Human Pathology[JOURNAL]
Sun
200 papers
High-grade cribriform morular thyroid carcinoma: A clinicopathologic analysis of six patients and a review of the literature.
Whaley RD, Gupta S, Erickson LA
Hum Pathol · 2026 Aug · PMID 42082158 · Publisher ↗
Cribriform morular thyroid carcinoma was formally considered a subtype of papillary thyroid carcinoma due to its architecture and nuclear features. The genomic landscape and immunophenotype of cribriform morular thyroid...
Cribriform morular thyroid carcinoma was formally considered a subtype of papillary thyroid carcinoma due to its architecture and nuclear features. The genomic landscape and immunophenotype of cribriform morular thyroid carcinoma are distinct from papillary thyroid carcinoma. Given this constellation of findings, questions were raised regarding its histogenesis and the 5th edition of the WHO endocrine and neuroendocrine tumors placed cribriform morular thyroid carcinoma in the thyroid tumors of uncertain histogenesis category. This distinction excludes cribriform morular thyroid carcinoma from the high-grade follicular cell-derived non-anaplastic thyroid carcinoma. Thus, we sought to investigate if the criteria for differentiated high-grade thyroid carcinoma would be applicable to cribriform morular thyroid carcinoma tumor category. Herein, we report six patients with high-grade cribriform morular thyroid carcinoma and review of the literature for additional patients. There are at least 10 probable high-grade cribriform morular thyroid carcinomas in the English literature. The study population included 5 females and 1 male aged 19-48 years (median 34.5 years). Two patients had documented syndromes Familial adenomatous polyposis and Gardner syndrome. One patient presented with distant metastatic disease while four patients recurred with distant metastatic disease. Three patients had pathogenic alterations involving the APC gene and one patient had a pathogenic CTNNB1 alteration. Two cases had pathogenic alterations in genes associated with aggressive thyroid carcinoma: TERT and PIK3CA. In this limited series only one patient died of disease. Even so, three were alive with disease at distant metastatic sites. Whether this is a consistent finding in this tumor category remains to be addressed as more patient series are published.
Performance of the 2023 Bethesda System for Reporting Thyroid Cytopathology in a pediatric cohort: a single-center experience.
Straccia P, Fiorentino V, Padial Urtueta B … +4 more , Zhang Q, Piermattei A, Mule' A, Rossi ED
Hum Pathol · 2026 Aug · PMID 42069008 · Publisher ↗
BACKGROUND: Pediatric thyroid nodules are uncommon but have higher malignancy risk than adult nodules. The 2023 TBSRTC updated ROM estimates and expanded pediatric guidance, but data remain limited. METHODS: We reviewed...
BACKGROUND: Pediatric thyroid nodules are uncommon but have higher malignancy risk than adult nodules. The 2023 TBSRTC updated ROM estimates and expanded pediatric guidance, but data remain limited. METHODS: We reviewed 63 thyroid FNAs from patients aged 21 years or younger at a tertiary center (January 2023-October 2025). Cases were classified according to the 2023 TBSRTC. Observed ROM was calculated in resected nodules with exact 95% CIs. Bethesda III nodules were subclassified as AUS with nuclear atypia or AUS-other. RESULTS: Diagnoses were Bethesda I in 5/63 (7.9%), Bethesda II in 32/63 (50.8%), Bethesda III in 3/63 (4.8%), Bethesda IV in 10/63 (15.9%), Bethesda V in 13/63 (20.6%), and Bethesda VI in 0/63 (0%). Histologic follow-up was available for 36 nodules. Observed ROM among resected nodules was 0/1 (0.0%) for Bethesda I, 1/11 (9.1%) for Bethesda II, 2/3 (66.7%) for Bethesda III, 4/8 (50.0%) for Bethesda IV, and 12/13 (92.3%) for Bethesda V. The two malignant Bethesda III cases were AUS with nuclear atypia; the AUS-other case was benign. Overall malignant yield was 19/36 (52.8%). CONCLUSIONS: The 2023 TBSRTC was applicable in this pediatric cohort. Bethesda II, IV, and V ROM estimates were broadly consistent with published pediatric data, whereas Bethesda III was imprecise because only three nodules were resected. Larger multicenter studies with standardized follow-up and explicit AUS subclassification are needed.
EWSR1-rearranged renal neoplasia: Clinicopathologic and molecular characterization of 39 cases from a single institution.
Colef RG, Pujari GP, Sill DR … +13 more , Pitel BA, Zhang P, Tekin B, Lucas PC, Whaley RD, Herrera Hernandez L, Jimenez RE, Erickson LA, Cheville JC, Kipp BR, Halling KC, Greipp PT, Gupta S
Hum Pathol · 2026 Aug · PMID 42067069 · Publisher ↗
We report the clinicopathologic features of EWSR1-rearranged renal neoplasia from our institution. A retrospective cohort of 39 EWSR1-rearranged renal tumors was identified using fluorescence in situ hybridization (FISH)...
We report the clinicopathologic features of EWSR1-rearranged renal neoplasia from our institution. A retrospective cohort of 39 EWSR1-rearranged renal tumors was identified using fluorescence in situ hybridization (FISH) and RNA-based next generation sequencing (NGS). A final diagnosis of Ewing sarcoma (EWS) was established in 34 of 39 cases (87%), with the remaining cases diagnosed as desmoplastic small round cell tumor (DSRCT; n = 2), sclerosing epithelioid fibrosarcoma (SEF; n = 2), and thyroid-like follicular renal cell carcinoma (TLFRCC; n = 1). Fusion partners identified in EWS included FLI1 (n = 17) and ERG (n = 2). WT1 (n = 2), CREB3L1 (n = 1) and CREB3L2 (n = 1), and PATZ1 (n = 1) fusions were found in DSRCT, SEF, and TLFRCC, respectively. The mean age at EWS diagnosis was 31.4 years (range 6-73), with a similar sex distribution (18 females, 16 males), and a mean tumor size of 10.7 cm (range 3-24 cm). Both DSRCT cases occurred in males aged 6 and 29 years, diagnosed on renal biopsy and brain metastasis, respectively. The SEF cases involved primary tumors in 22-year-old and 43-year-old females. The one case of TLFRCC was identified in a 41-year-old female that underwent radical nephrectomy. Cases with available immunohistochemistry showed most EWS tumors (24/26, 92%) expressed a combination of CD99, FLI1, and ERG, while both SEF cases were positive for MUC4. Our results highlight the importance of molecular testing in providing an integrated diagnosis and are informative regarding the spectrum of renal neoplasia that harbor EWSR1 rearrangements, including EWS, DSRCT, SEF, and TLFRCC as these tumors can exhibit significant clinicopathologic heterogeneity.
Clinicopathologic spectrum of renal-pelvic fibroepithelial polyps: A series of five patients with emphasis on mimicry of malignancy.
Zhang GN, Eugene HC, Argani P … +3 more , Baraban EG, Gross JM, Matoso A
Hum Pathol · 2026 Aug · PMID 42061470 · Publisher ↗
Renal-pelvic fibroepithelial polyps (FEPs) are rare benign mesodermal lesions that can radiologically and clinically mimic urothelial carcinoma, sometimes prompting radical surgery. We reviewed five consultation cases of...
Renal-pelvic fibroepithelial polyps (FEPs) are rare benign mesodermal lesions that can radiologically and clinically mimic urothelial carcinoma, sometimes prompting radical surgery. We reviewed five consultation cases of renal pelvis or proximal-ureter FEPs, integrating histology, immunohistochemistry, and targeted molecular testing. Patients were all females, tumors measured 3.3-9.0 cm (mean 5.2 cm), and four arose in the renal pelvis with variable ureteral extension. Three patients underwent nephroureterectomy for presumed malignancy. Histologically lesions shared a polypoid architecture with fibrovascular cores lined by benign -appearing urothelium; stromal cellularity separated lesions into hypercellular (patients 1-2) and hypocellular stromal patterns. Hypocellular lesions displayed fibrocollagenous stroma with bland spindle cells and were lined by benign urothelium. Hypercellular examples showed epithelioid smooth muscle type or primitiveappearing-stromal proliferations with occasional mitoses and focal Ki-67 elevation but lacked significant atypia, necrosis, infiltrative growth, or lymphovascular invasion. Immunoprofiles confirmed urothelial epithelial differentiation (AE1/AE3, GATA3, PAX8) with areas of anastomosing cords and pyelitis cystica and variable stromal labeling for desmin, CD10, ER, and PR; myogenin/MyoD1 were negative. A fusion/cancer gene- NGS panel (including GLI1 and NCOA1/2) was negative in the tested case. No recurrences were observed with mean followup of 24 months. We emphasize distinguishing features from papillary urothelial carcinoma, mixed -epithelialstromal tumor/smooth muscle adenoma-like renal tumor (SMART), rhabdomyosarcoma, and -translocation associated mesenchymal neoplasms, noting that focal -fibroadenoma like- stromal areas can occur in FEPs. Recognition of the confined polypoid growth beneath intact urothelium, bland cytology, supportive immunohistochemistry, and selective molecular testing when stromal atypia raises concern, can avoid misclassification and unnecessary radical surgery.
Diagnostic utility of MUC4 expression for distinguishing pancreatic ductal adenocarcinoma from extrahepatic cholangiocarcinoma and its clinicopathological significance.
Funakoshi S, Shibayama T, Nakamura H … +7 more , Ho YJ, Kato K, Nagahama K, Shibata T, Sakamoto Y, Shibahara J, Hayashi A
Hum Pathol · 2026 Aug · PMID 42061469 · Publisher ↗
AIMS: Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (EHCC) arise from anatomically adjacent sites and often present with overlapping clinical and pathological features; thus, accurate differ...
AIMS: Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (EHCC) arise from anatomically adjacent sites and often present with overlapping clinical and pathological features; thus, accurate differentiation is challenging. Precise distinction is essential for appropriate treatment selection and prognostic assessment. The aims of this study were to identify molecular markers that facilitate the pathological differentiation of PDAC and EHCC and to evaluate their diagnostic utility. METHODS AND RESULTS: Publicly available bulk tumor and cell-line RNA sequencing datasets were systematically compared to identify genes with differential expression between PDAC and EHCC. Candidate markers were subsequently evaluated by immunohistochemistry of surgical specimens from 87 patients who underwent pancreaticoduodenectomy for PDAC (n = 58) or EHCC (n = 29) between 2018 and 2023. Transcriptomic analysis identified MUC4 as a candidate differential marker. Immunohistochemical analysis demonstrated significantly higher MUC4 expression in PDAC than in EHCC (median H-score [range]: 108 [0-190] vs. 50 [5-170]; P = 0.019). In PDAC, elevated MUC4 expression was significantly associated with obstructive jaundice, invasion of the anterior pancreatic surface, and perineural invasion. Receiver operating characteristic curve analysis showed that MUC4 demonstrated discriminatory performance comparable to that of serum CA19-9. Notably, the diagnostic performance of MUC4 remained preserved in cases with low CA19-9 levels. CONCLUSIONS: MUC4 expression is significantly higher in PDAC than in EHCC, and it may serve as a practical pathological biomarker for distinguishing these malignancies. Because MUC4 immunohistochemistry is readily applicable in routine pathology practice, its evaluation may provide a useful adjunct for the differential diagnosis of periampullary tumors.
Comparison of the somatic mutations in breast carcinomas in sporadic and BRCA1 carrier patients through targeted next generation sequencing.
Barron CR, Ramineni M, Finkelman BS … +5 more , Zhang H, Turner BM, Love T, Hicks DG, Wang X
Hum Pathol · 2026 Aug · PMID 42055234 · Publisher ↗
OBJECTIVES: Women who carry a germline mutation in BRCA1 have an increased lifetime risk of developing breast cancer (BC). Prior Next-Generation Sequencing (NGS) studies on BCs from patients with germline BRCA1 mutations...
OBJECTIVES: Women who carry a germline mutation in BRCA1 have an increased lifetime risk of developing breast cancer (BC). Prior Next-Generation Sequencing (NGS) studies on BCs from patients with germline BRCA1 mutations (gBRCA1) were limited, mostly with small cohorts and had generally been conducted on unselected BC cases, which may bias the results. The goal of this study was to analyze the somatic mutational landscape of gBRCA1 BC and compare it to sporadic BC, controlling for tumor grade and hormone receptor (HR) status. MATERIAL AND METHODS: Next-generation sequencing (NGS) was performed on 72 BCs using one of two panels, including 134 genes and 50 genes, respectively, with 44 genes shared between the two panels. Twenty-six BCs were from gBRCA1 patients, 45 from sporadic patients, and one case with BRCA1 mutation in tumor but without germline information. Missense or nonsense single-nucleotide variants (SNV) with a variant allele frequency >3% and coverage >150 reads were considered as altered. Pathogenicity was determined using ClinVar and Varsome systems. Fisher's Exact Test was used for statistical analysis. RESULTS: gBRCA1 BCs were diagnosed at younger age than sporadic BCs (median age 51 vs 63), with more high-grade (HG, 65% vs. 43%) and ER/PR/HER2 negative (TN) tumors (42% vs. 16%), compared with sporadic BCs in the TCGA dataset. Pathogenic/likely pathogenic mutations were identified in 12 genes in at least one BC. Seventy-six percent of sporadic BCs had at least one gene with pathogenic/likely pathogenic mutations, compared to 46% of gBRCA1 BCs (p = 0.020). TP53 was the most commonly mutated gene with pathogenic/likely pathogenic mutations in a total of 28 of 72 (39%) BCs, mostly in HG BCs compared with non-HG BCs, in both sporadic (57% vs 6.7%, p = 0.001) and gBRCA1 (53% vs 0%, p = 0.009) cohorts. However, we did not observe a significant difference in TP53 mutation frequency between sporadic and gBRCA1 when stratifying by tumor grade (p > 0.99 for both non-HG and HG) and HR status (p > 0.99 for HR+, p = 0.70 for TN). PIK3CA was the second most commonly mutated gene, with 27% in sporadic and 7.7% in gBRCA1 BCs (p = 0.067). Twenty-nine percent of TP53 mutated tumors (including both sporadic and gBRCA1) had additional somatic pathogenic/likely pathogenic mutations, while 25% of tumors with other than TP53 gene mutations had additional somatic pathogenic/likely pathogenic mutations (p > 0.99). CONCLUSION: Our study is one of the largest studies analyzing somatic mutations in gBRCA1 BCs. Although we used relatively small NGS panels, a similar gene mutation trend in BCs was observed as in other large NGS studies on BCs. Furthermore, while gBRCA1 had higher frequency of HG and triple negative BCs, we did not observe higher TP53 mutation frequency in this group of BCs, compared with grade- and HR status-matched sporadic BCs. Additionally, sporadic BCs appeared to have an overall higher frequency of pathogenic/likely pathogenic mutations than gBRCA1 BCs, a phenomenon shown by other studies as well. Having a TP53 somatic mutation did not increase the likelihood of other pathogenic/likely pathogenic somatic mutations in either gBRCA1 or sporadic BCs.
Chondroblastoma with prominent secondary aneurysmal bone cyst-like changes: The role of H3.3 K36 M.
Suster D, Gross JM, Charville GW
Hum Pathol · 2026 Aug · PMID 42055233 · Publisher ↗
Secondary aneurysmal bone cyst (ABC)-like changes are a well-recognized phenomenon observed in a variety of primary bone tumors that can pose diagnostic difficulties. We have investigated the role of H3.3 K36 M immunohis...
Secondary aneurysmal bone cyst (ABC)-like changes are a well-recognized phenomenon observed in a variety of primary bone tumors that can pose diagnostic difficulties. We have investigated the role of H3.3 K36 M immunohistochemistry for the diagnosis of patients with chondroblastoma of bone in which extensive secondary ABC-like changes masked the underlying tumor. A total of 25 patients with bone tumors showing equivocal histologic and radiologic features of chondroblastoma were identified in the files of the respective institutions. The patients included 4 women and 21 men, aged 12-36 years (average: 18.8 years); they arose in the femur (8), tibia (4), calcaneus (4), humerus (3), scapula (2), fibula (1), talus (1), ischium (1), and temporal bone (1). Imaging studies showed well-defined radiolucent lesions showing prominent multicystic spaces with fluid-fluid levels; only rare tumors showed internal matrix mineralization. All tumors were treated by curettage. On histology, multiple blood-filled cystic spaces separated by connective tissue septa containing scattered osteoclastic giant cells were present. Additionally, focal microscopic areas containing a monotonous polygonal cell population suggestive of chondroblastoma could also be identified on careful examination. Immunohistochemical staining revealed nuclear positivity for H3.3 K36 M in 24/25 cases (96%), helping to support a diagnosis of chondroblastoma. Immunostaining for H3.3 K36 M can serve as a useful adjunct for the diagnosis of chondroblastoma in cases with prominent ABC-like changes, particularly in small biopsies or bone curettage specimens in which the diagnostic cytomorphological and architectural features of the tumor may not be readily appreciated.
Morphology spectrum and molecular landscape in eosinophilic solid and cystic renal cell carcinoma.
Wang Q, Xu Z, Wang J … +9 more , Huang Z, Guo F, Xu Z, Jiang Z, Wu T, Teng Y, Song M, Yang S, Chen W
Hum Pathol · 2026 Aug · PMID 42055232 · Publisher ↗
Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a novel renal tumor entity incorporated in the 2022 WHO classification with a female predilection. To further investigate its morphological and molecular fe...
Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a novel renal tumor entity incorporated in the 2022 WHO classification with a female predilection. To further investigate its morphological and molecular features, we analyzed 17 ESC RCC cases with comprehensive morphological, clinicopathological and next-generation sequencing data, and reviewed 63 previously reported cases with confirmed TSC gene mutations. Clinically, our cohort had a male-to-female ratio of 1.4:1. Fifteen patients with a median follow-up of 55 months (range, 5-144 months) remained disease-free. Morphologically, 10/17 tumors showed classic solid-cystic growth and 7/17 showed predominant solid growth. Two distinctive morphological features were identified: a novel phenotype of condensed eosinophilic cytoplasm forming inclusion-like appearance (5 cases) and the recently described xanthomatous giant cell feature (4 cases). Immunohistochemically, CK20 was positive in 15/17 cases, and all cases showed strong positivity for mTOR downstream markers (GPNMB, p-S6, p-4EBP1). Molecularly, TSC1 mutations were detected in 8/17 cases, and TSC2 mutations in 9/17. All 5 cases with condensed eosinophilic cytoplasm uniformly harbored TSC1 mutations. Analysis of our 17 cases and 63 reported cases showed TSC2 mutations in 50/80 (62.5%), TSC1 mutations in 31/80 (38.8%), and concurrent TSC1/2 mutations in 1/80 (1.3%). Totally 110 distinct mutation sites were found with only 7.3% being repeatedly reported in no more than 3 patients. Truncating variants (frameshift, nonsense, splice site) were the predominant type (90.9%), while missense mutations only account for 9.1%. Collectively, our research expanded the morphological spectrum of ESC RCC, depicted a wide molecular mutation landscape and confirmed its indolent behavior without gender predilection in Chinese patients.
Margin status in ductal carcinoma in situ of the breast: radiological-pathological correlation in slice radiographs and histological large-format slides of breast conserving surgery specimens.
Loebsin T, Radzinski B, van Diest PJ … +4 more , Gläser D, Kiesel L, Heindel W, Focke CM
Hum Pathol · 2026 Aug · PMID 42055231 · Publisher ↗
AIM: Positive margins in breast conserving surgery (BCS) specimens are a risk factor for local recurrence in ductal carcinoma in situ (DCIS). As DCIS often bears microcalcifications, intraoperative specimen or slice radi...
AIM: Positive margins in breast conserving surgery (BCS) specimens are a risk factor for local recurrence in ductal carcinoma in situ (DCIS). As DCIS often bears microcalcifications, intraoperative specimen or slice radiographs are widely used to guide BCS. As in some DCIS parts microcalcifications may be absent, margin widths based on imaging of microcalcifications may differ from final DCIS margin status. Our aim was to analyse the correlation of radiological and final pathological DCIS margin widths in slice radiographs of BCS specimens. METHODS: A total of 646 whole slices of 46 BCS specimens were analysed. 168 slices contained both DCIS and microcalcifications. Margin width of microcalcifications in the slice radiograph was measured by two radiologists and compared with final histopathological DCIS margins in whole slice large-format slides. RESULTS: The overall correlation between radiological and pathological margin widths was weak (r = 0.390; p < 0.001). Radiological overestimation of pathological margin widths occurred in 499 (74%) and underestimation in 77 (11 %) of 672 margins. The rate of histologically compromised margins depended on radiological margin width and was 36.8% for <2 mm, 29.3% for 2 to 5 mm, 12.2% for 6 to 9 mm, 7.1% for 10 to 19 mm, and 4% for ≥20 mm, respectively. CONCLUSION: Radiological margin widths tend to be considerably wider than those based on histological evaluation. A radiologically free rim of ≥10 mm in the BCS specimen reduces the rate of histologically compromised margins to <9%.
Prognostic value of nuclear versus cytoplasmic cyclin D1 in human prostate cancer.
Ayala A, Ding Y, Bu P … +2 more , Miles B, Ayala G
Hum Pathol · 2026 Aug · PMID 42055230 · Publisher ↗
BACKGROUND: Cyclin D1 (CCND1) as a regulator of the cell cycle has been implicated in disease progression and prognosis of human malignancies. However, its prognostic significance in cytoplasmic versus nuclear localizati...
BACKGROUND: Cyclin D1 (CCND1) as a regulator of the cell cycle has been implicated in disease progression and prognosis of human malignancies. However, its prognostic significance in cytoplasmic versus nuclear localizations has not been well established in human prostate cancer (PCa). METHODS AND MATERIALS: We used 640 PCa cases with radical prostatectomy to build tissue microarrays. Normal prostate tissue and index tumor were cored in triplicate (0.6 mm). Slides were immunostained and then digitized. Spearman-test was used for correlations between CCND1 expression, clinicopathological variables, and biological markers. Kaplan-Meier, logrank, and Cox proportional hazard tests were used to evaluate the prognostic value of CCND1. RESULTS: The CCND1 expression index was higher in PCa compared to normal prostate for nuclear and cytoplasmic CCND1. Increased nuclear CCND1 in PCa was associated with preoperative PSA and Gleason scores. High expression of nuclear CCND1 was correlated with increased expression of MKI67, p-Akt, PIM2, p-FKHR, MYC, and SKP2. High levels of cytoplasmic CCND1 were correlated with increased p-Akt, PIM2, and MYC. Increased nuclear expression of CCND1 was associated with biochemical recurrence in PCa. Cytoplasmic expression was not. CONCLUSIONS: Our data suggested that expression of nuclear CCND1 was associated with clinopathological and biological markers that are involved in proliferation and survival in PCa. Cytoplasmic CCND1 shared some of these findings, but they were less statistically significant. These findings provide evidence that increased CCND1 promotes proliferation and facilitate disease progression, especially in the nucleus. Cyclin D1 might become a potential biomarker for the prediction of biochemical recurrence in PCa.
ATP binding cassette subfamily D member 1: A highly sensitive diagnostic marker for solid pseudopapillary neoplasm of pancreas in biopsy samples--A multi-institutional study.
Liu Y, Peng J, He R … +13 more , Xue X, Cui J, Li M, Liu YA, Xu W, Gao X, Wang Y, Zhang Z, Lu H, Song Z, Hu P, Zhao Y, Wang W
Hum Pathol · 2026 Aug · PMID 42002112 · Publisher ↗
Solid pseudopapillary neoplasm of pancreas (SPN) is a rare low-grade malignant pancreatic tumor. The morphology of SPN exhibits considerable diversity. Accurate diagnosis is crucial due to the morphological similarity of...
Solid pseudopapillary neoplasm of pancreas (SPN) is a rare low-grade malignant pancreatic tumor. The morphology of SPN exhibits considerable diversity. Accurate diagnosis is crucial due to the morphological similarity of SPN to other pancreatic tumors, including pancreatic neuroendocrine tumors (NETs), acinar cell carcinoma (ACC) and pancreatoblastoma (PB), especially in the preoperative biopsy specimen. Image-guided biopsy techniques are essential for preoperative diagnosis, but the limited tissue in biopsy samples can complicate the diagnosis of SPN from other tumors. In this study, we evaluate the diagnostic utility of ATP Binding Cassette Subfamily D Member 1 (ABCD1), a novel immunohistochemical (IHC) marker previously identified in surgically resected SPN specimens, for distinguishing SPN in biopsy samples. We analyzed biopsy samples from a cohort of 55 SPN patients (55 biopsy samples and 6 paired surgical resected samples) and compared them with samples from 61 pancreatic ductal adenocarcinoma (PDAC), 90 NET, 13 intraductal papillary mucinous neoplasm (IPMN), 7 ACC and 3 PB patients from four institutions. Our findings show that ABCD1 positively marks SPN biopsy samples consistently as surgical resected samples, with 100% overall positivity and 96.37% exhibiting moderate to strong expression. In contrast, moderate to strong ABCD1 expression was significantly lower in PDAC (3.28%) and NET (6.66%). However, strong expression was observed in 57.14% of acinar cell carcinomas (ACC). Furthermore, ABCD1 complements β-catenin in cases where nuclear β-catenin staining is ambiguous (100% ABCD1 positivity). ROC curve analysis revealed that ABCD1 exhibits excellent diagnostic performance for distinguishing SPN from other pancreatic tumors, achieving a sensitivity of 96.36% and a specificity of 93.10%, establishing it a reliable complementary diagnostic marker in biopsy samples. These results suggest that ABCD1 could serve as a valuable tool for the accurate preoperative diagnosis of SPN, thereby improving clinical management and patient outcomes.
Renal tumors harboring FLCN mutations: Case series from clinical practice.
Ding CC, Chan E, Lotan TL … +5 more , Hang JF, Greenland NY, Stohr BA, Simko JP, Sirohi D
Hum Pathol · 2026 Jul · PMID 42000053 · Publisher ↗
BACKGROUND: Renal cell neoplasms with FLCN mutations, classically seen in Birt-Hogg-Dubé (BHD) syndrome typically include oncocytoma, chromophobe RCC, and hybrid oncocytic/chromophobe tumors (HOCT). Recent studies have h...
BACKGROUND: Renal cell neoplasms with FLCN mutations, classically seen in Birt-Hogg-Dubé (BHD) syndrome typically include oncocytoma, chromophobe RCC, and hybrid oncocytic/chromophobe tumors (HOCT). Recent studies have highlighted FLCN-mutated renal cell carcinomas (RCCs) with unclassified morphologies, raising diagnostic challenges. METHODS: We retrospectively identified renal tumors with FLCN mutations by targeted next-generation sequencing at our institution (2015-2024). Clinical records, tumor morphology, immunohistochemistry, and genomic profiles were reviewed. RESULTS: Seven patients were identified. Four exhibited unclassified morphologies with features overlapping with translocation RCC, as well as papillary RCC and eosinophilic solid and cystic (ESC) RCC. One clear cell RCC harbored a secondary probable germline FLCN mutation and TFEB locus amplification, while two were consistent with conventional oncocytic morphology. Germline FLCN mutation was confirmed in two patients with BHD syndrome. Recurrent copy number changes in these tumors included loss of 1p, 15q, 17p and 14q, and gain of 17q. CD117 and CK7 were negative to focal in majority of the cases, TFE3 showed diffuse to focal positivity, while GPNMB was diffusely positive in all 5 cases with material available. Clinical outcomes ranged from indolent disease to metastasis and late recurrence. CONCLUSIONS: FLCN-mutated RCCs comprise a morphologically heterogeneous yet molecularly defined group. Conventional oncoytic morphology was associated with germline alterations while unclassified morphologies could be associated with somatic alterations and possibly germline mutations. FLCN mutations may also be incidental germline mutations in other RCC subtypes. Tumors with unclassified morphologies evoked morphological and immunohistochemical diagnostic consideration of other oncocytic and papillary RCCs and could be associated with adverse outcomes. Recognition may be aided by diffuse GPNMB expression, but definitive classification, especially in cases without conventional morphology, requires molecular testing. These findings broaden the spectrum of FLCN-driven tumors and support their distinction as a unique molecular entity.
Osteosarcomas with H3F3A mutation a clinicopathological and molecular genetic study of 7 cases with review of the literature.
Wei Q, Zhong L, Zhou H … +5 more , Jiang L, Wang Q, Li D, Lai S, Yang Q
Hum Pathol · 2026 Jul · PMID 41990998 · Publisher ↗
Some studies have suggested that osteosarcomas with H3F3A mutations (OS-H3F3A) may represent a subtype of primary malignant giant cell tumor of bone (GCTB). Previous research has been limited in case number, highlightin...
Some studies have suggested that osteosarcomas with H3F3A mutations (OS-H3F3A) may represent a subtype of primary malignant giant cell tumor of bone (GCTB). Previous research has been limited in case number, highlighting the need for further investigation. In this study, we present seven cases of OS-H3F3A and review an additional 24 documented cases in the literature. Among 189 osteosarcoma cases, we identified seven (3.7%) with H3F3A mutations by surrogate immunohistochemistry and next-generation sequencing (NGS), including six (85.7%) with p.G35W and one (14.3%) with a p.G35R mutation. The cohort consisted of four males and three females with a mean age of 43 years (range: 20-66). The primary sites included the distal femur (n = 5), proximal tibia (n = 1) and sacrum (n = 1). Pain was the main clinical manifestation, lasting an average of 8.3 months (range: 1-48 months). Microscopically, tumors were classified into three types: spindle cell (n = 3; low-grade), epithelioid cell (n = 3; high-grade), and pleomorphic cell (n = 1; high-grade). A complete loss of H3K27me3 expression was observed in 3 of 6 cases, with concurrent mutant overexpression of p53 in 1 case. Clinical follow-up data were available for all patients over a mean period of 44 months (range: 5-110 months). At the last follow-up, one patient died from the disease, one was alive with the disease, and five were alive without evidence of the disease. Our findings support the hypothesis that OS-H3F3A may a distinct subtype of primary malignant GCTB. OS-H3F3A showed significant heterogeneity in morphological features and clinical behavior. We recommend routine screening for these tumors.
GDNF methylation is associated with pathological parameters in colorectal adenocarcinoma and the roles of circulating tumour cells.
Chen Z, Woon JY, Moetamedirad N … +7 more , Islam MS, Vidanapathirana G, Nurujjaman M, Lu CT, Qiao B, Gopalan V, Lam AK
Hum Pathol · 2026 Jul · PMID 41985722 · Publisher ↗
Circulating tumour cells (CTCs) provide a minimally invasive platform for disease monitoring and molecular profiling in colorectal carcinoma (CRC). This study aimed to identify prognostically relevant DNA methylation bio...
Circulating tumour cells (CTCs) provide a minimally invasive platform for disease monitoring and molecular profiling in colorectal carcinoma (CRC). This study aimed to identify prognostically relevant DNA methylation biomarkers and assess their translational potential in CTC-based liquid biopsy. Candidate CpG sites were first screened in silico using differential methylation analysis, LASSO regression, and Cox proportional hazards modelling based on The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) dataset, which included 430 tumour and 39 non-tumour colon mucosa samples. Three representative CpG sites (GPR125, GDNF, and ADCY9) were subsequently validated in an independent cohort of 62 CRC patients using quantitative methylation-specific polymerase chain reaction (PCR), with paired comparisons between CTCs and tumour tissues available in 32 cases. A five-CpG prognostic model derived from TCGA data was significantly associated with overall survival (hazard ratio = 4.23, p < 0.001), with time-dependent area under the curves (AUC)s of 0.718, 0.765, and 0.787 at 1, 3, and 5 years. In tumour tissues, GDNF methylation showed significant associations with age, tumour site, histological grade, T stage, and lymphovascular invasion, while GPR125 methylation was associated with lymphovascular invasion, and ADCY9 showed no significant clinicopathological correlations. Network analysis further identified GDNF as a distinct methylation module linked to multiple adverse pathological features. These findings suggest that DNA methylation biomarkers, particularly GDNF, are closely associated with tumour aggressiveness in CRC and support their potential application in both tissue-based assessment and CTC-driven molecular profiling.
Pathological response to herceptin-containing neoadjuvant therapy in HER2 IHC2+/ISH+ and IHC3+ early-stage invasive ductal carcinoma.
Jordan T, Chan NNN, Rimm DL … +1 more , Zhan H
Hum Pathol · 2026 Jul · PMID 41985721 · Publisher ↗
BACKGROUND: HER2-positive breast cancers exhibit heterogeneous responses to neoadjuvant therapy. This study compared pathologic response between IHC 3+ and IHC 2+/FISH + invasive ductal carcinomas (IDCs) treated with tra...
BACKGROUND: HER2-positive breast cancers exhibit heterogeneous responses to neoadjuvant therapy. This study compared pathologic response between IHC 3+ and IHC 2+/FISH + invasive ductal carcinomas (IDCs) treated with trastuzumab/pertuzumab-containing chemotherapy. METHODS: We identified 202 patients with HER2-positive early-stage IDC who received neoadjuvant T/P-containing chemotherapy followed by surgery between 2017 and 2024. Patients were categorized as IHC 3+ (n = 165) or IHC 2+/FISH+ (n = 37). Clinicopathologic parameters from pretreatment biopsies and post-treatment excisions were reviewed. Residual cancer burden (RCB) score and recurrence-free survival (RFS) at 36 months were analyzed. RESULTS: The complete pathologic response (pCR) rate was significantly higher in IHC 3+ compared with IHC 2+/FISH + tumors (67% vs. 27%, p < 0.001). IHC 3+ tumors were more frequently ER-/PR- than IHC 2+/FISH + tumors (56% vs. 16%, p < 0.001). In the subset with complete FISH data (n = 49), increasing RCB class was inversely associated with both HER2/CEP17 ratio and HER2 copy number. At 36 months, recurrence rates were numerically lower in IHC 3+ compared with IHC 2+/FISH + tumors (1.7% vs. 9.4%, p = 0.07). Kaplan-Meier analysis demonstrated a non-significant trend toward improved RFS in IHC 3+ tumors among hormone receptor-positive cases (p = 0.14). CONCLUSIONS: Compared with IHC 3+ IDC, IHC 2+/FISH + IDC demonstrated lower pCR rates and inferior RFS in hormone receptor-negative subset following neoadjuvant trastuzumab/ pertuzumab-containing therapy. Pathologic response correlated inversely with HER2/CEP17 ratio and HER2 copy number. Reassessment of HER2 expression with more sensitive quantitative methods, particularly in IHC 2+/FISH + tumors, may improve therapeutic stratification.
Next-generation sequencing for lymphoid neoplasms: Real-world utility from a clinical assay.
Chen C, Artymiuk CJ, Schwab TL … +9 more , Feldman AL, Jevremovic D, McPhail ED, Rech KL, Viswanatha DS, Hampel PJ, Wang Y, He R, King RL
Hum Pathol · 2026 Jul · PMID 41974312 · Publisher ↗
Although next-generation sequencing (NGS) has become the standard of care in myeloid neoplasms, the utility of lymphoma NGS (LNGS) in the clinical setting has not been well established. The goal of this study was to docu...
Although next-generation sequencing (NGS) has become the standard of care in myeloid neoplasms, the utility of lymphoma NGS (LNGS) in the clinical setting has not been well established. The goal of this study was to document the real-world use of LNGS panels and assess their prognostic, predictive, and diagnostic value. A total of 384 cases were retrospectively reviewed in conjunction with pathology reports, including 121, 183, and 80 tested for the limited B-cell lymphoma panel (25 genes), expanded B-cell lymphoma panel (46 genes), or T-cell lymphoma panel (22 genes), respectively. Specimen types included 170 (44.3%) bone marrow, 120 (31.3%) peripheral blood, and 93 (24.2%) formalin-fixed paraffin-embedded tissue. 248/384 (64.6%) cases showed at least one mutation; 245/347 (70.6%) when excluding specimens known to be negative for lymphoma. Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL/CLL, 40.6%) and mantle cell lymphoma (MCL, 9.6%) were the most common lymphoma types tested. Mutations with prognostic value were found in 228/384 (59.4%) cases. 125 (32.6%) tests provided predictive value for response or resistance to a specific therapy. 36 tests (9.4%) provided diagnostic value, aiding the pathologist in classifying disease or rendering a more definitive diagnosis. LNGS results are most useful as being prognostic in CLL/SLL and MCL, diagnostic in angioimmunoblastic T-cell lymphoma and hairy cell leukemia, theranostic in lymphoplasmacytic lymphoma, and diagnostic and prognostic in follicular lymphoma and T/NK-cell large granular lymphocytic leukemia. Although clinical guidelines have not yet widely incorporated LNGS, when carefully designed and selectively ordered by clinicians and pathologists, the majority of tests do offer prognostic and predictive data which can aid in optimization of clinical management. The diagnostic value of LNGS testing is likely to increase with its further use and availability.
Push pin induced artifact: A mimic of iron pill injury in gastrointestinal pathology.
Olave MC, Manrai P, Nalbantoglu I … +2 more , Jain D, Barbieri AL
Hum Pathol · 2026 Jul · PMID 41967648 · Publisher ↗
BACKGROUND: Dissection push pins (PP) are commonly used during formalin fixation to secure gastrointestinal (GI) resection specimens, allowing proper specimen fixation. We have observed iron diffusion from the PPs into t...
BACKGROUND: Dissection push pins (PP) are commonly used during formalin fixation to secure gastrointestinal (GI) resection specimens, allowing proper specimen fixation. We have observed iron diffusion from the PPs into the tissues that results in an artifact that can be confused with iron deposition described with iron pill associated mucosal injury and gastric glandular siderosis. We sought to characterize this tissue artifact in GI resection specimens. METHODS: Sections from 20 GI specimens (colon 11, small intestine 5, stomach 3, esophagus 1) were obtained from areas where PPs were applied after 24 (n = 15) and 48 (n = 5) hours of fixation. One control section from an area distant from the PP was also taken in each case. Prussian blue stain was performed on all sections and the pattern of iron deposition, diameter of diffusion, and any associated histologic changes were documented. Clinical charts and final diagnosis in each case was reviewed, and history of any iron supplementation was noted. Five cases each of iron pill associated gastritis and gastric glandular siderosis were included for comparison. RESULTS: Fourteen cases (14/20; 70%) exhibited iron deposition where PP were applied (8 large intestine, 3 small intestine, 2 stomach, 1 esophagus) of which 7 showed crystalline green to black iron deposits along the mucosal surface and/or within the lamina propria and a fine and diffuse deposition throughout the wall was observed in twelve cases. This was seen largely as a circular ring-like area centered around the area of PP insertion and was easily evident on H&E stains but was better highlighted with Prussian blue stain. The maximum diameter of iron diffusion was 6.5 mm, with a median of 1.5 mm (IQR = 0-5), and the diameter seemed to increase with longer fixation, but this was not statistically significant. The fine granular staining was not confined to any specific cell type or layer of the bowel wall and involved epithelial and stromal tissues. There was no evidence of mucosal injury and none of the patients were on iron supplements. The control sections in each case lacked evidence of any iron deposition. The pattern of the PP associated iron deposition was compared with iron pill associated mucosal injury and gastric glandular siderosis and key differences were noted. CONCLUSIONS: PPs can result in artificial iron deposition with crystalline and granular deposits that shows some morphologic overlap with iron pill (IP) induced mucosal injury. However, the circular pattern of deposition, absence of inflammatory response and lack of any cell or tissue specificity helps to distinguish it from iron pill induced injury or gastric glandular siderosis. Pathologists need to be aware of PP iron deposition artifact to differentiate it from other diagnoses with clinical relevance.
Gene expression and immunohistochemical phenotypes of high-grade epithelioid mesothelioma.
Gagnon MF, Rozenova K, Lu C … +7 more , Sosa C, Pitel B, Petersen M, Clausen S, Roden AC, Halling KC, Lo YC
Hum Pathol · 2026 Jul · PMID 41967647 · Publisher ↗
Grading of epithelioid mesothelioma (EM) has recently been reported to be predictive of survival. We investigated whether RNA expression profiles and immunohistochemical (IHC) markers could refine EG grading and potentia...
Grading of epithelioid mesothelioma (EM) has recently been reported to be predictive of survival. We investigated whether RNA expression profiles and immunohistochemical (IHC) markers could refine EG grading and potentially identify therapeutic targets. Forty-seven pleural mesothelioma biopsies were studied, including 6 sarcomatoid/desmoplastic mesothelioma (SM), 6 biphasic mesothelioma (BM), and 35 EM. We subclassified EM cases into low-(LG) and high-grade (HG) based on WHO classification. FFPE slides were used for RNA expression and IHC (BAP1, EZH2 and PD-L1) studies. RNA expression was profiled by nCounter PanCancer Pathways Panel (NanoString, 770 genes). In 35 EM, 14 were classified as EM-HG and 21 as EM-LG. RNA expression heat mapping demonstrated that EM-LG predominantly cluster together while EM-HG exhibit more heterogeneity with some cases exhibiting proximity to SM/BM. SM/BM demonstrated a noticeable different IHC profile compared to EM-LG: fewer BAP1 loss (25% vs 86%), higher expression of PD-L1 (mean 30.1%, range 0-80% vs mean 1.3%, 0-10%) and higher EZH2 (mean H score 136.3, 10-250 vs mean 57.1, 5-150). Similarly to EM-LG, EM-HG exhibited low PD-L1 expression with a mean TPS of 1.2%, suggesting limited clinical utility for PD-L1 IHC for EM-LG and EM-HG. A non-statistically significant trend for higher EZH2 expression in EM-HG (mean H score 88.3, 60-140) compared to EM-LG was seen. In conclusion, in addition to supporting histology grading of EM, our findings highlight that EM-HG cases display more heterogeneous expression profiles than EM-LG with some features in between EM-LG and SM/BM. Further data is needed to explore the potential clinical utility EZH2 IHC in the clinical management of pleural mesothelioma.
A lipoleiomyosarcoma of the ligamentum rotundum mimicking dedifferentiated liposarcoma at recurrence.
Gül D, Erbağci A, Aknar F … +2 more , Ökten İN, Kir G
Hum Pathol · 2026 Apr · PMID 41951056 · Publisher ↗
Abstract loading — click title to view on PubMed.
Is it justified to order an upfront cytomegalovirus immunohistochemical stain in patients with severe inflammatory bowel disease and ulceration?
Ertekin R, Hu J, Hosseini M … +3 more , Patel C, Vavinskaya V, Pezhouh MK
Hum Pathol · 2026 Jul · PMID 41935692 · Publisher ↗
BACKGROUND: Cytomegalovirus (CMV) infection is common amongst both immunocompetent and immunocompromised patients. Patients with inflammatory bowel disease (IBD) are more prone to suffer from CMV complications. In this s...
BACKGROUND: Cytomegalovirus (CMV) infection is common amongst both immunocompetent and immunocompromised patients. Patients with inflammatory bowel disease (IBD) are more prone to suffer from CMV complications. In this study, we investigated the utility of immunohistochemistry to diagnose CMV infection in patients with severe IBD. METHODS: We searched our pathology data system to identify patients with IBD from January 1, 2017 to December 31, 2021. We identified 5782 IBD cases, out of which 784 cases had severe activity with ulceration. CMV immunohistochemical stain (IHC) was performed on all 784 cases. Hematoxylin and eosin (H&E) staining slides were reviewed to evaluate the presence of characteristic nuclear or cytoplasmic CMV inclusions. H&E and IHC results were categorized as "single" if 1 cell stained positive or had characteristic inclusions, "rare" if 2-5 cells stained positive or had characteristic inclusions and "many" if more than 5 cells stained or had characteristic inclusions. Clinical outcomes, treatment and serum CMV viral loads were examined. RESULTS: A total of 29 cases out of 784 cases (3.7%) were positive for CMV by IHC. Seven cases (0.9%) showed many positive cells, 14 (1.8%) had rare positive cells and 8 cases (1%) showed single positive cells on IHC. The most frequently involved specimen type was the left colon. Twelve out of 29 cases (41%) didn't show characteristic cytoplasmic or nuclear inclusions on H&E stains prior to IHC. Out of these 12 cases, CMV IHC showed rare cells in 7 cases (58%) and single cells in 5 cases (42%). None of these cases show many positive cells on IHC. CMV viral load PCR was tested in 10 out of 29 cases (34%) and was positive in 80% of tested patients (8 out of 10). The majority of positive cases by PCR had many CMV inclusions on IHC (5 out of 8, 63%). Only 3 out of 12 patients with no H&E inclusions were tested with CMV PCR with 2 cases being positive (2 out of 12, 17%). These 2 cases were treated with antiviral treatment. Overall, CMV IHC helped to detect CMV positivity in only 12 out of 784 cases (1.5%) that were otherwise not apparent on H&E. CONCLUSIONS: These results suggest that CMV infection is rare in IBD patients with severe activity and ulceration and H&E should be used as a first line to detect viral inclusions in such patients. CMV IHC could only help to identify the CMV infection in a minority of cases with no characteristic inclusions on H&E stain.
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