Apoptosis Pathway-Associated Proteins Are Frequently Expressed in Melanoma: A Study of 32 Cases With Focus on Acral Lentiginous Melanoma.

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

Gene Expression Profile of Benign, Intermediate, and Malignant Spitz and Spitzoid Melanocytic Lesions.

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions.

Metastatic Tonsil Squamous Cell Carcinoma: An Important Consideration in the Differential Diagnosis of Malignant Basaloid Neoplasms in the Skin: Case Report and Review of the Literature.

ABSTRACT: Malignant basaloid neoplasms of the skin are frequent, and their accurate diagnosis holds paramount importance for treatment and prognosis. However, these neoplasms can present diagnostic challenges because of their extensive differential diagnosis, which encompasses cutaneous metastasis among many other possibilities. We present a case of a 74-year-old man with a history of p16-positive palatine tonsil squamous cell carcinoma (SCC) treated with surgery and adjuvant radiation with no prior evidence of recurrence who presented to the dermatologist with 2 chin papules. The initial histopathologic evaluation of these lesions showed poorly differentiated malignant basaloid neoplasms. Subsequently, these biopsies were compared with the previous biopsies from his tonsil and lymph node, which showed similar findings including positive p16 staining and positive molecular testing for human papillomavirus-16, confirming the diagnosis of cutaneous metastasis from his previously diagnosed human papillomavirus-related tonsil SCC. Additional imaging studies found metastases to internal organs including the brain, and he was started on chemotherapy, immunotherapy, and radiation therapy. Cutaneous metastases from tonsil SCC are exceedingly rare, and only 5 cases have been described. Furthermore, this is the first case confirming the presence of high-risk human papillomavirus by molecular studies within the cutaneous metastases. The presented case underscores the importance of recognizing this unusual manifestation of tonsil SCC metastatic to the skin along with a good clinical patient history, ensuring accurate and prompt diagnosis and treatment of this condition.

Editorial for Special Issue "Molecular Mechanisms and Signaling Pathways in Melanoma".

Melanoma represents the leading cause of death from cutaneous malignancy [...].

Sentinel lymph node assessment in melanoma: current state and future directions.

Assessment of sentinel lymph node status is an important step in the evaluation of patients with melanoma for both prognosis and therapeutic management. Pathologists have an important role in this evaluation. The methodologies have varied over time, from the evaluation of dimensions of metastatic burden to determination of the location of the tumour deposits within the lymph node to precise cell counting. However, no single method of sentinel lymph node tumour burden measurement can currently be used as a sole independent predictor of prognosis. The management approach to sentinel lymph node-positive patients has also evolved over time, with a more conservative approach recently recognised for selected cases. This review gives an overview of past and current status in the field with a glimpse into future directions based on prior experiences and clinical trials.

Malignant Melanoma in a Retrospective Cohort of Immunocompromised Patients: A Statistical and Pathologic Analysis.

BACKGROUND: Malignant melanoma is the leading cause of death due to cutaneous malignancy. Immunocompromised individuals have an elevated risk of developing melanoma. We aimed to provide histopathologic and statistical characterization of melanoma development in immunocompromised patients. METHODS: We reviewed our institution's databases to identify all patients with a confirmed history of immunosuppression who subsequently developed melanoma, focusing on diagnoses during the follow-up period of 2011-2019. A total of 93 patients with a combined 111 melanoma lesions were identified. RESULTS: Common causes of immunosuppression included transplantation and lymphoproliferative disorders. Superficial spreading and lentigo malignant melanoma were the most common malignant melanoma subtypes. Median Breslow depth was 0.7 mm, and the most common primary tumor stage was T1a. Our transplant sub-cohort had an overall melanoma incidence of 0.9 per 1000 person-years (95% CI 0.66 to 1.20) and a standardized incidence ratio (SIR) of 1.53 (95% CI 1.12 to 2.04) relative to a general population cohort from the Surveillance, Epidemiology, and End Results Program (SEER). CONCLUSIONS: We report histopathologic characteristics of immunocompromised patients developing melanoma at a large academic tertiary-care center. Differences in age, sex, time since transplantation, and transplant type may play a significant role in melanoma SIR in this patient demographic.

MET Receptor Tyrosine Kinase Inhibition Reduces Interferon-Gamma (IFN-γ)-Stimulated PD-L1 Expression through the STAT3 Pathway in Melanoma Cells.

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

MACC1 and MET as markers associated with progression and metastasis in cutaneous melanoma.

Cutaneous melanoma is the most common lethal malignancy among skin cancers and has a high propensity for metastasis. Understanding the mechanisms governing tumorigenesis, progression and metastasis as well as identifying biomarkers guiding risk stratification and management of the disease is essential. MACC1 has been found to play key roles in cancer cell migration, invasion, epithelial-to-mesenchymal transition, and metastasis in various types of cancer, through activation of MET signaling. In this study, we examined the extent of MACC1 and MET protein expression by immunohistochemical staining in a tissue microarray constructed from twenty-three melanomas and ten melanocytic nevi. We observed significantly higher levels of MACC1 expression on average in metastatic melanomas, comparing to primary melanomas and nevi. MET expression in metastatic melanomas was also significantly higher than in nevi. MACC1 expression does not appear to correlate with MET expression in nevi and primary melanomas. However, this correlation appears stronger in metastatic melanomas, where seven (78%) of nine cases show intermediate to high expression of both MACC1 and MET. The expressions of MACC1 and MET do not show significant differences based on other clinicopathologic factors including patient age, gender, histologic subtypes, depth of invasion, and staging. Our study suggests that high expression of MACC1 or both MACC1 and MET is associated with metastasis of cutaneous melanoma.

Recurrent Nevus Phenomenon Developing within a Keloid.

The recurrent nevus phenomenon represents the persistence of a nevus within a scar from a prior biopsy site, with the acquisition of clinical and histologic features frequently overlapping with those of melanoma, posing relevant diagnostic challenges. Similar features are recognized in nevi that have undergone recent or chronic trauma and in sclerosing nevi. Any type of nevus may be subject to this phenomenon. Keloids are exuberant scars with an exaggerated accumulation of dense dermal collagen. Here we report a case of a 42-year-old woman with the incidental finding of an atypical melanocytic proliferation developing within a keloidal scar. The patient presented with a progressively enlarging auricular lesion three years after a piercing procedure. Upon histological examination, attentive scrutiny of the margin revealed an atypical compound melanocytic proliferation, predominantly single-celled at the junction but occasionally nested, with cytologic atypia and architectural disorder. This atypical proliferation was found emerging above a keloid. We interpreted the lesion as an atypical melanocytic lesion with features resembling the recurrent nevus phenomenon. This case raises awareness in recognizing these melanocytic lesions as benign, thereby avoiding overdiagnosis and unnecessary treatment.

Expression and Prognostic Evaluation of the Receptor Tyrosine Kinase MET in Canine Malignant Melanoma.

The overexpression and activation of the MET receptor tyrosine kinase has been identified in many human malignancies, but its role in canine cancer has only been minimally investigated. In this study we evaluated the expression of MET in two canine malignant melanoma (CMM) cell lines as well as in 30 CMM tissue samples that were collected from the clinical service at our institution. We were able to confirm the expression of the MET protein in both melanoma cell lines, and we demonstrated MET activation by its ligand, HGF, through phosphorylation, in Western blot analysis. We were also able to demonstrate, by immunohistochemistry, the expression of MET in 63% of the tumor tissue samples analyzed, with the majority demonstrating a relatively low expression profile. We then evaluated the association of MET expression scores with histologic parameters, metastasis, and survival. While statistically significant associations were not found across these parameters, an inverse relationship between MET expression levels and time to lymph node versus distant metastasis was suggested in our cohort. These findings may require assessment in a larger group of specimens to further evaluate the role of MET expression in the homing of metastasis in lymph nodes versus that in distant organs.

Erythema nodosum after azacitidine in a patient with acute myeloid leukemia.

INTRODUCTION: Nodular skin lesions in patients with acute myeloid leukemia (AML) raise clinical suspicion for leukemia cutis versus fungal infections. Here, we report a rare case of treatment-related erythema nodosum (EN) in a patient with AML. CASE REPORT: Approximately 5 weeks after the initiation of sorafenib and one week after azacitidine initiation, a 32-year-old man with primary refractory AML presented with several painful red nodules on the lower extremities. Histological examination established a diagnosis of EN. MANAGEMENT AND OUTCOME: Treatment with topical and oral steroids led to complete resolution of the nodules. However, once the dose of steroids was reduced, the lesions rapidly recurred. Higher dose steroids were reinitiated, again with a resolution of the nodules, confirming steroid responsiveness of the underlying process. DISCUSSION: Given the onset of lesions one week after the initiation of azacitidine and 5 weeks after the initiation of sorafenib, azacitidine was considered the more likely culprit. Only 2 cases of EN-like eruption after azacitidine and 1 case after sorafenib have been reported. Although fungal infections and leukemia cutis are the top differentials considered for skin nodules in a patient with AML, EN should be considered as an alternative diagnosis. Correct diagnosis is critical because it will guide treatment.

Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.

AIMS: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. METHODS AND RESULTS: A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range = 9-72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H-score range = 1-110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B-negative (H-score range = 1-8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). CONCLUSION: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

The mixed spongiotic and interface reaction pattern: A study of clinical and histopathologic findings.

BACKGROUND: Categorization of biopsy specimens into inflammatory reaction patterns is central to dermatopathologic assessment. Mixed inflammatory patterns are poorly characterized and may represent clinicopathologic challenges. The purpose of this study was to identify clinical and histopathologic findings associated with the mixed spongiotic-interface dermatitis (SID) histopathologic pattern. METHODS: Fifty-one institutional biopsy specimens of SID were identified over a 2-year period by retrospective natural language search. Histopathologic and clinical features were identified. RESULTS: The most common histopathologic features associated with SID were mild spongiosis (51%), focal vacuolar interface change (72%), lymphocytic exocytosis (92%), and superficial-dermal lymphocytic infiltrate (94%) with variable eosinophils (61%). Clinically, 80% of subjects presented with a symmetric morbilliform eruption. Polypharmacy (94%), immunosuppression (47%), and history of malignancy (47%) were common. The most common diagnoses were drug reaction (37%), possible drug reaction (12%), and viral exanthem (12%). Drug reaction with eosinophilia and systemic symptoms represented 25% of all confirmed cutaneous adverse drug reactions (CADR). Average time from drug initiation to symptom initiation was 20 days (SD: 22.3, range: 0-90); median disease duration was 25.5 days. Spongiotic vesicles and Langerhans cells were less common in patients with a strong clinicopathologic diagnosis of drug reaction compared to non-drug eruptions (p = 0.04). CONCLUSIONS: The mixed SID pattern is commonly encountered in CADR but may represent a more subacute course, implying consideration for inciting medication(s) started before the typical 7- to 14-day window.

Angiosarcoma-like Kaposi Sarcoma: A Distinctive Histomorphologic Variant Representing an Important Diagnostic Pitfall.

Kaposi sarcoma (KS) is a rare low-grade angioproliferative neoplasm associated with human herpesvirus 8 (HHV-8) infection with multiple clinical subtypes and varying histopathologic patterns. Histologically, many different variants of KS have been reported, yet all can be difficult to recognize and must be differentiated from other vascular tumors. In this report, we studied fourteen cases of a newly described variant of KS reminiscent of a well-differentiated angiosarcoma (angiosarcoma-like KS). All cases showed a diffuse, ill-defined infiltrative dermal-based lesion composed of numerous anastomosing vascular channels of varying caliber lined by a single layer of endothelium with minimal pleomorphism. The vascular proliferation ramified through the dermis and dissected the collagen bundles along with infiltration into the subcutaneous fat and around skin appendages. All cases showed expression of vascular markers (CD31, CD34, and ERG) and were positive for HHV-8. None showed the classic histopathology associated with KS. Without clinical guidance these tumors can be difficult to recognize as KS, creating significant diagnostic challenges. Our study expands on a rare histologic variant of KS that ought to be considered in the differential diagnosis of any cutaneous well-differentiated angiosarcoma. Awareness of this variant of KS is of important for proper diagnosis and management of these patients; thus, careful attention to the histomorphology and clinical history can help lead the pathologist to the correct diagnosis.

The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification.

Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as "atypical Spitz tumors" (or Spitz melanocytoma) and malignant Spitz melanoma. More recently a large body of work has uncovered the molecular underpinning of Spitz tumors, including mutations in the HRAS gene and several gene fusions involving several protein kinases. Here we present an overarching view of our current knowledge and understanding of Spitz tumors, detailing clinical, histopathological and molecular features characteristic of these lesions.

Histopathologic Features of Maculopapular Drug Eruption.

BACKGROUND: Cutaneous adverse drug reaction (CADR) is common in both inpatient and outpatient clinical settings and has been associated with a large variety of medications. Drug reactions represent a significant burden to the healthcare system due to increased hospital stay durations and associated costs. Moreover, some of these reactions may be life-threatening. The most common clinical manifestation of a CADR is a maculopapular drug eruption (MDE). Due to its many clinical mimics and associations with a variety of histopathologic patterns, maculopapular drug eruption is difficult to definitively diagnose from both a clinical and histopathological perspective. SUMMARY: We reviewed the clinical and histopathologic features of 327 cases of MDE from several studies in the literature and summarized characteristic histopathologic findings and their frequencies of occurrence. We found that the most common and suggestive histopathologic features of MDE were epidermal spongiosis, lymphocytic infiltrate, and occasional necrotic keratinocytes; interface change at the DEJ; superficial perivascular and interstitial lymphocytic infiltrate with or without eosinophils and neutrophils in the mid-to-deep dermis and mild papillary dermal edema; and dilation of superficial vessels. The presence of multiple histopathologic patterns within the same tissue specimen is also suggestive of MDE. This review and analysis suggest that a biopsy may improve the diagnostic accuracy by both establishing common and uncommon features associated with MDE and reviewing features that help to exclude other causes of maculopapular eruption. KEY MESSAGE: Histopathologic criteria for the diagnosis of MDE, while not entirely specific, may aid in establishing a differential that includes a drug eruption. Thus, a biopsy can be a helpful diagnostic tool when MDE is suspected by demonstrating findings suggestive of MDE or by ruling out clinical mimics. However, biopsy results cannot be used in isolation as clinical-pathologic correlation is paramount in MDE.

The Current State of Treatment and Future Directions in Cutaneous Malignant Melanoma.

Malignant melanoma is the leading cause of death among cutaneous malignancies. While its incidence is increasing, the most recent cancer statistics show a small but clear decrease in mortality rate. This trend reflects the introduction of novel and more effective therapeutic regimens, including the two cornerstones of melanoma therapy: immunotherapies and targeted therapies. Immunotherapies exploit the highly immunogenic nature of melanoma by modulating and priming the patient's own immune system to attack the tumor. Treatments combining immunotherapies with targeted therapies, which disable the carcinogenic products of mutated cancer cells, have further increased treatment efficacy and durability. Toxicity and resistance, however, remain critical challenges to the field. The present review summarizes past treatments and novel therapeutic interventions and discusses current clinical trials and future directions.

Solid Organ Transplant Graft-Versus-Host Disease in a Kidney/Pancreas Transplant Patient: Use of Chimerism Testing and a Rare Presentation of Cutaneous GVHD.

Introduction. Solid organ transplant graft-versus-host disease (SOT-GVHD) is a rare phenomenon in which recipients of solid organ transplant develop GVHD due to the presence of donor lymphocytes in the graft. SOT-GVHD most often occurs in patients receiving small bowel or liver transplants. Diagnosis is typically via identification of lymphocytic infiltration on histopathology and molecular demonstration of donor T cell chimerism in the target organ. The gastrointestinal (GI) system is the most common target of SOT-GVHD, and one estimate places long-term survival of patients with SOT-GVHD at 20% at 5 years. In this report, we present the case of a patient with sequential kidney and pancreas transplant who developed SOT-GVHD targeting host lymphocytes, skin, and liver, with a long period of stability before treatment with antithymocyte globulin. Peripheral blood chimerism testing was used to track response to therapy. Remarkably, he survived 1.5 years despite recurrent infections before dying of unrelated causes.

Molecular characterization of biphenotypic epithelioid and plexiform melanoma with deep penetrating nevus-like features.

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