Virchows Archiv

Perren, Aurel; Scognamiglio, Theresa

doi: 10.1007/s00428-026-04395-4pmid: 41572001

Kasajima, Atsuko; Perren, Aurel; Klöppel, Günter

doi: 10.1007/s00428-025-04296-ypmid: 41483302

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.

Marinoni, Ilaria; Avanthay, Simona; Alcala, Nicolas

doi: 10.1007/s00428-025-04311-2pmid: 41238828

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.

Jesinghaus, Moritz; Schmitt, Maxime Philipp; Foersch, Sebastian; Konukiewitz, Björn

doi: 10.1007/s00428-025-04241-zpmid: 40931236

Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNEN) represent a heterogeneous group of bidirectionally differentiated epithelial malignancies that are, in most cases, highly aggressive. They are defined by the presence of morphologically distinct, yet clonally related, neuroendocrine and non-neuroendocrine components, each comprising at least 30% of the tumor mass according to current guidelines. Tumors that fall within the differential diagnostic spectrum of MiNEN include amphicrine carcinomas—characterized by the co-expression of neuroendocrine and non-neuroendocrine features within the same tumor cell—as well as conventional carcinomas that lack neuroendocrine morphology but exhibit immunohistochemical expression of neuroendocrine markers. However, these entities do not fulfill the current diagnostic criteria for MiNEN. In this review, we aim to outline the current diagnostic framework for MiNEN and examine the conceptual and classification boundaries of amphicrine carcinomas and conventional carcinomas with aberrant neuroendocrine marker expression in relation to what is presently defined as a MiNEN. In addition, we highlight key unresolved questions that should be addressed in future guidelines to streamline the diagnostic process and improve consistency. Finally, we provide an outlook on emerging technologies and future perspectives that may further refine the classification and clinical management of these complex neoplasms.

Bahceci, Dorukhan; Adsay, Volkan; Basturk, Olca

doi: 10.1007/s00428-025-04336-7pmid: 41276674

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.

Tihy, Matthieu; Hercent, Agathe; Cros, Jérôme; Couvelard, Anne

doi: 10.1007/s00428-025-04320-1pmid: 41160108

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.

Uccella, Silvia; La Rosa, Stefano

doi: 10.1007/s00428-025-04340-xpmid: 41273419

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.

Dioufa, Nikolina; Baloch, Zubair W.

doi: 10.1007/s00428-025-04375-0pmid: 41413696

Encapsulated thyroid gland lesions, defined by complete or partial confinement within a fibrous capsule, are common findings in endocrine pathology but frequently pose diagnostic challenges. The primary difficulty lies in distinguishing benign, low-risk, and malignant neoplasms, particularly within the spectrum of follicular-patterned tumors. Accurate classification can be hindered by pitfalls such as differentiating true tumor capsule from peritumoral fibrosis, identifying capsular or vascular invasion versus reactive changes from preoperative fine-needle aspiration, and accounting for histologic and cytologic heterogeneity. In this review, we discuss the definition of true capsule and vascular invasion and how to contrast from mimics. We describe the wide spectrum of both follicular and non-follicular lesions encountered in the thyroid, and we propose a systematic diagnostic approach to encapsulated thyroid neoplasms, integrating ultrasonographic, cytologic, histologic, immunohistochemical, and molecular data, in an effort to optimize diagnostic accuracy and guide appropriate clinical management.

Dettmer, Matthias S.

doi: 10.1007/s00428-025-04334-9pmid: 41242985

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.

Rossi, Esther Diana; Piermattei, Alessia; Cianfrini, Federica; Cappoli, Natalia; Mulè, Antonino; Pantanowitz, Liron

doi: 10.1007/s00428-025-04349-2pmid: 41273420

Thyroid lesions are a common finding, especially in the adult population, based on the evidence that more than 50% of individuals have thyroid nodules. The increasing detection of these lesions is mostly due to frequent ultrasonographic head and neck evaluation, which can now identify small subcentimeter nodules. Fortunately, most of these nodules are benign (70%), with only 5–10% of them attributed as malignant lesions. However, the remaining 20% falling into the category of indeterminate lesions which can lead to some pitfalls and tricky evaluations. Since 1996, different classification systems have been introduced and among them, the most worldwide adopted is the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). It is well-known that TBSRTC as well as other classification systems, subclassified indeterminate lesions into subgroups which specifically for the TBSRTC include a) atypia of undetermined significance (AUS), b) follicular or oncocytic cell neoplasm (FN) and c) suspicious for malignancy (SFM). However, despite the high positive predictive value (97%-99%), sensitivity (65%-99%) and specificity (72%-100%) of thyroid FNAC, diagnostic pitfalls exist that can lead to false positive and/or false negative results. This inconvenience is mostly due to the overlapping of morphological features in terms of cells and even background. This review discusses the most important potential pitfalls in the cytologic evaluation of thyroid lesions that can lead to such diagnostic errors.