Virchows Archiv最新文献

Intra-adrenal (historically "pheochromocytoma") and extra-adrenal paragangliomas (PPGLs) represent a unique subset of non-epithelial neuroendocrine neoplasms that feature remarkable biological diversity with significant diagnostic complexity. Over the past decade, advances in molecular genetics, biomarker discovery, and integrative tumor classification have transformed our understanding of PPGL pathobiology and redefined the pathologist's role in their diagnosis and clinical management. This review outlines the current multidisciplinary approach to PPGLs, emphasizing practical diagnostic strategies, germline susceptibility testing, and evolving concepts in molecular risk stratification. Pathologists are now central to identifying heritable disease through a thorough morphology assessment and molecular immunohistochemistry, interpreting germline variants of uncertain significance, and integrating genomic and biochemical data into diagnostic reports that inform clinical management. Traditional morphology-based scoring systems such as PASS and GAPP have demonstrated limited prognostic reliability, leading to their replacement by dynamic, multidimensional models that combine histopathological, clinical, biochemical, and molecular features. The 5th edition of the WHO Classification of Endocrine and Neuroendocrine Neoplasms recognizes all PPGLs as malignant non-epithelial (paraneuronal) neuroendocrine neoplasms with variable metastatic potential, underscoring the importance of cell proliferation (Ki67, mitotic count), and accurate biomarker profiling-including SDHB, FH/2SC, CAIX, and molecular cluster-specific markers-to guide the dynamic risk assessment and genetic counseling. By taking into account common daily practice challenges, this review summarizes the evolving pathology practice in PPGLs, highlights the role of biomarkers in the diagnostic workup of these neoplasms, and provides practical pitfalls in the distinction of metastatic disease from germline susceptibility-related multifocal PPGL. It also expands on a modern framework for pathology practice rooted in dynamic risk assessment and integrative endocrine oncology principles.

Gastric neuroendocrine neoplasms (gNENs) encompass all the spectrum of NENs including neuroendocrine carcinomas (gNECs), mixed neuroendocrine/non-neuroendocrine neoplasms (gMiNENs) and neuroendocrine tumors (gNETs). Differently from other digestive sites, gNETs are subclassified according to the clinicopathologic setting in which they arise, with important prognostic implications. Since gastric endoscopic biopsies represent a high-volume daily activity in both referral and community hospitals, pathologists should be increasingly aware of this disease. This will allow to correctly identify the different entities and, when present, their precursor lesions, giving useful information to clinicians for the best patient management. This review paper aims to provide morphologic, immunophenotypic, and, when necessary, molecular criteria for the correct diagnosis and subtyping of gNENs. In addition, a simplified prognostic classification schema of enterochromaffin-like (ECL)-cell NETs is proposed, based on gastrin serum levels and the status of gastric acid secretion.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms encompassing both well differentiate neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs). This classification is supported by distinct histological, clinical, and molecular profiles. NETs are typically slow-growing and hormone-producing, with organoid architecture and frequent associations with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) disease. In contrast, NECs are highly malignant, rapidly proliferating tumors characterized by mutations in adenocarcinoma-driver genes and in addition to TP53 mutations and RB1 inactivation, without hereditary links to endocrine tumor syndomes. Recent WHO classifications introduced site-specific grading systems, including NET G3 in the digestive, urogenital, gynecological and head and neck organs. There is growing evidence of progression from NET G1 to G3 with occasionally NEC-like features via acquired TP53 mutations. Advances in transcription factor profiling related to hormonal expression, molecular alterations resulted in further subtyping especially in pancreatic, pulmonary, and pituitary NETs. These tools support more precise treatment strategies. Genomic studies focusing on pancreatic NETs highlighted mutations in MEN1, DAXX, ATRX, and targets in mTOR pathway. NECs display higher tumor mutation burdens and harbor various actionable alterations. Approximately 5-10% of NETs are associated with hereditary syndromes, though recent findings suggest germline pathogenic variants, which were present in additional 5% of apparently sporadic NETs and NECs, requiring further study. An integrated histological, molecular, and clinical approach is essential to improve the classification, prognostication, and management of NENs, while recognizing the distinct biology of individual subtypes.

Pancreatic neuroendocrine tumours (PanNETs) are well-differentiated neoplasms that present with a variable clinical picture and prognosis. This makes accurate classification essential for guiding treatment and assessing outcomes. The current WHO classification system categorises PanNETs according to their proliferative activity. A morphological assessment combined with immunohistochemistry is central to the diagnosis, as it confirms neuroendocrine differentiation and rules out differential diagnoses. Nevertheless, panels targeting neuroendocrine and lineage-specific markers can enhance diagnostic confidence. Both histological and molecular predictive biomarkers are playing an increasingly significant role in tumour classification, prognosis and therapeutic decision-making. This review highlights the current morphological and immunohistochemical criteria for PanNET diagnosis and emphasises the growing importance of predictive biomarkers.

The 5th edition of the WHO classification of endocrine and neuroendocrine tumors represents a significant advancement in the diagnostic approach to adrenocortical carcinoma (ACC), integrating novel molecular insights with established histopathological criteria to enhance diagnostic accuracy and to refine prognostic assessment. This review outlines key histopathological features and diagnostic strategies for ACC, offering a practical framework for evaluation and grading in daily practice. The updated WHO classification reaffirms the central role of histopathology, employing multiparametric scoring systems that assess invasion, architectural and cytological features, mitotic activity, and necrosis. However, these parameters often pose interpretive challenges, and no single algorithm ensures complete sensitivity, specificity, or reproducibility. Therefore, combining diagnostic approaches is advisable, particularly in morphologically ambiguous cases. For tumor grading, the WHO employs a two-tiered system based on a mitotic count cut of 20 per 10 mm², aiming to improve interinstitutional consistency. Immunohistochemistry remains essential for diagnostic confirmation and prognostic evaluation. Among available markers, SF1 is the most specific for adrenocortical origin, while Ki-67, mismatch repair proteins, p53, and β-catenin are useful for predicting patient outcomes or screening for hereditary predisposition. In this complex diagnostic setting, artificial intelligence holds potential to support ACC diagnostics. However, its application is limited by the rarity of the disease, histological variability, and the scarcity of large, well-annotated datasets necessary for algorithm development.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors. The rarity of the disease, together with the lack of mutations in the classical tumor suppressor genes and the paucity of models, has impaired our understanding of the mechanisms of progression and the cell of origin of these tumors. Due to their higher frequency, this review focuses on Gastro-Entero-Pancreatic (GEP) and Lung NENs. While recent molecular profiling has shed light on the possible cell of origin of GEP- and lung NENs, many questions remain unanswered and further studies using proper in vitro and in vivo models are needed, combined with the latest technologies such as single-cell and spatial sequencing and deep-learning for digital pathology. Genomic and epigenomic evidence suggests that pancreatic NENs originate from adult pancreatic cells rather than common progenitor cells; however, ultimate proof in vitro or in vivo is still lacking. Similarly, emerging molecular evidence suggests that lung NENs may have very diverse origins, encompassing most lung cell types, but much work is still needed to pinpoint their cell of origin. Further, tumors with mixed endocrine and non-endocrine composition suggest the possibility of trans-differentiation and acquisition of neuroendocrine features in different cell types. This review aims to summarize emerging insights on this topic, highlight future directions for identifying the cell of origin of NENs in these organs and explore how this knowledge may ultimately translate into clinical advances.

Gastroenteropancreatic well-differentiated neuroendocrine tumors (NETs) exhibit markedly different behavior and responses to therapy compared to poorly-differentiated neuroendocrine carcinomas (NECs). However, in certain NETs-particularly grade 3 (Ki-67 > 20%) and the more recently recognized subgroup of G2b (Ki-67 of 10%- ≤ 20%)-often display ambiguous morphology or overlap with NECs and are associated with more aggressive clinical behavior, leading oncologists to consider whether these tumors may require management approaches similar to NECs. In some cases, a more aggressive clonal population evolves from a pre-existing NET. This may present as a distinct focus at diagnosis (suggesting intratumoral heterogeneity), or more commonly, a NET adopts NEC-like morphology and behavior over time (suggesting transformation). To distinguish these challenging cases, we recommend thorough pathological evaluation and a multidisciplinary approach. Particular attention should be given to necrosis, especially comedo-type patterns. Immunohistochemistry (IHC), including p53, Rb, and, if feasible, p16, ATRX, DAXX, and POU2F3 may provide insights Functional imaging-especially the DOTATATE to FDG uptake ratio-can further assist in assessing tumor behavior. These principles also apply to neuroendocrine neoplasms (NENs) associated with adenomas or adenocarcinomas. Occasionally, post-neoadjuvant resections reveal morphologically classic neuroendocrine component that were not identified in initial biopsies, raising questions about unsampled components, clonal selection, or therapy-induced change. In such cases, even when the Ki-67 index is low, NEC-like morphology should be documented in the report and the patient monitored closely due to the potential for progression. In conclusion, all gastroenteropancreatic neuroendocrine neoplasms should be extensively sampled for NEC-like features. A formal Ki-67 index must be determined using standardized methods. Cases with Ki-67 > 10% require careful evaluation. At minimum, patients should undergo close surveillance, with treatment plans reassessed if rapid progression or PET changes are observed.

Thyroid nodules represent a common clinical challenge, with 20-30% of fine-needle aspiration biopsies yielding indeterminate cytology results that complicate management decisions. While fine-needle aspiration cytology (FNAC) remains the gold standard for initial evaluation, up to 30% of cases produce indeterminate results, often leading to unnecessary diagnostic surgeries. This comprehensive review examines the transformative role of molecular diagnostics in thyroid pathology, focusing on their clinical utility, prognostic implications, and future directions. Molecular testing platforms, including Afirma GSC, ThyroSeq v3, and ThyroidPrint, have transformed the management of indeterminate thyroid nodules through gene expression profiling, mutation analysis, and microRNA signatures. The third-generation tests exhibit high sensitivity (91-100%) and negative predictive values (90-100%), thereby enabling surgical avoidance rates of 50.3-68.6% for patients with indeterminate cytology. The platforms employ both "rule-out" strategies (high sensitivity/NPV) and "rule-in" approaches (high specificity/PPV) to guide clinical decision-making. The paradigm of classifying thyroid tumors based on BRAF-like and RAS-like molecular profiles is becoming increasingly entrenched in clinical and diagnostic practice, affording pathologists and clinicians the ability to render diagnoses that are both more precise and reproducible. Within this molecular framework, the identification of markers such as TERT promoter and TP53 mutations, along with gene fusions, provides not only refined prognostic information but also facilitates the selection of patients for targeted therapeutic regimens including BRAF/MEK inhibitors and RET inhibitors. Nevertheless, the implementation of these advances is not without its impediments. The field continues to grapple with platform heterogeneity, economic constraints, and geographic disparities affecting access to comprehensive molecular diagnostics-factors that necessitate ongoing efforts to standardize testing and expand global availability. The future of this field is marked by several key developments, including the expansion of next-generation sequencing, the advancement of liquid biopsy technologies, the integration of artificial intelligence, and the adoption of multi-omic approaches. International guidelines are increasingly recommending molecular testing for advanced thyroid cancers and indeterminate nodules. These guidelines emphasize the need for standardized protocols and equitable access to such testing. Molecular diagnostics should be embraced as complementary tools within multidisciplinary care to optimize patient outcomes while reducing unnecessary interventions in thyroid nodule management.

Familial non-medullary, follicular cell-derived thyroid neoplasms represent a genetically diverse and under-recognized group of tumors arising from follicular epithelial cells. These familial thyroid tumors are subclassified into syndromes where thyroid tumors represent the major disease manifestation and syndromes with a predominance of non-thyroid neoplasms. Among the latter group, germline mutations in the DICER1 and PTEN genes are increasingly implicated in syndromic forms of follicular-derived thyroid disease. DICER1 syndrome and PTEN-hamartoma tumor syndrome, encompassing Cowden syndrome and related entities, confer a high organ-specific predisposition to benign and malignant thyroid lesions. Both syndromes demonstrate distinctive clinicopathologic patterns, including early-onset thyroid follicular nodular disease, multifocal follicular adenomas, and increased risk for thyroid malignancies. Recognizing clinical, anatomical, and histomorphological clues when evaluating thyroid specimens (particularly bilateral nodules, multinodularity, histologically distinct neoplasms, multiple adenomatous nodules, macrofollicular pattern, oncocytic features, unusual adenoma subtypes, young male gender, or early presentation) can prompt genetic evaluation. Here, we review the molecular pathogenesis, clinical features, histologic spectrum, and diagnostic strategies associated with familial follicular cell-derived thyroid tumors caused by DICER1 and PTEN germline alterations. Increased awareness of these entities by pathologists and clinicians is critical to ensure timely diagnosis, risk-appropriate surveillance, and cascade testing in affected families.