Context.— Genetic alterations in tricarboxylic acid cycle enzymes such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase promote tumorigenesis and are increasingly identified across genitourinary tumors. Objectives.— To review the clinical and pathologic features of genitourinary tumors associated with mutations in succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. Data Sources.— This study is based on published literature and personal experience of the authors. Conclusions.— Genitourinary tumors associated with mutations in tricarboxylic acid cycle enzymes have distinctive morphologic and molecular features and may be part of hereditary tumor syndromes. A systematic approach to understanding these neoplasms can help recognize the underlying syndromic predisposition in clinical practice, which permits appropriate surveillance not only for the patients but also for their families. Additionally, shared pathogenic mechanisms among these tumors provide insights into potential targeted and systemic therapies.
Context.— The Breast Cancer Radiology-Pathology Project Extension for Community Health Outcomes (RAD-PATH ECHO), by Memorial Sloan Kettering Cancer Center and the African Research Group for Oncology, is an interactive, virtual program connecting radiologists and pathologists from North America and Nigeria and aims to address challenges in breast cancer diagnosis in low-resource settings. Objective.— To evaluate the RAD-PATH ECHO program and its impact on participants. Design.— The evaluation included a survey of participants to assess learning preferences, training needs, perceived barriers in breast cancer diagnosis, and the perceived impact of RAD-PATH ECHO on building local capacity. In addition, following each RAD-PATH ECHO session, participants received a free-text survey with the prompt “What were the 3 main learning points of today’s session?” Results.— Twenty-one participants responded to the online survey. Insufficient equipment (62%; 13 of 21) and poor communication between medical specialties (52%; 11 of 21) were identified as primary challenges in breast cancer diagnosis. Respondents preferred interactive case-based learning (81%; 17 of 21) and felt RAD-PATH ECHO improved their ability to manage patients (57%; 12 of 21). Recommendations for improvement included adding more institutions and increasing the number of sessions per year. Post-session surveys revealed the following 3 key themes: (1) Importance of communication to improve radiology-pathology diagnostic correlation; (2) transfer of diagnostic knowledge; and (3) guidance on biopsy procedure–related issues. Conclusions.— RAD-PATH ECHO is beneficial for enhancing knowledge and promoting multidisciplinary discussion in Nigeria and can serve as a supplementary resource for practicing radiologists and pathologists. Future initiatives should focus on developing strategies to increase participation and disseminate the program.
Context.— The diagnosis of soft tissue tumors is becoming increasingly complex as the number of entities and associated ancillary studies continues to increase. Mesenchymal tumors with prominent associated inflammation are challenging, given that the pathologist might not consider soft tissue entities in the differential diagnosis. This review will cover selected inflammatory soft tissue tumors commonly encountered in surgical pathology practice or associated with recurrent diagnostic pitfalls, namely,inflammatory well-differentiated liposarcoma/atypical lipomatous tumor, angiomatoid fibrous histiocytoma, myxoinflammatory fibroblastic sarcoma, inflammatory myofibroblastic tumor, and mass-forming fibroinflammatory lesions, as well as key vascular tumors with associated inflammation. Objective.— To review inflammatory soft tissue tumors most commonly encountered in surgical practice or prone to significant diagnostic challenges. This article will also cover relevant ancillary studies and provide a brief differential diagnosis. Data Sources.— Literature review through PubMed search. Conclusions.— With advancements in musculoskeletal medicine leading to more targeted treatments, precise histologic classification is key to improving patient outcomes. This is particularly important for inflammatory soft tissue lesions, as some malignant conditions may be mistaken for reactive processes. Achieving an accurate diagnosis relies on identifying morphologic characteristics, considering the clinical presentation, and using appropriate ancillary studies.
Context.— Mismatch repair deficiency (MMRd) is a key diagnostic and predictive biomarker, yet its mechanisms in upper gastrointestinal (UGI) and pancreaticobiliary (PB) malignancies remain incompletely defined. Objective.— To evaluate real-world clinical practices and multimodal molecular assessments of MMRd UGI and PB malignancies at a tertiary academic medical center. Design.— We analyzed 91 MMRd UGI and PB cancers from 90 patients. MMRd immunohistochemistry (IHC) patterns and use of ancillary molecular tests (MSI-PCR, MLH1 promoter methylation, germline testing, and tumor next-generation sequencing [NGS]) were reviewed. Results.— The most common primary sites were stomach (40 of 91; 44%), esophageal (15 of 91; 16%), and small bowel carcinoma (11 of 91; 12%), with pancreatic (8 of 91; 9%), biliary tract (7 of 91; 8%), and ampullary (4 of 91; 4%) carcinomas less frequent. Paired MLH1 of PMS2 loss was the predominant MMRd IHC pattern (71 of 91, 78%), followed by unusual patterns of loss (11 of 91, 12%), and paired MSH2 of MSH6 loss (9 of 91, 10%). Among the subset with MSI testing, MMRd by IHC and MSI were discordant in 16% (3 of 19) of cases. MLH1 promoter methylation was present in 80% (37 of 46) of the tested MLH1 of PMS2-deleted tumors. Lynch syndrome (LS) was identified in 17% (6 of 36) of patients with genetic testing. In addition, somatic MMR gene variants were identified in 43% (9 of 21) of tumors sequenced by NGS. Conclusions.— MMRd in UGI and PB cancers arises from diverse mechanisms, including MLH1 promoter methylation, somatic MMR gene alterations, and LS. A multimodal approach integrating IHC, MSI-PCR, tumor NGS, and MLH1 promoter methylation is essential for accurate biomarker characterization and optimized LS screening.
Context.— KMT2A (lysine methyltransferase 2A) and MYC (MYC proto-oncogene, bHLH transcription factor) amplifications are reportedly rare in myeloid neoplasms, and there is a lack of studies comparing KMT2A and MYC amplifications in myeloid neoplasms. Objective.— To compare the cytogenomic and mutational features and the clinical outcomes of myeloid neoplasms with KMT2A or MYC amplification, and to characterize 4 cases with co-amplification of KMT2A and MYC . Design.— This study characterized and compared the cytogenomic, molecular, and clinical features of a large cohort of myeloid neoplasms with KMT2A and/or MYC amplification. Results.— This cohort of 52 myeloid neoplasms included acute myeloid leukemias (n = 44), myelodysplastic neoplasms (MDS) (n = 6), and MDS/myeloproliferative neoplasms (n = 2). There were KMT2A amplifications (n = 35), MYC amplifications (n = 13), and co-amplification of KMT2A and MYC (n = 4). KMT2A amplifications were exclusively intrachromosomal (32 of 32; 100%), whereas MYC amplifications were mainly extrachromosomal (9 of 13; 69.2%). Compared to MYC amplifications, KMT2A amplifications exhibited greater genomic complexity and a higher prevalence of monosomal karyotype, 5q deletion, and 17p/ TP53 (tumor protein 53) deletion. TP53 mutations were most common in KMT2A amplifications, while TET2 (tet methylcytosine dioxygenase 2) mutations were most frequent in MYC amplifications. Microarray analysis showed oscillating copy number changes on chromosome 11, indicating chromoanasynthesis, in KMT2A -amplified myeloid neoplasms. Simple excision and chromothripsis are likely the mechanisms underlying MYC amplifications. Co-amplification of KMT2A and MYC was associated with older age, complex karyotype, 17p/ TP53 aberrations, and dismal outcomes. Myeloid neoplasms with KMT2A amplification showed a trend for shorter overall survival than those with MYC amplification ( P = .08). Conclusions.— Myeloid neoplasms with KMT2A or MYC amplification display distinct cytogenomic and molecular profiles and differ in clinical outcomes.
