Human Pathology[JOURNAL]
Sun
200 papers
Insights from single cell and bulk RNA sequencing: increased NOTCH signaling is correlated with oncogenic transformation of juxtaglomerular cells to juxtaglomerular cell tumors.
Gupta S, Dasari S, Shen W … +3 more , Kipp BR, Erickson LA, Cheville JC
Hum Pathol · 2025 Nov · PMID 41033418 · Publisher ↗
Renin-expressing juxtaglomerular cells in the kidney are the cell of origin for rare juxtaglomerular cell tumors, and affected patients often experience prolonged diagnostic odysseys as they present with relatively nonsp...
Renin-expressing juxtaglomerular cells in the kidney are the cell of origin for rare juxtaglomerular cell tumors, and affected patients often experience prolonged diagnostic odysseys as they present with relatively nonspecific symptoms related to secondary hypertension. While NOTCH1-3 gene rearrangements are the predominant molecular finding in similar (non-renin producing) "myopericytic" cell-derived glomus tumors that occur at renal and non-renal sites, such alterations have been reported in only isolated cases of juxtaglomerular cell tumors. As pathogenic mechanisms contributing to the oncogenic transformation of juxtaglomerular cells to renin-producing tumors are poorly defined due to their extreme rarity, we compared single cell RNA sequencing data for (non-neoplastic) juxtaglomerular cells to bulk whole transcriptomic data for a series of six fusion-negative juxtaglomerular cell tumors. Unsupervised clustering revealed substantial alterations in gene expression in juxtaglomerular cell tumors compared to their cell of origin, including significant over-expression of markers that are diagnostically relevant (renin/GATA3), and other (upregulated) markers of interest including CD34, NOTCH2/3, PDGFRB, JAG1, and NTRK3. Finally, the majority of juxtaglomerular cell tumors showed increased NOTCH pathway signaling. These findings help better define the pathologic basis of oncogenic transformation of juxtaglomerular cells to renin-expressing tumors and may be informative regarding therapeutic options in unresectable or rare cases of metastatic juxtaglomerular cell tumors.
Evaluation of nuclear pseudoinclusions, GATA3, 34βE12, and GPNMB performances in CK7 diffuse positive clear cell renal cell neoplasms.
Chen M, Liu Y, Wu Y … +5 more , Xu H, Dong L, Zhou L, Yang X, Yang X
Hum Pathol · 2025 Nov · PMID 40975181 · Publisher ↗
Recent studies have revealed histological diversity among clear cell renal cell neoplasms demonstrating diffuse CK7 positivity. While prior research established the utility of GATA3 and 34βE12 immunohistochemistry in cle...
Recent studies have revealed histological diversity among clear cell renal cell neoplasms demonstrating diffuse CK7 positivity. While prior research established the utility of GATA3 and 34βE12 immunohistochemistry in clear cell papillary renal cell tumors (CCPRCT) and GPNMB in TSC/mTOR pathway-altered RCC with fibromyomatous stroma (TSC/mTOR RCC FMS), this study employed next-generation sequencing to analyze 36 CK7-diffuse positive clear cell renal neoplasms. These were classified as ELOC-mutated RCC (n = 17), TSC/mTOR RCC FMS (n = 12), CCPRCT (n = 4), and clear cell RCC (n = 3). Cystic architecture was uncommon in TSC/mTOR RCC FMS (2/12) and common in ELOC-mutated RCC (15/17), and nuclear pseudoinclusions were rare in ELOC-mutated RCC (1/17), but common in TSC/mTOR RCC FMS. GATA3 and 34βE12 expression was common in CCPRCT (2/4 and 4/4) and TSC/mTOR RCC FMS (5/11 and 8/11), though rare ELOC-mutated RCC exhibited focal expression (1/12 and 3/10). Limited weak cytoplasmic granular GPNMB expression occurred in one ELOC-mutated RCC and CCPRCT; however, diffuse GPNMB expression was exclusively identified in neoplasms with TSC/mTOR pathway alterations. These results emphasize that GATA3 and 34βE12 expression are not specific to CCPRCT, as they also occur in ELOC-mutated RCC and TSC/mTOR RCC FMS. While focal weak GPNMB expression may be observed in some ELOC-mutated RCC and CCPRCT, diffuse strong expression remains distinctive for TSC/mTOR pathway-altered neoplasms. The frequent nuclear pseudoinclusions observed in TSC/mTOR RCC FMS may aid differential diagnosis.
Tumour budding and tumour-stroma ratio in hepatocellular carcinoma.
Sarelin N, Kairaluoma V, Saarnio J … +5 more , Kauppila JH, Böhm J, Huhta H, Väyrynen JP, Helminen O
Hum Pathol · 2025 Nov · PMID 40975180 · Publisher ↗
OBJECTIVES: Tumour budding has been linked with poor prognosis in hepatocellular carcinoma (HCC), while the prognostic value of tumour-stroma ratio (TSR) remains unclear. We assessed the prognostic value of tumour buds a...
OBJECTIVES: Tumour budding has been linked with poor prognosis in hepatocellular carcinoma (HCC), while the prognostic value of tumour-stroma ratio (TSR) remains unclear. We assessed the prognostic value of tumour buds and TSR in HCC. METHODS: 506 HCC cases were included. Survival analysis was performed separately for surgical (n=101) and non-surgical patients (n=405) based on the presence of tumour buds, and having low TSR (<50 %) and high TSR (≥50 %). Bud-positive patients were further categorised according to tumour bud quantity (1-4 buds, 5-9 buds, and ≥10 buds), and the presence of tumour buds accross multiple sections of the same tumour was evaluated. We also analysed the correlation of tumour buds and TSR between biopsy and resection samples. RESULTS: Positive tumour budding was not associated with increased 5-year overall mortality in multivariable analysis (HR 2.00, 95 % CI, 0.98-4.07), but was an independent risk factor for disease-specific mortality (HR 2.53, 95 % CI, 1.06-6.02, P = 0.036). The presence of ≥10 buds was an independent risk factor of overall- and disease-specific mortality in multivariable analysis. Tumour buds were found in 77% of slides in bud-positive patients. TSR was not linked with 5-year overall survival or disease-specific survival. Biopsy samples demonstrated a low sensitivity of 22 % in identifying tumour budding compared to the resection samples. CONCLUSION: Tumour budding was an independent risk factor for disease-specific mortality in surgically treated HCC patients, with higher bud counts indicating poorer outcomes. Tumour buds were consistently found across slides. Furthermore, our results suggest that tumour buds are most reliably evaluated using resection samples.
GNAQ-/GNA14-mutated hepatic vascular malformation with capillary proliferation in adults and children.
Fischer AK, Heydt C, Siemanowski-Hrach J … +5 more , Alibegovic V, Hauptmann K, Vokuhl C, Büttner R, Fischer HP
Hum Pathol · 2025 Nov · PMID 40946929 · Publisher ↗
AIMS: Congenital hepatic vascular malformation with capillary proliferation (HVMCP) is a rare pseudo-tumourous liver lesion, to date only known in children. Diagnostic pitfalls in infant and, for the first time, in adult...
AIMS: Congenital hepatic vascular malformation with capillary proliferation (HVMCP) is a rare pseudo-tumourous liver lesion, to date only known in children. Diagnostic pitfalls in infant and, for the first time, in adult cases are histomorphologically characterised and molecularly analysed on driver mutations playing a role in angiogenesis and angioproliferation. METHODS AND RESULTS: We histomorphologically characterised 4 early childhood and 2 adult cases, which showed malformed venous, cavernous and dissecting CD34-positive, GLUT1-negative capillary formations, followed by trabecular disarrangement of the involved liver parenchyma. As shown exemplarily, infant cases can lead to misdiagnosis as Glypican 3-positive hepatoblastoma. In adults, broadened capillarized liver trabecules might imitate hepatocellular carcinoma and dense capillary formations can resemble endothelial tumours, particularly hepatic small vessel neoplasia. In all cases, vascular malformation was the diagnostic key feature. Custom hybrid-capture-based sequencing assays were conducted, covering a broad range of genes active in angiogenesis and angioproliferation. Of the cases, 3, including 1 adult case, showed pathogenic activating driver mutations in GNAQ/GNA14. One adult lesion proved to be wild-type. Two wedge biopsies did not allow for molecular analysis. CONCLUSIONS: HVMCP has to be differentiated from true vascular neoplasms, particularly from hepatic congenital haemangioma, hepatic infantile haemangioma and hepatic small vessel neoplasia but also from solid malignant hepatocellular tumours. Recognition of the underlying vascular malformation might disclose the pseudotumourous nature even in biopsies. Detection of driver mutations in the Gqα-protein-coding gene family with activation of the downstream MAPK/ERK pathway may open up a future treatment option for non-resectable lesions with MAPK/ERK inhibitors. CLINICAL TRIAL NUMBER: Ethic Votum BioMaSota No.13-091.
CTNNB1 mutations in serum amyloid A-positive hepatocellular neoplasm/inflammatory hepatocellular adenoma arising in alcoholic cirrhosis.
Sasaki M, Sato Y, Nakanuma Y
Hum Pathol · 2025 Oct · PMID 40946928 · Publisher ↗
BACKGROUND: Serum amyloid A-positive hepatocellular neoplasm (SAA-HN) arising in alcoholic cirrhosis is now regarded as a specific type of inflammatory hepatocellular adenoma (IHCA) associated with advanced liver disease...
BACKGROUND: Serum amyloid A-positive hepatocellular neoplasm (SAA-HN) arising in alcoholic cirrhosis is now regarded as a specific type of inflammatory hepatocellular adenoma (IHCA) associated with advanced liver disease. Since recent studies reported various glutamine synthetase (GS) expression patterns corresponding to CTNNB1 mutations in β-catenin mutated HCA, SAA-HN/IHCAs were herein re-evaluated for CTNNB1 mutations. METHODS: GS expression was examined in 33 SAA-HN/IHCAs (23 patients) and 15 IHCAs (14 patients) from our archives and classified into patterns (P) 1-3 (P1, a diffuse homogeneous pattern suggesting an exon 3-non-S45 mutation; P2, diffuse heterogeneous, suggesting an exon 3-S45 mutation; P3, rim and focal heterogeneous, suggesting exon-7/8 mutations) and P4 (negative). Hotspot genetic mutations in CTNNB1, exons-3, 7, and 8 were examined by direct sequencing. RESULTS: Thirty-three SAA-HN/IHCAs were classified into 3 P1, one P3, and 29 P4 and 15 HCAs into 3 P1, 1 P2, 2 P3, and 9 P4. A genetic analysis revealed 3 SAA-HN/IHCAs with CTNNB1, exon-3 mutations and 1 exon-7 mutation, consistent with GS expression patterns P1 and P3, respectively. Two SAA-HN/IHCAs were associated with CTNNB1, exon-8 mutation, and both were regarded as P4 based on GS expression patterns. No significant differences were observed in clinicopathological features between SAA-HN/IHCAs with and without CTNNB1 mutations (p > 0.05). CONCLUSIONS: Some SAA-HN/IHCAs may be b-IHCA, exon-3 or exon-7/8 mutations. Careful evaluation of immunoreactivity for GS and a genetic analysis of CTNNB1 mutations are crucial for the accurate diagnosis of b-IHCA, exon-3 mutation, for which the risk of malignant transformation is high, and better clinical management.
Undifferentiated embryonal sarcoma of the liver: A clinicopathological and genomic study of 10 cases from a single institution.
Zamiara P, Shillingford N, Wang LL … +3 more , Schmidt RJ, Raca G, Zhou S
Hum Pathol · 2025 Nov · PMID 40945619 · Publisher ↗
AIMS: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy with limited clinicopathological and genomic characterization. This study aimed to investigate the genomic abnormalities in...
AIMS: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy with limited clinicopathological and genomic characterization. This study aimed to investigate the genomic abnormalities in a cohort of UESL cases. METHODS: We analyzed ten UESL cases diagnosed at our institution from 2018 to 2025. Tumor specimens underwent DNA and RNA-based next-generation sequencing using the OncoKids® panel, along with chromosomal microarray analysis. RESULTS: The median age at diagnosis was 13.0 years (range: 0.8-18.3), and the median tumor size was 14.4 cm (range: 7.5-26.0). Lung metastases were present in three patients, and six tumors exhibited capsule rupture. Histology revealed pleomorphic, hyperchromatic oval, spindle, or stellate-shaped cells, with CD56 positivity. TP53 was the sole recurring mutated gene, identified in nine of ten cases. Biallelic TP53 inactivation (mutation plus copy number loss, n = 7) correlated with greater chromosomal complexity compared to monoallelic TP53 mutations (n = 2). Segmental gain at 19q13.42-q13.43, including chromosome 19 microRNA cluster (C19MC), was observed only in tumors with biallelic TP53 inactivation. No clinically significant RNA fusions were detected. All patients underwent tumor resection and ARST0332-based chemotherapy; four of six patients with tumor rupture also received whole abdominal radiation. At a median follow-up of 32.0 months (range: 3.0-81.2), all nine patients with follow-up were alive. CONCLUSIONS: TP53 mutation is a defining molecular event in UESL, with biallelic inactivation linked to increased chromosomal complexity and C19MC locus gain. Despite its aggressive nature, favorable outcomes are achievable with multimodal therapy.
Clinicopathological characteristics and immune infiltration analysis of esophagogastric junction adenocarcinoma with alterations in SWI/SNF complex.
Cheng N, Wang B, Xu J … +2 more , Wang Z, Xue L
Hum Pathol · 2025 Oct · PMID 40939949 · Publisher ↗
BACKGROUND: Alterations in SWI/SNF complex were mostly detected in poorly differentiated or undifferentiated gastric/esophagogastric junction adenocarcinoma (EGJA). However, there was a lack of studies investigating thes...
BACKGROUND: Alterations in SWI/SNF complex were mostly detected in poorly differentiated or undifferentiated gastric/esophagogastric junction adenocarcinoma (EGJA). However, there was a lack of studies investigating these alterations in a consecutive series of cases regardless of the morphology. Therefore, our study aimed to clarify the clinicopathological, prognostic, molecular and immune infiltration characteristics of a consecutive series cases with altered SWI/SNF complex in EGJA. METHODS: We retrospectively analysed 266 patients who underwent surgery without neoadjuvant therapy. Tissue microarrays were constructed for evaluating molecular markers (INI1, ARID1A, BRM, BRG1, MLH1, PMS2, MSH2, MSH6, EGFR, c-MET, HER2, p53 and PD-L1) and immune cell markers (CD3, CD4, CD8, CD68 and CD163). Immune cell counts were quantified using Qupath. RESULTS: Among the 266 patients, 36 (13.5 %) cases exhibited alterations in SWI/SNF complex. Specifically, 14 (5.3 %) cases were identified with ARID1A alteration, 21 (7.9 %) cases with BRG1 alteration, 7 (2.7 %) cases with altered BRM and 2 (0.8 %) cases with INI1 alteration. Alterations in ARID1A correlated with deficient mismatch repair (dMMR) (p < 0.001), increased CD3T-cell (p = 0.017) and relatively increased CD8 T-cell infiltration (p = 0.057), whereas alterations of BRG1 correlated with reduced CD3T-cell infiltration(p = 0.036). There were no significant differences in clinicopathological or prognostic characteristics in EGJA patients with or without SWI/SNF or its subunits alterations. CONCLUSION: Our findings indicate that the SWI/SNF complex demonstrates a notable frequency of alteration within the consecutive series of cases of EGJA. Alterations in ARID1A and BRG1 may correlate with distinct tumor microenvironment, which may provide new insights for optimizing treatment strategies in patients with SWI/SNF complex alterations.
Interdisciplinary analysis of cues to triage gastric lymphoid proliferations: Role of the surgical pathologist revisited.
Sekhri R, Tian X, Chai J … +5 more , Malik P, Edema U, Shakeri H, Lo Y, Panarelli NC
Hum Pathol · 2025 Oct · PMID 40930391 · Publisher ↗
Surgical pathologists who examine gastric biopsies must triage exuberant lymphoid infiltrates for hematopathology consultation, a task that should account for resource and time utilization. We assembled all cases of chro...
Surgical pathologists who examine gastric biopsies must triage exuberant lymphoid infiltrates for hematopathology consultation, a task that should account for resource and time utilization. We assembled all cases of chronic gastritis sent by surgical pathologists to hematopathology due to concern for low-grade lymphoma over a 4-year interval. The cases were ultimately classified as reactive (n = 37), atypical (n = 9), or lymphoma (n = 18). A surgical pathologist assessed lymphoid aggregates for their distribution and density, the presence of lymphoepithelial lesions, destruction of native structures, and monocytoid and/or centrocytoid and/or high grade cytology. Endoscopic findings, Helicobacter pylori infection, and any history of lymphoma were documented. Most reactive infiltrates displayed only one of the aforementioned concerning features, whereas atypical cases tended to have at least two and lymphomas at least 3 histologic hallmarks of lymphoma. Logistic regression analysis showed that history of lymphoma, and presence of >3 concerning histologic features were significantly associated with final classification of atypical or lymphoma. The presence of full thickness lymphoid infiltrates approached significance. Combination of these three features produced an area under a receiver operating characteristic (ROC) curve of 0.9, indicating excellent discrimination between reactive and atypical lymphoid infiltrates/lymphomas. We conclude that surgical pathologists can reliably triage gastric lymphoid infiltrates for consultation and ancillary studies by combining clinical data with evaluation of histologic features.
Centrosome dysfunction and autophagy dysregulation in renal cell carcinoma: Implications for tumor progression and therapy.
Huang HH, Wang WJ, Peng YC
Hum Pathol · 2025 Oct · PMID 40925490 · Publisher ↗
Renal cell carcinoma (RCC) is a heterogeneous kidney malignancy driven by complex genetic, molecular, and metabolic alterations. Emerging evidence implicates centrosome dysfunction and autophagy dysregulation in RCC init...
Renal cell carcinoma (RCC) is a heterogeneous kidney malignancy driven by complex genetic, molecular, and metabolic alterations. Emerging evidence implicates centrosome dysfunction and autophagy dysregulation in RCC initiation, progression, and resistance to therapy. The centrosome plays a critical role in mitotic fidelity, and its dysfunction often leads to chromosomal and genomic instability. Autophagy, a lysosome-dependent process essential for cellular homeostasis, exhibits a dual role in RCC. It functions as a tumor suppressor in early stages but promotes tumor survival and resistance to therapy in advanced disease. Notably, recent studies indicate that TFEB/TFE3, transcription factors that regulate autophagy and lysosomal biogenesis, mediate a functional interplay between centrosome status and autophagy. This review aims to explore the mechanistic crosstalk between centrosome dysfunction and autophagy in RCC, with a special focus on MiT family translocation RCC, and to discuss emerging therapeutic strategies targeting these pathways.
Leukemic phase of MYC/BCL2 double-hit high-grade B-cell lymphoma: A report of 35 cases.
Medeiros LJ, Zhou J, Wang X … +3 more , Wang W, Tang G, Hu S
Hum Pathol · 2025 Oct · PMID 40925489 · Publisher ↗
We report 35 patients who had a leukemic phase of diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements, also known as double-hit lymphoma (DHL). There were 23 men and 12 women with a...
We report 35 patients who had a leukemic phase of diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements, also known as double-hit lymphoma (DHL). There were 23 men and 12 women with a median age of 57 years (range, 29-82). Eight patients had an established DHL diagnosis and subsequently developed a leukemic phase of disease and 27 presented with DHL and a leukemic phase of disease at initial diagnosis. Thirty patients had not received any therapy specific for DHL at time of diagnosis. For these 30 patients, the median leukocyte count was 16.6 × 10/L (range, 1.6-191.3) and the median percentage of lymphoma cells in the blood was 39 % (range, 10-97). Many patients presented with a clinical picture mimicking acute leukemia. Laboratory studies revealed elevated serum lactate dehydrogenase levels in all patients assessed, with a median level of 7507 U/L (range, 377-39,022). All patients had bone marrow involvement, with a median of 82% lymphoma cells in aspirate smears and approximately 80% replacement in biopsy specimens. Twenty-nine of 31 (94%) patients with complete information had extramedullary disease, most commonly lymph nodes. Immunophenotypic analysis showed a CD10-positive, germinal center B-cell immunophenotype in 34 cases. Conventional cytogenetic analysis was successful in 27 cases, all showing a complex karyotype. MYC partners were known in 22 cases, with immunoglobulin (IG) gene partners in 19 and non-IG partners in 3 cases. Despite treatment with chemotherapy regimens, overall survival was poor with a median of 7 months from onset of leukemic phase of disease. In summary, a small subset of patients with DHL can present with or develop a leukemic phase of disease which is a harbinger of very poor prognosis.
Severe eosinophilic gastritis is associated with peripheral eosinophilia and multi-organ involvement.
Wang X, Hao Y, Lam H … +2 more , Liu Q, Ko HM
Hum Pathol · 2025 Oct · PMID 40925488 · Publisher ↗
Histologic gastric eosinophilia (HGE), characterized by dense eosinophil infiltration in gastric mucosa, is an understudied disease with unclear etiology. Unlike its counterpart, eosinophilic esophagitis (EoE), which has...
Histologic gastric eosinophilia (HGE), characterized by dense eosinophil infiltration in gastric mucosa, is an understudied disease with unclear etiology. Unlike its counterpart, eosinophilic esophagitis (EoE), which has defined diagnostic eosinophil thresholds and characteristic endoscopic findings, proposed eosinophil thresholds for the diagnosis of HGE vary and endoscopic findings are not well characterized. This study aimed to assess the clinical, histological, and endoscopic features of HGE in adults and children. A cohort of 50 HGE patients were identified (20 children, 30 adults; 58.0 % male). The majority (70.0 %) had an allergic/atopic history. Pediatric patients with HGE were significantly more likely to have a history of food allergy (P = 0.013) and less likely to have drug allergy (P = 0.001) compared to adults. The most common endoscopic finding was ulceration/erosion (34.0 %). Multiorgan GI-tract involvement was seen in 40.9 % of patients, primarily affecting the esophagus (39.0 %) and duodenum (15.4 %). HGE cases were stratified by severity into G1 (50-100 eosinophils/HPF; 11 patients) and G2 (>100 eosinophils/HPF; 39 patients) groups for comparison. Patients with G2 HGE had higher rates of peripheral eosinophilia (P = 0.010) and multiorgan GI involvement (P = 0.047) compared to those with G1 HGE. In conclusion, HGE often presents as a gastric ulcer and is strongly associated with food allergy in children and drug allergy in adults. Severe HGE is more likely than moderate HGE to present with peripheral eosinophilia and concomitant eosinophilia elsewhere in the GI tract, therefore, noting the presence of severe HGE may be helpful in guiding clinical follow up.
Assessment of Nectin4-expression in vulvar squamous cell carcinomas (VSCC): correlation with HPV-associated and HPV-independent molecular subtypes.
Höhn AK, Hiller GGR, Wolf B … +7 more , Forberger M, Brambs CE, Gilks B, Hoang L, McAlpine JN, Jamieson A, Horn LC
Hum Pathol · 2025 Oct · PMID 40907720 · Publisher ↗
BACKGROUND: The development of antibody-drug conjugates (ADC) for cancer treatment has achieved promising results in different solid tumors and targets. Enfortumab-Vedotin (EV), a humanised anti-Nectin4-IgG1 monoclonal a...
BACKGROUND: The development of antibody-drug conjugates (ADC) for cancer treatment has achieved promising results in different solid tumors and targets. Enfortumab-Vedotin (EV), a humanised anti-Nectin4-IgG1 monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE), is an FDA-approved Nectin4-directed ADC for the treatment of locally advanced or metastatic pre-treated urothelial cancer. Targeted therapy with EV requires the expression of Nectin4 within the tumor cells. The present study evaluates Nectin4 expression in vulvar squamous cell carcinomas (VSCC) and its correlation to different VSCC molecular subtypes. METHODS: Immunohistochemical Nectin4-expression was evaluated semiquantitatively on diagnostic biopsies of VSCC using an immunoreactive score (IRS). There was a correlation between IRS and different molecular subtypes of VSCC. RESULTS: All 55 cases showed at least weak Nectin4 expression within the tumor cells with a median IRS of 6.0 (range 2-6) indicating high expression levels in most tumors. Moderate/high expression (IRS ≥4) was more frequent in HPV-associated tumors (p16/p53 molecular subtype: 12/14 (85.7 %) when compared to HPV-independent VSCC (22/35 (62.9 %) in p16/p53 and 0 % in four p16/p53 ) VSCC, a difference that is not statistically significant. CONCLUSION: Most VSCC show high expression of Nectin4, including the HPV-independent VSCC containing a TP53-mutation (p16/p53 molecular subtype), that are associated with the worst prognosis. Therefore, Nectin4-directed ADC such as Enfortumab-Vedotin (EV) may present a potential treatment option in VSCC. Nectin4-expression can easily be assessed by immunohistochemistry on diagnostic biopsies. Clinical trials exploring Nectin4-directed ADCs such as EV are necessary.
Impact of neoadjuvant chemotherapy on PD-L1 expression in oral squamous cell carcinoma: A matched biopsy-resection study.
Agrawal D, Anand N, Husain N … +5 more , Srivastava P, Tamrakar A, Sharma V, Singhal A, Khurana R
Hum Pathol · 2025 Oct · PMID 40886778 · Publisher ↗
BACKGROUND: Programmed death ligand 1 (PD-L1) is essential for immune evasion and serves as a significant biomarker for immunotherapy in oral squamous cell carcinoma (OSCC). Nevertheless, the changes in its expression af...
BACKGROUND: Programmed death ligand 1 (PD-L1) is essential for immune evasion and serves as a significant biomarker for immunotherapy in oral squamous cell carcinoma (OSCC). Nevertheless, the changes in its expression after neoadjuvant chemotherapy (NACT) are not well understood. This research sought to assess the variations in PD-L1 expression between matched pretreatment biopsy samples and post-NACT surgical specimens, while also correlating these results with clinicopathological characteristics. MATERIALS AND METHODS: The study comprised 130 patients with OSCC, of which 95 were treated with NACT while 35 acted as controls who did not receive NACT. PD-L1 expression was measured via immunohistochemistry (SP263 clone) on pretreatment biopsy samples and corresponding post-NACT resection specimens, employing Tumor Proportion Score (TPS), Immune Proportion Score (IPS), and Combined Positive Score (CPS) at several cut-off points (≥1 %, ≥10 %, ≥25 %, and ≥50 %). Statistical evaluations were performed using SPSS version 24.0. RESULTS: In post NACT, there was a significant variation in PD-L1 expression. A marked reduction in PD-L1 TPS was noted in T1 tumors, decreasing from 43.4 % to 13.0 % (p = 0.039), as well as in tumors with a depth of invasion (DOI) less than 5 mm, which dropped from 40.7 % to 14.8 %. Conversely, an increase in PD-L1 expression was observed in tumors at advanced nodal stages and those exhibiting lymphovascular invasion (LVI), perineural invasion (PNI), and tumor budding. The change in combined positive score (CPS) was significantly correlated with tumor budding (p = 0.008), the worst pattern of invasion (WPOI) (p = 0.036), DOI (p = 0.030), and prognostic stage (p = 0.026). In control cases, only minor alterations in PD-L1 status were detected between biopsy and resection specimens. CONCLUSION: NACT did not lead to uniform or widespread changes in PD-L1 expression in OSCC. Significant alterations were limited to TPS in T1 tumors and CPS associations with certain pathological features, while most other comparisons showed no statistical significance. These findings suggest that PD-L1 expression after NACT should be interpreted cautiously, and larger studies are needed to clarify its clinical relevance.
High-grade endometrioid carcinomas with pilomatrix-like features lacking CTNNB1 Mutations: Clinicopathologic characteristics and novel molecular events.
Qin L, Lin W, Huang S … +2 more , Zheng W, Zhou F
Hum Pathol · 2025 Oct · PMID 40886777 · Publisher ↗
CONTEXT: Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) represents a recently described, aggressive variant of endometrial carcinoma. Prior reports have linked PiMHEC with CTNNB1 exon 3 mutations and abnormal...
CONTEXT: Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) represents a recently described, aggressive variant of endometrial carcinoma. Prior reports have linked PiMHEC with CTNNB1 exon 3 mutations and abnormal nuclear β-catenin expression. OBJECTIVE: We aimed to expand the understanding a potential subclassification of PiMHEC by analyzing three new cases that lack CTNNB1 mutations and β-catenin nuclear accumulation. DESIGN: Three cases of high-grade endometrioid carcinomas with pilomatrix-like features were identified and their clinical presentations and pathologic features reviewed. Immunohistochemistry (IHC) and targeted next-generation sequencing (NGS) were performed. RESULTS: All tumors demonstrated two components: a high-grade basaloid component with solid sheets of atypical basaloid cells, geographic necrosis, and focal "ghost" cells, and an associated low-grade FIGO grade 1 endometrioid carcinoma component. Notably, none of the three cases showed nuclear β-catenin expression by IHC, and all lacked CTNNB1 exon 3 mutations. Despite this, the tumors fulfilled the morphologic criteria for PiMHEC described in prior studies and displayed aggressive clinical behavior. All the patients presented with advanced-stage disease (stages IIC-IVB), and two patients had a recurrence within 12 months. NGS revealed no CTNNB1 mutations in any case, but identified alternative likely oncogenic alterations: one tumor harbored an FGFR4 p. T259A mutation, two tumors had pathogenic TSC2 mutations, one had a KRAS p.G12D mutation, and two showed MYC amplification, among other genetic changes. CONCLUSIONS: High-grade endometrioid carcinomas with pilomatrix-like features lacking CTNNB1 mutations may represent a potential subclassification of PiMHEC, which exhibit aggressive behavior. CTNNB1-wildtype cases appear to rely on alternative oncogenic drivers, indicating that CTNNB1 mutation maybe not an absolute requirement for the PiMHEC phenotype.
Eosinophil-rich esophagitis pattern in patients with allogenic hematopoietic stem cell transplantation: a multicenter experience.
Youssef R, Wen KW, Alipour Z … +4 more , Hu S, Schechter S, Cheng J, González IA
Hum Pathol · 2025 Oct · PMID 40854346 · Publisher ↗
Eosinophil-rich esophagitis is a pattern of inflammation characterized by increased intraepithelial eosinophils which is associated with a wide range of disorders including eosinophilic esophagitis (EoE). In hematopoieti...
Eosinophil-rich esophagitis is a pattern of inflammation characterized by increased intraepithelial eosinophils which is associated with a wide range of disorders including eosinophilic esophagitis (EoE). In hematopoietic stem cell transplant (HSCT) patients, eosinophil-rich esophagitis is exceedingly rare and associated in one prior case to transplant-acquired allergy (TAA). The goal of this multicenter study was to characterize the clinical and pathologic features of esophageal biopsies with an eosinophil-rich esophagitis pattern in HSCT patients. 10 cases were identified presenting with a median age of 45 years (range: 10-76), including 7 men. The median time lapsed from HSCT to biopsy was 6 months (range: 0-3). 3 patients presented within 21 days of HSCT, 2 of which showed apoptotic bodies. The median number of eosinophils/HPF was 25 (range: 16-102), 6 cases showed eosinophilic degranulation, 3 cases had eosinophilic abscesses, 5 cases showed apoptotic bodies, and 3 cases had dyskeratotic cells. Of the 5 patients presenting after 21 days of HSCT, features of GVHD were seen in 2 patients (apoptotic bodies and dyskeratotic cells) and 1 patient (apoptotic bodies only), with all of them having extra-gastrointestinal GVHD. 2 patients developed TAA to medications, levofloxacin and diphenhydramine, and 1 patient had an allergic transfusion reaction. Only 1 patient met diagnostic criteria for EoE. Based on these limited cases, HSCT patients presenting with an eosinophilic-rich esophagitis pattern were associated with conditioning regimen-induced injury and GVHD and seen in patients with TAA.
Idiopathic cholestasis in adults: Genetics as another lens for liver pathologists.
Tamburro C, Mentzinger A, Jain D … +1 more , Vilarinho S
Hum Pathol · 2025 Nov · PMID 40854348 · Publisher ↗
Chronic liver disease (CLD) is a significant global health problem, responsible for approximately two million deaths annually. Despite extensive diagnostic evaluations, a proportion of patients with CLD remain undiagnose...
Chronic liver disease (CLD) is a significant global health problem, responsible for approximately two million deaths annually. Despite extensive diagnostic evaluations, a proportion of patients with CLD remain undiagnosed, making the study and quantification of these cases challenging. Genetic testing has emerged as a critical diagnostic tool, identifying monogenic causes in a substantial portion of undiagnosed cases. In addition, nearly 50 % of known genetic liver diseases were identified in the past 20 years, underscoring the rapid expansion of genetic knowledge. Notably, recent data demonstrates that genetic testing provides diagnoses in up to nearly half of adult patients with idiopathic cholestasis. Furthermore, wide application of genetic testing in adult populations is revealing that genetic cholestatic liver diseases primarily thought to be of pediatric presentation are now often recognized in adulthood. As genomic medicine continues to evolve rapidly in the context of cholestatic liver disease, pathologists must stay informed about genetic diseases and their implications for liver biopsy interpretation. Interdisciplinary efforts merging hepatologists, clinical geneticists and pathologists' expertise, such as Hepatology Genome Rounds, are envisioned to become standard practice, enhancing disease understanding and patient care.
A real-world study on the expression and clinical application of IMP3 immunohistochemistry in bone tumors.
Wei Q, Zhong L, Zhou H … +4 more , Jiang L, Wang Q, Li D, Yang Q
Hum Pathol · 2025 Oct · PMID 40854347 · Publisher ↗
Previous studies have confirmed that insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) is widely expressed in various malignant tumors. However, no systematic study has assessed the expression of IMP3 in bone tu...
Previous studies have confirmed that insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) is widely expressed in various malignant tumors. However, no systematic study has assessed the expression of IMP3 in bone tumors. We immunohistochemically examined 1381 bone tumor specimens for IMP3 expression, analyzed its differential expression among various types of bone tumors, and evaluated its potential application in surgical pathology. Our results demonstrated that IMP3 positivity was observed in 7.5 % (55/732) of benign bone tumors and 55.2 % (358/649) of malignant bone tumors, with statistically significant differences (P < 0.0001). Notably, higher levels of IMP3 expression were observed in high-grade malignant bone tumors than in their low-grade counterparts. The incidence of IMP3 positivity exceeds 80 % in diffuse large B-cell lymphoma, high-grade osteosarcoma, lymphoblastic lymphoma, and undifferentiated pleomorphic sarcoma. Additionally, we detected IMP3 positivity in 63.5 % (80/126) of metastatic bone cancers, specifically in 83.6 % (46/55) of lung cancers, 70 % (7/10) of liver cancers, and 87.5 % (7/8) of colorectal cancers. We also observed high levels of IMP3 expression in three benign bone tumor types: chondroblastoma, epithelioid hemangioma, and Langerhans cell histiocytosis. In conclusion, IMP3 immunostaining may serve as a diagnostic biomarker for malignant bone tumors, especially osteosarcoma and lymphoma. The high expression of IMP3 observed in bone metastases of lung cancer, liver cancer, and colorectal cancer indicates that IMP3 could be associated with bone metastasis in these malignancies. Future research should focus on elucidating the relationship between IMP3 expression and various clinicopathological parameters as well as prognostic outcomes in malignant bone tumors.
Continuous cast-like intrabiliary extension of biliary neoplasm associated with mass-forming invasive carcinoma may be a hitherto poorly-described progression of intraductal tubulopapillary neoplasm of the bile duct.
Nakanuma Y, Kakuda Y, Matsubayashi H … +1 more , Oishi T
Hum Pathol · 2025 Dec · PMID 40789527 · Publisher ↗
Abstract loading — click title to view on PubMed.
Intracranial low-grade tumors with ALK rearrangement: diverse tumor types with shared molecular alterations.
Mu K, Zhang Y, Yang Y … +4 more , Wang W, Ma R, Wang Y, Gong J
Hum Pathol · 2025 Oct · PMID 40789526 · Publisher ↗
Although anaplastic lymphoma kinase (ALK) gene fusions are increasingly recognized in newly classified pediatric high-grade gliomas, intracranial low-grade tumors harboring ALK rearrangements remain under characterized i...
Although anaplastic lymphoma kinase (ALK) gene fusions are increasingly recognized in newly classified pediatric high-grade gliomas, intracranial low-grade tumors harboring ALK rearrangements remain under characterized in the literature. Herein, we present five cases of low-grade intracranial tumors with ALK rearrangements that were diagnosed at a single institution over a continuous 24-month period. Comprehensive clinicopathological evaluation integrating morphological analysis, immunohistochemical profiling, and molecular characterization of fusion partners was performed. Microscopic examination was performed to assess histologic features. A panel of antibodies were used to evaluate protein expression including ALK, desmin, GFAP, Olig2, S100, NeuN, EMA, and CD34. DNA and RNA sequencing was performed, and potential fusion transcripts were analyzed using seed count and structural chromosomal aberrations. All five tumors harbored structural aberrations involving the ALK locus 2p23, and no additional pathogenic mutations, amplifications, deletions, or fusions were identified in all the cases. Among them, two tumors were inflammatory myofibroblastic tumors (IMT) with SQSTM1::ALK, and NPM1::ALK fusion, respectively. One was a tanycytic supratentorial ependymoma (ST-EPN) with HNRNPA1::ALK fusion, and another was ganglioglioma (GG) with PPP1CB::ALK fusion. Interestingly, one case presented as a low-grade myxoid mesenchymal neoplasm with ATIC::ALK rearrangement that did not fit any existing tumor category. All patients underwent complete tumor resection, and were alive with no signs of recurrence during a follow-up period ranging from 1 to 18 months. In summary, ALK fusions may be shared features of a group of low-grade intracranial tumors including IMT, tanycytic ST-EPN, GG, and ALK-rearranged low-grade myxoid mesenchyma neoplasm. Future studies using larger cohorts are warranted to further characterize their clinical and pathological features.
Fluorescence in situ hybridization (FISH)-based detection of paracentric inversions leading to RBM10::TFE3 rearrangement.
Gupta S, Sill DR, Herrera Hernandez LP … +4 more , Cheville JC, Al-Kateb H, Whaley RD, Greipp PT
Hum Pathol · 2026 Apr · PMID 40784415 · Publisher ↗
Abstract loading — click title to view on PubMed.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe