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The immunohistochemical (IHC) marker PReferentially expressed Antigen in MElanoma (PRAME) has shown promise in the diagnosis of melanocytic lesions. A few studies have investigated PRAME IHC expression in acral melanomas, but PRAME expression in subungual melanomas is largely unknown. We evaluated the utility of PRAME IHC expression in distinguishing subungual melanomas (SUM) and non-subungual acral melanomas (AM) from acral nevi (AN).Twenty-two SUM, 20 AM, and 14 AN were identified. IHC studies were performed using an anti-PRAME antibody. The percentage of lesional cells with PRAME expression was recorded and categorized as follows: 0%, 0; 1%-25%, 1+; 26%-50%, 2+; 51%-75%, 3+; and75%, 4+. Patient demographics and other relevant clinicopathologic parameters were recorded.Diffuse (4+) PRAME IHC expression was identified in 55% (12/22) SUM and 70% (14/20) AM, respectively. Any PRAME expression (1+ to 4+) was identified in 73% (16/22) SUMs and 95% (19/20) AM, respectively. One of 14 (7%) AN exhibited PRAME expression; interestingly, the pattern of expression was diffuse.In our study, PRAME IHC expression was useful in identifying AM, including SUM. However, there are exceptions of PRAME-negative melanomas and PRAME-positive nevi.

Merkel cell carcinoma (MCC) is an aggressive, highly metastatic, cutaneous neuroendocrine malignancy with poor prognosis. Here, we describe a MCC excision specimen with a rare case of tumor-associated amyloid deposition in the absence of residual tumor cells. A 72-year-old man presented with a lesion of 5-6 months' duration on his left elbow, clinically thought to be a ganglion cyst. The biopsy specimen revealed a Stage IIA MCC with classic histomorphologic and immunophenotypic findings, with tumor extending to the tissue edges. The patient underwent wide local excision with negative margins and a negative sentinel lymph node biopsy. Although the patient did not receive any presurgical chemotherapy, immunotherapy, or targeted therapy, the re-excision specimen showed only amphophilic, feathery deposits that were salmon-pink with Congo red stain and further confirmed as amyloid by electron microscopy; there were no residual carcinoma cells. Amyloid deposition in MCC has been described in rare case reports. Our case was extraordinary in that there was only amyloid deposition and an associated granulomatous reaction, without identifiable MCC cells. This case demonstrates that amyloid deposition may be evidence of a prior MCC at the site of a prior procedure and may warrant careful evaluation for residual MCC.

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.

Cutaneous lymphoid hyperplasia (CLH) is a benign reactive process with T-cell or B-cell lymphocytic infiltration in the skin, which can simulate cutaneous lymphomas both clinically and histologically. Various antigenic stimuli have been implicated in the development of CLH, including tick bites. Finding histologic evidence of such triggering factors, however, is often difficult. Moreover, the presence of clonality in CLH can potentially be interpreted as a neoplastic process, posing a further diagnostic challenge to dermatopathologists, if one is not aware of such peculiar phenomena. Herein, we describe a case of CLH secondary to a tick bite, featuring both T-cell clonality and monotypic plasma cells with lambda light chain restriction; the diagnostic clue being tick parts, which became evident on assessment of deeper levels. To the best of our knowledge, this is the first reported case of a tick-associated clonal CLH with simultaneous detection of monoclonal T cells and monotypic lambda light chain restriction, mimicking primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and Borrelia-associated primary cutaneous marginal zone B-cell lymphoma, respectively.

We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1–E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members (BCL-2 and MCL-1), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo. In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment–induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment–induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo. Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.

Context.— Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management. Objective.— To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management. Design.— We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not. Results.— A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients. Conclusions.— Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified, thus, resulting in critical changes in recommendations for clinical management.

We present an 81-year-old man who presented for evaluation of an indurated plaque with an exophytic, pearly, skin-red-brown colored nodule with central ulceration on his chest that evolved over the course of several months and was initially suspected to be basal cell carcinoma. Biopsy demonstrated histological features of dermal spindle cell proliferation in a storiform fashion with CD34 positivity confirming a diagnosis of dermatofibrosarcoma protuberans (DFSP). Dermatofibrosarcoma protuberans are rare, slowly progressive soft tissue sarcomas. The rate of DFSP is greatest among African Americans (8.3/1,000,000), occurring nearly twice as frequently when compared to Caucasians. Aside from race/ethnicity, age, and skin trauma, no specific risk factors are associated with DFSP. Complete excision is curative. Given its pearly skin colored appearance, papular/nodular/atrophic morphology variants, and tendency to form indurated plaques, DFSP may be mistaken for nodular and morpheaform basal cell carcinoma subtypes, as well as a variety of other conditions. This case highlights the importance of maintaining DFSP on the differential diagnosis of slowly progressive nodules and indurated plaques, especially in African Americans.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.

We present a rare case of a pembrolizumab-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). A 55-year-old woman with a history of metastatic cervical squamous cell carcinoma presented with a widespread mucocutaneous rash. Seventeen days after receiving her first cycle of pembrolizumab, she presented with fever, difficulty breathing, watery eyes, and painful oral ulcers. Physical examination revealed widespread erythematous papules and papulovesicles involving the trunk, upper extremity, and lower extremity and hemorrhagic plaques on the lower lip and buccal mucosa. Biopsy confirmed a diagnosis of SJS/TEN. This case highlights the importance of awareness of SJS/TEN as a possible adverse reaction for patients receiving pembrolizumab, a medication increasingly being used to treat metastatic or unresectable malignancies.

Background Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. Methods We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) MAP kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis. Results Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features were associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs. Conclusions Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology". This article is protected by copyright. All rights reserved.

Localized cutaneous argyria is a rare cutaneous disorder that has been associated with occupational exposure, dental procedures, topical agents, acupuncture, earrings, and nasal piercings. In this paper, we review the current literature on localized cutaneous argyria, highlight its clinical and histologic diagnostic features, and then discuss the clinical and histological differential diagnoses for blue-gray skin and black dermal pigment, respectively. We also discuss the utility of ancillary techniques, such as deeper histologic levels, special stains, darkfield microscopy, and advanced micro-analytical techniques in helping diagnose localized cutaneous argyria. Furthermore, we emphasize that a thorough clinical history and astute clinico-pathologic correlation can be the most important diagnostic techniques in correctly diagnosing this rare disorder. Our review aims serve as a reminder to clinicians and pathologists of the importance of including localized cutaneous argyria in the clinical and histological differential diagnosis of pigmented lesions.

Identifying tumor characteristics that correlate with metastasis and survival in patients with conjunctival melanoma can potentially lead to better outcomes through a better selection of patients for adjuvant treatments including potentially life-saving new melanoma therapy. The objective of this study was to validate the conjunctival melanoma staging criteria in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th edition) and explore the prognostic importance of tumor thickness, histologic ulceration, and sentinel lymph node biopsy (SLNB) findings in patients with conjunctival melanoma. This is a case series of 88 consecutive patients with conjunctival melanoma. Clinicopathologic characteristics were analyzed. Associations between pathologic characteristics and outcomes were studied using Kaplan-Meier survival analysis. Local recurrence, lymph node metastasis, distant metastasis, and disease-specific survival (DSS) were the main outcome measures. The study included 56 women and 32 men; the median age was 62 years. At presentation, 41 patients had T1 disease, 23 had T2 disease, 23 had T3, and 1 had T4 disease. Sixty-six patients had invasive conjunctival melanoma (median thickness, 1.56 mm), 17 had conjunctival melanoma in situ, and in 5 patients, tumor thickness could not be determined. Overall, 22 patients had ulceration. In total, 31 patients underwent SLNB, and 4 had a positive sentinel lymph node (SLN). The median follow-up time was 46.6 months. Overall, 12 patients had nodal metastasis at presentation or during follow-up, 19 patients had distant metastasis at last follow-up, and 14 patients died of the disease. Tumor thickness and ulceration were associated with increased risks of nodal metastasis, distant metastasis, and death from the disease. Overall, greater clinical T category at presentation was associated with increased risks of distant metastasis and disease-related death; however, the risks of distant metastasis and disease-related death did not differ between T1 (bulbar) and T2 (nonbulbar) tumors or between T2c,d (caruncular) and T1-T2a,b (noncaruncular) tumors. In patients who underwent SLNB, a positive SLN was associated with worse distant metastasis free survival and DSS. Consideration should be given to adding ulceration and emphasizing tumor thickness as the main determinants of pathologic T category for conjunctival melanoma in future AJCC classifications. The significant association between a positive SLN and worse DSS highlights the importance of SLNB for prognosis in patients with conjunctival melanoma and selecting high-risk patients for adjuvant drug treatment.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.

The presence of multiple BAP1-negative melanocytic neoplasms is a hallmark of familial cancer susceptibility syndrome caused by germline mutations in BAP1. Melanocytic tumors lacking BAP1 expression may also present as sporadic lesions in patients lacking a germline BAP1 mutation. Here, we report histomorphologic and clinical characteristics of cutaneous melanomas with loss of BAP1 expression in 4 patients with no known history of BAP1-associated cancer susceptibility syndrome. The lesions were nodular melanomas composed predominantly of intradermal large epithelioid (Spitzoid) melanocytes with nuclear pseudoinclusions as well as scattered multinucleated cells, arising in association with a typical intradermal nevus. Of the 4 patients, only 1 had recurrence. This patient had multiple recurrences with in-transit and regional lymph node metastases. To the best of our knowledge, this is the first reported series of cutaneous melanomas with loss of BAP1 expression arising in patients without a family history of cancer.

Purpose: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies. Experimental Design: We present next-generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA sebaceous carcinomas from 29 patients. Results: We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 [20/29 (70%) patients, including 10 patients whose primary tumors contained coexisting TP53 and RB1 mutations] with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype [9/29 (31%) patients] lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence. Conclusions: Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.

Melanomas, like nonmelanoma skin cancers, are known to be causally related to sun exposure. It is therefore not surprising to see benign nevi and melanomas in a background of solar damage, which at times may complicate their distinction. Because of their long-standing nature, nevi often occur before the development of solar elastosis and as such are intimately associated with the solar elastosis. In contrast, visible solar elastosis often occurs before the development of melanoma, in which case the band of solar elastosis is displaced downward from the overlying invasive melanoma and/or its host response. We describe 4 cases in which invasive melanoma cells were intimately admixed with actinically damaged elastin fibers in the absence of a prominent host response. In each case, melanoma cells were admixed with prominent solar elastosis and lacked a significant host response, suggesting that they were either histiocytes or an associated melanocytic nevus. Recognition of this potential pitfall may be helpful in the diagnosis of primary/in-transit/satellite/metastatic melanoma as well as when evaluating marginal status and determining Breslow thickness.

Advancements in cancer therapy with monoclonal immune checkpoint antibody blockade have impacted the practice of all medical specialties. Cutaneous immune-related adverse events (irAEs) are a frequent, unintended, off-target consequence of immune checkpoint inhibitor (ICI) therapy that have ushered in the era of oncodermatopathology. Knowledge of the diverse morphologic types of cutaneous irAEs from ICI therapy allows further classification of cutaneous irAEs according to major histopathologic reaction patterns. Early studies suggest that immune mechanisms of lichenoid dermatitis irAE, psoriasiform dermatitis irAE, and bullous pemphigoid irAE show some similarities and differences from their histopathologic counterparts not associated with ICI therapy.

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.

Context.— Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established. Objective.— To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma. Design.— Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses. Results.— No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02–2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival. Conclusions.— Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma.

Context.— Molecularly distinct from cutaneous melanomas arising from sun-exposed sites, acral lentiginous melanomas (ALMs) typically lack ultraviolet-signature mutations, such as telomerase reverse transcriptase (TERT) promoter mutations. Instead, ALMs show a high degree of copy number alterations, often with multiple amplifications of TERT, which are associated with adverse prognosis. The prognostic value of TERT protein expression in acral melanomas, however, is not established. Objective.— To evaluate the frequency and pattern of TERT immunoreactivity and assess the potential utility of TERT expression as a prognostic indicator in ALMs. Design.— TERT expression by immunohistochemistry was analyzed in a series of 57 acral and nonacral melanocytic lesions, including 24 primary and 6 metastatic ALMs. Clinical outcome in patients with ALMs by TERT expression was assessed. Results.— TERT expression was more frequent in ALMs than in nonlentiginous acral melanomas and nonacral cutaneous melanomas, and was absent in acral nevi (P = .01). When present, TERT expression in ALMs was cytoplasmic and more intense than TERT expression in other melanocytic lesions (P = .05) with a higher H-score (P = .01). There was a trend toward decreased overall survival in patients with ALMs with TERT immunoreactivity, but it did not reach statistical significance. Furthermore, no correlation was found between TERT expression and disease-specific survival in patients with ALMs. Conclusions.— Although TERT protein expression was frequently detected in both primary and metastatic ALMs, TERT immunoreactivity in ALMs did not correlate with survival in our study. Further studies with larger cohorts are needed to elucidate the prognostic value of TERT expression in ALMs.

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and β -catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies. This article is protected by copyright. All rights reserved.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.

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.

Post-radiation vascular lesions are a rare complication most commonly seen in patients previously treated for breast cancer. The main two entities include angiosarcoma (AS), which are malignant tumors that have a poor prognosis, and atypical vascular lesions (AVL), which typically behave in a benign manner and only rarely progress to angiosarcoma. The overall incidence of these lesions is low, but it appears to be increasing. Histopathologic distinction of AVL and AS is essential due to different clinical outcomes and treatment. However, due to the occasional existence of overlapping clinical and histopathologic features, it may be sometimes difficult to render a definite diagnosis, particularly in small biopsies. Ancillary techniques are, in general, of little help for separating the borderland cases but, in some instances, immunohistochemical study (IHC) for Ki67 and IHC or fluorescence in situ hybridization analysis for MYC may help in the diagnosis of angiosarcoma. Herein we discuss the clinical characteristics, histopathologic features, management strategies, and outcome of these lesions, with special emphasis on their differential diagnosis.

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.

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.

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.

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.

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.

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.

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.

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

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.

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 (