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; 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; Paula Toro, MD, assistant professor of pathology, Emory University/Grady Memorial Hospital, Atlanta; and Kristen Brao, MD, PhD, cytopathology fellow, Mass General Brigham, Boston.
Assessment of endometrial carcinomas with a somatically-derived yolk sac tumor component
October 2026—Primary endometrial carcinomas with somatically-derived yolk sac tumor components are rare. Therefore, the authors performed detailed clinicopathologic, immunohistochemical, and molecular analyses to better understand and address these entities. They analyzed 23 patients who were a median age of 68 years. Elevated serum alpha-fetoprotein (AFP) was detected in 76.9 percent (10 of 13) of those tested. FIGO 2009 stages were I (n = 12, 55 percent), II (n = 1, five percent), III (n = 5, 23 percent), IV (n = 4, 18 percent), and unknown (n = 1). Histologic yolk sac tumor patterns included glandular (87 percent), papillary (52 percent), solid (48 percent), endodermal sinus (17 percent), hepatoid (17 percent), and reticular (13 percent) architectures. The associated Müllerian-type neoplasms were endometrioid carcinoma (n = 17), carcinosarcoma (n = 3), serous carcinoma (n = 2), and clear cell carcinoma (n = 1). Immunohistochemically, 17 (74 percent) patients exhibited mutation-type p53 staining, and two (nine percent) were mismatch repair-deficient (MMRd). Yolk sac tumor components uniformly expressed glypican-3 and spalt-like transcription factor, while 17 (74 percent) also expressed AFP. HER2 positivity was seen in 13 of 21 (62 percent; four 3+, three 2+, six 1+) patients tested. Molecular analysis revealed TP53 variants in 16 of 22 (73 percent) cases without POLE hotspot mutations. According to the Cancer Genome Atlas molecular classification, 17 tumors were p53 abnormal (74 percent), two (nine percent) were MMRd, four (17 percent) were no specific molecular profile, and none were POLE ultramutated. Recurrent copy number gains involved CCNE1 (nine of 22, 41 percent), 1q44 (12 of 14, 86 percent), and 3q26.32 (eight of 14, 57 percent). Features reminiscent of germ cell tumors included amplifications at 7p21.2 (eight of 14, 57 percent) and 9p21.3 (11 of 14, 79 percent), polysomy or amplification of chromosome 12p (six of 22, 27 percent), deletion at 11q24.3 (eight of 14, 57 percent), and a high frequency of T>C nucleotide substitutions. Follow-up showed that 13 patients had died of disease and two were alive with disease. Twelve of the 15 cases were p53 abnormal. Overall survival was significantly poorer than for those with other molecular subtypes of endometrial carcinoma. Therefore, these tumors should be regarded as high grade (grade 3) by definition. The authors concluded that endometrial carcinomas with a somatically-derived yolk sac tumor component are highly aggressive and predominantly p53 abnormal, with smaller subsets classified as MMRd or no specific molecular profile. Recognition of the yolk sac tumor component is crucial, and biomarker profiling may reveal therapeutic targets.
Li JJX, Chui MH, McCluggage WG, et al. Endometrial carcinomas with a somatically-derived yolk sac tumor component share molecular similarities to p53-abnormal endometrial carcinomas and germ cell tumors. Mod Pathol. 2026. doi.org/10.1016/j.modpat.2026.100976
Correspondence: Dr. Philip Ip at philipip@hku.hk
Justification for ordering cytomegalovirus IHC stain for severe IBD and ulceration
Cytomegalovirus infection is common among immunocompetent and immunocompromised patients. Those with inflammatory bowel disease (IBD) are more prone to suffer from cytomegalovirus (CMV) complications. The authors investigated the utility of IHC for diagnosing CMV infection in patients with severe IBD. They searched their pathology data system for patients with IBD from Jan. 1, 2017 to Dec. 31, 2021 and identified 5,782 IBD cases, 784 of which had severe activity with ulceration. CMV IHC stain was performed on all 784 cases. H&E-stained slides were reviewed to evaluate for the presence of characteristic nuclear or cytoplasmic CMV inclusions. H&E and IHC results were categorized as “single” if one cell stained positive or had characteristic inclusions, “rare” if two to five cells stained positive or had characteristic inclusions, and “many” if more than five cells stained positive or had characteristic inclusions. Clinical outcomes, treatment, and serum CMV viral loads were examined. The authors reported that 29 of 784 (3.7 percent) cases were positive for CMV by IHC: seven (0.9 percent) had many positive cells, 14 (1.8 percent) had rare positive cells, and eight (1.0 percent) had single positive cells. The most frequently involved specimen type was the left colon. Twelve of 29 (41 percent) cases did not show characteristic cytoplasmic or nuclear inclusions on H&E stain prior to IHC. Of these 12 cases, CMV IHC showed rare cells in seven (58 percent) and single cells in five (42 percent). None of these cases showed many positive cells on IHC. CMV viral load polymerase chain reaction (PCR) was tested in 10 of 29 (34 percent) cases and was positive in eight of 10 (80 percent). Most positive cases by PCR had many CMV inclusions on IHC (five of eight, 63 percent). Only three of 12 patients with no H&E inclusions were tested with CMV PCR, and two of the 12 (17 percent) cases were positive. Both patients received antiviral treatment. Overall, CMV IHC helped detect CMV positivity in only 12 of 784 (1.5 percent) cases that were otherwise not apparent on H&E. The authors concluded that CMV infection is rare in IBD patients with severe activity and ulceration, and H&E should be used as the initial tool to detect viral inclusions in such patients. CMV IHC only helped identify CMV infection in a minority of cases with no characteristic inclusions on H&E stain.
Ertekin R, Hu J, Hosseini M, et al. Is it justified to order an upfront cytomegalovirus immunohistochemical stain in patients with severe inflammatory bowel disease and ulceration? Hum Pathol. 2026. doi.org/10.1016/j.humpath.2026.106113
Correspondence: Dr. M. K. Pezhouh at mpezhouh@health.ucsd.edu
Automatic detection of ganglion cells as a supporting tool for Hirschsprung disease diagnosis
Hirschsprung disease is a congenital disorder characterized by the absence of ganglion cells in colonic nervous plexuses, resulting in bowel obstruction and various complications. Diagnosis of the disease demands expertise, experience, and use of ancillary tests. The authors sought to design an artificial intelligence tool to facilitate the diagnosis of Hirschsprung disease and evaluate the tool’s performance in terms of sensitivity, specificity, and average area under the curve. Using a camera-equipped microscope, they digitized 222 high-power fields of view obtained from H&E-stained slides. Nuclei were segmented using a deep-learning algorithm and manually annotated by an expert pathologist. From these, 2,076 nuclei were selected, including 346 ganglion cells and 1,730 nonganglion cells. One hundred features related to shape, color, and texture were extracted from the nuclei. A cross-validation methodology was employed to evaluate their utility in differentiating between ganglion and nonganglion nuclei. The nuclei were randomly divided into training (70 percent) and validation (30 percent) sets. The Wilcoxon signed-rank test was employed to identify the top features in the training set, which were used to train an AI classifier to distinguish between ganglion and nonganglion cells. The classifier’s performance was assessed using the validation set, yielding an average area under the curve of 0.98. The authors’ findings indicate that this AI-driven framework may serve as a valuable support tool for pathologists, facilitating the diagnosis of Hirschsprung disease in routine clinical practice.
Siabatto-Cleves A, Toro P, Olaya N, et al. Automatic detection of ganglion cells as a supporting tool for Hirschsprung disease diagnosis. Int J Surg Pathol. 2026. doi.org/10.1177/10668969261437754
Correspondence: Dr. Germán Corredor at gcorred@emory.edu
Incidence, molecular features, and distinction of endometrial carcinoma of gastrointestinal type
Endometrial carcinoma of gastrointestinal type (EMCG) is an aggressive endometrial cancer characterized by gastric or intestinal-type mucinous morphology, minimal or no estrogen receptor expression, and at least focal gastrointestinal marker immunoexpression. The authors conducted a study in which they presented a clinicopathologic characterization of four EMCG—two that were prospectively diagnosed and two found on retrospective screening of 274 endometrial carcinomas performed to identify undetected EMCG and characterize gastrointestinal marker expression within the endometrial carcinoma population at the authors’ institution. All four EMCG expressed CDX2 and were negative for SATB2. CK20 was diffuse in one, focal in another, and absent in two. None showed strong membranous claudin-18. One was MMR deficient and two had PTEN loss. Sequencing revealed a variety of molecular findings, including pathogenic/likely pathogenic variants in KRAS, PIK3CA, POLE, PTEN, SMARCA4, and TP53. Thirty-six percent of retrospectively screened endometrial carcinomas expressed at least one gastrointestinal marker. However, the majority had strong estrogen receptor co-expression, precluding EMCG classification. Other than the two cases of true EMCG identified on screening, only one screen-positive tumor had convincing gastrointestinal-type morphology in concert with estrogen receptor negativity—this case showed SALL4 and AFP expression consistent with a somatically-derived yolk sac tumor. These data increase understanding of the molecular underpinnings of EMCG, in part by describing a SMARCA4 frameshift variant in this entity, and demonstrate that while gastrointestinal marker immunoexpression is relatively common among endometrial carcinomas, strictly defined EMCG remains rare, at less than one percent of cases. As awareness of this entity grows, pathologists should take care not to overinterpret gastrointestinal marker expression as standalone evidence of an EMCG diagnosis.
Alzayadneh E, Smith VL, Mills AM. Endometrial carcinoma of gastrointestinal-type (EMCG): Incidence, molecular features, and distinction from other endometrial cancers with gastrointestinal marker immunoexpression. Int J Gynecol Pathol. 2026;45(2):107–119.
Correspondence: Dr. Anne M. Mills at amm7r@uvahealth.org
Mismatch repair protein nonclassic expression loss pattern in colorectal cancer
The authors conducted a study that evaluated the clinical and molecular significance of nonclassic mismatch repair protein expression patterns in colorectal cancer, challenging the traditional binary interpretation of MMR IHC as either intact or complete loss. The authors retrospectively analyzed 569 colorectal cancer cases, categorizing staining patterns into intact expression, complete loss, regional or patchy loss, and weak expression relative to internal controls. Tumors with nonclassic patterns of MMR expression were defined as those demonstrating patchy loss or reduced staining intensity involving a significant proportion of tumor cells. The results showed that tumors exhibiting both classic and nonclassic loss patterns were consistently associated with microsatellite instability–high (MSI-H) status. Importantly, a subset of tumors with only nonclassic loss patterns also demonstrated MSI-H status and harbored pathogenic mutations in MMR genes, including somatic and potential germline alterations. These findings indicate that nonclassic MMR expression patterns may represent true biologic MMR deficiency and should not be dismissed as technical artifacts. Recognizing these patterns is critical, as failure to identify them may lead to underdiagnosis of MSI-H tumors and Lynch syndrome. This study underscores the need for increased awareness and careful evaluation of atypical MMR staining patterns in routine diagnostic practice.
Yu J, Xiao X, He W, et al. Mismatch repair protein “nonclassic expression loss” pattern in colorectal cancer: an important staining pattern that is not well understood. Am J Clin Pathol. 2026. doi.org/10.1093/ajcp/aqag070
Correspondence: Dr. Junqiu Yue at yuejunqiu@hotmail.com