Mod. Pathol. [JOURNAL]
Sun
200 papers
Loss of Methylthioadenosine Phosphorylase (MTAP) Expression: A Potentially Useful Tool for Distinguishing Sarcomatoid Urothelial Carcinoma From Inflammatory Myofibroblastic Tumor.
Li H, Argani P, Gross JM … +7 more , Zhu J, Pallavajjala A, Baras AS, Lotan TL, Dudley JC, Matoso A, Baraban EG
Mod Pathol · 2026 Apr · PMID 41730366 · Publisher ↗
Inflammatory myofibroblastic tumor (IMT) and sarcomatoid urothelial carcinoma (SarUC) can have striking histologic overlap but have significantly different prognoses and clinical management paradigms. Loss of methylthioa...
Inflammatory myofibroblastic tumor (IMT) and sarcomatoid urothelial carcinoma (SarUC) can have striking histologic overlap but have significantly different prognoses and clinical management paradigms. Loss of methylthioadenosine phosphorylase (MTAP) protein expression by immunohistochemistry (IHC) serves as a useful surrogate for homozygous 9p21 deletion, a recurrent genomic alteration in urothelial carcinoma (UC). We analyzed MTAP expression by IHC in 65 SarUCs and 27 urinary tract IMTs to evaluate its utility in navigating this challenging differential diagnosis. Overall, MTAP loss was significantly more frequent in SarUC (55%) compared with IMT (4%) (P < .0001). Among 46 biphasic SarUCs with independently evaluable epithelial and mesenchymal components, divergent expression patterns were frequent. The most common pattern was retention of MTAP staining in both epithelial and mesenchymal components (19/46; 41% of cases), followed by selective retention of MTAP in the epithelial component and loss in the mesenchymal component (16/46; 35% of cases). MTAP loss was observed in both the epithelial and mesenchymal components in 11 out of 46 (24%) SarUC cases. None of the 46 biphasic SarUC cases showed selective MTAP loss in the epithelial component but retention in the mesenchymal component. MTAP IHC was also particularly valuable in assessing clonal relationships in 2 challenging biphasic cases in which the differential diagnosis included a collision between a noninvasive low-grade papillary UC and an IMT versus a subtle IMT-like SarUC arising in association with an overlying noninvasive low-grade papillary UC. Next-generation sequencing on a subset of cases (n = 11) was useful for confirming 9p deletion in cases with MTAP loss by IHC, and for demonstrating molecular hallmarks of urothelial neoplasia thereby providing additional diagnostic support for morphologically challenging SarUC cases with IMT-like morphology. Therefore, MTAP IHC can be useful in evaluating spindle cell lesions of the urinary tract, as loss is significantly more common in SarUC than in IMT, and enriched in the mesenchymal component of biphasic SarUC. However, MTAP loss can be seen in both entities, and the diagnosis of IMT-like spindle cell tumors in the urinary tract requires careful integration of morphologic, immunohistochemical, and molecular data.
Estrogen Receptor, GATA-3, TTF-1, and KRAS in Endometrial Carcinoma of No Specific Molecular Profile: Prognostic or Diagnostic Markers?
Siili E, Loukovaara M, Bützow R … +1 more , Pasanen A
Mod Pathol · 2026 Apr · PMID 41713573 · Publisher ↗
Endometrial carcinoma with no specific molecular profile (NSMP) is a clinicopathologically heterogeneous group of diseases with an overall intermediate prognosis. Prognostic refinement is needed for better personalized t...
Endometrial carcinoma with no specific molecular profile (NSMP) is a clinicopathologically heterogeneous group of diseases with an overall intermediate prognosis. Prognostic refinement is needed for better personalized treatment. The updated European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology-European Society of Pathology guidelines for endometrial carcinoma stratify NSMP according to histotype and estrogen receptor (ER) status. ER (with other ancillary markers) also helps differentiate histotypes of endometrial carcinoma. This study describes clinicopathological characteristics of ER-positive and -negative-NSMP endometrial carcinoma. Furthermore, we investigate the prognostic and diagnostic significance of ER, GATA3, TTF1, and KRAS in a large and relatively unselected NSMP carcinoma cohort. POLE sequencing results and immunohistochemistry for p53, mismatch repair proteins, and ER were available for 930 samples of endometrial carcinoma. Within NSMP cases (n = 377), 22 samples presented ER staining in <1% of the carcinoma cells, 5 cases in 1% to 9%, and 350 cases in ≥10%. ER expression ≥10% predicted an excellent outcome (comparable with POLE-mutated cases) in univariable analysis, where ER negativity (<10%) was associated with a poor outcome (comparable with p53 abnormal cases). Most ER-positive NSMP cases were low-grade endometrioid carcinomas, whereas most ER-negative NSMP cases were nonendometrioid or high-grade endometrioid carcinomas. In addition to high-risk histotype, ER negativity was associated with various other clinicopathological risk factors. In multivariable analysis adjusting for histotype and other risk factors, ER did not independently predict disease progression (P = .814). No disease-related deaths were observed in the rare (n = 3) patients with ER-negative-low-grade endometrioid carcinoma. GATA3/TTF1 positivity and KRAS mutation were discovered not only in mesonephric-like carcinoma but also in endometrioid carcinoma. No prognostic relevance was found for these markers. In conclusion, the different prognosis of ER-positive vs ER-negative-NSMP endometrial carcinoma is not attributable to ER status itself but rather to its strong correlation with histotype and other clinicopathological risk factors. Limited specificity of GATA3, TTF1, and KRAS warrants caution in their use as diagnostic markers of mesonephric-like carcinoma.
Detection of Prostate Cancer in 3-Dimensional Pathology Datasets via Generative Immunolabeling.
Serafin RB, Lopez JS, Chow S … +11 more , Wang R, Zhao Y, Baraznenok E, Lan L, Bishop K, Downes M, Farre X, True LD, Lal P, Madabhushi A, Liu JTC
Mod Pathol · 2026 Apr · PMID 41692323 · Full text
Recent advancements in nondestructive 3-dimensional (3D) pathology offer a complement to standard histology by enabling comprehensive volumetric analyses of intact clinical specimens (eg, biopsies). Previous studies have...
Recent advancements in nondestructive 3-dimensional (3D) pathology offer a complement to standard histology by enabling comprehensive volumetric analyses of intact clinical specimens (eg, biopsies). Previous studies have demonstrated the added prognostic value of 3D pathology for prostate cancer (PCa) risk stratification by correlating 3D microarchitectural features with long-term patient outcomes. However, these analyses relied on coarse manual annotations of cancer-enriched regions for downstream analysis without fine-grained delineation between often-intermixed cancerous and benign glands. To automate and improve the process of delineating between benign and PCa-enriched regions in 3D pathology data sets, we have developed a 3D computational pipeline: Synthetic Immunolabeling for Generative Heatmaps of Tumor (SIGHT). SIGHT relies on deep learning-based 3D image translation models, trained in a fully supervised manner, to convert hematoxylin and eosin analog 3D pathology data sets into multiplexed 3D immunofluorescence data sets that facilitate tumor detection. Our implementation of SIGHT synthetically labels 2 cytokeratin markers that are differentially expressed in cancerous and benign prostate glands, which are used to generate explainable 3D heatmaps of cancer-enriched regions in prostate tissues. Validation of SIGHT against ground truth annotations from a panel of genitourinary pathologists (X.F., M.D., L.D.T.) yields an average F1 score of 0.88, which is comparable with the average interpathologist agreement F1 score of 0.90. To demonstrate how SIGHT can automate and improve a pipeline for risk stratification based on 3D pathology data sets of PCas, we developed preliminary machine classifiers of recurrence risk based on 3D glandular histomorphometric features from 75 patients. Volumetric glandular analysis in SIGHT-identified cancer-enriched regions versus all tissue regions yields a Kaplan-Meier hazard ratio of 3.57 (CI, 1.6-7.9) versus 0.92 (CI, 0.45-1.89).
Corrigendum to "Non-neoplastic Orthopedic Pathology Updates: Common Problems and Pitfalls and How to Avoid Them" [Modern Pathology. 2025;38(12):100911].
Kilpatrick SE
Mod Pathol · 2026 Mar · PMID 41691954 · Publisher ↗
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Endometrial Carcinomas With a Somatically Derived Yolk Sac Tumor Component Share Molecular Similarities to p53-abnormal Endometrial Carcinomas and Germ Cell Tumors.
Li JJX, Chui MH, McCluggage WG … +8 more , Fadare O, Cheng GHW, Ko JMK, Dungog CC, Lee JHS, Ma ESK, Tse KY, Ip PPC
Mod Pathol · 2026 Apr · PMID 41690477 · Publisher ↗
Primary endometrial carcinomas with somatically derived yolk sac tumor (YST) components are rare. We analyzed 23 such cases using detailed clinicopathologic, immunohistochemical, and molecular methods. The median patient...
Primary endometrial carcinomas with somatically derived yolk sac tumor (YST) components are rare. We analyzed 23 such cases using detailed clinicopathologic, immunohistochemical, and molecular methods. The median patient age was 68 years. Elevated serum alpha-fetoprotein (AFP) was detected in 76.9% (10/13) of tested cases. International Federation of Gynecology and Obstetrics (FIGO) 2009 stages were I (n = 12, 55%), II (n = 1, 5%), III (n = 5, 23%), IV (n = 4, 18%), and unknown in one. Histologic YST patterns included glandular (87%), papillary (52%), solid (48%), endodermal sinus (17%), hepatoid (17%), and reticular (13%) 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 cases (74%) exhibited mutation-type p53 staining, and 2 (9%) were mismatch repair-deficient (MMRd). YST components uniformly expressed glypican-3 and spalt-like transcription factor 4 (SALL4), whereas 17 (74%) also expressed AFP. HER2 positivity was seen in 13 of 21 tested (62%; four 3+, three 2+, and six 1+). Molecular analysis revealed TP53 variants in 16 of 22 cases (73%) without POLE hotspot mutations. According to The Cancer Genome Atlas molecular classification, 17 tumors were p53-abnormal (74%), 2 (9%) MMRd, 4 (17%) were no specific molecular profile, and none was POLE-ultramutated. Recurrent copy number gains involved CCNE1 (9/22, 41%), 1q44 (12/14, 86%), and 3q26.32 (8/14, 57%). Features reminiscent of germ cell tumors included amplifications at 7p21.2 (8/14, 57%) and 9p21.3 (11/14, 79%), polysomy or amplification of chromosome 12p (6/22, 27%), deletion at 11q24.3 (8/14, 57%), and a high frequency of T>C nucleotide substitutions. Follow-up showed 15 patients (75%) had died of disease or were alive with disease; 12 of these 15 cases were p53-abnormal. Overall survival was significantly poorer than in other molecular subtypes of endometrial carcinoma. These tumors should therefore be regarded as high grade (grade 3) by definition. In summary, endometrial carcinomas with a somatically derived YST component are highly aggressive, predominantly p53-abnormal, with smaller subsets classified as MMRd or no specific molecular profile. Recognition of the YST component is crucial, and biomarker profiling may reveal therapeutic targets.
ELOC-mutated Renal Cell Carcinoma: Clinicopathologic, Immunohistochemical, and Molecular Genetic Analysis of 35 Cases.
Hou J, Xiong Y, Yang Y … +11 more , Pan X, Qian J, Guo X, Zhong J, Zheng L, Yin X, Yu T, Chen X, Nie L, Zhou Q, Chen N
Mod Pathol · 2026 Apr · PMID 41690476 · Publisher ↗
ELOC-mutated renal cell carcinoma (RCC) is a recently recognized, molecularly defined entity incorporated into the 2022 World Health Organization classification of genitourinary tumors. Approximately 50 cases of ELOC-mut...
ELOC-mutated renal cell carcinoma (RCC) is a recently recognized, molecularly defined entity incorporated into the 2022 World Health Organization classification of genitourinary tumors. Approximately 50 cases of ELOC-mutated RCC have been reported, and the clinicopathologic and molecular features of this rare tumor require further clarification. Herein, we reported the pathologic and molecular characteristics of 35 cases of ELOC-mutated RCC, representing the largest series from a single medical center to date. This cohort demonstrated an overwhelming male predominance (34/35), with a median age of 48.8 years, and low stage (predominantly T1aN0M0). Macroscopically, the tumors were well-circumscribed, measuring 1.0 to 5.0 cm in diameter (median, 2.5 cm), and were either solid (20/35, 57.1%) or mixed solid and cystic (15/35, 42.9%). Microscopically, the tumors showed acinar, branching tubular, papillary, or solid growth patterns and were composed of tumor cells with voluminous, clear cytoplasm and variable fibromuscular stroma. Uncommon patterns included markedly dilated cysts with small papillary tufts, myxoid areas, lymphocyte-rich stroma, and a thyroid follicle-like architecture. The nuclear grade was low. A minority of cases (5/35, 14.3%) exhibited focal areas with nuclei arranged linearly away from the basal aspect. Immunohistochemically, all tumors showed diffuse strong carbonic anhydrase IX positivity and moderate or weak cytokeratin 7 positivity. Variable CD10 expression (32/34, 94.1%), weak reactivity for alpha-methylacyl-CoA racemase (18/24, 63.2%), and negativity for glycoprotein nonmetastatic melanoma protein B (28/28, 100%) were also observed. ELOC mutations were identified in all 35 patients by Sanger sequencing and/or next-generation sequencing. The mutated amino acid sites included Y79C (30/35, 85.7%), Y79S (2/35, 5.7%), I95N (1/35, 2.8%), E92K (1/35, 2.8%), and C112fs (1/35, 2.8%). All next-generation sequencing-analyzed cases harbored ELOC mutations (28/28). Other recurrent mutations included CDH23 (6/28), ELP1 (4/28), POLE (4/28), and KMT2C (4/28). Among the 26 specimens evaluated for copy number analysis, all showed deletion of chromosome 8q, and 12/26 (46.2%) exhibited loss of 8p, consistent with biallelic ELOC inactivation. None showed 3p loss using fluorescence in situ hybridization. All patients with follow-up data were alive without evidence of disease progression. Our findings expanded the clinical, histologic, immunohistochemical, and molecular spectrum of ELOC-mutated RCC and further support its classification as a distinct renal neoplasm.
Elevated T Cell Immunoreceptor with Ig and ITIM Domains (TIGIT) Expression and Immune Cell Dysfunction Characterize Complex Proteins Associated With SET1 (COMPASS)-Like Complex Gene-Mutated Pancreatic Ductal Adenocarcinoma (PDAC).
Zhang S, Daniels ER, McGue J … +9 more , Sudharshan R, Kim HC, Thomas DG, Krishnan S, Frankel TL, Hissong E, Rao A, Assarzadegan N, Shi J
Mod Pathol · 2026 Apr · PMID 41638576 · Full text
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. Limited biomarkers, such as mismatch repair proteins, have been used to identify those who may respond to immunotherapy. We identified a su...
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. Limited biomarkers, such as mismatch repair proteins, have been used to identify those who may respond to immunotherapy. We identified a subset of aggressive PDACs (⁓25%) carrying mutations in the complex of proteins associated with SET1-like complex genes (CLCGs), which can be used as new biomarkers for targeted immunotherapy. In this study, we compared the immune microenvironment of PDACs harboring CLCG mutations with matched wild-type PDACs using multiplex fluorescent immunohistochemistry and computational imaging techniques. We observed that CLCG-mutant PDACs were infiltrated with fewer CD4 T cells and antigen-presenting cells (APCs) but elevated immune checkpoint T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression on CD4 T cells and APCs. There was no difference in the expressions of other immune checkpoints, such as programmed death-1 receptor ligand and T-cell immunoglobulin and mucin domain-containing protein 3. More CD4 T cells near epithelial cells (tumor cells) and APCs expressed TIGIT in CLCG-mutant PDACs. Additionally, CLCG-mutant PDACs displayed a malfunctional immune cell crosstalk. Single-cell RNA-sequencing data confirmed the elevated TIGIT expression on CD4 T cells and increased exhausted CD4 T cells in CLCG-low PDACs. These findings uncovered the unique underlying mechanisms of immune suppression in CLCG-deficient PDACs and identified CLCG as potential biomarkers to identify those who may benefit from TIGIT-targeting immunotherapies.
Clinicopathologic and Molecular Features of Tubo-Ovarian Carcinosarcomas With an Emphasis on p53 Wild-Type, KRAS-Mutated Tumors.
Hammer PM, Kingsley LG, Sasse SA … +1 more , Howitt BE
Mod Pathol · 2026 Apr · PMID 41638575 · Publisher ↗
Tubo-ovarian carcinosarcomas (OCS) are uncommon, aggressive tumors. Recent literature in uterine carcinosarcomas has shown prognostic differences by the molecular classification established by The Cancer Genome Atlas. Ou...
Tubo-ovarian carcinosarcomas (OCS) are uncommon, aggressive tumors. Recent literature in uterine carcinosarcomas has shown prognostic differences by the molecular classification established by The Cancer Genome Atlas. Our aim was to delineate the molecular subtypes within OCS and associated clinicopathologic, immunohistochemical, and additional molecular features. A total of 57 OCS were identified at our institution. The overall median follow-up period was 32.3 months, and 5-year survival rates were 71% (stage I/II), 42% (stage III), and 17% (stage IV). Fifty-one (89%) tumors were of the p53-abnormal molecular subtype. Five (9%) tumors were of no specific molecular subtype, and all 5 of these tumors harbored canonical mutations in KRAS (codon 12). We also identified the first reported primary POLE-mutated OCS in a patient with Lynch syndrome; this case was assigned as of a double-classifier POLE-mutated/mismatch repair-deficient molecular subtype. No tumors were of the single-classifier mismatch repair-deficient or POLE-mutated molecular subtype. Compared with the p53-abnormal tumors, KRAS-mutated tumors occurred in younger women at lower stages, but did recur in 2 out of 5 (40%) patients. They always showed endometrioid rather than high-grade serous morphology and were usually ER, PR, and WT1 negative. Three KRAS-mutated tumors also had at least focal mesonephric-like histology. Although rare, p53 wild-type tumors represent a small subset of OCS that show distinct clinical and histologic features and are largely driven by KRAS mutations.
Proteomics Profiling Identifies MCM4 as a Prognostic Biomarker for Postoperative Metastasis in Solid Pseudopapillary Neoplasms of the Pancreas.
He R, Liu Y, Dun R … +15 more , Ren S, Tian W, Gao H, Shi Y, Pan X, Ge X, Zhang J, Chen Y, Wang X, Chen Y, Wu J, Zhang R, Wang W, Zhao Y, Peng J
Mod Pathol · 2026 Apr · PMID 41638574 · Publisher ↗
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor with generally indolent behavior, and surgical resection yields a 5-year survival rate >95%. However, 5% to 10% of patients develop metastases, undersc...
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor with generally indolent behavior, and surgical resection yields a 5-year survival rate >95%. However, 5% to 10% of patients develop metastases, underscoring the need for reliable prognostic biomarkers to identify individuals at a higher metastatic risk and to optimize postoperative management. In this study, we performed data-independent acquisition mass spectrometry based proteomics profiling on resected primary tumors from 59 SPN patients to identify proteins differentially expressed between metastatic and nonmetastatic cases. A candidate protein, MCM4, was further examined for potential pathogenic functions in vitro. An independent multicenter cohort of 255 patients was subsequently analyzed for MCM4 positivity by immunohistochemistry. Prognostic performance for postoperative metastasis was evaluated using Kaplan-Meier analysis, Cox regression, and time-dependent receiver operating characteristic curves, with histopathological invasion defined as neural, vascular, or peripancreatic invasion. MCM4 protein was aberrantly upregulated in tumors from patients who developed metastasis, and functional assays demonstrated a proproliferative role of MCM4. In the validation cohort, MCM4-positive tumors (MCM4 index, >3%) exhibited a higher Ki-67 index (P = .0006). Patients with MCM4-positive tumors had a higher incidence of metastasis (20.6% vs 4.1%; P = .0019) and significantly shorter metastasis-free survival (MFS; log-rank P < .0001). In univariate Cox regression analysis, MCM4 positivity was significantly associated with reduced MFS (hazard ratio, 12.78; 95% CI, 3.01-54.31; P = .0006). In multivariate Cox regression analysis, MCM4 positivity remained an independent prognostic biomarker for shorter postoperative MFS after adjustment for histopathological invasion (hazard ratio, 11.55; 95% CI, 2.76-48.37; P = .0008). Time-dependent receiver operating characteristic analyses demonstrated that MCM4 positivity achieved area under the curves of 0.817 (95% CI, 0.763-0.864) at 3 years and 0.777 (95% CI, 0.720-0.828) at 5 years for postoperative metastasis assessment. Taken together, these findings identify MCM4 positivity as an independent prognostic biomarker for postoperative metastasis risk assessment in SPN.
Genomic Characterization of Lung Cancer in Never-Smokers Using Deep Learning.
Saha M, Tran TV, Bhawsar PM … +18 more , Zhang T, Zhao W, Hoang PH, Mutreja K, Lawrence SM, Rothman N, Lan Q, Homer R, Baine MK, Sholl LM, Joubert P, Leduc C, Travis WD, Chanock SJ, Shi J, Yang SR, Almeida JS, Landi MT
Mod Pathol · 2026 Apr · PMID 41638573 · Full text
Despite promising results in using deep learning to infer genetic features from histologic whole-slide images (WSIs), no prior studies have specifically applied these methods to lung adenocarcinomas from subjects who hav...
Despite promising results in using deep learning to infer genetic features from histologic whole-slide images (WSIs), no prior studies have specifically applied these methods to lung adenocarcinomas from subjects who have never smoked tobacco (never-smoker lung adenocarcinoma [NS-LUAD])-a molecularly and histologically distinct subset of lung cancer. Existing models have focused on LUAD from predominantly smoker populations, with limited molecular scope and variable performance. Here, we propose a customized deep convolutional neural network based on ResNet50 architecture, optimized for multilabel classification for NS-LUAD, enabling simultaneous prediction of 16 molecular alterations from a single hematoxylin and eosin-stained WSI. Key architectural modifications included a simplified 2-layer residual block without bottleneck layers, selective shortcut connections, and a sigmoid-based classification head for independent prediction of each alteration, designed to reduce computational complexity while maintaining predictive accuracy. The model was trained and evaluated on 495 WSIs from the Sherlock-Lung study (70% training with 10% internal test set for 10-fold cross-validation and 30% held-out validation set for final evaluation). For the held-out validation data, our model achieved high areas under the receiver operating characteristic curve [AUROC] values = 0.84 to 0.93 for detecting 11 features: EGFR, KRAS, TP53, RBM10 mutations, MDM2 amplification, kataegis, CDKN2A deletion, ALK fusion, whole-genome doubling, and EGFR hotspot mutations (p.L858R and p.E746_A750del). Performance was low to moderate for tumor mutational burden (AUROC = 0.67), APOBEC mutational signature (AUROC = 0.57), and KRAS hotspot mutations (p.G12C: AUROC = 0.74, p.G12V: AUROC = 0.55, p.G12D: AUROC = 0.43). Compared with results from established architectures such as Inception-v3 on the same WSIs, our model demonstrated significantly improved performance for most features. With further optimization, our model could support triaging for molecular testing and inform precision treatment strategies for patients with NS-LUAD.
Predictors of Response to Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Pathological Evaluation of HER2 Heterogeneity.
Hu J, Tsang JY, Liu J … +3 more , Hu H, Guo D, Tse GM
Mod Pathol · 2026 Mar · PMID 41620175 · Publisher ↗
Human epidermal growth factor receptor 2 (HER2) gene amplification and heterogeneity influence anti-HER2 therapy efficacy, but quantitative assessment of HER2 expression heterogeneity remains scarce. This study evaluates...
Human epidermal growth factor receptor 2 (HER2) gene amplification and heterogeneity influence anti-HER2 therapy efficacy, but quantitative assessment of HER2 expression heterogeneity remains scarce. This study evaluates HER2 protein heterogeneity and its effect on neoadjuvant therapy (NAT) outcomes in HER2-positive breast cancer. In total, 295 patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy were included. HER2 expression was quantified by the percentage of HER2-stained cells across intensities, and heterogeneity was assessed using quadratic entropy. The overall pathological complete response (pCR) rate was 51.86%. Patients with HER2 heterogeneity showed a 24.5% pCR rate, significantly <62.5% in patients with HER2 homogeneity (P < .001). HER2 heterogeneity quadratic entropy (HER2-HQE) correlated with the percentage of HER2 immunohistochemistry (IHC) 3+ tumor cells and hormone receptor (HR) status (P < .001). Residual cancer burden (RCB) was significantly associated with HR status, tumor stage, lymph node stage, HER2 IHC 3+ cell percentage, and HQE grade (P ≤ .017). No correlation was found with age, histologic grade, or Ki67 index. In the HER2 IHC 3+ ≥95% subgroup, neither pCR rate nor RCB grade after NAT was associated with traditional clinicopathological parameters, even HER2-HQE and HR status (P ≥ .154). The American Joint Committee on Cancer anatomical stage significantly improved post-NAT for low/intermediate HER2-HQE subgroups (P < .001) but not for high HQE cases. In summary, HER2 heterogeneity and HR status are key predictors of anti-HER2 NAT outcomes. Higher HER2-HQE is associated with increased RCB. Quantifying HER2 heterogeneity via HQE and percentage of HER2 IHC 3+ may help optimize therapeutic strategies in clinical practice.
Fibrillary Light Chain Proximal Tubulopathy: A Distinct Subtype Within the Spectrum of Light Chain Proximal Tubulopathy.
Zhang X, Yu X, Xu J … +6 more , Yao Y, Chen Y, Ren Y, Zhou F, Zhao M, Wang S
Mod Pathol · 2026 Mar · PMID 41616976 · Publisher ↗
Light chain proximal tubulopathy (LCPT) is a rare kidney disorder associated with monoclonal gammopathy, traditionally defined by crystalline inclusions in proximal tubular epithelial cells. A poorly recognized variant,...
Light chain proximal tubulopathy (LCPT) is a rare kidney disorder associated with monoclonal gammopathy, traditionally defined by crystalline inclusions in proximal tubular epithelial cells. A poorly recognized variant, fibrillary LCPT, is characterized by large nonamyloid fibrillar aggregates but has remained inconsistently classified, leading to diagnostic uncertainty. We aimed to clarify its clinicopathologic features and refine its position within the LCPT spectrum. We retrospectively analyzed 41 biopsy-proven LCPT cases, reclassified by ultrastructural features into crystalline LCPT (n = 22), fibrillary LCPT (n = 11), amyloid LCPT (n = 2), and LCPT with lysosomal indigestion (n = 6). Fibrillary LCPT showed irregular cytoplasmic fibrils measuring 6 to 18 nm in diameter, arranged in intersecting, fishbone-like, or compact bundle-like patterns, confined to proximal tubular epithelial cells. These fibrils were Congo red negative and not apparent on light microscopy. Conventional immunofluorescence (IF) on frozen tissue was uniformly negative in fibrillary LCPT, and pronase-digested paraffin IF detected κ restriction in only 7 of 11 cases; immunoelectron microscopy confirmed κ light chain labeling in all paraffin IF-negative cases, yielding 100% diagnostic sensitivity. Clinically, most fibrillary LCPT cases were associated with monoclonal gammopathy of renal significance (72.7%), with the remainder linked to multiple myeloma (27.3%). This subtype was commonly associated with Fanconi syndrome and reduced estimated glomerular filtration rate, with a subset of cases developing acute kidney injury. Following clone-directed therapy, a majority of patients achieved stable renal function, and 85% showed improvement in tubular dysfunction, although proteinuria reduction was less pronounced than in crystalline LCPT. Fibrillary LCPT represents a distinct, nonamyloid entity characterized by Congo red-negative fibrils, κ light chain restriction, and frequent association with Fanconi syndrome and monoclonal gammopathy of renal significance. We propose a refined 4-tier ultrastructural classification comprising 4 LCPT subtypes (crystalline LCPT, fibrillary LCPT, amyloid LCPT, and LCPT with lysosomal indigestion) to improve diagnostic precision and guide management.
Deep Learning-Based Virtual Elastin Staining Improves Visceral Pleural Invasion Assessment in Lung Cancer.
Wang CL, Zhang L, Zou LF … +13 more , Cao XJ, Wang LJ, Li JW, Xiong JB, Ouyang X, Luo YY, He L, Peng Y, Deng T, Li M, Gao MN, Peng L, Yu SS
Mod Pathol · 2026 Mar · PMID 41616975 · Publisher ↗
Accurate assessment of visceral pleural invasion is essential for staging and prognostication in non-small cell lung cancer, yet distinguishing elastin-rich pleural layers on routine hematoxylin and eosin (H&E) sections...
Accurate assessment of visceral pleural invasion is essential for staging and prognostication in non-small cell lung cancer, yet distinguishing elastin-rich pleural layers on routine hematoxylin and eosin (H&E) sections remains a diagnostic challenge. To overcome the cost and workflow delays associated with special elastic stains, we developed a deep-learning pipeline that generates a virtual elastin stain, termed synthetic eosin-based elastin fluorescence, directly from standard brightfield H&E slides. A key innovation of this study was the use of intrinsic eosin fluorescence from the same H&E section to create a perfectly coregistered, high-fidelity ground truth for training a conditional generative adversarial network, eliminating the spatial mismatches common in multislide approaches. In a multi-institutional validation, supplementing H&E review with synthetic eosin-based elastin fluorescence significantly improved pathologists' diagnostic accuracy for visceral pleural invasion compared with H&E alone (P < .0001). Notably, the preanalytical factors that optimized model performance, including thinner tissue sections (1-3 μm) and high-resolution scanning, also enhanced the perceptual contrast of elastin for pathologists, demonstrating a strong synergy between computational and conventional diagnostic optimization. This study establishes and validates a robust framework for high-fidelity virtual staining that improves diagnostic accuracy and provides a scalable pathway for integrating deep learning-based tools into routine digital pathology. The proposed approach offers a practical and cost-effective alternative to ancillary special stains in non-small cell lung cancer evaluation.
Tumor Deposits in Colorectal Cancer: Definitions for Ninth Edition of the Tumor Node Metastasis Staging System.
Nagtegaal ID, Washington K, Brierley JD … +5 more , Chang GJ, Goldberg RM, Shi Q, Kakar S, Kaur H
Mod Pathol · 2026 Jan · PMID 41591951 · Publisher ↗
Tumor deposits (TDs) have been a contentious element of the tumor node metastasis staging system for colorectal cancer since their introduction in 1997. Classified within the nodal category, their definition has changed...
Tumor deposits (TDs) have been a contentious element of the tumor node metastasis staging system for colorectal cancer since their introduction in 1997. Classified within the nodal category, their definition has changed repeatedly due to unclear distinctions from lymph node metastases, extramural vascular invasion, and perineural invasion. Despite updates in the tumor node metastasis system eight edition, ambiguity remains, with current criteria relying heavily on pathologist discretion. The fact that TDs are among the most powerful prognostic indicators warrants standardization, based on scientific evidence. A Delphi consensus among expert pathologists confirmed the lack of specificity and reproducibility in the current definition. In response, a new definition was developed, identifying TDs 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 TDs separately when there is unequivocal tumor extension in relation to vessels or nerves. Size and distance from the primary tumor are debated as potential criteria, although they are not part of the proposed definition. The new definition is a first step to incorporate a more robust, biologically relevant definition of TDs into cancer staging.
Development of an Artificial Intelligence Model to Aid in Measurement of Invasion, Comprehensive Histologic Subtyping, and Grading of Pulmonary Adenocarcinoma.
Boland JM, Stetzik L, Roden AC … +6 more , Maleszewski JJ, Jenkins SM, Kroneman TN, Yi ES, Lo YC, Aubry MC
Mod Pathol · 2026 Jan · PMID 41591950 · Publisher ↗
The World Health Organization classification of pulmonary adenocarcinoma is complex, posing challenges for pathological reporting. Key difficulties include assessing invasive size in lepidic-predominant tumors and perfor...
The World Health Organization classification of pulmonary adenocarcinoma is complex, posing challenges for pathological reporting. Key difficulties include assessing invasive size in lepidic-predominant tumors and performing comprehensive histologic subtyping. Although these evaluations inform tumor stage, grade, and prognosis, they are time consuming and subjective, leading to interobserver variability. Artificial intelligence (AI) may help streamline these tasks and improve consistency. One representative hematoxylin and eosin slide was selected from each of 100 resected pulmonary adenocarcinomas, which were divided into training (n = 35) and validation (n = 65) sets. Slides were scanned and uploaded to Aiforia for AI model creation. Annotations were completed on the training set by 6 expert pulmonary pathologists and used to train a nested AI model, which was used to evaluate whole slide images of the training and validation sets. Manual assessment of tumor size, invasive size, and comprehensive histologic subtyping was performed by 3 pulmonary pathologists. In both the training and validation sets, the mean and median difference between manual and AI estimations of tumor size was ≤1.3 mm and invasive size was ≤3 mm. The median and mean differences in invasive percentage were ≤15.3% in both the training and validation sets for all patterns except for acinar and lepidic. However, ranges were wide, indicating examples with substantial disagreement. Predominant pattern agreement between AI and each observer ranged from 65.7% to 71.4% in the training set and 45.3% to 54.7% in the validation set. Agreement in grade ranged from 77.1% to 88.6% in the training set and 62.5% to 67.2% in the validation set. There was moderate agreement in grade between the 3 pathologists in the training set and moderate to substantial agreement between AI and each observer. In the validation set, there was substantial agreement in grade between the 3 pathologists and moderate agreement between AI and each observer. Although the AI model shows promise and warrants further refinement, manual pathologist review and potential revision of AI assessments are necessary to ensure the diagnostic accuracy needed for clinical use because disagreement clearly occurs.
Pulmonary Solid and Granular Adenocarcinomas Expressing HepPar1/CPS1: Highly Aggressive Tumors Exhibiting Mitochondrial Adaptation to STK11 Mutations Rather Than Hepatoid Differentiation.
Febres-Aldana CA, Vanderbilt CM, Aly R … +17 more , Saliba M, Seshan SV, Frosina D, Jungbluth AA, Richards AL, Bodd F, Wilson C, Park KJ, Kezlarian-Sachs B, Ladanyi M, Cui C, Rudin CM, Baine MK, Travis WD, Chang JC, Srivastava A, Rekhtman N
Mod Pathol · 2026 Apr · PMID 41580239 · Publisher ↗
Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of lung origin are reported t...
Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of lung origin are reported to commonly express only hepatocyte paraffin 1 (HepPar1)-a hepatocellular marker, which recognizes mitochondrial enzyme carbamoyl-phosphate synthetase-1 (CPS1). Recently, HepPar1/CPS1 was found to accumulate in lung adenocarcinomas (LUADs) harboring STK11mutations, presumably as a genotype-associated metabolic adaptation. The impact of these insights on the concept of hepatoid lung carcinoma has not been explored. Here, we performed a detailed clinicopathologic and genomic analysis of carcinomas prospectively regarded as hepatoid with isolated HepPar1 expression (n = 17). We found that although robustly positive for HepPar1, these tumors were entirely negative for an extended panel of other hepatocellular markers (alpha-fetoprotein, Arginase1, Glypican3, and albumin-in situ hybridization). Morphologically, tumors exhibited solid-trabecular architecture with expanded granular-vacuolated-clear cytoplasm, thus evoking hepatoid morphology; however, focal-to-moderate intracytoplasmic mucin was consistently present, and hepatoid resemblance was variable. Pneumocytic markers (TTF1 and Napsin A) were entirely negative (except for cytoplasmic TTF1), commonly leading to diagnostic challenges at metastatic sites. Remarkably, next-generation sequencing revealed invariable STK11 mutations/loss (P < .00001 vs unselected LUAD, n > 2.5K). Patient survival was dismal (median, 5.8 vs 25 months for stage-matched LUAD, P = .0002). Tumors harbored high mitochondrial content by electron microscopy and other methods. For comparison, we reviewed conventional, predominantly acinar LUAD with HepPar1 expression (n = 22) and found that they also lacked any other hepatocellular markers, had invariable STK11 mutations/loss, increased granular cytoplasm, lower TTF1, and poor prognosis. We conclude that isolated HepPar1 expression in LUAD reflects mitochondrial adaptation to STK11 mutations rather than bona fide hepatocellular differentiation, and that HepPar1-expressing solid and granular adenocarcinomas represent an undifferentiated (solid, TTF1 negative) variant in this spectrum of tumors. Recognition of these tumors is warranted due to their exceptionally aggressive behavior, distinct pathogenomic features, and common association with diagnostic challenges.
A Worldwide Survey on Pathological Measurement of Residual Breast Cancer After Neoadjuvant Therapy: Different Interpretations of the ypTNM Classification.
Kwakkenbos K, Van Bockstal MR, Shaaban AM … +18 more , Brogi E, Cserni G, Ellis IO, Foschini MP, Fox SB, Bago-Horvath Z, Jaffer S, Jager A, Pinder SE, Provenzano E, Quinn CM, Rakha EA, Raymond WA, Tan PH, Tse GM, Varga Z, Wen HY, van Deurzen CHM
Mod Pathol · 2026 Mar · PMID 41580238 · Publisher ↗
The extent of residual disease after neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC) holds prognostic value. However, current practices for reporting post-NAC BC specimens according to the ypTNM classi...
The extent of residual disease after neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC) holds prognostic value. However, current practices for reporting post-NAC BC specimens according to the ypTNM classification vary. This study aimed to map these practices and provide recommendations for standardization. A survey was developed and globally circulated to pathologists with a special interest in BC through personal networks and working group mailing lists. The survey included general questions about tumor diameter assessment, as well as graphical scenarios presenting different distributions of tumor cells. We did not provide definitions mentioned in reporting guidelines to capture unbiased current real-world practices. A total of 208 pathologists from 35 countries completed the survey. Almost all responding pathologists (97.1%) reported the ypTNM in daily practice. Despite self-reported strict adherence to the eighth edition of the international ypTNM classification, we found substantial variation in practice concerning the application of this staging system, particularly in cases with an uneven distribution of scattered residual disease. Notably, 57.2% of respondents reported measuring the largest "continuous cluster of tumor cells," but the interpretation of this definition varied widely. This international survey identifies the challenges and practice heterogeneity in the current application of the ypTNM staging system, which hampers the value of ypTNM reporting in daily practice. To enhance reproducibility and to provide more reliable post-NAC risk stratification, we recommend adopting standardized reporting with clearer pattern-based definitions of the ypTNM guidelines, supplemented with the elements of the residual cancer burden system.
Alternative Lengthening of Telomeres in Malignant Perivascular Epithelioid Cell Neoplasms: Correlation With Molecular Features Including ATRX Gene Mutation Status.
Lin R, Gross JM, Xing D … +4 more , Argani P, Lotan T, Meeker AK, Baraban EG
Mod Pathol · 2026 Mar · PMID 41577032 · Publisher ↗
A subset of perivascular epithelioid cell neoplasms (PEComas) is histologically malignant and at high risk for metastasis, and there is limited literature available on the genetic features of these lesions. In addition t...
A subset of perivascular epithelioid cell neoplasms (PEComas) is histologically malignant and at high risk for metastasis, and there is limited literature available on the genetic features of these lesions. In addition to driver alterations in the tuberous sclerosis complex/mammalian target of rapamycin pathway or TFE3 fusions, recurrent ATRX mutations have been identified in malignant PEComas. ATRX mutations have been tightly associated with the alternative lengthening of telomeres (ALT) phenotype in a variety of other tumor types. Whether malignant PEComas-regardless of ATRX mutational status-harbor the ALT phenotype has not been characterized. We conducted immunohistochemistry (IHC), next-generation sequencing (NGS), and telomere-specific fluorescence in situ hybridization (FISH) on a cohort of 32 malignant PEComas to evaluate for the ALT phenotype and to correlate with underlying genomic features. TSC1/2/mTOR/RICTOR mutations or TFE3 translocations were detected in 16 of 31 (52%) cases by NGS. Recurrent ATRX alterations were identified in 10 (32%) cases. Sixteen cases underwent ALT FISH, 8 of which harbored ATRX alterations by NGS and/or ATRX loss based on IHC, and 8 cases without detectable ATRX alterations by NGS or loss based on IHC. Twelve (75%) of these 16 cases demonstrated the ALT phenotype by FISH. All 8 (100%) cases with ATRX mutations were ALT positive by FISH. In 8 (50%) cases without ATRX alterations based on NGS, 4 cases demonstrated ALT by FISH. Of these 4 ALT-positive cases lacking ATRX genomic alterations, IHC revealed ATRX protein loss in 1 case. Overall, ATRX alterations were identified in 75% of ALT-positive tumors. Our study provides the first correlation between ALT and genomic features of malignant PEComas, demonstrating that ATRX alterations invariably predict ALT, but that a subset of tumors without mutations in known ALT suppressor genes also activate ALT. These findings confirm that the association between ATRX alterations and ALT observed in other tumor types applies to PEComas and indicates that in a subset of cases, ALT may be activated by ATRX-independent mechanisms.
Complex Genetics in Somatic Mosaic Disorders: Evaluating the Rate of Multiple "Hits" in Nonmalignant Lesions.
Nguyen B, Gillentine MA, Myers CT … +10 more , Bhatia S, Narayanan J, Rogge L, Emery L, Perkins J, Eng W, Wandler A, Paschal CR, Bennett JT, Nelson ND
Mod Pathol · 2026 Mar · PMID 41544971 · Publisher ↗
Vascular anomalies encompass a heterogeneous group of vascular tumors and malformations and are most often caused by singular somatic variants that arise in utero. The presence of multiple variants, including those in at...
Vascular anomalies encompass a heterogeneous group of vascular tumors and malformations and are most often caused by singular somatic variants that arise in utero. The presence of multiple variants, including those in at least 2 different genes (multigenic variants), is rare in these mosaic disorders, and their contribution to histology and phenotype has not been well characterized. We present our molecular and histologic experience with multiple variants in a large cohort of individuals with vascular anomalies and other suspected somatic mosaic disorders. We performed a retrospective review of 1299 individuals with suspected somatic mosaic disorders who were sequenced at our institution and identified 92 (7%) individuals with at least 2 clinically reportable variants. Our cohort includes 18 individuals with multigenic variants with unknown phenotypic implications and 13 individuals with well-described multigenic variants with clear phenotypic significance. For many individuals, the multiple variants had clear clinical implications, including variants that may respond to targeted therapy (n = 73) or germline variants (n = 33) with surveillance implications for that individual and their immediate relatives. Provided clinical information and available hematoxylin and eosin-stained slides (n = 37) were reviewed, and lesions were classified according to established guidelines whenever possible. The majority of lesions had histologic features concordant with the observed genetic variants. However, 4 out of 18 lesions with multigenic variants and unknown phenotypic implications had unique or unusual histologic features that did not fit into a specific diagnostic category. Our results demonstrate that broad sequencing of vascular anomalies, even in patients with known pathogenic variants, can be useful to identify additional clinically relevant variants that may refine diagnosis, respond to targeted therapy, or reveal a germline disorder that contributes to phenotype and may require increased surveillance.
Genetic Profiling of Mammary Periductal Stromal Tumors With Histologic Correlation Highlights High-Grade and Low-Grade Groups and Similarities to Phyllodes Tumors.
Krings G, Bean GR, Hosfield EM … +3 more , Rowe JJ, Geradts J, Chen YY
Mod Pathol · 2026 Mar · PMID 41534841 · Publisher ↗
Periductal stromal tumors (PDST) of the breast are rare biphasic neoplasms with morphologic similarities to phyllodes tumors (PTs). The histologic spectrum of PDST is broad but has not been well characterized, and its ge...
Periductal stromal tumors (PDST) of the breast are rare biphasic neoplasms with morphologic similarities to phyllodes tumors (PTs). The histologic spectrum of PDST is broad but has not been well characterized, and its genetic underpinnings remain unknown. We profiled PDST by targeted next-generation sequencing in correlation with their histomorphology, immunophenotype, and clinical characteristics (n = 15). All patients were female, including 2 with Li-Fraumeni syndrome (LFS), with a mean age of 48 years. Forty-two percent had synchronous or metachronous PT and/or fibroadenoma. Most PDST expressed CD34 (15/15), smooth muscle actin (12/14), and at least focal nuclear HMGA2 (8/12) and/or beta-catenin (6/12). High-grade PDST (HGPDST, n = 8) were defined by marked nuclear pleomorphism (8/8), and most had high (≥10 mitoses/10 high-power field) and/or atypical mitotic activity (7/8) and pleomorphic multinucleated tumor cells (7/8). All HGPDST had p53 (88%, 7/8) and/or Rb/CDKN2A (75%, 6/8) alterations by next-generation sequencing or immunohistochemistry. p53 Aberrations correlated with the presence of pleomorphic multinucleated tumor cells. Both patients with LFS had HGPDST with loss of heterozygosity of the germline TP53 variant. Other altered genes in HGPDST included EGFR (25%, 2/8), NF1 (25%, 2/8), TERT promoter, PIK3CA, CDKN2A/B, LZTR1, KMT2B, and ARID2 (1 case each). Low-grade PDST, which lacked marked pleomorphism, high mitotic activity, or atypical mitoses (n = 7), had simpler genomes than HGPDST and lacked bona fide cancer gene alterations, with TERT promoter mutation in 1 case. Copy number alterations in PDST overlapped with those reported in PT, including 13q loss in all HGPDST. Copy number profiling revealed shared clonality of synchronous low-grade PDST and PT in 1 patient. In summary, we describe herein the genetic landscape of PDST, demonstrate correlation of genetic features with high-grade vs low-grade histology, and identify TP53 among key oncogenic drivers of HGPDST, including in LFS. The genetics of HGPDST overlap with borderline or malignant PT, consistent with their classification as PT variants that arise through a MED12-independent pathway.
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