Loss of the myoepithelial cell (MEC) layer at the epithelial-stromal interface is a key histological marker of invasion in malignant breast lesions. However, certain benign and non-invasive entities may exhibit diminishe...Loss of the myoepithelial cell (MEC) layer at the epithelial-stromal interface is a key histological marker of invasion in malignant breast lesions. However, certain benign and non-invasive entities may exhibit diminished or absent MECs, creating significant diagnostic challenges and occasionally leading to erroneous interpretation as invasive carcinoma. Despite their bland cytology, some of these lesions, such as microglandular adenosis (MGA) and pleomorphic adenoma, display infiltrative-like growth patterns. Loss of MECs around proliferating epithelium-lined clefts accompanied by spindled stroma in malignant phyllodes tumours may mimic metaplastic carcinoma. Atypical MGA lacking MECs may resemble acinic cell carcinoma. Diagnostic clues include the benign or hyperplastic appearance of the lesional cells, their immunoprofile and the absence of a sudden transition between areas with and without peripheral MECs. Awareness of such entities is key to preventing overdiagnosis and inappropriate clinical management. This review discusses these lesions, highlights their differential diagnoses and outlines key diagnostic pitfalls. Practical guidance is also provided on the optimal use and interpretation of myoepithelial markers to improve diagnostic accuracy and reduce the risk of misclassification.
We present an update on the molecular pathology of prostate cancer, including its molecular classification, key driver gene and other somatic alterations, as well as current concepts around biomarker testing, with an emp...We present an update on the molecular pathology of prostate cancer, including its molecular classification, key driver gene and other somatic alterations, as well as current concepts around biomarker testing, with an emphasis on information pertinent to the surgical pathologist for their daily practice and communications with clinicians. For in depth coverage of the molecular and clinical features of potential prostate cancer precursors, including high grade prostatic intraepithelial neoplasia, the readers are directed to recent publications.
BACKGROUND: Gastric-type adenocarcinoma in situ (gAIS) is a rare, HPV-independent precursor of cervical adenocarcinoma with incompletely defined histogenesis. AIMS: To report a case of gAIS and its association with pylor...BACKGROUND: Gastric-type adenocarcinoma in situ (gAIS) is a rare, HPV-independent precursor of cervical adenocarcinoma with incompletely defined histogenesis. AIMS: To report a case of gAIS and its association with pyloric-type gastric metaplasia. MATERIALS AND METHODS: A case of gAIS in a 70-year-old woman with atypical glandular cells (Pap test) and negative HPV molecular testing was evaluated histologically and immunohistochemically. RESULTS: Conization revealed atypical glandular epithelium. The lesion was CK7/CDX2 positive, with mutant-type p53 expression, and negative for CK20, PAX8 and p16. Adjacent pyloric-type gastric metaplasia was identified. DISCUSSION: The association with pyloric-type metaplasia supports a possible metaplastic origin and highlights diagnostic challenges in limited samples. CONCLUSION: This case supports a possible link between gAIS and pyloric-type gastric metaplasia, underscoring the importance of accurate recognition in HPV-independent cervical lesions.
Yilmaz O, Aktaş BK, Tezcan N
… +3 more, Deshpande V, Adsay V, Vyas M
Histopathology
· 2026 Mar · PMID 41905349
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AIMS: Acinar cell carcinoma (ACC) is a lineage-specific carcinoma that occurs nearly exclusively in the pancreas. We report, to our knowledge, the first series of gallbladder carcinoma demonstrating extensive acinar diff...AIMS: Acinar cell carcinoma (ACC) is a lineage-specific carcinoma that occurs nearly exclusively in the pancreas. We report, to our knowledge, the first series of gallbladder carcinoma demonstrating extensive acinar differentiation in the absence of a pancreatic primary. METHODS: Three gallbladder carcinomas with extensive acinar differentiation were identified from an international cohort. Clinical, radiologic, macroscopic, histologic, immunophenotypic and molecular features were reviewed. RESULTS: All tumours lacked an associated pancreatic primary on imaging and clinical evaluation. Two tumours formed well-demarcated mural nodules lacking an exophytic mucosal component, while one tumour was associated with wall thickening. The neoplasms showed mural-based infiltrative lesions composed of nests and acinar structures of cells with amphophilic cytoplasm and prominent nucleoli. One tumour arose in association with high-grade dysplasia and BCL10-positive pyloric-type glands. Two tumours showed pure acinar morphology, while one demonstrated a mixed acinar cell carcinoma and small-cell carcinoma. Immunohistochemically, all tumours showed diffuse expression of trypsin, and two tumours showed diffuse BCL10 positivity. Molecular profiling revealed heterogeneous alterations including TP53 mutations in two cases, RB1 inactivation in the mixed tumour. CONCLUSIONS: Gallbladder carcinomas may rarely exhibit acinar differentiation that closely mirrors pancreatic ACC. Recognition of this phenotype expands the morphologic repertoire of gallbladder carcinomas.
AIMS: De-escalated treatment for ductal carcinoma in situ (DCIS) aims to prevent overtreatment of patients. However, patients diagnosed preoperatively with pure DCIS via core needle biopsy (CNB) may be upgraded to invasi...AIMS: De-escalated treatment for ductal carcinoma in situ (DCIS) aims to prevent overtreatment of patients. However, patients diagnosed preoperatively with pure DCIS via core needle biopsy (CNB) may be upgraded to invasive cancer upon excision. Therefore, it is essential to stratify patients at low risk for upgrade to invasive disease during the biopsy to inform management decisions. METHODS AND RESULTS: In this study, we reviewed a cohort of patients with pure DCIS diagnosed by CNB and their corresponding excision specimens to identify predictive features for upgrading to microinvasion or invasive breast cancer (IBC). Of the 228 CNB cases, 82 (36%) were upgraded at excision, with 26.8% classified as microinvasion and 73.2% as frank invasion. Significant tumour intrinsic features associated with DCIS upgrade included larger tumour size, palpable mass, high grade and presence of necrosis (P ≤ 0.026). Factors related to sampling adequacy, such as the number of cores, total core length and length of the longest core, were also predictive features (P ≤ 0.027). Additionally, tumour microenvironment (TME) characteristics, including calcification and stromal tumour-infiltrating lymphocytes (sTIL), were linked to upgrades, particularly in the human epidermal growth factor 2 (HER2)-negative subgroup (P ≤ 0.004). These features were independently associated with frank invasion in HER2-negative cancers. CONCLUSIONS: Our results provide valuable insights into additional predictive features for DCIS upgrade. When combined with adequate sampling and intrinsic tumour characteristics, TME features-namely tumour infiltrating lymphocytes (TILs) and calcification-are useful in predicting DCIS upgrades, especially in HER2-negative cases.
André E, Mebarki L, Ilie M
… +8 more, Subtil F, Bournaud C, Borson-Chazot F, Descotes F, Lifante JC, Bertholon-Grégoire M, Lasolle H, Decaussin-Petrucci M
Histopathology
· 2026 Mar · PMID 41902450
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OBJECTIVE: To validate whether the 2022 WHO classification improves the prediction of radioactive iodine refractory (RAIR) disease in advanced-stage thyroid carcinomas and to identify associated histological predictive f...OBJECTIVE: To validate whether the 2022 WHO classification improves the prediction of radioactive iodine refractory (RAIR) disease in advanced-stage thyroid carcinomas and to identify associated histological predictive factors. METHODS AND RESULTS: A prospective cohort of 253 patients with pT3, pT4, or M1 thyroid carcinomas (TNM 2010), who underwent surgery between 2009 and 2018 and received at least one radioactive iodine dose, was analysed. Histological slides were reviewed using the 2022 WHO criteria, and clinical data were collected. Cox survival analyses and ROC curve evaluations were performed to identify factors associated with RAIR progression and assess the predictive performance of the new classification. Reclassification identified 28 low-risk neoplasms, all with favourable outcomes. Among the remaining 225 malignant cases, 155 were well-differentiated carcinomas (including 146 papillary carcinomas, 56 of which were aggressive subtypes) and 70 were high-grade carcinomas (39 high-grade differentiated and 31 poorly differentiated carcinomas). Forty patients (17.7%) developed RAIR disease. The 2022 WHO classification showed superior predictive performance compared with the 2004 WHO (AUC: 0.81 versus 0.60, P < 0.001). Multivariate analysis identified tumour necrosis as independent predictive factor of RAIR disease, regardless of the mitotic index. CONCLUSION: The 2022 WHO classification improves RAIR disease prediction, notably by recognizing high-grade carcinomas as a distinct entity. High-grade factors, especially tumour necrosis, which emerges as a key predictive factor, should be systematically reported in thyroid carcinoma pathology reports to enhance patient management and follow-up.
Histopathology
· 2026 Mar · PMID 41902447
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AIMS: Kaposiform haemangioendothelioma (KHE) is a rare vascular neoplasm of infancy and childhood that typically affects the soft tissues of the extremities; however, a variety of visceral sites have been reported. When...AIMS: Kaposiform haemangioendothelioma (KHE) is a rare vascular neoplasm of infancy and childhood that typically affects the soft tissues of the extremities; however, a variety of visceral sites have been reported. When KHE is located within the liver hilum, it may involve hilar structures and lead to secondary changes in the hepatic parenchyma. We report the histological changes in the explant livers of two patients transplanted for liver failure secondary to clinically unsuspected KHE at the hepatic hilum. METHODS AND RESULTS: Patient A initially presented with the signs and symptoms of liver failure at the age of 6. Despite extensive clinical work up, no aetiology was identified and she was diagnosed with 'cryptogenic cirrhosis'. The patient underwent liver transplantation at age 23, and her explanted liver revealed a vasoformative tumour within the hilum surrounding branches of the portal vein. Immunohistochemistry confirmed a diagnosis of KHE. Her peripheral liver showed features of obliterative portal venopathy and nodular regenerative hyperplasia. There was no evidence of cirrhosis. Patient B presented at age 7 with obstructive features of liver failure. Based on imaging studies and initial liver biopsies, a diagnosis of 'primary sclerosing cholangitis' (PSC) was rendered. However, liver transplantation at age 11 revealed KHE at the hepatic hilum surrounding the common hepatic duct. The peripheral liver demonstrated biliary-pattern cirrhosis with periductal fibrosis and ductular reaction, supporting a diagnosis of secondary sclerosing cholangitis rather than PSC. CONCLUSIONS: In conclusion, changes seen in peripheral liver biopsies can sometimes be a consequence of unsampled lesions at the liver hilum. KHE is a very rare example of this, but this scenario should be considered when liver biopsy findings do not correlate well with the clinical history.
Miyaoka M, Carreras J, Kikuti YY
… +19 more, Ikoma H, Nagase S, Ito A, Orita M, Kawada H, Sakai R, Sato Y, Nishimura MF, Tsukasaki K, Momose S, Kameoka Y, Yoshida M, Satou A, Kato S, Oishi N, Saito A, Sadahira K, Masugi Y, Nakamura N
Histopathology
· 2026 Jun · PMID 41883013
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AIMS: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent...AIMS: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent triple hit with BCL6 translocation (TH). DHL with MYC and BCL6 (DH-BCL6) can also occur. The differences among these three DLBCL/HGBCL subtypes have not yet been definitively determined. METHODS AND RESULTS: This study characterized the clinicopathological features and transcriptomic profiles of a series of 101 cases of DLBCL/HGBCL that were subclassified according to MYC, BCL2 and BCL6 FISH data, including cell-of-origin (COO)-like, molecular high-grade (MHG)-like and double-hit/dark-zone (DHIT/DZsig)-like signatures. DLBCL/HGBCL-DH-BCL2 was characterized by higher HGBCL morphology, CD10 positivity, GCB Hans's, GCB COO and MHG molecular subtype. DLBCL/HGBCL-TH had higher LDH levels and worse overall survival. DLBCL/HGBCL-DH-BCL6 had higher MUM1 expression, non-GCB Hans', ABC/Unclassified COO, non-MHG and low DHIT/DZ signatures. Transcriptomic analysis showed that DLBCL/HGBCL-DH-BCL2 and DLBCL/HGBCL-TH were close but separated from DLBCL/HGBCL-DH-BCL6. Gene set enrichment analysis (GSEA) revealed different levels of enrichment between the subtypes. CONCLUSIONS: DLBCL/HGBCL-DH-BCL6 differs from the DLBCL/HGBCL-DH-BCL2, and the DLBCL/HGBCL-TH is associated with the worst survival. Analysis of all three genes of MYC, BCL2 and BCL6 is recommended in the context of DLBCL/HGBCL diagnosis.
Koong JET, Shafique A, Md Nasir ND
… +7 more, Han A, Harada O, Lee S, Nishimura R, Ohi Y, Tizhoosh HR, Tan PH
Histopathology
· 2026 Mar · PMID 41853872
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BACKGROUND: Breast phyllodes tumours (PT) are rare biphasic neoplasms consisting of epithelial and stromal components. They are classified into benign, borderline and malignant categories. Diagnosing and grading PTs pres...BACKGROUND: Breast phyllodes tumours (PT) are rare biphasic neoplasms consisting of epithelial and stromal components. They are classified into benign, borderline and malignant categories. Diagnosing and grading PTs present a challenge for pathologists, as there are multiple histological parameters and their own tiers. We aim to investigate the potential role of artificial intelligence (AI) as a diagnostic aid in determining PT grade. MATERIALS AND METHODS: We investigated 15 PT whole slide images (WSIs), comprising 5 benign, 5 borderline and 5 malignant cases. We sought to classify and retrieve the most relevant WSIs by matching histological features at different patch sizes, using the Yottixel framework for WSI processing. Patches were extracted at a 20× magnification level. We then used the KimiaNet to extract feature vectors and transformed these into barcode representations. Barcodes of a query WSI were compared with those of others in the archive, allowing us to identify the most similar WSI and determine the PT grades from histological similarities. RESULTS: We utilized 'majority-n accuracy' as a measure of correctness, that is when the majority of the top-n search results have the correct diagnosis as the query patient. We achieved a maximum reported accuracy of 67%, with a 3000 × 3000 patch size when grading PT at majority voting with n = 4. CONCLUSION: Despite the small sample size and absence of fine-tuning, our study demonstrated the potential of AI-based PT grade stratification using various patch sizes through histological matching. This serves as a preliminary proof of concept, with the prospect of refinement for potential routine clinical application.
AIM: Whole slide imaging (WSI) scanners are fundamental to digital pathology, providing high-resolution digitized histology slides. While scanner models vary in throughput, usability and image quality, the impact of thes...AIM: Whole slide imaging (WSI) scanners are fundamental to digital pathology, providing high-resolution digitized histology slides. While scanner models vary in throughput, usability and image quality, the impact of these differences on pathologists' diagnostic performance remains insufficiently understood. This study evaluates the perceived image quality and diagnostic sufficiency of four commonly used high-throughput WSI scanners. METHODS AND RESULTS: We selected four bright-field WSI scanners: Leica's Aperio GT 450 DX, Hamamatsu's NanoZoomer S360, 3DHISTECH's Pannoramic 1000 DX and Philips' IntelliSite Ultra Fast Scanner (first generation). A set of 601 slides was digitized on each scanner, and 96 representative slides were selected for evaluation. Fourteen pathologists from the University Hospital of Augsburg's Institute of Pathology assessed sharpness, brightness, contrast, colour realism and artefact frequency. To evaluate diagnostic sufficiency, pathologists were asked whether each scanned image was adequate for making a precise diagnosis when considering brightness/contrast/colour realism, sharpness and artefact frequency. Significant differences in perceived quality were observed across scanners, yet diagnostic sufficiency was rated more positively overall. Here, the Aperio GT 450 DX and NanoZoomer S360 scanners were ranked equally, each achieving the highest median rating for all image quality aspects. The Pannoramic 1000 DX and IntelliSite UFS scanners closely followed with deficits in colour realism and sharpness, respectively. Depending on the scanner model, 4.2% to 22.2% of images were deemed insufficient for diagnosis, with performance varying by tissue type and staining method. CONCLUSION: Scanner differences in diagnostic sufficiency ratings were less pronounced than differences in perceived image quality. These findings highlight the importance of selecting appropriate scanning solutions based on workload and tissue characteristics.
Angerilli V, Vink-Börger ME, van Roermund NS
… +7 more, van Lijnschoten G, Kuijpers CCHJ, van Grieken NCT, Fassan M, Ijspeert JE, van der Post RS, Nagtegaal ID
AIM: Sessile serrated lesions with dysplasia (SSLd) are direct precursors of colorectal carcinomas (CRCs) but pose a diagnostic challenge. We aim to explore contemporary practice leading to recommendations to improve det...AIM: Sessile serrated lesions with dysplasia (SSLd) are direct precursors of colorectal carcinomas (CRCs) but pose a diagnostic challenge. We aim to explore contemporary practice leading to recommendations to improve detection of dysplasia. METHODS AND RESULTS: (i) The frequency of dysplasia in SSLs was estimated through a nationwide study of individuals undergoing colonoscopy in the Netherlands (2014-2022). Out of 186 427 SSLs, 17 456 showed dysplasia, yielding a frequency of 9.4%. (ii) A national audit evaluating diagnostic practices and interobserver variability revealed diagnostic discrepancies in 11% of SSLd cases, while ancillary immunohistochemistry (IHC) was used by only 20% of participating laboratories. (iii) The additional value of biomarkers (MLH1, p16, p53, beta-catenin and c-myc) was assessed using retrospective (n = 213) and prospective (n = 348) SSL cohorts. MLH1 emerged as the only useful biomarker for identifying dysplasia among SSLs, increasing SSLd diagnoses from 33 to 41 cases in the retrospective cohort (P = 0.008) and from 35 to 43 cases in the prospective cohort (P = 0.013). (iv) Misdiagnosis of SSLd among conventional adenomas was investigated using BRAF IHC in a cohort of 1572 advanced adenomas and was found to be very rare, occurring in only 2 cases. CONCLUSIONS: The diagnosis of SSLd appears to have good reproducibility among pathologists and positive diagnostic trends that are observed in recent years. MLH1 is the only IHC marker with robust clinical utility to identify SSLd that do not meet the morphologic criteria for overt dysplasia but should be used only in selected cases due to its low prevalence.
Lucà S, Montella M, Fordellone M
… +16 more, Monti R, Disanto MG, Zannini G, Accardo M, Ali M, Di Guida G, Della Corte CM, Leonardi B, Campione S, Nardone V, Morgillo F, Fiorelli A, Righi L, Barbareschi M, Brcic L, Franco R
AIMS: Accurate diagnosis of lung adenocarcinoma (LUAD), particularly in small biopsy specimens, can be challenging due to limited tissue availability and the presence of histological mimickers. Claudin-18 (Cldn18), a tig...AIMS: Accurate diagnosis of lung adenocarcinoma (LUAD), particularly in small biopsy specimens, can be challenging due to limited tissue availability and the presence of histological mimickers. Claudin-18 (Cldn18), a tight junction protein with a lung-specific isoform (Cldn18.1), is normally expressed in alveolar epithelium and is implicated in maintaining alveolar integrity. Loss of Cldn18 has been linked to LUAD development through dysregulated YAP signalling. This study evaluated Cldn18 expression across lung cancer subtypes, with particular focus on LUAD. METHODS AND RESULTS: Cldn18 immunohistochemical expression was retrospectively assessed in 391 lung resection specimens and 53 small biopsy samples. Normal alveoli and reactive pneumocytes consistently expressed Cldn18, whereas LUADs, especially non-mucinous LUADs (NM-LUADs), typically showed marked loss. Complete absence of Cldn18 was observed in 83% of NM-LUAD resections and 84.8% of NM-LUAD biopsies. ROC analysis demonstrated excellent diagnostic accuracy (AUC 0.992), with sensitivity of 98.4% and specificity of 100%. Lepidic NM-LUAD components, a frequent diagnostic pitfall especially in small specimens, showed low expression in most cases (>50% of tumour cells in 24/26). Similarly, 6/7 atypical adenomatous hyperplasia (AAH) cases exhibited low expression, while all reactive pneumocyte proliferations retained staining. By contrast, mucinous LUADs (M-LUADs) preserved Cldn18 expression in 35/54 cases, providing a clear distinction from NM-LUADs with mucin production. CONCLUSIONS: Cldn18 loss is a promising diagnostic biomarker for NM-LUAD. Complete loss of Cldn18 expression could serve as an ancillary tool for distinguishing malignant lesions from NM-LUAD mimickers and for differentiating NM-LUADs with mucin production from true M-LUADs, particularly in small or challenging biopsies.