AIMS:Despite its clinical importance, histological steatosis assessment remains poorly standardized and highly variable among pathologists. We examined determinants of this variability by comparing pathologist estimates with quantitative artificial intelligence (AI) based measurements. METHODS AND RESULTS:Ten experienced liver pathologists from four institutions evaluated a limited set of 20 permanent H&E-stained whole-slide images (WSIs) from metabolic dysfunction-associated steatotic liver disease (MASLD) cases (10 core biopsies, 7 wedge biopsies and 3 resections) and 6 additional 500 × 500-μm image fields from separate permanent H&E-stained cases selected to represent varying droplet compositions. The WSIs spanned the full spectrum of steatosis severity. Assessments used four phases: default method, steatosis proportionate area (SPA), percentage of hepatocytes containing fat (%HCF) and Banff large-droplet criteria. Image fields were also assessed using no size cut-off or cut-offs based on hepatocyte, nuclear or 2-3× nuclear size. AI models quantified SPA, %HCF and droplet size for comparison with pathologists' assessments. Pathologists differed substantially in terminology, droplet-size definitions and quantification methods. Method choice (SPA vs. %HCF) was a major determinant of estimate dispersion and discrepancy from AI measurements. Visual estimates exceeded AI quantification by 1.4-3.6×. Pathologists' SPA estimates were increasingly higher than the corresponding AI measurements with increasing burden of droplets with area below 50 μm2, whereas, in exploratory analysis, %HCF estimates remained relatively stable relative to the corresponding AI measurements. Mixed-effects calibration equations were derived to relate visual and digital assessment scales. CONCLUSION:Steatosis assessment lacks standardized terminology and measurement practices. SPA and %HCF are conceptually distinct, and their interchangeable use amplifies discrepancies, particularly in small-droplet-rich cases. These findings support standardized, AI-compatible quantification; the exploratory conversion equations require independent validation before clinical application.
AIMS:Digital papillary adenocarcinoma is a rare, aggressive adnexal tumour with a significant risk of recurrence and metastasis. Recent studies have identified human papillomavirus (HPV) 42 in most cases, suggesting potential diagnostic specificity. As HPV42-specific sequencing is not routinely available, we evaluated the utility of commercially available low-risk HPV chromogenic in situ hybridization (CISH), which includes HPV42, in digital papillary adenocarcinoma and characterized its staining pattern. METHODS AND RESULTS:Twelve cases of digital papillary adenocarcinoma were retrieved from the surgical pathology archives of our institution and compared with eight cases of tubular adenoma. Low-risk HPV CISH was performed in all cases, and BRAF p.V600E immunohistochemistry in selected cases. Clinical, histological and immunohistochemical findings were reviewed. All digital papillary adenocarcinoma cases occurred in male patients (median age: 62 years, range 34-94) and involved the fingers. All were positive for low-risk HPV CISH, whereas all tubular adenomas were negative. Conversely, all tubular adenomas were positive for p.BRAF V600E, while nine tested digital papillary adenocarcinoma cases were negative. The hybridization signal in digital papillary adenocarcinoma was consistently punctate and nuclear rather than diffuse, and in some cases was appreciable only at high magnification. CONCLUSIONS:Low-risk HPV CISH is a practical and reliable method for detecting HPV42-associated digital papillary adenocarcinoma. Recognition of its punctate nuclear staining is important, as this pattern may be subtle in some cases and could be overlooked if diffuse nuclear staining is expected with low-risk HPV assays. These findings support the diagnostic utility of low-risk HPV CISH in digital papillary adenocarcinoma.
BACKGROUND:The 6th edition of the WHO Classification of Digestive System Tumours distinguishes amphicrine-like carcinomas (ALCs) from mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Acinar cell carcinomas (ACCs) with an intimately admixed and not separated neuroendocrine component comprising >30% of the tumour are classified as amphicrine-like ACCs (AL-ACCs). We characterised the genomic landscape of pancreatic ACCs and AL-ACCs to validate current classification and identify therapeutic targets. METHODS:Among 2,151 pancreatic biopsy and resection cases that underwent targeted next-generation sequencing using the OncoPanel AMC v4.3 or v4.5 (DNA-based hybrid capture, targeting 323 genes (v4.3) or 343 genes (v4.5)), eight ACCs, seven AL-ACCs originally diagnosed as MiNENs under the 5th edition of the WHO classification scheme, and four neuroendocrine tumours (NETs) were identified, diagnosed between 2020 and 2026. RESULTS:Homologous recombination deficiency (HRD)-associated alterations, involving BRCA1/2, ATM and FANCD2, were identified in 87.5% (7/8) of ACCs and 29% of AL-ACCs. One ACC had an ATRX nonsense mutation. Genomic heterogeneity was observed in molecular profiling of AL-ACCs; two demonstrated a 'true hybrid' signature with co-occurrence of lineage-specific drivers: MEN1 deletion and splice site mutation (neuroendocrine-associated), APC, SMAD4 and CTNNB1 alterations (exocrine-associated). Two others exhibited 'ACC-like' signatures, including missense BRCA1 and nonsense TP53 mutations and MDM4 and AKT3 amplifications, located on chromosome 1q, despite their neuroendocrine differentiation. CONCLUSIONS:Pancreatic ACCs frequently harbour HRD-related alterations, suggesting potential for PARP-inhibitor therapy. AL-ACCs comprise molecularly heterogeneous groups, including true hybrid and ACC-like patterns. Larger studies are required to elucidate the molecular distinction between true hybrid AL-ACCs and those with single-lineage alterations to refine their classification.
INTRODUCTION:MET (c-MET) is a receptor tyrosine kinase implicated in numerous cancers, including pancreatic neuroendocrine tumours (pNETs), by promoting cell proliferation, survival, invasion and angiogenesis. Recognizing its oncogenic potential, there is significant interest in MET-targeted therapies for malignancies like pNETs, which often develop treatment resistance. Immunohistochemistry (IHC) has become a practical method for detecting MET overexpression in cancers. This study evaluates MET expression in pNETs by IHC and assesses its correlation with prognostic variables and survival outcomes. METHODS AND RESULTS:Tissue microarrays containing well-differentiated neuroendocrine tumours from the gastrointestinal tract were analysed. The study included 125 pNET cores from 112 patients after application of inclusion criteria. MET expression was determined using the H-score system. Different variables were assessed for H-score distribution and cross-tables. Survival analyses were conducted based on progression-free survival and overall survival. Positive MET expression was found in 83.5% of cases. Higher MET H-scores were seen in patients with lymphovascular invasion (LVI), distant metastases and higher tumour grade (P < 0.05). When assessing different variables for higher MET H-scores, a significant association emerged at the 150-cut-off-point for LVI, perineural invasion, radiological evidence of progression and overall survival. For survival analysis, at a MET H-score threshold of 200, high MET expression was significantly associated with shorter progression-free survival (mean 8.7 versus 13.4 years, P < 0.05) and overall survival (mean 3.6 versus 7.7 years, P < 0.05). CONCLUSION:Elevated MET expression is linked to adverse histopathological features and worse clinical outcomes in pNET. Standardizing MET IHC evaluation is critical as anti-MET therapies develop, and identifying patients likely to benefit from these treatments remains essential.
AIMS:The Updated Sydney System is the most widely used framework for histological grading of gastritis, but complete grading in routine gastric biopsies is time-consuming and subject to interobserver variability. We developed an artificial intelligence (AI) system to support comprehensive and reproducible grading of all five Updated Sydney attributes in gastric biopsies. METHODS AND RESULTS:We developed SydneyMTL, a weakly supervised multi-task multiple instance learning framework trained on 50,765 whole-slide images from routine practice. The model jointly predicts mononuclear cell infiltration, neutrophil activity, glandular atrophy, intestinal metaplasia and Helicobacter pylori density, with atrophy including a separate not applicable category when muscularis mucosae is absent. Performance was assessed against routine labels from 24 board-certified pathologists and against a consensus-adjudicated Golden dataset. SydneyMTL achieved a mean lenient accuracy of 89.1% across the 24 pathologists, with >80% agreement for 21 of 24 readers on the retrospective dataset. In a two-reader randomized crossover study, AI assistance improved interobserver agreement and reduced review time by 34.2% for complete Updated Sydney grading. CONCLUSIONS:AI can support more reproducible and efficient grading of Updated Sydney histological attributes in gastric biopsies. By combining multi-pathologist validation, consensus-based evaluation and explicit handling of non-assessable atrophy, SydneyMTL provides a clinically realistic decision-support approach for routine digital pathology.
INTRODUCTION:IDH1 mutations occur in approximately 10%-20% of intrahepatic cholangiocarcinoma (iCCA) and constitute an established target for molecularly guided therapy. As routine molecular diagnostics are commonly based on a single tumour sample, intratumoral heterogeneity could affect the reliable detection of actionable mutations. This study assessed the spatial heterogeneity of IDH1 mutations in iCCA. METHODS:Patients with histologically confirmed iCCA who underwent routine next-generation sequencing (NGS) and had multiple available formalin-fixed paraffin-embedded (FFPE) tumour samples were retrospectively analysed. Baseline IDH1 status was determined by NGS. All available tumour regions were subsequently tested using the Idylla™ IDH1-2 Mutation Assay. Blocks where the Idylla™ IDH1 mutational status was discordant with baseline status were validated by digital polymerase chain reaction (dPCR). RESULTS:Thirty-five patients with iCCA were included, yielding 117 FFPE samples from spatially distinct tumour regions. Baseline NGS identified IDH1 mutations in 22.8% (8/35) of patients. Idylla™ testing revealed discordant results in 5 of 117 samples (4.2%). Validation by dPCR demonstrated that these discordances were attributable to technical limitations or assay-related errors rather than true biological heterogeneity. Following validation, all IDH1-mutated tumours showed concordant mutation status across all analysed tumour regions. CONCLUSIONS:IDH1 mutations appear to be spatially homogeneous in iCCA, supporting their role as an early clonal event. These findings indicate that single-sample molecular testing is sufficient for reliable determination of IDH1 status and patient selection for IDH1-targeted therapies.
INTRODUCTION:Spermatocytic tumours (ST) are uncommon germ cell tumours generally considered unrelated to germ cell neoplasia in situ (GCNIS). Morphologically, ST can occasionally mimic seminoma, while CD117 can be positive in both. Intratubular spread of ST can also mimic intratubular seminoma/GCNIS, further raising diagnostic consideration for seminoma. METHODS:Herein, we performed a morphological and immunohistochemical investigation of ST focusing on the intratubular component to raise awareness of this potential diagnostic pitfall. RESULTS:Twenty cases of ST demonstrating intratubular spread were collected, re-reviewed and stained (OCT4, CD117, SSX C-terminus and DMRT1). Intratubular ST involved a variable number of tubules (range 3 to >50) typically along the periphery of the invasive ST (90%) and rarely diffusely throughout the testes (10%). ST cells usually filled the entire tubule (95%); rarely, ST cells were present at the base, seemingly in the spermatogonial niche (5%). Intratubular ST typically consisted of homogeneous intermediate-sized cells (80%); only a subset showed the characteristic tripartite morphology (20%). Unlike GCNIS, intratubular ST lacked thickened basement membranes and often demonstrated concomitant spermatogenesis (60%). All cases were SSX C-terminus positive and OCT4 negative. CD117 was variably positive in 80% of cases (1 case only positive in the invasive tumour, 3 cases only positive in intratubular components). DMRT1 was variably positive in all cases, with differing extents/intensities between the invasive tumour and intratubular components. CONCLUSION:Intratubular spread of ST is not an uncommon finding. Awareness of the morphological features as well as judicious use of immunohistochemistry can help avoid mistaking this entity for GCNIS/seminoma.
Molecular advances have expanded the spectrum of cutaneous soft tissue tumours, leading to the recognition of several recently described entities with distinct genetic drivers. This review outlines the defining histopathological, immunophenotypic and molecular features of hybrid superficial ALK-rearranged myxoid spindle cell neoplasm/epithelioid fibrous histiocytoma, superficial neurocristic tumour, ALK-rearranged epithelioid vascular neoplasm and MITF pathway-activated melanocytic tumour. Key diagnostic features and differential considerations are highlighted, with attention to areas of morphological overlap and current gaps in biological characterization. This synthesis aims to facilitate accurate recognition and classification of these emerging tumours in routine dermatopathology practice.
AIMS:Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) and TFEB-amplified renal cell carcinoma (TFEB-amplified RCC, a subset of TFEB-altered RCC) are rare eosinophilic renal cell tumours that can be difficult to distinguish on the basis of morphology and immunohistochemistry alone. In this study, we compared the clinicopathological and molecular features of these entities to identify distinguishing characteristics. METHODS AND RESULTS:Nine cases of ESC-RCC and six cases of TFEB-amplified RCC from our institutional archives were evaluated for clinical, morphological, immunohistochemical and molecular features. Despite morphological overlap, each entity exhibited somewhat distinctive features. ESC-RCC frequently exhibited solid and cystic architecture with tightly packed tubules, flocculent to coarsely granular cytoplasm with basophilic stippling and prominent admixed macrophages. In comparison, TFEB-amplified RCC more frequently demonstrated solid growth of pseudopapillae and loose tubules, dense eosinophilic granular cytoplasm without basophilic stippling, focally apical nuclei and extracellular magenta globules. However, neither morphology nor immunohistochemistry was sufficiently specific to completely distinguish these entities. Ancillary molecular testing identified pathogenic TSC1 or TSC2 gene variants in ESC-RCC and TFEB gene locus amplification in TFEB-amplified RCC. CONCLUSIONS:Although ESC-RCC and TFEB-RCC share overlapping morphological and immunohistochemical features, each demonstrates somewhat characteristic histological findings. Definitive distinction requires molecular testing to identify the underlying molecular alterations. As molecular testing assumes an increasingly important role in RCC diagnosis and classification, recognition of these rare entities and their overlapping and distinguishing features is essential for appropriate testing and accurate diagnosis.
AIMS:DICER1 is a microRNA biogenesis enzyme that, when mutated, results in a rewiring of the transcriptome. Germline pathogenic variants (PVs) in DICER1 result in DICER1-related tumour predisposition (DRTP) characterized by 30 or more different, generally rare, paediatric or adolescent-onset tumours. One of these, pituitary blastoma, upregulates let-7 targets such as HMGA2, with overexpression at the protein level. In this study, we determined if HMGA2 upregulation involves other tumours characteristic of DRTP. METHODS AND RESULTS:Seventy-eight lesions with confirmed DICER1 PVs were studied including CNS spindle cell sarcoma, Sertoli-Leydig cell tumour of the ovary, pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma of ovary or cervix, thyroid follicular nodular disease and seven other more rare diagnoses. Using immunohistochemistry and scoring any degree of nuclear staining for HMGA2 as positive, we found that all lesion types were positive. This was seen in all samples within each category (except one case), but in only 50% of thyroid lesions. Normal control tissues were uniformly negative. CONCLUSIONS:The widespread expression in DICER1-related lesions, benign or malignant, suggests that HMGA2 expression is an early event in the pathogenesis. As HMGA2 is implicated in epithelial to mesenchymal transition, over-expression of HMGA2 in DICER1-related lesions could be driving this transition. Excluding thyroid lesions, immunostaining for HMGA2 shows 98% positivity in DICER1-related lesions, in DRTP or in tumours with somatic mutations. HMGA2 immunostaining could serve as a useful exclusion test; patients with lesions suspected of being DICER1-related, but negative for HMGA2, would be unlikely to benefit from germline DICER1 testing.
AIM:Germline BRCA1/2 pathogenic variant carriers are at increased risk for high-grade serous carcinoma (HGSC) and are therefore advised to have a risk-reducing salpingo-oophorectomy (RRSO) around the age of 40. A risk of 0.9% to develop peritoneal HGSC (pHGSC) remains, which increases up to 27.5% when serous tubal intraepithelial carcinoma (STIC) is detected at RRSO. The relationship between the detection of STIC and the occurrence of pHGSC is still poorly understood. Here, we investigated the role of tissue sampling by examining deeper sections of the tubal tissue of RRSO specimens. METHODS:Four groups of patients were included: (1) STIC without pHGSC (n = 5); (2) STIC with pHGSC (n = 4); (3) no STIC and no pHGSC (n = 5); and (4) no STIC and pHGSC (n = 5). Follow-up time was 10 years or until the development of pHGSC. Deeper sections were cut at 150 μm intervals. A deep learning model was used to support STIC detection. RESULTS:A focus of isolated STIC or HGSC was found in the deeper sections of all patients who developed pHGSC, while these patients did not have STIC or HGSC at the initial diagnosis. No patients with STIC and pHGSC showed HGSC in the deeper sections. We observed that five STICs presented as serous tubal intraepithelial lesions (STILs) in adjacent slides based on low Ki-67 expression. CONCLUSIONS:Our findings underscore the hypothesis that pHGSC originates in the fallopian tube and confirm that invasiveness is not necessary for disease progression of STIC towards pHGSC. Furthermore, deeper sections might be of additional value when STIL is diagnosed.
OBJECTIVE:Histological grading is a key predictor of progression in non-muscle-invasive bladder cancer (NMIBC). The WHO 1973 three-tier system is limited by heterogeneity within the G2 category, whereas the WHO 2004/2016 binary classification reduces prognostic resolution by grouping biologically diverse tumours into broad low-grade (LG) and high-grade (HG) categories. We aimed to evaluate the prognostic performance of hybrid grading systems compared with WHO 2004/2016, while further characterizing the histomorphological continuum of non-invasive papillary urothelial carcinoma. METHODS:Non-invasive papillary urothelial carcinomas (2012-2023; n = 472) were reviewed and reclassified by two urological pathologists according to WHO 2004/2016, hybrid three-tier and four-tier systems, and an investigational five-tier framework (Grades I, IIA, IIB, IIIA, IIIB) integrating architectural, cytological and proliferative features. Primary endpoints were recurrence, grade progression and T1+ stage progression, assessed using ROC analysis, Cox proportional hazards regression and model-performance metrics (AIC, BIC, C-index). RESULTS:Increasing morphological atypia was associated with larger tumour size, greater multifocality and progressively higher progression risk, with events concentrated in Grades IIIA and IIIB. All systems showed limited recurrence discrimination (C-index 0.54-0.56). For T1+ progression, discrimination improved with increasing stratification (AUC 0.754 for WHO 2004/2016 vs. 0.815, 0.828 and 0.827 for the hybrid three-tier, four-tier and five-tier systems, respectively; all P < 0.001). The Hybrid 3-Tier model achieved the most favourable AIC and BIC, while the five-tier model yielded the highest C-index (0.818). CONCLUSIONS:Hybrid grading systems improve progression-risk stratification in non-invasive papillary urothelial carcinoma compared with WHO 2004/2016, with most benefit achieved by the Hybrid 3-Tier framework. These findings support the concept of a histomorphological continuum of progression risk and favour continued refinement of biologically informed hybrid grading for NMIBC risk stratification.
INTRODUCTION:Accurate assessment of mitotic activity is an important component of melanoma prognostication but remains challenging due to interobserver variability and difficulties in identifying representative mitotic hotspots. We developed and evaluated a deep learning-based mitosis detection algorithm for whole-slide images (WSIs) of melanoma and investigated its utility for hotspot identification and spatial analysis of mitotic distribution. METHODS:The model was trained on manually annotated histopathology images and applied to a cohort of 114 melanoma cases comprising 378 WSIs. Performance was assessed against expert annotation using sensitivity, precision, and F1-score. Algorithm-identified hotspots were reviewed by a pathologist and compared with mitotic counts reported in routine clinical practice. Spatial organization of mitotic figures was evaluated using nearest-neighbour distance analyses. RESULTS:The algorithm achieved a sensitivity of 88%, precision of 75%, and an F1 score of 0.81, demonstrating strong agreement with expert assessment. Across the cohort, 30,547 mitotic figures were detected, enabling comprehensive whole-slide analysis of proliferative activity. AI-assisted hotspot identification yielded significantly higher mitotic counts than those reported in routine pathology practice (5.35 ± 7.9 versus 2.96 ± 3.73 mitoses/mm2, P = 0.004), suggesting improved identification of regions with maximal proliferative activity. Whole-slide analysis further enabled characterization of mitotic spatial organization. Distinct patterns ranging from clustered to relatively uniform distributions were observed across tumours. Moreover, melanomas arising in chronically sun-damaged (CSD) sites demonstrated significantly greater nearest-neighbour distances than melanomas from non-CSD sites (423.3 μm versus 285.4 μm, P = 0.023), indicating differences in the spatial organization of proliferating tumour cells. CONCLUSION:Our findings demonstrate that AI-assisted mitosis detection can accurately identify mitotic figures while improving hotspot detection compared with routine assessment. Beyond mitotic quantification, large-scale whole-slide analysis enables novel spatial characterization of mitotic organization, providing additional insights into melanoma biology and highlighting new opportunities for computational pathology-based biomarker discovery.
BACKGROUND:In primary aldosteronism (PA), the HISTALDO framework classifies aldosterone-producing lesions as 'classical' (solitary nodule) or 'non-classical' (multinodular or diffuse) based on CYP11B2 immunohistochemistry, but interpretation is complicated by frequent micronodules, even in patients without PA. The CYP11B2 size ratio (B2R), a quantitative measure of size disproportion between CYP11B2-positive nodules, offers an objective way to assess lesion architecture and has shown value in predicting cure versus relapse. In this study, diagnostic classification was intentionally B2R-guided, generating a modified HISTALDO B2R system in clinical routine. OBJECTIVE:Prospective evaluation of the prognostic value of B2R-guided classification in routine pathology and assessment of postoperative outcomes across B2R-defined subgroups. METHODS:Specimens of 70 adrenalectomies underwent multisection CYP11B2 staining; 61 patients had at least 6 months of follow-up (mean age 53 years, 54% were females). All had adrenal vein sampling and confirmatory testing before unilateral laparoscopic adrenalectomy. Imaging showed unilateral findings in 51%, bilateral in 8% and no detectable nodules in 41%. A B2R ≥8.1 defined classical lesions; B2R < 8.1 non-classical. Outcomes at 6-12 months were assessed using PASO criteria, which classify biochemical and clinical success as absent, partial or complete. RESULTS:Biochemical cure was achieved in 95% of patients with classical B2R morphology, compared with 40% of those with non-classical B2R morphology (p < 0.001). Complete clinical success was also significantly more frequent in the classical B2R group than in the non-classical group (57% versus 25%, p = 0.0235). Medication-based measures supported these findings: patients with classic histology showed a trend towards reductions in antihypertensive medication expressed as defined daily doses (DDD) (median ΔDDD 2.83 versus 2.00, p = 0.1254), and a significantly greater reduction in potassium supplementation (median ΔDDD 1.25 versus 0.00, p < 0.001) compared to those with non-classical histology. CONCLUSIONS:B2R-guided HISTALDO yields biologically distinct subgroups with clear prognostic separation. Earlier work using the original HISTALDO definition reported ~40%-45% persistent biochemical aldosteronism in non-classical cases. Our findings reproduce this poor non-classical outcome profile in a larger and more consistently defined B2R-classified cohort. Importantly, incorporating B2R reduces misclassification of tumours as non-classical when background nodularity is present despite a dominant CYP11B2-positive lesion.
AIMS:To characterize the endoscopic features of periappendiceal lesions and histopathological features of appendiceal lesions in patients with conventional ulcerative colitis (UC), particularly in relation to disease duration, and compare these findings to those observed in patients with primary sclerosing cholangitis-associated UC (PSC-UC) to clarify differences in appendiceal involvement and underlying pathophysiology. METHODS AND RESULTS:This retrospective, two-centre study included 158 UC patients and 7 PSC-UC patients undergoing total colectomy involving the appendix between 2011 and 2025. Twenty-five non-UC patients served as controls. Pathologists blindly evaluated appendiceal sections for active inflammation, fibrous obliteration (FO) and crypt architectural distortion. Among patients with UC, 92% of the appendices exhibited active inflammation or FO, frequently accompanied by chronic architectural distortion and mucosal destruction, whereas no controls showed active inflammation. Appendiceal lesions in patients with UC demonstrated time-dependent changes: active inflammation was predominant (64%) within 5 years of disease onset, whereas complete FO was most frequent (75%) after 20 years. In cases with preoperative periappendiceal red patch, histological continuity from distal FO to proximal active inflammation was confirmed within the same appendix. Conversely, despite extensive colonic inflammation, no PSC-UC cases exhibited active appendiceal inflammation, and most appendices remained histologically intact. CONCLUSIONS:Appendiceal lesions in patients with conventional UC show a time-dependent transition from active inflammation to long-term fibrous obliteration. These findings suggest that appendiceal inflammation may be more relevant in the early phase of disease, with possible implications for appendectomy-based therapeutic strategies. The absence of appendiceal inflammation in patients with PSC-UC further supports a pathophysiological difference from conventional UC.
AIMS:Neoadjuvant chemotherapy (NACT) is becoming the standard of care for lymph node (LN)-positive breast cancers. Residual disease in the breast and LN serves as a critical prognostic indicator and guides adjuvant therapy. The histological patterns of LN treatment response (TE) vary significantly, and criteria for evaluating TE remain underdeveloped. METHODS AND RESULTS:We analysed 114 clinical node-positive cases that underwent NACT, reviewed post-NACT LN TE, and correlated them with clinicopathological characteristics. TE was identifiable in 77% of all cases and 92% of post-NACT nodal conversion cases. The histological patterns of TE include a special "rounded" pattern of fibrosis (86%), LN architectural irregularity with aggregates of histocytes, foamy macrophages, and haemosiderin deposition (54%), and fine-needle aspirated site changes (34%). Microscopically identifiable TE, except fibrosis, diminishes as the interval between LN sampling and surgery increases. Specifically, among the four cases that failed to identify TE in the nodal conversion group, 3 (75%) surgeries were performed >6 months after initial LN sampling. In cases with multiple clinically suspicious LNs, only one of which was sampled pre-NACT, recognition of a specific fibrosis pattern allowed identification of TE in unsampled LNs (9 cases, 18%) post-NACT, contributing to an accurate post-NACT assessment. Post-NACT nodal-positive cases correlated with poor outcomes. CONCLUSIONS:Given the paradigm shift of increased NACT, evaluation of TE in LN is critically important. Awareness of the histological features of TE is crucial for LN assessment to ensure accurate nodal removal and guide post-NACT clinical management for best patient care.
AIMS:The nosology of primary cutaneous apocrine carcinoma remains controversial, as the term has often been used as a heterogeneous diagnostic category. The aim of this study was to clarify the clinicopathological and molecular features of strictly defined apocrine carcinoma using modified diagnostic criteria. METHODS AND RESULTS:Thirty cases were collected from three institutions. Male predominance (28/30, 93%), predominance in elderly patients (median age, 72 years; range, 33-89 years) and the favourite site of the axilla (29/30, 97%) were observed. Lymph node and distant metastases occurred in 64% (16/25) and 28% (7/25) of cases, respectively. Two patients died of the disease (2/25, 8%), with a median follow-up period of 2 years and 1 month. Histopathologically, all tumours harboured cytoplasmic zymogen-like granules; however, some (8/30, 27%) lacked apocrine secretion features. Nucleoli were either moderately prominent (n = 17) or prominent (n = 13). Apocrine gland hyperplasia was identified in 5 (17%) of the 30 cases. Immunoexpression of androgen receptor, BerEP4, cytokeratin 7, GATA3 and GCDFP15 was observed in all tested cases. In contrast, BCL2, CEA, oestrogen receptor and progesterone receptors were negative in all tested cases. Only 13 cases underwent molecular studies. PIK3CA hotspot mutations were detected in 8 of the 13 cases. Panel sequencing revealed KMT2D (MLL2/4) mutations in three cases, all of which have no PIK3CA mutations. CONCLUSIONS:Primary cutaneous apocrine carcinoma is a distinct entity characterized by remarkably consistent clinical, cytopathological, immunohistochemical and molecular features.
Merkel cell carcinoma (MCC) is an aggressive, poorly differentiated neuroendocrine cutaneous carcinoma that has rapidly increased in incidence over the past decades. Due to the significant risk of recurrence, metastasis and mortality, prompt diagnostic recognition of MCC is essential to guide timely management. Definitive diagnosis can be challenging, especially in the context of limited sampling, morphological variants, immunophenotypic aberrancy or metastatic disease of unknown primary. The differential diagnosis can include other small cell malignancies, especially extracutaneous small cell carcinoma. Small cell carcinoma of the vulva carries substantial risk for misdiagnosis due to immunohistochemical overlap with MCC. Cutaneous carcinomas may also enter the differential diagnosis, especially the recently described WNT/Beta-catenin-activated nonpilomatrical carcinoma that can also express CK20 and neuroendocrine markers. In certain contexts, there is risk of diagnostic confusion with basal cell carcinoma or squamous cell carcinoma. This review details pitfalls and nuances for MCC diagnosis, including an updated differential diagnosis. The utility of recently proposed markers SATB2, H3K27me3 and POU4F3 is described, alongside important caveats for more traditional markers such as CK20, TTF1, neurofilament and Merkel cell polyomavirus. Molecular analysis can assist in certain cases. These recent advances help to ensure more definitive diagnosis of MCC in most cases.
