Virchows Archiv最新文献

Prostate cancer diagnosis primarily relies on histological confirmation via needle core biopsy, with systematic 12-core biopsies (SB) being commonly used. Multiparametric magnetic resonance imaging (mpMRI) and MRI-targeted biopsies have shown enhanced detection of clinically significant prostate cancer. This study compares two tumor grading methods-aggregate and individual grading-used in MRI-targeted biopsies to assess their correlation with the final ISUP Grade Group (GG) of the RPE. A cohort of 108 patients with ≥ 2 positive cores in at least one MRI-targeted biopsy, totaling 179 positive lesions, was analyzed. Systematic and MRI-targeted biopsies were correlated with RPE specimens. The mean highest ISUP GG for systematic biopsies was 2.77 (SD ± 1.29), compared to 2.62 (SD ± 1.13) for targeted biopsies using the aggregate method. Comparing the highest ISUP GG in systematic as well as targeted biopsies with the final ISUP GG of the RPE, exact correlation between GG was found in 70.1% (aggregate) and 66.4% (individual) for targeted biopsies and 58.1% for systematic biopsies. The results of the individual method showed slightly better correlation with the final ISUP GG from the RPE specimen in only 0.93%, while in 2.8% of cases, it resulted in inferior correlation compared to the aggregate method. Our findings suggest that the aggregate grading method of targeted biopsies is preferable due to its comparable predictive accuracy, lower workload, and alignment with existing clinical guidelines. This supports the ISUP's recommendation to use the aggregate method for MRI-targeted biopsies in clinical practice. Further research is needed to standardize reporting protocols for MRI-targeted biopsies and refine their integration into prostate cancer risk stratification models.

Ceruminous adenomas are benign neoplasms that arise from ceruminous glands in the external auditory canal. While these tumors are currently regarded as a single entity, they are divided into three histologically diverse subtypes: ceruminous syringocystadenoma papilliferum, ceruminous pleomorphic adenoma, and ceruminous adenoma not otherwise specified (NOS). Given the similarities of two of these subtypes to other tumors that occur at multiple anatomic sites, it is currently unclear whether ceruminous adenomas are truly a unified group. In this study, we performed targeted molecular profiling of 11 cases of ceruminous adenoma to clarify their classification. We identified BRAF V600E mutations (via PCR and/or immunohistochemistry) in five ceruminous syringocystadenomas papilliferum. We also identified HMGA2::WIF1 fusions (via RNA sequencing) in five ceruminous adenomas NOS and one ceruminous pleomorphic adenoma. Tumors with HMGA2::WIF1 fusion did not display the canalicular adenoma-like morphology seen in salivary gland pleomorphic adenomas with this fusion. Overall, these findings suggest that the three subtypes of ceruminous adenoma represent two biologically distinct groups. Recurrent BRAF V600E mutations in ceruminous syringocystadenoma papilliferum are parallel to those in cutaneous syringocystadenoma papilliferum. Histologic and molecular concordance suggests that ceruminous syringocystadenoma papilliferum should be part of the broader syringocystadenoma papilliferum category rather than a subtype of ceruminous adenoma. Conversely, HMGA2::WIF1 fusions in ceruminous adenoma NOS and ceruminous pleomorphic adenoma suggest that a stromal component may not be an essential point of distinction between these groups. These residual true ceruminous adenomas all likely represent a specialized form of mixed tumor unique to the external ear.

"Spin" - the overinterpretation of research findings - has been assessed in experimental and synthesis designs of interventional evidence. Little attention has been given to the assessment of spin in diagnostic evidence bases. Therefore, we conducted a cross-sectional study to assess for spin found within diagnostic accuracy meta-analyses published in top pathology journals. We searched PubMed for diagnostic test accuracy meta-analyses published in top 20 pathology journals from past to present. We applied published methodology to identify the presence of 10 items of actual overinterpretation and 9 items of potential overinterpretation. Authors screened and extracted relevant data from sample studies in a masked duplicate fashion to reduce extraction errors. On September 21st, 2023, we identified 207 articles from PubMed for potential inclusions. After screening, 55 abstracts and full-texts were available for full data extraction. with 80% (44/55) having positive conclusions germane to accuracy or clinical implications. Every meta-analysis contained one item of spin. Most positive conclusions in abstracts (75%; 33/44) and full-texts (79.6%; 35/44) did not adequately reflect pooled estimates while 19 (34.5%) studies employed non-recommended statistical approaches for pooling accuracy measures. Diagnostic test accuracy meta-analyses found within top pathology journals consistently overstate their conclusions. Authors should contextualize diagnostic summary effects within predetermined diagnostic performance. Further, authors should ensure that summary estimates are pooled using bivariate or hierarchical approaches that maintain threshold effects throughout meta-analytic calculations. Readers should cautiously interpret meta-analyses that fail to report sample sizes and confidence intervals of summary estimates.

The last decades have seen a constant decline in non-forensic clinical autopsy rates worldwide. In this context, post-mortem computed tomography (PMCT) and post-mortem magnetic resonance imaging (PMMR) might offer an alternative to the clinical autopsy. So far, post-mortem imaging is used routinely only in forensic medicine, but it has not yet been implemented into routine clinical pathology casework. This study aimed to assess the diagnostic accuracy of unenhanced PMCT and PMMR for basic pathology groups and specific diagnoses compared to the clinical autopsy. Post-mortem imaging (PMCT and PMMR) was conducted before autopsy on n = 120 non-forensic patients deceased in hospitals in a prospective study. Imaging findings were compared to autopsy findings, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for causes of death and specific pathologic findings. Some of the diagnoses recorded showed high specificity and NPV of over 85% for both PMCT and PMMR. However, even the combined use of PMCT and PMMR could not visualize various relevant autopsy findings such as those related to sepsis, hematologic malignancies, chronic liver congestion, endomyocardial, myocardial, and liver fibrosis, acute tubular necrosis, aortic valve stenosis, duodenal ulceration, and small macroscopic findings in general. For specific findings, post-mortem imaging showed no significant differences to autopsy and high diagnostic accuracy with over 85% sensitivity. Examples for such findings included the diagnosis of acute myocardial infarction and pulmonary embolism in PMMR, pneumonia in PMCT, as well as pancreatitis, abscesses, metastases, and aortic dissection in both PMCT and PMMR.

Eosinophilic/oncocytic renal cell neoplasms represent a diagnostically challenging group of tumors with overlapping morphologic and immunophenotypic features. Recent advances in molecular genetics have expanded the spectrum of FLCN-mutated renal tumors, including both Birt-Hogg-Dubé (BHD) syndrome-associated and sporadic cases. This study aimed to characterize the clinicopathologic and molecular features of five FLCN-mutated eosinophilic renal tumors, emphasizing their diagnostic pitfalls and heterogeneity. The cohort included three male and two female patients (median age: 61 years) with solitary renal masses (median size: 3 cm), all incidentally detected and managed surgically (partial/radical nephrectomy). All patients lacked clinical stigmata of BHD syndrome (cutaneous fibrofolliculomas, pulmonary cysts) or relevant family history. Histologically, tumors exhibited diverse patterns (solid-nested, tubuloacinar, trabecular) with uniform eosinophilic cytoplasm, low-grade nuclei, hemorrhagic and edematous stroma, and prominent branching dilated vasculature, along with distinctive features such as intraluminal foamy histiocytes, psammomatous calcification, and thyroid follicle-like secretions (all classified as non-conventional FLCN-mutated tumors). None of the cases showed renal oncocytosis in the surrounding renal parenchyma. Immunohistochemically, all cases showed diffuse GPNMB expression, while TFE3 was weakly expressed in one case. Molecular profiling identified pathogenic/likely pathogenic FLCN mutations (truncating mutations in four cases, missense variant in one) without concurrent alterations in TSC1/2, MTOR, FH, SDHx, or MiT family genes. Over a median follow-up of 38 months, no recurrence or metastasis occurred, suggesting an indolent behavior. These findings highlight the morphologic mimicry of FLCN-mutated tumors with a spectrum of renal neoplasms characterized by low-grade eosinophilic features, particularly TSC/MTOR-altered or MiT family renal neoplasms, underscoring the necessity of integrated immunohistochemical (GPNMB) and molecular testing for accurate diagnosis. Despite their heterogeneity, FLCN-mutated tumors typically follow a benign clinical course, though rare aggressive variants warrant vigilance.

In recent years, multiple molecularly defined entities have emerged in head and neck pathology, especially among sinonasal squamous and basaloid carcinomas, including NUT carcinoma, SWI/SNF-deficient carcinoma, and DEK::AFF2 carcinoma. These tumors show significant morphological and immunophenotypic diversity. We present five novel head and neck carcinomas harboring AFF2 rearrangements involving previously unreported fusion partners. Five cases (3 males, 2 females; ages 35-72 years) presented with tumors in the sinonasal region (n = 4) and parotid gland (n = 1), measuring between 3.3 and 6.3 cm. RNA sequencing identified fusions involving AFF2 with H3-3A, EWSR1, CHD4 (two cases: neck lymph node metastasis, which turned out to be sinonasal primary and parotid mass), and NUCKS1. Tumors harboring H3-3A::AFF2 and NUCKS1::AFF2 fusions exhibited bland transitional cell-like morphology with acantholytic changes similar to classic DEK::AFF2 carcinoma; the NUCKS1 fusion also demonstrated clear cell features. In contrast, the EWSR1::AFF2 fusion tumor showed high-grade adenocarcinoma morphology with focal neuroendocrine marker expression, lacking p63 and CK5/6. The two CHD4::AFF2 fusion cases demonstrated neuroendocrine differentiation; one was a cytokeratin-negative small blue round cell carcinoma, and the other showed mixed squamoid-neuroendocrine features with strong cytokeratin and p63 expression. All tumors demonstrated consistent AFF2 immunoreactivity. These findings suggest that AFF2-rearranged tumors form a spectrum of carcinomas with diverse morphologies, immunophenotypes, and differentiation patterns. Given the consistent involvement of the AFF2 gene and uniform AFF2 immunohistochemical positivity despite morphological heterogeneity, we propose naming this entity AFF2 carcinoma.

Epithelioid leiomyosarcoma (ELMS) of the uterus is an uncommon and diagnostically challenging variant of leiomyosarcoma. We report, to our knowledge, the first ELMS harboring an HMGA2::RAD51B fusion and delineate its clinicopathologic and molecular features. A 64-year-old woman underwent total hysterectomy with bilateral salpingo-oophorectomy for a large myometrial mass initially favored as endometrial stromal sarcoma. Histology showed a multinodular, infiltrative tumor composed of epithelioid cells in trabecular and solid nests within hyalinized stroma, with moderate atypia and brisk mitotic activity (up to 14/10 high-power fields; ~ 6 mitoses/mm²). Infarct-type necrosis was present without unequivocal tumor cell necrosis. Immunohistochemistry supported smooth-muscle differentiation (alpha-smooth muscle actin diffuse; desmin focal; h-caldesmon rare) with estrogen receptor and HMGA2 positivity and negativity for melanocytic markers (HMB45 and Melan-A). RNA-based targeted sequencing (Archer FusionPlex Sarcoma) detected a high-confidence, in-frame HMGA2 (exon 3)::RAD51B (exon 11) fusion. The integrated morphologic, immunophenotypic, and molecular profile excluded endometrial stromal sarcoma with smooth-muscle differentiation, perivascular epithelioid cell tumor, and uterine tumor resembling ovarian sex-cord tumor, establishing ELMS. The patient remains disease-free at 4 months. This case expands the molecular spectrum of ELMS and, concomitantly, broadens the emerging morphologic spectrum of RAD51B-rearranged uterine sarcomas, underscoring the diagnostic value of fusion testing in unusual uterine mesenchymal neoplasms.

The promising efficacy of novel anti-HER2 antibody-drug conjugates in breast cancer has led to the recognition of HER2-low and HER2-ultra-low in advanced solid tumors, including salivary gland carcinomas. In this study, we explore the frequency of HER2-low and HER2-ultra-low immunoexpression in a retrospective cohort of 81 salivary gland carcinomas, including 35 salivary duct carcinomas (SDC) and 46 non-SDCs. HER2 immunohistochemistry was interpreted according to ASCO/CAP guidelines. Among SDCs, the frequency of HER2-positive (3 +), HER2-low (1 + and 2 +), and HER2-ultra-low (0 +) was 34%, 63%, and 0%, respectively. None of the non-SDCs was HER2-positive (3 +). The rate of HER2 2 + , 1 + , and 0 + was 4%, 32%, and 24%, respectively, in non-SDCs. HER2-low (1 + or 2 +) was seen in 62% of myoepithelial carcinomas, 0% of adenoid cystic carcinomas, 56% of acinic cell carcinomas, and 33% of carcinomas not otherwise specified. HER2-ultra-low (0 +) was observed in 23% of myoepithelial carcinomas, 33% of adenoid cystic carcinomas, 22% of acinic cell carcinomas, and 11% of carcinomas not otherwise specified. Although HER2-positive (3 +) was seen only in SDC, HER2-low and HER2-ultra-low expressions were not uncommon across salivary gland carcinomas, including SDCs and various non-SDC types. These findings suggest the potential applicability of HER2-targeted therapy in salivary gland carcinomas.