Virchows Archiv最新文献

Adenosquamous carcinoma is an uncommon cervical malignancy which is composed of a morphologically recognisable malignant squamous and glandular component. In the current 5th edition WHO Classification of Female Genital Tumours, adenosquamous carcinoma of the cervix is regarded as a high-risk human papillomavirus (HPV)-associated neoplasm. However, in recent years, there have been occasional reports of cervical HPV-independent adenosquamous carcinomas. We report a series of 5 cervical HPV-independent adenosquamous carcinomas in women aged 45 to 68 years; 4 of 5 patients were postmenopausal. The percentage of the squamous component ranged from 10 to 90%. In all cases, the glandular component was gastric-type. All tumours exhibited negative/non-block-type staining with p16 and were also negative for HPV on molecular testing. Molecular testing (4 of 5 cases) revealed no recurrent variants. However, in individual cases, pathogenic or likely pathogenic variants were present in BRAF, CDK12, RB1, FGFR2, FGFR3, BRCA1, KRAS, CDKN1A, CDKN2A, TP53, and STK11. In addition, deletions of CDKN2A/CDKN2B and TP53 were present in 1 case. The tumours were advanced stage at diagnosis: stage IIB (1 case), IIIC1 (2 cases), and IVB (2 cases). Our findings suggest that cervical adenosquamous carcinoma should be classified into HPV-associated and HPV-independent types and this should be reflected in updated WHO Classifications.

Up to 10% of small cell lung carcinomas do not express any neuroendocrine markers and are characterized by an expression of the transcription factor POU2F3. Recently, few cases of poorly differentiated carcinomas harboring POU2F3 expression have been described in the breast, cervix, and bladder. Herein, we report the morphological, immunohistochemical, and molecular characterization of two primary cutaneous POU2F3-expressing small cell carcinomas. The cases arose in the temple and on the occipital region in a 92-year-old woman and a 78-year-old man respectively. Microscopic examination revealed in both cases a large and ulcerated poorly differentiated neoplasm infiltrating the full thickness of the dermis with extension into the subcutaneous tissues in case #1. The tumors harbored solid and trabecular growth patterns and were composed of poorly differentiated highly mitotic cells. Immunohistochemical investigation revealed diffuse pancytokeratin positivity while no expression of cytokeratin 20, chromogranin A, synaptophysin, CD56, or INSM1 was detected. Diffuse nuclear expression of POU2F3 was observed. Transcriptomic analysis revealed a SBS7 mutation signature related to UV-induced DNA damages in one case and evidenced an expression profile similar to the one observed in POU2F3-expressing small cell lung cancers in both. Methylation analysis confirmed the proximity of the two cases with other skin cancers. To conclude, we report herein the first description of primary cutaneous small cell carcinoma POU2F3 subtype.

Mixed yolk sac tumors (YST) with carcinoma or carcinosarcoma (Ca/CS) of the uterus and ovary represent exceptionally rare and aggressive malignancies with poorly characterized genetic drivers. Through an integrated clinicopathologic and molecular analysis of nine cases using immunohistochemistry, fluorescence in situ hybridization, and targeted next-generation sequencing, we identified recurrent somatic driver mutations in TP53 (8/9), PIK3CA (3/9), and PTEN (2/9), and absence of i(12p), confirming their somatic origin. Multi-region sequencing revealed that YST and Ca/CS components share truncal mutations yet harbor divergent genetic alterations, supporting a model of clonal origin and lineage-specific evolution. Therapeutically, we identified a high frequency of actionable alterations, including homologous recombination repair (HRR) gene mutations (4/9), HER2 amplification or low expression (7/9), and biomarkers for immunotherapy (positive PD-L1 in 3/9, TMB > 10 mutations > 10 /Mb in 2/9). Consistent with these findings, two patients derived profound clinical benefit from matched PARP inhibitors or anti-HER2 antibody-drug conjugate. Our findings definitively establish the somatic and clonal nature of these mixed tumors and provide a compelling rationale for molecularly guided treatment.

Choriocarcinoma (CHC) is an aggressive tumor that expresses Nectin-4, which makes it a potential target for enfortumab vedotin (EV). However, only a few cases have been analyzed so far, and the correlation between Nectin-4 and clinical-pathological features has never been investigated. Twenty-one testicular CHCs were collected and stained for Nectin-4. Cytoplasmatic expression was positive in 17/20 primary CHCs (4/20: moderate expression). Membrane expression was positive in 16/20 primary CHCs (5/20: moderate expression). Cytoplasmatic expression was associated with higher % of CHC (p = 0.028) and β-HCG serum levels (p = 0.007); moderate/strong cytoplasmatic expression was associated with younger age (p = 0.0039). The only post-chemotherapy and metastatic CHC showed the highest membrane expression (H-score: 155), especially if paired with its primary (H-score: 33). The Nectin-4 stain was primarily confined to syncytiotrophoblasts rather than to cytotrophoblasts/intermediate trophoblasts. These findings confirm that testicular CHC expresses Nectin-4 and may be potentially targetable with EV. Future studies are needed to verify whether metastasis and chemotherapy up-regulate Nectin-4 and increase the sensitivity to EV, and whether the absence of Nectin-4 expression by cytotrophoblasts (the proliferative population of CHC) influences its potential efficacy.

SMARCA4 (BRG1)-deficient undifferentiated tumor is a rare and highly aggressive malignant tumor. Cases arising in the bladder are exceedingly rare, and their molecular pathogenesis remains poorly understood. Here, we present the first, to our knowledge, report of a case of bladder SMARCA4 (BRG1)-deficient undifferentiated tumor incorporating comprehensive genomic profiling. Ultra-deep sequencing analysis using a 601-gene panel targeting tumor molecular targeted therapy, immunotherapy, and hereditary susceptibility revealed a novel oncogenic nonsense mutation in the SMARCA4 gene (p.K867*), with a high mutant allele frequency of 71%. This mutation has not been previously reported in any tumor type. Meanwhile, loss of heterozygosity was also found in the SMARCA4 gene. Additionally, seven variants with potential clinical significance-TP53 (c.919 + 1G > A), TP53 (c.823dup), FGF19 amplification, FGF3 amplification, CCND1 amplification, FGF4 amplification, and STAG2 (c.289-2A > T)-and nine variants of uncertain clinical significance-BRIP1, EPHA3, FLT4, GLI1, KMT2C, KMT2D, LGMN, MGA, and RICTOR-were detected. This suggests that besides SMARCA4 deficiency, alterations in other genes may cooperatively contribute to the tumorigenesis of bladder undifferentiated tumors. These findings provide a reference for subsequent exploration of precise diagnostic and prognostic assessment and treatment strategies for this disease.

The molecular pathogenesis of uterine adenosarcoma (uAS; synonym: Müllerian adenosarcoma) is confounded by its pathologic heterogeneity, with DICER1 mutations and TP53 pathway alterations reported in most tumors with high-grade morphology, stromal overgrowth and/ or rhabdomyoblastic differentiation. However, a small subset of tumors harbor gene fusions, but their molecular spectrum and clinicopathological correlations have not been defined. We identified 12 uAS-like neoplasms in our files carrying ESR1 gene fusions and reviewed 4 previously reported cases (total: 16). Patient's age range was 34 - 76 years (median, 54). The tumors originated in the uterus body (5), unspecified uterus segment (5), cervix (1) and isthmus (1). Follow-up was available for 6 patients (median 44 months, range 9 months-20 years). One patient developed lung metastasis 52 months later and one had an abdominopelvic recurrence > 20 years later. Four patients were disease-free at 9-55 months. All tumors harbored in-frame ESR1 fusions (10 with ESR1::NCOA3, 1 ESR1:NCOA2 and 1 ESR1::MAMLD1). Nine tumors were low-grade and 3 high-grade. All lacked heterologous elements. Stromal overgrowth was recorded in three (all high-grade) and sex cord-like elements in 4 tumors. Phyllodiform architecture, admixed Mullerian glands, and periglandular stromal condensation distinguished the 4 tumors with sex cord-like elements from conventional uterine tumors resembling ovarian sex cord tumor (UTROSCT). This study expands the overlapping morphologic and molecular spectrum of uterine neoplasms resembling uAS showing recurrent fusions (mostly ESR1::NCOA3/2), associated with mostly low-grade histology, lack of heterologous elements and paucity of stromal overgrowth. The nosological relationship of these uAS-like tumors to UTROSCT (driven similarly by ESR1::NCOA3/2 fusions) and to fusion-negative high-grade uAS remains to be verified in future studies utilizing epigenetics and other tools.

STK11-mutated non-small cell lung cancers (NSCLC) show distinct clinicopathologic features, often with co-occurring KRAS and TP53 mutations that drive more aggressive disease. This study investigates the mutational landscape and clinical characteristics of STK11-mutated lung adenocarcinomas. We retrospectively reviewed 1,068 primary lung cancer cases from 2018 to 2022, identifying 14 STK11-mutant lung adenocarcinomas. We collected clinicopathologic data (demographics, histology, treatment), performed genomic profiling for co-mutations, and used immunohistochemistry to evaluate associated phenotypes. Patients with STK11 mutations (median age 67) were predominantly male smokers. KRAS or TP53 co-mutations appeared in 50% of cases. STK11/KRAS tumors showed higher metastatic rates, while STK11/TP53 tumors had increased necrosis and mitotic activity. Early-stage patients had longer survival, whereas advanced-stage cases faced significantly worse. Those treated with PD-1/PD-L1 inhibitors (Pembrolizumab) had limited benefit, with a median overall survival of 4.1 ± 2.8 months. STK11-mutant NSCLCs-especially with KRAS or TP53 co-mutations-demonstrate aggressive behavior and poor response to current immunotherapies. Comprehensive genomic profiling may help refine understanding of tumour biology and potentially inform treatment decisions. Larger studies are needed to validate these findings, but integrating genomic, pathologic, and clinical data may advance personalized therapy for these patients.

POU2F3 defines tuft cell-like carcinomas, yet POU2F3-driven neuroendocrine neoplasia in the urinary bladder remains incompletely characterized and can morphologically mimic basaloid carcinomas. We report a case of an octogenarian woman with a diverticular bladder tumor composed of conventional high-grade urothelial carcinoma juxtaposed with a sharply demarcated basaloid component. Although the basaloid component lacked classical small-cell morphology and showed scant conventional neuroendocrine marker expression, it was diffusely POU2F3-positive, underscoring a potential diagnostic pitfall with human papillomavirus (HPV)-associated basaloid squamous cell carcinoma. Both components showed concordant aberrant tumor-suppressor immunoprofiles (p53 overexpression and Rb loss), and high-risk HPV RNA in situ hybridization (RNAscope) was negative. This case expands the recognized morphologic spectrum of bladder neuroendocrine carcinoma to include POU2F3-defined non-small cell neuroendocrine carcinoma with basaloid architecture, supporting the practical value of incorporating POU2F3 into immunohistochemical panels for poorly differentiated basaloid bladder tumors.

Germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) cause early-onset autoimmunity, lymphoproliferation, and immune dysregulation. Enteropathy is frequent, but longitudinal histopathological data remain limited. We report the clinical course and histological evolution of autoimmune enteropathy in an infant with a previously described STAT3 GOF mutation (c.2144C > T, p.Pro715Leu). Over 29 months, four endoscopies with duodenal biopsies conducted during different treatments revealed progressive villous atrophy and persistent inflammation despite clinical remission under Janus kinase (JAK) inhibitor therapy. Immunohistochemical staining showed consistent STAT3 expression, whereas phosphorylated STAT3 (pSTAT3) markedly decreased in epithelial and lamina propria lymphocytes under JAK inhibition. Additionally, initially altered goblet cell morphology normalized. This case demonstrates that JAK inhibitor therapy can induce clinical remission and reduce tissue pSTAT3 despite ongoing histological inflammation, supporting its role as targeted treatment in STAT3 GOF syndrome. The potential relevance of goblet cell restoration in STAT3 GOF-associated enteropathy is highlighted.