The risk of recurrence and metastasis in patients with endometrial carcinoma varies widely, making evaluation of risk in individual patients critically important for planning effective adjuvant treatment. Tumor histotype and grade have been used, along with stage and lymphovascular space invasion (LVSI), but suboptimal reproducibility of histotype assignment (especially for high-grade tumors) and tumor grade have made risk assessment challenging. Similarly, single biomarkers such as L1CAM and beta-catenin have shown potential but none have emerged as well-validated and reproducible markers of risk in endometrial carcinoma. This changed with the finding of The Cancer Genome Atlas that there are 4 molecular subtypes of endometrial carcinoma, based on genomic architecture. Subsequently, a clinically applicable approach to endometrial carcinoma molecular subtype has emerged, based on sequencing of POLE to detect a limited number of pathogenic mutations, and immunostaining for mismatch repair (MMR) proteins and p53. This approach places each endometrial carcinoma into one of 4 molecular subtypes ( POLE mut, MMRd, p53abn, and no specific molecular profile [NSMP]) that can be reproducibly diagnosed, show excellent concordance between the biopsy and hysterectomy specimen, are of prognostic significance, predict response to specific adjuvant therapies, and can be used to screen for underlying hereditary cancer susceptibility syndromes. Molecular subtype is now integrated into widely used endometrial carcinoma risk assessment guidelines and is a key component of the 2023 update to the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma. Recently, prognostic refinement of the 4 molecular groups introduces a possible fifth group showing absence of estrogen receptor (ER) expression and/or high histologic grade within the NSMP subtype. We will review the key features of endometrial carcinoma molecular subtypes, focusing on recent advances in molecular subtype diagnosis in practice.
About 10% of neuroendocrine tumors (NETs) can occur in the context of several different hereditary tumor syndromes, and, in a not negligible number of cases, their diagnosis precedes the clinical identification of the hereditary syndrome. In this context, the role of a pathologist can be crucial in identifying these sentinel cases. Indeed, early recognition of inherited NETs has significant clinical value, both for guiding therapeutic strategies and for managing at-risk family members. Modern pathologists play a central role not only in the accurate diagnosis and subtyping of NETs but also in recognizing specific morphologic features that may point to a germline etiology. When morphology does not show peculiar features suggestive of a hereditary context, integrating morphology with clinical context may, however, help identify appropriate genetic testing. In the present paper, we provide an organ-based overview of the most important morphologic and immunohistochemical features, along with their molecular correlates, of pituitary, parathyroid, thoracic, and digestive NETs arising in the context of hereditary tumor syndromes.
Testicular germ cell tumors (TGCTs) are the most common malignancies in young-adult males and represent a biologically heterogeneous group of neoplasms. Despite excellent overall prognosis, conventional serum tumor markers lack sufficient sensitivity and specificity in several key clinical settings, including early metastatic disease, postchemotherapy residual masses, and surveillance. Over the past decade, microRNAs of the miR-371~373 cluster have emerged as highly accurate biomarkers in this setting. Among them, circulating miR-371a-3p has demonstrated sensitivity and specificity exceeding 90% for viable, nonteratomatous TGCTs across multiple cohorts, consistently outperforming traditional markers. miR-371a-3p levels closely reflect tumor burden, showing rapid decline after orchiectomy and during effective chemotherapy, and rising at relapse, enabling near real-time disease monitoring. Importantly, miR-371~373 is differentiation-dependent (which can be used as readout for studies on the pathobiology of TGCT phenotypes). It is present in nonteratomatous germ cell components, uniformly absent in teratoma and absent/low in somatic-type malignancies, a feature that both underpins its clinical utility and defines one of its main limitations. This review summarizes the biological rationale underlying miR-371~373 expression in TGCTs and examines current clinical applications of miR-371a-3p across diagnosis, staging, surveillance, and postchemotherapy assessment. Moreover, we discuss analytical considerations, health-economic implications, and emerging data in the biologically related ovarian and extragonadal germ cell tumors. Remaining challenges and future directions for standardized clinical implementation are also addressed.
Germ cell tumors of the testis are the most common malignant tumor in young adults. The introduction of the use of cisplatin-based chemotherapy for testicular germ cell tumors from certain tumor stages in the 1970s has significantly improved the prognosis for these tumors. The resection of tumors that have undergone prior chemotherapy, usually in the area of retroperitoneal lymph node metastases or other sites of tumor metastasis, is an important part of the treatment for these patients. But prior treatment with chemotherapy might lead to the development of different special biological forms of germ cell tumors, including the so-called growing teratoma syndrome, somatic-type malignancies, sarcomatoid yolk-sac tumors, vasculogenic mesenchymal lesions, and trophoblastic tumors as well as unspecific changes. Pathologists should be aware of these different histopathologic changes associated with chemotherapy in germ cell tumor patients, as these might even occur years after the initial therapy. This article discusses the classic morphologic subtypes of germ cell tumors and the development of chemotherapy resistance and examines special morphologic forms and the diagnostic handling of postchemotherapy resection specimens.
