell expression of PD-L1 correlated with higher density of PD-1+ tumor-associated T cells (p = 0.021). Since a CD3+ CD8+ PD-1 + T-cell infiltrate represents a "suppressed T-cell phenotype" apparently permissive toward OASC progression, our findings provide a mechanistic rationale for the effective application of immune checkpoint blockade in OASC to abrogate PD-1/PD-L1 interaction and effectively unleash the immune infiltrate to treat higher-stage tumors.

Mycosis fungoides is a potentially fatal skin condition whose variable clinical appearance may mimic a variety of benign, inflammatory dermatoses, making it a diagnostic challenge. Three patients with mycosis fungoides, treated with multiple approved topical and systemic therapies, presented with acquired verrucous lesions on the extremities. The verrucous presentation of mycosis fungoides is one of the many atypical forms of the disease, with a paucity of documented cases in the medical literature. Although rare, verrucous and hyperkeratotic lesions in mycosis fungoides may increase the risk of considerable diagnostic delay if clinicians do not maintain a high degree of suspicion in cases of acquired verrucous lesions in the appropriate clinical setting.

Anaplastic thyroid carcinoma is a highly aggressive cancer accounting for 1-2% of thyroid malignancies. Cutaneous metastases from anaplastic thyroid carcinoma are exceedingly rare. We report a 65-year-old woman with anaplastic thyroid carcinoma (BRAF V600E mutation) who had lymph node metastases (pT4 N1b) treated by total thyroidectomy, postoperative radiotherapy, adjuvant chemotherapy (paclitaxel and pazopanib) and targeted therapy (vemurafenib). Nine months after initial diagnosis, radiographic studies revealed multiple pulmonary metastases. A dermatologic examination showed a solitary 1.2-cm chest nodule. Skin biopsy from this nodule revealed infiltrative dermal spindle cells arranged in poorly formed fascicles. Immunohistochemical studies demonstrated the tumor cells to be PAX-8 (+), pancytokeratin (+, focally), TTF-1 (-) and SOX-10 (-). Comparison with the patient's primary anaplastic thyroid carcinoma revealed focal areas of poorly differentiated spindle cells morphologically similar to the malignant spindle cells in the skin biopsy. Together, these findings confirmed the diagnosis of anaplastic thyroid carcinoma metastatic to skin. Cutaneous metastasis of anaplastic thyroid carcinoma composed exclusively of spindle cells broadens the histologic differential diagnosis of cutaneous spindle cell malignancies and presents further diagnostic challenges. PAX-8 may be useful in discerning the spindle cell component of anaplastic thyroid carcinoma from other spindle cell malignancies in the skin.

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.