Histopathology
· 2026 Jan · PMID 41384687
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Histopathology parameters are generally critical for the management of prostate cancer. Current practice is focussed on accuracy, precision, reproducibility, standardization and completeness of this data collection. This...Histopathology parameters are generally critical for the management of prostate cancer. Current practice is focussed on accuracy, precision, reproducibility, standardization and completeness of this data collection. This review discusses issues with this reporting practice and suggests a simpler alternative approach focussed on the clinical utility of pathology data and effective communication of the histopathology 'message'. The principles of prostate cancer detection and management are significantly different from those of other cancers. These differences could have important implications for the histopathological diagnosis and reporting of prostate cancer. Management decisions are often based on pathology data from nontargeted prostate biopsies that are subject to significant sampling error, which precludes accurate determination of tumour size and grade. In contrast to other solid tumours, definitive tumour size, grade, and stage are available only in the minority of patients who have undergone complete tumour excision (radical prostatectomy). The availability of a serum marker (prostate-specific antigen) for monitoring patients after prostate biopsy or prostatectomy would also significantly impact the clinical utility of histopathological data in these specimens. While it is necessary to report all mandatory data items, pathologists should focus their resources on data that are of clinical significance in an individual case. A pragmatic approach to prostate biopsy reporting with less emphasis on precise determination of tumour extent and grade is recommended.
Harrs CF, Pusala S, Cheng L
… +2 more, Jazayeri B, Li R
Histopathology
· 2026 Jan · PMID 41384686
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BACKGROUND: Genitourinary (GU) malignancies remain a global health challenge. While tissue biopsy is the diagnostic gold standard, its invasive nature and inability to fully capture tumour heterogeneity or minimal residu...BACKGROUND: Genitourinary (GU) malignancies remain a global health challenge. While tissue biopsy is the diagnostic gold standard, its invasive nature and inability to fully capture tumour heterogeneity or minimal residual disease (MRD) highlight the need for non-invasive alternatives. Liquid biopsy, analysing tumour-derived material in plasma or urine, has emerged as a promising tool for diagnosis, surveillance and response monitoring. METHODS: PubMed was searched to identify studies on liquid biopsy in GU cancers. Eligible studies reported diagnostic or prognostic performance of assays using circulating tumour DNA (ctDNA), urinary tumour DNA (utDNA), extracellular vesicles or RNA. Reviews and case reports were excluded. Articles were screened independently by three reviewers using Rayyan.Ai, with evidence synthesised narratively. RESULTS: In bladder cancer, utDNA-based assays-including methylation panels (BladMetrix, Bladder CARE), mutation assays (UroMuTERT) and capture-based sequencing-consistently achieved sensitivities of 80%-94% and specificities of 85%-95%, outperforming urine cytology and enabling detection of tumours years before clinical diagnosis. In upper tract urothelial carcinoma, utDNA methylation and mutation analysis demonstrated sensitivities of 80% and specificities up to 95%. In kidney cancer, ctDNA levels are relatively low; however, cell-free DNA methylation signatures (VHL, RNF185, RASSF1A) and cfMeDIP-Seq approaches have shown strong discriminatory power, with plasma-based assays achieving near 100% sensitivity in small studies. In prostate cancer, urinary RNA (PCA3, TMPRSS2:ERG), miRNA and metabolite-based assays achieved sensitivities and specificities ranging from 70% to 95%, with composite multigene panels (MyProstateScore2, utLIFE-PC) improving risk stratification beyond PSA alone. CONCLUSIONS: Liquid biopsy demonstrates strong diagnostic and prognostic potential across GU cancers. While bladder and prostate cancer assays are most advanced, emerging evidence in UTUC and kidney cancer is encouraging. Prospective, longitudinal validation remains essential before widespread clinical adoption.
Akgul M, George RS, Siegmund SE
… +4 more, Oktay M, Sangoi AR, Williamson SR, Cheng L
Histopathology
· 2026 Jan · PMID 41384685
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Molecularly defined renal carcinomas (MDRC) represent a heterogeneous group of tumours characterized by disease-defining genetic alterations, and the documentation of these mutations is necessary for their diagnosis. Thi...Molecularly defined renal carcinomas (MDRC) represent a heterogeneous group of tumours characterized by disease-defining genetic alterations, and the documentation of these mutations is necessary for their diagnosis. This group includes TFE3-rearranged renal cell carcinoma (RCC), TFEB-rearranged RCC, TFEB-amplified RCC, fumarate hydratase (FH)-deficient RCC, succinate dehydrogenase (SDH)-deficient RCC, SMARCB1-deficient renal medullary carcinoma (RMC), ALK-rearranged RCC, and ELOC-mutated RCC. Although they account for only about 5% of RCC, they are clinically significant due to distinctive biology, frequent diagnostic pitfalls, and therapeutic implications. Many pathology laboratories lack immediate access to fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) to confirm MDRC; this review emphasizes morphologic recognition and immunohistochemical surrogates, followed by rational triage for ancillary testing when available.
Shah RB, Varma M, Zhou M
… +29 more, Paner GP, Amin MB, Berney DM, Cheng L, Deng FM, Downes M, Eggener S, Ehdaie B, Epstein JI, Evans A, Fine SW, Greenland N, Guo C, Han B, Hirsch MS, Izkowski KA, Kench JG, Lotan TL, Magi-Galluzzi C, Miyamoto H, Nguyen JK, Tsuzuki T, van der Kwast TH, van Leenders GJ, Williamson SR, Wobker SE, Wu CL, Yang X, Kristiansen G
Histopathology
· 2026 Jan · PMID 41384645
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Conflicting practice recommendations regarding the grading of intraductal carcinoma of the prostate (IDCP) from two leading uropathology societies, the Genitourinary Pathology Society (GUPS) and the International Society...Conflicting practice recommendations regarding the grading of intraductal carcinoma of the prostate (IDCP) from two leading uropathology societies, the Genitourinary Pathology Society (GUPS) and the International Society of Urological Pathology (ISUP), are confusing for both pathologists and treating clinicians. The objectives of this consultation were to clarify unresolved issues regarding IDCP and atypical intraductal proliferation (AIP) terminology, diagnostic criteria, grading, and management implications, as well as to develop uniform reporting guidelines for IDCP and AIP, endorsed by both societies. A 32-member expert panel, composed of five core members, 25 expert urological pathologists, and two expert urologists, employed a modified Delphi process consisting of multiple rounds of consultation and voting. These were supplemented by discussions at the 2025 United States and Canadian Academy of Pathologists Annual Meeting to achieve expert consensus (defined as at least 67% agreement). Consensus was reached on several key issues. IDCP was regarded most commonly as reflecting the retrograde spread of invasive prostate cancer (PCa). IDCP diagnosis should be based on the Guo and Epstein criteria, supported by basal cell immunohistochemistry in cases that are difficult to distinguish from invasive PCa. The term AIP should be used only in equivocal proliferations where IDCP is favoured but the criteria are not fully met, and these should be reported as 'AIP, suspicious for IDCP'. In the presence of invasive PCa, IDCP should generally be incorporated into Gleason grading irrespective of Grade Group (GG). However, a significant minority (30%) favoured excluding IDCP from the Gleason score if the invasive component was solely Gleason pattern (GP) 3. Pure IDCP (not associated with invasive PCa) and AIP, suspicious for IDCP, should not be graded. IDCP should not be incorporated in the grading of invasive PCa when it is spatially distinct from invasive PCa. A second opinion from a senior or dedicated GU pathologist and discussion within a multidisciplinary management setting should be considered, in the rare settings of pure IDCP or GP3 + IDCP (formerly GG1 + IDCP scenario). This joint GUPS-ISUP consultation provides unified recommendations for the diagnosis, terminology, grading, and reporting of IDCP and AIP, and will pave the way for the development of future IDCP/AIP WHO guidelines. Their adoption should reduce interobserver variation, facilitate consistent communication with clinicians, and improve patient management.
Delgado Guillena PG, Cuatrecasas M, Montori S
… +27 more, Felipez Varela N, Llach J, Archilla I, Florez-Diez P, Barreiro-Alonso E, Tejedor-Tejada J, Vicente R, Soria MT, Huerta A, Ortega SP, Nuñez H, Patrón O, Mangas C, Zaffalon D, Hernández L, Yip LE, Hontoria G, Hijos G, Domper-Arnal MJ, Zarraquiños S, Herreros De Tejada A, Córdoba A, Cuestas A, Fernández-Esparrach G, Moreira L, Albéniz E, EpiGASTRIC/EDGAR Consortium
Histopathology
· 2026 Mar · PMID 41293900
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INTRODUCTION: The risk stratification of gastric cancer (GC) is graded by assessing well-established precursor lesions, glandular atrophy (GA), and intestinal metaplasia (IM), resulting in both the operative link on gast...INTRODUCTION: The risk stratification of gastric cancer (GC) is graded by assessing well-established precursor lesions, glandular atrophy (GA), and intestinal metaplasia (IM), resulting in both the operative link on gastritis assessment (OLGA), and intestinal metaplasia (OLGIM) systems. Although the OLGIM stage is reproducible among pathologists, the OLGA system is laborious to calculate and has poor reproducibility. In addition, it does not comprehensively address the severity of both GA and IM as recommended by the Sydney consensus. We aimed to propose the Operative Link on Gastric Intestinal Metaplasia and Glandular Atrophy Assessment (OLGIMA) system, which identifies OLGIM III-IV and upstages 0-II with advanced GA. METHODS: A cross-sectional study of consecutive diagnostic gastroscopies in adults was designed. Systematic gastric biopsies were taken. The updated Sydney guidelines were used for histological grading of GA and IM. Higher GC risk was defined as OLGIM III-IV and advanced GA. RESULTS: The OLGIMA stage was assessed based on the most severe GA and/or IM findings in both antrum and corpus. We included 998 patients (median age 57; 64% women; 35% Helicobacter pylori infection). Thirty-nine (3.9%) patients had higher GC risk: 17 (1.7%) with OLGIM III-IV; 12 (1.2%) with advanced GA, and 10 (1%) meeting both criteria. Among OLGIM 0-II, 12 (1.2%) patients had advanced GA. The OLGIMA system upstaged 39 (3.9%) patients to III-IV, being more sensitive than OLGIM. CONCLUSIONS: The new OLGIMA system identifies patients at higher GC risk (OLGIMA III-IV), encompassing all OLGIM III-IV patients, and upstaging those OLGIM 0-II with advanced GA. This approach addresses the OLGA and OLGIM limitations by integrating GA and IM severity as recommended by the Updated Sydney consensus.
Zanfagnin V, Hsu Lin L, Devins KM
… +2 more, Oliva E, Turashvili G
Histopathology
· 2026 Mar · PMID 41293895
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AIMS: Endometrial atypical hyperplasia and low-grade endometrioid carcinoma are often associated with morular squamous metaplasia. Limited evidence suggests that the finding of isolated morular squamous metaplasia withou...AIMS: Endometrial atypical hyperplasia and low-grade endometrioid carcinoma are often associated with morular squamous metaplasia. Limited evidence suggests that the finding of isolated morular squamous metaplasia without concomitant glandular neoplasia in biopsies is associated with a 6.5% risk of endometrial cancer in subsequent samples and warrants close follow-up. However, its prognostic value has not been clearly determined. METHODS AND RESULTS: The Massachusetts General Hospital pathology database was queried to identify endometrial samples with a diagnosis of 'adenoacanthosis', 'morular metaplasia', 'squamous metaplasia' or 'morular squamous metaplasia' between 2012 and 2024. Cases associated with endometrioid carcinoma, non-atypical or atypical hyperplasia, atypical polypoid adenomyoma and gland crowding insufficient for diagnosis of atypical hyperplasia were excluded. Clinicopathologic data were collected. Outcomes were categorized as regression, persistence and progression to carcinoma. Of 32,800 endometrial samples reported during the study period, isolated morular squamous metaplasia was diagnosed in 57 (0.17%), including 42 (73.7%) biopsies and 15 (26.3%) curettings. The median patient age was 45 (21-70) years. Histologic follow-up (at least one follow-up sample) was available in 22 patients (median 30 months, 1-120) and included endometrial biopsy, curettage or hysterectomy. Of these 22 patients, a single follow-up biopsy was performed in 9 (40.9%), a single curettage in 1 (4.5%), hysterectomy in 6 (27.3%), a single biopsy followed by hysterectomy in 2 (9.1%), multiple biopsies in 3 (13.6%) and a curettage followed by multiple biopsies and hysterectomy in 1 (4.5%). The median number of follow-up samples was 2 (2-9) per patient. Histologically, the follow-up samples were unremarkable (regression) in most patients (19/22, 86.4%), 2 (9.1%, aged 49 and 57 years) were diagnosed with grade 1 endometrioid carcinoma in subsequent hysterectomies, and 1 (4.5%, age 62) had persistent squamous morular metaplasia (follow-up 69 months). In 15 patients with clinical follow-up but no further pathology sampling, none had clinical symptoms at their last visit (100% clinical regression). Thus, the overall rate of endometrioid carcinoma was 5.4% (2/37). CONCLUSIONS: Isolated squamous morular metaplasia without associated glandular neoplasia is a rare finding, reported only in 0.17% of endometrial samples. The risk of subsequent endometrioid neoplasia appears to be low (5.4%), although the possibility of undersampled atypical hyperplasia/endometrioid carcinoma cannot be completely ruled out without additional sampling. Persistent squamous morular metaplasia is relatively uncommon (4.5%) and may not lead to the subsequent diagnosis of endometrial cancer, questioning the utility of numerous repeat samplings in patients without progression after one repeat sample.
Kroon LJ, Remmers S, de Vos II
… +5 more, Kweldam CF, Rijstenberg LL, van den Bergh RCN, Roobol MJ, van Leenders GJLH
Histopathology
· 2026 Mar · PMID 41293883
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INTRODUCTION: The Gleason grading system for prostate cancer (PCa) is based on the proportions of Gleason patterns (GP) 3-5. While pure GP3 has minimal metastatic potential, it is unclear whether GP3 quantity in the pres...INTRODUCTION: The Gleason grading system for prostate cancer (PCa) is based on the proportions of Gleason patterns (GP) 3-5. While pure GP3 has minimal metastatic potential, it is unclear whether GP3 quantity in the presence of GP4 and GP5 affects oncological outcomes. OBJECTIVE: To assess the predictive value of PCa biopsy GP lengths on long-term metastasis-free survival (MFS). METHODS: Prostate biopsies of 1,881 men with screen-detected PCa who participated in the Dutch part of the European Randomized Study of Screening for Prostate Cancer (ERSPC) between 1993 and 2007 were revised for GP 3-5 length. Multivariable Cox regression analyses were used to evaluate the relationship between GP lengths and MFS truncated at 20 years, adjusting for clinical-tumour stage (cT), prostate-specific antigen (PSA), percentage positive biopsies and the presence of invasive cribriform/intraductal carcinoma (CR/IDC). RESULTS AND LIMITATIONS: On multivariable analysis, ≥cT2, PSA, percentage positive cores and absolute length of GP4 and GP5 were all significantly associated with MFS. The discriminative ability was improved by adding CR/IDC to the model. Total GP3 length was neither associated with MFS in the model with (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.97-1.00, P = 0.3) nor without CR/IDC (HR 0.98, 95% CI 0.96-1.01, P = 0.2). A limitation is the lack of targeted biopsies. CONCLUSION AND CLINICAL IMPLICATIONS: GP3 length does not have an impact on the prediction of MFS in biopsies, once GP4/GP5 lengths are known. Although GP3 percentage is essential in Gleason grading, MFS is related to absolute GP4 and GP5 quantity rather than their proportion to GP3.
Cordier F, Van Dorpe J, Sciot R
… +10 more, Flucke U, Van Gorp J, Debiec-Rychter M, Van Belle S, Loontiens S, Van der Meulen J, Van Gaever B, Ferdinande L, Dedeurwaerdere F, Creytens D
Histopathology
· 2026 Mar · PMID 41293881
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CONTEXT: Nodular fasciitis (NF), myositis ossificans/fibro-osseous pseudotumor of the digits (MO/FP) and aneurysmal bone cyst (ABC) are grouped under the category of 'USP6-associated neoplasms' (UANs) due to their shared...CONTEXT: Nodular fasciitis (NF), myositis ossificans/fibro-osseous pseudotumor of the digits (MO/FP) and aneurysmal bone cyst (ABC) are grouped under the category of 'USP6-associated neoplasms' (UANs) due to their shared characteristic of an underlying USP6 rearrangement. OBJECTIVE: Our aim in this study is to investigate the diversity of USP6 rearrangements in UANs. DESIGN: We performed a clinicopathological and molecular investigation using targeted RNA sequencing on 124 cases of NF, 19 cases of MO/PF and 32 cases of ABC. Additionally, NF cases were scored for the presence of typical morphological features to assess their correlation with the detected USP6 fusion partner. RESULTS: In 85.4% of NF cases (88/103), we identified a USP6 rearrangement, with 46.6% exhibiting the classic MYH9::USP6 fusion and 53.4% displaying non-MYH9::USP6 fusions. Notably, classic histological features of NF strongly correlated with the presence of the MYH9::USP6 fusion, while specific NF locations (e.g. intramuscular, intra-articular and intradermal) were significantly associated with non-MYH9 fusions. This study identified 22 novel USP6 fusion partners, demonstrating the fusion diversity within UANs. Additionally, there was minimal overlap in USP6 fusion partners between different UAN types. CONCLUSIONS: A significant entity- and location-specific USP6 fusion partner diversity was revealed among the UAN members. This supports the hypothesis that this diversity may be linked to the cell of origin. Additionally, molecular analysis can be valuable in diagnosing non-classical NF.
Hung YP, Wannasai K, Meador CB
… +4 more, Ganci ML, Rider AB, Wang CI, Mino-Kenudson M
Histopathology
· 2026 Mar · PMID 41293870
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AIMS: Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be difficult to diagnose due to histological overlap with small cell lung carcinoma (SCLC). SCLC comprises multiple transcription factor-based subtypes. We...AIMS: Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be difficult to diagnose due to histological overlap with small cell lung carcinoma (SCLC). SCLC comprises multiple transcription factor-based subtypes. We aimed to evaluate the clinicopathological significance of transcription factor-based subtyping in pulmonary LCNEC. METHODS AND RESULTS: We identified a consecutive series of 117 patients in 2010-2024 with samples diagnosed as pulmonary LCNEC (n = 70) or high-grade neuroendocrine carcinoma with combined or intermediate morphology (n = 47). Cytomorphological score was assessed as a weighted average from two areas. Immunohistochemistry (IHC) for ASCL1, NeuroD1, POU2F3, YAP1, and HNF4A was evaluated using H-scores, with subtype assignment based on the highest H-score. Next-generation sequencing (NGS) was performed in selected cases. IHC subtyping identified 73 (62%) ASCL1-dominant, 20 (17%) YAP1-dominant, 9 (8%) NeuroD1-dominant, 7 (6%) POU2F3-dominant, 2 (2%) HNF4A-dominant, and 6 (5%) quintuple-negative samples. While YAP1 was often co-expressed with other subtypes and HNF4A was frequently co-expressed with ASCL1, POU2F3 was mutually exclusive from ASCL1/NeuroD1/HNF4A. Unlike ASCL1/NeuroD1/POU2F3, YAP1 and HNF4A H-scores each correlated with large-cell morphology-both across the entire cohort and in the lung resection subgroup. NeuroD1 dominance was more common in tumours with combined/intermediate morphology than LCNEC. Some of the tumours with intermediate morphology straddling between prototypical LCNEC and SCLC harboured POU2F3 dominance, or EGFR or other non-KRAS driver mutations. In 19 patients with multiple samples (including nine with paired pre- and post-treatment samples), all showed concordant subtypes after accounting for codominance. CONCLUSION: YAP1 and HNF4A expression correlated significantly with large-cell morphology.
Ricci C, de Biase D, Maloberti T
… +18 more, Orsatti A, Ulbright TM, Idrees MT, Oliva E, Cornejo K, Lobo J, Michalova K, Raspollini MR, Williamson SR, van Leenders GJ, Kao CS, Maclean F, Sangoi AR, Osunkoya AO, Fiorentino M, De Leo A, Tallini G, Acosta AM
Histopathology
· 2026 Mar · PMID 41263790
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AIMS: Testicular adult granulosa cell tumours (AGCTs) are rare and show several clinical-pathological differences with their ovarian counterparts. In a limited number of prior studies, FOXL2 p.Cys134Trp, the hallmark mol...AIMS: Testicular adult granulosa cell tumours (AGCTs) are rare and show several clinical-pathological differences with their ovarian counterparts. In a limited number of prior studies, FOXL2 p.Cys134Trp, the hallmark molecular alteration of ovarian AGCT, appeared to be infrequent in testicular AGCTs. However, the number of cases analysed to date is relatively small. METHODS AND RESULTS: Twenty testicular AGCTs were analysed de novo using two different next-generation sequencing (NGS) panels that cover sex cord-stromal tumour (SCST)-relevant genes, including FOXL2, CTNNB1, FH and DICER1. Among 12 tumours (12/20; 60%) that were sequenced successfully, none harboured FOXL2 mutations. Eight tumours (8/12, 66.7%) showed a wild-type (WT) status for all genes assessed with the panels. Three tumours harboured pathogenic or likely pathogenic CTNNB1 alterations. One of these exhibited predominant spindle cell morphology, while the other two showed focal tubular architecture. Immunohistochemistry performed in one of these tumours with available material showed β-catenin expression in ~70% of tumor cell nuclei. The remaining AGCTs showed variants of uncertain significance (likely benign) in KIT and MED12. Considering the tumors asseseed in this study and those previously reported in the literature, only 2 of 29 neoplasms classified as testicular AGCTs have shown a FOXL2 p.Cys134Trp mutation to date. CONCLUSIONS: The present study confirms that SCSTs classified as AGCTs differ from their ovarian counterparts in that they largely lack FOXL2 mutations.
Xu Z, Zhu H, Wang X
… +4 more, Tang Y, Huang Y, Chi P, Sun Y
Histopathology
· 2026 Mar · PMID 41263782
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BACKGROUND: Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) does not eliminate tumor recurrence risk, with distant metastasis remaining a crit...BACKGROUND: Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) does not eliminate tumor recurrence risk, with distant metastasis remaining a critical challenge. This study aimed to identify novel prognostic factors for risk stratification in pCR patients after nCRT. METHODS: We enrolled 149 LARC patients who achieved pCR between 2016 and 2020. Acellular mucin pools (AMP) were classified by the deepest tissue layer of AMP (A0: absent; A1: within the muscularis propria; A2: exceeding the muscularis propria). The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and recurrence patterns. RESULTS: After a median follow-up of 75.3 months, the 5-year OS and DFS rates were 95.3% and 89.9%, respectively. Among 15 recurrence events, all were distant metastases (80% pulmonary). AMP were present in 17.4% (26/149) of patients. Multivariate analysis identified AMP exceeding the muscularis propria (HR = 3.996, 95% CI: 1.073-14.660, P = 0.039), preoperative neutrophil-to-lymphocyte ratio (NLR) >4.4 (HR = 3.658, 95% CI: 1.304-10.263, P = 0.014) and tumour distance from the anal verge on pretreatment magnetic resonance imaging (MRI) (HR = 0.667, 95% CI: 0.481-0.925, P = 0.015) as independent predictors of distant metastasis-free survival (DMFS). A nomogram integrating these factors showed robust discriminative performance for 1-, 3-, and 5-year DMFS (AUC = 0.689, 0.815, 0.795). Meanwhile, AMP exceeding the muscularis propria (HR = 6.632, P = 0.010) and pretreatment MRI-assessed tumour distance from the anal margin (HR = 0.614, P = 0.018) were independent predictors for pulmonary metastasis. CONCLUSIONS: AMP exceeding the muscularis propria and high pretreatment NLR are complementary prognostic markers that refine risk stratification in pCR patients, enabling personalized surveillance and treatment strategies to improve outcomes.
Nakamura H, Kukita Y, Kittaka N
… +7 more, Kusama H, Nakayama T, Tamaki Y, Yoshida KI, Kunimasa K, Imamura F, Yagi T
Histopathology
· 2026 Mar · PMID 41263779
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AIMS: Apocrine carcinoma (AC) is a rare and distinct subtype of invasive breast carcinoma, typically characterized by androgen receptor (AR) positivity and negative expression of oestrogen and progesterone receptors. Thi...AIMS: Apocrine carcinoma (AC) is a rare and distinct subtype of invasive breast carcinoma, typically characterized by androgen receptor (AR) positivity and negative expression of oestrogen and progesterone receptors. This study aimed to clarify the metabolic and molecular characteristics of AC, with a particular focus on protein expression related to lipid metabolism and the frequency and nature of PIK3CA mutations. METHODS: We analysed tissue specimens from 40 cases with AC and 59 cases with other breast cancer subtypes (ER+/HER2-, ER+/HER2+, ER-/HER2+ and triple-negative breast cancer [TNBC]). Immunohistochemistry was performed for a panel of lipid metabolism-related proteins including FASN, AMACR, ACOX1, ACSL1 and catalase. mRNA Expression of ACSL1 was assessed by RT-qPCR and PIK3CA mutations were analysed via targeted sequencing. RESULTS: AC showed significantly higher expression of enzymes involved in fatty acid synthesis and peroxisomal β-oxidation compared to other subtypes. Notably, ACSL1 was upregulated at both protein and mRNA levels, and catalase was upregulated at the protein level, indicating an increase in peroxisomes. PIK3CA Mutations, particularly the hotspot p.H1047R variant, were detected at a significantly higher frequency in AC (68.4%) compared to the other subtypes: ER+/HER2- (52.6%), ER+/HER2+ (27.3%), ER-/HER2+ (50.0%) and TNBC (33.3%) (P < 0.05). CONCLUSIONS: AC is characterized by distinct metabolic reprogramming, with preferential upregulation of peroxisomal β-oxidation rather than mitochondrial pathways. These metabolic features are accompanied by a high prevalence of activating PIK3CA mutations, suggesting a link between genomic alterations and metabolic phenotype. These findings provide new insights into the pathobiology of AC and may assist in its histopathological differentiation from other breast cancer subtypes.
Choiniere R, Boellaard WPA, Dinkelman-Smit M
… +1 more, van Leenders GJLH
Histopathology
· 2026 Mar · PMID 41263775
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BACKGROUND AND OBJECTIVES: Testicular frozen section examination on excisional biopsy (FSEB) is an underused pathological and surgical approach, considering the increasing number of small benign testicular lesions found...BACKGROUND AND OBJECTIVES: Testicular frozen section examination on excisional biopsy (FSEB) is an underused pathological and surgical approach, considering the increasing number of small benign testicular lesions found on radical orchidectomy specimens. This study aims to determine the diagnostic accuracy of FSEB and to provide a pathological summary of the most frequent diagnoses and pitfalls. METHODS: We report the pathological findings and definitive outcome of 135 FSEB for small testicular masses performed between 2005 and 2024 in a single institute. RESULTS: The median tumour size was 0.9 cm (Interquartile Range [IQR] 0.5-1.3 cm). The most common FSEB diagnoses were Leydig cell hyperplasia/tumour (n = 37; 28%) and seminoma (n = 36; 27%). On FSEB, benign diagnoses represented 58% of cases which allowed us to avoid 81 unnecessary radical orchidectomies. The sensitivity and specificity of FSEB for malignancy were 100% and 96.3%, respectively. Excluding three indeterminate cases on FSEB, the concordance rate was 97.7% (129/132). On definitive assessment, the majority of cases were benign (84/135, 62%) and 51 (38%) cases were malignant. The three indeterminate cases were ultimately confirmed as benign. There were three false-positive diagnoses of (favoured) malignancy and no false negatives. CONCLUSIONS: FSEB is accurate for patient management of small testicular lesions, allowing us to save young men from unnecessary radical orchidectomy. We provide an in-depth overview of the most prevalent pathological diagnoses encountered.
Ungureanu IA, Le Quang M, Azmani R
… +5 more, Ancelle M, Margot H, Chotard G, Le Loarer F, Truffaux N
Histopathology
· 2026 Mar · PMID 41263773
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INTRODUCTION: Myofibromas are part of the pericytic tumour family, which includes myopericytomas, glomus tumours and angioleiomyomas. While they typically display benign behaviour when arising in the skin and subcutaneou...INTRODUCTION: Myofibromas are part of the pericytic tumour family, which includes myopericytomas, glomus tumours and angioleiomyomas. While they typically display benign behaviour when arising in the skin and subcutaneous tissues of the head and neck, rare aggressive variants have been reported, particularly those with visceral or intracranial involvement. The most frequently identified molecular alterations in myofibromas are PDGFRB gain-of-function mutations, primarily single-nucleotide substitutions. CASE PRESENTATION: Herein, we report two cases of myofibroma: one aggressive case with central nervous system involvement in a newborn, exhibiting a monophasic morphology, and a second, subcutaneous case in an adult. RNA sequencing was performed on both tumours, and data analysis was conducted using a four-pipeline fusion-calling approach (Arriba, FusionCatcher, FusionMap and STAR-Fusion). This analysis identified a novel somatic internal tandem duplication (ITD) in the NOTCH3 gene, affecting exons 26 and 27, specifically involving the C-terminal heterodimerization domain of the NOTCH3 receptor. Unsupervised hierarchical clustering demonstrated that myofibromas with ITDs segregate distinctly from conventional myofibromas and other pericytic tumours. DISCUSSION AND CONCLUSION: Our findings suggest that NOTCH3 ITDs represent a novel oncogenic mechanism in pericytic tumour pathogenesis, likely driving constitutive activation of the NOTCH signalling pathway. Given the potential therapeutic relevance, particularly in aggressive or life-threatening cases with CNS involvement, our findings highlight the importance of extensive molecular profiling. Targeted therapy with NOTCH inhibitors may represent a promising strategy in the management of aggressive cases of ITD-driven pericytic tumours.
Goldman-Lévy G, Barnhill R, Bastian BC
… +27 more, Kempf W, Elder D, Gerami P, Grayson W, Kazakov D, Massi D, Messina J, de la Fouchardière A, Lazar AJ, Brenn T, Rous B, Field A, Gill A, Hodge JC, Khoury JD, Leite K, Sayed S, Tan PH, Elenitsas R, Calonje E, Duncan LM, Zhiyong L, Moch H, Singh R, Wijesinghe H, Cree I, Lokuhetty D
Histopathology
· 2026 Feb · PMID 41263762
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The 5th edition of the World Health Organization Classification of Tumours (WCT) serves as a foundation for global diagnostic standards in tumour pathology. Similar to other volumes in this series, the Skin Tumours (Skin...The 5th edition of the World Health Organization Classification of Tumours (WCT) serves as a foundation for global diagnostic standards in tumour pathology. Similar to other volumes in this series, the Skin Tumours (Skin5) edition follows a standardized approach. This edition introduces two new chapters: 'Tumours of the nail unit' and 'Metastases to skin', along with new entities across relevant chapters. This review article provides an overview of the updates in Skin5 based on currently published evidence, with emphasis on newly introduced chapters and newly described entities that involve the skin, in particular, epidermal, melanocytic and appendageal tumours.
Kain ZE, Baez-Navarro X, Linn SC
… +1 more, van Deurzen CHM
Histopathology
· 2025 Dec · PMID 41219136
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AIMS: In breast cancer (BC) pathology reports, small differences around cut-off values can impact staging and consequently, clinical decision-making. Several pathology variables are not very exact, leaving room for inter...AIMS: In breast cancer (BC) pathology reports, small differences around cut-off values can impact staging and consequently, clinical decision-making. Several pathology variables are not very exact, leaving room for interpretation by the pathologist. Therefore, the aim of this study was to investigate pathologists' decision-making around clinically relevant cut-off values. METHODS: We performed a retrospective, population-based analysis of primary invasive BC specimens using real-world data from the Dutch National Pathology Registry. Data collection included tumour diameter and oestrogen receptor (ER)/progesterone receptor (PgR) status from patients diagnosed between 2014 and 2022. RESULTS: Overall, 64,099 BCs were analysed for tumour diameter. For larger tumours (>2 cm), rounding was observed to the nearest half or whole centimetre. For smaller tumours, rounding occurred only to half centimetres, while there was an avoidance of the 1.0 and 2.0 cm thresholds. For ER/PgR assessment, 74,502 BCs were analysed. In cases with low ER expression, rounding was observed at multiples of 5%. However, around the clinically relevant cut-off value of 10% in the Netherlands, pathologists tend to semiquantify the percentage of ER and/or PgR expression by also using 9% and 11%, with a trend to classify a case as just positive (10% or 11%). CONCLUSION: Pathologists take clinical cut-off values into account in their decision-making process. For tumour size, they tend to avoid the 1.0 and 2.0 cm thresholds. For ER/PgR, they tend to categorize the tumour as positive around the threshold. Further research is needed to determine the implication of this for treatment decisions.
Ma Z, Wang L, Liu J
… +13 more, Saxena R, Chen Z, Zhang X, Wang H, Vij M, Komuta M, Soon G, Zheng W, Zhang J, Wang B, Li M, Yang Y, Zhao X
Histopathology
· 2026 Feb · PMID 41207798
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BACKGROUND AND AIMS: To validate the applicability of the new histological criteria for autoimmune hepatitis (AIH) proposed by the International AIH Pathology Group (IAIH-PG) among Chinese patients with AIH and drug-indu...BACKGROUND AND AIMS: To validate the applicability of the new histological criteria for autoimmune hepatitis (AIH) proposed by the International AIH Pathology Group (IAIH-PG) among Chinese patients with AIH and drug-induced liver injury (DILI). METHODS: The gold standard for diagnosis relied on clinical response: discontinuing treatment without relapse supported DILI, while relapse or ongoing immunosuppressive treatment confirmed AIH. This two-centre retrospective cohort study included inpatients with DILI or AIH from January 2002 to March 2023. Cases that underwent liver biopsy were selected according to inclusion and exclusion criteria. The diagnostic performance of the criteria was assessed by an area under the receiver operating characteristic curve (AUROC). RESULTS: Out of 69 patients: AIH (41, 59%) and DILI (28, 41%). The accuracy, sensitivity and specificity of the new histological criteria for likely and possible AIH were 70%, 98% and 29%, respectively, with an AUROC of 0.8236 [95% confidence interval (CI): 0.7533-0.8938]. For likely AIH, the accuracy, sensitivity and specificity were 73%, 61% and 89%, respectively, with an AUROC of 0.9177 [95% CI: 0.8757-0.9596]. Moreover, for possible AIH, significant differences were found in serum alanine aminotransferase levels [178.4 (87.0, 435.0) versus 536.5 (206.9, 930.4) U/L] and antinuclear antibody (ANA) ≥1:160 [10 (67%) versus 1 (6%)], as well as in lobular lymphoplasmacytic infiltrate [15 (100%) versus 12 (71%)] and more than mild inflammation [13 (87%)versus 6 (35%)] between AIH and DILI (all P values were <0.05). CONCLUSION: The new histological criteria exhibit good diagnostic efficacy in distinguishing AIH from DILI in China, with high AUROC. Key discriminators include low aminotransferase, ANA ≥1:160, lobular lymphoplasmacytic infiltrate and more than mild inflammation, which may further improve diagnostic accuracy for AIH.
Lunardi F, Ferro A, Vedovelli L
… +9 more, Pezzuto F, Tzorakoleftheraki SE, Kilitci A, Kuzyk Y, Zanella S, Schiavon M, Rea F, Pasello G, Calabrese F
Histopathology
· 2026 Feb · PMID 41207797
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BACKGROUND: Non-small cell lung cancer (NSCLC) patients undergoing neoadjuvant chemotherapy (NACT) followed by surgery represent an ideal clinical setting to identify prognostic factors. To date, major pathological respo...BACKGROUND: Non-small cell lung cancer (NSCLC) patients undergoing neoadjuvant chemotherapy (NACT) followed by surgery represent an ideal clinical setting to identify prognostic factors. To date, major pathological response (MPR) and complete pathological response (pCR) have been used as surrogates of NACT response and clinical outcome. The aim of the study was to investigate the role of additional clinico-pathological features, taking advantage of morphometry and artificial intelligence (AI). METHODS: Seventy stage III NSCLC patients undergoing surgery after NACT were studied. A granular evaluation of histological parameters with morphometrical quantification of the stromal components (fibrosis/inflammation) in addition to the tumour bed analysis (2020 IASLC statement) was carried out in all cases. An AI algorithm of the different immunophenotypes was also applied on immunohistochemistry-stained whole-slide images. A ClinPATH combined score including MPR, baseline blood lymphocytes, perineural invasion, vascular invasion, proliferative index, fibrosis extension percentage and AI-quantified CD4+ cell % was tested. RESULTS: MPR and pCR were related to disease-free survival (DFS) and overall survival (OS) but also vascular/perineural/pleural invasion and Ki-67 were useful in stratifying the study population. Concerning the tumour bed stromal components, only morphometrical quantification highlighted the prognostic role of fibrosis and inflammation, particularly when distinguishing CD4+ and FOXP3+ cells, mainly in adenocarcinomas. Interestingly, the combination of the most impactful clinico-pathological parameters in a ClinPATH combined score correlated better with DFS and OS than any individual parameter, including MPR or pCR. CONCLUSION: AI-based method can be used to accurately decipher the complexity of tumour bed stromal components, providing extra information for outcome prediction. The combination of different clinico-pathological features could be highly valuable in guiding therapeutic decisions and ultimately improve patient outcomes.