Virchows Archiv最新文献

Introduction: Neoadjuvant concurrent chemoradiotherapy (CCRT) is routinely used before surgery in patients with locally advanced rectal cancer to reduce tumor size and decrease the risk of local recurrence. However, the disease-specific survival has not improved in most cases due to distant metastases. In selected individuals exhibiting a clinical complete response, non-operative management may be allowed; however, those who presented no or little response tend to have an inferior prognosis. Consequently, refined molecular characterization could aid in predicting which patients would benefit from neoadjuvant chemoradiotherapy.

Methods: The mRNA level (by transcriptomic profiling) and protein expression (by immunohistochemical staining) of C-X-C motif chemokine ligand 11 (CXCL11) were integrated to predict neoadjuvant chemoradiotherapy efficacy. For survival analysis, clinicopathological features and CXCL11 immunoreactivity that were statistically significant in univariate analysis were included in multivariate analysis using the Cox proportional hazards regression model.

Results: We identified that the CXCL11 level exhibits the most significant downregulation among neoadjuvant chemoradiotherapy non-responders. Using tumor samples from our rectal cancer cohort (n = 343) with immunohistochemistry validation, we demonstrated that low CXCL11 immunoexpression shows significant correlations with advanced disease and positive lymph nodes both prior to and following CCRT (all p < 0.001), vascular and perineural invasion (p < 0.001 and p = 0.006), and poor response to CCRT (p < 0.001). Moreover, low CXCL11 immunoexpression was an independent adverse prognostic factor significantly associated with patient survival. Additionally, we further identified pyroptotic cell death as an unrevealed role of CXCL11 in rectal cancer through bioinformatic analysis.

Conclusion: CXCL11 expression may serve as an early predictor of clinical outcomes and aid in therapeutic decision-making by identifying individuals likely to respond to neoadjuvant chemoradiotherapy in rectal cancer.

Recurrent mutations in the CTNNB1 or APC genes leading to the activation of the Wnt/betacatenin pathway are observed in adnexal tumors with matrical differentiation. While most pilomatricomas arise sporadically and harbor CTNNB1 mutations, cutaneous hybrid cysts combining epidermal and matrical differentiations have been mostly reported in a context of the familial adenomatosis polyposis/Gardner's syndrome related to germinal mutations of APC. The objective of this study is to understand the pathogenesis of hybrid cysts combining epidermal and matrical differentiations. The 287 cases diagnosed as pilomatricoma/hybrid cysts registered between January 1, 2015 and February 21, 2023 in the Pathology Department at Tours University Hospital Center were considered for inclusion. After diagnosis confirmation, all cases were classified as pilomatricomas or hybrid cysts. Clinical data and microscopic features of the two groups were compared. Immunohistochemical detection of the betacatenin and CTNNB1/APC genes sequencing were performed in all hybrid cysts. Among the cohort, ten cases were classified as hybrid cysts (4%). None had a personal or familial history of familial adenomatosis polyposis. The immunochemistry confirmed a betacatenin nuclear expression in the matrical component in all excepted one cases, while no nuclear accumulation was observed in the epidermal component of most hybrid cysts (n = 8, 80%). CTNNB1 mutations were detected in all hybrid cysts with interpretable sequencing data (n = 7/10). By contrast, only a variant of uncertain significance (class 3) was detected in APC in association with a pathogenic CTNNB1 mutation in one case. Hybrid cysts are rare entities consisting in 4% of the tumors analyzed in our study. Our results suggest that most hybrid cysts occur sporadically and are associated with CTNNB1 somatic mutations.

A new era in cancer therapy emerged with the arrival of immune-checkpoint inhibitors (ICIs), followed by a new cadre of immune-related adverse events that affect up to 40% of patients. Literature on the pathological features associated with these events is still limited. Therefore, to expand our knowledge of the histopathologic spectrum of pulmonary changes, we conducted a case study series analysis on 16 non-neoplastic lung samples collected during or after ICI therapy. A set of predefined histological features related to the four different "compartments" (interstitium, pneumocyte, alveolar space, and bronchial mucosa), the CD4/CD8 T cell ratio, and the SP263 PD-L1 expression in the immune cells was assessed in three study categories [ICI + radiotherapy with/without chemotherapy (RT-based), ICI + chemotherapy (CT-based), ICI-based monotherapy (ICI-mono)]. Our results identified interstitial thickening, interstitial lymphocytic infiltrate, pneumocyte desquamation, intra-alveolar fibrin, or foamy macrophages in at least half of the cases in each of the study categories; all five features were present in 4 (RT-based), 3 (CT-based) and 1 (ICI-mono) patients. Hyaline membrane was a frequent finding in CT-based (80%) and ICI-mono (100%) compared to RT-based (44%) category. Moreover, CD4/CD8 ratio was ≤ 1 for almost all cases of the three study categories. Finally, a positive SP263 PD-L1 expression was identified in 50% or more of each study category. In conclusion, our results indicate that histopathologic findings in patients treated with ICI therapy are not diagnostic and varied. Additionally, these results are in line with recent studies showing an expansion on CD8⁺ T cell subset in patients under ICI treatment and highlight the synergism of polytherapy.

Our study aimed to investigate the clinicopathologic and molecular features of endocervical adenocarcinoma with a micropapillary component (EAC-MP) in the setting of current classification schema. We investigated 26 EAC-MP from consecutive 511 adenocarcinomas. HER2 status was analyzed by immunohistochemistry and fluorescence in situ hybridization. Four cases were performed with targeted next-generation sequencing (NGS). We found that HPV-associated adenocarcinomas (HPVA) with a micropapillary component (HPVA-MP) (n = 12) had a higher frequency of large tumor size (> 2 cm), Silva pattern C (12/12, 100%), invasion of the deep cervical wall (> 2/3) (8/12, 66.7%), lymphovascular space invasion (LVSI) (11/12, 91.7%), lymph node metastasis (4/11, 36.4%), FIGO stage III/IV (4/12, 33.3%), and HER2 amplification (3/12, 25%, P = 0.015), compared to those without (HPVA-NMP (all P < 0.05). HPV-independent adenocarcinomas (HPVI) with a micropapillary component (HPVI-MP) (n = 14) had LVSI more commonly than those without (HPVI-NMP) (P = 0.033). Survival analysis indicated that HPVA-MP was associated with worse overall survival and recurrence-free survival than HPVA-NMP (P < 0.01). Particularly, in patients with Silva pattern C, HPVA-MP appeared to have more adverse clinical outcomes (P < 0.01). No survival differences were found in HPVI-MP versus HPVI-NMP (P > 0.05). NGS identified significant mutations in STK11, TERT, ERBB2, TP53, PIK3CA, ARID1A, and NTRK2. We conclude that the micropapillary structure is an indicator for unfavorable clinical outcomes in HPVA, and can aid in the prognostic stratification of Silva pattern C EAC. The presence of HER2 amplification and specific gene mutations raise the possibility for targeted therapy in the future.

This report documents the first case of a conventional (bone-type) giant cell tumor of the larynx, in which the diagnosis was confirmed by molecular genetic analysis. A 50-year-old non-smoking man experienced progressive hoarseness lasting for 3 months. Imaging showed a 40-mm tumor arising from the right thyroid cartilage. The total laryngectomy was performed. Grossly, the tumor was solid and whitish, with areas of hemorrhage. Microscopically, the tumor consisted of a biphasic population with mononuclear cells with round to oval nuclei, small nucleoli, and pale eosinophilic cytoplasm admixed with evenly distributed dispersed osteoclast-like giant cells. Immunohistochemically, the neoplastic mononuclear cells expressed diffusely vimentin and p63 and focally SATB2. Admixed mononuclear histiocytes coexpressed CD68 and CD163, while the osteoclast-like giant cells showed only CD68 expression. Most importantly, all mononuclear tumor cells showed strong nuclear expression of anti-histone H3.3 G34W antibody. Subsequent next-generation sequencing confirmed the missense mutation of gene H3-3A: c.103G>T (p.Gly35Trp).

The majority of mastocytosis cases are characterized by an activating mutation in the KIT gene in codon 816. The detection of this alteration is of importance for proper diagnostic workup. Therefore, reliable and sensitive methods for the detection of KIT Codon 816 hotspot mutations in various types of patient samples are required. Since mutated cancer genes are often overexpressed, we evaluated the feasibility and sensitivity of KIT p.D816V detection by analysing mRNA/cDNA instead of genomic DNA. From 80 bone marrow trephines harboring a KIT p.D816 mutation, seven were only mutated by mRNA/cDNA pyrosequencing and 11 only by digital PCR analysis of genomic DNA. These results clearly demonstrate that detection of clinically relevant mutations in mRNA extracted from routinely processed decalcified archival bone marrow trephines is not only possible in a reliable fashion but under many circumstances advantageous. This enables the direct correlation of genomic data with high-quality morphological evaluation.

Sclerosing mucoepidermoid carcinoma (SMEC) of the salivary glands is a rare variant of low-grade mucoepidermoid carcinoma with scanty cellular atypia characterized by marked fibrosis/sclerosis and a rich inflammatory infiltrate. Herein, we report 25 unpublished cases of SMEC, two of them with prominent eosinophilia (2/25; 8%) and three with abundant IgG4-positive plasma cells (3/25; 12%). In our series of salivary SMEC, molecular analysis using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) provided evidence of MAML2 gene rearrangement in 18 cases of the 21 analyzable cases tested (86%), while this gene locus was intact in 3 cases (14%). This study focuses on the diagnostic criteria of salivary SMEC given its challenge of abundant collagenous stroma, minimal residual neoplastic areas, and inconspicuous mucous cells. Follow-up data of our cases indicate that salivary SMECs have favorable outcomes. Molecular analysis for MAML2 gene rearrangement suggests that SMECs of salivary glands represent a rare variant of conventional low-grade MECs of salivary glands. In contrast, SMECs of the thyroid gland are genetically distinct from salivary-type thyroid MECs.

This review article focuses on the various primary osseous tumors of the orbit. Due to overlapping clinical, radiologic, and histologic features, differentiating these entities can pose significant challenges diagnostically. In this review, emphasis is placed on key distinguishing clinical, morphologic, immunophenotypic, and molecular characteristics. Also described are important prognostic details, recurrence risks, and the gold standard treatment methods for each entity. Relevant genetic syndrome associations are additionally covered. Orbital bone entities discussed include osteoma, osteoid osteoma, osteoblastoma, ossifying fibroma, fibrous dysplasia, aneurysmal bone cyst, osteosarcoma, Ewing sarcoma, and mesenchymal chondrosarcoma.

Ki-67 index (Ki-67i) is integral to the grading of many tumours. There remains considerable variability across pathologists in methods used to determine Ki-67i and in their results. Manual counting (or "eyeballing") is widely used, but digital pathology tools such as web-based image analysis and artificial intelligence-assisted cell detection software have become available in daily pathology practice. This study aims to compare the accuracy and efficiency of manual and two digital methods of Ki-67i determination. H&E and Ki-67 immunohistochemical (IHC) slides/images of 12 gastrointestinal neuroendocrine tumours (GI-NETs) were provided to 8 pathologists to evaluate Ki-67i via manual estimation (ME; the "past"), web-based image analysis using cellular segmentation (AI4Path.ca; the "present"), and software-based image analysis with built-in AI algorithms (QuPath; the "future"). Data collected include Ki67i, time expended, total cells counted, and pathologists' confidence level in the reported result. Deviation of Ki-67i from a gold standard result (GS) was analyzed using multiple linear regression, and results were compared via paired t test. Our results found no statistically significant differences in Ki-67i deviation from GS when comparing ME and AI4P methods for all 12 cases. The QP Ki-67i detection accuracy varied significantly. ME was the method with the least time expenditure. Junior pathologists are less confident in ME. Grading consensus was comparable among all three methods. These findings suggest that while digital pathology can confer increased Ki-67i accuracy in some cases of GI-NETs, higher time expenditure and proper hotspot selection may represent barriers to the adoption of digital pathology methods in the future.