Human Pathology[JOURNAL]
Sun
200 papers
Epigenetic profiling of biphenotypic sinonasal sarcoma across fusion variants and high-grade transformation.
Gomes YM, de Castro JVA, Gomes NM … +15 more , Abreu RF, Kulikowski LD, Wolff BM, Pinto CA, Nascimento AG, Toledo RN, Meyer A, Fernandes IL, Neto CS, Jurmeister P, Capper D, Dermawan JK, Fritchie KJ, Bezerra SM, Costa FD
Hum Pathol · 2026 Jun · PMID 41720166 · Publisher ↗
Biphenotypic sinonasal sarcoma (BSS) is a rare mesenchymal neoplasm characterized by dual neural and myogenic differentiation, recurrent PAX3 gene rearrangements, and low-grade morphology. High-grade transformation has b...
Biphenotypic sinonasal sarcoma (BSS) is a rare mesenchymal neoplasm characterized by dual neural and myogenic differentiation, recurrent PAX3 gene rearrangements, and low-grade morphology. High-grade transformation has been described, posing significant diagnostic challenges due to overlap among sinonasal tumors. DNA methylation profiling has emerged as a powerful diagnostic tool for sinonasal neoplasms, although BSS was not included in previous cohorts. In this study, we investigated the DNA methylation profile of BSS and its relationship with fusion type and high-grade transformation. Fourteen BSS samples were retrospectively collected from four academic institutions. All cases underwent genome-wide methylation profiling using the Illumina Infinium MethylationEPIC array, and available clinical, radiological, histopathologic, and immunohistochemical data were reviewed. RNA sequencing was performed when sufficient material was available. Methylation profiles were analyzed using t-distributed stochastic neighbor embedding (t-SNE) and compared with a reference cohort of sinonasal tumors. The median patient age was 52.7 years, with a female predominance (M:F ratio 1:2.25). The most common fusion was PAX3::MAML3 (6/12, 50.0%), followed by PAX3::FOXO1 and other rare rearrangements, including PAX3::NCOA2, PAX3::YAP1, and FUS::POU2AF3, detected in one case each (1/12, 8.3%). Most importantly, all BSS samples formed a cohesive epigenetic group upon dimensionality reduction, clearly separated from other sinonasal tumors. No specific clustering was seen among different fusion types or tumor grade. Our findings support that BSS represents a unique and molecularly distinct sinonasal sarcoma with a characteristic DNA methylation signature, independent of gene fusion partners or histologic progression, providing a valuable tool for the classification of challenging cases.
Navigating diagnostic shifts: A comparative review of the WHO 5th edition and ICC 2022 classifications of myeloid neoplasms.
Koorse Germans S, Weinberg OK
Hum Pathol · 2026 Mar · PMID 41720165 · Publisher ↗
The near-simultaneous publication of the World Health Organization (WHO) 5th Edition classification of hematolymphoid tumors (WHO-HAEM5) and the International Consensus Classification (ICC) in 2022 represents a pivotal m...
The near-simultaneous publication of the World Health Organization (WHO) 5th Edition classification of hematolymphoid tumors (WHO-HAEM5) and the International Consensus Classification (ICC) in 2022 represents a pivotal moment in the taxonomy of myeloid neoplasms. Both systems emphasize integration of morphology, cytogenetics, and molecular genetics, yet they diverge in several clinically meaningful areas, including blast thresholds for acute myeloid leukemia (AML), definition of the myelodysplastic syndrome (MDS)-AML interface, and categorization of TP53-mutated disease [TP53mut MN] [1-3]. These differences extend beyond nomenclature, influencing prognostic stratification, therapeutic decision-making, and eligibility for clinical trials [4-7]. Recent comparative cohort studies demonstrate substantial reclassification rates, particularly among MDS with excess blasts, AML with myelodysplasia-related features, and TP53-mutated neoplasms, with prognosis driven largely by underlying molecular features rather than blast percentage alone [8-11]. This review provides a comprehensive comparison of WHO-HAEM5 and ICC 2022, synthesizes emerging real-world outcome data, and discusses implications for diagnostic practice, harmonization efforts, and future refinement of myeloid neoplasm classification [12-14].
Global vs. individual scoring when prostate needle cores from a single systematic biopsy site show Gleason score heterogeneity.
Lanipekun OK, Wang Y, Miyamoto H
Hum Pathol · 2026 May · PMID 41698512 · Publisher ↗
It remains controversial how Gleason score/Grade Group (GG) should be reported when prostate needle cores from a single systematic biopsy site show different scores. One method is to grade globally, while another is to r...
It remains controversial how Gleason score/Grade Group (GG) should be reported when prostate needle cores from a single systematic biopsy site show different scores. One method is to grade globally, while another is to report multiple scores in the respective cores. To determine the optimal method for reporting, we assessed two sets of patients showing GG2 or GG3 cancer by global scoring in a single site of systematic sextant biopsy (typically two cores/site), along with their controls, all of whom underwent radical prostatectomy without neoadjuvant therapy. In the first set of patients (n = 50), one core showed GG3 and the other GG1-2. In the second set of patients (n = 35), one core showed GG4 and the other GG1-3. Control patients for the first (n = 72) or second (n = 45) set had GG2 or GG3 cancer, respectively, in both cores from a single biopsy site. Up-grading on prostatectomy occurred in 26 (52.0%) of GG3/GG1-2 (overall GG2) patients versus 12 (16.7%) of GG2/GG2 controls (P < 0.001), as well as in 19 (54.3%) of GG4/GG1-3 (overall GG3) patients versus 6 (13.3%) of GG3/GG3 controls (P < 0.001). Univariate (hazard ratio 3.442, 95% confidence interval 1.387-8.542, P = 0.005) and multivariable (hazard ratio 3.177, 95% confidence interval 1.180-8.551, P = 0.022) analyses further revealed that the presence of a GG3 core in cases with overall GG2 cancer (vs. GG2/GG2) was associated with a significantly higher risk of postoperative biochemical recurrence. Compared with global scoring, individual scoring within a single systematic biopsy site with multiple core involvement may provide more accurate risk stratification of prostate cancer.
Fascin expression is associated with aggressive clinicopathological features in parathyroid tumors.
Omi Y, Yamamoto T, Nagashima Y … +2 more , Kurata A, Horiuchi K
Hum Pathol · 2026 May · PMID 41687791 · Publisher ↗
BACKGROUND: Parathyroid tumors are classified by the World Health Organization as adenomas, atypical tumors, or carcinomas. While the loss of parafibromin expression and a Ki-67 labeling index >5% are well known markers...
BACKGROUND: Parathyroid tumors are classified by the World Health Organization as adenomas, atypical tumors, or carcinomas. While the loss of parafibromin expression and a Ki-67 labeling index >5% are well known markers of malignancy, the role of fascin, an actin-bundling protein implicated in cancer invasion and metastasis, has not yet been investigated in parathyroid tumors. METHODS: We examined fascin expression by immunohistochemistry in 19 carcinomas, 16 atypical tumors, 23 adenomas and 14 normal parathyroid tissues. Staining for parafibromin and Ki-67 was also performed. Fascin expression was evaluated semiquantitatively, with cases scoring ≥3 considered positive. Associations with parafibromin and Ki-67 were analyzed, and clinicopathological correlations were assessed. RESULTS: Fascin positivity was observed in 0% of normal tissues, 21.7% of adenomas, 50.0% of atypical tumors, and 42.1% of carcinomas. Nuclear fascin expression was more frequent in atypical tumors (25.0%) and carcinomas (42.1%) than in adenomas (4.3%). Parafibromin loss was detected in 43.7% of atypical tumors and 89.5% of carcinomas but not in adenomas or normal tissues. Ki-67 labeling index >5% was detected in 31.3% of atypical tumors, and 63.2% of carcinomas. Fascin-positive cases showed a higher rate of parafibromin negativity (p = 0.0071), whereas fascin expression was not correlated with Ki-67. All recurrent cases were fascin-positive, parafibromin-negative, and had a Ki-67 labeling index >5%. CONCLUSION: Although fascin immunostaining was not superior to parafibromin or Ki-67 for differential diagnosis, its higher expression in atypical tumors and carcinomas and its presence in recurrent cases indicate that fascin expression is associated with aggressive clinicopathological features.
Correlation of NPM1 immunohistochemistry with mutation subtypes, clinicopathologic variables and molecular testing in AML with NPM1 mutation.
Germans SK, Weinberg OK, Chen W … +5 more , Cantu M, Chen M, Oliver D, Koduru P, Bigham L
Hum Pathol · 2026 May · PMID 41679345 · Publisher ↗
BACKGROUND: Nucleophosmin 1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML). Although RT-PCR and next-generation sequencing (NGS) remain the gold standard for diagnosis and minimal/measu...
BACKGROUND: Nucleophosmin 1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML). Although RT-PCR and next-generation sequencing (NGS) remain the gold standard for diagnosis and minimal/measurable residual disease (MRD) assessment, NPM1 mutant-specific immunohistochemistry (NPM1m IHC) using monoclonal antibodies presents a rapid and cost-effective alternative. Correlation between NPM1m IHC patterns and specific NPM1 mutation subtypes remain underexplored. OBJECTIVES: Evaluate the diagnostic utility of NPM1m IHC in AML with NPM1 mutation and to assess its correlation with mutation subtypes, morphologic features, cytogenetic profiles, co-mutations, and clinical outcomes. METHODS: A retrospective cohort of 36 AML cases with confirmed NPM1 mutations (2018-2024) were analyzed for clinicopathologic variables, cytogenetics, PCR/NGS data, and NPM1m IHC results with subgroup analysis between Type A (n = 28) and non-Type A (n = 8) mutations. RESULTS: NPM1m IHC positivity was observed in all insertional NPM1 mutation subtypes with two distinct staining patterns: homogeneous and two-toned, with two-toned pattern more frequent in Type A mutations. Non-Type A mutations were more often associated with complex karyotypes and showed a trend toward less frequent FLT3 co-mutations. Monocytic differentiation and cup-like nuclear morphology were assessed in both subgroups. No significant difference in survival or remission rates was observed between groups, although Type A mutations exhibited higher rates of dysplasia (p = 0.03). CONCLUSION: NPM1m IHC is a sensitive and timely surrogate marker for insertional NPM1 mutations, correlating well with molecular results and useful in both immediate diagnosis and MRD evaluation. This study reveals subtype-specific morphologic and cytogenetic associations and highlights the need for further investigation into non-insertional NPM1 mutations and their detection challenges.
The molecular profile of ovarian struma ovarii.
Calejero I, Mobarki M, Musawi S … +2 more , Péoc'h M, Karpathiou G
Hum Pathol · 2026 May · PMID 41655861 · Publisher ↗
INTRODUCTION: Struma ovarii is a rare type of ovarian teratoma consisting predominantly of thyroid tissue and showing a usually benign clinical course which cannot be predicted by its histology. Thus, their molecular ana...
INTRODUCTION: Struma ovarii is a rare type of ovarian teratoma consisting predominantly of thyroid tissue and showing a usually benign clinical course which cannot be predicted by its histology. Thus, their molecular analysis could help to better classify these tumors. However, the molecular profile of struma ovarii, especially the benign one, has been rarely studied. MATERIAL AND METHODS: We performed a retrospective, non-interventional study of 23 benign ovarian struma ovarii using formalin-fixed paraffin-embedded tissues for DNA extraction and next-generation sequencing. RESULTS: Two tumors harbored interesting molecular alterations. The first tumor, diagnosed in an adult patient, harbored two DICER1 variants: c. 4738 C > T and c. 5429 A > T. The second one was a struma ovarii harboring a POLD1 c.961G > A, p.(Gly321Ser) variant. None of the tumors harbored BRAF mutations. CONCLUSION: Benign struma ovarii do not harbor BRAF alterations. DICER1 and POLD1 variants need further investigation in this tumor pathology.
Follicular lymphoma with signet ring cell morphology: Clinicopathologic analysis of 31 cases.
Parisi X, Medeiros LJ
Hum Pathol · 2026 May · PMID 41655860 · Publisher ↗
We report 31 cases of follicular lymphoma (FL) with signet ring (SR) cells, representing <0.05% of FLs diagnosed at our institution. The cohort includes 16 women and 15 men with a median age of 65 years (range, 26-87). A...
We report 31 cases of follicular lymphoma (FL) with signet ring (SR) cells, representing <0.05% of FLs diagnosed at our institution. The cohort includes 16 women and 15 men with a median age of 65 years (range, 26-87). All patients presented with lymphadenopathy. Twenty-three (74%) patients had advanced stage disease and 8 (26%) had localized (stage I or II) disease. Twenty-one (68%) patients underwent excisional biopsy, 8 core needle biopsy and 2 fine needle aspiration. All 29 neoplasms with biopsy specimens had a follicular pattern, at least in part, but 9 had diffuse areas. These neoplasms were grade 1-2 in 19 cases and grade 3A in 10 cases. In addition, 1 patient had FL grade 1-2 in the nasopharynx and FL grade 3A FL in a regional lymph node and 1 patient had FL grade 3A (25% of the specimen) associated with diffuse large B-cell lymphoma. We semi-quantified the percentage of SR cells as follows: 5-10% in 3 cases, 11-25% in 8, 26-50% in 9, 51-75% in 10 and > 75% in 1 neoplasm. Immunophenotypic analysis using immunohistochemistry was performed in all cases and flow cytometry immunophenotypic analysis was performed in 24 cases. All neoplasms were positive for pan-B-cell markers and lacked T-cell antigens. CD10 was positive in 28 of 30 (93%) cases, and BCL2 and BCL6 were positive in all 20 and 18 cases assessed, respectively. IGH::BCL2 was detected in all 10 cases tested by fluorescence in situ hybridization. Targeted next-generation sequencing analysis performed successfully on 4 cases identified recurrent mutations in genes often involved in FL, such as KMT2D and TNFRSF14. In conclusion, in this retrospective study we provide the largest case series of FL-SR. We show that SR cells can be numerous in FL, but otherwise these cases resemble classic FL. We also provide results of next generation sequencing data on 4 cases which heretofore has not been reported.
Focal active colitis: Diagnostic relevance and long-term clinical outcomes.
Soubra AB, Nasser SM
Hum Pathol · 2026 May · PMID 41655859 · Publisher ↗
BACKGROUND: Focal active colitis (FAC) is a histopathologic finding characterized by focal neutrophilic crypt injury without chronic architectural changes. Its clinical implications, particularly its association with inf...
BACKGROUND: Focal active colitis (FAC) is a histopathologic finding characterized by focal neutrophilic crypt injury without chronic architectural changes. Its clinical implications, particularly its association with inflammatory bowel disease (IBD), remain debated. METHODS: We retrospectively reviewed colorectal biopsies diagnosed as FAC (2005-2024) at a tertiary center in Lebanon. Adult patients (>18 years) with isolated FAC and available clinical follow-up were included. Clinical outcomes, endoscopy, and subsequent diagnoses were analyzed. RESULTS: 419 patients had complete follow-up data. Mean age was 52.5 years; 51.5% were female. Abdominal pain was the most common presentation (57.5%). Colonoscopy was normal in 73%. During a mean 26-month follow-up, 9 patients (2.15%) developed IBD (4 Crohn's disease, 3 ulcerative colitis, 2 unclassified). IBS was diagnosed in 33.2%, infectious colitis in 11.2%, drug-induced colitis in 8.6%, diverticular disease in 4.5%, and ischemic colitis in 0.7%. 25.3% had no identifiable etiology with negative follow-up. FAC was incidental in 10.5% and persistent in 3.8%. No histologic features predicted progression to IBD. CONCLUSION: In this 19-year, 419-patient study, FAC was most often linked to IBS, infection, or drug-induced injury, with only 2.15% progressing to IBD. No predictive histologic features were identified. FAC remains a nonspecific finding; careful follow-up is warranted in symptomatic patients, while incidental cases are usually clinically insignificant.
S100 expression and SDHB status define distinct biological subsets of bladder paraganglioma.
Li H, Matoso A
Hum Pathol · 2026 May · PMID 41655858 · Publisher ↗
Bladder paraganglioma is an exceptionally rare neuroendocrine tumor with important diagnostic and prognostic implications. We retrospectively analyzed 110 bladder paragangliomas diagnosed between 2000 and 2025 to better...
Bladder paraganglioma is an exceptionally rare neuroendocrine tumor with important diagnostic and prognostic implications. We retrospectively analyzed 110 bladder paragangliomas diagnosed between 2000 and 2025 to better characterize clinicopathologic features, immunophenotypic patterns, and clinical outcomes, with particular emphasis on S100, SOX10, and SDHB immunohistochemistry. The cohort showed a slight female predominance (F:M = 1.34) and a mean age at diagnosis of 62.7 years. Most tumors involved the muscularis propria, supporting a bladder wall origin. Among cases with available S100 staining, nearly half (48.5%) demonstrated diffuse, strong S100 expression in both chromaffin and sustentacular cells, an unusual pattern that frequently caused diagnostic confusion and was the reason for consultation. In contrast, SOX10 expression remained restricted to sustentacular cells in all tested tumors, underscoring its reliability as a Schwannian marker. Loss of SDHB expression was identified in 14.5% of tumors and was significantly associated with younger age, male sex, absence of diffuse S100 expression, and metastatic disease. All S100-positive tumors retained SDHB expression. Among patients with available follow-up, 20% developed metastatic disease, with a 5-year metastatic rate of 38.5%; most metastatic tumors showed SDHB loss and were S100-negative. No paraganglioma-related deaths were documented. These findings demonstrate that diffuse S100 positivity in bladder paraganglioma is relatively common and represents a significant diagnostic pitfall. Importantly, S100-positive tumors appear to be associated with intact SDHB expression and a potentially less aggressive phenotype, whereas SDHB loss identifies a higher-risk subset with increased metastatic potential.
Four pressing problems in liver pathology.
Albayrak NE, Umetsu SE, Soon G … +2 more , Kakar S, Torbenson M
Hum Pathol · 2026 Mar · PMID 41611021 · Publisher ↗
Four important challenges in liver pathology are explored. Recognizing challenges in diagnostic pathology is one of the most important ways the field grows and improves, and this is reflected in the four challenges selec...
Four important challenges in liver pathology are explored. Recognizing challenges in diagnostic pathology is one of the most important ways the field grows and improves, and this is reflected in the four challenges selected for review. The first problem considers the best approach to low-grade hepatocellular lesions in livers with chronic vascular disease. The second problem addresses the difficulties in making a diagnosis of portal vein disease and in choosing the best nomenclature. Problem 3 focuses on best practices for primary carcinomas of the liver that are difficult to classify as hepatocellular carcinoma versus cholangiocarcinoma. Problem 4 discusses the good and the bad of ongoing efforts to change established names of disease entities. All of these problems are discussed in their historical contexts and emphasize the practical aspects relevant to surgical pathology.
Correlation analysis of TP53 missense mutations and p53 protein expression patterns in endometrial carcinoma.
Yang Y, Sun S, Xi Y … +5 more , Xu C, Zhu R, Yin W, Zhan Y, Su D
Hum Pathol · 2026 May · PMID 41581707 · Publisher ↗
p53 abnormality (p53 abn) subtype is a critical category in endometrial carcinoma (EC) molecular classification, yet clinical diagnosis often relies solely on p53 immunohistochemistry (IHC) staining or TP53 gene sequenci...
p53 abnormality (p53 abn) subtype is a critical category in endometrial carcinoma (EC) molecular classification, yet clinical diagnosis often relies solely on p53 immunohistochemistry (IHC) staining or TP53 gene sequencing. This study aimed to explore the correlation between TP53 genotype and p53 protein expression in EC with TP53 missense mutations, as well as the clinical and prognostic significance of their discordance. A total of 253 EC specimens from Zhejiang Cancer Hospital (January 2021-November 2023) were retrospectively collected; 103 cases with isolated TP53 missense mutations were screened via next-generation sequencing (NGS) and subjected to p53 IHC. Variant interpretation revealed that six mutations in six patients were of uncertain significance. Among the remaining patients, 54 (involving 36 variants) showed concordance between IHC phenotype and genotype: high frequency mutations such as R273H, Y220C, M237I, and V272L all exhibited mutant p53 expression, whereas V31I showed wild-type expression. Another 43 patients (involving 13 variants) displayed discordance between genotype and IHC phenotype. Clinicopathological comparison revealed that the discordant group was younger (<60 years) and dominated by non-aggressive histology (all P < 0.05). The discordant group showed better survival trends than the concordant group, with no statistically significant difference in disease-free survival (DFS) (P = 0.057). In conclusion, p53 expression is heterogeneous in EC with TP53 missense mutations; gene-protein discordance correlates with distinct clinicopathological features. Integrating genetic and protein detection results is recommended for risk stratification and individualized treatment.
Discovery and clinical significance of 1p36 chromosomal aberrations in differentiating hepatocellular carcinoma from other hepatobiliary cancers.
Ngamsangiam W, Techa-Ay S, Sa-Ngiamwibool P … +6 more , Watcharadetwittaya S, Deenonpoe R, Techasen A, Luechine A, Loilome W, Thanee M
Hum Pathol · 2026 May · PMID 41581706 · Publisher ↗
Differentiating among hepato-pancreato-biliary (HPB) cancers like cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC) can be challenging. To address this, our st...
Differentiating among hepato-pancreato-biliary (HPB) cancers like cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC) can be challenging. To address this, our study used fluorescence in situ hybridization (FISH) to identify 1p36 chromosomal abnormality patterns in 100 HPB cancer patients. We found consistent 1p36 loss in CCA, IPNB, GBC, and PC, while HCC uniquely exhibited normal, loss, and gain patterns. Notably, this 1p36 gain showed a sensitivity was 45.71 % and specificity was 100 % for differentiating HCC from CCA and other HPB cancers, while 1p36 loss proved highly sensitive (100 %) and specific (85.71 %) for distinguishing CCA from HCC, though its ability to differentiate CCA from others was limited. Beyond diagnosis, a high burden of 1p36 loss was a significant prognostic factor for shorter overall survival in CCA (p = 0.024) and in the combined CCA/IPNB cohort (p = 0.015). More importantly, 1p36 loss also significantly correlated with tumor differentiation in CCA (p < 0.05). These results suggest that assessment of 1p36 status by FISH may serve as a complementary molecular approach to conventional histopathology and immunohistochemistry, providing additional differential diagnostic HCC from CCA and other diagnostically challenging HPB cancers and serve as promising prognostic biomarkers for CCA and IPNB.
Acute leukemia with BCL11B rearrangements: Genetic landscape, BCL11B expression, and therapeutic response.
Tang G, Wang SA, Jen WY … +8 more , Medeiros LJ, Wang W, Fang H, Hu S, Jain N, Jabbour EJ, Zou YS, Xu J
Hum Pathol · 2026 May · PMID 41581705 · Publisher ↗
Rearrangements involving BCL11B have emerged as important structural variants in acute leukemias with T lineage differentiation, yet their prevalence and biological significance remain incompletely defined. Using optical...
Rearrangements involving BCL11B have emerged as important structural variants in acute leukemias with T lineage differentiation, yet their prevalence and biological significance remain incompletely defined. Using optical genome mapping (OGM), we identified BCL11B rearrangements in 25 of 2325 hematologic malignancies, restricted to T-lymphoblastic leukemia particularly early T precursor (ETP) subtype, mixed phenotype acute leukemia T/myeloid, and rare acute myeloid leukemia. Breakpoints at 14q32.2 were highly variable and largely cryptic by karyotyping. Twelve putative partner genes were detected, including four previously reported (TLX3, ARID1B, CDK6, and CCDC26) and 8 novel partners (FOXF1, TLX1, NUP98, LMO2, GAPDHP71, GRM4, TNFAIP3, and TRRAP). Evaluation of BCL11B expression showed that rearrangements involving partners currently considered "BCL11B-activated", such as ARID1B, CCDC26, and CDK6, did not uniformly associate with BCL11B overexpression. Conversely, cases with TLX3::BCL11B, previously thought to upregulate TLX3, demonstrated strong BCL11B expression (3 of 4 cases). Clinically, newly diagnosed patients, most treated with venetoclax based regimens, achieved high remission rates. Our data delineate the structural diversity of BCL11B rearrangements identified by OGM and show that BCL11B activation cannot be reliably inferred from partner gene identity alone. BCL11B immunohistochemistry as a practical surrogate for assessing BCL11B activation is recommended in routine practice.
Polymorphic central nervous system (CNS) immune deficiency/dysregulation-associated lymphoproliferative disorders show a uniquely aggressive clinicopathologic profile compared to their extra-CNS counterparts.
Alvarez FR, Nayman EI, Chen YH … +4 more , Chen QC, Jamshidi P, Dixit K, Tariq H
Hum Pathol · 2026 Apr · PMID 41580209 · Publisher ↗
BACKGROUND: Primary central nervous system immunodeficiency/dysregulation-associated lymphoproliferative disorders (PCNS-IDD-LPDs) are a rare and heterogeneous group of lymphoid lesions that arise within the CNS of immun...
BACKGROUND: Primary central nervous system immunodeficiency/dysregulation-associated lymphoproliferative disorders (PCNS-IDD-LPDs) are a rare and heterogeneous group of lymphoid lesions that arise within the CNS of immune compromised patients. Among PCNS-IDD-LPDs, monomorphic IDD-LPDs are relatively well studied; however, data regarding PCNS polymorphic IDD-LPDs is very limited. It remains unclear whether polymorphic PCNS IDD-LPDs follow a similarly indolent clinical course as observed in their systemic polymorphic counterparts, or whether the unique immune microenvironment of the CNS imparts a more aggressive disease biology. METHODS: In this study, we compared the clinical, pathologic, and survival profile of PCNS polymorphic IDD-LPDs (N = 15) with extra-CNS polymorphic IDD-LPDs (N = 21) as well as PCNS monomorphic IDD-LPDs (N = 12). RESULTS: Compared to extra-CNS polymorphic IDD-LPDs, patients with PCNS polymorphic IDD-LPDs showed a significantly stronger association with kidney transplants, longer latency, worse performance status, more frequent monoclonal populations and necrosis, and a greater need for aggressive chemoimmunotherapy in addition to reduction in immunosuppression and/or rituximab. The overall survival (OS) of PCNS polymorphic IDD-LPDs was significantly inferior to that of extra CNS polymorphic IDD-LPDs (median survival: 7.1 years vs. not reached; log-rank p = 0.023) and not significantly different from PCNS monomorphic IDD-LPDs (median survival: 7.1 vs. 3.6 years; log-rank p = 0.852). CONCLUSION: We conclude that PCNS polymorphic IDD-LPDs have a uniquely aggressive clinicopathologic and prognostic profile compared to their systemic counterparts and are comparable to their monomorphic PCNS counterparts. CNS localization supersedes the histological subtype as the primary determinant of disease biology in IDD-LPDs, likely ascribed to the immune sanctuary status of the CNS.
Morphologic and immunohistochemical study of HPV-related cervical adenosquamous carcinoma: Reappraisal of a poorly defined entity.
Zhang Z, Quddus MR, Sung CJ … +1 more , Singh K
Hum Pathol · 2026 Apr · PMID 41580208 · Publisher ↗
OBJECTIVE: Current WHO criteria require distinct glandular and squamous differentiation for diagnosis of adenosquamous carcinoma (AdSq). However, a subset of poorly differentiated cervical carcinoma exhibits ambiguous mo...
OBJECTIVE: Current WHO criteria require distinct glandular and squamous differentiation for diagnosis of adenosquamous carcinoma (AdSq). However, a subset of poorly differentiated cervical carcinoma exhibits ambiguous morphology with diffuse growth pattern. The current study explores whether these tumors belong to the adenosquamous subtype. METHODS: After IRB approval, we retrieved 41 AdSq cases diagnosed at our institution between 2007 and 2024. H&E slides were reviewed. Immunohistochemical staining for p16, p40, p63, BerEP4, and Claudin-4 was performed. IHC was scored. Statistical analysis was performed with Python packages. RESULTS: Based on morphology only, out of the 41 AdSq cases, 11 fulfilled the WHO proposed criteria for classic AdSq (cAdSq). Twenty cases were classified as non-classic AdSq (nAdSq). All the rest also exhibited a solid growth pattern, but were reclassified as endocervical (3), endometrioid (6), and squamous carcinoma (1). Histologically, nAdSq lacked distinct spatially separate components of squamous or glandular differentiation. Instead, tumor cells exhibited ambiguous morphology with diffuse growth or, less frequently, in nests, characteristic vacuolated/foamy cytoplasm, pleomorphic nuclei, and inflamed stroma. All nAdSq showed block positivity for p16 like cAdSq. Significant portion of AdSq cases expressed the squamous marker p40 (58 % in nAdSq vs. 50 % in cAdSq). In contrast to pure adenocarcinomas or squamous cell carcinomas, 47 % (7/15) of nAdSq cases expressed both squamous and adenocarcinoma markers (p40 and BerEP4), with 5 (33 %) cases showing positivity for all four markers. Similarly, two cAdSq cases (22 %) showed universal positivity for all four markers, though p40 positivity was more focal and weaker in other instances. Despite morphological differences, the overall survival outcomes between nAdSq and cAdSq was not significantly different (p = 0.49). CONCLUSIONS: Many cervical carcinomas with diffuse growth pattern are likely the non-classic AdSq that do not contain spatially separate squamous and glandular components. Immunostaining may help in identifying this "non-classic" subtype of AdSq.
Epstein-Barr virus associated gastric carcinoma: A clinicopathologic study with recognition of a distinctive reticular histologic pattern.
Gallardo J, Gumusgoz E, Mitchell JM … +4 more , Hammer S, Chi Z, Gopal P, Karamchandani DM
Hum Pathol · 2026 May · PMID 41580207 · Publisher ↗
Existing data characterize "classic" Epstein-Barr virus (EBV) positive gastric carcinoma (GC) histologically as GC with lymphoid stroma (or lymphoepithelioma-like or medullary) exhibiting sheets or syncytia of malignant...
Existing data characterize "classic" Epstein-Barr virus (EBV) positive gastric carcinoma (GC) histologically as GC with lymphoid stroma (or lymphoepithelioma-like or medullary) exhibiting sheets or syncytia of malignant cells with prominent intratumoral lymphocytes. This diagnosis has clinical implications, given the associated frequent programmed death-ligand 1 gene amplification, and clear benefit from immunotherapy. However, there appears to be a paucity of published data regarding characteristic histologic features of EBV-GC. We evaluated 19 EBV-GC specimens (11 biopsies; 8 resections) retrieved from 13 patients and found that a unique reticular pattern was identified in 17 of 19 (89 %) specimens, either as an exclusive pattern in 26 %, or as a mixed pattern in 63 % specimens. Most patients were male (85 %), with an average age of 61.5 years, mostly of Hispanic or Black (77 %) ethnicity, and showed a predilection for proximal stomach (69 %). Associated prominent intratumoral inflammation was seen in cases retrieved from all patients (lymphocytic: 7, mixed: 6). Although a similar lace-like pattern has been implicitly cited in association with early stage EBV-GC, we report a unique reticular pattern with intratumoral inflammation that was seen more commonly than widely known "classic" histology and was even seen in association with advanced pathologic stage. We propose that ancillary EBV testing be performed on all gastric tumors with this distinctive pattern, and with other patterns with prominent (including mixed) intratumoral inflammation, to screen for EBV-GC cases, thus detecting patients who may be eligible for immunotherapy with important therapeutic implications.
Prostatic adenocarcinoma identified on transurethral resection of bladder tumor: A clinicopathologic series of a diagnostically relevant potential pitfall.
Wu DJ, Pacheco R, Chan E … +2 more , Lowe AC, Sangoi AR
Hum Pathol · 2026 May · PMID 41580206 · Publisher ↗
Over the past 2 decades, we have increasingly encountered prostatic adenocarcinoma (PCA) presenting as urinary bladder tumors in routine practice as well as among consultation/medicolegal cases. Given the ramifications o...
Over the past 2 decades, we have increasingly encountered prostatic adenocarcinoma (PCA) presenting as urinary bladder tumors in routine practice as well as among consultation/medicolegal cases. Given the ramifications of a potential misdiagnosis of PCA as urothelial carcinoma (UC), herein we explore clinicopathologic features among a large cohort of PCA identified on transurethral bladder tumor resection (TURBT). A retrospective re-review identified 54 TURBTs containing PCA from a single tertiary care academic hospital (2003-2025). Of the 27 patients with prior PCA history, urologists were concerned for PCA in 86 %, but history/suspicion was only conveyed in 32 % of accompanying specimen requisition sheets. For patients without PCA history, urologists were occasionally (29 %) suspicious for PCA, mentioning this possibility on requisition sheets in all (100 %) of cases. Most tumors were from the bladder neck or base (72 %). Pseudopapillary/papillary-like growth pattern was often seen (46 %). The predominant architecture was solid or nested/corded (70 %) followed by glandular (26 %) and acinar (4 %). Nuclei in most cases were uniform/round (89 %) with prominent nucleoli predominant in most cases (56 %) while the cytoplasm was more often "pale/bubbly" (72 %) versus "dense/glassy" (28 %). Pseudopapillary/papillary-like growth compounded with solid to nested architecture within PCA can mimic UC on TURBT specimens, although nuclear features/prominent nucleoli can be a helpful clue. While clinical/cystoscopic findings (e.g. tumor site) may suggest PCA on TURBT, this information does not always accompany the specimen, requiring confirmatory chart review for putative cases as well as judicious use of immunohistochemistry.
Solid, cystic, and mucinous spindle cell thymomas (WHO type A): A clinicopathological and immunohistochemical study of 7 cases.
Weissferdt A, Moran CA
Hum Pathol · 2026 Apr · PMID 41580205 · Publisher ↗
Seven cases of an unusual thymoma subtype are presented. Patients included five men and two women, aged 43-57 years (mean: 50). Five patients presented with non-specific symptoms of cough, chest pain and shortness of bre...
Seven cases of an unusual thymoma subtype are presented. Patients included five men and two women, aged 43-57 years (mean: 50). Five patients presented with non-specific symptoms of cough, chest pain and shortness of breath; two patients were asymptomatic. Diagnostic imaging revealed anterior mediastinal masses in all patients and surgical resection was accomplished via thoracotomy. Grossly, the tumors were well circumscribed with focal cystic changes, measuring 2.7 cm-4.8 cm. Six tumors were encapsulated; one was minimally invasive. Histologically, the tumors exhibited cystic changes and solid areas composed of bland spindle cells with scant thymocytes, consistent with spindle cell thymomas (WHO type A). Notably, focal mucinous differentiation was observed, including glandular structures with mucinous epithelium, scattered mucinous cells, extracellular mucin, and partial cyst wall lining by mucinous epithelium. Immunohistochemistry demonstrated that the spindle cell component was positive for pancytokeratin, CK5/6, p63 and CD20 and negative for CK7, CK20, PAX8, GATA-3, TTF-1, CDX2, STAT6 and SS18-SSX while the mucinous cells were variably positive for CK7, CK20 and CDX2; mucicarmine histochemical staining confirmed mucin content. Four patients remained alive and well at 18 months postoperatively while 3 patients were lost to follow-up. The current cases represent a previously undescribed variant of spindle cell thymoma that may pose diagnostic challenges and give rise to a wide differential diagnosis.
GRHL-rearranged sebaceoma: expanding the clinical and morphologic spectrum.
Dileep A, Ko CJ, LeBlanc RE … +2 more , Panse GG, Cloutier JM
Hum Pathol · 2026 Apr · PMID 41580204 · Publisher ↗
Sebaceoma is a benign sebaceous neoplasm with broad architectural variability, and outside of mismatch repair (MMR)-deficient tumors, its molecular features have remained poorly defined. Recent work identified recurrent...
Sebaceoma is a benign sebaceous neoplasm with broad architectural variability, and outside of mismatch repair (MMR)-deficient tumors, its molecular features have remained poorly defined. Recent work identified recurrent GRHL1/GRHL2 rearrangements in a subset of sebaceomas, suggesting the presence of a molecularly distinct group. We report three additional sebaceomas harboring RCOR1::GRHL2 fusions identified by RNA-based next-generation sequencing and integrate the clinical, morphologic, and molecular features of all 11 currently known GRHL-rearranged sebaceomas. Patients ranged from 40 to 84 years; two tumors arose on the head and neck, and one represented the first documented extracranial example (axilla). All tumors were macronodular to multinodular basaloid proliferations with variably complex corded ("organoid") architecture; infundibulocystic structures were present in one case. One tumor demonstrated partially cystic growth and rounded basaloid nests, expanding the recognized morphologic spectrum. All three tumors were microsatellite stable without pathogenic MMR gene alterations. Across the combined cohort, no recurrences have been reported. These findings broaden the clinicopathologic spectrum of GRHL-rearranged sebaceoma and support this group as a sporadic, MMR-proficient subset characterized by distinctive organoid-patterned architecture. Further studies are needed to determine whether GRHL rearrangements represent a unifying driver of organoid morphology in sebaceoma.
CDK12 paradox in breast Cancer: Loss-of-Function fusion and oncogenic amplification as dual therapeutic Targets.
Yu C, Yao F, Li D … +5 more , Lv Q, Chen S, Chen H, Xiao S, Wang Y
Hum Pathol · 2026 Jan · PMID 41577204 · Publisher ↗
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