Jennifer Susan Ko

Aims: Digital papillary adenocarcinoma is a rare, aggressive adnexal tumour with a significant risk of recurrence and metastasis. Recent studies have identified human papillomavirus (HPV) 42 in most cases, suggesting potential diagnostic specificity. As HPV42‐specific sequencing is not routinely available, we evaluated the utility of commercially available low‐risk HPV chromogenic in situ hybridization (CISH), which includes HPV42, in digital papillary adenocarcinoma and characterized its staining pattern. Methods and results: Twelve cases of digital papillary adenocarcinoma were retrieved from the surgical pathology archives of our institution and compared with eight cases of tubular adenoma. Low‐risk HPV CISH was performed in all cases, and BRAF p.V600E immunohistochemistry in selected cases. Clinical, histological and immunohistochemical findings were reviewed. All digital papillary adenocarcinoma cases occurred in male patients (median age: 62 years, range 34–94) and involved the fingers. All were positive for low‐risk HPV CISH, whereas all tubular adenomas were negative. Conversely, all tubular adenomas were positive for p.BRAF V600E, while nine tested digital papillary adenocarcinoma cases were negative. The hybridization signal in digital papillary adenocarcinoma was consistently punctate and nuclear rather than diffuse, and in some cases was appreciable only at high magnification. Conclusions: Low‐risk HPV CISH is a practical and reliable method for detecting HPV42‐associated digital papillary adenocarcinoma. Recognition of its punctate nuclear staining is important, as this pattern may be subtle in some cases and could be overlooked if diffuse nuclear staining is expected with low‐risk HPV assays. These findings support the diagnostic utility of low‐risk HPV CISH in digital papillary adenocarcinoma.

Malignant transformation is known to occur with many nevi, such as nevus sebaceus. However, cases of secondary tumors developing in an epidermal nevus (EN) are rare, with only a few case reports documented in the literature. We present three unique cases of syringocystadenoma papilliferum (SCAP), syringofibroadenoma, trichilemmoma, and basal cell carcinoma (BCC) arising in EN. The first case is a 40‐year‐old female who presented with a verrucal plaque extending from mons pubis to the left lateral thigh since birth. Histologic examination revealed EN with areas of syringofibroadenoma, SCAP, and BCC. The second case is a 31‐year‐old male who had EN since birth on his left axilla, trunk, and buttock. Over time, several verrucous pink nodules developed on these areas. Microscopic evaluation of these nodules demonstrated characteristic features of SCAP and trichilemmoma. The third case is a 29‐year‐old female who developed a suspicious flesh‐colored papule within a pre‐existent EN on her left knee. Upon excision, the papule was diagnosed as a trichilemmoma. The occurrence of epithelial/adnexal tumors in EN remains elusive as to whether these lesions are clonally related or simply independent tumors that have coincidentally collided. We highlight the importance of considering the development of secondary neoplasms in the setting of EN, underscoring the need for regular patient follow‐up.

Most Spitz tumors exhibit recurrent gene fusions involving receptor tyrosine kinase or MAPK pathway genes. Here, we describe a Spitz tumor with a novel fusion involving MAP3K2 . The lesion occurred on the penile shaft of an 18‐year‐old. Histopathologically, tumor cells were predominantly dermal, arranged in irregularly shaped nests and cords showing minimal maturation with dermal descent, and accompanied by pseudoepitheliomatous epidermal hyperplasia. Melanocytes displayed abundant eosinophilic to amphophilic cytoplasm, variably enlarged rounded nuclei, fine chromatin, and scattered nucleoli or chromocenters. There were occasional dermal mitotic figures (1/mm ² ). The lesion involved the deep aspect of the biopsy specimen. SOX10, S100 protein, and MITF immunohistochemical stains were diffusely positive, while Melan‐A and HMB45 staining was only focal. PRAME was negative. FISH showed copy number gains at 6p25 ( RREB1 ) and 11q13 ( CCND1 ) narrowly exceeding cutoff values. Next‐generation sequencing revealed a CPEB2::MAP3K2 fusion and a low tumor mutation burden (2.1/Mb). To our knowledge, this fusion has not been previously reported in melanocytic lesions or other human tumors. A conservative re‐excision was performed, and a PET/CT scan showed no evidence of dissemination. With 16 months of follow‐up available, longer‐term monitoring will be required to determine the clinical behavior and biologic potential of this tumor.

Epithelioid vascular tumors range from benign to malignant, including epithelioid hemangioma, cutaneous epithelioid angiomatous nodule, epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Vascular tumors with epithelioid morphology and TPM3/4::ALK fusions have recently been added to this list, in a cohort of five cases. Herein, we report the sixth case (second case with TPM4::ALK specifically). Consistent with the previous report, the current case occurred in a young boy (lateral upper back, 11 years old) and demonstrated a circumscribed tumor with an epidermal collarette, peripheral ectatic thin vessels, and variably solid to vasoformative epithelioid cells with small, somewhat crescent‐shaped vascular channels. CD34, ERG, and ALK immunohistochemical stains were positive and further highlighted vascular structures. RNA sequencing revealed an in‐frame fusion between TPM4 Exon 8 and ALK Exon 20. Conservative excision was performed and recurrence has not been observed at one‐year follow‐up.

Background: Next‐generation sequencing (NGS) is becoming more commonly used for diagnosis in dermatopathology. It's critical to appraise its efficacy and limitations. Distinguishing benign deep penetrating nevi (DPN) from deep penetrating like‐melanoma (DPN‐M) is a challenging diagnostic scenario even for experienced dermatopathologists. Methods: We sent a two‐phase survey (pre‐and postgenomics) to 32 experienced dermatopathologists to evaluate 39 diagnostically challenging cases from the DPN/WNT‐activated family of melanocytic neoplasms. Results: With NGS data, interobserver agreement improved from 0.41 to 0.51 ( p < 0.0001) in distinguishing DPN‐M from nonmelanoma cases. Overall diagnostic accuracy improved, mostly driven by a 16% increase in accurate diagnosis of DPN‐M. However, in two cases, the inclusion of genomics shifted the majority vote from a correct to an incorrect diagnosis. A total of 218 diagnostic changes occurred between Survey 1 and 2. Among the changes, 132 votes moved toward the correct diagnosis while 86 moved toward an incorrect diagnosis. The shift in voting which resulted in improved diagnostic accuracy was statistically significant ( p = 0.0001). Conclusions: NGS has the potential to improve interobserver agreement and diagnostic accuracy. We provide guidance on the utilization of bioinformatic data to maximize its benefits and improve diagnostic accuracy and interobserver agreement.

Purpose:Patients with stage II and resected stage III melanomas have variable clinical outcomes, providing evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease) has created a pressing need to develop biomarkers to accurately distinguish patients at low risk versus high risk for recurrence and death from melanoma. miRNAs are promising biomarkers because of their stability in tissues and fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would classify 5-year survival outcomes more accurately than clinical factors alone.Experimental Design:Using a NanoString miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium and examined associations between miRNA expression and melanoma-specific death.Results:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve for patients in stage II from 0.71 for a “clinical factors–only” model to 0.81 for a “clinical plus miRNA” model in an independent test set, an improvement of 0.10 with a 95% confidence interval (0.03–0.19). The improvement was more modest for patients in stage III who were included in the analysis.Conclusions:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models and potentially aid in the selection of patients with melanoma for adjuvant treatment and clinical trials.

Primary cutaneous Ewing Sarcoma (PCES) is a rare superficial subtype of Ewing sarcoma that typically presents above the fascia and is associated with a relatively favorable prognosis compared to its deep soft tissue and osseous counterparts. This review, conducted by the American Society of Dermatopathology Appropriate Use Criteria Committee Soft Tissue Subgroup, focuses on the ancillary diagnostic methodologies for PCES. This work provides an overview of current immunohistochemical, cytogenetic, and molecular tests used to support a diagnosis of PCES. A total of 37 articles were reviewed, identifying 140 confirmed superficial cases: 26 from case reports and 114 from 10 retrospective studies (ranging from 1 to 56 cases). Immunohistochemically, CD99 demonstrated a positive membranous staining rate of 100% in PCES when reported. While NKX2.2 and PAX7 have not been widely tested in PCES, data from the broader sarcoma literature indicate NKX2.2 sensitivity ranging from 92.7% to 100%, and specificity from 85% to 87.5%. PAX7 showed sensitivity of 90% to 99% and a specificity of 83%. Molecularly, EWSR1 rearrangement by FISH was detected in 57 of 64 tested PCES cases (89%). Next‐Generation Sequencing (NGS) revealed EWSR1::FLI1 rearrangement in all three tested PCES cases (100%). In conclusion, the accurate diagnosis of PCES requires a comprehensive approach, integrating detailed morphologic assessment with immunohistochemical studies and potentially cytogenetics/molecular assays.