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.
Atypical intraductal proliferations of the prostate span a spectrum from high-grade prostatic intraepithelial neoplasm (HGPIN) to intraductal carcinoma of the prostate (IDCP), with progressively more atypical architectural and cytologic features and at least partial retention of basal cells. IDCP is strongly associated with coexisting high-grade, advanced invasive prostate cancer (PCa). In contrast, unifocal HGPIN is not associated with a significantly increased risk of PCa on subsequent biopsies. Atypical intraductal proliferation (AIP), the term recommended by WHO for proliferations with morphologic features borderline between HGPIN and IDCP, shares molecular and clinicopathological traits with IDCP and serves as a marker of unsampled adverse pathology. Despite progress in understanding IDCP and AIP, their accurate diagnosis and reporting remain challenging. This review provides recommendations on the diagnosis and reporting of IDCP and AIP, stemming from a recent joint expert consultation of the Genitourinary Pathology Society and the International Society of Urological Pathology, to help surgical pathologists optimally diagnose and report atypical intraductal proliferations. The diagnosis of IDCP in biopsies and resections should follow the updated Guo and Epstein criteria, with basal cell immunohistochemistry as needed. Rarely, marked (pleomorphic/bizarre) intraductal cytologic atypia alone may suffice for an IDCP diagnosis. The term AIP should be used only when proliferations are equivocal yet favor IDCP; such cases should be reported as "AIP, suspicious for IDCP." The diagnosis of cribriform HGPIN should not be made on biopsy; instead, such atypical lumen-spanning proliferations with loose cribriform architecture should be reported as "AIP, suspicious for IDCP." When available, ERG and PTEN immunohistochemistry can help differentiate from HGPIN. Adopting these recommendations would reduce interobserver variability, promote consistent communication with clinicians, and enhance patient management.
MiT/TFE family of transcription factors, including MiTF, TFE3, TFEB, and TFEC genes, control transcriptional programs for autophagy and lysosome biogenesis and regulate energy metabolism in many cancers. Chromosomal translocations and amplifications involving the MiT/TFE genes contribute to the etiology and pathophysiology of renal cell carcinoma, melanoma, sarcomas, and many other tumors. Understanding the roles of MiT/TFE factors in cellular homeostasis, oncogenic, and stress-adaptive regulation through transcriptionally regulated pathways may reveal new strategies for cancer diagnostics, prognostication, and treatment.
Paratesticular soft tissue tumors are infrequently encountered in surgical pathology and can often pose diagnostic challenges. A wide range of mesenchymal neoplasms may arise in this region, encompassing entities that vary significantly with regard to their clinicopathologic features, molecular characteristics, and biological behavior. In recent years, there have been significant advances in this area of pathology, largely due to the application of molecular studies, and these have included the discovery of novel entities, refinements in classification, and improvements in ancillary diagnostic techniques. In this review, we highlight selected updates and advances most relevant to mesenchymal entities arising in the paratesticular region.
Mesothelial lesions of the testis and paratestis encompass a spectrum of reactive, benign, and malignant processes that may overlap morphologically with one another and with other intra- and extratesticular neoplasms, including Müllerian-type tumors as well as Sertoli cell and yolk sac tumors. Providing an accurate diagnosis has important consequences for patient care, dictating significant changes in treatment modality. While immunohistochemical stains specific to mesothelial cells are helpful in differentiating mesothelial from nonmesothelial lesions, the distinction between benign and malignant processes has only recently been facilitated by molecular testing and immunohistochemical staining for BAP1 and MTAP. Although benign mesothelial lesions are usually easily classified with routine histopathologic evaluation, certain cases of florid reactive mesothelial hyperplasia and infarcted adenomatoid tumors may pose a diagnostic challenge. Well-differentiated papillary mesothelial tumors are bland papillary tumors with indolent behavior and TRAF7 or CDC42 mutations. Architecturally more complex forms within this spectrum exist and have been labelled as having “uncertain malignant potential.” Malignant mesothelioma of the tunica vaginalis is an uncommon but aggressive tumor that may show loss of BAP1 or MTAP immunostaining, supporting a distinct molecular pathogenesis. This review summarizes the clinicopathologic, immunohistochemically, and molecular features of mesothelial lesions of the paratestis, emphasizing their morphologic overlap, diagnostic pitfalls, and evolving framework for classification.
Hereditary renal cancer syndromes account for approximately 5% to 8% of all renal cell carcinomas (RCCs) and are caused by germline alterations, mainly in tumor suppressor genes. Advances in molecular testing have led to the identification of new hereditary syndromes and expanded our understanding of the genetic landscape of renal neoplasia. This review summarizes both well-established and recently described hereditary renal cancer syndromes, highlighting their clinical, pathologic, and molecular features. Emphases are placed on genotype-phenotype correlations and the relationship between germline and somatic alterations in tumors. Understanding these correlations is critical for diagnosis, risk assessment, surveillance, and management and underscores the importance of a high index of clinical suspicion for early detection to optimize patient outcomes.
Thyroid carcinoma is the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) comprising most cases and arising from follicular epithelial cells. Although most follicular cell-derived thyroid carcinomas are sporadic and driven by acquired genetic alterations, a subset reflects an inherited predisposition. Increasing recognition of familial thyroid carcinoma has been prompted by advances in molecular genetics and by heightened awareness of recurring clinicopathologic patterns, including early age at onset, multifocal and bilateral disease, associated benign follicular proliferations, and, in some cases, multiorgan tumor involvement. Awareness of these features is essential, as they may represent the first diagnostic clue to an underlying familial tumor syndrome. The 2022 World Health Organization classification formally recognizes familial thyroid carcinoma and subdivides these tumors into familial medullary thyroid carcinoma and familial nonmedullary thyroid carcinoma (FNMTC). FNMTC comprises a genetically heterogeneous and underrecognized group of follicular-cell-derived neoplasms, most commonly presenting as multifocal PTC, and includes both syndromic forms associated with extra-thyroidal tumors and nonsyndromic forms in which thyroid carcinoma predominates. In contrast, familial medullary thyroid carcinoma arises from parafollicular C cells, often with bilateral tumors and C-cell hyperplasia as a precursor lesion, and is most frequently encountered in the setting of multiple endocrine neoplasia. This review highlights histopathologic features that should prompt consideration of familial thyroid carcinoma and underscores the pathologist's vital role in identifying these entities and facilitating appropriate molecular evaluation and clinical management.
BACKGROUND:Familial cancer aggregation has been recognized for more than 150 years. For much of that period, hereditary tumor predisposition was incorporated into tumor classification in a fragmented, organ-specific manner. Across successive editions, the WHO classification of tumours moved from morphology-based histologic typing toward an integrated classification that includes molecular pathology, inherited predisposition and, in the fifth edition, a dedicated framework for genetic tumour syndromes. SCOPE:This review traces the historical development of genetic tumor syndrome recognition, from 19th-century familial cancer pedigrees and mid-20th-century clinical syndrome delineation to the molecular definition of classic predisposition syndromes. It also examines how these entities were gradually incorporated into the WHO Blue Book editions. Particular emphasis is placed on the transition from organ-based coverage to a pathway-based classification organized around major cellular mechanisms, molecular pathways, clinical syndromes, and affected genes or genomic loci. CONCLUSIONS:The dedicated WHO framework for genetic tumour syndromes represents an important classificatory shift. It recognizes that constitutional and mosaic cancer predisposition cannot be adequately represented by organ-specific tumor taxonomy alone. For pathologists, this framework reinforces the diagnostic importance of tumor morphology, immunohistochemistry, and molecular findings as sentinel indicators of possible genetic predisposition. It also provides a standardized structure for comparing established syndromes, incorporating emerging entities and supporting clinical genetics, surveillance, family counseling, and epidemiological ascertainment.
Germline predisposition contributes to at least 10% of human malignancies and is identified in ∼8.5% to 10% of pediatric cancers, with notably higher frequencies in specific tumor types, including over 60% in adrenocortical carcinoma and 17% to 20% in osteosarcoma. In certain tumors, hereditary predisposition is a defining or highly characteristic feature. Advances in next-generation sequencing have significantly reshaped our understanding of hereditary tumor biology, revealing molecularly distinct neoplasms linked by shared germline alterations and enabling the recognition of new cancer predisposition syndromes. This evolving knowledge is reflected in the WHO Classification of Tumors: Genetic Tumor Syndromes, which provides an integrated, cross-disciplinary diagnostic framework. Surgical pathologists play a central role in this landscape. Careful morphologic assessment, supported by targeted immunohistochemistry and clinical context, often allows the pathologist to identify features of germline predisposition-sometimes as the first or only clinician to do so, even in the absence of a relevant family history. This review highlights 13 practical morphologic and clinicopathological clues that should prompt consideration of a hereditary tumor syndrome, summarizes key immunohistochemical tools for syndromic triage, and presents an organ-based overview of major hereditary cancer syndromes. The goal is to provide a practical framework to support the pathologist's role in recognizing hereditary cancer.
Succinate dehydrogenase (SDH)-deficient tumors form an expanding, clinically important group of neoplasms driven by disruption of mitochondrial complex II through germline or somatic alterations in SDHA-D or SDHAF2 , or by epigenetic silencing within the pathway. For the surgical pathologist, recognition of SDH deficiency has immediate implications for risk stratification, treatment selection, and identification of patients who may require genetic counseling and family surveillance. This review provides a practical, pathology-focused overview of SDH-deficient tumor syndromes, emphasizing the clinicopathologic spectrum of paraganglioma-pheochromocytoma syndromes (PGL1-5), SDH-deficient gastrointestinal stromal tumor, SDH-deficient renal cell carcinoma, Carney-Stratakis syndrome, and Carney triad. We highlight recurring morphologic cues across tumor types, outline a stepwise workflow integrating histology, SDHB and SDHA immunohistochemistry and targeted molecular testing, and discuss interpretive pitfalls.
DICER1 syndrome is an autosomal dominant tumor predisposition disorder caused by pathogenic variants in the microRNA-processing gene DICER1. Since its initial recognition in families with pleuropulmonary blastoma, the phenotypic spectrum has expanded to encompass a wide array of benign and malignant neoplasms-including thyroid follicular nodular disease, Sertoli-Leydig cell tumor, cystic nephroma, pituitary blastoma, and embryonal rhabdomyosarcoma of the cervix-often presenting in childhood or early adulthood. This updated review synthesizes current knowledge of DICER1 biology, the historical evolution of the syndrome, the distinctive clinicopathologic features of associated tumors, provides a practical diagnostic algorithm to guide pathologists in recognizing sentinel lesions and initiating germline testing, and recent advances in the study of this syndrome and the DICER1 gene. By integrating molecular mechanisms with evolving clinical practice, this article aims to equip diagnostic pathologists and multidisciplinary teams with diagnostic tools and correlations for the detection and management of DICER1 syndrome.
The focus of this review is the clinical and pathologic presentations of hereditary cancer syndromes with cutaneous manifestations, with the goal of providing a reference for the multidisciplinary care teams involved in the diagnosis and management of these conditions. Advancements in genomics have led to newly recognized syndromes and a deeper understanding of established syndromes. We focus on those with the most relevant cutaneous manifestations. Clinical and histopathologic images provide visual context for these findings, many of which are rare. We summarize the established literature and incorporate new research and noteworthy case reports.
Molecular profiling is becoming crucial for accurate classification, prognostication, and therapeutic stratification for central nervous system (CNS) tumor classification since the advent of the WHO 2021 CNS tumor classification. However, in most of the low-income countries and middle-income countries, access to advanced molecular platforms remains limited due to cost, technical complexity, and turnaround time. Surrogate immunohistochemistry markers for mutation-specific or fusion-specific antibodies that reliably predict underlying genetic alterations offer a rapid, cost-effective alternative. The manuscript systematically discusses a spectrum of CNS tumor entities where morphology supplemented with immunohistochemistry can, in many cases, support an integrated molecular diagnosis, including “Astrocytoma, IDH-mutant“ (IDH R132H, ATRX, and p53), “Oligodendroglioma, IDH-mutant, and 1p/19q codeleted“ (HIP1R, H3K27me3 loss, and vimentin), “Diffuse midline glioma, H3K27-altered“ (H3K27M, EZHIP), “Diffuse hemispheric glioma, H3G34-mutant“ (H3G34R/V), “Infant-type hemispheric glioma“ (Pan-TRK, ALK), “Epithelioid glioblastoma“ and “Pleomorphic xanthoastrocytoma“ (BRAF V600E)), “Astroblastoma, MN1-altered“ (MN1), “Ependymoma“ subtypes (p65, L1CAM, EZHIP), “Medulloblastoma“ subgroups (β-catenin, LEF1, YAP1, GAB1), “Atypical teratoid/rhabdoid tumor“ (SMARCB1, SMARCA4), “CNS neuroblastoma, FOXR2-activated“ (FOXR2), “CNS tumor with BCOR ITD“ (BCOR), and various sarcomas and sellar tumors (STAT6, NKX2.2, DUX4, β-catenin, BRAF V600E). For each entity, detailed morphologic features, immunoprofiles, sensitivity/specificity data, and diagnostic caveats have been described. The review emphasizes that when interpreted alongside histomorphology and conventional markers, surrogate immunohistochemistry can significantly reduce reliance on molecular testing, expedite diagnosis, and improve accessibility of precision diagnostics. Standardization, validation, and awareness of pitfalls remain essential to maximizing their clinical utility in neuropathology practice.
Small round cell tumors (SRCT) affecting soft tissue and bone are a distinct category of malignancies. These lesions frequently exhibit similar clinical and radiologic features, may harbor overlapping histologic and immunophenotypic features, and generally have distinct prognostic outcomes. Therefore, in some instances, the diagnosis and accurate subclassification require molecular confirmation. We aimed to provide a comprehensive overview of the morphologic, immunohistochemical, and molecular features of SRCTs of soft tissue and bone in pediatric and young adult patients, with an emphasis on both commonly encountered tumors and rare, recently described entities, accompanied by illustrative material from our TruSight platform. The literature data were mined from the PubMed/Medline, Scopus, and Cochrane databases covering the period from January 1, 2014, to December 31, 2024, and the authors' personal experience with diagnostic cases at their institutions. We reviewed tumors that include sarcoma with EWSR1-non-ETS fusion, CIC-rearranged sarcoma, BCOR-rearranged sarcoma, Ewing sarcoma, alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, high-grade/round cell myxoid liposarcoma, poorly differentiated synovial sarcoma, small-cell type osteosarcoma, mesenchymal chondrosarcoma, and extraskeletal myxoid chondrosarcoma. Immunohistochemistry plays a crucial role in interpreting a specific diagnosis or narrowing the differential diagnosis of SRCTs. Molecular genetic investigations are essential, particularly in cases exhibiting atypical or overlapping histologic and immunohistological features.
Idiopathic adulthood ductopenia (IAD) is a rare chronic cholestatic liver disorder characterized by progressive loss of interlobular bile ducts in the absence of an identifiable etiology. Its histologic hallmark, ductopenia, is nonspecific and occurs across many cholestatic disorders, which complicates its recognition. IAD is therefore a diagnosis of exclusion, requiring thorough evaluation to rule out immune-mediated cholangiopathies, infections, genetic or metabolic diseases, drug-induced injury, and neoplasia. Advances in molecular diagnostics have increasingly uncovered monogenic cholangiopathies in adults previously classified as IAD, thereby narrowing the truly idiopathic category. In this article, we provide a comprehensive review of the disease, with emphasis on its clinical presentation, histopathologic characteristics, differential diagnoses, and emerging concepts.
Ex vivo digital microscopy uses light in the visible and adjacent spectra to obtain digital images of tissues. They are optical imaging techniques that allow the acquisition of digital images of tissues with minimal or no tissue preparation and are currently available for evaluation of fresh and/or fixed tissues. This review will provide an overview of the different types of ex vivo digital microscopy techniques, including confocal microscopy (CM), optical coherence tomography (OCT), stimulated Raman Spectroscopy (SRS), light sheet microscopy (LSM), microscopy with ultraviolet excitation (MUSE), structured illumination microscopy (SIM), and nonlinear microscopy (NLM). Except for OCT and SRS, all the other tissue imaging techniques require labeling of tissues with fluorescent dyes to obtain digital images. An advantage of several of these techniques, including fluorescence CM, SRS, LSM, MUSE, SIM, and NLM, is that they can produce hematoxylin and eosin-like images. The promising potential of ex vivo digital microscopy techniques in surgical pathology practice is supported by several retrospective and limited prospective studies. Applications of ex vivo digital microscopy techniques include real-time evaluation of fresh tissue at the bedside in clinics and radiology suites, as well as intraoperatively in pathology laboratories. These techniques have great potential for incorporation into standard-of-care surgical pathology practice.
Prostatic ductal adenocarcinoma (PDA) is a rare histological subtype of prostate carcinoma, first described by Melicow and Pachter in 1967 as "endometrial carcinoma of the uterus masculinus." The case for defining PDA as a separate entity rests on its distinctive morphology, aggressive clinical course, and, at times, unusual metastatic patterns. Yet, the frequent coexistence of PDA with acinar adenocarcinoma, together with molecular evidence pointing to a shared clonal origin-such as overlapping ERG rearrangements and other genomic alterations-suggests that PDA may instead represent a histologic variant of acinar prostate cancer. In this review, we explore what is currently known about PDA, tracing its epidemiology, clinical presentation, histopathology, molecular underpinnings, prognosis, and therapeutic challenges.
Hereditary renal cancer syndromes account for approximately 5% to 8% of all renal cell carcinomas (RCCs) and are caused by germline alterations, mainly in tumor suppressor genes. Advances in molecular testing have led to the identification of new hereditary syndromes and expanded our understanding of the genetic landscape of renal neoplasia. This review summarizes both well-established and recently described hereditary renal cancer syndromes, highlighting their clinical, pathologic, and molecular features. Emphases are placed on genotype-phenotype correlations and the relationship between germline and somatic alterations in tumors. Understanding these correlations is critical for diagnosis, risk assessment, surveillance, and management and underscores the importance of a high index of clinical suspicion for early detection to optimize patient outcomes.
