Human Pathology[JOURNAL]
Sun
200 papers
Practical and challenging issue in thyroid cytopathology.
Zhang Q, Urtueta BP, Merenda E … +9 more , Rotondaro G, Morelli N, Piermattei A, Straccia P, Cianfrini F, Feraco A, Granitto A, Mule A, Rossi ED
Hum Pathol · 2026 Mar · PMID 41412443 · Publisher ↗
The detection of thyroid lesions is a frequently encountered especially in the adult population. Data from literature emphasize that they are found in more than 65 % of individuals. Most of these lesions are benign (90-9...
The detection of thyroid lesions is a frequently encountered especially in the adult population. Data from literature emphasize that they are found in more than 65 % of individuals. Most of these lesions are benign (90-92 %), even though the incidence of malignancy has been increasing due to frequent ultrasonographic head and neck evaluation, which can now identify small subcentimeter suspicious nodules. However, a 20 % of them, falling into the category of indeterminate lesions can lead to some pitfalls and tricky evaluations. Globally Fine needle aspiration (FNA) has been established as a safe, useful, first-line diagnostic tool, with a high positive predictive value for identifying malignancy. The development of classification system originated in order to obtain a practical classification system, able to combine each entity with a category and then with a specific risk of malignancy (ROM) and management. It is well-known that, among the others, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) represent the most worldwide used system. The 3r edition of TBSRTC, published in July 2023, subclassified indeterminate lesions into: a) atypia of undetermined significance (AUS) with nuclear atypia or other atypia, b) follicular neoplasm (FN) and c) suspicious for malignancy (SFM). However, despite the high positive predictive value (97 %-99 %), sensitivity (65 %-99 %) and specificity (72 %-100 %) of thyroid FNAC, diagnostic pitfalls exist that can lead to false positive (FP) and/or false negative (FN) results. This inconvenience is mostly due to the overlapping of morphological features in terms of cells and even background. This review discusses the most important practical issue also related to the application of TBSRTC and the evaluation of morphological challenges that can lead to pitfalls and diagnostic errors.
Prognostic value of baseline peritoneal fluid cytology in 224 patients with unresectable peritoneal metastasis treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).
Jørgensen MS, Ainsworth AP, Fristrup CW … +3 more , Mortensen MB, Graversen M, Detlefsen S
Hum Pathol · 2026 Feb · PMID 41401889 · Publisher ↗
Patients with peritoneal metastasis (PM) from gastrointestinal and gynecological cancer can be treated palliatively with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC). Only few prognostic markers for stratific...
Patients with peritoneal metastasis (PM) from gastrointestinal and gynecological cancer can be treated palliatively with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC). Only few prognostic markers for stratification of PM-patients treated with PIPAC exist. The prognostic value of peritoneal fluid (PF) cytology has only been examined to a limited extent. Our primary aim was to investigate the prognostic value of baseline PF cytology in unresectable PM treated with PIPAC. We performed a retrospective analysis of prospectively collected data from all PM patients treated with PIPAC at Odense PIPAC Center from 2015 to 2024. Positive baseline PF cytology was defined as malignant cells or cells suspicious of malignancy. Survival data were analyzed using the Kaplan-Meier graphs, log rank test and multivariable Cox proportional hazards regression. Inclusion criteria were fulfilled by 224 patients, of which 139 (61 %) had positive cytology at PIPAC 1. Patients with positive baseline cytology had a significantly higher ascites volume (150 mL vs. 20 mL, p < 0.001), higher peritoneal cancer index (PCI) (15 vs. 3.5, p < 0.001) and higher mean histological Peritoneal Regression Grading Score (PRGS) (3.0 vs. 1.0, p < 0.001), compared to patients with negative baseline cytology. Positive baseline cytology was associated with shorter overall survival (OS) for the entire cohort (P < 0.01), PM from gastric cancer (GC-PM) (P = 0.007), and PM from colon cancer (CC-PM) (P = 0.02), but not for PM from ovarian cancer (OC-PM) or pancreatic cancer (PC-PM). However, at multivariate analysis, baseline PF cytology had no independent prognostic value. The PRGS, on the other hand, showed independent prognostic value in all multivariable models used. In conclusion, our data from this retrospective cohort study indicate that baseline PF cytology holds no independent prognostic value. However, for classification of a given patient as having complete response to treatment, this modality is still recommended, together with histological response assessment (PRGS).
Three practice updates in non-Hodgkin lymphoma for 2026.
King RL, Ondrejka SL, Cook JR
Hum Pathol · 2026 Mar · PMID 41389901 · Publisher ↗
Lymphoid neoplasms present many challenges in routine surgical pathology practice, given the numerous forms of non-Hodgkin lymphoma that must be distinguished from each other through careful morphologic evaluation supple...
Lymphoid neoplasms present many challenges in routine surgical pathology practice, given the numerous forms of non-Hodgkin lymphoma that must be distinguished from each other through careful morphologic evaluation supplemented by an ever-growing battery of ancillary studies that may include immunohistochemistry, flow cytometry, in situ hybridization studies, and, increasingly, next generation sequencing. A further complicating factor is the existence of two partially-overlapping but distinct classification systems currently in widespread clinical practice, the 5th edition World Health Organization classification and the International Consensus Classification. This review provides practical updates in three important areas. First, we discuss the evaluation and classification of follicular lymphoma, one of the most common small B-cell neoplasms, and highlight how to distinguish conventional follicular lymphoma from other forms of follicular lymphoma with very different clinical features and management. Secondly, we describe the current approach to high grade B-cell lymphomas, including "double hit" lymphomas and high-grade B-cell lymphoma, not otherwise specified, and how these challenging cases should be distinguished from the much more common diffuse large B-cell lymphoma, not otherwise specified. Finally, we briefly describe the features of common nodal T-cell lymphomas, including the T-follicular helper cell lymphomas, anaplastic large cell lymphoma, and peripheral T-cell lymphoma, NOS. In each of these areas, we provide guidance on helpful ancillary studies and advice for navigating current classification systems.
Endometrial carcinomas - Challenges and updates on selected topics.
Buza N, Sun T, Hui P
Hum Pathol · 2026 Mar · PMID 41389900 · Publisher ↗
Endometrial carcinoma comprises a heterogeneous group of tumors with distinct histologic, immunophenotypic, and molecular profiles that have important diagnostic and clinical implications. This review focuses on selected...
Endometrial carcinoma comprises a heterogeneous group of tumors with distinct histologic, immunophenotypic, and molecular profiles that have important diagnostic and clinical implications. This review focuses on selected subtypes of endometrial carcinomas with the most update. Endometrial serous carcinoma, though representing ∼10 % of endometrial cancers, accounts for a disproportionate number of endometrial cancer deaths; its early forms - serous endometrial intraepithelial carcinoma and superficial serous carcinoma, collectively termed minimal uterine serous carcinoma (MUSC) - predominantly arise in an endometrial polyp and demonstrate a paradoxically high rate of extrauterine spread despite minimal tumor volume, mandating comprehensive staging. Corded and hyalinized endometrioid carcinoma (CHEC) and pilomatrix-like high-grade endometrial carcinoma (PiMHEC) are CTNNB1/β-catenin-driven variants of endometrioid carcinoma with biphasic or basaloid morphology that may mimic carcinosarcoma, serous, or squamous carcinoma and show variable, sometimes aggressive behavior. Mesonephric-like adenocarcinoma (MLA) is an ER/PR-negative, KRAS-mutated carcinoma with mesonephric-type morphology, frequent deep myometrial and lymphovascular invasion, and a predilection for pulmonary metastasis. Primary endometrial squamous cell carcinoma (PESCC) and endometrial gastric (gastrointestinal)-type mucinous carcinoma (EmGA) are exceptionally rare entities that require stringent exclusion of cervical or metastatic primaries and are typically associated with p53-abnormal and/or gastrointestinal-type molecular signatures and poor outcomes. Across these variants, integration of morphology with immunohistochemistry and molecular testing (including p53, MMR status, POLE) is essential for accurate classification and risk stratification. HER2 overexpression and/or amplification occurs in 25-30 % endometrial serous carcinoma and HER2 testing has become a standard biomarker for selecting patients with recurrent or advanced disease for trastuzumab, and more recently trastuzumab-deruxtecan therapy.
Every day a new fusion? - An update on recent discoveries in dermatopathology.
Honaker EC, Guo RR, Dehner CA
Hum Pathol · 2026 Mar · PMID 41389899 · Publisher ↗
The expanding integration of molecular diagnostics into dermatopathology has transformed the recognition and classification of cutaneous neoplasms, revealing an increasingly diverse landscape of oncogenic gene fusions ac...
The expanding integration of molecular diagnostics into dermatopathology has transformed the recognition and classification of cutaneous neoplasms, revealing an increasingly diverse landscape of oncogenic gene fusions across melanocytic, mesenchymal, and adnexal tumors. These fusion-driven entities often display distinctive histopathologic, immunophenotypic, and clinical features that can directly inform diagnostic accuracy, prognostication, and, in select cases, therapeutic decision-making. In this review, we summarize recent advances in fusion-associated cutaneous tumors encountered in routine practice, highlighting emerging molecular subsets within Spitz neoplasms, MITF pathway-activated tumors, fusion-driven mesenchymal neoplasms, and adnexal tumors characterized by recurrent kinase or transcriptional regulator rearrangements. We discuss key morphologic correlations that may provide clues to the underlying fusion, the value and limitations of ancillary immunohistochemical surrogates, and the expanding role of next-generation sequencing in resolving diagnostically challenging cases. As the catalog of identified fusions continues to grow, an updated understanding of these entities is essential for accurate classification and for anticipating potential therapeutic vulnerabilities. This review aims to provide a practical, contemporary reference for the diagnostic pathologist navigating the rapidly evolving field of fusion-driven dermatopathology.
High fidelity of Claudin-18.2 expression in primary and matched metastatic (lymph nodes, peritoneum, and liver) pancreatic ductal adenocarcinoma: a foundation for targeted therapy.
Franzina C, Bevere M, Bersani S … +10 more , Mattiolo P, Ceccon C, Piccoli P, Malleo G, Lawlor RT, Salvia R, Milella M, Fassan M, Scarpa A, Luchini C
Hum Pathol · 2026 Feb · PMID 41389898 · Publisher ↗
Claudin-18.2 (CLDN18.2) is a tight-junction protein that can be expressed in various neoplasms, including pancreatic ductal adenocarcinoma (PDAC). Anti-CLDN18.2 targeted therapies have already been approved for CLDN18.2-...
Claudin-18.2 (CLDN18.2) is a tight-junction protein that can be expressed in various neoplasms, including pancreatic ductal adenocarcinoma (PDAC). Anti-CLDN18.2 targeted therapies have already been approved for CLDN18.2-positive gastric cancer and are currently being tested in clinical trials for PDAC. This study aims to define the expression patterns and concordance rate of CLDN18.2 in primary and matched metastatic PDAC. Whole-slide immunohistochemistry for CLDN18 was performed on primary PDAC and matched metastases, and was assessed by cell percentage (range: 0-100 %) and intensity of CLDN18-positivity (scores 0, 1+, 2+, and 3+), and also using the H-score. Tumor positivity for CLDN18 was determined if ≥ 75 % of tumor cells exhibited 2+/3+ staining. The study's cohort was composed of 20 patients with PDAC and concomitant lymph node metastases (LNM), 30 patients with PDAC and matched peritoneal metastases (PM), and 12 patients with PDAC and concomitant liver metastases (LIVM). The mean value of the percentages of 2+/3+ cells for primary tumors was 46.5 %, for LNM was 60 %, for PM was 31 %, and for LIVM was 22 %. The mean value of the H-score for primary tumors was 123.9, for LNM was 183, for PM was 89.1, and for LIVM was 54.6. The correspondence rate between primary PDAC and the matched metastatic sites was: 70.0 % for PDAC/LNM, 93.3 % for PDAC/PM, and 100.0 % for PDAC/LIVM. This study shows a high rate of correspondence of CLDN18-positivity between primary PDAC and different metastatic sites, providing a strong rationale for further exploring and testing anti-CLDN18.2 therapeutic strategies in this lethal malignancy.
Gastric neuroendocrine tumors associated with acid suppressant drugs are frequently associated with very prolonged drug use and may show unconventional morphologies.
Azimpouran M, Waters KM, Hendifar AE … +6 more , Gangi A, Kozak M, Guindi M, Lai KK, Larson BK, Hutchings DA
Hum Pathol · 2026 Feb · PMID 41389897 · Publisher ↗
BACKGROUND: Gastric well-differentiated neuroendocrine tumors (gNETs) arising in association with prolonged acid suppressant drug use, including proton pump inhibitors (PPIs) and/or histamine type 2 receptor antagonists...
BACKGROUND: Gastric well-differentiated neuroendocrine tumors (gNETs) arising in association with prolonged acid suppressant drug use, including proton pump inhibitors (PPIs) and/or histamine type 2 receptor antagonists (H2RAs), are an emerging subtype of gNET presumably arising from drug-related chronic hypergastrinemia. The clinicopathologic features of these gNETs were examined in an institutional cohort. DESIGN: 23 patients with 39 gNETs were included. gNETs were considered acid suppressant-associated in patients with documented PPI and/or H2RA use for >1 year or ≥2 features of drug effect (parietal and/or enterochromaffin-like (ECL)-cell hyperplasia and/or elevated serum gastrin) in those with limited clinical information. Histomorphologic features were assessed. RESULTS: The median patient age was 65 years (range: 37-84) with a female predominance (female:male 1.6:1). Hypergastrinemia was present in 69 % (11/16) of tested patients (median: 232 pg/mL, range 130-407). In patients with documented drug use (n = 16), 50 % used for ≥10 years. Most gNETs were ≤1 cm and were restricted to the mucosa. Regional lymph node metastasis was rare (2/21; 9 %). Unconventional morphology included 15 % with secretory cribriform morphology and 3 % with mixed pseudopapillary and conventional morphology. 30 % of patients had multiple tumors diagnosed over spans ranging from 0.75 to 9 years, though none developed distant disease (median follow-up: 3 years, range 0-15), including 2 patients with lymph node metastasis (10- and 13-year follow-up). CONCLUSIONS: Acid suppressant-associated gNETs have an indolent course, are often multiple, and are frequently associated with very prolonged PPI/H2RA use. Unconventional morphologies like those described in type 1 gNETs may be observed.
Clinical significance of the relative location of perineural cancer invasion on prostate biopsy: Detection within 1-mm of the core tip as an independent prognosticator.
Lanipekun OK, Wang Y, Miyamoto H
Hum Pathol · 2026 Feb · PMID 41389896 · Publisher ↗
Perineural invasion (PNI) detected on prostate biopsy is a recognized indicator of aggressive disease including extraprostatic extension. However, the clinical relevance of its relative location within the biopsy core re...
Perineural invasion (PNI) detected on prostate biopsy is a recognized indicator of aggressive disease including extraprostatic extension. However, the clinical relevance of its relative location within the biopsy core remains poorly understood. We herein assessed corresponding radical prostatectomy findings and long-term oncologic outcomes in 180 prostate cancer patients exhibiting only a single focus of PNI on the entire systematic biopsy. PNI was located at <1-mm (n = 26; 14.4 %), ≥1 to <2-mm (n = 43; 23.9 %), ≥2 to <3-mm (n = 36; 20.0 %), ≥3 to <4-mm (n = 27; 15.0 %), ≥4 to <5-mm (n = 28; 15.6 %), or ≥5-mm (n = 20; 11.1 %) from the closest tip of the core. Univariate survival analysis in the dichotomized cohort based on the distance revealed significantly higher risks of biochemical recurrence (P < 0.001) and cancer-specific mortality (P = 0.042) in patients with PNI located <1-mm from the core tip than in those with PNI ≥1-mm. There were no significant differences in the clinicopathologic features examined, including total tumor length on biopsy or estimated tumor volume on prostatectomy, tumor grade on biopsy or prostatectomy, pT or pN category, and surgical margin status, between the <1-mm vs. ≥1-mm groups. In multivariable Cox regression analysis, PNI <1-mm from the tip (vs. ≥1-mm) showed significantly worse recurrence-free survival both before (hazard ratio 3.435, P < 0.001) and after (hazard ratio 3.228, P = 0.002) adjusting for prostatectomy factors. PNI detected within 1-mm of the biopsy core tip was thus found to independently predict a worse postoperative prognosis. This spatial detail of PNI on needle core biopsy may enhance the risk stratification of prostate cancer.
Ovarian GLI1 fusion tumors mimicking sex cord-stromal Tumors: Clinicopathological and molecular characterization of a five-case series.
Yang F, Liu Y, Wang Y … +3 more , Yang J, Liu L, Liu C
Hum Pathol · 2026 Jan · PMID 41380915 · Publisher ↗
Ovarian GLI1 fusion tumors are rare mesenchymal neoplasms that closely mimic sex cord-stromal tumors (SCSTs) in both morphology and immunophenotype, frequently leading to misdiagnosis. In this study, we identified five s...
Ovarian GLI1 fusion tumors are rare mesenchymal neoplasms that closely mimic sex cord-stromal tumors (SCSTs) in both morphology and immunophenotype, frequently leading to misdiagnosis. In this study, we identified five such cases through re-evaluation of SCST-like ovarian tumors. Histologically, three distinct patterns were observed: the spindle pattern, the stellate/microcystic pattern and the epithelioid pattern. Immunophenotypically, all cases showed overlapping features with SCSTs, including CD10 expression and variable positivity for sex cord-stromal markers such as FOXL2, SF1, and Calretinin. Molecular analysis revealed recurrent ACTB::GLI1 fusions in four cases and a novel FUBP1::GLI1 fusion in one. Meta-analysis integrating our cases with ten previously reported ovarian GLI1 fusion tumors showed that these tumors predominantly occur in middle-aged women and present as significantly larger masses than their soft tissue and solid organ counterparts (P < 0.05). Notably, the relapse and metastasis rates of ovarian GLI1 fusion tumors were similar to adult granulosa cell tumors (AGCTs). In contrast, their recurrence rate was significantly higher than that of microcystic stromal tumors (MCSTs) (P < 0.05), indicating a more aggressive clinical course. Transcriptomic analysis revealed no significant correlation between ovarian GLI1 fusion tumors and sclerosing stromal tumors. These findings underscore the necessity of molecular testing for GLI1 rearrangements in SCST-like ovarian tumors to ensure accurate diagnosis and appropriate clinical management.
Plasmacytoid variant in Lynch syndrome-associated urothelial carcinoma.
Li XL, Yuan GW, Qi MZ … +3 more , Sun YP, Nie YC, Yao ZG
Hum Pathol · 2026 Aug · PMID 41371510 · Publisher ↗
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Analysis of discordance between mismatch repair and microsatellite instability testing in endometrial cancer.
Xi Y, He C, Fang X … +10 more , Yin JC, Wang Y, Wang H, Wu C, Fang J, Lai Q, Liu P, Chu F, Yin W, Su D
Hum Pathol · 2026 Feb · PMID 41371509 · Publisher ↗
Accurate molecular classification of endometrial carcinoma (EC) is critical for guiding therapy, particularly concerning mismatch repair-deficient (MMRd). However, the consistency of MMRd detection across different diagn...
Accurate molecular classification of endometrial carcinoma (EC) is critical for guiding therapy, particularly concerning mismatch repair-deficient (MMRd). However, the consistency of MMRd detection across different diagnostic modalities and the molecular basis of discordant results remain insufficiently characterized. In this retrospective study, 220 EC patients treated at Zhejiang Cancer Hospital from January 2021 to March 2024 underwent histopathological review, immunohistochemistry (IHC), and targeted next-generation sequencing (NGS) with a 196-gene panel. Discordant cases were further assessed by polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, MLH1 promoter methylation analysis, and extended mutational profiling. The median age of the study cohort was 57.0 years. IHC revealed deficient mismatch repair (dMMR) in 65 cases (29.6 %), while NGS detected high MSI (MSI-H) in 44 cases (20.0 %), yielding an overall 90.5 % concordance. All 21 discordant cases (9.5 %) displayed dMMR by IHC but microsatellite stable (MSS) by NGS. PCR reclassified five cases as MSI-H, whose MSIsensor scores were significantly higher than proficient MMR (pMMR)/MSS tumors (p = 0.01) but lower than dMMR/MSI-H tumors (p = 0.0007). Of the remaining 16 unresolved cases, 43.8 % exhibited isolated MSH6 loss, likely due to the functional compensation of MSH3, while 56.2 % showed MLH1 loss, predominantly due to MLH1 promoter methylation (77.8 %). In conclusion, discordance between IHC- and NGS-based MMR/MSI detection is primarily attributable to MSH6 loss with MSH3 compensation and MLH1 promoter methylation. Recognizing these mechanisms is essential for accurate molecular subtyping and clinical decision-making in EC.
PIK3R1 acts as a prominent biomarker for tumor immune microenvironment modulation in intravenous leiomyomatosis.
Zhang Z, Feng P, Ge Z … +3 more , Liang Z, Chen R, Li J
Hum Pathol · 2026 Feb · PMID 41354163 · Publisher ↗
BACKGROUND: In current clinical practice, intravenous leiomyomatosis (IVL) can be surgically resected using either one-step or two-step approach. However, several challenges persist, including a high rate of postoperativ...
BACKGROUND: In current clinical practice, intravenous leiomyomatosis (IVL) can be surgically resected using either one-step or two-step approach. However, several challenges persist, including a high rate of postoperative recurrence, the difficulty in achieving complete resection in complex cases, and the inability to timely identify a substantial number of early-stage IVL cases. The mainstream theory regarding the pathogenesis and development mechanism of IVL is that it originates from uterine leiomyomas, yet the specific molecular mechanisms underlying this process remain to be elucidated. METHODS: In this study, high-throughput transcriptome sequencing and molecular detection methods such as immunohistochemistry were employed to analyze the molecular expression differences at the transcriptome and immune microenvironment levels between 5 cases of IVL and paired uterine leiomyomas. These findings were subsequently validated in a cohort consisting of 45 IVL cases. RESULTS: The cross-enrichment analysis of differentially expressed genes (DEGs) at the transcriptome and immune level in paired samples yielded significant results. Notably, the up-regulated gene PIK3R1 and the down-regulated gene BMP4 emerged as two of the most critical representatives. Further investigation into the function of the PIK3R1 gene in IVL and its relationship with the immune microenvironment revealed that this gene was highly expressed in IVL and positively correlated with the abundance of plasma cells, while negatively correlated with follicular helper T cells and resting dendritic cells. The overall immune microenvironment of IVL was inactive, leading to tumor cells being less likely to be recognized and eliminated by immune cells. CONCLUSIONS: This study has conducted an in-depth analysis of the molecular expression, immune microenvironment characteristics, and related mechanisms of IVL. Further studies on larger cohort are warranted to demonstrate the potential value of inhibiting PIK3R1 as the adjuvant medicine for IVL therapy.
Detection of targetable genetic alterations in SMARCA4-deficient neoplasms of the lung - further evidence of a relationship between SMARCA4-deficient undifferentiated tumor and non-small cell carcinoma.
D'Ambrosio D, Frazzette N, Snuderl M … +6 more , Jour GK, Shaffer EM, Zhou F, Narula N, Moreira AL, Mantilla JG
Hum Pathol · 2026 Jan · PMID 41354162 · Publisher ↗
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4d-UT) is an uncommon, aggressive lung neoplasm associated with smoking and characterized by loss of SMARCA4 (BRG-1) expression. Although originally considered to...
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4d-UT) is an uncommon, aggressive lung neoplasm associated with smoking and characterized by loss of SMARCA4 (BRG-1) expression. Although originally considered to be a primary sarcoma, there is growing evidence that these lesions may represent transformation of conventional non-small cell carcinoma. In this study, we probe this relationship based on the clinical, histologic and molecular findings of 18 SMARCA4-deficient malignancies of the lung. Cases diagnosed as SMARCA4d-UT and SMARCA4-deficient carcinoma were retrospectively reviewed, including histologic and immunophenotypic features, and next generation sequencing studies. Of the 18 tumors, 5 were considered to represent undifferentiated SMARCA4d-UT, and 13 SMARCA4-deficient carcinomas, including 11 adenocarcinomas, 1 squamous cell carcinoma, and 1 poorly differentiated non-small cell carcinoma. All 13 carcinomas had a morphologically identifiable undifferentiated component. Survival outcomes were similar in both SMARCA4d-UT and carcinomas. Genetic alterations often seen in lung cancer were identified in 8 cases, including mutations in EGFR (in 2 SMARCA4-deficient adenocarcinomas), KRAS (1 SMARCA4d-UT and 1 SMARCA4-deficient adenocarcinoma), MAP2K1 (1 SMARCA4-deficient adenocarcinoma), and a gene fusion involving EML4::ALK (1 SMARCA4d-UT). The patient with EML4::ALK fusion was treated with alectinib with partial response. Fusions involving BRAF::CHCHD3 and FGFR1::FILIP1 were identified in 2 SMARCA4-deficient adenocarcinomas. High expression of PD-L1 (TPS >50 %) was seen in 12 cases (67 %). These finding further suggest that SMARCA4d-UT and carcinomas with SMARCA4 loss may be on the same spectrum of disease, and accurate histologic distinction between these lesions may be challenging. A unified terminology may be beneficial for appropriate diagnosis and treatment.
CYP11B2 expression patterns in primary aldosteronism: Assessment of cortisol co-secretion and the B2 ratio criteria.
Chen Cardenas SM, Matoso A, Li H
Hum Pathol · 2026 Jan · PMID 41354161 · Publisher ↗
Primary aldosteronism (PA) is the most common form of endocrine hypertension, with a prevalence of 5-15 %. Unilateral PA accounts for approximately 30 % of PA and has been associated with excellent post-operative results...
Primary aldosteronism (PA) is the most common form of endocrine hypertension, with a prevalence of 5-15 %. Unilateral PA accounts for approximately 30 % of PA and has been associated with excellent post-operative results. Introduction of CYP11B2 immunostain led to the histopathology of primary aldosteronism (HISTALDO) consensus and the classification into classical and non-classical histology. We retrospectively reviewed 62 consecutive adrenalectomy cases of PA from routine clinical practice, including 46 with PA-only and 16 with cortisol cosecretion (PA-C). We also examined 3 adrenals from non-PA patients. We found that aldosterone-producing micronodules (APM/MAPM) were commonly present in the background adrenal of PA patients (59/62) and non-PA related adrenal cortex (3/3). Therefore, regardless of the presence of APM/MAPM, the presence of a solitary APA or APN was defined as classical histology, and the remaining CYP11B2-positive patterns were classified as non-classical histology (mHISTALDO). PA patients with classical histology were significantly associated with smaller APM/MAPM compared to those with non-classical histology. We validated that classical histology was significantly associated with more complete clinical and biochemical responses. We found that the PA-only group was significantly associated with smaller tumors, classical histology, more complete clinical response, and reduction in antihypertensive medication, compared to PA-C. We also explored a recently proposed criterion, the B2R (size ratio of the largest to the second largest CYP11B2-positive lesion), for defining classical and non-classical histology, which was relatively easy to use, yielding a consistent classification rate of 90.3 % (56/62) and similar associations and trends with clinical and biochemical outcomes, compared to the mHISTALDO. In summary, we validated that classical histology was associated with better outcomes by both mHISTALDO and B2R. APM/MAPM were commonly seen in the adrenal cortex. In the presence of a large solitary APA or APN, APM/MAPM should not change the classical histology classification.
Genome-wide DNA methylation profiling of pleomorphic carcinoma of the lung.
Nakagomi T, Fujimoto M, Kuriyama S … +5 more , Hishida T, Asamura H, Asakura K, Kanai Y, Arai E
Hum Pathol · 2026 Jan · PMID 41354160 · Publisher ↗
The aim of this study was to clarify the significance of DNA methylation alterations in the histological and clinicopathological diversity of pleomorphic carcinoma of the lung. Eleven samples of non-cancerous lung tissue...
The aim of this study was to clarify the significance of DNA methylation alterations in the histological and clinicopathological diversity of pleomorphic carcinoma of the lung. Eleven samples of non-cancerous lung tissue (N), and 10 and 11 samples of non-sarcomatoid and sarcomatoid components of cancerous tissue (T), respectively, were microdissected from formalin-fixed paraffin-embedded specimens of 11 patients with pleomorphic carcinoma of the lung. Genome-wide DNA methylation analysis was performed on all 32 microdissected tissue samples using the Infinium MethylationEPIC BeadChip. Principal component analysis revealed that DNA methylation alterations are associated with lung carcinogenesis and that the diversity of DNA methylation profiles may increase during transition of the non-sarcomatoid component to the sarcomatoid component. Genes showing differences in DNA methylation level between 11 N samples and all 21 T samples regardless of whether they were non-sarcomatoid or sarcomatoid, and whose transcription levels are potentially regulated by DNA methylation, were accumulated in the cadherin, Wnt and angiogenesis pathways. Significant differences in DNA methylation level between non-sarcomatoid and sarcomatoid components potentially resulting in transcription alterations were observed in the OCIAD2, LAMB1 and DKK3 genes. Sarcomatoid component-specific DNA hypomethylation relative to N samples of C2orf27A and COX6C was correlated with clinicopathological parameters such as lymph vessel invasion and higher pathological stage, respectively. Sarcomatoid component-specific DNA hypomethylation of TSKU, PLAU, PLEKHG4, RPSAP52, XBP1 and TRIM2 was correlated with both recurrence-free and overall survival. These data suggest that the DNA methylation alterations associated with sarcomatoid change may participate in malignant progression and determine patient outcome.
Quantitative assessment of cribriform intraductal carcinoma of the prostate is useful for risk stratification after radical prostatectomy.
Wang Y, Miyamoto H
Hum Pathol · 2026 Jan · PMID 41354159 · Publisher ↗
It remains uncertain if the extent of intraductal carcinoma of the prostate (IDC) exhibiting cribriform (Crib) morphology impacts on patient outcomes. We retrospectively analyzed long-term oncologic outcomes in 182 conse...
It remains uncertain if the extent of intraductal carcinoma of the prostate (IDC) exhibiting cribriform (Crib) morphology impacts on patient outcomes. We retrospectively analyzed long-term oncologic outcomes in 182 consecutive radical prostatectomy patients exhibiting Grade Group 2-4 conventional/acinar prostatic adenocarcinoma, along with Crib-IDC but no Gleason grade 5 patterns. A single Crib-IDC focus in the entire prostatectomy specimen was identified in 46 (25.3 %) cases, while others showed 2 (n = 36; 19.8 %), 3 (n = 27; 14.8 %), 4 (n = 11; 6.0 %), or ≥5 (n = 62; 34.1 %) Crib-IDC foci. The maximum Crib-IDC diameter in each case was ≤1-mm (n = 66; 36.3 %), >1/≤2-mm (n = 90; 49.5 %), >2/≤3-mm (n = 21; 11.5 %), or >3-mm (n = 5; 2.7 %). The summed maximum Crib-IDC diameters were ≤1-mm (n = 38; 20.9 %), >1/≤2-mm (n = 39; 21.4 %), >2/≤3-mm (n = 30; 16.5 %), >3/≤4-mm (n = 17; 9.3 %), >4/≤5-mm (n = 9; 4.9 %), or >5-mm (n = 49; 26.9 %). On univariate analyses, the risks of postoperative biochemical recurrence were significantly higher in cases with 3 (P = 0.022) or ≥3 (P < 0.001) Crib-IDCs (vs. 1-2) or ≥4 Crib-IDCs [P < 0.001 (vs. 1-3); P = 0.032 (vs. 3)]. Similarly, the recurrence risk was significantly higher in Crib-IDC cases with the maximum diameter of >1-mm (vs. ≤1-mm; P = 0.002) or the summed diameter of >3-mm (vs. ≤3-mm; P < 0.001). On multivariable Cox regression analyses, 3 [hazard ratio (HR) 2.742, P = 0.016], ≥3 (HR 3.969, P < 0.001), or ≥4 (HR 4.520, P < 0.001) Crib-IDCs (vs. 1-2) and the summed diameter of >3-mm (HR 3.074, P < 0.001) remained significantly predictive of recurrence. Quantitative assessment of Crib-IDC, particularly its number and cumulative diameter on prostatectomy, may thus enhance the postoperative risk stratification of Grade Group 2-4 prostate cancer.
Correlation of lymphocytic infiltration and degree of pleomorphism with tumor mutation burden in high-grade urothelial carcinoma.
Kayraklioglu N, Zhang L, Cornelia Ding CK … +5 more , Greenland NY, Stohr BA, Koshkin VS, Simko JP, Sirohi D
Hum Pathol · 2026 Jan · PMID 41354158 · Publisher ↗
Histopathological features and genomic biomarkers are integral to the management of patients with high-grade urothelial carcinoma (HGUC). Morphological features are often reflective of underlying genomic alterations. In...
Histopathological features and genomic biomarkers are integral to the management of patients with high-grade urothelial carcinoma (HGUC). Morphological features are often reflective of underlying genomic alterations. In this study, we investigate the correlation between tumor mutation burden (TMB) and specific histopathological features in HGUC to identify surrogate markers for TMB when molecular testing may not be available. We hypothesized that increased nuclear pleomorphism and intense lymphocytic infiltration might correlate with higher TMB, aiding treatment decisions. In this retrospective study, 119 cases with TMB analysis by Next Generation Sequencing (NGS) were evaluated for cytological and nuclear pleomorphism, lymphocytic infiltration, and histological subtypes. Pleomorphism and lymphocytic infiltrate were classified into binary categories (mild versus marked) for improved reproducibility. TMB ≥10 mutations/Mb was defined as high TMB. Both marked pleomorphism and marked lymphocytic infiltration were associated with higher TMB (10.3 vs 7.2 muts/Mb, p = 0.027 and 12.4 vs. 8.9 muts/Mb, p = 0.005 respectively). Micropapillary, squamous, and sarcomatoid subtypes demonstrated higher median TMB, although the differences did not reach statistical significance. In summary, our findings suggest that marked nuclear pleomorphism and lymphocytic infiltrate are associated with higher TMB, indicating their potential as surrogate markers for immunotherapy response.
Gene expression signatures of shortened-telomere-associated fibrotic interstitial lung disease.
Naso JR, Sosa C, Schefter LE … +8 more , Petersen MJ, Nikaido-Landry T, Lim E, Ferrer A, Patnaik MM, Scott JP, Halling KC, Roden AC
Hum Pathol · 2026 Jan · PMID 41354157 · Publisher ↗
Shortened telomeres contribute to the pathogenesis of a subset of pulmonary fibrosis through mechanisms that remain unclear. We compared the expression of fibrosis-related genes in explanted lungs of pulmonary fibrosis p...
Shortened telomeres contribute to the pathogenesis of a subset of pulmonary fibrosis through mechanisms that remain unclear. We compared the expression of fibrosis-related genes in explanted lungs of pulmonary fibrosis patients with versus without shortened telomeres, to identify possible molecular mechanisms of pulmonary fibrosis pathogenesis in these patients. Telomere length was assessed using flow cytometry fluorescence in-situ hybridization on peripheral blood. Lymphocyte telomere length <10th percentile was considered shortened. Gene expression was assessed using the NanoString Human Fibrosis v2 Panel (782 genes) on whole slide sections of explanted lungs with pulmonary fibrosis. Gene expression data was obtained for 39 patients (17 with and 22 without shortened telomeres). Gene set enrichment analysis identified significant differential regulation of cholesterol metabolism and the 'regulation of tumor necrosis factor-mediated signaling pathway' gene ontology term in the shortened telomere group. Thirty-six genes were significantly differentially expressed in the shortened telomere samples, including increased expression of tumor necrosis factor pathway (NCF4, NR1H4) and cholesterol metabolism (APOA1, APOH, LIPC) genes in the shortened telomere group. Differential expression of these 36 genes was most pronounced in 5 of the 17 shortened telomere cases. This study highlights molecular heterogeneity within explanted lung tissue of patients with shortened telomeres and pulmonary fibrosis, with signatures of altered cholesterol metabolism and tumor necrosis factor signaling in a subset of shortened telomere cases. We highlight NCF4, NR1H4, APOA1, APOH and LIPC as differentially expressed genes in a subgroup of shortened telomere pulmonary fibrosis patients.
Porto-sinusoidal vascular disease-like alterations in transplant liver biopsies: A clinicopathologic observation of transplant-associated portal vasculopathy.
Khandakar B, Joldoshova A, Zhang X
Hum Pathol · 2026 Jan · PMID 41297617 · Publisher ↗
OBJECTIVE: Non-cirrhotic portal hypertension (NCPH) encompasses hepatic vascular disorders without cirrhosis, now grouped under porto-sinusoidal vascular disease (PSVD). While PSVD features are well described in native l...
OBJECTIVE: Non-cirrhotic portal hypertension (NCPH) encompasses hepatic vascular disorders without cirrhosis, now grouped under porto-sinusoidal vascular disease (PSVD). While PSVD features are well described in native livers, their significance in the liver transplant setting remains unclear and may present diagnostic challenges. This study aimed to investigate PSVD-like histologic alterations in liver allografts and their clinical relevance. DESIGN: We retrospectively analyzed 95 liver biopsies from 43 transplant recipients (2020-2022). Biopsies were reviewed for PSVD-specific features (obliterative portal venopathy [OPV], nodular regenerative hyperplasia [NRH], incomplete septal fibrosis) and nonspecific features (portal tract abnormalities, architectural disturbance, mild perisinusoidal fibrosis, non-zonal sinusoidal dilatation). Clinical data, including liver function tests (LFTs) and rejection status, were recorded. RESULTS: Among 95 biopsies, 37% showed OPV, 33% NRH, and 16% incomplete septal fibrosis. Nonspecific findings were frequent with portal tract abnormalities in 99%, sinusoidal dilatation in 68%, and architectural disturbance in 67%. PSVD alterations appeared more common at longer post-transplant intervals but showed no significant association with acute cellular rejection or abnormal LFTs. CONCLUSIONS: PSVD-like histologic alterations are common in post-transplant biopsies which do not correlate with acute cellular rejection or liver function abnormalities. These findings suggest the presence of PSVD-like alterations is likely multifactorial and may be better characterized as transplant-associated poral vasculopathy rather than true PSVD. Recognizing these changes in the transplant setting is essential to avoid misinterpretation and ensure accurate diagnosis. An evidence-based terminology and well-defined criteria for the diagnosis of PSVD are needed.
Immune profiling may improve risk stratification in early-stage colorectal carcinoma.
Oganesyan R, Aktas BK, Lee SH … +5 more , Pankaj A, Yilmaz O, Patil D, Deshpande V, Yilmaz O
Hum Pathol · 2026 Jan · PMID 41290119 · Publisher ↗
Treatment decisions for pT1 colorectal cancer often rely on traditional histologic features, but these may incompletely predict metastatic risk. We evaluated whether features of the tumor immune microenvironment could en...
Treatment decisions for pT1 colorectal cancer often rely on traditional histologic features, but these may incompletely predict metastatic risk. We evaluated whether features of the tumor immune microenvironment could enhance risk stratification, particularly in distinguishing indolent from aggressive disease. We analyzed 116 pT1 colorectal carcinomas, including 94 AJCC Stage I tumors (non-metastatic) and 22 AJCC Stage III/IV tumors (advanced/metastatic). Clinical, histologic, and molecular features, such as tumor grade, vascular invasion, perineural invasion, tumor budding, tumor deposits, and mismatch repair (MMR) status, were assessed. Immune profiling using tissue microarrays and digital image analysis included CD8, FOXP3, CD163, PD-L1, LAG3, HLA-I, HLA-II, and beta-2-microglobulin (B2M). Advanced-stage tumors (Stage III/IV) more frequently showed high-risk histologic features, including lymphovascular invasion (40.9 % vs. 8.6 %, p = 0.007), intramural venous invasion (27.3 % vs. 3.2 %, p = 0.0015), extramural venous invasion (13.6 % vs. 0 %, p = 0.0061), and tumor deposits (mean 0.23 vs. 0.00, p < 0.001). Cribriform morphology was also more common in advanced-stage tumors (38.5 % vs. 8.2 %, p = 0.015). Immune profiling revealed significantly higher densities of CD8 T-cells (503.15 vs. 326.58 cells/mm, p = 0.010), PD-L1 immune cells (90.79 vs. 12.68, p = 0.011), and higher tumor B2M expression (0.21 vs. 0.05, p = 0.020) in AJCC stage I tumors, while the other examined immune biomarkers revealed no significance. While the overall impact of the immune microenvironment remains unclear, this study suggests that combining immune profiling of CD8 T-cell infiltration, PD-L1-positive immune cells, and tumor B2M expression may be useful as an adjunct to conventional histologic assessment to improve prognostic accuracy and guide management of early colorectal cancer.
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