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Background: Melanocytic tumors driven by MAP2K1 in-frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well-known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable., Materials and Methods: We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in-frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single-nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations., Results: Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in-frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque-like or wedge-shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1-2/mm 2 ). Five cases (83%) had a small component of nevic-looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in-frame deletion involving the p.I103_K104del locus while two cases (33%) showed in-frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus., Discussion and Conclusion: Melanocytic tumors with MAP2K1 in-frame deletion could represent another spectrum of melanocytic tumors with close genotypic-phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology., (© 2023 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Malakoplakia is a rare chronic inflammatory condition that most commonly involves the urogenital tract. Cutaneous malakoplakia is extremely rare and many patients diagnosed with skin involvement are immunosuppressed. While the clinical presentation of cutaneous malakoplakia is variable, the histopathologic features are quite distinct and include sheets of closely packed dermal histiocytes with foamy-appearing cytoplasm and Michaelis-Gutmann bodies that are positive with certain immunohistochemical stains. While the exact pathogenesis of malakoplakia is unknown, it has been associated with certain bacterial infections. Treatment generally involves a combination of surgery and antimicrobial agents and/or modulation of immunosuppressant therapy if appropriate. Herein, the authors report a unique case of cutaneous malakoplakia arising in a patient on chronic immunosuppressive therapy for the management of pyoderma gangrenosum., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation., Methods: Fluorescence in situ hybridization (FISH)-tested spitzoid neoplasms at our institution (2013-2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH., Results: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months-74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC-stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16-retained/BRAF V600E-negative lesions had low FISH-positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%-75% of cases; p < 0.001)., Conclusions: p16/BRAF V600E IHC predicts FISH results. "Low-risk" lesions (p16 + /BRAF V600E - ) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting., (© 2022 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests., Methods: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2., Results: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain.", Limitations: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded., Conclusions: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery., (© 2021 John Wiley & Sons A/S. 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.)

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as "animal-type melanomas" and "epithelioid blue nevi." Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in-depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3-SCAPER gene fusion., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Accurate diagnosis of melanoma remains histologically challenging. Dermal mitoses support malignancy, but are only occasionally seen in melanomas. As melanomagenesis is thought to begin at the dermal-epidermal junction, we investigated the significance of epidermal melanocytic mitoses (EMM) in a spectrum of lesions with molecular characterization., Methods: Epidermal mitoses density (EMD) was evaluated in 46 straightforward lesions (24 benign and 22 malignant) and 30 challenging lesions with expert interpretation, fluorescence in situ hybridization and myPath-score characterization (12 favor-benign, 9 favor-malignant and 9 ambiguous). EMD was correlated with clinicopathologic parameters and myPath., Results: In straightforward cases, 25% nevi and 77% melanomas had EM. Median EMD was significantly lower in nevi vs. melanomas (0/mm vs. 0.04/mm, p = 0.001). EMD (0.01/mm-cutoff) had 77% sensitivity, 79% specificity discriminating melanomas from nevi. In challenging cases, 17% favor-benign, 67% favor-malignant and 78% ambiguous lesions had EM. EMD (0.01/mm-cutoff) had 67% sensitivity, 82% specificity on 21 non-ambiguous lesions, similar to myPath. EMD was less accurate in Spitzoid lesions, which have high EMD and dermal mitoses., Conclusion: While EMD is not an adequate single criterion in diagnosing melanoma, our results validate its discriminatory potential, suggesting that EM should prompt closer investigation for malignancy. Expanded studies with clinical follow up are warranted to further assess the EM utility in classifying melanocytic lesions., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Currently, little is known regarding the potential prognostic value of histologic features in primary cutaneous neuroendocrine (Merkel cell) carcinomas (MCC)., Methods: In a retrospective review of the tumor histology and clinical outcome data (median follow-up, 51 months; range, 3-224 months) of 156 patients with a diagnosis of MCC, the following histologic features were evaluated: tumor thickness, tumor size (greatest dimension of the tumor), microanatomic compartment involved by tumor (dermis and/or subcutis and/or deeper), tumor growth pattern (nodular circumscribed vs infiltrative), lymphovascular invasion (LVI), tumor-infiltrating lymphocytes, tumor necrosis, ulceration, and solar elastosis., Results: The overall 5-year survival rate was 67.5%. On univariate analysis, parameters that were associated significantly with survival were tumor thickness (P= .001), tumor size (P= .0002), deepest anatomic compartment involved by tumor (P= .0003), tumor growth pattern (P= .003), LVI (P< .00001), tumor-infiltrating lymphocytes (P= .05), and solar elastosis (P= .04). On multivariate analysis, the presence of a nodular growth pattern, low tumor depth, and absence of LVI were associated with longer survival., Conclusions: In addition to the known prognostic value of tumor stage, 3 histologic features were identified to have prognostic significance: tumor thickness (depth of tumor invasion), the presence of LVI, and tumor growth pattern.

Background: Multicentric breast carcinomas have a higher frequency of axillary lymph node metastasis than unifocal tumors of similar stage. It remains unclear whether this merely reflects larger tumor volumes or a different biologic behavior. The authors have shown previously that when aggregate tumor diameter are used for staging, unifocal and multifocal tumors have a similar frequency of axillary lymph node metastasis. However, summing diameter overestimates actual tumor volume because volume is proportional to the third power of the diameter. Therefore, the aim of the current study was to reanalyze the relation between size and axillary lymph node status by correcting for tumor volumes and surface areas., Methods: Volumes and surface areas of 122 breast tumor specimens with multiple macroscopic nodules (two foci: n = 95; three foci: n = 22; three foci: n = 5) were calculated by approximating the shape of each tumor nodule to an ellipsoid (for volume) or to a prolate spheroid (for area). For comparison, the authors used an internal control series, comprised of 469 macroscopic unifocal tumors. For all patients, multiple assessments of largest tumor size and combined size of all foci were correlated with the status of axillary lymph nodes. The associations between lymph node status, tumor volume or area, and multifocality were modeled using univariate and multivariate logistic regression., Results: When either the largest or the aggregate tumor volume was used as a size estimate, tumor specimens with multiple nodules had a higher frequency of lymph node involvement compared with unifocal tumors of a similar volume or area. The odds ratio (OR) for having positive lymph nodes was 2.34 for aggregate volume measurement (P < 0.001). Surface area estimates yielded similar results (OR = 2.2, P < 0.001)., Conclusions: Breast tumors with multiple macroscopic nodules had a different biology, with a propensity to dissemination at smaller tumor volumes (i.e., there was another factor besides volume alone that accounted for the differences in behavior)., (Copyright 2003 American Cancer Society.)