Aim The current American Joint Committee on Cancer (AJCC8) manual grades colorectal adenocarcinoma (CRC) based on the percentage of gland formation. The World Health Organization 5th ed (WHO5) and 6th ed (WHO6) grade based on the least differentiated component; WHO6 specifies a minimum 0.196 mm 2 area of the least‐differentiated component away from the invasive front to merit a high‐grade diagnosis. We studied the interobserver agreement and challenges among pathologists when grading CRC using the above grading systems. Methods and results Five gastrointestinal pathologists reviewed 100 scanned CRC slides and graded each slide per the provided criteria in (a) WHO5, (b) WHO6, (c) AJCC8 and (d) their clinical practice. A post‐survey questionnaire was also provided. The Fleiss multirater kappa among the five reviewers was similar using WHO6 (0.730, P < 0.001) and two‐tiered (low vs. high) AJCC8 (0.731, P < 0.001) and was higher than WHO5 (0.655, P < 0.001) grading criteria; the agreement was substantial for all 3 grading systems. Significantly more tumours were called high‐grade when using WHO6 (average: 34.4 cases) and WHO5 (average: 33.6 cases) as compared to AJCC8 (average: 11.8 cases) grading criteria ( P < 0.01). All reviewers were unanimous in handling certain scenarios (e.g. discounting invasive front tumour buds with WHO grading), but were discordant on certain scenarios (e.g. assessment of stroma‐rich areas). Conclusions While inter‐observer agreement improved with WHO6 versus WHO5, the persistent upgrading of tumours using the WHO scheme may affect treatment algorithms. Synchronization of grading criteria with validation in prospective studies with clinical outcomes is crucial.
Introduction Different molecular subtypes of hepatocellular adenoma (HCA) can occur at the same time within the same patient, defining inter‐tumour heterogeneity (ITH). We describe a series of HCA‐ITH cases, most identified in Bordeaux with additional cases contributed by other international centres. Methods ITH‐HCA cases were subtyped by immunohistochemistry, confirmed by molecular analysis in most cases. The resulting diagnoses were HNF1A ‐HCA (H‐HCA), inflammatory HCA (IHCA), b‐catenin‐mutated HCA (b‐HCA) involving exon 3 or 7/8, b‐catenin‐mutated IHCA (b‐IHCA) involving exon 3 or 7/8, sonic hedgehog HCA (sh‐HCA) and unclassified HCA (UHCA). Results We identified 26 patients with ITH‐HCA including 17 women; none had underlying liver disease, whereas most men did (8/9). The largest subgroup comprised 22 patients with IHCA combined with another subtype: H‐HCA (five patients); H‐HCA and b‐IHCA‐exon 3 borderline (one patient); b‐IHCA‐exon 3 (six patients); b‐HCA and b‐IHCA exon 3 (four patients); b‐IHCA‐exon7/8 (two patients); sh‐HCA (three patients); UHCA (one patient). The remaining four patients had sh‐HCA combined with UHCA (one patient) or b‐IHCA ex3 (one patient), and 2 patients with HNF1A adenomatoses, one with malignant transformation, the other associated with a b‐IHCA exon3 progressed to HCC. The largest nodule was a 13 cm IHCA. One of the sh‐HCA presented with bleeding. Conclusion ITH‐HCA covers the whole spectrum of the HCA classification. It is rare but poses significant clinical challenges, particularly in terms of identifying those lesions at risk of malignant transformation (b‐HCA or b‐IHCA exon 3) or bleeding (sh‐HCA). Referral to a special tertiary centre is recommended.
Aims Hybrid lesions containing distinct components of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) within a single nodule are exceptionally rare. This study aimed to investigate the biological nature of these unusual lesions. Methods and results The two cases identified to date were examined by histopathological, immunohistochemical and targeted next‐generation sequencing analyses. In case 1, the hybrid tumour (6.0 cm) consisted of approximately equal proportions of HNF1α‐inactivated HCA and FNH, which were intimately admixed but remained histologically distinct. In case 2, the tumour (9.5 cm) consisted predominantly of HNF1α‐inactivated HCA but contained a small peripheral nodule of FNH, resulting in a nodule‐in‐nodule appearance. The HCA components in both cases showed loss of FABP1 expression, whereas the FNH components retained FABP1 expression and showed a map‐like pattern of glutamine synthetase expression. Next‐generation sequencing in case 1 demonstrated that the mutations were not shared between the HCA and FNH components, with HNF1A and FLT1 mutations identified only in the HCA component. In case 2, the same HNF1A splice‐site mutation was identified in both the HCA and FNH components, but was also present in the non‐neoplastic gallbladder, confirming its germline origin. The HCA component, but not the FNH component, additionally harboured somatic mutations in ATM and FAT4 . Conclusion HCA, particularly the HNF1α‐inactivated subtype, rarely coexists with FNH. The distinct molecular and immunohistochemical profiles of the two components support a collision mechanism, indicating that the FNH component represents a separate non‐neoplastic lesion and arguing against one component arising from the other.
Neoadjuvant therapy has been recently established as the standard of care in surgically resectable stage III melanoma. Insofar as the extent of tumour response correlates with metrics of patient survival, this underscores the critical ongoing need for rigorous and reproducible approaches to pathological response assessment following surgery. In the current review, we provide a historical overview of early trials assessing safety and efficacy of neoadjuvant targeted and immune therapy, and we summarize the earliest and revised recommendations for pathological response assessment of treated melanoma specimens. Moreover, we highlight that not only the extent of response but also the composition of that response correlates with recurrence‐free survival in these high‐risk patients.
Aims High‐grade B‐cell lymphoma with 11q aberration is a rare neoplasm of mature B‐cell lineage, and large‐scale clinicopathological studies of this disease remain scarce. To bridge this research gap, we conducted a retrospective analysis of HGBCL with 11q aberration, aiming to elucidate its pathogenesis, clinicopathological features and molecular profiles. Methods and results By reviewing our hospital's case database from 2021 to 2025, we retrospectively screened 92 cases of high‐grade or diffuse large B‐cell lymphoma that had 11q fluorescence in situ hybridization (FISH) testing. Among them, 27 cases were confirmed to harbour 11q aberration and were enrolled in the present study. This cohort consisted of 24 males and 3 females with a median age of 61 years (range, 6–85). Eighteen (67%) patients presented with extranodal disease and nine (33%) had nodal disease. The gastrointestinal tract was the most commonly involved extranodal site (13 patients); two of these patients had concurrent lymph node involvement in the head and neck. Fourteen (52%) patients had advanced Ann Arbor stage (III, IV) disease. Eight (30%) patients had a history of immunocompromise including HIV infection, liver or kidney transplantation and other malignant tumours. The bone marrow was negative for lymphoma at initial diagnosis in all 21 patients assessed. Histologically, 20 (74%) cases had Burkitt‐like or blastoid morphology and seven (26%) cases showed diffuse large B‐cell‐like morphology. Most cases (96%, 26/27) had a germinal centre B‐cell immunophenotype. c‐MYC was positive in all 26 tested cases and BCL2 was negative in 24 of 27 (89%) of cases. Mutational analysis was performed in 14 cases and potential driver mutations were identified in all involving 44 genes. The most frequently affected genes included TP53 , IGLL5, DDX3X, BTG2, FOXO1, HIST1H1E and MYC . Following therapy, 24 patients achieved complete remission and disease‐free survival. The prognosis was not related to the morphological features, Ann Arbor stage, co‐occurrence of MYC aberrations or the chemotherapy regimens. Conclusions High‐grade B‐cell lymphoma with 11q aberration may occur across all ages and confers a favourable prognosis. These tumours manifest morphological heterogeneity, and most cases display a Burkitt lymphoma‐like immunophenotype characterized by CD10 positivity and BCL2 negativity. The most frequently mutated genes in our cohort are TP53 , IGLL5 , DDX3X , BTG2 , FOXO1 , HIST1H1E and MYC .
