Virchows Archiv最新文献

Pancreatic heterotopia (PH) is a well-characterized entity that can arise in the gastrointestinal tract. Many pancreatic disease processes, ranging from inflammatory to neoplastic, can also be seen in PH. Neoplastic transformation in PH remains exceedingly rare. A retrospective review of PH cases (1990 to 2020) excised at our institution was performed. Cases were selected based on prior criteria for identifying neoplastic transformation in PH. Clinical information was obtained through the electronic medical record. A total of 163 gastrointestinal tract PH cases were identified. Of these, seven had a neoplastic process in the heterotopic pancreas: two with well-differentiated neuroendocrine tumors, three with pancreatic intraepithelial neoplasia, and one each developed ductal adenocarcinoma or neuroendocrine microadenoma. The majority were men (71.4%) with a median age of 64 years. Seven patients had clinical symptoms including weight loss, abdominal pain, and small bowel obstruction. Five cases arose in the small intestine and two cases arose in the stomach. Lesions involved the submucosa (42.8%), serosa (28.6%), and muscularis propria (28.6%). In all cases, the PH was composed of acini, ducts, and islet cells. The mean follow-up time was 55 months (range: 3-159 months). One patient had regional lymph node metastasis and died with disease from surgical complications. No cases of distant metastasis were identified. Neoplasia in PH is a rare phenomenon that can occur, including malignant entities such as ductal adenocarcinoma, but also other tumor types. Recognition of this entity remains important for pathologists to avoid diagnostic confusion and provide accurate tumor staging.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of significant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic differences in populations or differences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will find an overview of the mutational profile of conventional HNSCC according to published results on massive parallel sequencing data that confirm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also find a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identified in HNSCCs before the development of these techniques, the differences that can be site-specific, such as the different mutational signatures that indicate specific carcinogens for various subsites of the head and neck, and finally, the actionability of these findings that should allow more personalized therapy for patients.

This study provides an analysis of 37 ovarian Sertoli-Leydig cell tumors (SLCT), focusing on their morphological, immunohistochemical, and molecular features. The cohort was comprised of 9 well-differentiated, 25 moderately differentiated, and 3 poorly differentiated tumors. The immunohistochemical analysis was performed with 28 markers, including diagnostic markers and markers with possible predictive significance. The results showed high expression of sex cord markers (FOXL2, SF1, inhibin A, CD99, calretinin, ER, PR, AR), and variable expression of other markers such as CKAE1/3 (83%), CAIX (14%), and MUC4 (1%). Loss of PTEN expression was present in 14% of cases, and CTLA4 expression was seen in 43% of cases. All tumors were MMR proficient and HER2 and PD-L1 negative. The molecular analysis showed DICER1 mutations in 54.5% of cases, and a FOXL2 mutation in 6% of tumors. In addition, we detected 2 cases with TERT promoter mutation. RNA NGS sequencing identified significant differences in mRNA expression between DICER1^MUT and DICER1^WT tumors. The DICER1^WT tumors showed increased expression of PRKCA, HNF1A, LDLR, and MAP2K5. On the contrary, the DICER1^MUT cases showed increased expression of CDK6, NOTCH2, and FGFR2. The results of our study show that SLCTs exhibit distinct molecular features based on their degree of differentiation. We have confirmed that DICER1 mutations are characteristic of moderately and poorly differentiated SLCTs, while well-differentiated SLCTs may represent a distinct entity. DICER1^MUT and DICER1^WT tumors showed different mRNA expression profiles. The FOXL2 mutation is less common in these tumors and is mutually exclusive with the DICER1 mutation.

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.

Several distinctive round cell sarcomas have emerged by leveraging new testing modalities to include immunohistochemistry, next-generation sequencing, methylation array, and others. While Ewing sarcoma has led the way as the prototypic round cell sarcoma, more recently described round cell sarcomas of bone and soft tissue are now recognized which have unique clinical, morphologic, immunophenotypic, and genetic signatures. While each of these entities is less common than Ewing sarcoma, it is important to distinguish these tumors for correct diagnosis, prognostication, and potential treatment management. The focus of this review will cover CIC-rearranged sarcoma, BCOR-altered sarcomas, and EWSR1-non-ETS sarcomas to include recent developments in desmoplastic small round cell tumor as well as sarcomas with EWSR1/FUS::NFATc2 and EWSR1::PATZ1 gene fusions, highlighting the clinical, morphologic, and immunophenotypic clues to the diagnosis with recognition of each molecular diagnostic hallmark.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.