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Abstract: Cutaneous melanoma can lead to metastasis, and it is associated with high mortality. Currently, there are no widely accepted immunohistochemistry markers for melanoma prognosis in routine staging. Preferentially expressed antigen in melanoma (PRAME) is a possible biomarker for prognosis in several noncutaneous neoplasms. Ki-67 is a cell proliferation marker correlated with poor outcomes in many cancers. This study assessed PRAME and Ki-67 as potential prognostic markers for sentinel lymph node outcomes and survival among melanoma patients. This is a retrospective study analyzing cutaneous melanoma cases from a Brazilian cancer center (2005-2021). All cases were tested using immunohistochemistry to evaluate PRAME expression and Ki-67 index. Descriptive analysis, Spearman correlations, means comparison, Kaplan-Meier analysis, χ 2 , and Cox models were performed. In univariate analysis of 123 cutaneous melanoma cases, high extent ( P = 0.0267) and elevated intensity ( P = 0.043) of PRAME were associated with decreased overall survival. The Ki-67 index was associated with overall survival ( P = 0.05) and sentinel lymph node status ( P = 0.0403), with a positive correlation between the markers ( P = 0.0004) and between Ki-67 and Breslow thickness ( P = 0.0001). However, in multivariate analysis, only Breslow thickness significantly influenced overall survival ( P = 0.0003). Then, the present results can suggest that elevated PRAME and Ki-67 expression are associated with poor overall survival in cutaneous melanoma; however, in multivariate analysis, only the Breslow thickness had a significant influence. These findings highlight the potential of PRAME and Ki-67 as prognostic markers, opening frontiers that could improve strategies for treating cutaneous melanoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The diagnosis of cutaneous T-cell lymphoma (CTCL) remains challenging. Demonstration of a clonal T-cell population using T-cell receptor (TCR) gene rearrangement studies by next-generation sequencing (NGS) has been explored in several studies. This review summarizes the current literature on NGS-based sequencing methods for the assessment of TCR clonality in the evaluation of atypical cutaneous lymphoid infiltrates and CTCL on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (lymphoproliferative subgroup). PubMed was searched for relevant articles, including CTCL and NGS, for clonality from 1967 to 2022. Thirteen studies were included in the analysis. The skin was the most commonly assayed compartment with TCR NGS. Sensitivity for TCR NGS in the skin ranged between 69% and 100%, compared to 44%-72% for polymerase chain reaction (PCR)-capillary electrophoresis. Specificity for TCR NGS in the skin ranged from 86% to 100%, compared to 77%-88% for PCR capillary electrophoresis. TCR NGS was also reported to have potential prognostic value in CTCL and can also be used to detect relapse and/or minimal residual disease after treatment., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: S100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME., Objectives: To compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case-control study., Methods: A previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0-4%; 2 = 5-25%; 3 = 26-50%; 4 = 51-75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1-50%; 3 = > 50%). A positive test was defined as > 50% staining., Results: The area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6-52.8%] and 98.2% (95% CI 93.6-99.8%) for S100A8, and 79.8% (95% CI 70.5-87.2%) and 87.3% (95% CI 79.6-92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7-49.7%) and specificity of 99.1% (95% CI 95.0-100.0%)., Conclusions: S100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma., Competing Interests: Conflicts of interest M.K. reports a pending patent application. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Floating Sign is a histopathologic clue to the diagnosis of autoimmune sclerosing skin disorders such as morphea and interstitial granulomatous dermatitis (IGD). On the other hand, the "free-floating" sign has been associated with neoplasms, for example, dermatofibroma and interstitial mycosis fungoides. Herein, we report the Free Sign in sclerosing skin disorders., Methods: In a case-control study, we applied detailed histopathologic definitions of Floating Sign and Free Sign to assess their presence in morphea, IGD, and other sclerosing disorders., Results: Free Sign was present in most cases of morphea (46/55, 84%) and IGD (7/13, 54%) but not necrobiosis lipoidica (NL) (6/14, 42.8%) or sclerodermoid graft versus host disease (SGVHD) (2/7, 28.5%). The sensitivity and specificity of Free Sign for morphea versus other disorders was 84% and 56%, respectively. Floating Sign was not identified in most cases: NL (3/14, 21.4%), SGVHD (1/7, 14.2%), morphea (5/55, 9%), IGD (1/13, 7.7%). The diagnostic sensitivity of Floating Sign in morphea was 9%., Conclusions: The Free Sign was present in most cases of morphea in our series and may represent a clue to the presence of evolving sclerosis. Free Sign may be seen in other sclerosing disorders. Technical artifact is a potential cause of a false-positive Free Sign., (© 2023 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background and Objective: Located on chromosome locus 5p15.33, telomerase reverse transcriptase (TERT or hTERT) encodes the catalytic subunit of telomerase which permits lengthening and preservation of telomeres following mitosis. Mutations in TERT promoter (TERT-p) upregulate expression of TERT, allowing survival of malignant cells and tumor progression in wide variety of malignancies including melanoma. The objective of this review is to examine the roles of TERT and TERT-p in the pathogenesis, diagnosis, and prognostication of cutaneous melanoma., Methods: All studies of TERT or TERT-p in cutaneous melanocytic neoplasms with the following inclusion criteria were reviewed: publication date between 2010 and 2019, English language, and series of ≥3 cases were reviewed for evidence supporting the role of TERT in pathogenesis, diagnosis, and prognosis. Studies with <3 cases or focused primarily on mucosal or uveal melanocytic tumors were excluded., Results and Conclusion: TERT-p mutations are frequent in chronic and non-chronic sun damage melanoma and correlate with adverse prognosis, inform pathogenesis, and may provide diagnostic support. While TERT-p mutations are uncommon in acral melanoma, TERT copy number gains and gene amplification predict reduced survival. Among atypical spitzoid neoplasms, TERT-p mutations identify biologically aggressive tumors and support the diagnosis of spitzoid melanoma. TERT-p methylation may have prognostic value in pediatric conventional melanoma and drive tumorigenesis in melanoma arising within congenital nevi. Finally, TERT-p mutations may aid in the differentiation of recurrent nevi from recurrent melanoma., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A subset of melanomas carrying a B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E mutation, which is the most common targetable mutation in melanoma, arise in association with a melanocytic nevus that is also harboring a BRAF V600E mutation. The detailed histomorphologic characteristics of nevi positive for BRAF V600E have not been systematically documented., Objective: To identify histomorphologic features correlating with BRAF V600E status in nevi., Methods: We retrospectively identified melanocytic nevi from our laboratory reporting system. We performed a histomorphologic analysis and analysis of BRAF V600E expression by immunohistochemistry., Results: Thirteen nevi (14.8%) were negative and 76 (86.4%) were positive for BRAF V600E. The nevi positive for BRAF V600E were predominantly dermal (predominantly dermal growth in 55.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P = .01]) and showed a congenital growth pattern (congenital growth pattern in 51.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P = .02]). Compared with nevi negative for BRAF V600E, those that were positive for BRAF V600E often exhibited predominantly nested intraepidermal melanocytes, larger junctional nests, abrupt lateral circumscription, and larger cell size. Architectural disorder and inflammatory infiltrates were seen more often in nevi negative for BRAF V600E. BRAF sequencing of a subset of nevi confirmed the immunohistochemical results., Limitations: Limitations include the study's retrospective design and the small sample size of nevi negative for BRAF V600E., Conclusions: BRAF V600E is associated with distinct histomorphologic features in nevi. These features may contribute to improving the accuracy of classification and diagnosis of melanocytic neoplasms., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Acantholytic squamous cell carcinoma (aSCC) is regarded as a high-risk variant of cutaneous squamous cell carcinoma (SCC). Acantholytic actinic keratosis (aAK) has been regarded as a precursor risk factor for aSCC. However, supporting evidence is limited., Objective: We sought to document clinical features, histologic features, management, and outcomes in a series of aSCC cases., Methods: Definitions of aSCC, aAK, and aSCC arising in association with aAK were applied to a consecutive series of aSCC cases. Clinical characteristics and outcomes were obtained from electronic medical records., Results: Of 115 aSCC cases (103 patients, mean age 71.8 years), actinic keratosis was present in 23% (27/115) but only 7.8% (9/115) exhibited associated aAK. Ten cases (10/115, 9%) fulfilled strict histologic criteria for follicular SCC as previously defined, but 50 of 115 (43%) of our aSCC cases exhibited predominant involvement of follicular epithelium rather than epidermis. Clinical outcome (median follow-up, 36 months) was available in 106 of 115 (92%). One patient experienced regional extension (parotid), and 1 patient experienced a local recurrence (nose). No disease-related metastases or deaths were documented., Limitations: This was a single-institution retrospective study from the United States., Conclusions: The presence of acantholysis in cutaneous SCC does not specifically confer aggressive behavior, a finding that may inform clinical practice guidelines., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients with cutaneous melanoma metastases have experienced excellent responses to intralesional interleukin (IL)-2. This has led to its recent inclusion into the US National Comprehensive Cancer Network guidelines for management of cutaneous melanoma metastases. Despite this, intralesional IL-2 has not been highlighted in the US literature nor have US physicians adopted it., Objective: We sought to evaluate the effectiveness of intralesional IL-2 combined with topical imiquimod and retinoid for treatment of cutaneous metastatic melanoma., Methods: A retrospective case series of 11 patients with cutaneous metastatic melanoma were treated with intralesional IL-2 combined with topical imiquimod and retinoid., Results: A 100% complete local response rate with long-term follow-up (average of 24 months) was seen in all 11 patients treated with this proposed regimen. Biopsy specimens of treated sites confirmed absence of malignant cells. The most common treatment-related adverse event was rigors., Limitations: Small number of patients, retrospective review of charts, and lack of a comparison group were limitations., Conclusion: Intralesional IL-2 administered concomitantly with topical imiquimod and a retinoid cream is a promising therapeutic option for managing cutaneous melanoma metastases. The regimen was well tolerated and should be considered as a reasonable alternative to surgical excision., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The complex and fascinating spectrum of inflammatory skin disease, and the comprehension of it, is ever expanding and evolving. During the first decade of the 21st century, numerous advances in the understanding of inflammatory disease mechanisms have occurred, particularly in psoriasis and atopic dermatitis. Continuation of this trend will assure a future in which molecular tests for biomarkers of immediate clinical relevance are used in routine patient care, not only for diagnosis but also for prognosis and management. This article focuses on selected recent or noteworthy developments that are clinically relevant for the histologic diagnosis of inflammatory skin diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

There are limited treatment options for metastatic melanoma, which is almost universally fatal. We report the successful treatment of 64 of 64 cutaneous and subcutaneous melanoma metastases in three patients using high-dose (22 million units per 1.2 ml) intralesional interleukin 2 (IL-2) in combination with topical imiquimod and a retinoid cream. Before intralesional therapy, all patients had been treated surgically and were no longer considered surgical candidates. Rebiopsy of 15 of the treatment sites and long-term follow-up (10, 12, and 27 months) showed regression of all treated tumors. Six months after discontinuation of therapy, one patient developed multiple new cutaneous metastases, but these were also responsive to treatment with intralesional therapy. The other two patients did not experience recurrence of their cutaneous melanoma. However, one of the two patients developed lymph node and brain metastases 18 months after initiation of intralesional therapy, but is still alive, now at 27 months. The concentration of IL-2 used for the intralesional therapy was much higher than in previously reported cases, which may explain the excellent responses that were observed. These results support intralesional high-dose IL-2 as a very effective therapy for controlling cutaneous metastatic melanoma. Additional studies are needed to determine whether this therapy is associated with a survival benefit.

We report a case of cutaneous postradiation angiosarcoma of the breast exhibiting pseudoepidermotropism that resembled metastatic adenocarcinoma on hematoxylin and eosin. The patient is a 74-year-old woman with history of breast carcinoma treated with mastectomy, chemotherapy, and radiotherapy who complained of an erythematous "rash" along the central portion of the mastectomy scar. Radiography showed widespread osseous metastasis. Biopsy revealed an infiltrative tumor with single file growth and tumor cells obscuring the dermal--epidermal junction in multiple foci, imparting an appearance of epidermotropism. The tumor cells were positive for CD31, CD34, and D2-40 and negative for Cam 5.2. This novel case of pseudoepidermotropic angiosarcoma highlights a potential pitfall in the histomorphologic assessment of poorly differentiated angiosarcoma.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm of possible viral origin and is known for its aggressive behavior. The incidence of MCC has increased in the last 15 years. Merkel cell carcinoma has the potential to metastasize, but rarely involves the central nervous system. Herein, we report three consecutive surgical cases of MCC presenting at a single institution within 1 year. We used intracavitary BCNU wafers (Gliadel(®)) in two cases. Pathological features, including CK20 positivity, consistent with MCC, were present in all cases. We found 33 published cases of MCC with CNS involvement. We suggest that the incidence of neurometastatic MCC may be increasing, parallel to the increasing incidence of primary MCC. We propose a role for intracavitary BCNU wafers in the treatment of intra-axial neurometastatic MCC.

Syringotropic cutaneous T-cell lymphoma (SCTCL) is a variant of mycosis fungoides that is characterized by the presence of lymphocytic infiltration of eccrine glandular structures and the absence of the classic features of MF, such as epidermotropism and Pautrier's microabscesses. We report a patient with SCTCL who presented with multiple hypopigmented patches and localized alopecia who was treated with local radiotherapy with excellent local control. In our experience, local electron radiation offers local control in early stage SCTCL, and it may be possible to reserve systemic therapy for more advanced stages of the disease.

An 88-year-old woman presented with an 8-year history of a slowly enlarging growth on the suprapubic area. A shave excision of this lesion demonstrated fibroepithelioma of Pinkus (FEP). Fibroepithelioma of Pinkus is an indolent growing tumor that traditionally has been classified as a variant of the basal cell carcinoma. More recent evidence favors the classification of FEP as a variant of trichoblastoma. In this case report, we identified a large FEP with benign histologic features suggestive of a follicular origin as demonstrated in part by CK 20 staining and the presence of scattered Merkel cells within the tumor. The pathogenesis of FEP remains enigmatic, and the genetic basis has yet to be fully elucidated. Complete surgical resection is considered curative.

Background: Numerous treatments have been used to treat the mycosis fungoides (MF) and Sezary syndrome (SS) variants of cutaneous T-cell lymphoma (CTCL). The relative efficacy of different treatments is largely unknown., Objective: To determine the frequency of therapies ranked most effective and least effective for treatment of MF and SS in a sampling of dermatologists in the United States., Methods: Fellow members in the American Academy of Dermatology in the United States between the ages of 35 and 65 years were surveyed regarding demographic variables and treatment efficacy for patch/plaque MF (stages Ia-Ib CTCL), tumor stage MF (stage IIb), and erythrodermic MF/SS (stage III)., Results: Based on 1,399 responses, PUVA was preferred for the management of patch/plaque MF. Total skin electron beam (TSEB) therapy was preferred for tumor stage MF. Photopheresis (extracorporeal photochemotherapy) was preferred for erythrodermic MF/SS, followed closely by TSEB. Especially for tumor stage and erythrodermic MF/SS, physicians without a clear preference comprised the largest group. No significant variation depending on practice type, degree of practitioner experience, or geographic location was identified., Conclusion: PUVA was the preferred treatment for Stage Ia and Ib MF. The predominance of surveys with indeterminate responses suggests limited experience and in the treatment of CTCL, especially in advanced stages.

Background: Heat shock proteins (HSPs) are a family of highly conserved proteins found ubiquitously in mammalian cells, believed to be regulators of normal cell physiology and the cellular stress response. In addition, the small 27-kDa heat shock protein (HSP27) has previously been found to be a differentiation marker for keratinocytes and a prognostic marker associated with increased survival in certain cancerous tumors., Methods: Using immunohistochemistry on routinely processed paraffin sections, we examined skin biopsies from 15 invasive melanomas, 13 intradermal nevi, and two compound nevi immunostained with a mouse monoclonal antibody to HSP27. In addition, cultured melanocytes were heat stressed at 45 degrees C for 1 h and then fixed and immunostained in order to localize HSP27 expression intracellularly., Results: We found cytoplasmic and strong perinuclear staining of HSP27 in melanocytes in normal skin, in melanomas, and in nevi. Nuclear reactivity was absent. In addition, in cultured non-malignant melanocytes, HSP27 expression relocated from the cytoplasm to the nucleus with heat stress., Conclusions: To our knowledge, this investigation is the first to demonstrate that HSP27 is expressed in melanocytes in normal skin, in nevi, and in non-malignant cultured melanocytes.

Unlabelled: Accurate evaluation of patients with suspected or known cutaneous lymphoma requires the integration of many sources and types of information, including clinical evaluation, microscopic analysis of tissue, immunophenotyping, gene rearrangement studies, clinical staging, and longitudinal observation. Diagnoses should be based on knowledge of specific lymphoma types as described in modern classification systems. Management of patients with cutaneous lymphoma requires collaboration among dermatologists, dermatopathologists, hematopathologists, and medical, surgical and radiation oncologists. (J Am Acad Dermatol 2002;46:325-57.), Learning Objective: At the conclusion of this learning activity, participants should better understand how to evaluate and manage patients for suspected or established lymphoma of the skin. Components include the clinical history and physical examination, optimal biopsy and tissue handling, interpretation of pathology and adjunctive test results, clinicopathologic correlation, and therapy. Participants should also understand the basis for establishing a specific diagnosis of cutaneous lymphoma based on current classification and staging.