Human pathology最新文献_第6页

Ovarian GLI1 fusion tumors mimicking sex cord-stromal Tumors: Clinicopathological and molecular characterization of a five-case series 卵巢GLI1融合肿瘤模拟性索间质肿瘤：5例系列的临床病理和分子特征。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-09 DOI: 10.1016/j.humpath.2025.106003

Fei Yang , Yan Liu , Yuxiang Wang , Jing Yang , Lingchao Liu , Congrong Liu

Ovarian GLI1 fusion tumors are rare mesenchymal neoplasms that closely mimic sex cord-stromal tumors (SCSTs) in both morphology and immunophenotype, frequently leading to misdiagnosis. In this study, we identified five such cases through re-evaluation of SCST-like ovarian tumors. Histologically, three distinct patterns were observed: the spindle pattern, the stellate/microcystic pattern and the epithelioid pattern. Immunophenotypically, all cases showed overlapping features with SCSTs, including CD10 expression and variable positivity for sex cord-stromal markers such as FOXL2, SF1, and Calretinin. Molecular analysis revealed recurrent ACTB::GLI1 fusions in four cases and a novel FUBP1::GLI1 fusion in one. Meta-analysis integrating our cases with ten previously reported ovarian GLI1 fusion tumors showed that these tumors predominantly occur in middle-aged women and present as significantly larger masses than their soft tissue and solid organ counterparts (P < 0.05). Notably, the relapse and metastasis rates of ovarian GLI1 fusion tumors were similar to adult granulosa cell tumors (AGCTs). In contrast, their recurrence rate was significantly higher than that of microcystic stromal tumors (MCSTs) (P < 0.05), indicating a more aggressive clinical course. Transcriptomic analysis revealed no significant correlation between ovarian GLI1 fusion tumors and sclerosing stromal tumors. These findings underscore the necessity of molecular testing for GLI1 rearrangements in SCST-like ovarian tumors to ensure accurate diagnosis and appropriate clinical management.

卵巢GLI1融合瘤是一种罕见的间充质肿瘤，在形态和免疫表型上与性索间质瘤（SCSTs）非常相似，经常导致误诊。在本研究中，我们通过对scst样卵巢肿瘤的重新评估，确定了5例此类病例。组织学上观察到三种不同的模式：纺锤形、星状/微囊状和上皮样。在免疫表型上，所有病例都表现出与SCSTs重叠的特征，包括CD10表达和性索间质标志物（如FOXL2、SF1和Calretinin）的可变阳性。分子分析显示，4例患者出现复发性ACTB::GLI1融合，1例患者出现新的FUBP1::GLI1融合。综合我们的病例和先前报道的10例卵巢GLI1融合肿瘤的荟萃分析显示，这些肿瘤主要发生在中年妇女，并且比软组织和实体器官的肿瘤明显更大

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引用次数: 0

Analysis of discordance between mismatch repair and microsatellite instability testing in endometrial cancer 子宫内膜癌错配修复与微卫星不稳定性检测的不一致性分析。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-08 DOI: 10.1016/j.humpath.2025.106004

Yun Xi , Chunhong He , Xianhua Fang , Jiani C. Yin , Yihua Wang , Hui Wang , Chaoqi Wu , Jianfei Fang , Qian Lai , Pan Liu , Fangfang Chu , Wenjuan Yin , Dan Su

Accurate molecular classification of endometrial carcinoma (EC) is critical for guiding therapy, particularly concerning mismatch repair-deficient (MMRd). However, the consistency of MMRd detection across different diagnostic modalities and the molecular basis of discordant results remain insufficiently characterized. In this retrospective study, 220 EC patients treated at Zhejiang Cancer Hospital from January 2021 to March 2024 underwent histopathological review, immunohistochemistry (IHC), and targeted next-generation sequencing (NGS) with a 196-gene panel. Discordant cases were further assessed by polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, MLH1 promoter methylation analysis, and extended mutational profiling. The median age of the study cohort was 57.0 years. IHC revealed deficient mismatch repair (dMMR) in 65 cases (29.6 %), while NGS detected high MSI (MSI-H) in 44 cases (20.0 %), yielding an overall 90.5 % concordance. All 21 discordant cases (9.5 %) displayed dMMR by IHC but microsatellite stable (MSS) by NGS. PCR reclassified five cases as MSI-H, whose MSIsensor scores were significantly higher than proficient MMR (pMMR)/MSS tumors (p = 0.01) but lower than dMMR/MSI-H tumors (p = 0.0007). Of the remaining 16 unresolved cases, 43.8 % exhibited isolated MSH6 loss, likely due to the functional compensation of MSH3, while 56.2 % showed MLH1 loss, predominantly due to MLH1 promoter methylation (77.8 %). In conclusion, discordance between IHC- and NGS-based MMR/MSI detection is primarily attributable to MSH6 loss with MSH3 compensation and MLH1 promoter methylation. Recognizing these mechanisms is essential for accurate molecular subtyping and clinical decision-making in EC.

子宫内膜癌（EC）的准确分子分类对于指导治疗至关重要，特别是在错配修复缺陷（MMRd）方面。然而，不同诊断方式的MMRd检测的一致性和不一致结果的分子基础仍然没有充分表征。在这项回顾性研究中，2021年1月至2024年3月在浙江省肿瘤医院接受治疗的220例EC患者进行了组织病理学检查、免疫组化（IHC）和196个基因面板的靶向下一代测序（NGS）。不一致的病例通过基于聚合酶链反应（PCR）的微卫星不稳定性（MSI）测试、MLH1启动子甲基化分析和扩展突变谱进一步评估。研究队列的中位年龄为57.0岁。免疫组化显示65例（29.6%）患者存在错配修复缺陷（dMMR），而NGS检测到44例（20.0%）患者存在高MSI (MSI- h)，总体一致性为90.5%。21例不一致病例（9.5%）IHC显示dMMR， NGS显示微卫星稳定（MSS）。5例MSI-H组患者的mssensor评分显著高于熟练MMR (pMMR)/MSS组（p = 0.01），低于dMMR/MSI-H组（p = 0.0007）。在其余16例未解决的病例中，43.8%表现出孤立的MSH6缺失，可能是由于MSH3的功能补偿，而56.2%表现出MLH1缺失，主要是由于MLH1启动子甲基化（77.8%）。总之，基于IHC和基于ngs的MMR/MSI检测之间的不一致主要归因于MSH6缺失和MSH3补偿和MLH1启动子甲基化。认识到这些机制对于EC准确的分子分型和临床决策至关重要。

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引用次数: 0

Plasmacytoid variant in Lynch syndrome-associated urothelial carcinoma. Lynch综合征相关尿路上皮癌的浆细胞样变异。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-08 DOI: 10.1016/j.humpath.2025.106009

Xue-Long Li, Guang-Wen Yuan, Meng-Ze Qi, Yi-Ping Sun, Yi-Cong Nie, Zhi-Gang Yao

引用次数: 0

CYP11B2 expression patterns in primary aldosteronism: Assessment of cortisol co-secretion and the B2 ratio criteria 原发性醛固酮增多症中CYP11B2表达模式：评估皮质醇共分泌和B2比值标准。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106010

Stanley M. Chen Cardenas , Andres Matoso , Huili Li

Primary aldosteronism (PA) is the most common form of endocrine hypertension, with a prevalence of 5–15 %. Unilateral PA accounts for approximately 30 % of PA and has been associated with excellent post-operative results. Introduction of CYP11B2 immunostain led to the histopathology of primary aldosteronism (HISTALDO) consensus and the classification into classical and non-classical histology. We retrospectively reviewed 62 consecutive adrenalectomy cases of PA from routine clinical practice, including 46 with PA-only and 16 with cortisol cosecretion (PA-C). We also examined 3 adrenals from non-PA patients. We found that aldosterone-producing micronodules (APM/MAPM) were commonly present in the background adrenal of PA patients (59/62) and non-PA related adrenal cortex (3/3). Therefore, regardless of the presence of APM/MAPM, the presence of a solitary APA or APN was defined as classical histology, and the remaining CYP11B2-positive patterns were classified as non-classical histology (mHISTALDO). PA patients with classical histology were significantly associated with smaller APM/MAPM compared to those with non-classical histology. We validated that classical histology was significantly associated with more complete clinical and biochemical responses. We found that the PA-only group was significantly associated with smaller tumors, classical histology, more complete clinical response, and reduction in antihypertensive medication, compared to PA-C. We also explored a recently proposed criterion, the B2R (size ratio of the largest to the second largest CYP11B2-positive lesion), for defining classical and non-classical histology, which was relatively easy to use, yielding a consistent classification rate of 90.3 % (56/62) and similar associations and trends with clinical and biochemical outcomes, compared to the mHISTALDO. In summary, we validated that classical histology was associated with better outcomes by both mHISTALDO and B2R. APM/MAPM were commonly seen in the adrenal cortex. In the presence of a large solitary APA or APN, APM/MAPM should not change the classical histology classification.

原发性醛固酮增多症（PA）是内分泌性高血压最常见的形式，患病率为5-15%。单侧PA约占PA的30%，并具有良好的术后效果。引入CYP11B2免疫染色导致原发性醛固酮增多症（HISTALDO）的组织病理学一致，并分为经典和非经典组织学。我们回顾性分析了62例常规临床连续肾上腺切除术的PA病例，包括46例单纯PA和16例皮质醇共分泌（PA- c）。我们也检查了非pa患者的3个肾上腺。我们发现醛固酮生成微模块（APM/MAPM）普遍存在于PA患者的背景肾上腺（59/62）和非PA相关的肾上腺皮质（3/3）。因此，无论是否存在APM/MAPM，单独存在APA或APN被定义为经典组织学，其余cyp11b2阳性模式被归类为非经典组织学（mHISTALDO）。典型组织学的PA患者与非典型组织学的PA患者相比，APM/MAPM更小。我们证实经典组织学与更完整的临床和生化反应显著相关。我们发现，与PA-C组相比，PA-C组与更小的肿瘤、经典的组织学、更完整的临床反应和降压药物减少显著相关。我们还探索了最近提出的定义经典和非经典组织学的标准B2R，该标准相对容易使用，与mHISTALDO相比，其分类率一致为90.3%(56/62)，与临床和生化结果有相似的关联和趋势。总之，我们通过mHISTALDO和B2R验证了经典组织学与更好的预后相关。APM/MAPM多见于肾上腺皮质。在存在较大的孤立性APA或APN时，APM/MAPM不应改变经典的组织学分类。

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引用次数: 0

Detection of targetable genetic alterations in SMARCA4-deficient neoplasms of the lung – further evidence of a relationship between SMARCA4-deficient undifferentiated tumor and non-small cell carcinoma 检测smarca4缺陷肺癌中可靶向的基因改变——进一步证明smarca4缺陷未分化肿瘤与非小细胞癌之间的关系。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106007

Danielle D'Ambrosio , Nicholas Frazzette , Matija Snuderl , George K. Jour , Emily M. Shaffer , Fang Zhou , Navneet Narula , Andre L. Moreira , Jose G. Mantilla

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4d-UT) is an uncommon, aggressive lung neoplasm associated with smoking and characterized by loss of SMARCA4 (BRG-1) expression. Although originally considered to be a primary sarcoma, there is growing evidence that these lesions may represent transformation of conventional non-small cell carcinoma. In this study, we probe this relationship based on the clinical, histologic and molecular findings of 18 SMARCA4-deficient malignancies of the lung.

Cases diagnosed as SMARCA4d-UT and SMARCA4-deficient carcinoma were retrospectively reviewed, including histologic and immunophenotypic features, and next generation sequencing studies.

Of the 18 tumors, 5 were considered to represent undifferentiated SMARCA4d-UT, and 13 SMARCA4-deficient carcinomas, including 11 adenocarcinomas, 1 squamous cell carcinoma, and 1 poorly differentiated non-small cell carcinoma. All 13 carcinomas had a morphologically identifiable undifferentiated component. Survival outcomes were similar in both SMARCA4d-UT and carcinomas. Genetic alterations often seen in lung cancer were identified in 8 cases, including mutations in EGFR (in 2 SMARCA4-deficient adenocarcinomas), KRAS (1 SMARCA4d-UT and 1 SMARCA4-deficient adenocarcinoma), MAP2K1 (1 SMARCA4-deficient adenocarcinoma), and a gene fusion involving EML4::ALK (1 SMARCA4d-UT). The patient with EML4::ALK fusion was treated with alectinib with partial response. Fusions involving BRAF::CHCHD3 and FGFR1::FILIP1 were identified in 2 SMARCA4-deficient adenocarcinomas. High expression of PD-L1 (TPS >50 %) was seen in 12 cases (67 %).

These finding further suggest that SMARCA4d-UT and carcinomas with SMARCA4 loss may be on the same spectrum of disease, and accurate histologic distinction between these lesions may be challenging. A unified terminology may be beneficial for appropriate diagnosis and treatment.

胸部SMARCA4缺陷未分化肿瘤（SMARCA4 - ut）是一种罕见的侵袭性肺肿瘤，与吸烟相关，以SMARCA4 （BRG-1）表达缺失为特征。虽然最初认为是原发性肉瘤，但越来越多的证据表明这些病变可能代表传统非小细胞癌的转化。在这项研究中，我们基于18例肺部smarca4缺陷恶性肿瘤的临床、组织学和分子研究结果来探讨这种关系。我们回顾性回顾了SMARCA4d-UT和smarca4缺陷癌的病例，包括组织学和免疫表型特征，以及下一代测序研究。在18例肿瘤中，5例被认为是未分化的smarca4 - ut， 13例smarca4缺陷癌，包括11例腺癌、1例鳞状细胞癌和1例低分化非小细胞癌。所有13例癌均有形态学上可识别的未分化成分。SMARCA4d-UT和癌患者的生存结果相似。在8例肺癌中发现了常见的遗传改变，包括EGFR（2例smarca4缺陷腺癌）、KRAS（1例smarca4 - ut和1例smarca4缺陷腺癌）、MAP2K1（1例smarca4缺陷腺癌）的突变，以及涉及EML4::ALK（1例smarca4 - ut）的基因融合。EML4::ALK融合患者用alectinib治疗，部分缓解。在2例smarca4缺陷腺癌中发现了BRAF::CHCHD3和FGFR1::FILIP1的融合。PD-L1高表达12例（67%）。这些发现进一步表明，SMARCA4 - ut和SMARCA4缺失的癌可能在同一疾病谱上，这些病变之间的准确组织学区分可能具有挑战性。统一的术语可能有利于适当的诊断和治疗。

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引用次数: 0

Correlation of lymphocytic infiltration and degree of pleomorphism with tumor mutation burden in high-grade urothelial carcinoma 高级别尿路上皮癌淋巴细胞浸润和多形性程度与肿瘤突变负荷的关系。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106005

Neslihan Kayraklioglu , Li Zhang , Chien-Kuang Cornelia Ding , Nancy Y. Greenland , Bradley A. Stohr , Vadim S. Koshkin , Jeffry P. Simko , Deepika Sirohi

Histopathological features and genomic biomarkers are integral to the management of patients with high-grade urothelial carcinoma (HGUC). Morphological features are often reflective of underlying genomic alterations. In this study, we investigate the correlation between tumor mutation burden (TMB) and specific histopathological features in HGUC to identify surrogate markers for TMB when molecular testing may not be available. We hypothesized that increased nuclear pleomorphism and intense lymphocytic infiltration might correlate with higher TMB, aiding treatment decisions. In this retrospective study, 119 cases with TMB analysis by Next Generation Sequencing (NGS) were evaluated for cytological and nuclear pleomorphism, lymphocytic infiltration, and histological subtypes. Pleomorphism and lymphocytic infiltrate were classified into binary categories (mild versus marked) for improved reproducibility. TMB ≥10 mutations/Mb was defined as high TMB. Both marked pleomorphism and marked lymphocytic infiltration were associated with higher TMB (10.3 vs 7.2 muts/Mb, p = 0.027 and 12.4 vs. 8.9 muts/Mb, p = 0.005 respectively). Micropapillary, squamous, and sarcomatoid subtypes demonstrated higher median TMB, although the differences did not reach statistical significance. In summary, our findings suggest that marked nuclear pleomorphism and lymphocytic infiltrate are associated with higher TMB, indicating their potential as surrogate markers for immunotherapy response.

组织病理学特征和基因组生物标志物是管理高级别尿路上皮癌（HGUC）患者不可或缺的一部分。形态学特征通常反映潜在的基因组改变。在本研究中，我们研究了HGUC中肿瘤突变负荷（tumor mutation burden， TMB）与特定组织病理学特征之间的相关性，以便在无法进行分子检测的情况下确定TMB的替代标志物。我们假设增加的核多形性和强烈的淋巴细胞浸润可能与较高的TMB相关，有助于治疗决策。在这项回顾性研究中，通过下一代测序（NGS）分析119例TMB患者，评估其细胞学和核多形性，淋巴细胞浸润和组织学亚型。多形性和淋巴细胞浸润分为两类（轻度和显著），以提高再现性。TMB bbb10个突变/Mb定义为高TMB。显著的多形性和显著的淋巴细胞浸润均与较高的TMB相关（分别为10.3 vs 7.2 muts/Mb, p=0.027和12.4 vs 8.9 muts/Mb, p=0.005）。微乳头状、鳞状和肉瘤样亚型表现出较高的中位TMB，尽管差异没有达到统计学意义。总之，我们的研究结果表明，显著的核多形性和淋巴细胞浸润与较高的TMB相关，表明它们有可能作为免疫治疗反应的替代标志物。

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引用次数: 0

Gene expression signatures of shortened-telomere-associated fibrotic interstitial lung disease 端粒缩短相关纤维化间质性肺病的基因表达特征

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106006

Julia R. Naso , Carlos Sosa , Lauren E. Schefter , Matthew J. Petersen , Taysia Nikaido-Landry , Emilia Lim , Alejandro Ferrer , Mrinal M. Patnaik , John P. Scott , Kevin C. Halling , Anja C. Roden

Shortened telomeres contribute to the pathogenesis of a subset of pulmonary fibrosis through mechanisms that remain unclear. We compared the expression of fibrosis-related genes in explanted lungs of pulmonary fibrosis patients with versus without shortened telomeres, to identify possible molecular mechanisms of pulmonary fibrosis pathogenesis in these patients. Telomere length was assessed using flow cytometry fluorescence in-situ hybridization on peripheral blood. Lymphocyte telomere length <10th percentile was considered shortened. Gene expression was assessed using the NanoString Human Fibrosis v2 Panel (782 genes) on whole slide sections of explanted lungs with pulmonary fibrosis. Gene expression data was obtained for 39 patients (17 with and 22 without shortened telomeres). Gene set enrichment analysis identified significant differential regulation of cholesterol metabolism and the 'regulation of tumor necrosis factor-mediated signaling pathway’ gene ontology term in the shortened telomere group. Thirty-six genes were significantly differentially expressed in the shortened telomere samples, including increased expression of tumor necrosis factor pathway (NCF4, NR1H4) and cholesterol metabolism (APOA1, APOH, LIPC) genes in the shortened telomere group. Differential expression of these 36 genes was most pronounced in 5 of the 17 shortened telomere cases. This study highlights molecular heterogeneity within explanted lung tissue of patients with shortened telomeres and pulmonary fibrosis, with signatures of altered cholesterol metabolism and tumor necrosis factor signaling in a subset of shortened telomere cases. We highlight NCF4, NR1H4, APOA1, APOH and LIPC as differentially expressed genes in a subgroup of shortened telomere pulmonary fibrosis patients.

缩短的端粒通过尚不清楚的机制参与肺纤维化亚群的发病机制。我们比较了端粒缩短和端粒未缩短的肺纤维化患者的外植肺中纤维化相关基因的表达，以确定这些患者肺纤维化发病的可能分子机制。采用流式细胞术、荧光原位杂交法测定外周血端粒长度。淋巴细胞端粒长度的百分位数被认为缩短。利用NanoString Human Fibrosis v2 Panel（782个基因）对肺纤维化的全切片切片进行基因表达评估。获得了39例患者（17例端粒缩短，22例端粒未缩短）的基因表达数据。基因集富集分析发现，短端粒组在胆固醇代谢调控和“肿瘤坏死因子介导的信号通路调控”基因本体术语上存在显著差异。36个基因在缩短的端粒样本中有显著差异表达，包括肿瘤坏死因子通路基因（NCF4、NR1H4）和胆固醇代谢基因（APOA1、APOH、LIPC）在缩短的端粒组中表达增加。这36个基因的差异表达在17例端粒缩短病例中的5例中最为明显。这项研究强调了端粒缩短和肺纤维化患者的移植肺组织中的分子异质性，在一部分端粒缩短的病例中具有改变胆固醇代谢和肿瘤坏死因子信号的特征。我们强调NCF4， NR1H4, APOA1， APOH和LIPC是缩短端粒肺纤维化患者亚组中的差异表达基因。

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引用次数: 0

PIK3R1 acts as a prominent biomarker for tumor immune microenvironment modulation in intravenous leiomyomatosis PIK3R1在静脉平滑肌瘤病中作为肿瘤免疫微环境调节的重要生物标志物。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106002

Zijuan Zhang , Penghui Feng , Zhitong Ge , Zhiyong Liang , Rong Chen , Jianchu Li

Background

In current clinical practice, intravenous leiomyomatosis (IVL) can be surgically resected using either one-step or two-step approach. However, several challenges persist, including a high rate of postoperative recurrence, the difficulty in achieving complete resection in complex cases, and the inability to timely identify a substantial number of early-stage IVL cases. The mainstream theory regarding the pathogenesis and development mechanism of IVL is that it originates from uterine leiomyomas, yet the specific molecular mechanisms underlying this process remain to be elucidated.

Methods

In this study, high-throughput transcriptome sequencing and molecular detection methods such as immunohistochemistry were employed to analyze the molecular expression differences at the transcriptome and immune microenvironment levels between 5 cases of IVL and paired uterine leiomyomas. These findings were subsequently validated in a cohort consisting of 45 IVL cases.

Results

The cross-enrichment analysis of differentially expressed genes (DEGs) at the transcriptome and immune level in paired samples yielded significant results. Notably, the up-regulated gene PIK3R1 and the down-regulated gene BMP4 emerged as two of the most critical representatives. Further investigation into the function of the PIK3R1 gene in IVL and its relationship with the immune microenvironment revealed that this gene was highly expressed in IVL and positively correlated with the abundance of plasma cells, while negatively correlated with follicular helper T cells and resting dendritic cells. The overall immune microenvironment of IVL was inactive, leading to tumor cells being less likely to be recognized and eliminated by immune cells.

Conclusions

This study has conducted an in-depth analysis of the molecular expression, immune microenvironment characteristics, and related mechanisms of IVL. Further studies on larger cohort are warranted to demonstrate the potential value of inhibiting PIK3R1 as the adjuvant medicine for IVL therapy.

背景：在目前的临床实践中，静脉内平滑肌瘤病（IVL）可采用一步或两步手术切除。然而，一些挑战仍然存在，包括术后复发率高，复杂病例难以完全切除，以及无法及时识别大量早期IVL病例。关于IVL的发病和发展机制，主流理论认为其起源于子宫平滑肌瘤，但其具体的分子机制尚不清楚。方法：本研究采用高通量转录组测序和免疫组织化学等分子检测方法，分析5例IVL和配对子宫平滑肌瘤在转录组和免疫微环境水平上的分子表达差异。这些发现随后在由45例IVL病例组成的队列中得到验证。结果：配对样本中转录组和免疫水平的差异表达基因（DEGs）交叉富集分析取得了显著结果。值得注意的是，上调基因PIK3R1和下调基因BMP4是两个最关键的代表。进一步研究PIK3R1基因在IVL中的功能及其与免疫微环境的关系发现，该基因在IVL中高表达，与浆细胞丰度呈正相关，与滤泡辅助性T细胞和静息树突状细胞负相关。IVL整体免疫微环境处于失活状态，导致肿瘤细胞不易被免疫细胞识别和清除。结论：本研究对IVL的分子表达、免疫微环境特征及相关机制进行了深入分析。为了证明抑制PIK3R1作为IVL治疗辅助药物的潜在价值，需要进一步进行更大规模的研究。

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引用次数: 0

Quantitative assessment of cribriform intraductal carcinoma of the prostate is useful for risk stratification after radical prostatectomy 前列腺筛状导管内癌的定量评估有助于根治性前列腺切除术后的风险分层。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106008

Ying Wang , Hiroshi Miyamoto

It remains uncertain if the extent of intraductal carcinoma of the prostate (IDC) exhibiting cribriform (Crib) morphology impacts on patient outcomes. We retrospectively analyzed long-term oncologic outcomes in 182 consecutive radical prostatectomy patients exhibiting Grade Group 2–4 conventional/acinar prostatic adenocarcinoma, along with Crib-IDC but no Gleason grade 5 patterns. A single Crib-IDC focus in the entire prostatectomy specimen was identified in 46 (25.3 %) cases, while others showed 2 (n = 36; 19.8 %), 3 (n = 27; 14.8 %), 4 (n = 11; 6.0 %), or ≥5 (n = 62; 34.1 %) Crib-IDC foci. The maximum Crib-IDC diameter in each case was ≤1-mm (n = 66; 36.3 %), >1/≤2-mm (n = 90; 49.5 %), >2/≤3-mm (n = 21; 11.5 %), or >3-mm (n = 5; 2.7 %). The summed maximum Crib-IDC diameters were ≤1-mm (n = 38; 20.9 %), >1/≤2-mm (n = 39; 21.4 %), >2/≤3-mm (n = 30; 16.5 %), >3/≤4-mm (n = 17; 9.3 %), >4/≤5-mm (n = 9; 4.9 %), or >5-mm (n = 49; 26.9 %). On univariate analyses, the risks of postoperative biochemical recurrence were significantly higher in cases with 3 (P = 0.022) or ≥3 (P < 0.001) Crib-IDCs (vs. 1–2) or ≥4 Crib-IDCs [P < 0.001 (vs. 1–3); P = 0.032 (vs. 3)]. Similarly, the recurrence risk was significantly higher in Crib-IDC cases with the maximum diameter of >1-mm (vs. ≤1-mm; P = 0.002) or the summed diameter of >3-mm (vs. ≤3-mm; P < 0.001). On multivariable Cox regression analyses, 3 [hazard ratio (HR) 2.742, P = 0.016], ≥3 (HR 3.969, P < 0.001), or ≥4 (HR 4.520, P < 0.001) Crib-IDCs (vs. 1–2) and the summed diameter of >3-mm (HR 3.074, P < 0.001) remained significantly predictive of recurrence. Quantitative assessment of Crib-IDC, particularly its number and cumulative diameter on prostatectomy, may thus enhance the postoperative risk stratification of Grade Group 2–4 prostate cancer.

导管内前列腺癌（IDC）表现筛状（Crib）形态的程度是否影响患者的预后仍不确定。我们回顾性分析了182例连续根治性前列腺切除术患者的长期肿瘤预后，这些患者表现为2-4级组常规/腺泡性前列腺癌，伴有Crib-IDC，但没有Gleason 5级模式。46例（25.3%）患者在整个前列腺切除术标本中发现单个Crib-IDC病灶，而其他患者则发现2例（n=36; 19.8%）、3例（n=27; 14.8%）、4例（n=11; 6.0%）或≥5例（n=62; 34.1%） Crib-IDC病灶。各病例最大Crib-IDC直径≤1 mm （n=66, 36.3%）、>1/≤2 mm （n=90, 49.5%）、>2/≤3 mm （n=21, 11.5%）、>3 mm （n=5, 2.7%）。总结最大Crib-IDC直径是≤1毫米(n = 38。20.9%),> 1 /≤2毫米(n = 39; 21.4%) > 2 /≤3毫米(n = 30; 16.5%), > 3 /≤4毫米(n = 17; 9.3%) > 4 /≤5毫米(n = 9。4.9%),或> 5毫米(n = 49。26.9%)。在单因素分析中，3 （P=0.022）或≥3 (P1-mm （vs.≤1-mm； P=0.002）或> - 3-mm (vs.≤3-mm; P3-mm （HR 3.074, P . 0.002）的患者术后生化复发的风险明显更高

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引用次数: 0

Genome-wide DNA methylation profiling of pleomorphic carcinoma of the lung 多形性肺癌的全基因组DNA甲基化分析。

IF 2.6 2区医学 Q2 PATHOLOGY

Human pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.humpath.2025.106001

Takahiro Nakagomi , Mao Fujimoto , Shoji Kuriyama , Tomoyuki Hishida , Hisao Asamura , Keisuke Asakura , Yae Kanai , Eri Arai

The aim of this study was to clarify the significance of DNA methylation alterations in the histological and clinicopathological diversity of pleomorphic carcinoma of the lung. Eleven samples of non-cancerous lung tissue (N), and 10 and 11 samples of non-sarcomatoid and sarcomatoid components of cancerous tissue (T), respectively, were microdissected from formalin-fixed paraffin-embedded specimens of 11 patients with pleomorphic carcinoma of the lung. Genome-wide DNA methylation analysis was performed on all 32 microdissected tissue samples using the Infinium MethylationEPIC BeadChip. Principal component analysis revealed that DNA methylation alterations are associated with lung carcinogenesis and that the diversity of DNA methylation profiles may increase during transition of the non-sarcomatoid component to the sarcomatoid component. Genes showing differences in DNA methylation level between 11 N samples and all 21 T samples regardless of whether they were non-sarcomatoid or sarcomatoid, and whose transcription levels are potentially regulated by DNA methylation, were accumulated in the cadherin, Wnt and angiogenesis pathways. Significant differences in DNA methylation level between non-sarcomatoid and sarcomatoid components potentially resulting in transcription alterations were observed in the OCIAD2, LAMB1 and DKK3 genes. Sarcomatoid component-specific DNA hypomethylation relative to N samples of C2orf27A and COX6C was correlated with clinicopathological parameters such as lymph vessel invasion and higher pathological stage, respectively. Sarcomatoid component-specific DNA hypomethylation of TSKU, PLAU, PLEKHG4, RPSAP52, XBP1 and TRIM2 was correlated with both recurrence-free and overall survival. These data suggest that the DNA methylation alterations associated with sarcomatoid change may participate in malignant progression and determine patient outcome.

本研究的目的是阐明DNA甲基化改变在多形性肺癌的组织学和临床病理多样性中的意义。从11例多形性肺癌患者的福尔马林固定石蜡包埋标本中，分别显微解剖了11个非癌性肺组织(N)和10个癌性组织非肉瘤样成分和11个癌性组织肉瘤样成分(T)。使用Infinium MethylationEPIC BeadChip对所有32个微解剖组织样本进行全基因组DNA甲基化分析。主成分分析显示，DNA甲基化改变与肺癌发生有关，并且DNA甲基化谱的多样性可能在非肉瘤样成分向肉瘤样成分过渡期间增加。无论是非肉瘤样还是肉瘤样，11个N样本与所有21个T样本之间DNA甲基化水平存在差异的基因，其转录水平可能受到DNA甲基化的调节，这些基因在cadherin、Wnt和血管生成途径中积累。在OCIAD2、LAMB1和DKK3基因中，非肉瘤样成分和肉瘤样成分之间的DNA甲基化水平存在显著差异，可能导致转录改变。相对于N个样本C2orf27A和COX6C的肉瘤样成分特异性DNA低甲基化分别与淋巴管侵袭和较高的病理分期等临床病理参数相关。TSKU、PLAU、PLEKHG4、RPSAP52、XBP1和TRIM2的肉瘤样成分特异性DNA低甲基化与无复发和总生存率相关。这些数据表明，与肉瘤样改变相关的DNA甲基化改变可能参与恶性进展并决定患者预后。

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