Histopathology[JOURNAL]
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200 papers
Response to the Letter to the Editor: further clarifications on the new histological criteria for autoimmune hepatitis.
Ma Z, Zhao X
Histopathology · 2026 Jun · PMID 42265054 · Publisher ↗
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Consistency of c-Met protein overexpression over time in patients with non-squamous non-small cell lung cancer.
Cortot AB, Dubois R, Grégoire V … +12 more , Gibier JB, Labreuche J, Deprez V, Dubrulle D, Chretien T, Wasielewski E, Behal H, Feng D, Lind A, Ansell P, Thiébaut-Millot R, Hader C
Histopathology · 2026 Jun · PMID 42262061 · Publisher ↗
AIMS: The c-Met signalling pathway is dysregulated in non-small cell lung cancer (NSCLC), with c-Met protein overexpression emerging as a potentially actionable biomarker given the development of c-Met-targeted antibody-...
AIMS: The c-Met signalling pathway is dysregulated in non-small cell lung cancer (NSCLC), with c-Met protein overexpression emerging as a potentially actionable biomarker given the development of c-Met-targeted antibody-drug conjugates. This retrospective study assessed the consistency of c-Met protein overexpression over time in patients with non-squamous NSCLC and two or more longitudinal biopsy samples (one before treatment, one post-treatment). METHODS AND RESULTS: Samples from 160 patients were analysed for c-Met protein expression. The concordance rate for c-Met protein overexpression between samples was 81.3%, indicating most patients had consistent expression status. Patients with an EGFR mutation had a lower concordance rate (65.8%). Fourteen patients with high discordance (negative to positive) between sampling time points showed a high frequency of oncogenic driver alterations, hence often received targeted therapy before the second sample and had high percentages of cells at 2+ intensity in c-Met immunohistochemistry before treatment. CONCLUSIONS: These results indicate c-Met protein overexpression can be assessed before or after treatment since most patients maintain consistent c-Met status. As targeted therapies may elevate c-Met overexpression over time, retesting may be necessary in those with an oncogenic driver alteration initially diagnosed as c-Met negative.
Secretory carcinoma of the breast: a report of six cases with different immunophenotypes and molecular subtypes.
López-García MÁ, Galán L, Meléndez B … +5 more , Eizaguirre B, Masero JM, Biscuola M, Benavent M, Vieites B
Histopathology · 2026 Jun · PMID 42261827 · Publisher ↗
AIM: Secretory carcinoma is a rare and well-recognized subtype of breast carcinoma generally associated with a favourable prognosis. Although it was initially described in young patients, it is now known to occur at any...
AIM: Secretory carcinoma is a rare and well-recognized subtype of breast carcinoma generally associated with a favourable prognosis. Although it was initially described in young patients, it is now known to occur at any age and in both sexes. Histologically, it is characterized by a combination of solid, microcystic and tubular architectural pattern with the presence of intracellular and extracellular secretory material that provides its distinctive histological appearance. This tumour is associated with a balanced chromosomal translocation t(12;15) resulting in the ETV6-NTRK3 gene fusion, a translocation rearrangement with well-established oncogenic potential. Secretory carcinoma has traditionally been considered an unusual example of a triple-negative tumour, yet with a favourable clinical outcome. METHODS AND RESULTS: In this study, we report six cases exhibiting both typical histological and molecular features of secretory carcinoma, but with varying expression of HER2 and hormone receptors. An extensive immunohistochemical and molecular analysis has been performed, including in situ hybridization and gene expression assays. CONCLUSION: These findings support the existence of greater variability in surrogate and intrinsic molecular subtypes within secretory carcinomas, providing potential personalized therapeutic strategies for the treatment of these patients.
NFE2L2-mutated urothelial carcinomas frequently show concomitant myxoid and squamous features and have high PD-L1 expression.
Wuori D, Guzzetta A, Tjota MY … +3 more , Wang P, Antic T, Kwon JW
Histopathology · 2026 Jun · PMID 42249733 · Publisher ↗
AIMS: NFE2L2 encodes the transcription factor, NRF2, which is a regulator of cellular oxidative stress responses and metabolic homeostasis. NFE2L2 alterations are implicated in multiple cancers, with significant study in...
AIMS: NFE2L2 encodes the transcription factor, NRF2, which is a regulator of cellular oxidative stress responses and metabolic homeostasis. NFE2L2 alterations are implicated in multiple cancers, with significant study in thoracic oncology, with an adverse prognosis, aggressive behaviour, metabolic reprogramming and diminished responses to chemotherapy and immunotherapy and increased PD-L1 expression. However, the clinicopathological significance of NFE2L2 mutations in urothelial carcinoma is not well understood. METHODS AND RESULTS: To address this, we identified six urothelial carcinomas harbouring NFE2L2 mutations from a cohort of 156 muscle-invasive cases that underwent next-generation sequencing (NGS). Histological review of the five in-house cases showed concomitant squamous and myxoid features. Immunohistochemical analysis revealed high PD-L1 expression, with three of the five cases showing strong, membranous staining in >90% of tumour cells. NGS showed frequent mutations in other genes in addition to the NFE2L2 mutation, most commonly in CDKN2A and TERT promoter. Clinically, all patients presented with or developed metastatic disease and all patients who were not lost to follow up died from the disease (median overall survival: 12 months). CONCLUSIONS: These findings suggest that NFE2L2-mutated urothelial carcinomas frequently have concomitant squamous and myxoid features, aggressive behaviour and high PD-L1 expression. Recognition of the NFE2L2-mutated urothelial carcinomas may have diagnostic and prognostic utility, particularly with immunotherapy and possible targeted therapy against the NRF2 signalling pathway. Further investigation with larger cohorts is warranted to expand the data surrounding NFE2L2 mutations in urothelial carcinoma.
The 2025 ATS/ERS update of the international multidisciplinary classification of the interstitial pneumonias: implications for the pathologist.
Nicholson AG, Cooper WA, Fabre A … +5 more , Travis W, Hariri LP, Adegunsoye A, Piciucchi S, Ryerson CJ
Histopathology · 2026 Jun · PMID 42249728 · Publisher ↗
A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach...
A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach was best clinical practice. This comprised seven histological patterns that had corresponding idiopathic multidisciplinary diagnoses. This classification was updated in 2013, with the addition of an eighth histological pattern. Since 2013, there have been further advances in our understanding of interstitial pneumonias, in particular relating to idiopathic versus secondary disease, advances in molecular pathology and recognition of progressive pulmonary fibrosis (PPF), which have led to a further update in 2025. This review highlights the changes relevant to pathologists reporting interstitial pneumonias. Major changes include (1) expansion beyond idiopathic interstitial pneumonias to also include secondary causes, (2) subclassification as interstitial (fibrotic vs non-fibrotic) and alveolar filling disorders, (3) expansion to include additional patterns (e.g. bronchiolocentric interstitial pneumonia), (4) improved terminology that better reflects histogenesis and (5) consideration of diagnostic confidence in biopsy evaluation. Pathologists also need to be aware of the advantages and limitations of cryobiopsy interpretation and the importance of reporting features that point towards a secondary cause rather than idiopathic disease. The 2025 classification provides a framework for a methodological approach to reporting biopsies in patients with interstitial pneumonia, which should be used prospectively for both diagnosis and research.
Landscape of genetic alterations affecting cancer genes in primary and advanced malignant phyllodes tumours.
Yeni Yildirim S, Selenica P, Gazzo A … +5 more , Djerroudi L, Ross D, Brogi E, Weigelt B, Pareja F
Histopathology · 2026 Jun · PMID 42236264 · Publisher ↗
BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remai...
BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remain poorly understood. Prior studies suggest two evolutionary pathways according to MED12 mutational status. We sought to determine the repertoire of somatic genetic alterations in cancer genes in primary versus metastatic/recurrent MPTs, and according to MED12 mutational status and genetic ancestry. MATERIALS AND METHODS: We analysed the paired tumour-normal targeting sequencing data (up to 505 cancer-related genes) of 31 MPTs (primary, n = 20; metastatic/recurrent, n = 11). RESULTS: Metastatic/recurrent MPTs harboured a numerically higher frequency of genetic alterations in CDKN2A/2B (55% vs. 25%). Moreover, analysis of an MPT case with paired primary and metastatic samples revealed a CDKN2A/2B homozygous deletion restricted to the metastatic sample, suggesting a role for CDKN2A/2B in progression. Compared with MED12-wild type MPTs, MED12-mutant MPTs had higher tumour mutation burden (P = 0.002), frequency of TERT promoter (82% vs. 35%; P = 0.02) and RB1 mutations (45% vs. 5%; P = 0.01). Genetic alterations in the PI3K pathway, including PIK3CA and PTEN, were only present in MED12-wild type MPTs, and absent in MED12-mutant cases (15% vs. 0%; P > 0.05). Furthermore, genetic alterations in EGFR were restricted to MPTs from patients of European genetic ancestry and absent in those of Asian ancestry (43% vs. 0%; P > 0.05). CONCLUSIONS: Taken together, the repertoire of genetic alterations in primary and metastatic/recurrent MPTs shows overlap, and CDKN2A/2B homozygous deletions may play a role in progression. Additionally, molecular profiles of MPTs may vary according to genetic ancestry and MED12 mutational status.
Spatial transcriptomics reveals clonal relationships between intraductal carcinoma and adjacent invasive prostate cancer.
Harikumar H, de Waard-van Baardwijk M, de Haan M … +8 more , van Beek G, Lila K, van Royen ME, van den Bosch TP, Sanders MA, Bindels E, Stubbs A, van Leenders GJ
Histopathology · 2026 Jun · PMID 42236150 · Publisher ↗
AIMS: The pathogenesis of intraductal carcinoma (IDC) is still controversial. Contrary to current opinion, where IDC represents retrograde spread of invasive prostate cancer (PCa), we recently presented an alternative, u...
AIMS: The pathogenesis of intraductal carcinoma (IDC) is still controversial. Contrary to current opinion, where IDC represents retrograde spread of invasive prostate cancer (PCa), we recently presented an alternative, unifying hypothesis named 'Repetitive Invasion, Precursor Progression' (RIPP). Little is known about genomic alterations in high-grade Prostatic Intraepithelial Neoplasia (HGPIN), IDC and adjacent invasive PCa. Our objective was to clarify the mutual clonal relationships among HGPIN, IDC, and adjacent PCa using spatial transcriptomics. METHODS AND RESULTS: Regions of interest containing HGPIN, IDC and adjacent invasive PCa were selected from six Gleason score 3 + 4 = 7 radical prostatectomy specimens. Spatial transcriptomic profiling and library preparation were executed according to the Visium workflow. Pathologist-guided manual annotations were utilized to delineate regions of interest for the integrated analysis of chromosomal copy number variants (CNV) and spatiotemporal trajectories. Adjacent HGPIN, IDC and invasive PCa shared common CNV signatures across all samples, with various subclonal events. Unsupervised clonal analysis revealed that across three samples, the adjacent invasive subclone had acquired additional genomic alterations. In two samples, HGPIN, IDC and adjacent invasive PCa had identical CNVs. Finally, in one sample, IDC had additional CNVs compared with HGPIN and invasive glands. Supervised trajectory analysis consistently placed adjacent invasive PCa as the final step in the trajectory, after HGPIN and/or IDC. CONCLUSIONS: Spatial transcriptomics revealed strong clonal relationships among adjacent HGPIN, IDC and invasive PCa. Supervised trajectory analysis did not support retrograde spread in this limited number of samples, while unsupervised analysis revealed a complex mutual relationship among HGPIN, IDC and adjacent PCa.
Breast core needle biopsy diagnosis and personalized treatment: navigating pitfalls and challenging lesions.
Rakha EA, Quinn C, Tan PH … +1 more , Callagy G
Histopathology · 2026 Jun · PMID 42233872 · Publisher ↗
Most breast lesions can be diagnosed accurately on core needle biopsy (CNB); however, certain entities remain diagnostically challenging due to limited tissue sampling, morphological overlap with other lesions, unusual i...
Most breast lesions can be diagnosed accurately on core needle biopsy (CNB); however, certain entities remain diagnostically challenging due to limited tissue sampling, morphological overlap with other lesions, unusual immunoprofiles or lack of reliable ancillary markers. These challenges are compounded by modern clinical requirements, particularly the increasing shift towards neoadjuvant therapy (NAT) where a definitive diagnosis is required before surgical excision. Misclassification may have clinically significant consequences, including inappropriate initiation of NAT or undertreatment of aggressive disease. This review provides a structured diagnostic approach to breast lesions that are particularly prone to misinterpretation on CNB. We discuss malignant lesions that should not trigger NAT, while highlighting the diagnostic and reporting pitfalls associated with microinvasive disease, where definitive confirmation of established invasion is often elusive on limited material. Key morphological clues, immunohistochemical strategies and the selective role of molecular testing in resolving differential diagnoses of overlapping and challenging lesions are emphasized. A transparent reporting style that acknowledges uncertainty, together with multidisciplinary collaboration and selective expert consultation, optimizes patient management. The review aims to provide practical guidance, avoid diagnostic pitfalls and promote safe decision-making when dealing with complex breast lesions on limited biopsy material.
Bronchiolar adenoma and glandular papilloma/mixed squamous cell and glandular papilloma represent a continuous disease spectrum: revelations from combined histological and genetic analysis.
Piao Z, Xu J, Li L … +3 more , Ao S, Chen H, Chen J
Histopathology · 2026 Jun · PMID 42233862 · Publisher ↗
AIMS: Despite their common bronchial/bronchiolar origin, the relationship between glandular/mixed papillomas (GPs/MPs) and bronchiolar adenomas (BAs) remains uncertain; therefore, this study aimed to elucidate it. METHOD...
AIMS: Despite their common bronchial/bronchiolar origin, the relationship between glandular/mixed papillomas (GPs/MPs) and bronchiolar adenomas (BAs) remains uncertain; therefore, this study aimed to elucidate it. METHODS AND RESULTS: We performed a combined clinicopathological and next-generation sequencing analysis of 6 GP/MP and 14 BA cases. The cases were classified into three groups based on histopathological features: Group A (classic GP/MP), Group B (transitional morphology) and Group C (glandular predominant BA, lacks papillary structure). Analysis revealed a morphological continuum from Group A to Group C, characterized by a gradual transition from endobronchiolar papillary growth to alveolar glandular structures and a shift in the lining epithelium from pseudostratified ciliated columnar to cuboidal/flat. Clinically, compared with Group C, Group A showed a higher proportion of males and larger tumour size, while Group B exhibited intermediate features. Genetically, GP/MP frequently harboured BRAF (83.3%) and AKT1 (66.6%) mutations, whereas BAs displayed a more diverse profile, including BRAF (28.5%), AKT1 (21.4%), EGFR (28.5%) and KRAS (14.2%) mutations. BRAF and AKT1 mutations were predominantly found in Groups A and B, whereas EGFR and KRAS mutations were more common in Group C. CONCLUSION: GP/MP and BA represent the same disease spectrum, showing a continuous histomorphological change along the proximal-to-distal bronchial tree. BRAF and AKT1 mutations are more frequently observed in GP/MP and proximal-type BA with papillary architecture, whereas BA lacking papillary structures is mainly characterized by EGFR or KRAS mutations. However, the BRAF mutation rate in BA varies across geographical regions and appears to be associated with factors such as smoking.
Traditional serrated adenoma of the colorectum: Evolving concepts in histological classification and terminology.
Rosty C, Loughrey MB, Hashimoto T … +5 more , Mäkinen M, Pai RK, Sekine S, Yantiss RK, Nagtegaal ID
Histopathology · 2026 Jun · PMID 42227059 · Publisher ↗
Traditional serrated adenoma (TSA) is the least common of the currently recognized serrated colorectal polyps and, thus, elucidating its pathogenesis, spectrum of morphological features and biological risk has been chall...
Traditional serrated adenoma (TSA) is the least common of the currently recognized serrated colorectal polyps and, thus, elucidating its pathogenesis, spectrum of morphological features and biological risk has been challenging. Most TSAs harbour either KRAS or BRAF mutations and may progress to adenocarcinoma via distinct carcinogenic pathways. TSAs with KRAS mutation are more commonly located in the distal colorectum, whereas BRAF-mutant TSAs typically arise proximal to the transverse colon, may be associated with a background sessile serrated lesion and represent putative precursors of biologically aggressive BRAF-mutant, mismatch repair-proficient colorectal carcinomas. This review summarizes the evolution of the concept of TSA as a distinct pathological entity and its relationship to other neoplasms within the serrated neoplastic pathway. The molecular and histopathological characteristics of TSAs are outlined, with particular emphasis on the classification of lesions with mixed morphology, including those associated with non-dysplastic serrated components and those showing progression to severe dysplasia, with the hope of improving their recognition. Although further studies are required to validate the proposed terminology, consistent classification of these lesions is essential to improve recognition and to advance understanding of this uncommon pathway to colorectal carcinoma.
Low-risk HPV-associated invasive carcinoma with squamous and glandular features arising in a Buschke-Löwenstein tumour.
Tezcan N, Shia J, Bahceci D
Histopathology · 2026 May · PMID 42216651 · Publisher ↗
AIMS: Low-risk human papillomavirus (LR-HPV) types 6 and 11 are classically associated with benign anogenital condylomas and are only rarely implicated in malignant transformation. Reported carcinomas associated with LR-...
AIMS: Low-risk human papillomavirus (LR-HPV) types 6 and 11 are classically associated with benign anogenital condylomas and are only rarely implicated in malignant transformation. Reported carcinomas associated with LR-HPV have exclusively demonstrated purely squamous morphology. We describe an unusual LR-HPV-associated invasive anal carcinoma with mixed squamous and glandular differentiation arising in a Buschke-Löwenstein tumour (BLT). METHODS AND RESULTS: A 70-year-old woman underwent abdominoperineal resection for an anal mass associated with a perirectal abscess and rectovaginal fistula. Histological examination demonstrated a circumferential papillary-verrucous lesion consistent with condyloma acuminatum/BLT with areas transitioning to invasive carcinoma. The invasive tumour extended through the anal wall and showed intimately admixed squamous and mucinous glandular components, including pure glandular and pure squamous areas. The glandular component was CK7 positive and negative for CDX2 and CK20, supporting a non-colorectal phenotype. High-risk HPV in situ hybridization was negative, and p16 showed only patchy, non-block-type staining. In situ hybridization for LR-HPV (types 6/11) demonstrated positive signals in both the condylomatous and invasive glandular and squamous components. CONCLUSIONS: This case expands the morphological spectrum of LR-HPV-associated anal neoplasia by documenting invasive carcinoma with true glandular and squamous differentiation arising in a BLT in the absence of detectable high-risk HPV. The findings support the capacity of LR-HPV-associated lesions, although exceptionally rarely, to undergo malignant transformation with divergent glandular differentiation.
Perineurioma-like EMA-positive calvarial neoplasms: clinicopathological study of eight cases.
Rizwan R, Mok Y, Dermawan JK … +7 more , Isaacson A, Ulici V, Kilpatrick SE, Reith JD, Yeaney G, Ilaslan H, Fritchie KJ
Histopathology · 2026 May · PMID 42216621 · Publisher ↗
BACKGROUND: Incidental skull lesions are increasingly detected due to the widespread use of brain imaging. We have encountered an unusual cohort of unclassifiable calvarial spindle cell lesions showing phenotypic overlap...
BACKGROUND: Incidental skull lesions are increasingly detected due to the widespread use of brain imaging. We have encountered an unusual cohort of unclassifiable calvarial spindle cell lesions showing phenotypic overlap with perineurioma and meningioma, which we sought to further characterize. MATERIAL AND METHODS: Cases of unclassifiable low-grade spindle cell lesions arising in the calvarium were collected. Clinical, radiological and pathological findings were reviewed. All cases were uniformly stained for a panel of meningothelial and perineurial immunomarkers. RESULTS: Eight cases were identified (6 females, 2 males; 51-81 years), arising in the parietal (n = 4), frontal (n = 3), parietal-occipital (n = 1) bones. Radiologically, the lesions appeared as lytic with non-aggressive features, but progressive enlargement was documented in cases with serial imaging. Histologically, all cases were composed of uniform, bland spindle cells with elongated, tapered cytoplasm and inconspicuous nuclei arranged in short fascicles and whorls. Immunohistochemically, all cases were positive for EMA (8/8) and Collagen IV (3/3). The lesions showed consistent but limited staining for SSTR2a (2 cases, 6%-50%; 4 cases, 1%-5%). The lesional spindle cells were negative for PR (0/7), GLUT1 (0/6), S100 (0/6), CD34 (0/5), SOX10 (0/4) and claudin 1 (0/3). Follow-up (available in 6 patients; range 6-61 months, median 15.5 months) showed no evidence of recurrence after curettage or excision. CONCLUSION: Perineurioma-like, EMA-positive calvarial neoplasms are a rare group of spindle cell tumours for which no local recurrence or distant metastasis has been documented to date, although they do show a propensity for progressive growth. Recognition of their distinctive clinicopathological and radiological features is important for accurate diagnostic classification and appropriate patient management.
Intramuscular myxoma with chondroid features: two cases expanding the morphological spectrum.
Batson B, Neyaz A, Lobo LDG … +3 more , Naous R, Lee SJ, John I
Histopathology · 2026 May · PMID 42216582 · Publisher ↗
BACKGROUND: Intramuscular myxoma is a benign mesenchymal tumour typically composed of bland spindle to stellate cells in abundant myxoid stroma and usually characterized by GNAS mutations. Chondroid matrix has not been p...
BACKGROUND: Intramuscular myxoma is a benign mesenchymal tumour typically composed of bland spindle to stellate cells in abundant myxoid stroma and usually characterized by GNAS mutations. Chondroid matrix has not been previously reported in intramuscular myxoma. METHODS: We describe two intramuscular myxomas with chondroid-type matrix and review the relevant radiological, histological, immunohistochemical and molecular findings, with emphasis on differential diagnostic considerations. RESULTS: Case 1 occurred in the triceps of a 64-year-old woman and showed focal cartilaginous differentiation, including chondrocytes within lacunar spaces, in an otherwise classic intramuscular myxoma background. The lesional cells were negative for MUC4, S100, cytokeratin, SMA, desmin, CD34, ERG, STAT6 and EMA, and targeted sequencing detected no pathogenic alteration. Case 2 occurred in the vastus medialis of a 48-year-old woman and showed bland spindle to stellate cells in myxoid to collagenous stroma with foci of chondromyxoid matrix, patchy lacunar-type spaces, and territorial basophilia. The lesional cells were positive for CD34, focally positive for SMA and negative for S100, desmin, cytokeratin and SOX10. Whole transcriptome sequencing detected no gene fusion, and targeted sequencing identified GNAS c.602G>A (p.R201H). Both tumours were deep intramuscular and markedly T2 hyperintense and showed peripheral and septal enhancement on MRI. CONCLUSIONS: These cases expand the morphological spectrum of intramuscular myxoma by documenting chondroid and chondromyxoid matrix, likely representing cartilaginous metaplasia. Awareness of this variant is important to avoid misclassification as other chondromyxoid neoplasms.
Updates and controversies in contemporary grading of clear cell renal cell carcinoma and papillary renal cell carcinoma.
Paner GP, Amin MB, Kwon JW … +2 more , Cheng L, Moch H
Histopathology · 2026 May · PMID 42212433 · Publisher ↗
A decade into the formal adoption of the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system for clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma...
A decade into the formal adoption of the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system for clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC), newer grading concepts, innovative approaches and some issues have emerged. A comprehensive review of the literature on the WHO/ISUP grading system and other grading approaches for CCRCC and PRCC was conducted. Updates and issues are presented on the following: (1) validation studies on WHO/ISUP grading; (2) grade elements including heterogeneity, grades 1 versus 2, types of multinucleated tumour cells, 'grade spectrum' of spindle cells, impact of sarcomatoid change in grade 4 RCC, percent (%) high grade, % sarcomatoid change and rhabdoid change versus sarcomatoid change; (3) grade applications including observer agreement, needle biopsy grade accuracy (correlation with nephrectomy grade) and grading of multifocal RCCs; (4) grade in papillary tumours including heterogeneity and on small (≤1.5 cm) neoplasms; and (5) novel grading or risk categories including incorporation of necrosis into grading and pattern or architectural-based grading. Practice guidance for some of the issues is provided when feasible or where data are sufficient. This review highlights the recent updates and controversies in the use of WHO/ISUP grading and on novel approaches to grading for CCRCC and PRCC. This review may serve as a best practice guide in addressing some of the grading issues and will help identify gaps in our understanding and use of grading for CCRCC and PRCC that can inform future research.
Unveiling the molecular profile of adenosquamous gallbladder carcinoma: characterization of a Caucasian cohort.
Gasparello J, Angerilli V, Rizzato MD … +18 more , Maffii E, Ceccon C, Callegarin M, Sabbadin M, Niero M, Toffolatti L, Bergamo F, Parente P, Mastracci L, Grillo F, Vanoli A, Mattiolo P, Luchini C, Tos APD, Cillo U, Zanus G, Lonardi S, Fassan M
Histopathology · 2026 May · PMID 42212406 · Publisher ↗
AIMS: Gallbladder carcinoma (GBC) is a rare and highly aggressive malignancy associated with poor clinical outcomes. While most GBCs are adenocarcinomas, only a small subset shows squamous differentiation. Tumours contai...
AIMS: Gallbladder carcinoma (GBC) is a rare and highly aggressive malignancy associated with poor clinical outcomes. While most GBCs are adenocarcinomas, only a small subset shows squamous differentiation. Tumours containing more than 25% squamous component are classified as gallbladder adenosquamous carcinomas (GBASC), a rare histological subtype characterized by a significantly worse prognosis than conventional adenocarcinomas. Due to their rarity, the molecular landscape and biological basis underlying the aggressive behaviour of GBASCs remain poorly understood. METHODS AND RESULTS: In this study, 25 retrospectively collected GBASC cases were comprehensively characterized at both immunohistochemical and molecular levels. Predictive biomarkers including programmed death-ligand 1 (PD-L1), mismatch repair proteins (MMR), human epidermal growth factor receptor 2 (HER2) and claudin 18.2 (CLDN18.2) were evaluated. Nearly all tumours (96%) showed PD-L1 positivity with a combined positive score (CPS) greater than 1. CLDN18.2 expression was identified in 28% of cases, although its confinement to the glandular component may limit its therapeutic applicability. All tumours were mismatch repair proficient (MMRp), and none demonstrated HER2 overexpression, in contrast to a subset of gallbladder adenocarcinomas. Molecular profiling revealed recurrent alterations in TP53 (64%), KRAS (16%) and CDKN2A (20%), partially overlapping with the genomic profile of gallbladder adenocarcinomas. However, GBASCs showed a significant enrichment of alterations involving the PI3K pathway, particularly PIK3CA (44%) and PTEN (24%) mutations, representing their most distinctive molecular feature. CONCLUSIONS: Overall, these findings support the recognition of GBASC as a distinct molecular entity potentially requiring dedicated therapeutic strategies.
Extra-appendiceal low-grade mucinous neoplasm-like lesions: clinicopathologic and molecular characteristics.
Lee SH, Aktas BK, Kim A … +3 more , Deshpande V, Vyas M, Yilmaz O
Histopathology · 2026 May · PMID 42187007 · Publisher ↗
AIMS: We identified three extra-appendiceal low-grade appendiceal mucinous neoplasms (LAMN)-like lesions occurring in the absence of appendiceal involvement, raising uncertainty regarding their classification, biologic n...
AIMS: We identified three extra-appendiceal low-grade appendiceal mucinous neoplasms (LAMN)-like lesions occurring in the absence of appendiceal involvement, raising uncertainty regarding their classification, biologic nature, and clinical significance. METHODS: We identified three cases of LAMN-like lesions arising in duplication cysts, anatomically separate from the appendix. These cases were evaluated by detailed histologic and immunohistochemical analysis and compared with other gastrointestinal duplication cysts diagnosed at the same institution. Whole-exome sequencing was performed in all three LAMN-like cases. RESULTS: All three lesions demonstrated defining histologic features of LAMN, including low-grade mucinous epithelium with apical mucin, abundant luminal mucin, undulating or papillary architecture, obliteration of the lamina propria, effacement of the muscularis mucosae and mural fibrosis. Features of a background duplication cyst were at least focally present, and appendiceal involvement was absent in all cases. The epithelium showed an intestinal immunophenotype with strong CK20 and CDX2 expression and absent or minimal CK7 staining. Molecular analysis revealed activating KRAS or GNAS mutations in all three cases, including one case with co-occurring mutations, mirroring the molecular profile of conventional appendiceal LAMN. CONCLUSIONS: We describe extra-appendiceal LAMN-like lesions that recapitulate the morphologic, immunophenotypic, and molecular features of appendiceal LAMN despite the absence of appendiceal involvement. These findings support the interpretation of these lesions as true neoplastic proliferations arising within non-lumen-communicating cystic epithelial compartments, such as duplication cysts. Recognition of this rare phenomenon is critical to avoid misclassification and may have implications for staging, surveillance, and clinical management analogous to appendiceal LAMN.
Expression of melanocytic markers in uterine smooth muscle tumours.
Mirzabeigi Y, Abulaban A, Bahmad HF … +2 more , Schlumbrecht MP, Pinto A
Histopathology · 2026 May · PMID 42186998 · Publisher ↗
AIMS: Uterine smooth muscle tumours (SMTs) conventionally express myogenic markers such as desmin, h-caldesmon and smooth muscle actin by immunohistochemistry. In contrast, the frequency and extent of melanocytic marker...
AIMS: Uterine smooth muscle tumours (SMTs) conventionally express myogenic markers such as desmin, h-caldesmon and smooth muscle actin by immunohistochemistry. In contrast, the frequency and extent of melanocytic marker (MM) expression, commonly assessed in the differential diagnosis with perivascular epithelioid cell tumours (PEComas), remain poorly defined. This study aimed to evaluate the positivity of MMs and Cathepsin K in a large cohort of SMTs. METHODS AND RESULTS: In total, 102 tumours were retrospectively identified, including 72 leiomyomas of various subtypes, 4 cases of SMT of uncertain malignant potential and 26 leiomyosarcomas. Immunohistochemistry for HMB-45, Melan-A, PRAME and Cathepsin K was performed on whole-tissue sections and assessed for the presence, extent and intensity of staining. A chi-square test was used to determine statistical significance. Thirty-eight tumours (37.2%) expressed at least one MM (excluding Cathepsin K). PRAME was the most frequently expressed marker (30/102, 29.4%), showing strong nuclear staining in 27 tumours (26%), predominantly in a focal distribution (<50% of cells; 27/30, 90%). HMB-45 was positive in 16/102 tumours (15.6%), with focal expression in all cases (16/16, 100%), and Melan-A was focally positive only in 2/102 tumours (1.9%). Cathepsin K expression was seen in 32/102 tumours (31.4%), being focal in most positive cases (28/32, 87.5%). Co-expression of PRAME and HMB-45 was observed in 10 cases (9.8%), while no SMT demonstrated co-expression of HMB-45 and Melan-A. In 4 of the 7 HMB-45-positive conventional leiomyomas, staining was observed only in the hyalinized areas. There was no significant difference in the frequency of MM staining between benign/uncertain behaviour (leiomyomas/SMTs of uncertain malignant potential) (36.8%) and malignant tumours (leiomyosarcomas) (38.5%; P = 0.88). CONCLUSION: We observed that a subset of SMTs may express MMs, typically in a focal and weak pattern. In our series, no SMT showed concurrent positivity for both HMB-45 and Melan-A; therefore, when evaluating a tumour with equivocal morphology that demonstrates dual and/or diffuse expression of these markers, the diagnosis should be carefully reconsidered.
Borderline breast lesions and the limits of classification: insights from the UK National Breast Screening EQA scheme.
Rakha EA, Provenzano E, Kingham A … +4 more , Bennet R, Lee K, Pinder SE, Ellis IO
Histopathology · 2026 May · PMID 42169446 · Publisher ↗
BACKGROUND: Previous concordance studies in breast pathology have demonstrated high levels of diagnostic agreement. This study aimed to characterize breast lesions associated with the lowest levels of concordance within...
BACKGROUND: Previous concordance studies in breast pathology have demonstrated high levels of diagnostic agreement. This study aimed to characterize breast lesions associated with the lowest levels of concordance within the UK NHS Breast Screening Programme external quality assessment (EQA) scheme. METHODS: A total of 263 consecutive breast cases circulated between 2015 and 2025 were reviewed. Each case was assessed by up to 22 coordinators (expert reference panel assessors) and an average of 678 participants (all other pathologists enrolled in the EQA scheme). Cases with <80% concordance among coordinators were analysed in detail. RESULTS: Overall performance was high, with 67.4% of participants achieving 100% concordance across all circulated cases. Fifteen cases (5.7%) failed to meet the ≥80% concordance threshold. Mean diagnostic agreement in these cases was 57% (range 25%-79% among coordinators; 25%-87% among participants). Discordant cases predominantly involved atypical epithelial proliferations and papillary lesions, particularly those situated at diagnostic thresholds between established categories. Persistent challenges included distinguishing among lobular neoplasia subtypes, apocrine atypia, flat epithelial atypia, and related lesions, as well as between in situ and invasive papillary carcinoma. CONCLUSIONS: While overall concordance remains high, a small subset of biologically borderline lesions continues to generate significant diagnostic variability. These findings support further refinement of diagnostic criteria and targeted educational strategies to improve reproducibility in challenging breast lesions.
Optimizing breast core needle biopsy biomarker throughput using an AI-based workflow.
Deman F, Broeckx G, Degotte Q … +5 more , Siozopoulou V, Del Carmen Tavares M, Declercq S, Salgado R, Dendooven A
Histopathology · 2026 May · PMID 42163037 · Publisher ↗
AIMS: To evaluate the feasibility, appropriate relevance and impact on turnaround time (TAT) of an AI-supported workflow in which AI, integrated in the Laboratory Information System (LIS) as well as in the daily workflow...
AIMS: To evaluate the feasibility, appropriate relevance and impact on turnaround time (TAT) of an AI-supported workflow in which AI, integrated in the Laboratory Information System (LIS) as well as in the daily workflow, autonomously triggers breast biomarker testing (ER, PR, HER2, Ki-67) for breast core needle biopsies with a high AI-based likelihood of invasive breast cancer. METHODS AND RESULTS: This retrospective, unicentric implementation study utilized an AI system (IBEX™ Breast) to stratify H&E slides. For cases classified as 'high likelihood for invasive carcinoma', the LIS automatically ordered the standard biomarker panel (ER, PR, HER2 and Ki67), bypassing initial pathologist slide reading. The TAT was measured from the moment of the case assignment to both the availability of IHC staining (TAT) and the moment of reporting of the biomarkers (TAT). A pre-implementation phase (December 2024-May 2025; June 2024-November 2025) was compared with a post-implementation phase (June 2025-November 2025). The appropriate relevance of the automated ordering was assessed by evaluating the AI-initiated testing and the relevance of the ordered stains for the final diagnosis. Implementation of the AI-enhanced workflow resulted in a statistically significant reduction in TAT from approximately 32 h to 23 h, (-30%, P < 0.01) and TAT reduction of approximately 1 working day (P ≤ 0.03) demonstrating that technical gains translate directly into faster biomarker reporting. Diagnostic accuracy was maintained throughout, with no unnecessary stains triggered by the system. CONCLUSIONS: Integrated, LIS-embedded AI in the daily workflow significantly optimizes breast cancer biomarker turnaround time without compromising the diagnostic process of a pathology laboratory. This demonstrates the transformative potential of AI to enhance laboratory efficiency and support more rapid patient-centred oncologic care.
DICER1-associated 'yolk sac tumour' or 'foetal-type adenocarcinoma?': questioning historical terminology.
Devins KM, McCluggage WG
Histopathology · 2026 May · PMID 42152756 · Publisher ↗
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