Human Pathology[JOURNAL]
Sun
200 papers
Breast myoepithelial markers: Problems and pitfalls for the practicing pathologist.
Bachert SE, Chapel E, Schnitt SJ
Hum Pathol · 2025 Aug · PMID 40784414 · Publisher ↗
Immunohistochemical stains for myoepithelial cell (MEC) markers are commonly used in breast pathology to help distinguish benign and in situ lesions from invasive carcinomas. Benign and in situ lesions typically demonstr...
Immunohistochemical stains for myoepithelial cell (MEC) markers are commonly used in breast pathology to help distinguish benign and in situ lesions from invasive carcinomas. Benign and in situ lesions typically demonstrate an associated MEC layer, whereas invasive carcinomas typically lack associated MECs. However, there are some benign lesions and in situ carcinomas in which a MEC layer is partially or completely absent, and there are malignant lesions that contain a component of MECs. An understanding of these exceptions is critical to ensure the correct diagnosis. This review will focus on benign and in situ breast lesions in which associated MECs are reduced or entirely lacking, and malignant breast lesions that contain a population of MECs.
PAX5 as a diagnostic tool in unconventional acute leukemia: Establishing immunohistochemical evidence of B-cell lineage.
Hidalgo Cedeno EF, Germans S, Pan Z … +3 more , Mendez L, Weinberg OK, Xu ML
Hum Pathol · 2025 Sep · PMID 40782987 · Publisher ↗
Acute leukemia lineage assignment is critical for clinical management. When CD19 expression is dim by flow cytometry, it becomes challenging to meet criteria for B-lymphoblastic leukemia/lymphoma (B-ALL) or B-lineage in...
Acute leukemia lineage assignment is critical for clinical management. When CD19 expression is dim by flow cytometry, it becomes challenging to meet criteria for B-lymphoblastic leukemia/lymphoma (B-ALL) or B-lineage in mixed phenotype. While many B-lineage specific markers are available by immunohistochemistry (IHC), they have not been systematically validated. This study highlights the utility of PAX5, BOB.1 and OCT2 in lineage assignment when CD19 is dim, allowing for consideration as additional diagnostic criteria. The databases of two academic institutions were searched for cases: acute undifferentiated leukemia (AUL), acute myeloid leukemia (AML) with minimal differentiation, mixed phenotype acute leukemia (MPAL), and all acute leukemias with weak CD19-expression. Cases were stained with PAX5, BOB.1 and OCT2. The IHCs were scored by intensity and percentage of positive blasts. A total of 55 cases had weak CD19 expression: 18 B-ALL and 37 acute leukemias with weak CD19-expression (14 MPAL). For negative controls, we selected 21 AML with minimal differentiation, 5 T/myeloid cases, 5 near early T-cell precursor (ETP) T-ALLs and 3 ETP T-ALLs. By PAX5 IHC, 18/18 (100 %) B-ALL cases were positive; all minimal differentiation myeloid and T/myeloid leukemias were negative (0/26), and 36/37 (98 %) acute leukemias with weak CD19 were positive. Our multicenter data support PAX5 IHC as a sensitive marker of B-lineage assignment when CD19 is dim to negative, especially in acute leukemias with ambiguous lineage or MPAL. BOB.1 and OCT2 can also be helpful but these demonstrated lower sensitivity. In cases where CD19 is dim, with weak CD79a and/or CD22, PAX5 IHC can "rescue" the lineage assignment.
Biological behavior of DCIS with or without microinvasion. Same and different.
Scheidegger L, Frauchiger-Heuer H, Birindelli E … +8 more , Papassotiropoulos B, Elfgen C, Fansa H, Maccio U, Linsenmeier C, Rordorf T, Witzel I, Varga Z
Hum Pathol · 2025 Oct · PMID 40782986 · Publisher ↗
BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer, detected mostly due to associated calcifications. Although non-invasive and primarily treated with surgical excision, recurrence as in...
BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer, detected mostly due to associated calcifications. Although non-invasive and primarily treated with surgical excision, recurrence as in situ or invasive form occurs in a substantial subset of DCIS patients. Microinvasion, defined as less than or equal to 1 mm invasive focus poses a diagnostic, biological and therapeutic dilemma, as the exact biological behavior of DCIS with or without microinvasion is controversially understood. In this retrospective study based on standardized pathology reports from a single center, we addressed the question if DCIS with or without microinvasive foci represents biologically one disease or two distinct entities. MATERIALS AND METHODS: We identified 148 patients with surgically treated DCIS and complete clinico-pathological data and follow-up information, 126 of 148 (85.1 %) pure form, 22 of 148 (14.9 %) with microinvasive foci. Events in follow-up (in-situ, invasive recurrent disease, breast cancer related death) were correlated with the presence of microinvasive foci and with pathological parameters (DCIS size, nuclear grade, the presence of necrosis, margin status, biomarkers, hormone receptors and Ki67 index) and clinical information (therapy modalities). Overall time-to-event-probability (TTE) was assessed with Kaplan Meier curves. RESULTS: There was a total of 28 events (18.9 % of cohort). 12 of 148 (8.1 %) patients had recurrent DCIS, 16 of 148 (10.8 %) developed invasive breast cancer, 5 of 148 (3.4 %) patients died related to breast cancer in follow-up. DCIS with/without microinvasion did not differ significantly in TTE. There was a non-significant trend for worse 5-year breast cancer related death in DCIS with microinvasion. DCIS with microinvasion developed significantly more often in-situ or invasive recurrences in extensive disease (≥5 cm) (p = 0.040), with nuclear high grade (p = 0.045), with necrosis present (p = 0.045), with narrow resection margins (>1 mm) (p = 0.006), with younger age (≤50 years) in follow-up (p = 0.025) and in the absence of adjuvant radio- and/or endocrine therapy (p = 0.009, p = 0.034). No further factors such as calcification, positive margins, hormone receptor status had an impact on TTE on DCIS with or without microinvasive foci. CONCLUSION: Our data shows that biological behavior of DCIS with microinvasive foci per se does not differ from pure DCIS in TTE. However, in-situ or invasive recurrences (total or ipsilateral) occur more often in microinvasive DCIS with extensive disease, with nuclear high grade, present necrosis, with narrow resection margins and in younger age in follow-up. These data warrant for further studies to understand the biology of DCIS with microinvasion and to evaluate specific therapy options different from pure DCIS potentially involving adjuvant modalities.
Genomic aberration detection by fluorescence in situ hybridization.
Cheng L, Davidson DD, Zhang S
Hum Pathol · 2025 Nov · PMID 40782985 · Publisher ↗
Fluorescence in situ hybridization (FISH) is a simple, rapid, and reliable method for detecting genomic alterations relevant to a wide range of diseases, particularly neoplastic disorders, using routine surgical and cyto...
Fluorescence in situ hybridization (FISH) is a simple, rapid, and reliable method for detecting genomic alterations relevant to a wide range of diseases, particularly neoplastic disorders, using routine surgical and cytological specimens. By employing fluorescent-labeled nucleic acid or nucleotide analog probes to target specific DNA sequences on chromosomes, FISH facilitates accurate diagnosis, tumor classification, biomarker identification, selection of targeted therapies, and monitoring of treatment efficacy. As the technology continues to evolve, the demand for FISH is expected to grow, given its cost-effectiveness in supporting diagnostic and therapeutic decisions. However, to fully leverage the potential of this powerful technique, it is essential to be mindful of its underlying chemistry, potential artifacts, interpretive challenges, and the broader clinical context. This article provides an overview of the fundamental principles of FISH data analysis, addresses technical considerations and implementation challenges, and discusses diagnostic criteria, cutoff values, quality control measures, test validation processes, and interpretation of results - with a focus on its application in daily surgical pathology practice.
Mixed-grade papillary urothelial carcinoma with a minor high-grade component shows a significantly worse clinical outcome than low-grade papillary urothelial carcinoma.
Mi W, Zang C, Zhao J … +5 more , Kamat AM, Wei P, Hansel DE, Czerniak B, Guo CC
Hum Pathol · 2025 Sep · PMID 40780614 · Publisher ↗
Grade heterogeneity is common in papillary urothelial carcinoma (PUC) of the urinary bladder. Mixed-grade PUC is generally treated as high-grade if the high-grade component accounts for ≥5 % of the tumor. However, the cl...
Grade heterogeneity is common in papillary urothelial carcinoma (PUC) of the urinary bladder. Mixed-grade PUC is generally treated as high-grade if the high-grade component accounts for ≥5 % of the tumor. However, the clinical behavior of predominantly low-grade PUC with a minor high-grade (<5 %) component remains uncertain. We retrospectively searched our pathology files and identified 52 cases of non-invasive mixed-grade PUC (predominantly low-grade PUC with a minor high-grade (<5 %) component). These patients' clinical outcomes were compared with those of 2 other cohorts, 52 cases of pure low-grade PUC and 50 high-grade PUC. During follow-up, 27 patients with mixed-grade PUC developed cancer recurrence in an average of 25 months, and 12 patients experienced progression to high-grade PUC, including invasive UC in 3 patients, in an average of 17 months. For comparison, 35 patients with low-grade PUC experienced cancer recurrence in an average of 17 months, but only 1 (2 %) experienced progression to high-grade non-invasive PUC; 34 patients with high-grade PUC experienced recurrence in an average of 13 months, and 10 (20 %) experienced progression to invasive UC. There was no significant difference in cancer recurrence in the 3 cohorts; cancer grade and stage progression rates in patients with mixed-grade PUC were significantly higher than those in those with low-grade PUC, but stage progression rate in patients with mixed-grade PUC was significantly lower than that in high-grade PUC. In conclusion, patients with mixed-grade PUC had a significantly worse clinical outcome than those with pure low-grade PUC but a significantly better outcome than those with high-grade PUC. Our results suggest that mixed-grade PUC should be treated as a distinct category from low-grade PUC.
Association between p16 expression and a treatment response to CDK4/6 inhibitor in advanced breast carcinoma.
Huang X, Harada S, Wei S … +5 more , Siegal GP, Anderson SA, Sahin AA, Khoury K, Yalniz C
Hum Pathol · 2025 Sep · PMID 40780613 · Publisher ↗
INTRODUCTION: Endocrine therapy combined with cyclin-dependent kinase 4 and 6 inhibitors (1) has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast...
INTRODUCTION: Endocrine therapy combined with cyclin-dependent kinase 4 and 6 inhibitors (1) has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinomas. It has been known that the p16-CDK4/6-cyclin D1 axis regulates the S phase of the cell cycle. We investigated the association between p16 expression and the therapeutic response with CDK4/6i in advanced breast carcinoma. METHODS: Patients diagnosed with invasive breast carcinoma between 2019 and 2024 whose tumors underwent next-generation sequencing (NGS) based analysis were identified. The expression of p16 was assessed in tumor cells and stromal cells within the invasive carcinoma by immunohistochemistry. In tumor cells, p16 expression was subclassified as cytoplasmic (TC), nuclear (TN), or cytoplasmic and nuclear staining (TCN). In stromal cells, p16 expression was assessed in tumor-associated fibroblasts (TAF) and tumor-infiltrating immune cells (TILs) in any cellular compartment. RESULTS: Among the 35 cases, p16-TC, -TN, and -TCN were significantly associated with disease progression during CDK4/6i therapy. The positive association between p16-TC and progressive disease remained in the 24 CDK4/6i-treatment naïve tumors. In contrast, the tumors with p16 expression in TAF showed a numerically higher response rate than the p16-TAF-negative ones. We also observed a significant association between p16-TC expression and lymph node metastasis. CONCLUSION: Our study demonstrated a significant association between p16 expression in tumor cells and an unfavorable therapeutic response to CDK4/6i in advanced breast carcinoma. The clinical significance of p16 expression patterns as a predictive biomarker for CDK4/6i deserves further investigation.
Emerging molecular Therapeutic targets in breast Cancer: Pathologic identification and clinical implications.
Sahin AA, Chen H, Xiao H … +2 more , Senthil D, Meric-Bernstam F
Hum Pathol · 2025 Aug · PMID 40759284 · Publisher ↗
Breast carcinoma represents a biologically heterogeneous group of malignancies with diverse clinical behaviors, highlighting the need for robust molecular markers to support accurate diagnosis, prognosis, and therapeutic...
Breast carcinoma represents a biologically heterogeneous group of malignancies with diverse clinical behaviors, highlighting the need for robust molecular markers to support accurate diagnosis, prognosis, and therapeutic decision-making. Histopathologic evaluation and assessment of established biomarkers, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, remain central to clinical management, yet these biomarkers do not fully capture the disease complexity. Advances in genomics have enabled identification of intrinsic breast cancer subtypes, improving risk stratification and personalization of therapy. New molecular technologies such as next-generation sequencing and liquid biopsy approaches have uncovered actionable genomic alterations and allow for real-time monitoring. Emerging biomarkers such as cyclin E overexpression, BRCA1/2 mutations, and mismatch repair deficiency provide additional prognostic and predictive value, especially in guiding targeted therapies. The tumor microenvironment, including immune cell infiltration and stromal composition, has also gained recognition for its role in modulating tumor progression and therapeutic response. Liquid biopsy tools, including analysis of circulating tumor DNA, circulating tumor cells, and exosomes, offer promising non-invasive methods for disease surveillance and early detection of resistance. High-throughput techniques such as spatial transcriptomics and multiplex immunofluorescence are accelerating biomarker discovery with potential clinical application. Despite these advances, challenges remain in standardization, reproducibility, and clinical validation. This review summarizes current and emerging breast cancer biomarkers, emphasizing their role in advancing precision oncology. Continued translational research and methodological refinement are essential for successful integration of new biomarkers into clinical practice and for improving patient outcomes.
Invasive urothelial carcinoma with chordoid and myxoid features shows increased RAS/RAF pathway alterations.
Chan E, Stohr BA, Sangoi AR … +1 more , Sirohi D
Hum Pathol · 2025 Sep · PMID 40752735 · Publisher ↗
Invasive urothelial carcinoma (UCa) with chordoid and myxoid features is an uncommon but previously described subtype of UCa composed of distinctive elongated nests and cords of tumor cells floating within a prominent my...
Invasive urothelial carcinoma (UCa) with chordoid and myxoid features is an uncommon but previously described subtype of UCa composed of distinctive elongated nests and cords of tumor cells floating within a prominent myxoid stroma. The molecular features of chordoid and myxoid UCa are not known. We identified 9 cases of UCa with chordoid and myxoid features and performed a comprehensive next generation sequencing assay, targeting the chordoid and myxoid component. The cases included 7 TURBT and 2 nephroureterectomies in which the chordoid/myxoid component ranged from 10 to 80 % (mean 47 %). Available immunohistochemistry in the chordoid and myxoid component showed p63+ (9/9) and GATA3+ (8/9), supporting UCa. All cases were largely negative for SOX10 and CDX2 (one case showed weak CDX2 staining). On molecular analysis, chordoid and myxoid UCa showed a molecular profile typical of conventional UCa, with recurrent alterations in TERTp (7/9), chromatin remodeling genes (8/9) and cell cycle pathway genes (8/9). A high rate of DNA damage repair gene alterations was also seen (6/9). Interestingly, 5/9 cases demonstrated recurring alterations in RAS/RAF pathway genes, a finding typically more frequently seen in primary adenocarcinomas of the urinary bladder and less common in conventional UCa, and also suggesting possible alternative therapies for these patients. In conclusion, chordoid and myxoid UCa shows a genomic profile with both urothelial and adenocarcinoma features. Furthermore, the molecular profile reveals potentially actionable therapeutic targets in the RAS/RAF and DNA damage repair pathways and high tumor mutational burden.
Identification of constitutional MLH1 methylation in MLH1-deficient colorectal cancer.
Wang J, Zhang Z, Liu H … +6 more , Wang J, Cai Y, Zhang Y, Chen L, Wu H, Liang Z
Hum Pathol · 2025 Sep · PMID 40721001 · Publisher ↗
BACKGROUND: Constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for Lynch syndrome (LS), is usually overlooked due to current screening strategies that rely on tumor MLH1 methylation as an indica...
BACKGROUND: Constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for Lynch syndrome (LS), is usually overlooked due to current screening strategies that rely on tumor MLH1 methylation as an indication of sporadic mismatch repair-deficient (dMMR) colorectal cancer (CRC). We aimed to assess the frequency and clinicopathological characteristics of constitutional MLH1 methylation among dMMR CRC cases with tumor MLH1 methylation. METHODS: We conducted a retrospective study on two independent cohorts: a discovery cohort of 48 MLH1-deficient CRC cases (2017-2021) and a validation cohort of 159 consecutive CRC cases (2022-2024). Real-time methylation-specific PCR (qMSP) screened for tumor MLH1 methylation, followed by constitutional MLH1 methylation testing on paired normal colorectal mucosa (NCM) DNA, confirmed by CpG pyrosequencing. RESULTS: In the discovery cohort, constitutional MLH1 methylation was identified in 4 of 31 individuals (12.9 %) with tumor MLH1 methylation, including 2 with high-level and 2 with low-level mosaic methylation. These patients were generally younger (median age: 56 years) , and three of the four tested negative for the BRAF V600E mutation. When applying an age threshold of ≤55 years, the highest positivity rate for constitutional MLH1 methylation was achieved at 2 of 4 (50.0 %), and notably, both exhibited relatively high-level epimutations. A refined screening strategy specially targeting high-level constitutional MLH1 methylation was developed. In the validation cohort, 35 MLH1-deficient, BRAF V600E-negative cases were tested, including 18 individuals aged ≤55 years and 17 randomly selected controls aged >55 years. Constitutional MLH1 methylation was successfully identified in one patient from the younger group, while none was detected among the older controls. All five cases lacked a significant family history, and one patient developed three LS-associated cancers. In addition, heterogeneous MMR protein expression patterns, and early partial MLH1/PMS2 loss in precancerous lesions were observed. CONCLUSIONS: Our findings highlight a subset of younger patients with constitutional MLH1 methylation among MLH1-deficient, MLH1-methylated CRC cases. Patients aged ≤55 years, whose tumors exhibit MLH1 methylation or lack the BRAF V600E mutation, are recommended to undergo additional testing for constitutional MLH1 methylation to improve LS-related clinical management.
Impact of hormone sensitivity status on aberrant expression of CK7, CK20, CDX2, GATA3 and TTF1 in prostate cancer.
Wang QY, Benzerdjeb N, Jaquet S … +5 more , Stepanov A, Diop MK, Birlea M, Saad F, Trudel D
Hum Pathol · 2025 Sep · PMID 40714131 · Publisher ↗
Prostate cancer (PC) rarely expresses aberrant immunohistochemical markers such as CK7, CK20, CDX2, GATA3 and TTF1. This study evaluates whether expression of CK7, CK20, CDX2, GATA3 and TTF1 is increased in hormone-resis...
Prostate cancer (PC) rarely expresses aberrant immunohistochemical markers such as CK7, CK20, CDX2, GATA3 and TTF1. This study evaluates whether expression of CK7, CK20, CDX2, GATA3 and TTF1 is increased in hormone-resistant (HR) PC compared to hormone-sensitive (HS) disease. 64 patients undergoing transurethral resection of the prostate (TURP) for PC were included: 34 with HS disease, 22 with HR disease, and 8 whose status changed from HS to HR on a subsequent TURP (HS-HR). Overall, CK20 was the most frequently expressed aberrant marker (33.3 % of HS, 60.0 % of HR), followed by CK7 (16.7 % of HS, 13.3 % of HR) and CDX2 (11.9 % of HS, 16.7 % of HR). Compared to HS cases, HR tumors significantly overexpressed CK20 (p = 0.02). Positivity for aberrant markers was usually sparse and heterogeneous within ≤20 % of tumor cells. HR PC was significantly more likely to express aberrant markers among >20 % neoplastic cells than HS tumors (2.4 % and 20.0 % respectively, p = 0.008). The expression of an aberrant marker at >20 % positivity was also associated with loss of expression of ≥1 marker of prostatic origin (PSA, PSMA, P501S or NKX3), p = 0.01. For 21 patients with ≥2 TURPs separated in time, ≥1 aberrant marker was gained over time in 1/7 HS, 2/6 HR and 3/8 HS-HR patients. These results suggest that HR PC has increased likelihood of CK20 positivity and aberrant marker positivity in >20 % of tumor cells compared to HS cases, and that the aberrant immunohistochemical expression in a given PC patient may increase over time.
Biliary pseudo tumor associated with hepatic atrophy.
Joldoshova A, Khandakar B, Lee H … +2 more , Lam R, Jain D
Hum Pathol · 2025 Sep · PMID 40714130 · Publisher ↗
BACKGROUND: Extensive ductular proliferation can mimic well-differentiated cholangiocarcinoma, but such pseudo-tumorous lesion has not been well described in the literature. Our study sought to evaluate the clinicopathol...
BACKGROUND: Extensive ductular proliferation can mimic well-differentiated cholangiocarcinoma, but such pseudo-tumorous lesion has not been well described in the literature. Our study sought to evaluate the clinicopathologic features of such cases. DESIGN: Four cases with reactive ductular proliferation that mimicked cholangiocarcinoma microscopically and also appeared grossly to form a mass/nodule were identified from 1995 to 2024 at two large academic health institutions. The clinicopathological features were studied in detail. RESULTS: The study cases included 2 explants, 1 segmental hepatectomy and 1 wedge resection. One of the explants had thrombosis and obstruction of the right portal vein (PV) along with right lobe atrophy. Vascular abnormality was suspected in case 2 but could not be confirmed. However, atrophy of the left lobe along with caudate lobe hypertrophy and preserved right lobe was observed. Both cases had cirrhosis (case 1: HCV infection, case 2: alcoholic liver disease) with portal hypertension. Case 3 and 4 were from patients with metastatic colon cancer who had undergone trans-arterial chemoembolization (TACE). Upon gross examination of the two explants, the atrophic lobes were markedly pale-tan, shrunken, and well-demarcated from the uninvolved lobe mimicking a tumor, while the unaffected lobes were cirrhotic. Histologically the lesions in all cases comprised of marked ductular proliferation that led to an initial consideration of a well-differentiated intrahepatic cholangiocarcinoma. However, these lacked significant cytologic atypia and mitotic activity (ki-67 < 5 %) and had a non-infiltrative growth pattern. In case 3, the ductular proliferation was at the periphery of metastatic focus, while scattered metastatic tumoral glands were encased within proliferating ductules in case 4. The immunostains showed wild-type staining pattern with p53 and retained nuclear expression with p16 and BAP1. CONCLUSION: Biliary pseudo-tumors can be seen with lobar or segmental atrophy, likely secondary to ischemic parenchymal injury and can mimic a well-differentiated cholangiocarcinoma grossly as well as microsopically. Awareness of this phenomenon and careful attention to the clinical presentation, radiographic imaging and histology shows subtle differences that can facilitate an accurate diagnosis.
Incidence of MSI-H esophageal carcinoma and related identification of genomic alterations: A multi-center real-world study.
Jin J, Sun M, Yang X … +8 more , Ding Z, Zhou F, Hu Y, Yu J, Sun Q, Chen Y, Xue L, Cui X
Hum Pathol · 2025 Sep · PMID 40714129 · Publisher ↗
Microsatellite instability-high (MSI-H) is a favorable prognostic factor for neoadjuvant chemotherapy in several solid tumors, and large datasets are needed to provide robust evidence of its prognostic value in esophagea...
Microsatellite instability-high (MSI-H) is a favorable prognostic factor for neoadjuvant chemotherapy in several solid tumors, and large datasets are needed to provide robust evidence of its prognostic value in esophageal carcinoma (EC). We aimed to determine the incidence of MSI-H tumors in patients with EC and identify genomic alterations in MSI-H tumors. Data were obtained from three centers in China: Nanjing Drum Tower Hospital, Beijing Cancer Hospital, and the Cancer Hospital Chinese Academy of Medical Sciences. From June 2023 to December 2024, 1485 patients with EC were enrolled in this study. We investigated the incidence of MSI-H tumors and performed whole-exome sequencing of MSI-H tumor tissues. There were three patients with MSI-H from three centers (3/614, 0.49%) in Nanjing Drum Tower Hospital, five (5/644, 0.78%) in Beijing Cancer Hospital, and four (4/227, 1.76%) in the Cancer Hospital Chinese Academy of Medical Sciences. Among the 12 MSI-H tumor tissues, 6 were esophageal squamous cell carcinoma (ESCC) and 6 were esophageal adenocarcinoma (EAC). All MSI-H tumor tissues showed loss of PMS2 expression (100%), with concurrent loss of MLH1 in 9 (75%). Among the MSI-H tumors subjected to Whole Exome Sequencing (WES), all demonstrated high tumor mutation burden (TMB: 19.12-32.68 mutations/Mb) and harbored multiple somatic mutations. The consistency of MSI-H and high TMB scores showed that MSI-H could be an indicator of receiving immunotherapy in EC patients.
Comparative analysis of the tumor microenvironment in primary CNS and testicular large B-cell lymphomas using digital image analysis and its implications for immunotherapy.
Kim B, Chae SW, Kim HJ … +4 more , Roh J, Lee YJ, Jo JC, Cha HJ
Hum Pathol · 2025 Sep · PMID 40714128 · Publisher ↗
Primary large B-cell lymphomas of immune-privileged sites, including primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL), exhibit distinct clinicopathologic features contributing to aggr...
Primary large B-cell lymphomas of immune-privileged sites, including primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL), exhibit distinct clinicopathologic features contributing to aggressive behavior and immune evasion. While the molecular characteristics of PCNSL and PTL have been extensively studied, the tumor microenvironment (TME) remains insufficiently understood. In particular, no study has directly compared the TME of PCNSL and PTL, highlighting a critical gap in understanding their immunobiology. We analyzed 55 cases of diffuse large B-cell lymphoma involving the central nervous system (CNS) and testis using deep learning-based digital image analysis. Immunohistochemical staining was performed for key immune markers, including CD3, CD4, CD8, FOXP3, PD-1, TIM-3, CD68, and CD163, to characterize TME composition. PTL exhibited significantly higher levels of tumor-infiltrating lymphocytes, including CD3 and CD8 T-cells, compared to PCNSL (P < 0.001). The T-cell exhaustion index was significantly lower in PTL (P < 0.001), while CD163 macrophages were more predominant in PCNSL, suggesting a more immunosuppressive TME in the CNS. Correlation analyses of TME factors revealed differences between the CNS and testis, with stronger interrelationships among immune markers in PCNSL. Our findings highlight distinct TME characteristics between PCNSL and PTL. The predominance of CD163 macrophages and higher T-cell exhaustion in PCNSL suggests potential benefits of macrophage-targeted therapies. In contrast, PTL, with a more active TME, may be more responsive to immune checkpoint blockade. This study provides novel insights into the immune landscape of primary large B-cell lymphomas of immune-privileged sites, emphasizing the need for site-specific treatment approaches.
The occurrence and histopathological recognition of atypical endometriosis in patients with ovarian endometriosis - a retrospective cohort study.
Leenen S, Kooreman L, Bulten J … +5 more , Esch EMGV, de Vos van Steenwijk PJ, Nieboer TE, Bekkers RLM, van Altena AM
Hum Pathol · 2025 Sep · PMID 40706757 · Publisher ↗
OBJECTIVE: - Atypical endometriosis (AE) is considered a potential precursor of endometriosis-associated ovarian carcinoma (EAOC). Despite this, AE identification currently lacks established clinical implications and is...
OBJECTIVE: - Atypical endometriosis (AE) is considered a potential precursor of endometriosis-associated ovarian carcinoma (EAOC). Despite this, AE identification currently lacks established clinical implications and is not routinely incorporated in histopathological examinations of endometriosis. This study aimed to determine the interobserver variability in AE diagnosis and to classify the features that may attribute to consistent AE identification and diagnosis. METHODS: - Cases of ovarian endometriosis, collected between 1985 and 2017 at the Radboud University Medical Centre Nijmegen, were identified using the PALGA database. Pathology reports were reviewed for descriptions of atypical features and mentions of AE. Using a predefined set of criteria adapted from the literature, two independent pathologists re-evaluated the 266 most recent ovarian endometriomas for AE. After revision, the pathologist revised cases with AE to reach consensus when discrepancies occurred. RESULTS: - Among 266 cases of ovarian endometriosis, AE was reported in 31 (11.7 %) cases. The revising pathologists identified AE in 48 cases (18 %), a number that was reduced to 19 cases (7.1 %) after a consensus meeting between the pathologist. After consensus was reached, the diagnostic criteria, adapted from the literature, were adjusted. DISCUSSION/FUTURE DIRECTIONS: - High interobserver variability likely reflects AE's heterogeneous presentation, the uncertain role of inflammation-driven atypia and AE's undefined clinical significance. However, given AE's association with malignant transformation, consistent identification may be essential. Stricter criteria were developed for AE in order to encourage uniform identification. Furthermore, we encourage adequate documentation of AE in order to increase the insight in endometriosis behavior by linking endometriosis subtypes to clinical progression.
Subclassification of unilateral primary aldosteronism using an optimal cut-off value for positive CYP11B2 (aldosterone synthase) immunohistochemistry and modified histologic criteria in the Korean population.
Hong WG, Kim BC, Sung TY … +2 more , Lee SH, Song DE
Hum Pathol · 2025 Sep · PMID 40691953 · Publisher ↗
The histopathology of primary aldosteronism (HISTALDO) consensus indicates the necessity of CYP11B2 (aldosterone synthase) immunostaining in diagnosing primary aldosteronism (PA). However, proper threshold for positive i...
The histopathology of primary aldosteronism (HISTALDO) consensus indicates the necessity of CYP11B2 (aldosterone synthase) immunostaining in diagnosing primary aldosteronism (PA). However, proper threshold for positive interpretation of CYP11B2 immunostaining is yet to be established. Therefore, we aimed to correlate the subclassification of PA and postsurgical outcomes to define an optimal cut-off value for CYP11B2 immunostaining in 83 unilateral PA patients. Initial 73 classical PA patients using a 1 % cut-off value revealed a similar rate of absence of clinical success between classical PA (9.7 %) and non-classical PA (11.1 %, p > 0.999). The absence of biochemical success was lower in classical PA (4.4 %) than non-classical PA (20.0 %, p = 0.120). After establishing new 30 % cut-off value for CYP11B2 immunostaining, 68 of 83 (81.9 %) patients were re-classified as classical PA. Despite statistical insignificance, the absence of both clinical and biochemical success was lower in classical PA (8.8 % and 4.7 %, respectively) than non-classical PA (14.3 %, p = 0.158; 14.3 %, p = 0.218, respectively). Finally, a modified histologic subclassification was applied according to the presence of single aldosterone producing lesion using both 1 % and 30 % cut-off values. 69 (1 % cut-off) and 64 (30 % cut-off) cases were subclassified as modified classical PA. However, they were not superior to their non-classical counterparts in terms of both clinical and biochemical success using both cut-off values. In summary, the clinical and biochemical outcomes were not successfully predicted by either 1 % or 30 % cut-off values and modified histologic criteria. Further validation study on a larger patient cohort is needed.
IgG4-related disease of the tubular gastrointestinal tract: A rare cause of lymphoplasmacytosis, eosinophilia, and mass-forming lesions.
Chen T, Larman TC, Voltaggio L … +1 more , Birkness-Gartman JE
Hum Pathol · 2025 Sep · PMID 40684921 · Publisher ↗
IgG4-related disease (IgG4RD) is a systemic fibroinflammatory condition that can affect multiple organs, but rarely involves the tubular gastrointestinal (GI) tract. We identified patients with definitive or possible IgG...
IgG4-related disease (IgG4RD) is a systemic fibroinflammatory condition that can affect multiple organs, but rarely involves the tubular gastrointestinal (GI) tract. We identified patients with definitive or possible IgG4RD of the GI tract diagnosed at our institution. Our cohort included 8 patients with a median age of 37 years (range 15-73) and a slight male predominance (63 %). Sites of disease included the esophagus (5 biopsies), terminal ileum (2 biopsies), and colon (1 biopsy with subsequent resection). Two patients presented with masses (1 colon, 1 terminal ileum) and 1 with an esophageal stricture. All cases featured a prominent plasma cell-rich infiltrate with scattered eosinophils and neutrophils; a subset had variably prominent histiocytes (3 cases) and lymphoid aggregates (4 cases). The colonic resection specimen demonstrated subserosal storiform fibrosis and obliterative phlebitis, features not detectable in the biopsies. All cases had >50 IgG4-positive cells per high-power field and an IgG4:IgG ratio >40 % when evaluable (5 cases). One of two patients with terminal ileal involvement had serum IgG4 >135 mg/dL, and both patients responded to steroid treatment. Three patients with esophageal involvement had serum IgG4 <135 mg/dL. We conclude that IgG4RD is a rare cause of mass-forming lesions in the terminal ileum and colon, and a possible cause of esophageal inflammation and strictures. Diagnosing IgG4RD on biopsies is challenging, as the full histologic spectrum of features is not detectable in mucosa. Lymphoplasmacytic and eosinophilic infiltration, elevated IgG4-positive cell counts by immunohistochemistry, and correlation with serum IgG4 levels and response to steroids may aid in diagnosis.
Biliary adenofibroma and cholangiocarcinoma: neighbors or relatives? A systematic and critical review.
Mattiolo P, Zen Y, Zhang X … +3 more , Scarpa A, Luchini C, Graham RP
Hum Pathol · 2025 Nov · PMID 40659165 · Publisher ↗
Biliary adenofibroma (BAF) is currently classified as a benign intrahepatic biliary tumor. However, a growing body of literature has documented BAFs with invasive components or associated cholangiocarcinoma. To better ch...
Biliary adenofibroma (BAF) is currently classified as a benign intrahepatic biliary tumor. However, a growing body of literature has documented BAFs with invasive components or associated cholangiocarcinoma. To better characterize this challenging entity, we performed a systematic review of BAF. PubMed, SCOPUS, and Embase were searched through April 2025 to identify all studies on BAFs. Clinicopathological, immunohistochemical (IHC), and molecular data have been extracted and analyzed. A total of 55 cases of BAF were identified in the literature. Macroscopically, BAFs usually showed mixed features, ranging from cysts intermingled with solid nodules to spongy, non-capsulated lesions. Histologically, the lining epithelium consisted of non-mucin-secreting biliary cells (55/55, 100 %). BAFs with invasive components accounted for 52.7 % of the literature (29/55). In two cases, innocent-looking tubulocystic structures were present but showed frankly invasive components. Although most patients were alive and disease-free after resection (35/43, 81.4 %), two patients died of disease (2/43, 4.6 %) and six experienced relapses (6/43, 14 %). In 7 studies with a total of 13 cases, molecular investigations demonstrated gene alterations typically seen in small-duct cholangiocarcinoma, including mutations in ARID1A (2/13), BAP1, PBRM1, and TP53 (one per case), and FGFR2 fusion (1/13). Taken together, our findings reveal that BAF is frequently associated with invasive malignancy. The frequent presence of tubulocystic structures with invasive features warrants further investigation of this entity, particularly given the challenging spectrum of the lesions in the differential diagnoses, ranging from benign to malignant neoplasms.
Triple-negative lobular breast cancer: focus on pathology and clinical challenges.
Borella F, Gallio N, Giurdanella M … +3 more , Capella G, Cassoni P, Castellano I
Hum Pathol · 2025 Aug · PMID 40639624 · Publisher ↗
Triple-negative invasive lobular carcinoma is a rare and under-characterized subtype of breast cancer, distinct from the more common triple-negative invasive ductal carcinoma. While triple-negative invasive ductal carcin...
Triple-negative invasive lobular carcinoma is a rare and under-characterized subtype of breast cancer, distinct from the more common triple-negative invasive ductal carcinoma. While triple-negative invasive ductal carcinoma is generally recognized for its aggressive clinical behavior and lack of targeted treatment options, triple-negative invasive lobular carcinoma presents unique histopathological and molecular features that may influence its prognosis and therapeutic responsiveness. Despite these differences, triple-negative invasive lobular carcinoma remains poorly studied, leading to a reliance on treatment strategies adapted from ductal histotype, which may not fully address its biological complexities. This review aims to provide a comprehensive overview of triple-negative invasive lobular carcinoma by analyzing its clinicopathological characteristics, prognostic factors, and emerging therapeutic approaches. We explore the genetic alterations commonly observed in triple-negative invasive lobular carcinoma, their potential implications for treatment selection, and the challenges in current management strategies. Furthermore, we discuss the need for specialized research efforts and clinical trials to define treatment paradigms better. As precision oncology continues to evolve, understanding the biological distinctions of triple-negative invasive lobular carcinoma will be essential for optimizing patient outcomes and developing more effective treatment strategies.
BSND: An emerging immunohistochemical marker that reliably distinguishes benign from malignant oncocytic salivary gland tumors.
Tandon A, Sinehaa S, Saifi S … +3 more , Adhya AK, Kaur K, Kakkar A
Hum Pathol · 2025 Jul · PMID 40618964 · Publisher ↗
Oncocytic cells appear in various salivary gland lesions (SGLs) like oncocytic hyperplasia, metaplasia and several neoplasms. It is particularly challenging to distinguish oncocytoma and Warthin tumor from oncocytic and...
Oncocytic cells appear in various salivary gland lesions (SGLs) like oncocytic hyperplasia, metaplasia and several neoplasms. It is particularly challenging to distinguish oncocytoma and Warthin tumor from oncocytic and Warthin-like mucoepidermoid carcinoma (MEC) in the absence of molecular testing. A spectrum of oncocytic SGLs underwent immunohistochemistry for BSND, a novel marker of striated ducts and oncocytic tumor cells. MAML2 fluorescence in situ hybridization (FISH) was performed in suspected MECs. BSND immunoexpression was assessed in 138 SGLs, including 132 in-house and 4 consult cases. In-house cases comprised 5 non-neoplastic, 43 benign and 84 malignant SGLs. All nodular oncocytic hyperplasia (100 %) were BSND positive, while intercalated duct hyperplasia was negative. Among benign tumors, oncocytic cystadenomas (3/3), Warthin tumor (15/15), and oncocytoma (1/1) were BSND-positive (100 %). One clear cell oncocytoma reclassified as clear cell MEC on resection was BSND-negative. All remaining benign tumors were negative. Among all malignant tumors, one Warthin-like MEC was reclassified as infarcted metaplastic Warthin tumor on morphology and as it lacked MAML2 rearrangement; it was BSND positive. All remaining 83 malignant neoplasms were BSND-negative (100 %). All consult cases submitted as oncocytoma and oncocytic carcinoma were reclassified on ancillary testing, with BSND reliably distinguishing benign from malignant SGLs. In 21 cases with MAML2 FISH, MAML2 rearrangement was mutually exclusive with BSND immunopositivity. BSND is thus newly validated as an immunomarker to resolve diagnostic uncertainty in oncocytic SGLs. Use of BSND in routine practice could streamline the diagnostic process and improve patient management by reducing reliance on ambiguous morphological features, particularly in settings lacking molecular testing.
Secondary pancreatic tumors in endoscopic ultrasound-guided fine-needle biopsy: Clinicopathologic characteristics and morphological diagnostic challenges.
Cui M, Amed M, Reid MD … +1 more , Xue Y
Hum Pathol · 2025 Jul · PMID 40617520 · Publisher ↗
Pancreatic metastases are rare and often difficult to diagnose, especially in limited tissue samples. However, accurate diagnosis is crucial for guiding appropriate clinical management. This study evaluates the clinical,...
Pancreatic metastases are rare and often difficult to diagnose, especially in limited tissue samples. However, accurate diagnosis is crucial for guiding appropriate clinical management. This study evaluates the clinical, radiologic, and pathologic features of pancreatic metastases, with a focus on morphological patterns that mimic common primary pancreatic tumors in endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) specimens. Among 1054 pancreatic neoplasms diagnosed over a nine-year period, 62 cases (5.9 %) were identified as metastases. The interval from initial diagnosis to pancreatic involvement ranged from synchronous presentation to 24 years. Most metastatic lesions (74 %, n = 46/62) presented as solitary masses, and 58 % (n = 26/45) were initially misinterpreted as primary pancreatic tumors on imaging. Histologically, 73 % (n = 45/62) were epithelial neoplasms, most commonly of renal origin (11 cases, 17.8 %), followed by lung (9, 14.5 %), cutaneous (6, 9.7 %), and Müllerian-derived tumors (6, 9.7 %). Among non-epithelial neoplasms, hematopoietic malignancies were most common (9, 14.5 %), followed by mesenchymal tumors (5, 8.1 %) and melanoma (3, 4.8 %). Several metastatic tumor types-including renal cell carcinoma, lung adenocarcinoma, breast carcinoma, gastrointestinal adenocarcinoma, Merkel cell carcinoma, and adult granulosa cell tumor-closely mimicked the histology of primary pancreatic neoplasms such as pancreatic ductal adenocarcinoma, neuroendocrine neoplasm, and solid-pseudopapillary neoplasms. Accurate diagnosis requires correlation with clinical history and a comprehensive ancillary workup, including immunohistochemistry. In summary, pancreatic metastases present a significant diagnostic challenge due to their overlap with primary tumors across clinical, radiologic, and histologic dimensions. A multidisciplinary diagnostic approach is essential to ensure accurate classification and optimal patient care.
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