Human Pathology[JOURNAL]
Sun
200 papers
Mullerian adenosarcoma of the uterus, ovary and peritoneum: Whole transcriptomic digital spatial profiling (DSP) in a cohort of 42 tumors.
D'Angelo E, Kingsley LG, Espinosa I … +6 more , Cipriani V, Marotta A, Nasr S, Zdravkovic S, Howitt BE, Prat J
Hum Pathol · 2026 Jul · PMID 41932512 · Publisher ↗
Mullerian adenosarcoma (MA) is a rare biphasic tumor with a malignant stromal component and benign glandular epithelium with periglandular stromal condensation occurring mainly in the uterus. The diagnosis is essentially...
Mullerian adenosarcoma (MA) is a rare biphasic tumor with a malignant stromal component and benign glandular epithelium with periglandular stromal condensation occurring mainly in the uterus. The diagnosis is essentially morphologic and may be difficult particularly in distinguishing MA from other biphasic tumors at the lower end of the spectrum with histologic features similar to, but falling short-off adenosarcoma; i.e., uterine atypical polyp/low-grade or well-differentiated adenosarcoma with low mitotic count and lacking significant nuclear atypia. We investigated the transcriptomic profiles of 42 biphasic mesenchymal tumors, diagnosed as MAs, by whole transcriptomic Digital Spatial Profiling (DSP) and morphology marker antibody staining with PanCK, CD45 and SYTO 13 using the GeoMx platform on tissue microarrays (TMAs). Regions of interest (ROI) were segmented using morphology marker staining for tumor stromal component/periglandular cuffing and immune infiltrated areas of illumination (AOIs). The median age at diagnosis was 46.5 (39.0-64.8) years. Sarcomatous overgrowth was present in 9 (21.4%), myometrial invasion in 11 (26.2%), heterologous elements in 5 (11.9%), and sex-cord differentiation in 8 (19.0%). At follow-up, metastases occurred in 8 (19.0%) patients; 7 (16.6%) died of disease and 5 (11.9%) were alive with disease. DSP revealed two groups of tumors with significant differences in gene expression profiles; namely, conventional MAs and biphasic tumors exhibiting similar morphologic features but insufficient for the diagnosis. In addition, we explored in-depth the molecular profiles of MAs with and without sarcomatous overgrowth as well as MAs with and without myometrial invasion, and also found differentially expressed genes and gene-pathways. Our results revealed that MAs have distinct transcriptomic signatures and confirm the existence of a spectrum of mesenchymal biphasic mullerian tumors. Given the lack of consistent mutations in MAs, transcriptomic-based biomarkers may aid in their classification and should be further investigated.
The evolving landscape of pathologic interpretation in metabolic dysfunction-associated steatotic liver disease.
Allende DS
Hum Pathol · 2026 Apr · PMID 41932511 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. This article discussed updates in diagnosis and emerging issues. Key histologic findings include ste...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. This article discussed updates in diagnosis and emerging issues. Key histologic findings include steatosis, lobular inflammation, and hepatocyte ballooning. Updated histologic guidance, with more detailed definitions, has recently been published for features in the histologic spectrum. Studies in portal changes seen in MASLD have shown the importance of this finding in relation to fibrosis and outcome. Among the emerging issues, the importance of incidental findings and regression of fibrosis features is described. Digital pathology/machine learning algorithms, stain-free technologies, and molecular testing are being integrated into the diagnosis of MASLD, still mostly in the research setting but rapidly capturing the attention of the clinical community with the intent of aiding pathologists.
Concurrent presentation of appendiceal sessile serrated lesions with other appendiceal neoplasms.
Zhao M, Lowy AM, Baumgartner JM … +2 more , Veerapong J, Hosseini M
Hum Pathol · 2026 Jul · PMID 41932510 · Publisher ↗
BACKGROUND: Sessile serrated lesions (SSL) of the appendix are rare appendiceal neoplasms, often identified incidentally on appendix resection and only rarely discovered prior to surgery. This study aims to better charac...
BACKGROUND: Sessile serrated lesions (SSL) of the appendix are rare appendiceal neoplasms, often identified incidentally on appendix resection and only rarely discovered prior to surgery. This study aims to better characterize appendiceal SSL and their relation to other appendiceal neoplasms. METHODS: The anatomic pathology database was reviewed for all cases in which the appendix was resected from 2015 to 2023. Cases with a diagnosis of appendiceal sessile serrated lesion were included in the study. Indications for resection and available molecular testing were identified through the electronic medical record. RESULTS: A total of 103 cases of appendiceal SSL were identified. The majority of resections were performed for non-neoplastic indications, either for acute appendicitis or incidentally during a different surgical procedure. SSL was most commonly seen concurrently with low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm, and primary appendiceal adenocarcinoma, co-presenting in 15, 4, and 12 cases respectively. Molecular data was available for a small subset of cases co-presenting with cancer, with KRAS and GNAS being the most commonly mutated genes. CONCLUSIONS: We demonstrate that appendiceal SSL can be seen in conjunction with other appendiceal neoplasms, predominantly appendiceal mucinous neoplasms and primary appendiceal adenocarcinoma. Appendiceal mucinous neoplasia or adenocarcinoma typically presents at a high clinical stage when present concurrently with SSL. Similar to other studies, appendiceal SSL are most commonly an incidental diagnosis, typically in the context of appendectomy for acute appendicitis.
Spatially-resolved CD8 and CD34 computational immunohistochemistry indicators improve post-nephrectomy risk stratification in clear cell renal cell carcinoma.
Fabijonavicius M, Garnelyte A, Zilenaite-Petrulaitiene D … +5 more , Rasmusson A, Drachneris J, Cekauskas A, Jankevicius F, Laurinavicius A
Hum Pathol · 2026 Jul · PMID 41932509 · Publisher ↗
OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that may progress after nephrectomy as local or distant disease. The ccRCC tumor microenvironment (TME) hinges on two complementary pillars of...
OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that may progress after nephrectomy as local or distant disease. The ccRCC tumor microenvironment (TME) hinges on two complementary pillars of immune response and angiogenesis. We aimed to assess if spatial CD8 and CD34 profiles at the tumor-stroma interface predict progression-free survival (PFS). METHODS: We retrospectively analyzed 214 ccRCC patients treated at Vilnius University Hospital Santaros Klinikos (2009 - 2019). Immunohistochemistry for CD8 and CD34 was performed on surgical tumor excision samples, and digital image analysis was performed to quantify cell densities and vessel areas relative to their spatial patterns within the tumor-stroma interface. The impact on PFS of CD8 immunogradient and CD34 area fraction was tested. RESULTS: Two prognostic models were developed: a Baseline model using variables available after surgery and a Disease-Course model additionally incorporating follow-up information. In the Baseline model, higher CD8_m_CM independently predicted shorter PFS (HR 3.24, p = 0.001), together with tumor size >4.95 cm and coagulative tumor necrosis, while female sex predicted longer PFS. In the Disease-Course model, local recurrence was the strongest adverse predictor (HR 17.69, p < 0.001), while both spatial biomarkers remained independently associated with PFS: higher CD8_m_CM predicted shorter PFS (HR 5.14, p = 0.001), whereas higher VAF_m_CM predicted longer PFS (HR 0.32, p = 0.014). CONCLUSIONS: Spatial patterns of immune and vascular components at the tumor-stroma interface independently predict PFS in patients with ccRCC following nephrectomy and may improve current risk stratification schemes in both the immediate postoperative setting and during follow-up.
ALK protein expression and gene copy number alterations in triple-negative breast cancer: Clinical implications.
Qiu Y, Wang J, Jiao W … +3 more , Wei R, Li J, Zhang W
Hum Pathol · 2026 Jul · PMID 41932508 · Publisher ↗
Anaplastic lymphoma kinase (ALK) is a well-established oncogenic driver in non-small cell lung cancer (NSCLC), but its role in triple-negative breast cancer (TNBC) remains largely unexplored. In this study, we examined t...
Anaplastic lymphoma kinase (ALK) is a well-established oncogenic driver in non-small cell lung cancer (NSCLC), but its role in triple-negative breast cancer (TNBC) remains largely unexplored. In this study, we examined the expression and gene status of ALK in 208 TNBC cases using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). ALK protein positivity was identified in 19.2% of cases, significantly correlating with histological subtype, p53 mutation status, and Ki67 index. Among the 156 basal-like breast carcinoma (BLBC) cases, ALK presented three distinct localization patterns: diffuse cytoplasmic granular, cytoplasmic/membranous, and cytoplasmic/nuclear. ALK gene copy number abnormalities were detected in 16.8% of cases, with a higher prevalence in p53-mutant and high Ki67 expression tumors. Notably, ALK protein positivity and gene copy number gain were associated with poorer survival outcomes, including 5-year overall survival (OS) and 10-year recurrence-free survival (RFS). Our findings highlight the importance of ALK as a potential therapeutic target in TNBC, emphasizing the need for further investigation into its clinical significance.
DICER1-mutated renal neoplasia: A series of 5 cases demonstrating the spectrum of cystic nephroma, Wilms tumor, and anaplastic sarcoma.
Arizpe D, Schoettler PJ, Allen-Rhoades WA … +10 more , Attia S, Wu KJ, Swanson AA, Dasari S, Tekin B, Jimenez RE, Erickson LA, Cheville JC, Smith SC, Gupta S
Hum Pathol · 2026 Jun · PMID 41905669 · Publisher ↗
OBJECTIVES: The DICER1 gene encodes a ribonuclease essential for microRNA processing and regulates diverse cellular functions. Germline DICER1 alterations underlie DICER1-related tumor predisposition syndrome, which can...
OBJECTIVES: The DICER1 gene encodes a ribonuclease essential for microRNA processing and regulates diverse cellular functions. Germline DICER1 alterations underlie DICER1-related tumor predisposition syndrome, which can lead to renal neoplasia. Herein, we studied the spectrum of DICER1-altered renal neoplasia. METHODS: Our institutional archives were queried for DICER1-mutated renal neoplasia. Relevant clinicopathologic features and molecular profiling results were summarized. RESULTS: We report five renal tumors that reinforce the clinicopathologic spectrum of DICER1-associated renal neoplasia. These included the classic presentation of a 13-month-old male with sickle cell trait and a pediatric cystic nephroma eventually proven to harbor a germline DICER1 deleterious variant, while several other tumors demonstrated more complex genetic and phenotypic presentations. A 13-year-old female with xeroderma pigmentosum presented with a synchronous ovarian Sertoli-Leydig cell tumor and an anaplastic sarcoma of the kidney, each harboring distinct (somatic) DICER1 hotspot mutations, supporting the diagnosis of independent primary neoplasms. The third tumor was an aggressive blastemal-predominant Wilms tumor, with biallelic (somatic) DICER1 inactivation, in a 4-year-old male with congenital (contralateral) multicystic dysplastic kidney. The fourth and fifth cases involved a 24-year-old female and 11-year-old male with anaplastic sarcoma of the kidney, both presenting with venous extension and rupture, in which molecular profiling demonstrated biallelic pathogenic DICER1 alterations together with co-occurring TP53 alterations. CONCLUSIONS: These cases illustrate the pleiotropic role of DICER1 in renal tumorigenesis and the histologic heterogeneity of associated neoplasms. Our findings underscore the critical role of molecular diagnostics in pediatric renal tumors, with implications for management, surveillance, and genetic counseling.
Clinico-pathological diagnostic and prognostic biomarkers for duodenal adenocarcinoma from a UK retrospective cohort study.
Balarajah V, Fincham RE, Ullah D … +6 more , Clear A, Hughes CS, Chelala C, ChinAleong J, Kocher HM, UK Duodenal Cancer Study group
Hum Pathol · 2026 Jun · PMID 41895379 · Publisher ↗
Duodenal adenocarcinoma (DA), a very rare malignancy which is difficult to diagnose and has poor outcome. With increasing incidence of disease, identification of diagnostic and prognostic biomarkers is of paramount clini...
Duodenal adenocarcinoma (DA), a very rare malignancy which is difficult to diagnose and has poor outcome. With increasing incidence of disease, identification of diagnostic and prognostic biomarkers is of paramount clinic-pathological importance. Seven United Kingdom Duodenal Cancer Study Group (UKDCSG) centers contributed 98 quality assured DA cases undergoing surgical resection leading to creation of bespoke Tissue Micro-Array (TMA) which was interrogated with immunohistochemical and immunofluorescent stains for known diagnostic and prognostic markers following STROBE and REMARK guidelines on reporting. Variables with possible prognostic significance were assessed with Kaplan-Meier estimations (log-rank tests) and Cox proportional hazards univariate and multivariate models. The median estimated overall survival of 43 months (IQR: 38-84 months) after a median follow-up time of 37.5 (interquartile range: IQR 16-75) months. Lower tumor stage (T1-3 vs T4, hazard ratio (HR) 0.411 (95% confidence interval (CI) 0.208-0.812), absence of lymphovascular invasion (HR 0.457 (95%CI: 0.240-0.871), and lower CD20 (HR 0.450 (95%CI: 0.237-0.855)) immune infiltrate demonstrated better prognosis in multivariate analysis whilst Aurora-A, Beclin-1 expression and CD3 or CD4 or CD8 infiltration has no prognostic impact. Low CK20 expression may have pitfalls in diagnostic assessment. Our work presents the largest UK cohort of DA with long-term follow-up making it an excellent resource for future biomarker studies. Validation studies in prospective clinical studies are required for clinical application.
Risk of malignancy in PTEN-altered thyroid nodules detected on preoperative FNA molecular testing: a systematic review and meta-analysis.
Straccia P, Fiorentino V, Urtueta BP … +5 more , Zhang Q, Piermattei A, Cianfrini F, Mule A, Rossi ED
Hum Pathol · 2026 Mar · PMID 41865773 · Publisher ↗
AIMS: Phosphatase and tensin homolog (PTEN) alterations are increasingly encountered on molecular testing of thyroid fine-needle aspiration (FNA) specimens in Bethesda III/IV nodules. Unlike high-specificity alterations...
AIMS: Phosphatase and tensin homolog (PTEN) alterations are increasingly encountered on molecular testing of thyroid fine-needle aspiration (FNA) specimens in Bethesda III/IV nodules. Unlike high-specificity alterations (e.g., BRAF V600E), PTEN alterations can map to a broad morphologic spectrum and are influenced by the diagnostic pathway determining which nodules proceed to surgery. We performed a systematic review and meta-analysis to define risk of malignancy (ROM) for PTEN-altered thyroid nodules detected preoperatively. METHODS: Studies (2020-2025) reporting PTEN alterations detected preoperatively on FNA-based testing with surgical histopathology were reviewed. The primary meta-analysis included Bethesda III/IV-predominant cohorts with PTEN-altered nodules undergoing surgery. We pooled invasive malignancy ROM using random-effects meta-analysis and performed a sensitivity analysis counting noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) as an event. RESULTS: Three cohorts comprised 87 resected PTEN-altered nodules with 28 invasive malignancies. Pooled ROM for invasive malignancy was 32.4% (95% confidence interval (CI) 23.4-42.9; I = 0%). Malignant outcomes included follicular thyroid carcinoma, papillary thyroid carcinoma (including variants), and rare poorly differentiated or anaplastic thyroid carcinoma. Counting NIFTP as an event increased pooled ROM to 37.7% (95% CI 23.9-53.9). CONCLUSIONS: PTEN alterations detected preoperatively confer an intermediate ROM (∼32%) in surgically followed cohorts, but ROM is modulated by pathway-related selection for surgery and by how PTEN alteration is operationalized (sequence variant vs protein loss). A PTEN-altered preoperative result should be communicated as a moderate-risk molecular finding that frequently maps to follicular/oncocytic neoplasia yet includes differentiated carcinomas and rare high-grade disease, supporting integrated pathology-radiology-molecular decision-making.
Comprehensive study on clinic-histopathological correlation of Merkel-cell carcinoma: A retrospective, cohort, and single-institution study of 170 cases.
DaCosta A, Ozcan I, Torres-Mora J … +1 more , Guo RR
Hum Pathol · 2026 Mar · PMID 41850633 · Publisher ↗
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Absence of CD38 expression in mantle cell lymphoma correlates with distinct pathological and genetic features.
Abu Mehsen S, Monika F, Sharma S … +5 more , Idiaquez DW, Al-Othman Y, Tashkandi H, Zhang L, Yan M
Hum Pathol · 2026 Jun · PMID 41850632 · Publisher ↗
Although CD38 is commonly expressed in mantle cell lymphoma (MCL), a subset of cases lacks CD38 expression, and the biological significance of CD38 negativity remains incompletely understood. In this study, we analyzed 1...
Although CD38 is commonly expressed in mantle cell lymphoma (MCL), a subset of cases lacks CD38 expression, and the biological significance of CD38 negativity remains incompletely understood. In this study, we analyzed 188 MCL patients with available flow cytometry data and stratified cases into CD38-negative and CD38-positive groups based on median fluorescence intensity (MFI). CD38 expression was detected in 90.4% (161/178) of conventional nodal MCLs (cnMCLs), but in only 40% (4/10) of leukemic non-nodal MCLs (lnMCLs). Among the 178 cnMCL patients, CD38 negativity was associated with significantly higher frequencies of TP53 mutation (56% vs 23%, p = 0.0464), del(17p13) (50% vs 12%, p = 0.0077), and concurrent TP53 mutation and del(17p13) (57% vs 11%, p = 0.0101), compared with CD38-positive cases. Notably, cnMCLs harboring concurrent TP53 mutation and del(17p13) demonstrated significantly lower CD38 expression than cases with isolated TP53 mutation or del(17p13) alone. In addition, CD38-negative cnMCLs more frequently exhibited SOX11 negativity (80% vs 11%, p < 0.0001), mutated immunoglobulin heavy-chain variable region (IGHV) genes (55% vs 23%, p = 0.0622), and kappa light-chain restriction (77% vs 49%, p = 0.0407). Targeted mutational profiling further revealed that CD38-negative cnMCLs were enriched for mutations affecting cell-signaling pathways, including NOTCH1, NOTCH2, CD79B, CXCR4, and TRAF2, and were less likely to harbor mutations in ATM and chromatin-modifying or epigenetic regulators, particularly KMT2D and NSD2. Collectively, these findings indicate that CD38 negativity occurs in approximately 10% of cnMCLs and is associated with a distinct pathological and genetic profile that partially overlaps with, but is not identical to, that of lnMCL. Biologically, CD38-negative cnMCLs appear to be more likely driven by CD38-independent, alternative signaling pathways. From a clinical perspective, identification of CD38-negative cnMCLs by flow cytometry may help recognizing patients at increased risk for adverse genetic features, including TP53 inactivation.
RNA NGS testing provides additional diagnostic and prognostic information over metaphase karyotyping in routine clinical evaluation of acute leukemias and chronic myeloid neoplasms.
Malhotra S, Tu ZJ, Cook JR
Hum Pathol · 2026 Jun · PMID 41850631 · Publisher ↗
Pathogenic fusion genes are increasingly relevant to the diagnosis and classification of acute leukemias and chronic myeloid neoplasms per the new 2022 ICC and WHO-HAEM5 classifications. Although DNA based NGS testing is...
Pathogenic fusion genes are increasingly relevant to the diagnosis and classification of acute leukemias and chronic myeloid neoplasms per the new 2022 ICC and WHO-HAEM5 classifications. Although DNA based NGS testing is now commonly employed, RNA-based NGS is not yet widely performed in routine practice. Using techniques such as anchored multiplex PCR enrichment, RNA NGS is capable of detecting fusion genes even without knowledge of the fusion partner gene, and can also identify prognostically relevant splicing variants including KMT2A partial tandem duplications (PTD) and IKZF1 deletions. We reviewed the results of our in-house acute leukemia assay (63 DNA genes and 107 RNA genes) in a real world, consecutive series of 350 unique patients. RNA NGS analysis was abnormal in 70/350 patients (20%). Metaphase karyotyping was performed in 68/70 patients (97%) with RNA NGS abnormalities. Of these, 30 (44%) showed concordant RNA NGS and karyotype results, while 38 (56%) RNA abnormalities were not identified by karyotyping alone including 14 KMT2A-PTD, 7 IKZF deletions, and 17 cases carrying various fusions. The RNA NGS results defined a specific ICC or WHO diagnostic category in 51 cases and were prognostically relevant in an additional 21. RNA-based NGS testing identifies fusion genes or pathogenic splicing variants in a subset of acute leukemias and chronic myeloid neoplasms. The abnormalities detected by RNA NGS offer additional diagnostic and prognostic information which is often not available through metaphase karyotyping alone. RNA-based fusion testing is a useful adjunct in hematopoietic neoplasm diagnosis and management which can be readily incorporated into routine clinical practice.
Thymic cyst: A clinicopathological, immunohistochemical, and molecular study of 36 cases focusing on squamous- and ciliated-type epithelium.
Takata S, Horie M, Miyabe K … +11 more , Ito Y, Nakatani Y, Kudo-Asabe Y, Ishida H, Yamada S, Goto A, Kumanogoh A, Shintani Y, Morii E, Yachida S, Maeda D
Hum Pathol · 2026 Jun · PMID 41850630 · Publisher ↗
BACKGROUND: Thymic cysts are benign mediastinal lesions lined by various epithelial types, but the distribution of each type is unknown. In this study, we aimed to evaluate the clinicopathological and immunohistochemical...
BACKGROUND: Thymic cysts are benign mediastinal lesions lined by various epithelial types, but the distribution of each type is unknown. In this study, we aimed to evaluate the clinicopathological and immunohistochemical features of thymic cysts. DESIGN: We retrieved 36 resected primary thymic cysts. The lesions were initially evaluated morphologically, focusing on the type of epithelium. Immunohistochemical staining was performed for cytokeratin 7 (CK7), CK13, CK20, high molecular weight cytokeratin (HMWCK: CK34βE12), p63 and β5t. In addition, we investigated 15 occult cystic lesions (OCLs) associated with thymic epithelial tumors. RESULTS: Primary thymic cysts were classified as squamous/cuboidal (SC-type, N = 18), ciliated columnar (CC-type, N = 15), mucinous (N = 2), and mixed (N = 1) types. All cysts were CK7-positive. Linear-luminal pattern CK7 staining was observed more frequently in SC-type cysts (100%) than in CC-type cysts (40%) (P < 0.0001). CK20 was negative in all the cases except for the two mucinous cysts. Full-layer positivity for HMWCK was observed more frequently in SC-type cysts (78%) than in CC-type cysts (6.7%) (P < 0.0001). SC-type cysts were more frequently multilocular than CC-type (10/18, 55.6% vs 1/15, 6.7%; P = 0.0083). CK13 positivity was observed in 70.6% of SC-type cysts and 21.4% of CC-type cysts (P = 0.0113). Radiological findings showed that SC-type cysts were larger than CC-type cysts (P = 0.015), and the computed tomography (CT) values of SC-type cysts were markedly lower than those of CC-type cysts (P < 0.0001). The majority of OCLs were classified as SC-type (13/15). CONCLUSIONS: Based on morphological features, thymic cysts mainly comprise two types, SC-type and CC-type, which differ in their sizes, locularity, immunophenotypes, and CT features.
The impact of next generation sequencing studies on the diagnosis of BAP1 inactivated melanocytic tumors.
Braat J, Trichy NS, Holic LJ … +30 more , Olivares S, Bahrami A, Balamurugan T, Barnhill R, Blokx WAM, Busam KJ, Cerroni L, Cook M, Duncan L, Elder D, Ferguson P, Ferrara G, Ko J, Landman G, Lezcano C, Lowe L, Massi D, Mihic-Probst D, Parker D, Sargen M, Scolyer R, Shea C, Spatz A, Tetzlaff M, Torres-Cabala CA, Tron V, Yeh I, Yun SJ, Zembowicz A, Gerami P
Hum Pathol · 2026 Jun · PMID 41831527 · Publisher ↗
BAP1 inactivated melanocytic tumors (BIMTs) are recognized for their potential for significant morphologic atypia including nuclear atypia, expansile growth, and mitotic activity, making it difficult to form firm morphol...
BAP1 inactivated melanocytic tumors (BIMTs) are recognized for their potential for significant morphologic atypia including nuclear atypia, expansile growth, and mitotic activity, making it difficult to form firm morphologic criteria for malignancy. Next generation sequencing (NGS) is becoming increasingly utilized in melanocytic pathology. We conducted a two-phase survey with 26 dermatopathologists from the International Melanoma Pathology Study Group to assess the impact of NGS on diagnostic accuracy and interobserver agreement in 31 BIMTs. After NGS results, interobserver agreement improved from fair on Survey 1 (κ = 0.348) to moderate on Survey 2 (κ = 0.441). Respondents were 1.7 times more likely to be correct on Survey 2 after NGS results (OR = 1.67, 95% CI [1.16-2.44], p = 0.005). When accounting for case variability and difficulty, respondents were 8.7 times more likely to provide a correct diagnosis for a given case (CMH OR = 8.69, 95% CI [4.89-15.44], p < 0.001). Among the 8 BAP1 inactivated melanomas in this study, 3 transitioned from a majority of votes for benign/intermediate grade BIMT to a majority of votes for melanoma after seeing NGS data. Genomic aberrations exclusive to malignant cases included pathogenic variants in TERT-p, CDKN2A, PTEN, and amplification of MYC. Our study suggests NGS has the potential to improve diagnostic accuracy and interobserver agreement for BAP1 inactivated melanocytic tumors. With the advent of increasingly effective therapies for melanoma, there is value in forming a definitive diagnosis of melanoma when appropriate. Additional studies with greater case numbers and follow-up are needed to further validate these findings.
Detection of human papillomavirus with low-risk chromogenic in situ hybridization probes in seborrheic keratosis-like lesions of the male genital tract.
Gosnell HL, Myles JL, Przybycin CG … +5 more , Nguyen JK, Billings SD, Alaghehbandan R, Cox RM, Williamson SR
Hum Pathol · 2026 Jun · PMID 41812829 · Publisher ↗
Seborrheic keratosis (SK) most commonly occurs on the trunk of older individuals. However, lesions resembling SK have been reported at genital sites. In this situation, positivity for human papillomavirus (HPV) has been...
Seborrheic keratosis (SK) most commonly occurs on the trunk of older individuals. However, lesions resembling SK have been reported at genital sites. In this situation, positivity for human papillomavirus (HPV) has been documented, mostly in female patients, suggesting that these are more akin to condyloma than SK. We aimed to characterize genital SK-like lesions in men, including HPV status assessed by chromogenic in situ hybridization. We retrieved 40 specimens from 37 patients. The average patient age was 47, and most lesions were from the penis (75%), less commonly groin (12%), perineum (8%), or scrotum (5%). When a clinical impression was available, it was condyloma in 54%, but SK in some (15%). Recurrence was found in 36% of patients with follow-up. Acanthosis and hyperkeratosis were uniformly present, and most (83%) had horn cysts. Low-risk HPV chromogenic in situ hybridization was positive in 75%. The pattern of positivity was subtle in most patients, with 66% displaying only punctate granules of cytoplasmic/nuclear staining (66%). The remainder showed staining of entire nuclei (17%) or a mixture of both patterns (17%). The extent of staining was evenly divided between focal, moderate, and diffuse (each 33%). Control groups showed HPV positivity in 11/13 conventional condylomas (10 having a component of punctate staining) and 0/11 non-condyloma male genital skin specimens. Lesions of the male genital tract may histologically resemble SK; however, considerable rates of HPV positivity, concurrent or metachronous condyloma, and clinical suspicion of condyloma support these being more akin to condyloma than usual SK.
Expression characteristics of clinically relevant antibody-drug conjugate targets in gestational trophoblastic neoplasia.
Wang X, Wang W, Chen J … +2 more , Yang J, Xiang Y
Hum Pathol · 2026 Jun · PMID 41812828 · Publisher ↗
OBJECTIVES: Antibody-drug conjugates (ADCs) have demonstrated clinical benefit in a variety of malignancies. However, information regarding ADC target expression in gestational trophoblastic neoplasia (GTN) remains scarc...
OBJECTIVES: Antibody-drug conjugates (ADCs) have demonstrated clinical benefit in a variety of malignancies. However, information regarding ADC target expression in gestational trophoblastic neoplasia (GTN) remains scarce. This study aimed to characterize the immunohistochemical expression patterns of clinically relevant ADC targets in GTN and to assess their potential translational relevance. METHODS: Immunohistochemistry was performed on tumor tissues from 33 patients with GTN, including 16 choriocarcinomas, 6 placental site trophoblastic tumors, and 11 epithelioid trophoblastic tumors. Additionally, 10 normal placental tissues and 5 complete hydatidiform mole specimens were included. Expression of the following ADC targets was evaluated: FOLR1, Nectin4, TROP2, CEACAM5, HER3, CLDN6, CLDN18.2, and tissue factor. Target expression was assessed based on membranous staining using H-score methodology, and FOLR1 expression was additionally evaluated using PS2+ criteria. Associations with clinicopathologic parameters were examined. RESULTS: Nectin4 was detected in all GTN cases, with medium-to-high expression observed in 81.8% of tumors. FOLR1 was positive in 90.9% of cases, with high expression identified in 36.4% using PS2+ criteria. TROP2, CEACAM5, HER3, CLDN6, and tissue factor showed variable and generally low-to-moderate expression, whereas CLDN18.2 was consistently absent. TROP2 expression differed significantly among GTN subtypes and was highest in epithelioid trophoblastic tumor. No significant associations were observed between ADC target expression and FIGO stage, prognostic score, prior therapy, recurrence, or disease-specific mortality. CONCLUSION: GTN exhibits frequent expression of several established ADC targets, particularly Nectin4 and FOLR1. These findings provide a molecular rationale for biomarker-driven investigation of ADC-based therapeutic strategies in refractory or recurrent GTN.
Association between KSHV genotype and immune response to Kaposi sarcoma.
Yogi S, Ishikawa H, Yamakawa N … +10 more , Yara M, Kuninaka N, Uehara K, Tanabe Y, Kurima K, Kina S, Kina M, Takahashi K, Arakawa H, Kinjo T
Hum Pathol · 2026 Jun · PMID 41791430 · Publisher ↗
Kaposi sarcoma (KS) is a locally aggressive endothelial tumor that can be classified into four clinical types: classic, AIDS-related, iatrogenic, and endemic. KS usually affects the skin and soft tissues, but it can deve...
Kaposi sarcoma (KS) is a locally aggressive endothelial tumor that can be classified into four clinical types: classic, AIDS-related, iatrogenic, and endemic. KS usually affects the skin and soft tissues, but it can develop into mucosal, lymph node, and multiple-organ lesions. KS is caused by Kaposi sarcoma-associated herpes virus (KSHV), which has six genotypes (A, B, C, D, E, and F). However, it remains unclear whether the KSHV genotype affects clinical presentation. In this study, we investigated clinical stage, cellular proliferation, NF-κB activity, and lymphocyte infiltration around the tumor of KS lesions. Additionally, we evaluated the association between the parameters described above and the viral genotypes. Classic KS with genotype C exhibited elevated proliferative activity and most cases progressed to an advanced stage. Lesions in classic KS with genotype C were limited to the skin with high CD4 and CD8 cell infiltration. In contrast, some AIDS-related KS patients with genotype A showed lymph node and visceral involvement and a lower number of immune cells around the tumor, which suggests that host immunity against KSHV affects the clinical presentation. Among patients with AIDS-related KS, the numbers of CD3 and CD8 cells in genotype C were higher than those in genotype A. These results imply that genotype C induces more potent host tumor immunity than genotype A. Thus, the present study suggests that the clinical presentation of KS is associated with both host immunity and KSHV genotypes.
Clinical, pathologic, and molecular profiles of sarcomatoid and rhabdoid differentiated clear cell renal cell carcinoma: A series of 21 tumors.
Yu Y, Wang Y, Cheng X … +4 more , Chen X, Zhao W, Wang S, Zhang H
Hum Pathol · 2026 Jun · PMID 41785935 · Publisher ↗
Clear cell renal cell carcinoma (ccRCC) with sarcomatoid and/or rhabdoid differentiation-distinct dedifferentiation phenotypes-exhibits high aggressiveness and poor prognosis. Despite recent advances, their clinicopathol...
Clear cell renal cell carcinoma (ccRCC) with sarcomatoid and/or rhabdoid differentiation-distinct dedifferentiation phenotypes-exhibits high aggressiveness and poor prognosis. Despite recent advances, their clinicopathologic and molecular characteristics remain incompletely defined. This study analyzed 21 such cases, predominantly in males (19 patients), with a median age of 64 years (range: 29 - 83 years) and average tumor size of 6.1 cm (range: 3.5 - 14 cm). Among these, 14 cases showed sarcomatoid differentiation, 11 cases exhibited rhabdoid differentiation, and four cases demonstrated both types simultaneously. Most tumors (16/21, 76.19%) exhibited necrosis. Two patients presented with synchronous pulmonary metastases at diagnosis, and six developed distant metastases (bone/lung/liver/brain) 4 - 30 months postoperatively. Next-generation sequencing revealed that 90.5% (19/21) of samples harbored VHL gene alterations, which represent the initial driver mutation in ccRCC development. Additionally, chromatin remodeling genes showed enriched abnormalities, including PBRM1 (52.4%, 11/21), BAP1 (33.3%, 7/21) and SETD2 (19.0%, 4/21), suggesting a potential role for these genes in the transformation to sarcomatoid and/or rhabdoid morphology. Notably, 28.6% of tumors had TSC/MTOR pathway alterations, and TP53 mutations (33.3%) were significantly associated with poor prognosis (p = 0.049). No statistically significant differences in driver mutation prevalence or prognosis were observed between sarcomatoid and rhabdoid differentiation. These findings highlight the value of molecular stratification in elucidating pathogenesis and guiding targeted therapy for this aggressive ccRCC subtype, particularly emphasizing TP53 as a prognostic biomarker and TSC/MTOR alterations as potential therapeutic targets.
Syndromes Aassociated with Lipomatous Tumors (SALT): A comprehensive review.
Kao EY, Oliveira AM
Hum Pathol · 2026 Mar · PMID 41785934 · Publisher ↗
Lipomas are among the most common specimens encountered in surgical pathology. Beyond distinguishing a lipoma from an atypical lipomatous tumor or well-differentiated liposarcoma (ALT/WDLS), there are important clinical...
Lipomas are among the most common specimens encountered in surgical pathology. Beyond distinguishing a lipoma from an atypical lipomatous tumor or well-differentiated liposarcoma (ALT/WDLS), there are important clinical considerations to keep in mind, as lipomas and lipomatosis may occur in association with various syndromes. These syndromes can be inherited or sporadic, and some are linked to an increased risk of other malignancies. Moreover, several are associated with systemic findings that carry significant morbidity and mortality. Careful attention to specific clinicopathologic features-together with molecular testing when indicated-can facilitate early recognition of these syndromes, which is essential for appropriate counseling and long-term surveillance. Despite numerous case reports and isolated studies, a comprehensive synthesis of these syndromes remains lacking. In this review, we aim to summarize the Syndromes Associated with Lipomatous Tumors (SALT) and highlight key clinicopathologic features relevant to diagnosis and management. We also hope that this overview will stimulate further research by providing a succinct framework for exploring potential biologic networks underlying the origin and development of these common neoplasms.
Upgrade risk in intraductal papillomas: A retrospective analysis of real-world data and predictive model development.
Kotola J, Tamminen A
Hum Pathol · 2026 Jun · PMID 41780733 · Publisher ↗
BACKGROUND: In current practice, the traditional strategy of excising all IDPs has been replaced by more selective management. However, criteria for selecting patients for surveillance remain unclear, and no widely accep...
BACKGROUND: In current practice, the traditional strategy of excising all IDPs has been replaced by more selective management. However, criteria for selecting patients for surveillance remain unclear, and no widely accepted predictive model exists. METHODS: We retrospectively analyzed real-world data from 325 cases of IDPs diagnosed via core needle biopsy (CNB) at a tertiary teaching hospital between 2010 and 2023. We assessed upgrade rates to malignancy and evaluated potential predictive factors. Two previously published models were applied to our cohort, and a new model was developed based on our data. RESULTS: Overall, 17% (55/325) of IDPs were upgraded to malignancy. Among lesions without atypia on CNB (n = 215), the upgrade rate was 8.8% (19/215), compared to 40% (23/58) in those with atypia (p < 0.001). Previously suggested models yielded modest results when applied to our study population. First model would have spared 11% (24/215) of patients from surgery, while the second model would have spared 17% (36/215), with one missed upgrade. Our model identified all upgraded cases and would have spared 33% (72/215) of non-atypical IDPs from surgery. CONCLUSIONS: Atypia on CNB is a strong predictor of upgrade to malignancy. Existing models showed limited utility in reducing unnecessary surgeries. Our proposed model demonstrated improved performance and may support more individualized management of IDPs.
A special issue dedicated to general surgical pathology for 2026.
Gupta S, Erickson LA
Hum Pathol · 2026 Mar · PMID 41735103 · Publisher ↗
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