Mod. Pathol. [JOURNAL]
Sun
200 papers
Lung carcinoids with sustentacular cells and low keratin expression: A common yet under-recognized phenomenon with diagnostic and biological implications.
Willner J, Aly RG, Solanki P … +14 more , Khan I, Wilson CE, Bodd F, Linkov I, Basturk O, Tang LH, Srivastava A, Gopalan A, Chang J, Baine MK, Travis WD, June-Koo Lee J, Rudin CM, Rekhtman N
Mod Pathol · 2026 Jul · PMID 42401207 · Publisher ↗
Sustentacular cell presence and the absence of keratin expression represent diagnostic hallmarks for distinguishing paragangliomas from neuroendocrine tumors (NET)/carcinoids. However, based on the literature and our pra...
Sustentacular cell presence and the absence of keratin expression represent diagnostic hallmarks for distinguishing paragangliomas from neuroendocrine tumors (NET)/carcinoids. However, based on the literature and our practice, pulmonary carcinoids can exhibit both features. Here, we examined the prevalence and biological correlates of this phenomenon. Lung carcinoids (n=109) were analyzed with several common keratins including AE1/AE3, sustentacular cell markers (S100, SOX10), nuclear markers of lung carcinoids (OTP, TTF1, ASCL1) and paragangliomas (GATA3, PHOX2B), and 505-gene next-generation sequencing (NGS). AE1/AE3 was strikingly variable (mean H-score 127; SD=80), with 18 cases (17%) exhibiting low labeling (H-score <50), including 3 AE1/AE3-negative cases. CAM5.2 was similarly variable (mean H-score 105; SD=94) and was low/negative in 16/18 AE1/AE3-low cases. Conversely, pan-keratin OSCAR and CK18 were higher overall (mean H-scores 253 and 264, respectively), and showed unequivocal positivity in all AE1/AE3-low/negative cases. Sustentacular cells were present diffusely in 35% of carcinoids, with 15/18 AE1/AE3-low carcinoids containing sustentacular cells. Overall, 15/109 (14%) lung carcinoids were AE1/AE3-low and sustentacular cell-positive. In contrast, such features were seen in only 4/188 (2%) entero-pancreatic NETs. All AE1/AE3-low carcinoids were GATA3 and PHOX2B-negative while TTF1, OTP, and/or ASCL1-positive. By NGS, all cases lacked mutations typical of paragangliomas and many harbored alterations typical of lung carcinoids. Notably, lower AE1/AE3 was associated with the presence of sustentacular cells (S100: p=0.003, SOX10: p=0.005), spindle morphology, peripheral location and ASCL1+/TTF1+/OTP+/HNF4A- immunophenotype - the constellation reflecting the emerging concept of "proneuronal" carcinoids. We conclude that lung carcinoids are not keratin-negative, but instead keratin-variable and some may appear as negative in an antibody-dependent manner. Together with the common presence of sustentacular cells, this may yield a profile overlapping with paragangliomas. We suggest using additional keratins and tumor-specific transcription factors (e.g. OTP, GATA3) as the updated approach for this differential diagnosis. Potential biological implications of paraganglioma-like features in lung carcinoids are discussed.
Expanding the Spectrum of High-Risk Human Papilloma Virus (HPV)-Associated Glandular Neoplasms of the Anorectum.
Mirzabeigi Y, Birkness-Gartman JE, Voltaggio L … +5 more , Dahlke T, Bhalla A, Pinto A, Yantiss RK, Montgomery EA
Mod Pathol · 2026 Jul · PMID 42392453 · Publisher ↗
Human papilloma virus (HPV)-related glandular neoplasms were first described in the uterine cervix and later identified in the anorectum. Although anorectal tumors were initially described as indolent neoplasms, we have...
Human papilloma virus (HPV)-related glandular neoplasms were first described in the uterine cervix and later identified in the anorectum. Although anorectal tumors were initially described as indolent neoplasms, we have encountered several examples with aggressive features. Herein, we describe the findings in a larger series of cases to further characterize these tumors and expand upon understanding of the spectrum of their behavior. Materials from 10 patients with HPV-related anorectal glandular neoplasms were prospectively collected from 2020-2026 from two academic centers. Most (7/10) were consultation cases. Morphologic features, immunohistochemical stains, and in situ hybridization for high-risk HPV were assessed. Clinical and outcome data were obtained from electronic medical records. The neoplasms arose in 8 women and 2 men, ranging from 30 to 81 years (median, 66). All had areas of non-invasive lesions characterized by glandular or villoglandular architecture, apical mitoses, and conspicuous apoptotic bodies. In addition to an exophytic in situ lesion as initially described, three cases were associated with invasive carcinomas (one high-grade carcinoma with heterogenous components, one moderately differentiated adenocarcinoma and one small cell-type neuroendocrine carcinoma). Two patients had concurrent high-grade squamous dysplasia/intra-epithelial lesions (HSILs) and one had a concurrent low-grade squamous dysplasia/intra-epithelial lesion (LSIL). High-risk HPV transcripts were demonstrated in all cases by in situ hybridization in both the in situ and any invasive component. Follow-up data were available for 8 patients; two experienced a recurrence, one had multiple recurrences, one had persistent disease, and the patient with small cell-type neuroendocrine carcinoma died in hospice. HPV-associated anorectal glandular lesions arise in older adults, usually women. They can mimic colorectal adenomas and adenocarcinomas, co-exist with squamous intra-epithelial lesions, and may be associated with high-grade carcinomas. We propose the term "high-risk HPV-associated adenoma" for non-invasive lesions instead of the previously introduced terminology ("high-risk HPV-related adenocarcinoma") to avoid confusion, reserving carcinoma terminology for invasive neoplasms.
Deep Learning for Differentiating Pulmonary Metastasis from Primary Lung Cancer Constructed on Frozen Sections for Intraoperative Diagnosis.
Onozato Y, Sakairi Y, Kawana H … +6 more , Yamamoto T, Iwata T, Araki A, Itami M, Kawakami E, Suzuki H
Mod Pathol · 2026 Jul · PMID 42392452 · Publisher ↗
The surgical procedures for primary lung cancer and metastatic lung tumors differ. An intraoperative diagnosis is important for surgical procedure decisions. This study digitized frozen sections for intraoperative diagno...
The surgical procedures for primary lung cancer and metastatic lung tumors differ. An intraoperative diagnosis is important for surgical procedure decisions. This study digitized frozen sections for intraoperative diagnosis, developing and evaluating deep learning models to differentiate lung cancer from metastatic tumors. A total of 1,668 slides from 1,458 patients with lung cancer or metastatic tumors who underwent surgery with an intraoperative diagnosis at a single institution were included. Lung cancer comprised 1,170 slides, while metastatic tumors comprised 498. Models were constructed to calculate the prediction probability using attention-based multiple-instance learning. Diagnostic performance was assessed using accuracy and area under the curve for each histological type; the area under the curve was 0.888 (0.871-0.904) with an accuracy of 80.1%. Lung adenocarcinoma prediction accuracy was favorable at 87.5% (95.5% for the lepidic pattern and 88.7% for the papillary pattern), while that for squamous cell carcinoma was 62.0%. Colon cancer was the most common metastatic tumor, with an accuracy of 89.3%, followed by soft tissue sarcoma with an accuracy of 82.6%. When limited to adenocarcinoma of lung cancer and metastatic tumors, the accuracy was 85.9%, while that for squamous cell carcinoma was 63.6%. The results indicate that deep learning can provide reasonable support in differentiating metastatic lung tumors from primary lung cancer on frozen sections, with performance varying by histological subtype. Deep learning may assist in intraoperative decision-making under time and resource constraints, though further multi-institutional validation is needed.
Margin Adequacy in Phyllodes Tumours Revisited: Reappraisal of the Evidence Base and Knowledge Gaps.
Rakha EA, Quinn C, Farshid G … +28 more , Shaaban AM, Van Bockstal MR, Li X, Foschini MP, Cserni G, Schmitt F, Varga Z, Tse G, Sharaf Eldean ZM, Fuad Obiedat SF, van Deurzen CHM, Decker T, Brogi E, Wen H, Callagy G, Yang W, AlAjmi Z, Altrabulsi B, Walsh D, Grobmyer S, Matalkah A, Gehani SA, Ellis IO, Schnitt S, Fox SB, Raymond WA, Tan PH, Dalton L
Mod Pathol · 2026 Jun · PMID 42379272 · Publisher ↗
The optimal surgical margin to minimise local recurrence (LR) and distant metastasis (DM) in phyllodes tumours (PTs) remains controversial. Despite multiple observational cohorts, variation between studies limits the int...
The optimal surgical margin to minimise local recurrence (LR) and distant metastasis (DM) in phyllodes tumours (PTs) remains controversial. Despite multiple observational cohorts, variation between studies limits the interpretation of margin-outcome associations. We therefore performed a structured critical interpretative synthesis (CIS) to evaluate whether current evidence supports specific margin thresholds. The CIS incorporated a systematic review, random-effects meta-analysis, appraisal of existing meta-analyses and guidelines, and expert interpretative analysis of 40 single-cohort studies from 2015 to 2025 evaluating surgical margin width and outcomes in PT. Authors' recommendations regarding margin adequacy were extracted as interpretative "author conclusions". In parallel, LR and DM outcomes were pooled by tumour grade using random-effects models with prediction intervals. Final margin recommendations were derived by integrating CIS findings and multidisciplinary expert judgement. Current management guidelines do not recommend re-excision for positive or close margins in benign PTs. Contemporary guidelines are also concordant in advising negative margins for borderline and malignant PTs, although the specified margin width ranges from 1 mm to 10 mm. Within this range, no association has been established between increasing margin width and the risk of LR or malignant transformation upon LR. The estimated LR rates are 12.5% for borderline and 16.5% for malignant PTs. Malignant transformation on recurrence occurred in only 1% and 3% of all benign and borderline PTs, respectively. Around 14% of malignant PT metastasise, often without LR. Current heterogeneous evidence does not show lower recurrence with margins wider than a negative (≥1 mm) in PTs. For borderline and malignant PTs, a mandatory 10 mm threshold is insufficiently supported, as narrower negative margins may be adequate in selected cases. However, an optimal margin threshold cannot be defined from current data. These conclusions are practice-supporting rather than guideline-defining and reinforce the need for higher-quality evidence to establish harmonised, grade-specific margin recommendations.
Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.
Hung YP, Nardi V, Ligon AH … +11 more , Wang CI, Chang CY, Newman ET, Raskin KA, Lozano-Calderón SA, Sikkink K, Van Meter L, Linker K, Schmitt AD, Chebib I, Nielsen GP
Mod Pathol · 2026 Jun · PMID 42379271 · Publisher ↗
Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. W...
Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. We searched our pathology files in 2004-2024 for available cases and performed targeted next-generation sequencing, along with whole-genome single-nucleotide polymorphism arrays and 3D genomics/Hi-C sequencing in selected cases. Our cohort included 3 classic adamantinomas (2 females, 1 male; age 14-56 years), 5 OFDs (3 females, 2 males; age 9-25 years), and 2 OFD-like adamantinomas (1 female, 1 male; age 30-41 years). Of the 10 tumors, 9 arose from the tibiae; one classic adamantinoma originated from the radius. The 3 classic adamantinomas harbored multiple copy-number gains involving chromosomes 7/8/10/12/19. Focal deletion of chromosome 17, intergenic rearrangement involving FGFR1, and NRAS p.G12D were each present in one classic adamantinoma. Of the 5 OFDs, KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in one case; no additional copy-number/single-nucleotide variants were identified. Of the two OFD-like adamantinomas, one with tumor clusters visible only on cytokeratin immunostain harbored no variants, while another case with tumor clusters visible on light microscopy and cytokeratin/p40 immunostains showed gains of chromosomes 7/8/19/20. By Hi-C, one classic adamantinoma harbored a ∼9Mb tandem duplication on chromosome 12q, one OFD harbored a rearrangement with breakpoints near MECOM and HOOK3, and the OFD-like adamantinoma with tumor clusters visible only on cytokeratin immunostain harbored no structural variant. In conclusion, classic adamantinomas and OFD might be genetically distinct. Classic adamantinomas harbored multiple alterations including chromosome/arm-level copy-number gains, the detection of which could aid their distinction from OFDs. Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.
Immunophenotypic, Cytogenetic, and Molecular Characterization of NUP98-Rearranged Pediatric Myeloid Neoplasms.
Khanlari M, Wang W, Thakral B … +9 more , Cuglievan B, Issa GC, Blackburn PR, Umeda M, Key L, Westover T, Ma J, Rubnitz JE, Klco JM
Mod Pathol · 2026 Jun · PMID 42379270 · Publisher ↗
NUP98 rearrangements (NUP98r) are often cryptic and define a high-risk subgroup of pediatric myeloid neoplasms, predominantly acute myeloid leukemia (AML). Despite their clinical significance, the immunophenotypic signat...
NUP98 rearrangements (NUP98r) are often cryptic and define a high-risk subgroup of pediatric myeloid neoplasms, predominantly acute myeloid leukemia (AML). Despite their clinical significance, the immunophenotypic signatures that enable early recognition of NUP98r remain incompletely characterized. We retrospectively studied 62 pediatric and young adult patients (age ≤21 years at diagnosis) with NUP98-rearranged myeloid neoplasms diagnosed from 1994 to 2025. We integrated flow cytometry, morphology, cytogenetics, and molecular data and grouped cases by fusion partner-NUP98::NSD1 (n=35), NUP98::KDM5A (n=12), and other NUP98 fusions (NUP98::X; n=15)-and by flow-defined differentiation patterns. NUP98::NSD1 accounted for 56% of cases and was found in older children, with a median age at diagnosis of 13.2 years. These cases displayed an immature myeloid phenotype, with frequent expression of CD34 (33/35, 94%), CD117 (31/35, 89%), HLA-DR (34/34, 100%), and uniform CD123 positivity in all evaluable cases (22/22, 100%), along with FLT3-ITD and WT1 alterations (22/34 each, 65%) and mostly diploid karyotypes (61%). NUP98::KDM5A occurred in younger children (median age at diagnosis, 1.9 years) and was associated with erythroid/megakaryocytic differentiation, including CD41/CD61 positivity in 8/10 (80%) and Glycophorin A positivity in 3/9 (33%) evaluable cases. Chromosome 13 abnormalities and RB1 alterations were identified in 60% and 55% of evaluable cases, respectively, and complex karyotypes were present in 63% of cases. Other NUP98 fusions (NUP98::X; n=15, 24%) showed diverse phenotypes and were enriched for 11p abnormalities (79% of evaluable NUP98::X cases). Most 11p abnormalities were evident on conventional cytogenetics when karyotype data were available, in contrast to NUP98::NSD1 and NUP98::KDM5A cases, which were often cytogenetically cryptic. In summary, NUP98 fusion partner was associated with recurring, diagnostically useful immunophenotypic, cytogenetic, and molecular patterns. These patterns can facilitate prioritization of RNA-based fusion testing, anticipate partner-specific differentials, and design flow cytometry follow-up strategies.
Chromoanagenesis in Myelodysplastic Syndromes Is Associated With Highly Complex Karyotype, TP53 Disruption and Dismal Prognosis.
Wei Q, Medeiros LJ, Loghavi S … +8 more , Leighton JS, Hu S, Toruner GA, Ok CY, Kanagal-Shamanna R, Xu J, Garcia-Manero G, Tang G
Mod Pathol · 2026 Jun · PMID 42320760 · Publisher ↗
Chromoanagenesis (CAG) is a catastrophic genomic event characterized by extensive chromosomal rearrangements and copy number alterations. It has been associated with complex karyotypes and poor outcomes in acute myeloid...
Chromoanagenesis (CAG) is a catastrophic genomic event characterized by extensive chromosomal rearrangements and copy number alterations. It has been associated with complex karyotypes and poor outcomes in acute myeloid leukemia. However, its prevalence and associated clinicopathologic and cytogenomic features in myelodysplastic syndromes (MDS) remain incompletely defined. In this study, we performed optical genome mapping (OGM) in 332 patients with MDS, 205 newly diagnosed (ND) and 127 relapsed/refractory cases. CAG was identified in 15.9% of cases overall and in 17.6% of ND MDS. Among ND patients, 97% of CAG cases harbored highly complex karyotypes versus 9% of non-CAG cases (p<0.01). TP53 alterations were present in 97% of CAG cases, predominantly multi-hit events, whereas mutations in canonical MDS driver genes were uncommon in CAG cases. Recurrent oncogenic amplifications, including 11q23/KMT2A and 6p21/PIM1 and HMGA1, were enriched in CAG cases. Clinically, 80.6% of CAG cases were classified as very high risk by IPSS-M. Median overall survival of ND CAG patients was 9.9 months versus not reached in non-CAG cases (p<0.01), and survival of CAG cases remained inferior compared with non-CAG patients with very high IPSS-M risk (20.4 months) or multi-hit TP53 alterations (18.3 months). We conclude that CAG defines a biologically distinct, ultra-high-risk subset of MDS characterized by TP53 disruption, extreme genomic complexity, and dismal prognosis. OGM enables efficient CAG detection and may refine current risk stratification.
Co-Existent Endometrial and Fallopian Tube Carcinoma, Molecular and Pathological Features for Risk Stratification.
Keyhanian K, Gilks CB, Mathew EP … +7 more , Mack T, Sekhon H, Lo B, Greenstreet P, Grondin K, McAlpine JN, Jamieson A
Mod Pathol · 2026 Jun · PMID 42320759 · Publisher ↗
Patients with co-existent endometrial and ovarian carcinoma (CEOC) have been shown to have an excellent prognosis if their tumors meet the FIGO 2023 endometrial carcinoma (EC) stage IA3 criteria. In addition, excluding t...
Patients with co-existent endometrial and ovarian carcinoma (CEOC) have been shown to have an excellent prognosis if their tumors meet the FIGO 2023 endometrial carcinoma (EC) stage IA3 criteria. In addition, excluding the intermediate and high-risk molecular subtypes (mismatch repair deficient [MMRd], p53 abnormal [p53abn], and No Specific Molecular Profile [NSMP] ER-low/negative) has been recently shown to improve risk stratification in CEOCs. In contrast, co-existent EC with fallopian tube (FT) involvement is considered pathologic T3/FIGO stage III. Our objective was to assess whether the FIGO 2023 IA3 criteria for CEOC can identify a subset of patients with coexistent endometrial and FT carcinoma at low risk of recurrence and if incorporation of molecular features can aid in prognostic stratification. An institutional database search was carried out at 2 institutions to identify T3a EC with FT involvement. Cases with nodal, pelvic side wall, vaginal, parametrial, adnexal soft tissue or peritoneal involvement, or treatment with neoadjuvant therapy were excluded. A total of 71 patients were identified. Fourteen carcinomas recurred (14/71: 19.7%); of these 85.7% (12/14) were endometrioid FIGO grade 3 or non-endometrioid histotypes, and 85.7% (12/14) had intermediate or adverse molecular features. Eight (8/71: 11.3%) carcinomas met the FT-adapted FIGO 2023 IA3 criteria with no recurrences. Further modifying the criteria by excluding tumors with adverse molecular features while expanding the pathology criteria to include ovarian and/or bilateral adnexal involvement identified 11/71 patients (15.5%), none of whom experienced a recurrence. By adapting the FIGO 2023 criteria for low-risk CEOCs to assess co-existent endometrial and FT carcinomas, we identified a subset of patients with excellent outcomes, such that treatment de-escalation could be considered. Furthermore, it may be possible to expand this category of low-risk co-existent endometrial and FT carcinoma, based on refined molecular/pathological features, so more patients with uterus/adnexa confined carcinoma and indolent disease behavior can be identified.
RUNX2 Rearrangement as a Recurrent Molecular Event and Diagnostic Marker in Salivary Gland Keratocystoma.
Wang M, Qian JJ, Leng NN … +9 more , Yin R, He YN, Zhang CY, Gu T, Xue JQ, Tian Z, Li J, Wang LZ, Xia RH
Mod Pathol · 2026 Jun · PMID 42314909 · Publisher ↗
Keratocystoma is considered a rare, benign salivary gland tumor predominantly occurring in the parotid gland. Due to its rarity, insufficiently recognized clinicopathological features, immunohistochemical phenotype, and...
Keratocystoma is considered a rare, benign salivary gland tumor predominantly occurring in the parotid gland. Due to its rarity, insufficiently recognized clinicopathological features, immunohistochemical phenotype, and molecular characteristics, keratocystoma remains diagnostically challenging. This study aimed to investigate the clinical, histological, and molecular features of keratocystoma to refine the histological diagnostic boundaries. Nineteen cases of keratocystoma were analyzed using fluorescence in situ hybridization (FISH), targeted RNA sequencing, and immunohistochemistry (IHC). Histological mimics, including 20 cases of squamous cell carcinoma, 21 cases of metaplastic Warthin tumor, 20 cases of pleomorphic adenoma, 19 cases of mucoepidermoid carcinoma, 19 cases of necrotizing sialometaplasia, 21 cases of branchial cleft cyst, and 21 cases of epidermoid cyst, were incorporated for IHC comparative analysis. All keratocystoma cases arose in the parotid gland. Of 19 cases, 13 were female and 6 were male. The age ranged from 5 to 74 years with a median age of 29 years. Histologically, the multiple cystic spaces were lined by parakeratinized and/or orthokeratinized stratified squamous epithelium. Interestingly, a distinct granular layer was observed in two cases, albeit only in focal areas. Multinucleated giant cell infiltration, cholesterol clefts and calcification were noted in 13 cases, 11 cases, and 5 cases, respectively. Involvement of salivary gland parenchyma by solid squamous cells nests was observed in 9 cases. Two cases showed areas where ductal epithelium appeared to undergo transition to keratocystoma components. Two cases presented with few mitoses in the solid squamous cell nests. One case demonstrated perineural invasion. All keratocystoma cases showed RUNX2 rearrangements. RNA sequencing identified a recurrent IRF2BP2::RUNX2 fusion in all successfully tested cases. It revealed significantly higher rate of RUNX2 protein expression in keratocystoma compared to squamous cell carcinoma, epidermoid cyst and branchial cleft cyst. Two cases experienced recurrence. These findings confirmed that RUNX2 rearrangement and IRF2BP2::RUNX2 fusion were specific molecular features of keratocystoma. While molecular testing for RUNX2 gene rearrangement or fusion is diagnostically helpful, the RUNX2 IHC is not significantly helpful. Although keratocystoma is benign, recurrence may occur occasionally, warranting close postoperative follow-up.
Clinicopathological, Molecular and DNA Methylation Analysis of Ossifying Fibromyxoid Tumors Delineates the ZC3H7B::BCOR Subset as a Distinct Entity.
Klubíčková N, Dermawan JK, Ameline B … +28 more , Martínek P, Vaněček T, Hájková V, Ptáková N, Grossmann P, Šteiner P, Kormunda S, Perret RE, Le Loarer F, Dehner C, Torres-Mora J, Gross JM, Chrisinger JSA, Charville G, Kosemehmetoglu K, Wangsiricharoen S, Meis J, Špůrková Z, Zámečník M, Zambo IS, Klinger T, Švajdler M, Kinkor Z, Michalová K, Baumhoer D, Michal M, Antonescu CR, Michal M
Mod Pathol · 2026 Jun · PMID 42302912 · Publisher ↗
Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain lineage of differentiation driven by a broad spectrum of gene fusions. It manifests primarily in soft tissues of the extremities. In this stu...
Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain lineage of differentiation driven by a broad spectrum of gene fusions. It manifests primarily in soft tissues of the extremities. In this study, we performed a comprehensive clinicopathological, molecular-genetic, and epigenetic analysis of 70 cases of OFMT, with a specific focus on rare fusion subtypes, particularly ZC3H7B::BCOR, PHF1::TFE3 and MEAF6::PHF1. In addition, we included seven tumors with novel fusions, namely AFF3::PHF1, PHF1::KLF15, PHF1::PRKAG1, CREBBP::PHF1, EPC1::BMI1, MEAF6::BCOR, and EP300::BCORL1. The clinicopathological characteristics revealed a correlation between specific fusions and aggressive clinical behavior; notably, tumors with ZC3H7B::BCOR fusions were always classified as morphologically atypical or malignant and were associated with significantly higher recurrence and metastatic rates compared to other fusion groups, particularly EP400::PHF1. Immunohistochemical analysis further revealed a distinct immunophenotype in the ZC3H7B::BCOR group. While immunopositivity for cytokeratins and myogenic markers was observed in approximately one-quarter and more than one-third of OFMT cases overall, respectively, ZC3H7B::BCOR-rearranged tumors were negative for both. In contrast, the majority showed immunopositivity for pan-Trk. Additionally, DNA methylation profiling distinguished ZC3H7B::BCOR-rearranged cases from other fusion-positive OFMT, whereas the former clustered closely with a subset of high-grade endometrial stromal sarcomas. This study supports the recognition of ZC3H7B::BCOR-positive tumors as a distinct clinicopathological entity, contributing to the refined molecular taxonomy of this neoplasm.
Baseline Tumor Proliferation and Ki-67 Are Associated With Pathological Response to Neoadjuvant Chemoimmunotherapy in Non-Small Cell Lung Cancer.
Wu J, Sun W, Liu X … +6 more , Yang X, Mao L, Wang C, Diao X, Huang X, Lin D
Mod Pathol · 2026 Jun · PMID 42302911 · Publisher ↗
Heterogeneity in the pathological response to neoadjuvant chemoimmunotherapy underscores the need for predictive biomarkers in resectable non-small cell lung cancer (NSCLC). This study identified baseline molecular featu...
Heterogeneity in the pathological response to neoadjuvant chemoimmunotherapy underscores the need for predictive biomarkers in resectable non-small cell lung cancer (NSCLC). This study identified baseline molecular features-particularly tumor proliferation signatures-associated with pathological response. Two retrospective cohorts (test, n = 81; validation, n = 107) of patients with NSCLC who received neoadjuvant chemoimmunotherapy were analyzed. Bulk RNA sequencing was performed on baseline biopsies from the test cohort, with immunohistochemistry (IHC) for PD-L1 and Ki-67 in both cohorts. Outcomes included major pathological response (MPR), pathological complete response (pCR), and event-free survival. In the test cohort, transcriptomic analysis showed that responders had significant upregulation of proliferation-related genes (eg, TP63, SOX2, NTRK2, and HMGA2) and activation of proliferation signatures (eg, chromosomal instability signature and core embryonic stem cell-like module), without activation of canonical immune-inflamed pathways. PD-L1 expression had limited predictive value (area under the curves [AUCs], 0.56-0.59 for MPR and 0.52-0.54 for pCR). In contrast, proliferation markers demonstrated higher performance: MKI67 messenger RNA predicted both MPR and pCR with an AUC of 0.71, and the Ki-67 IHC index yielded AUCs of 0.71 for MPR and 0.64 for pCR. The predictive value of the Ki-67 IHC index was validated in the independent cohort, with AUCs of 0.74 for MPR and 0.70 for pCR, and this association was generally consistent across squamous cell carcinoma and adenocarcinoma. A Ki-67 index ≥50% was significantly correlated with improved event-free survival in both cohorts (both Ps < .05). These findings indicate baseline tumor proliferation, particularly MKI67/Ki-67, as predictors of pathological response in NSCLC patients receiving neoadjuvant chemoimmunotherapy, supporting its potential clinical utility for patient selection.
Pulmonary Neuroendocrine Tumor Artificial Intelligence-Assisted Prediction of Postoperative Recurrence From Tumor Biopsy Specimens.
Akram F, Trandafir TE, van Weert TJJ … +13 more , Vesterinen T, Moonen L, Hillen LM, den Bakker MA, Heijboer FWJ, Damhuis RAM, PALGA group, Stubbs AP, Speel EM, Li Y, Dingemans AC, Derks J, von der Thüsen JH
Mod Pathol · 2026 Jun · PMID 42302910 · Publisher ↗
The current World Health Organization (WHO) (2021) classification of lung neuroendocrine tumors (LNETs) into typical carcinoids (TC) and atypical carcinoids (AC) relies on resection material and is not applicable to smal...
The current World Health Organization (WHO) (2021) classification of lung neuroendocrine tumors (LNETs) into typical carcinoids (TC) and atypical carcinoids (AC) relies on resection material and is not applicable to small biopsies. However, accurate risk stratification at the preoperative stage remains clinically important. In this study, we developed an artificial intelligence (AI) model to predict postoperative recurrence in LNET patients directly from hematoxylin and eosin (H&E)-stained tissue fragments, including diagnostic biopsies, independent of the WHO classification. A multiscale vision transformer was trained and evaluated to predict disease recurrence following curative resection using a population-based cohort of pathologically confirmed stage I to III patients. H&E slides of tissue microarrays (TMAs) from 452 LNET patients (TC, 414; AC, 38; nonrecurrence, 381; and recurrence, 71) were included. For external validation, an independent TMA cohort of 120 surgically treated LNETs (TC, 91; AC, 29; nonrecurrence, 109; and recurrence, 11) was used. To evaluate clinical applicability, 93 routine preoperative biopsies (TC, 80; AC, 13; nonrecurrence, 76; and recurrence, 17) were analyzed. The AI model demonstrated robust cross-cohort performance with balanced accuracy of 0.79 to 0.89 and area under the curve of 0.84 to 0.95. Despite few recurrence cases, the model achieved high sensitivity (0.82-0.94), reliably identifying high-risk patients. Specificity was 0.70 to 0.85, and negative predictive value was consistently 0.98 across all data sets, enabling confident recognition of low-risk patients. Overall, the AI model outperformed the WHO-based recurrence prediction, correctly identifying 91 of 99 (92%) versus 31 of 99 (31%) high-risk cases. Performance improvements were statistically significant in the TMA cohorts (Wilcoxon signed-rank test; P < .05). This is the first AI-based approach capable of predicting recurrence in LNETs using only H&E-stained biopsies. These findings support AI-driven histopathological assessment as a complementary tool to improve preoperative risk stratification and guide clinical management of LNET patients.
Amplification and Overexpression of Cyclin D1 in Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Targeted Next-Generation Sequencing Study.
Chen YR, Chiang PM, Lin J … +11 more , Wang SH, Lee JC, Li HN, Ma YC, Lee CL, Huang WT, Chao WR, Wang RC, Chen BJ, Medeiros LJ, Chang KC
Mod Pathol · 2026 Jun · PMID 42302909 · Publisher ↗
Follicular dendritic cell sarcoma (FDCS) is subdivided into conventional type and inflammatory type (IFDCS). IFDCS is consistently associated with Epstein-Barr virus (EBV) infection and generally follows an indolent clin...
Follicular dendritic cell sarcoma (FDCS) is subdivided into conventional type and inflammatory type (IFDCS). IFDCS is consistently associated with Epstein-Barr virus (EBV) infection and generally follows an indolent clinical course. Although EBV is believed to contribute to the pathogenesis of IFDCS, the underlying mechanisms remain incompletely understood. Recent comprehensive next-generation sequencing studies have identified recurrent somatic alterations involving the major histocompatibility complex and epigenetic regulatory pathways as well as signaling pathways related to immune responses. In this study, we performed targeted DNA sequencing of 523 cancer-associated genes (TSO500) in 31 cases of IFDCS. The cohort included 13 men and 18 women, with a mean age of 62.6 years (range, 36-84). Tumors arose in the spleen (n = 20), liver (n = 8), colon (n = 2), and pancreas (n = 1), with a mean tumor size of 5.8 cm (range, 1.4-11.7). Genetic alterations were found in 71% of cases with CCND1 amplifications (3-5 copies) being the most common (45.5%), followed by EZH2 mutations (18.2%), MYC amplifications (3-4 copies, 13.6%), and ATM mutations (9.1%). Pathway analysis identified cell-cycle progression as the main activated signaling in IFDCS. RNA in situ hybridization and double immunohistochemical staining confirmed the overexpression of cyclin D1 and MYC in FDCs. Clinically, overexpression of cyclin D1 was frequently found in both TSO500-positive (88.9%) and TSO500-negative (71.4%) cases and showed no association with tumor behavior. No significant clinicopathologic difference was present between TSO500-positive and TSO500-negative tumors. Notably, splenic origin was associated with female predominance (P = .011) and larger tumor size (P = .048). In addition, tumor cells exhibited a type II EBV latency pattern (latent membrane protein 1 [LMP1]+/Epstein-Barr nuclear antigen-2-) in 84.6% of cases, and LMP1 expression correlated with larger tumor size (P = .021). Taken together, these findings support a role for EBV-driven activation of the cyclin D1 pathway and suggest that EBV-LMP1-CCND1 signaling may contribute to the pathogenesis of IFDCS.
Stratification by Ki-67 Labeling Index Increases Specificity of p16 Expression as a Surrogate Marker for CDKN2A Inactivation in Meningioma.
Zhang KY, Mirchia K, Perry A … +5 more , Eberhart CG, Raleigh DR, Solomon DA, Lucas CG, Tang V
Mod Pathol · 2026 Jun · PMID 42297142 · Publisher ↗
Meningiomas are the most common primary central nervous system tumors, with histologic grading predicting prognosis and guiding treatment decisions. Recent updates to the WHO Classification of Tumors of the Central Nervo...
Meningiomas are the most common primary central nervous system tumors, with histologic grading predicting prognosis and guiding treatment decisions. Recent updates to the WHO Classification of Tumors of the Central Nervous System have incorporated molecular criteria, including homozygous deletion of CDKN2A in grade 3 meningiomas. CDKN2A encodes the tumor suppressor protein p16, a key regulator of cell cycle progression, and loss is associated with increased proliferation, recurrence, and poor clinical outcomes. Previous studies have shown that p16 protein levels can serve as a surrogate immunohistochemical marker that correlates with CDKN2A status in higher-grade meningiomas. However, p16 utility in segregating cases for further testing remains unclear. In this study, we aimed to stratify meningiomas to identify cases that may benefit from molecular testing. We investigated whether Ki-67 labeling could serve as a stratification tool to identify meningiomas for which minimal expression of p16 is indicative of underlying CDKN2A inactivation. Using Ki-67 as a surrogate marker for tumor aggressiveness, we identified a threshold of 5% in tumors with low p16 expression as a sensitivity cutoff for predicting CDKN2A inactivation, suggesting that the subset of meningiomas with a higher labeling index could benefit from further molecular validation, whereas the subset with p16 expression is low yield to profile for CDKN2A status. Our findings support the clinical utility of Ki-67 and p16 expression as cost-effective screening tools to flag potentially aggressive meningiomas, particularly in resource-constrained settings.
When Seeing Is Not Believing: Understanding Uniform Manifold Approximation and Projection (UMAP) and t-Distributed Stochastic Neighbor Embedding (t-SNE) in Methylation-Based Tumor Classification.
Emert B
Mod Pathol · 2026 Jun · PMID 42285440 · Publisher ↗
DNA methylation profiling has become an important tool for tumor classification across multiple subspecialties of pathology. To visualize relationships among samples, many studies employ dimensionality-reduction techniqu...
DNA methylation profiling has become an important tool for tumor classification across multiple subspecialties of pathology. To visualize relationships among samples, many studies employ dimensionality-reduction techniques such as uniform manifold approximation and projection and t-distributed stochastic neighbor embedding. Although these techniques create visually compelling plots that summarize complex molecular data, they are visualization tools, not clustering or classification algorithms, and their appearance depends heavily on sample selection, data preprocessing, and parameter choices. This technical review outlines key considerations for the interpretation and reporting of visualization and classification methods in methylation-based tumor studies. We recommend a set of reporting standards covering full transparency of preprocessing and algorithmic parameters, pairing visualizations with quantitative clustering or classification analyses, and validating observed groupings with independent clinical, histologic, and molecular data. An accompanying online notebook allows readers to explore different settings on public tumor methylation data sets to visualize their effects on uniform manifold approximation and projection and t-distributed stochastic neighbor embedding. We focus on how to interpret methylation-based visualizations and classifier output in diagnostic settings, rather than providing a comprehensive comparison of profiling methods, classification tools, or clustering algorithms. Understanding these principles will help ensure the reproducibility and scientific rigor of pathology research incorporating methylation-based tumor classification.
PATZ1 Immunohistochemistry Aids in the Diagnosis of PATZ1-Rearranged Sarcomas.
Gildenberg MS, Folpe AL, Charville GW … +3 more , Hung YP, Hornick JL, Anderson WJ
Mod Pathol · 2026 Jun · PMID 42270011 · Publisher ↗
PATZ1-rearranged sarcomas are diagnostically challenging due to their rather non-specific morphology and immunophenotype. These tumors are characterized by bland, round-to-spindled cells within a fibromyxoid matrix with...
PATZ1-rearranged sarcomas are diagnostically challenging due to their rather non-specific morphology and immunophenotype. These tumors are characterized by bland, round-to-spindled cells within a fibromyxoid matrix with variable microcysts, fibrous septa, hyalinized vessels, and cellular whorls. PATZ1-rearranged sarcomas are often positive for neural, skeletal muscle, and epithelial markers. Identification of these tumors is further complicated by the cryptic nature of the characteristic EWSR1::PATZ1 fusion, which generally makes fluorescence in situ hybridization analysis unreliable if rearrangement is not detected. As a result, costly and time-intensive molecular assays are often currently necessary for definitive diagnosis. The purpose of this study was to assess immunohistochemistry (IHC) for PATZ1 as a surrogate for detecting the gene fusion. In total, 533 tumors from whole-tissue sections and tissue microarrays were evaluated, including 14 PATZ1-rearranged sarcomas as well as other benign and malignant mesenchymal neoplasms. IHC for PATZ1 was positive in 12/14 (86%) PATZ1-rearranged sarcomas. Of the remaining tumor types, 495 (95%) were negative for PATZ1. Notably, PATZ1 expression was observed in a subset of other tumor types, including myoepithelial carcinoma (2/4; 50%), myoepithelioma (2/15; 13%), rhabdomyosarcoma (13/99; 13%), desmoplastic small round cell tumor (1/10; 10%), dermatofibrosarcoma protuberans (1/10; 10%), myxoid liposarcoma (1/16; 6%), schwannoma (1/22; 5%), and malignant peripheral nerve sheath tumor (3/70; 4%). The 13 RMS cases that were positive were classified as embryonal (n=7), alveolar (n=5), and RMS, NOS (n=1). In conclusion, PATZ1 IHC is moderately sensitive and specific for PATZ1-rearranged sarcomas, and it may be a helpful diagnostic marker for this challenging tumor. While most tumors with morphologic overlap with PATZ1-rearranged sarcomas are negative for PATZ1 by IHC, expression in a subset of myoepithelial tumors and rhabdomyosarcomas represents a potential diagnostic pitfall.
Intratubular Spread in Renal Pelvic Urothelial Carcinoma: Prognostic Significance and Staging Implications.
Oga K, Teramoto Y, Kita Y … +2 more , Kobayashi T, Haga H
Mod Pathol · 2026 Jun · PMID 42270010 · Publisher ↗
Intratubular spread of renal pelvic urothelial carcinoma refers to tumor extension along preexisting collecting ducts and/or renal tubules with preservation of the tubular basement membrane at the involved profiles. Alth...
Intratubular spread of renal pelvic urothelial carcinoma refers to tumor extension along preexisting collecting ducts and/or renal tubules with preservation of the tubular basement membrane at the involved profiles. Although recognized as noninvasive for staging purposes, its prognostic role remains incompletely defined. We conducted a single-center retrospective cohort study of consecutive patients who underwent radical nephroureterectomy for renal pelvic urothelial carcinoma between April 2002 and April 2023, with blinded central slide review and American Joint Committee on Cancer eighth edition harmonization. The prespecified primary endpoint was non-urinary tract recurrence-free survival (NUTRFS), defined as recurrence outside the urinary tract (local/regional recurrence outside the urinary tract, lymph node metastasis, or distant metastasis) or death from any cause; urothelial tract recurrences were not counted as NUTRFS events. The key secondary endpoint was cancer-specific survival (CSS); disease-free survival and overall survival were additional endpoints. After exclusions, 158 patients were analyzed (median follow-up, 95.7 months), and intratubular spread was identified in 58 patients (36.7%). Within pT1/pT2 disease, the presence of intratubular spread strongly stratified NUTRFS (log-rank test, P < .001) and CSS (P = .0015), and outcomes for pT1/pT2 tumors with intratubular spread approximated those of pT3 tumors (NUTRFS, P = .938; CSS, P = .868). Within pT3, the presence of intratubular spread stratified NUTRFS (P = .043) but not CSS (P = .133). In prespecified multivariable Cox models restricted to invasive tumors with known nodal status and excluding pTa/pTis and pT4 (n = 71), the presence of intratubular spread remained independently associated with worse NUTRFS (hazard ratio, 2.85; 95% CI, 1.34-6.09; P = .0066) and CSS (hazard ratio, 2.98; 95% CI, 1.28-6.95; P = .0116) after adjustment for pT3 subclass and nodal status, with no evidence of interaction by pT3 subclass. Intratubular spread is a noninvasive but clinically relevant, stage-adjacent histologic feature in renal pelvic urothelial carcinoma that is best captured by NUTRFS and supported by concordant CSS findings, with particular utility for identifying high-risk pT1/pT2 disease.
Immune-Related Pathological Features and Predictive Score in Intrahepatic Cholangiocarcinoma Treated With Combined Conversion Immunotherapy.
Chen W, Sang Y, Soon GST … +9 more , Chew EJC, Wu G, Lin X, Luo R, Gao Q, Zhou J, Xia H, Zhu K, Shi R
Mod Pathol · 2026 Jun · PMID 42264036 · Publisher ↗
Immune checkpoint inhibitor (ICI)-based combined neoadjuvant/conversion therapy is increasingly used in the management of initially unresectable intrahepatic cholangiocarcinoma (iCCA). Reliable biomarkers in predicting t...
Immune checkpoint inhibitor (ICI)-based combined neoadjuvant/conversion therapy is increasingly used in the management of initially unresectable intrahepatic cholangiocarcinoma (iCCA). Reliable biomarkers in predicting treatment and survival outcome remain underdeveloped. Here, we assessed immune-related pathological features in pretreatment biopsy specimens of initially unresectable iCCA treated with ICI-based conversion therapy. A predictive scoring system (immune therapy predictive score [iTPS]) was developed to predict the patients' oncological outcome. We evaluated 13 immune-related pathological features (tumor-infiltrating lymphocytes, mature tertiary lymphoid structure, lymphoid aggregate, dense plasma cell infiltration, granuloma, neutrophil, foamy macrophage, necrosis, cholesterol cleft, hemosiderin deposition, giant cell formation, neovascularization, and mature fibrosis) in hematoxylin-eosin-stained biopsy specimen slides from 95 iCCA patients. Cox regression analysis was used to evaluate the correlation between these features and recurrence-free survival (RFS) and overall survival (OS). Features showing correlation with survival were selected for iTPS to develop a binary iTPS scheme. Four features (immature fibrosis, tumor-infiltrating lymphocytes, lymphoid aggregate, and hemosiderin) were included in iTPS. A binary iTPS scheme showed patients with low iTPS displaying significantly better RFS (hazard ratio, 1.83; 95% CI, 1.02-3.27; P = .04) and OS (hazard ratio, 12.9; 95% CI, 3.07-54.18; P < .001). In conclusion, we developed an iTPS scheme based on routine hematoxylin-eosin-stained pretreatment biopsy slides. The iTPS can predict the RFS and OS of iCCA patients treated with combined ICI-based conversion therapy. iTPS is a good candidate predictive biomarker in iCCA and provides a new perspective in understanding the tumor immune microenvironment in immunotherapy.
Corrigendum to "CDKN2A Deletions but not Point Mutations May Explain Discordant Phenotype of Human Papilloma Virus (HPV) DNA-Positive and p16-Negative HPV-Associated Squamous Cell Carcinoma" (Modern Pathology. 2026 May;39(5):100994).
Koller M, Ermakov MS, Regauer S … +1 more , Kashofer K
Mod Pathol · 2026 May · PMID 42202373 · Publisher ↗
Abstract loading — click title to view on PubMed.
Gynecologic Tumors and Precursor Lesions, Including p53-Aberrant Atypical Hyperplasia-like Endometrial Lesions, in Li-Fraumeni Syndrome.
Nishikawa Y, Ceyhan-Birsoy O, Selenica P … +2 more , Mandelkar D, Chui MH
Mod Pathol · 2026 May · PMID 42190817 · Publisher ↗
Li-Fraumeni syndrome (LFS), caused by germline TP53 (g-TP53) mutation, predisposes to a wide range of early-onset malignancies, but gynecologic tumors are relatively uncommon. We sought to define the spectrum of neoplasm...
Li-Fraumeni syndrome (LFS), caused by germline TP53 (g-TP53) mutation, predisposes to a wide range of early-onset malignancies, but gynecologic tumors are relatively uncommon. We sought to define the spectrum of neoplasms and atypical lesions of the female reproductive tract in LFS patients. A histomorphologic review was performed on tumors and gynecologic tissues from biopsy or resection specimens from 20 female patients with g-TP53 mutations. Gynecologic cancers (n = 7) comprised high-grade serous carcinomas of tubo-ovarian/primary peritoneal origin (n = 3), high-grade endometrioid ovarian carcinoma (n = 1), endometrial serous carcinoma (n = 1), and leiomyosarcomas (uterine, n = 1; and ovarian, n = 1). Morphologic features were indistinguishable from sporadic cases. With exception of 1 case, somatic inactivation of the remaining TP53 allele was identified by loss of heterozygosity or deep deletion. Other abnormal lesions, which exhibited aberrant p53 expression by immunohistochemistry, included serous tubal intraepithelial carcinomas (n = 2), a uterine smooth muscle tumor of uncertain malignant potential (n = 1), and endometrial glandular lesions, morphologically resembling atypical hyperplasia (n = 4; median age, 33 years). Immunohistochemistry on p53-aberrant atypical hyperplasia-like lesions revealed PAX2 loss (3/4), nuclear β-catenin (1/3), and decreased PTEN (2/3); molecular analysis on 2 cases revealed TP53 loss of heterozygosity, with concomitant KRAS or PTEN mutation. These lesions resolved with progestin therapy (n = 2) or did not recur following hysterectomy (n = 2). In morphologically benign tissues, p53 immunohistochemistry revealed variable staining patterns, including wild-type only, discrete foci of aberrant expression, or diffuse p53 overexpression in nearly all cells (associated with the g-TP53 p.Arg337His founder variant). Our findings demonstrate that g-TP53 mutations can drive the pathogenesis of gynecologic tumors that are usually defined by somatic TP53 mutations. A novel p53-aberrant endometrial glandular lesion, occurring in young patients with LFS, likely represents an unusual form of endometrial atypical hyperplasia rather than serous carcinoma. In morphologically benign tissues, aberrant p53 expression in numerous discrete foci or diffusely across nearly all cells should prompt consideration of an underlying g-TP53 mutation.
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