Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; S. Emily Bachert, MD, associate pathologist, Brigham and Women’s Hospital, Boston; Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Divya Sharma, MD, associate professor, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center; and Paula Toro, MD, gastrointestinal and hepatobiliary fellow, Cleveland Clinic.
Occurrence and histopathological recognition of atypical endometriosis in patients with ovarian endometriosis
June 2026—Atypical endometriosis is a potential precursor of endometriosis-associated ovarian carcinoma. Despite this, identification of atypical endometriosis (AE) lacks established clinical implications and is not routinely incorporated in histopathological examinations for endometriosis. The authors conducted a study to determine the interobserver variability in AE diagnosis and classify features that may contribute to consistent identification and diagnosis. Cases of ovarian endometriosis collected between 1985 and 2017 at Radboud University Medical Centre, Nijmegen, Netherlands, were identified using the PALGA (Automated National Pathological Anatomy Archive) database. Pathology reports were reviewed for descriptions of atypical features and mention of AE. Using a predefined set of criteria adapted from the literature, two independent pathologists re-evaluated the 266 most recent cases of ovarian endometriosis for AE. After revision, one pathologist revised cases with AE to reach consensus when discrepancies occurred. Among the 266 cases, AE was reported in 31 (11.7 percent). The two pathologists identified AE in 48 (18 percent) cases, which were reduced to 19 (7.1 percent) after a consensus meeting between the pathologists. After a consensus was reached, the diagnostic criteria, adapted from the literature, were adjusted. High interobserver variability likely reflects the heterogeneous presentation of AE, uncertain role of inflammation-driven atypia, and undefined clinical significance of AE. However, given the association of AE with malignant transformation, consistent identification may be essential. The pathologists identified criteria they deemed crucial for identifying AE, including a combination of architectural changes and striking architectural changes with small or no cytonuclear atypia. The authors encourage adequate documentation of AE to increase insight into the behavior of endometriosis by linking endometriosis subtypes to clinical progression of the disease.
Leenen S, Kooreman L, Bulten J, et al. The occurrence and histopathological recognition of atypical endometriosis in patients with ovarian endometriosis—a retrospective cohort study. Hum Pathol. 2025. doi.org/10.1016/j.humpath.2025.105875
Correspondence: Dr. Sterre Leenen at sterre.leenen@catharinaziekenhuis.nl
Use of an AI-informed computational pathology classifier to predict outcomes in urothelial carcinoma
Urothelial carcinoma is a leading cause of cancer-related mortality, and effective scalable biomarkers for treatment planning are limited. The authors developed UC-TIL, an artificial intelligence-based model that quantifies spatial patterns of tumor-infiltrating lymphocytes (TILs) from routine hematoxylin-and-eosin–stained slides to predict survival and immunotherapy response. They analyzed 558 whole slide images across three cohorts—The Cancer Genome Atlas (D0&1, n=292), Emory University (D2, n=161), and TRRC2819 (D3, n=105)—spanning chemotherapy and immune checkpoint inhibitor treatments. UC-TIL classification was associated with overall survival (hazard ratio [HR], 2.11; 95 percent confidence interval [CI], 1.01–4.41; p=.011) and progression-free survival (PFS) (HR, 3.68; 95 percent CI, 1.07–12.65; p=.0012) in locally advanced disease (D1 and D2), with consistent results in metastatic disease (D3) (HR, 1.73; 95 percent CI, 1.08–2.77; p=.043/PFS HR, 1.73; 95 percent CI, 1.07–2.81; p=.047). In the immune checkpoint inhibitor-treated D3 cohort, UC-TIL achieved area under the curve of 0.757 and identified nonresponders with 91 percent specificity. The authors concluded that UC-TIL enables reliable risk stratification and prediction of treatment response in locally advanced and metastatic urothelial carcinoma by analyzing spatial TIL patterns from standard pathology slides. These findings position UC-TIL as a readily deployable tool to guide personalized therapy across multiple clinical settings.
Hammouda K, Tokuyama N, Corredor G, et al. AI-informed computational pathology classifier predicts outcomes across treatment modalities in muscle-invasive urothelial carcinoma. Cancer Lett. 2025. doi.org/10.1016/j.canlet.2025.218059
Correspondence: Dr. Anant Madabhushi at anantm@emory.edu
Evidence of a relationship between SMARCA4-deficient undifferentiated tumor and nonsmall cell carcinoma
Thoracic SMARCA4-deficient undifferentiated tumor is an uncommon aggressive lung neoplasm associated with smoking and characterized by loss of SMARCA4 (BRG-1) expression. Although originally considered to be a primary thoracic sarcoma, growing evidence indicates that these lesions may represent transformation of conventional nonsmall cell lung carcinoma (NSCLC). Moreover, there appears to be no significant difference in patient survival outcomes between tumors classified as SMARCA4-deficient NSCLC and those diagnosed as SMARCA4d undifferentiated tumor (SMARCA4d-UT). The authors conducted a study in which they explored this relationship based on the clinical, histologic, and molecular findings of 18 SMARCA4d malignancies of the lung. Cases diagnosed as SMARCA4d-UT and SMARCA4d carcinoma were retrospectively reviewed, including histologic and immunophenotypic features, and next-generation sequencing studies were conducted. Of the 18 tumors, five represented undifferentiated SMARCA4d-UT and 13 SMARCA4d carcinomas. The latter included 11 adenocarcinomas, one squamous cell carcinoma, and one poorly differentiated NSCLC. All 13 carcinomas had a morphologically identifiable undifferentiated component. Survival outcomes were similar in SMARCA4d-UT and SMARCA4d carcinomas. Genetic alterations often seen in lung cancer were identified in eight cases, including mutations in EGFR (in two SMARCA4d adenocarcinomas), KRAS (in one SMARCA4d-UT and one SMARCA4d adenocarcinoma), MAP2K1 (in one SMARCA4d adenocarcinoma), and a gene fusion involving EML4::ALK (in one SMARCA4d-UT). The patient with the EML4::ALK fusion was treated with alectinib and had a partial response. Fusions involving BRAF::CHCHD3 and FGFR1::FILIP1 were identified in two SMARCA4d adenocarcinomas. High expression of PD-L1 (tumor proportion scores greater than 50 percent) was seen in 13 (72 percent) cases. These findings further suggest that SMARCA4d-UT and carcinomas with SMARCA4 loss may be on the same spectrum of disease and that distinguishing between these lesions may be challenging. The authors advocate for a unified terminology, which may assist with appropriate diagnosis and treatment.
D’Ambrosio D, Frazzette N, Snuderl M, et al. Detection of targetable genetic alterations in SMARCA4-deficient neoplasms of the lung—further evidence of a relationship between SMARCA4-deficient undifferentiated tumor and non-small cell carcinoma. Hum Pathol. 2026. doi.org/10.1016/j.humpath.2025.106007
Correspondence: Dr. Jose Mantilla at jose.mantillaarango@nyulangone.org
Characterization of cholangiocarcinomas with tubulocystic morphology associated with biliary adenofibroma or biliary adenofibroma-like lesions
Hepatic biliary adenofibroma is a benign neoplasm composed of tubuloglandular and microcystic structures within a fibrous stroma and resembles von Meyenburg complexes or ductal plate malformation. Intrahepatic cholangiocarcinoma with a ductal plate malformation pattern (iCCA-DPM) is an established variant of iCCA, whereas adenofibroma-like tubulocystic carcinoma (AL-TCC) is a newly proposed iCCA variant associated with hepatic biliary adenofibroma (BAF)-type lesions. The authors hypothesized that BAF, AL-TCC, and iCCA-DPM form a tumorigenic spectrum. They conducted a study in which they analyzed 10 cases of surgically resected iCCAs with BAF (n=1) or BAF-like (n=9) lesions compatible with AL-TCC and compared them with seven iCCA-DPM and 26 unspecified small duct iCCA (SD-iCCA). The median age of the AL-TCC cohort (six women and four men) was 62 years. Tumors were often multifocal (70 percent) and averaged 5.5 cm in size, with frequent lymphovascular invasion (40 percent) but no perineural invasion. Comparisons between AL-TCC and iCCA-DPM revealed no significant differences in patients’ age, sex, tumor size, focality, lymphovascular invasion, perineural invasion, and outcomes. When AL-TCC and iCCA-DPM were grouped together (n=17) and compared with other unspecified SD-iCCA, the combined AL-TCC/iCCA-DPM cohort showed a stronger association with von Meyenburg complexes, biliary cysts, and/or bile duct adenomas (seven of 17) than did the SD-iCCA cases (zero of 26). The combined cohort also showed less perineural invasion (P=.027), more frequent ARID1A loss (11 of 17 versus three of 26, P<.001), and better patient outcomes (P=.036). Kaplan-Meier analysis revealed that ARID1A loss significantly improved patient survival (P=.046). The authors concluded that their findings provide compelling evidence that AL-TCC with BAF or BAF-like lesions shares clinicopathologic and histogenetic characteristics with iCCA-DPM, suggesting that the entities are related and likely represent a continuum of tumorigenesis, distinct from other SD-iCCA.
Liao X, Agostini-Vulaj D, Li RX, et al. Characterization of cholangiocarcinomas with tubulocystic morphology associated with biliary adenofibroma or biliary adenofibroma-like lesions. Mod Pathol. 2025. doi.org/10.1016/j.modpat.2025.100815
Correspondence: Dr. Xiaoyan Liao at xiaoyanliao@urmc.rochester.edu
Clinical outcomes of mixed-grade PUC with a minor high-grade component versus low-grade PUC
Grade heterogeneity is common in papillary urothelial carcinoma of the urinary bladder. Mixed-grade papillary urothelial carcinoma (PUC) is generally treated as high grade if the high-grade component accounts for five percent or more of the tumor. However, the clinical behavior of predominantly low-grade PUC with a minor high-grade (less than five percent) component remains uncertain. The authors conducted a study in which they analyzed the clinicopathologic features of PUC with a minor high-grade component and compared cancer recurrence and progression rates in these patients with those for patients with pure low-grade and high-grade PUC. They retrospectively searched their pathology files and identified 52 cases of noninvasive mixed-grade PUC (predominantly low-grade PUC with a minor high-grade component). These patients’ clinical outcomes were compared with those of patients in two other cohorts—a cohort with 52 cases of pure low-grade PUC and a cohort with 50 cases of high-grade PUC. During follow-up, 27 patients with mixed-grade PUC developed cancer recurrence in an average of 25 months, and 12 patients experienced progression to high-grade PUC, including invasive urothelial carcinoma in three patients, in an average of 17 months. In comparison, 35 patients with low-grade PUC experienced cancer recurrence in an average of 17 months, but only one experienced progression to high-grade noninvasive PUC. Thirty-four patients with high-grade PUC experienced recurrence in an average of 13 months, and 10 experienced progression to invasive urothelial carcinoma. There was no significant difference in cancer recurrence in the three cohorts. Cancer grade and stage progression rates in patients with mixed-grade PUC were significantly higher than those in patients with low-grade PUC, but stage progression rates in patients with mixed-grade PUC were significantly lower than those in patients with high-grade PUC. The authors concluded that patients with mixed-grade PUC had significantly worse clinical outcomes than those with pure low-grade PUC but significantly better outcomes than those with high-grade PUC. The results suggest that mixed-grade PUC should be treated as a distinct intermediate category rather than as low-grade PUC.
Mi W, Zang C, Zhao J, et al. Mixed-grade papillary urothelial carcinoma with a minor high-grade component shows a significantly worse clinical outcome than low-grade papillary urothelial carcinoma. Hum Pathol. 2025. doi.org/10.1016/j.humpath.2025.105904
Correspondence: Dr. Charles C. Guo at ccguo@mdanderson.org
Updating definitions of tumor deposits in colorectal cancer for TNM staging system
Tumor deposits have been a contentious element of the tumor-node-metastasis staging system for colorectal cancer since they were introduced into the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system in 1997. Classified within the nodal category, their definition has changed repeatedly due to their unclear distinction from lymph node metastases, extramural vascular invasion, and perineural invasion. Despite updates in the eighth edition of the tumor-node-metastasis staging system, ambiguity remains, with current criteria relying heavily on pathologist discretion. Because tumor deposits are among the most powerful prognostic indicators, they warrant standardization based on scientific evidence. A Delphi consensus among expert pathologists confirmed the lack of specificity and reproducibility in the current definition. In response, the authors created a definition that identified tumor deposits as discrete tumor nodules in pericolic or perirectal fat, distinct from lymph nodes, extramural vascular invasion, or perineural invasion but possibly originating from them. This definition emphasizes the need to report tumor deposits separately when there is unequivocal tumor extension in relation to vessels or nerves. Size and distance from the primary tumor have been debated as potential criteria, but they are not part of the authors’ definition. The authors concluded that the new definition is a first step to incorporating a more robust, biologically relevant definition of tumor deposits into cancer staging.
Nagtegaal ID, Washington K, Brierley JD, et al. Tumor deposits in colorectal cancer: Definitions for ninth edition of the tumor node metastasis staging system. Mod Pathol. 2026. doi.org/10.1016/j.modpat.2025.100924
Correspondence: Dr. Iris Nagtegaal at iris.nagtegaal@radboudumc.nl