Virchows Archiv最新文献

Podocyte detachment is a major trigger in pathogenesis of focal segmental glomerulosclerosis (FSGS). Detachment via β1 integrin (ITGB1) endocytosis, associated with endothelial cell injury, has been reported in animal models but remains unknown in human kidneys. The objectives of our study were to examine the difference in ITGB1 dynamics between primary FSGS and minimal change nephrotic syndrome (MCNS), among variants of FSGS, as well as between the presence or absence of cellular lesions (CEL-L) in human kidneys, and to elucidate the pathogenesis of FSGS. Thirty-one patients with primary FSGS and 14 with MCNS were recruited. FSGS cases were categorized into two groups: those with CEL-L, defined by segmental endocapillary hypercellularity occluding lumina, and those without CEL-L. The podocyte cytoplasmic ITGB1 levels, ITGB1 expression, and degrees of podocyte detachment and subendothelial widening were compared between FSGS and MCNS, FSGS variants, and FSGS groups with and without CEL-L (CEL-L( +)/CEL-L( −)). ITGB1 distribution in podocyte cytoplasm was significantly greater in CEL-L( +) group than that in MCNS and CEL-L( −) groups. ITGB1 expression was similar in CEL-L( +) and MCNS, but lower in CEL-L( −) compared with others. Podocyte detachment levels were comparable in CEL-L( +) and CEL-L( −) groups, both exhibiting significantly higher detachment than the MCNS group. Subendothelial widening was significantly greater in CEL-L( +) compared with CEL-L( −) and MCNS groups. The findings of this study imply the existence of distinct pathological mechanisms associated with ITGB1 dynamics between CEL-L( +) and CEL-L( −) groups, and suggest a potential role of endothelial cell injury in the pathogenesis of cellular lesions in FSGS.

ChatGPT, an AI capable of processing and generating human-like language, has been studied in medical education and care, yet its potential in histopathological diagnosis remains unexplored. This study evaluates ChatGPT’s reliability in addressing pathology-related diagnostic questions across ten subspecialties and its ability to provide scientific references. We crafted five clinico-pathological scenarios per subspecialty, simulating a pathologist using ChatGPT to refine differential diagnoses. Each scenario, aligned with current diagnostic guidelines and validated by expert pathologists, was posed as open-ended or multiple-choice questions, either requesting scientific references or not. Outputs were assessed by six pathologists according to. (1) usefulness in supporting the diagnosis and (2) absolute number of errors. We used directed acyclic graphs and structural causal models to determine the effect of each scenario type, field, question modality, and pathologist evaluation. We yielded 894 evaluations. ChatGPT provided useful answers in 62.2% of cases, and 32.1% of outputs contained no errors, while the remaining had at least one error. ChatGPT provided 214 bibliographic references: 70.1% correct, 12.1% inaccurate, and 17.8% non-existing. Scenario variability had the greatest impact on ratings, and latent knowledge across fields showed minimal variation. Although ChatGPT provided useful responses in one-third of cases, the frequency of errors and variability underscores its inadequacy for routine diagnostic use and highlights the need for discretion as a support tool. Imprecise referencing also suggests caution as a self-learning tool. It is essential to recognize the irreplaceable role of human experts in synthesizing images, clinical data, and experience for the intricate task of histopathological diagnosis.

Graphical Abstract

The section on mesenchymal tumors in the 5th edition of WHO classification of skin tumors has undergone several changes, the most important of which is the inclusion of newly identified tumor entities, which will be the main focus of this review article. These specifically include three novel cutaneous mesenchymal tumors with melanocytic differentiation, and rearrangements of the CRTC1::TRIM11, ACTIN::MITF, and MITF::CREM genes as well as EWSR1::SMAD3-rearranged fibroblastic tumors, superficial CD34-positive fibroblastic tumors, and NTRK-rearranged spindle cell neoplasms. Some of the other most important changes will be briefly mentioned as well.

Embryonic-type neuroectodermal tumor (ENT) is a somatic-type malignancy characterized by overgrowth of embryonic-type neuroectodermal tissue (EtNT). In germ cell tumors, EtNT is frequently intermingled with other components that may exhibit significant morphologic overlap [mature neuro-glial tissue (MNGT), nephroblastomatous tissues, and primitive endodermal-type glands]. Therefore, the quantification of EtNT (crucial for the diagnosis of ENT) can be challenging. In this study, we investigated the immunohistochemical profile of ENT, EtNT, and MNGT using a broad immunohistochemical panel. We found that SOX2 was the most sensitive marker for EtNT (100%), but it also stained MNGT (28.6%). GFAP and S100 were relatively sensitive (71.4%) and highly specific (GFAP 100%, S100 85.8%) for MNGT, whereas synaptophysin stained both. Combining our results with those of previous studies, we propose that a combination of SOX11, SOX2, GFAP, S100, AFP, villin, CDX2, PAX8, and nuclear WT1 may help to identify and quantify EtNT in germ cell tumors.

Neural epidermal growth factor-like 1 protein (NELL1) is the second most common target antigen in membranous glomerulonephritis (MGN). However, data regarding the clinicopathological characteristics of NELL1-associated MGN are limited owing to its low prevalence. This study examined the prevalence and clinicopathological characteristics of NELL1-associated MGN in a Japanese cohort. Additionally, we compared the clinicopathological features of NELL1-positive MGN, phospholipase A2 receptor 1 (PLA2R1)-positive MGN, and MGN negative for all three antigens (NELL1, PLA2R1, and thrombospondin type-1 domain-containing 7A). Among 257 consecutive patients pathologically diagnosed with MGN at two centers in Japan, 24 (9.3%) were immunohistochemically positive for NELL1. Clinically, patients with NELL1-positive MGN were significantly older (p < 0.001) and had a higher frequency of bucillamine use (vs PLA2R1-positive MGN, p < 0.01). Histologically, NELL1-positive MGN exhibited significantly lower detection of spikes and crater formation (p < 0.001), higher prevalence of segmental spike distribution (vs PLA2R1-positive MGN: p < 0.001), and higher prevalence of stage I cases on electron microscopy (p < 0.01). There were no significant differences in the prognoses among the three groups. The characteristic histological feature of segmental distribution in NELL1-positive MGN may be related to bucillamine use and the early phase of the disease. Further investigations with larger numbers of patients may offer further insight into the prognosis of patients with NELL1-positive MGN.

Inguinal lymph node surgery is a standard treatment for penile cancer patients with intermediate or high risk for lymph node metastasis (LNM) according to European Association of Urology (EAU) risk grading. We are proposing a more objective histological prognostic grading system for inguinal LNM in these patients. We assessed worst pattern of invasion, lymphocytic host response, lymphovascular invasion, and perineural invasion in a population-based cohort of 306 penile cancer patients. Patients were classified into low, intermediate, and high risk for inguinal LNM. There was a significant association both between risk groups and pT stage (p < 0.001) and between risk groups and LNM. Univariate logistic regression showed 25.43 times higher odds of LNM for patients in the intermediate risk group compared with the low risk group (odds ratio (OR) 25.43; 95% confidence interval (CI): 5.94–108.97) and a 177.13 times higher odds in the high risk group compared to the low risk group (OR 177.13; 95% CI: 40.09–782.51). When comparing our histological risk grading with the EAU grading, we found a higher sensitivity, of 51.28% (95% CI: 45.68–56.88) versus 37.09% (95% CI: 31.68–42.50), as well as a higher area under the curve (0.86; 95% CI: 0.81–0.89; versus 0.65; 95% CI: 0.58–0.71) with our grading system. While our grading classified 111 patients as low risk, only 31 were considered low risk for LNM according to the EAU risk classification. The new histological risk grading system shows a higher sensitivity and includes a higher number of patients in the low risk group in whom lymph node surgery could be avoided, reducing morbidity and costs.

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21-52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.

Accelerated chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL/SLL) is a histologically aggressive subtype of CLL/SLL that lies in between conventional CLL/SLL (C-CLL/SLL) and Richter transformation (RT) on the biological spectrum. Although the histologic criteria for A-CLL/SLL were defined 14 years ago, the clinical and genetic characteristics and survival outcomes of these patients have yet to be studied in the era of novel therapies. We retrospectively analyzed the clinicopathologic, genetic, and survival characteristics of 34 patients with confirmed tissue diagnosis of A-CLL/SLL and compared them with 120 patients with C-CLL/SLL. Patients with A-CLL/SLL had significantly higher frequencies of B-symptoms, anemia and thrombocytopenia, splenomegaly, higher LDH, and more advanced Rai stages. A-CLL/SLL showed a significantly higher frequency of TP53 mutations (55.0% vs. 11.5%;p < 0.0001) and deletions (38.2% vs. 8.3%;p < 0.0001), lower isolated del(13q) (5.8% vs. 27.5%;p < 0.0001), and increased incidence of RT (11.76% vs. 0.83%;p = 0.0025). The overall survival of patients with A-CLL/SLL was significantly lower than C-CLL/SLL (median survival: 6.17 years vs. not reached; 2 and 5-year survival rates: 75.5% vs. 94.7% and 53.3% vs. 93.7%, respectively; p < 0.0001); however, novel agents have improved the outcomes dramatically compared to the previously published data in the pre-BTKi era. Our results support the categorization of A-CLL/SLL as a distinct biologically aggressive subtype of CLL/SLL and highlight the need to revise the diagnostic criteria utilizing a multifaceted approach that integrates the overall pathobiological profile of the disease, in addition to the histology.