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Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/β-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/β-catenin pathway without evidence of matrical differentiation, as well as 4 combined tumors in which a similar Wnt/β-catenin-activated carcinoma component was associated with Merkel cell carcinoma (MCC) or pilomatrical carcinoma. Among the pure tumor cases, 6 of 16 patients were women with a median age of 80 years (range, 58-98 years). Tumors were located on the head and neck (n = 7, 44%), upper limb (n = 4, 25%), trunk (n = 3, 18%), and leg (n = 2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in 1 patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%), and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but 1 case. Nuclear β-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%), and RB1 (n = 47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogeneous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, MCC, and squamous cell carcinoma), although the 3 other cases lacking such morphologic features did not. In addition, we identified 4 combined neoplasms in which there was a component showing a similar poorly differentiated rosette-forming carcinoma demonstrating Rb loss and β-catenin activation associated with either MCC (n = 3) or pilomatrical carcinoma (n = 1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/β-catenin-activated rosette-forming carcinoma," morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland., (© 2022 The Pathological Society of Great Britain and Ireland.)

Aims: To evaluate the accuracy of intraoperative frozen section histopathology for diagnosing periprosthetic joint infection (PJI) during hip revision surgery, both for patients with and without recent trauma to the hip., Patients and Methods: The study included all revision total hip replacement procedures where intraoperative frozen section histopathology had been used for the evaluation of infection in a single institution between 2008 and 2015. Musculoskeletal Infection Society criteria were used to define infection. 210 hips were included for evaluation. Prior to revision surgery, 36 hips had a dislocation or a periprosthetic fracture (group A), and 174 did not (group B)., Results: The prevalence of infection was 14.3% (5.6% in group A and 16.1% in group B). Using Feldman criteria, the sensitivity of histopathology was 50.0%, specificity 47.1%, positive predictive value 5.3% and negative predictive value 94.1% in group A. The sensitivity of frozen section histopathology was 75.0%, specificity 96.5%, positive predictive value 85% and negative predictive value 95.3% in group B., Conclusions: Intraoperative frozen section histopathology is reliable for the diagnosis of PJI if no dislocation or periprosthetic fracture has occurred prior to hip revision surgery.

Dialysis-related amyloidosis (DRA) or β2microglobulin (β2m)-amyloidosis is a disorder caused by the inability to clear a protein called β2m in patients with chronic kidney disease. It results in deposition of β2m as amyloid fibrils, most commonly in bones and joints. Infrequently, visceral organs may be involved. With modern high-flux haemodialysis, DRA has become a rare disease, yet it may occur. We present a case of DRA in an 86-year-old woman. This case is particularly notable for its rare presentation as chronic intestinal pseudo-obstruction. It is of paramount importance to recognise this entity in order to reduce delay in treatment and avoid patients being frustrated not getting a diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The advent of BRAF-targeted therapies led to increased survival in patients with metastatic melanomas harboring a BRAF V600 mutation (implicated in 46-48% of malignant melanomas). The Idylla(™) System (Idylla(™)), i.e., the real-time-PCR-based Idylla(™) BRAF Mutation Test performed on the fully-automated Idylla(™) platform, enables detection of the most frequent BRAF V600 mutations (V600E/E2/D, V600K/R/M) in tumor material within approximately 90 min and with 1% detection limit. Idylla(™) performance was determined in a multi-center study by analyzing BRAF mutational status of 148 archival formalin-fixed paraffin-embedded (FFPE) tumor samples from malignant melanoma patients, and comparing Idylla(™) results with assessments made by commercial or in-house routine diagnostic methods. Of the 148 samples analyzed, Idylla(™) initially recorded 7 insufficient DNA input calls and 15 results discordant with routine method results. Further analysis learned that the quality of 8 samples was insufficient for Idylla(™) testing, 1 sample had an invalid routine test result, and Idylla(™) results were confirmed in 10 samples. Hence, Idylla(™) identified all mutations present, including 7 not identified by routine methods. Idylla(™) enables fully automated BRAF V600 testing directly on FFPE tumor tissue with increased sensitivity, ease-of-use, and much shorter turnaround time compared to existing diagnostic tests, making it a tool for rapid, simple and highly reliable analysis of therapeutically relevant BRAF mutations, in particular for diagnostic units without molecular expertise and infrastructure.

Rhabdomyosarcomas are classified into three well-defined categories: embryonal, alveolar and pleomorphic rhabdomyosarcoma. Recently, seven cases of an unusual adult type of rhabdomyosarcoma with a prominent hyaline sclerosis have been described. We report the hitherto unreported cytogenetic changes of an adult sclerosing rhabdomyosarcoma. A 79-year-old woman underwent an amputation for a rapidly growing soft tissue mass in the anterior compartment of the right lower leg. The tumor infiltrated the tibia. On histology, a fascicular spindle to round cell proliferation, embedded in a prominent hyaline matrix, was seen. Immunohistochemistry showed focal desmin, myogenin and MyOD1 expression, and electron microscopy revealed Z-band material. Cytogenetic analysis disclosed a 44-49,XX,+del(1)(p22)[2],+11,+16[5],+18[12],+21[3],-22 [cp13] karyotype. Using fluorescent in situ hybridization (FISH) analysis, the tumor cells were negative for FOXO1A-disrupting translocations specific for alveolar rhabdomyosarcoma. The chromosomal composition of malignant cells resembled the pattern of numerical changes frequently observed in embryonal rhabdomyosarcoma, suggesting a close relationship of an adult sclerosing rhabdomyosarcoma with this entity.

Chromosomal aberrations involving chromosome segment 12q13-15 are a common finding in a variety of benign mesenchymal tumors. The target gene encodes for HMGIC, a member of the high mobility group protein family. These proteins act as architectural transcription factors. HMGIC plays a role as a common genetic denominator in benign mesenchymal tumorigenesis. We report a case of hyaline vascular Castleman's disease with intragenic HMGIC rearrangement, due to a clonal cytogenetic aberration involving the long arm of chromosome 12 [46,XX, add(1)(q21),der(6)t(6;12) (q23;q15),add(7)(p22), -9,inv(9)(p11q13),del(12)(q15),+mar] obtained after short-term primary cultures. A combined immunocytologic-cytogenetic approach enabled us to demonstrate the exclusive presence of HMGIC rearrangement in anti-CD21 reactive follicular dendric cells. This finding confirms that a clonal proliferation of follicular dendritic cells occurs in the hyaline vascular variant of Castleman's disease. It also provides a possible molecular pathway explaining stromal overgrowths and stromal neoplasms developing from this disorder.