Virchows Archiv最新文献

Trichogerminoma (TG) is a rare adnexal tumor with hair follicle differentiation with less than 50 cases reported in the literature. In 2022, by investigating the genetic profile of 21 cases, our group identified recurrent rearrangements of the GRHL1/2/3 genes in this tumor entity, suggesting such alteration as the main oncogenic driver in TG. Up to now, only one TG case of malignant transformation has been reported. In the present letter, we report a second case of TG with malignant transformation and provide molecular characterization of this tumor.

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic and associated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001 resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.

In non-papillary follicular cell-derived thyroid carcinomas, prognostic factors are scarce. Intratumoral fibrosis was identified as an adverse factor in papillary and medullary carcinomas, but it has not been investigated in other subtypes. We aimed at exploring the presence of intratumoral fibrosclerosis in a cohort of 132 non-papillary follicular cell-derived thyroid carcinomas (53 follicular and 31 oncocytic carcinomas, including 10 high grade differentiated thyroid carcinomas and 48 poorly differentiated carcinomas) and correlating its presence and extent with clinical and pathological features and survival. For each case, all available hematoxylin and eosin slides were reviewed, and the presence of fibrosclerosis was assessed as the percentage of tumor area and semi-quantitatively scored as absent, mild (≤ 10%) or extensive (> 10%). In addition, digital image analysis was applied in 65 cases. Scoring of intratumoral fibrosis showed a strong agreement between two observers and between observers and digital image quantification. The presence and extent of intratumoral fibrosis were significantly associated with poorly differentiated carcinoma histology, large tumor size, extent of vascular invasion, presence of necrosis, high mitotic index, positive nodal status, and aggressive clinical outcome, and with a shorter disease-free and disease-specific survival, the former also in follicular and oncocytic carcinomas analyzed separately. These data support the potential use of fibrosis in the clinical practice since it is both easily assessable and significantly associated with the presence of parameters of aggressiveness. In addition, fibrosis is correlated with decreased survival rate independently from the tumor histotypes, suggesting its potential role as novel prognostic factor in non-papillary follicular cell-derived thyroid carcinomas.

A case of cutaneous adnexal neoplasm with unusual squamoid morphology and harboring an in frame ACTB::ZMIZ2 fusion transcript was recently described. Herein, we report a second case of adnexal carcinoma harboring similar morphology and an identical in frame ACTB::ZMIZ2 fusion transcript. This 2.2-cm mass was removed from the axilla of a 17-year-old woman. Microscopic examination revealed a large nodular and infiltrative tumor invading the dermis composed of sheets and nests frequently centered by large areas of keratinization. Molecular investigation revealed an in frame ACTB::ZMIZ2 fusion transcript. Clustering analysis revealed close proximity of this case with the ACTB::ZMIZ2-fused adnexal tumor previously reported. Herein, we report a second case of adnexal tumor with ACTB::ZMIZ2 fusion arising in a young adult suggesting that ACTB::ZMIZ2 fusion might be a defining genetic event, specific of a rare and previously undescribed adnexal tumor entity.

Low-grade endometrial stromal sarcoma (LG-ESS) can present diagnostic challenges, due to its overlapping morphological features with other uterine mesenchymal tumors. Misdiagnosis rates remain significant, and immunohistochemical data for LG-ESS are limited to small series and inconsistent antibody panels. This study aimed to refine the IHC profile of LG-ESS by analyzing a large, molecularly confirmed series of 147 cases using a panel of 24 antibodies, including newer markers like transgelin and smoothelin. CD10 and IFITM1, key endometrial stromal markers, were expressed in 86% (92% of those extensively) and 69% (60% of those extensively) of cases, with fusion-positive tumors showing significantly higher expression. Smooth muscle markers (α-SMA, desmin, h-caldesmon, calponin, transgelin) were variably expressed, predominantly in focal or low-intensity patterns, with α-SMA reaching the highest frequency of expression (44%). However, the intensity of smooth muscle marker expression was usually very low. Smoothelin was rarely expressed. Hormone receptors were frequently positive, with PR showing a higher frequency (92% vs. 83%) and intensity than ER. Markers like S-100, HMB45, and CD117 were largely negative; all tumors were p53 wild-type, with preserved SMARCB1/SMARCA4 expression and ALK and ROS1 negativity. This work represents the largest molecularly validated IHC study on LG-ESS, providing a robust diagnostic profile for routine pathology. By addressing key diagnostic limitations and examining newer markers, our study supports a more standardized approach to diagnosing LG-ESS and underscores the value of immunohistochemical panels, particularly in fusion-negative tumors where diagnosis relies on morphological and immunohistochemical interpretation. These findings contribute critical data for improving diagnostic accuracy.

Pleomorphic adenoma (PA), the most prevalent salivary gland tumor, exhibits a diverse histological spectrum characterized by epithelial, myoepithelial, and mesenchymal patterns, and secretory products. However, a subset of PAs presents microscopic features suggestive of malignancy, leading to challenging and potentially significant diagnostic pitfalls. A comprehensive retrospective analysis was conducted on the Salivary Gland Tumor Registry, compiled by the authors. A total of 104 cases diagnosed between 1960 and 2023 were retrieved. Clinical findings, pathological features, and molecular genetic results were analyzed. In the study of 104 PA cases, 23 (22.1%) presented features suggestive of pseudoinvasion, with satellite nodules being the most common (43.5%) along with capsular penetration, irregular growth, pseudopodia, lipomatous changes, and vascular permeation. Features of pseudomalignant cytomorphology were found in 97 cases (93.3%), characterized by increased cellularity, cellular atypia, heightened proliferative activity, oncocytic metaplasia, and necrosis. Additionally, 30 cases (28.8%) displayed features resembling other defined malignant salivary gland tumors, particularly myoepithelial carcinoma, adenoid cystic carcinoma, and polymorphous adenocarcinoma. Despite PA's generally straightforward diagnosis, cases with these features may be mistakenly interpreted as malignant tumors. The shared morphocytological features underscore the complexity of an accurate diagnosis, emphasizing the need for meticulous examination and a comprehensive assessment, incorporating morphological, molecular, and immunohistochemical analyses to differentiate between benign and malignant salivary gland tumors, in selected cases.

Penile cancer (PeCa) is a rare disease with poor prognosis in the metastatic stage. Neither effective adjuvant nor palliative therapeutic options are available. Research efforts in this field have so far failed to establish robust predictors of survival. To identify prognostic targets in PeCa, the current project focused on characterizing the tumor microenvironment (TME). A study cohort of 93 men with PeCa was used for the construction of a tissue microarray and immunohistochemical staining for CD3, CD4, CD8, CD20, CD56, CD138, FoxP3, and PD-L1. The quantity and spatial distribution of tumor-infiltrating immune cells were analyzed using digital image analysis. PD-L1 staining of tumor and immune cells was manually scored (combined positivity score (CPS)). T cells, T helper cells, cytotoxic T cells (CTLs), and regulatory T cells were detected in > 90% of PeCa and B cells in 88%, plasma cells in 85%, and NK cells in 23%. Approximately 50% of the PeCa samples were PD-L1 positive. In the univariate survival analysis, high PD-L1 CPS, plasma cells, CTLs, and B cells were significantly associated with favorable overall survival (OS), and the latter two with adverse recurrence-free survival. In multivariate analysis, plasma cells remained a significant factor for favorable OS (p = 0.04). In this study, the immune cells in the TME, especially plasma cells, were favorably associated with patient survival compared to other established prognostic factors in PeCa. Contemporarily, plasma cells have been discussed in the light of contributing to responses to modern immunotherapies. The results of this study support this notion.

The family of PEComa encompasses a heterogeneous group of related mesenchymal neoplasms with myomelanocytic differentiation, a distinctive subset of which is characterized by TFE3 gene rearrangement. Recurrent YAP1::TFE3 fusion has been found in clear cell stromal tumor of the lung (CCST-L), and most recently, in two cases classified as inflammatory spindle cell PEComa. However, the potential relationship between CCST-L and PEComa remains unclear. Herein, we report a case of primary pulmonary malignant TFE3-rearranged PEComa with prototypical morphological and immunohistochemical features, unexpectedly harboring YAP1::TFE3 fusion. Our findings further expanded the morphological and molecular spectrum of PEComa-like mesenchymal neoplasms of the lung.