Histopathology[JOURNAL]
Sun
200 papers
Assessment of lymphovascular space invasion in cervical squamous cell carcinoma using digital pathology: a reproducibility study.
Talia KL, Soong TR, Kiyokawa T … +11 more , de Brot L, Wadee R, Wong R, Hodgson A, Dundr P, Ganesan R, Lax SF, Horn LC, McCluggage WG, Banet N, Stolnicu S
Histopathology · 2026 Jul · PMID 41804704 · Publisher ↗
INTRODUCTION AND AIMS: Lymphovascular space invasion (LVSI) is associated with increased nodal involvement and disease recurrence in cervical squamous cell carcinoma (SCC). While LVSI is currently included in some clinic...
INTRODUCTION AND AIMS: Lymphovascular space invasion (LVSI) is associated with increased nodal involvement and disease recurrence in cervical squamous cell carcinoma (SCC). While LVSI is currently included in some clinical risk assessment algorithms, the reproducibility of diagnosing LVSI remains understudied in cervical SCC. We aimed to assess the inter-observer agreement for LVSI diagnosis using digital whole slide images (WSIs) of haematoxylin and eosin-stained (H&E) slides with presumed true LVSI (n = 20) and LVSI mimics (n = 20) from early-stage cervical SCC identified in an international cohort. METHODS AND RESULTS: The reference diagnosis for LVSI status was established by 2 pathologists through consensus review. Ten independent pathologists from North and South America, Europe, Asia and South Africa were included for blinded scoring of true LVSI versus LVSI mimics. Complete concordance was seen in 57% of cases. Overall percent agreement was 88% with the κ value being 0.76, reflecting substantial agreement on LVSI diagnosis based on H&E WSIs. CONCLUSIONS: Our findings support the diagnostic feasibility and reliability of including LVSI as a parameter in routine histologic evaluation for risk stratification of cervical SCC. While the inter-observer agreement in our study is acceptable, there remains a need for standardised diagnostic criteria and guidance on the use of immunohistochemical studies for the detection or confirmation of LVSI in daily practice.
HMGA2 expression in CIC-rearranged sarcoma and other small round/epithelioid cell tumours.
Makise N, Kageyama H, Takeda N … +8 more , Oikawa M, Amano Y, Sugiyama T, Kinoshita H, Kamoda H, Hagiwara Y, Yonemoto T, Araki A
Histopathology · 2026 Jul · PMID 41804677 · Publisher ↗
AIMS: CIC-rearranged sarcoma (CRS), a highly aggressive sarcoma, is characterized by CIC fusion, with DUX4 being the most common partner. CRS is among the most difficult tumours to diagnose. Besides its relatively nonspe...
AIMS: CIC-rearranged sarcoma (CRS), a highly aggressive sarcoma, is characterized by CIC fusion, with DUX4 being the most common partner. CRS is among the most difficult tumours to diagnose. Besides its relatively nonspecific small round or epithelioid morphology, genetic analyses often fail to detect CIC rearrangements. Although several diagnostic markers for CRS, namely WT1, MUC5AC, ETV4 and DUX4, have been introduced, their accessibility and interpretability are limited. Prompted by previous RNA-seq studies, we investigated the diagnostic utility of HMGA2 immunohistochemistry. METHODS: HMGA2 immunohistochemistry was evaluated in institutional archival cases from 2000 to 2025. Nine CRS and 119 other small round/epithelioid cell tumours were included. GATA3 and FOSL1 were also tested in selected CRS cases. RESULTS: HMGA2 was frequently positive for CRS, with a sensitivity of 78% (strong expression) or 100% (any expression). It was positive in other small round epithelioid cell tumours, including a subset of Ewing sarcoma, EWSR1::NFATC2 sarcoma, sclerosing epithelioid fibrosarcoma, mesenchymal tumours with ACTB::GLI1 fusion, and malignant melanoma. Overall, the specificity was 82% (strong expression) and 70% (any expression). HMGA2 was more readily interpretable than WT1 and MUC5AC, and double-negative CRS cases were strongly positive for HMGA2. Three cases were negative for GATA3 and FOSL1. CONCLUSIONS: HMGA2 may be more readily implemented than ETV4 and DUX4, even in non-specialized hospitals. Thus, HMGA2 immunohistochemistry is a useful adjunct for CRS diagnosis. HMGA2 expression in CRS and other small round or epithelioid cell tumours should be tested in a larger series, particularly in non-DUX4 CRS and ATXN1/ATXN1L-rearranged sarcomas.
Why highly proliferative pancreatic neuroendocrine-like tumours require dual lineage assessment.
Sham S, Liu Q
Histopathology · 2026 Jun · PMID 41800484 · Publisher ↗
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Chronic ulcerative oesophagitis rich in IgG4-positive plasma cells - a distinct clinicopathological entity.
Henzinger H, Brown I, Gill AJ … +3 more , Slavik T, Zamboni G, Langner C
Histopathology · 2026 Jul · PMID 41800469 · Publisher ↗
AIMS: We present a series of patients with chronic, ulcerative oesophagitis refractory to proton-pump inhibitor therapy and rich in IgG4-positive plasma cells that do not strictly meet criteria for IgG4-related disease;...
AIMS: We present a series of patients with chronic, ulcerative oesophagitis refractory to proton-pump inhibitor therapy and rich in IgG4-positive plasma cells that do not strictly meet criteria for IgG4-related disease; aiming to characterize the clinical and histological pattern of this disorder. METHODS AND RESULTS: We retrieved cases of chronic ulcerative oesophagitis rich in IgG4-positive plasma cells, diagnosed from 2019 to 2025. Histological and immunohistochemical slides were re-evaluated and findings correlated with clinical data, including patients' symptoms, endoscopic findings and follow-up information. A total of 12 patients with a mean age of 63.1 years were included. Dysphagia was the most common symptom (9/12 patients), followed by heartburn (8/12 patients). Serum levels of IgG4 were elevated in four patients, in three accompanied by increased IgG levels. Other organ involvement by IgG4-RD was not observed. Endoscopy showed ulceration in 100% and stricture in 50% of cases, respectively; the lower third of the oesophagus was most commonly affected. Histology illustrated dense plasma cell-rich infiltration with a mean number of IgG4-positive plasma cells of 70/HPF (range 25-100) and a mean IgG4/IgG ratio of 73% (range 50%-90%). Corticosteroids led to improvement of symptoms in 8/9 and histological remission in 4/5 patients, respectively. CONCLUSION: Chronic ulcerative oesophagitis rich in IgG4-positive plasma cells may exert a severe clinical impact on affected individuals but appears to respond well to corticosteroid therapy. This case series demonstrates clinicopathological findings of the disorder and highlights the importance of IgG4 immunohistochemistry in therapy-refractory cases of chronic oesophageal ulceration with dense plasma cell-rich inflammation.
Identification of NTRK3 fusions in plaque-like CD34-positive dermal fibroma.
Cloutier JM, Lee M, Yeh I … +2 more , Jour G, Panse G
Histopathology · 2026 Jun · PMID 41755369 · Publisher ↗
AIMS: Plaque-like CD34-positive dermal fibroma (PDF), previously termed medallion-like dermal dendrocyte hamartoma, is a rare CD34-positive superficial spindle cell fibroblastic tumour that may closely mimic dermatofibro...
AIMS: Plaque-like CD34-positive dermal fibroma (PDF), previously termed medallion-like dermal dendrocyte hamartoma, is a rare CD34-positive superficial spindle cell fibroblastic tumour that may closely mimic dermatofibrosarcoma protuberans. Recent studies have identified recurrent kinase gene fusions in a subset of congenital and paediatric CD34-positive plaque-like superficial spindle cell tumours with overlapping clinicopathologic features, highlighting an emerging molecular framework for this group. However, the molecular spectrum of lesions meeting classic histopathologic criteria for PDF remains an area of active investigation. METHODS AND RESULTS: Four cases of PDF were identified retrospectively, and histopathologic and immunohistochemical findings were reviewed. RNA-based next-generation sequencing was performed to evaluate for potential oncogenic gene fusions. All cases demonstrated a superficial, dermal-based proliferation of bland spindle cells with a preserved Grenz zone and diffuse CD34 expression, without S100 expression. Two of four cases harboured in-frame NTRK3 fusions, including a novel SPTBN1::NTRK3 fusion and a PPFIBP1::NTRK3 fusion, both retaining the NTRK3 tyrosine kinase domain. Available clinical follow-up demonstrated indolent behaviour in all patients. CONCLUSIONS: NTRK3 gene fusions occur in a subset of plaque-like CD34-positive dermal fibromas, providing additional molecular insight into this rare superficial spindle cell lesion. Together with emerging literature, these findings support a role for recurrent kinase gene rearrangements in a subset of CD34-positive plaque-like superficial spindle cell tumours, while underscoring the continued importance of clinicopathologic correlation in defining this evolving spectrum.
3D virtual histology demonstrates tumour connectivity in spread through air spaces (STAS) of non-small cell lung cancer.
Saccomano G, Brun F, Martellani F … +5 more , Bottin C, Lovadina S, Troian M, Cova MA, Baratella E
Histopathology · 2026 Jul · PMID 41755362 · Publisher ↗
INTRODUCTION: As the nature of spread through air spaces (STAS) in non-small cell lung cancers (NSCLC) remains a matter of debate, this paper presented the first application of 3D X-ray virtual histology to shed light on...
INTRODUCTION: As the nature of spread through air spaces (STAS) in non-small cell lung cancers (NSCLC) remains a matter of debate, this paper presented the first application of 3D X-ray virtual histology to shed light on the origin of these elements. METHODS: Five adenocarcinomas and two squamous cell carcinomas were selected from a cohort of NSCLC cases to serve as representative examples of neoplasms in which the presence of STAS had already been assessed through conventional histology. Although available only for research purposes, synchrotron radiation X-ray phase-contrast micro-tomography (μCT) allows virtual sectioning of whole paraffin blocks with spatial and contrast resolution similar to that of histology, thus enabling examination of STAS patterns (e.g., single and clustered tumour cells, micropapillary, solid nests). RESULTS: The 3D results demonstrated that free-floating STAS (i.e., micropapillary and solid patterns) were observed to be only the edges of tumour cell clusters connected to the primary tumour. In contrast, STAS located near alveolar walls or vascular structures suggested tumour cell migration along these surfaces away from the primary tumour. CONCLUSION: These findings indicate that most STAS types are clusters of cells connected to the main tumour mass. 3D X-ray virtual histological investigation helps to understand the morphological composition and spatial evolution of the tumour, as well as the presence of a tumour larger than that visible in the histological slide. From a radiological and surgical perspective, these findings may influence the assessment of the extent of parenchymal involvement and help guide the surgical approach.
A series of extraskeletal myxoid chondrosarcomas with rare morphological and molecular variations.
Chen X, He X, Peng R … +2 more , Chen M, Zhang H
Histopathology · 2026 Jul · PMID 41755350 · Publisher ↗
AIMS: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma characterised by myxoid matrix, multilobular architecture, eosinophilic ovoid to short spindle cells arranged in cords, clusters or reticular...
AIMS: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma characterised by myxoid matrix, multilobular architecture, eosinophilic ovoid to short spindle cells arranged in cords, clusters or reticular patterns and NR4A3 gene rearrangement. However, some EMCs show morphological variations or non-EWSR1::NR4A3 fusion. We described herein five cases of variant EMCs. METHODS AND RESULTS: The five patients included two females and three males, aged 24-59 years (median: 49 years). The tumours were located in the dorsal region, buttock, thigh, paravertebral region and elbow, respectively. Grossly, the tumour sizes ranged from 4.0 to 16.0 cm (median: 6.5 cm) in greatest dimension. Morphological examination revealed tumours with varied growth patterns, including solid variants with eosinophilic proteinaceous fluid (n = 2), classic EMC morphology with rhabdoid cells (n = 1), a biphasic variant, composed of fibroblastic/myofibroblastic-like cells and oval to short spindle-shaped cells (n = 1), and a spindle-cell morphology with a myxoid stroma and prominent haemorrhagic cystic spaces (n = 1). Immunohistochemically, all cases showed variable expression of CD117. Next-generation sequencing (NGS) identified an EWSR1::NR4A3 fusion, a novel FUS::NR4A2 fusion, a novel ACTB::NR4A3 fusion, and two FUS::NR4A3 fusions. Follow-up for all five patients showed no signs of local recurrence or distant metastasis. CONCLUSION: These five cases of EMC highlight the continuous morphological spectrum of this tumour, demonstrating significantly greater histological diversity than classically described. The identification of novel fusion partners further expands its genetic landscape.
CD71 expression in Rosai-Dorfman disease: a useful adjunct marker in the differential diagnosis of histiocytic proliferations.
Ladak NN, Petrova-Drus K, Hameed MR … +3 more , Dogan A, Diamond EL, Yabe M
Histopathology · 2026 Jul · PMID 41749512 · Publisher ↗
AIMS: Accurate diagnosis of histiocytosis remains challenging due to overlapping morphologic and immunophenotypic features among subtypes, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease/xanthogran...
AIMS: Accurate diagnosis of histiocytosis remains challenging due to overlapping morphologic and immunophenotypic features among subtypes, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease/xanthogranuloma (ECD/XG) and Rosai-Dorfman disease (RDD). RDD is a rare disorder characterized by large S100-positive histiocytes with emperipolesis; however, emperipolesis may be difficult to recognize due to abundant admixed inflammatory cells or stromal fibrosis. Moreover, unlike LCH and ECD, RDD does not harbour BRAF V600E mutation, limiting the utility of high-sensitivity molecular analysis and mutant-specific immunohistochemistry for BRAF, which are available in many institutions. We observed the expression of CD71 in histiocytes in RDD. Therefore, we investigated the diagnostic utility of CD71 immunohistochemistry for RDD. METHODS AND RESULTS: We retrospectively reviewed electronic medical records to identify the cases of histiocytosis and reactive histiocytic proliferations. Clinical data and molecular results were also reviewed. The cohort comprised 58 cases, including RDD (n = 22), LCH (n = 6), non-LCH/ECD/XG (n = 14), histiocytic sarcoma (n = 4) and benign reactive cases (n = 12). CD71 demonstrated membranous and cytoplasmic staining in all RDD cases (22/22, 100%). In contrast, lesional cells in LCH were uniformly negative for CD71. Most non-RDD cases lacked CD71 expression, although dim cytoplasmic staining was observed in a subset of cases. Two sarcoidosis cases and one histiocytic sarcoma showed CD71 expression comparable to RDD. CONCLUSIONS: CD71 immunohistochemistry is a sensitive marker for identifying histiocytes in RDD and serves as a useful adjunct in distinguishing RDD from other histiocytic proliferations.
Characterizing pseudoangiomatous stromal hyperplasia (PASH) of the breast.
Koshy R, Jain PV, Jorns JM
Histopathology · 2026 Jul · PMID 41731999 · Publisher ↗
AIMS: To investigate the associated histopathology and immunohistochemical (IHC) profile of pseudoangiomatous stromal hyperplasia (PASH) of the breast in a large, contemporary cohort. METHODS AND RESULTS: We reviewed 193...
AIMS: To investigate the associated histopathology and immunohistochemical (IHC) profile of pseudoangiomatous stromal hyperplasia (PASH) of the breast in a large, contemporary cohort. METHODS AND RESULTS: We reviewed 193 benign breast biopsies with PASH from 185 patients without history of breast atypia or carcinoma. A tissue microarray was created and subjected to a panel of IHC. Ischemic fat necrosis was the most common finding in biopsies with PASH (181/193; 93.8%), while fibrocystic changes (170/193; 88.1%) were frequently present. PASH showed consistent, diffuse, strong staining for CD34 (193/193; 100%) and variable positivity for BCL-2 (66/193; 34.2%), SMA (47/193; 24.4%), desmin (11/193; 5.7%) and TRPS-1 (2/193; 1%), while all were negative for ERG and β-catenin. PR and ER positivity was identified in 33.7% (65/193) and 29% (56/193) of cases, respectively. Hormone receptor positive PASH was significantly associated with a higher rate of non-proliferative fibrocystic changes as compared to hormone receptor negative PASH (163/193; 84.5% vs 104/193; 53.9%, respectively) (P = 0.047). Subsequent breast atypia or carcinoma was uncommon (10/185; 5.4%), with median follow-up of 6.2 years (range 5.3-7.3 years). CONCLUSIONS: ER/PR expression in PASH is less frequent than previously reported by some studies. However, the frequency of fat necrosis and associated fibrocystic changes in PASH support a chronic, hormone-related process. Consistent CD34 positivity and absence of markers seen in histologic mimics aid in the diagnosis of PASH in challenging cases. PASH does not appear to impart increased cancer risk.
Ossifying spindled and epithelioid tumour: Expanding the clinical and morphologic spectrum of a recently described entity.
Sibira RM, Smith BF, Davis A … +7 more , Davis JL, Mohamed N, Zreik R, Papke DJ, Michal M, Wangsiricharoen S, Fritchie KJ
Histopathology · 2026 Jul · PMID 41731996 · Publisher ↗
BACKGROUND: Ossifying spindled and epithelioid tumour (OSET) is a recently defined soft tissue neoplasm with characteristic features, including a peripheral shell of bone or pseudocapsule, keratin expression, and indolen...
BACKGROUND: Ossifying spindled and epithelioid tumour (OSET) is a recently defined soft tissue neoplasm with characteristic features, including a peripheral shell of bone or pseudocapsule, keratin expression, and indolent behaviour. Here, we present five unique cases of OSET with novel clinical and morphologic features. MATERIALS AND METHODS: Cases of OSET were collected. Clinicopathologic and molecular features were documented. RESULTS: Cases of OSET were collected from lesions arising in the extremities of five patients, ranging in age from 8 to 58 years. Histologically, all tumours were well circumscribed and keratin-positive. Three showed a mixed spindle and epithelioid cell morphology, whereas two were composed predominantly of epithelioid cells. Two cases harboured mitotic rates of ≥5 mitotic figures per 10 high-power fields and contained necrosis. While peripheral pseudoencapsulation was consistent, two cases contained minimal peripheral ossification (approximately 5%), and two were entirely non-ossifying. One OSET case showed multifocal disease with synchronous tumours involving the elbow and wrist of the upper extremity; another represented a local recurrence 7 years after resection of the primary tumour; the remaining three patients are disease-free. Next-generation sequencing of tumour RNA revealed an SRSF7::NFATC3 fusion in the three cases evaluated. CONCLUSION: Our cohort expands the clinical and morphologic spectrum of this entity to include tumours with increased mitotic activity and necrosis, as well as highlights the first two examples of non-ossifying OSET. Moreover, while confirming the overall indolent behaviour of OSET, we described cases that demonstrate primary multifocal disease and local recurrence.
Real-world prevalence of PD-L1 positivity in early-stage/metastatic triple-negative breast cancer: primary results and pathology insights from the global retrospective observational VANESSA study.
D'Arrigo C, Tuzlali S, Barroso-Sousa R … +14 more , El Saghir NS, Dent R, Medić-Milijić N, Gong G, Sayed S, Anh TT, Zirtiloglu A, Hartleben G, Toro P, Estaytieh I, Weber E, Deurloo R, Mouta J, Popovic L
Histopathology · 2026 Jun · PMID 41725168 · Full text
AIM: To understand whether the worldwide implementation of PD-L1 testing in triple-negative breast cancer (TNBC) can be achieved in routine clinical practice. METHODS AND RESULTS: The multicentre retrospective observatio...
AIM: To understand whether the worldwide implementation of PD-L1 testing in triple-negative breast cancer (TNBC) can be achieved in routine clinical practice. METHODS AND RESULTS: The multicentre retrospective observational VANESSA study consecutively and uniformly enrolled patients treated with systemic therapy for early or metastatic (e/m)TNBC diagnosed between 2014 and 2017. PD-L1 status was retrospectively assessed locally and centrally using the VENTANA PD-L1 (SP142) Assay (PD-L1 expression on tumour-infiltrating immune cells covering ≥1% of the tumour area). The primary objective was to determine the prevalence of PD-L1 positivity assessed locally on primary and/or metastatic tumour tissue. Concordance between local and central testing was a secondary endpoint. PD-L1-positive prevalence was 38% in eTNBC (728/1902) and 20% in mTNBC (30/152) and was higher in submitted tissue size >5 versus <5 mm diameter (eTNBC: 43% versus 16%; mTNBC: 24% versus 13%). Among 1967 samples tested both centrally and locally, concordance was 75% (Cohen's κ coefficient 0.52, 95% CI 0.48-0.55) and was similar regardless of cohort (eTNBC versus mTNBC), sample collection method (biopsy versus resection) or sample origin (primary versus metastatic). PD-L1-positive prevalence was higher by central versus local assessment (eTNBC: 55% versus 39%; mTNBC: 26% versus 20%). CONCLUSION: In this real-world study, PD-L1-positive prevalence was lower than in prospective trials assessing PD-L1 status centrally, lower in mTNBC than eTNBC, lower in smaller than larger tissue samples and lower by local than central assessment. These findings underline the importance of central PD-L1 testing on sufficiently large samples to ensure optimal selection for therapies targeting PD-(L)1 in mTNBC.
Changes in the 6th edition of the World Health Organization classification of tumours of the digestive system.
Arends MJ, Esposito I, Gill AJ … +27 more , Hruban RH, Khoury JD, Kojima M, Montgomery EA, Abdulkareem F, Carneiro F, Costamagna G, Lauwers G, Polydorides AD, Rindi G, Rugge M, Schirmacher P, Srivastava A, Yao J, Hodge JC, Kench JG, Rekhi B, Reyes-Múgica M, Sepulveda AR, Shi C, Puspanathan P, Wijesinghe H, Giesen C, Ruiz BII, Lokuhetty D, WCT standing editorial board, Nagtegaal ID
Histopathology · 2026 Jun · PMID 41724188 · Full text
The 6th Edition of the WHO Classification of Digestive System Tumours represents a significant update to the 5th edition. It integrates pathological, new molecular, and clinical insights to refine the taxonomy of digesti...
The 6th Edition of the WHO Classification of Digestive System Tumours represents a significant update to the 5th edition. It integrates pathological, new molecular, and clinical insights to refine the taxonomy of digestive system neoplasms. The revised classification continues to emphasise standardisation in terminology, coding, and diagnostic criteria to facilitate global consistency in diagnosis, treatment, epidemiological reporting and research. Structural reorganisation of book chapters describes epithelial tumours by anatomical site, while separating neuroendocrine, mesenchymal and haematolymphoid tumours into dedicated chapters that are aligned with other WHO tumour volumes. Genetic tumour syndromes are classified by mechanisms, pathways and genes, whereas metastatic disease is comprehensively covered under other tumours and metastases. Key structural and diagnostic refinements include consolidation of gastric dysplasia entities; separation of duodenal/ampullary from jejuno-ileal tumours; clearer categorisation of colorectal serrated polyps and novel carcinoma grading; introduction of small- and large-duct intrahepatic cholangiocarcinoma as separate entities, and redefinition of undifferentiated carcinoma to include 'carcinoma with mesenchymal differentiation'. Several new entities are introduced, including oesophageal epidermoid metaplasia, colorectal intramucosal adenocarcinoma, low-grade tubuloglandular adenocarcinoma and lymphoglandular complex-like adenocarcinoma, intraductal tubulopapillary and intraductal oncocytic papillary neoplasms of the bile ducts and sonic hedgehog hepatocellular adenoma. The concept of amphicrine-like carcinoma (ALC) is distinguished from MiNEN and broadens the understanding of tumours with dual neuroendocrine-non-neuroendocrine differentiation. Grading systems are simplified to two-tier classifications (low/high grade) across precursor lesions, with enhanced criteria for neuroendocrine tumour grading. Anal canal neoplasia terminology is harmonised with human papillomavirus (HPV) related Lower Anogenital Squamous Terminology (LAST) and mass-forming biliary and gallbladder cancer precursors share similar terminology. Finally, carcinoma of unknown primary (CUP) is included in a separate section for the first time, classified by molecular and immunophenotypic profiles to guide therapy. Overall, the 6th edition strengthens tumour diagnostic precision and molecular alignment across the digestive system.
Diagnostic yield of OCT3/4 reflex testing in testicular biopsy.
Choiniere R, Boellaard WP, van Leenders GJ
Histopathology · 2026 Jul · PMID 41717809 · Publisher ↗
BACKGROUND AND OBJECTIVE: Occult germ cell neoplasia in situ (GCNIS) can occur in testicular biopsies prompted by male infertility with or without concomitant contralateral tumour. Immunohistochemistry can improve the di...
BACKGROUND AND OBJECTIVE: Occult germ cell neoplasia in situ (GCNIS) can occur in testicular biopsies prompted by male infertility with or without concomitant contralateral tumour. Immunohistochemistry can improve the diagnostic yield of GCNIS. The objective of this long-spanned retrospective single institutional series is to assess the value of OCT3/4 reflex testing on the detection of GCNIS. METHODS: Through a search of the pathology medical system, we included all men who underwent testicular biopsy for infertility, including cases with a known or suspected germ cell tumour (GCT) between 2010 and 2025. The detection of GCNIS was performed through histology and reflex use of OCT3/4 immunohistochemistry for all cases. RESULTS: The detection frequency of GCNIS was 48/3353 (1.4%) testicular biopsies from 42/1870 (2.2%) patients. Subtle interstitial seminoma was diagnosed in 3 patients adjacent to GCNIS. Patients with a concern for GCT were 6x more likely to be diagnosed with GCNIS on biopsy. Among patients with concern for GCT, no difference in GCNIS rate was found between patients with unilateral or bilateral sampling (P = 0.600). GCNIS was sometimes found adjacent to and even within tubuli with normal spermatogenesis. The frequency of GCNIS was similar (P = 0.277) among biopsies with no spermatogenesis, diminished spermatogenesis and intact spermatogenesis. CONCLUSIONS: This study assessed the diagnostic yield of OCT3/4 reflex testing in testicular infertility biopsies with a GCNIS rate of 1.4% and interstitial seminoma frequency of 0.2%. While a history of GCT or clinical suspicion of GCNIS was associated with a 6x higher risk of finding GCNIS, the level of spermatogenesis was not.
Clinicopathological and molecular genetic characteristics of Epstein-Barr virus-positive small cell neuroendocrine carcinoma of the nasopharynx.
Jian-Ping L, Yun-Li X, Xiao-Jiang W … +6 more , Huan-Huan Z, Shu-Yi L, Wen-Wen Z, Long-Feng K, Gang C, Yan-Ping C
Histopathology · 2026 Jun · PMID 41688220 · Publisher ↗
BACKGROUND: Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx) is exceptionally rare and aggressive, with poorly characterized molecular features. METHODS: Clinic...
BACKGROUND: Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx) is exceptionally rare and aggressive, with poorly characterized molecular features. METHODS: Clinicopathological, immunohistochemical (synaptophysin, INSM1, chromogranin A, CK-pan, EGFR, NUT, INI1), and molecular profiles of 15 EBV-positive SCNEC-nasopharynx cases (2012-2025) were analysed. EBV status was confirmed by EBER-ISH. Exploratory next-generation sequencing compared nine SCNEC with five EBV-positive nasopharyngeal non-keratinizing carcinomas (NKUC). RESULTS: Patients (median age 51; male:female = 2:1) presented with advanced-stage disease and cervical lymphadenopathy. Histology showed solid nests of small cells with high-grade features. All tumours were diffusely positive for synaptophysin and EBER, showed perinuclear dot-like CK-pan staining, and were negative for squamous markers and EGFR. NUT was negative and INI1 retained. Comparative genomics revealed greater mutational burden and unique alterations enriched in cell cycle/DNA damage pathways in SCNEC versus NKUC. After multimodal therapy, median overall survival was 33 months. CONCLUSION: This largest integrated study defines the distinct clinicopathological and molecular profile of EBV-positive SCNEC-nasopharynx. The identified diagnostic immunophenotype and potential oncogenic pathways provide a foundation for precise diagnosis and future targeted therapy development.
Human papillomavirus-associated adenoma of the anorectum.
Toro P, Fulmer C, Savage E … +1 more , Zhang X
Histopathology · 2026 Jun · PMID 41688214 · Full text
AIMS: Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States. HPV-associated invasive anorectal adenocarcinoma has been previously described. In this study, we report the clinicop...
AIMS: Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States. HPV-associated invasive anorectal adenocarcinoma has been previously described. In this study, we report the clinicopathological features of three HPV-associated anorectal adenomas. METHODS AND RESULTS: A retrospective review of anorectal adenomas identified 46 in-house cases. Chromogenic in situ hybridization (CISH) for low- and high-risk HPV subtypes was performed, and high-risk HPV was detected in one (2.1%) case. Additionally, two consultation cases of HPV-positive anorectal adenomas were included, yielding a total of three cases (two females and one male, ages 58-63). All three tumours were located in the surgical anal canal and exhibited similar histologic features, characterized by a predominantly villous or villoglandular architecture with slit-like serrations. The tumour cells exhibited eosinophilic to mucinous cytoplasm with apical mucin cups. The nuclei were crowded and oval- to cigar-shaped. The chromatin was mostly smooth and delicate without prominent nucleoli. Additional immunohistochemistry performed on these HPV-positive adenomas revealed diffuse positivity for p16, CK7 and MUC5AC, with variable CDX2 expression. CONCLUSIONS: HPV-associated anorectal adenomas are a distinct and rare entity. To the best of our knowledge, this is the first clinicopathological report of well-documented high-risk-HPV-associated anorectal adenomas. Increased awareness of this entity among pathologists will enable larger scale studies to further understand the pathogenesis of HPV-associated anorectal adenocarcinoma.
Malignant struma ovarii: Advances in molecular pathogenesis, classification, diagnosis and treatment.
Lin W, Zhou X, Wang Y … +1 more , Zhou F
Histopathology · 2026 Jul · PMID 41684192 · Publisher ↗
Malignant struma ovarii (MSO) is an extremely rare ovarian teratoma containing malignant thyroid tissue, typically presenting in middle-aged women. Molecularly and histologically, MSO mirrors thyroid carcinoma and includ...
Malignant struma ovarii (MSO) is an extremely rare ovarian teratoma containing malignant thyroid tissue, typically presenting in middle-aged women. Molecularly and histologically, MSO mirrors thyroid carcinoma and includes analogous subtypes as defined in the 2022 WHO classification: 'BRAF-like' tumours (commonly driven by BRAF^V600E mutations or kinase fusions) and 'RAS-like' tumours (driven by mutations in the RAS pathway), along with rare high-grade variants with aggressive behaviour. Next-generation sequencing shows that MSO harbours a mutational spectrum closely matching primary thyroid cancers. Genotype-guided targeted therapies (e.g. BRAF/MEK inhibitors, selective RET or NTRK inhibitors and multikinase inhibitors) are emerging as promising options for advanced or radioiodine-refractory cases. Surgical excision of the ovarian tumour is typically curative for localized disease. Thyroidectomy followed by radioactive iodine (RAI) is reserved for high-risk tumours. Long-term surveillance is essential, as late recurrences can occur. In this first comprehensive review of MSO, we integrate our own case series findings with published data to provide an up-to-date synthesis of its clinicopathologic spectrum and management.
Genomic and clinicopathological characteristics of low oncotype recurrent score breast cancers with subsequent metastasis.
Liu L, Graff SL, Hacking S … +2 more , Cheng L, Wang Y
Histopathology · 2026 Jun · PMID 41664643 · Publisher ↗
AIMS: Oncotype DX has played a critical role in guiding treatment decisions for hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. Clinically, a subset of patients with low Oncotype recurrent score...
AIMS: Oncotype DX has played a critical role in guiding treatment decisions for hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. Clinically, a subset of patients with low Oncotype recurrent score (RS) will still progress on standard therapy and ultimately develop metastasis. Our goal was to explore potential molecular mechanisms, including specific genetic alterations and pathway activity associated with disease progression. METHODS AND RESULTS: We retrospectively reviewed a small series of low RS breast cancers with subsequent metastasis and analysed the clinicopathological characteristics and comprehensive genomic profiling (CGP) data from tumour tissue and circulating tumour DNA (ctDNA) by liquid biopsy. RESULTS: These tumours demonstrated a range of histopathologic features and molecular profiles. Common findings included enrichment of PIK3CA and TP53 mutations and treatment-emergent ESR1 mutations, observed in both tissue and ctDNA. CDKN2A, SPEN, KIT, CTNNB1, MYC, EMSY, KMT2C, MAP3K1 gene alterations were only found in low RS group in low frequency. Copy number amplifications events were less common in low RS group. In cases with both tissue and ctDNA data, tissue CGP proved useful baseline for identifying driver mutations such as PIK3CA and for contextualizing ctDNA findings, and ctDNA analysis was adequate for disease monitoring and tracking molecular evolution over time. CONCLUSIONS: Using real-world CGP of tumour tissue and ctDNA, we identified key molecular features associated with endocrine resistance in patients with low RS who later developed metastases. PIK3CA mutation and other ER group-related mutations contributed to the low RS. Tissue CGP provides baseline for interpreting ctDNA, and ctDNA monitoring PIK3CA, TP53, ESR1 and other pathogenic or driver mutations in the early course of low RS cases may represent an excellent non-invasive option for identifying targets and early intervention to prevent disease progression, though a large validation study is needed.
PTEN frameshift mutation in two atypical meningiomas: case reports and review of the literature.
Yeldir N, Tahta A, Çakır A … +1 more , Şekerci Z
Histopathology · 2026 Apr · PMID 41652604 · Publisher ↗
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The role of rapid IHC in elevating STAS diagnostic accuracy during intraoperative frozen section for lung adenocarcinoma.
Lu J, Zhang L, Zhao S … +3 more , Ren Y, Wu C, Xie H
Histopathology · 2026 Jun · PMID 41652310 · Publisher ↗
AIM: The aim of this study was to evaluate whether the utility of cytokeratin (AE1/AE3) rapid immunohistochemistry (IHC) in combination with haematoxylin-eosin (H&E) staining improves the intraoperative diagnosis of spre...
AIM: The aim of this study was to evaluate whether the utility of cytokeratin (AE1/AE3) rapid immunohistochemistry (IHC) in combination with haematoxylin-eosin (H&E) staining improves the intraoperative diagnosis of spread through air spaces (STAS) on frozen sections (FS). METHODS AND RESULTS: This study included 153 patients. Three pathologists independently evaluated STAS on FS using either HE staining alone or in combination with rapid IHC, with postoperative paraffin sections serving as the gold standard. Sensitivity and specificity were compared, along with interobserver and intraobserver agreement (κ values), diagnostic time, and causes of misdiagnosis. Compared with HE alone, HE combined with rapid IHC staining increased mean diagnostic sensitivity from 73.7% to 87.8% and specificity from 85.5% to 89.9% across pathologists with varying levels of experience. Mean intraobserver agreement improved from κ = 0.644 (83.9%) to κ = 0.907 (95.9%), and mean interobserver agreement improved from κ = 0.485 (65.0%) to κ = 0.671 (77.2%). Average diagnostic time decreased from 2 min 53-23 s. Misdiagnoses were primarily attributable to a limited number of STAS clusters, confusion with macrophages, and artefacts. CONCLUSIONS: Intraoperative H&E combined with rapid IHC enhanced the sensitivity and specificity of STAS detection, improved interobserver/intraobserver agreement and reduced diagnostic time during FS evaluation without significantly extending the overall intraoperative FS processing time. Nevertheless, additional multicenter validation is required.
PAX8-positive conventional urothelial carcinomas of the urinary bladder and their distinct molecular profiles - A clinicopathologic study of 101 consecutive cases with next-generation sequencing in 20 cases.
Lammert SM, Luo W, Zhu AC … +3 more , Wang P, Antic T, Kwon JW
Histopathology · 2026 Jun · PMID 41652309 · Full text
AIMS: PAX8 immunohistochemistry (IHC) is often used to distinguish urothelial carcinomas (UCs) from tumours of renal and Mullerian origin. However, some UCs have been shown to be PAX8-positive. This study investigates th...
AIMS: PAX8 immunohistochemistry (IHC) is often used to distinguish urothelial carcinomas (UCs) from tumours of renal and Mullerian origin. However, some UCs have been shown to be PAX8-positive. This study investigates the frequency of PAX8-positive conventional UCs of the urinary bladder without subtype morphology and/or divergent differentiation and their molecular profiles. METHODS: One hundred and one consecutive transurethral resections of the urinary bladder from 2019 to 2022 with a diagnosis of conventional urothelial carcinoma (UC) without subtype morphology and/or divergent differentiation were retrospectively reviewed. Representative sections were selected for whole-slide PAX8 IHC (10336-1-AP; polyclonal). Next-generation sequencing (NGS) was performed on all PAX8-positive cases and on a subset of PAX8-negative cases. RESULTS: PAX8 IHC was positive in 10% (10/101) of cases. Twenty cases underwent NGS, including all 10 PAX8-positive UCs. All PAX8-positive UCs had TERT promoter mutations. TSC1 alterations, NOTCH1 loss and WT1 loss were more frequent in the PAX8-positive cases compared with the PAX8-negative cases. RB1 loss was not seen in the PAX8-positive UCs, while it was present in 40% of the PAX8-negative UCs. CONCLUSIONS: A subset of conventional UCs of the urinary bladder without subtype morphology and/or divergent differentiation are PAX8-positive and have frequent alterations in TERT promoter, TSC1, NOTCH1, and WT1, with an absence of RB1 loss. PAX8 positivity should be interpreted with caution if UC is in the differential, and NGS could be helpful in diagnostic workups as this study shows PAX8-positive UCs may have a distinct molecular profile.
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