Modern Pathology最新文献_第2页

Early Genetic Divergence of High-Grade Carcinomas Originating from Low-Grade Serous Ovarian Neoplasms 源自低级别卵巢浆液性肿瘤的高级别癌的早期基因分化。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-10-09 DOI: 10.1016/j.modpat.2024.100629

The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: KRAS (G12D, n = 4), BRAF (G469A, n = 1), NF2 (n = 1), and USP9X (n = 1). Transformation to HGSC was associated with a TP53 mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. TP53-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event.

目前的研究范式认为，输卵管前体是大多数卵巢高级别浆液性癌（HGSC）的起源。然而，有一种罕见的 HGSC 子集是通过与低级别浆液性卵巢肿瘤（即浆液性边界瘤和低级别浆液性癌）不同的途径发展而来的。人们对 HGSC 和其他分化不良的卵巢癌的另一种发展途径还不甚了解。为了阐明低分化浆液性肿瘤组织学转化的分子发病机制和进化轨迹，我们对 7 例浆液性边界瘤或低分化浆液性癌伴有同步或间期不确定/高级别癌的低分化和高级别成分进行了显微解剖全外显子组测序。在大多数病例中，与每种成分特有的体细胞突变相比，匹配的低分级和高分级肿瘤之间共享的体细胞突变相对较少（即系统发生树的树干短、树枝长）。在特定患者的所有肿瘤样本中都存在的干突变包括已知的低分化浆液性肿瘤的驱动因子：KRAS（G12D，n=4）、BRAF（G469A，n=1）、NF2（n=1）和 USP9X（n=1）。3例患者的HGSC转化与双等位基因失活的TP53突变有关，所有病例均伴有严重的核不典型性，并与全基因组拷贝数改变和等位基因失衡有关。TP53野生型肿瘤具有不同的形态学特征，包括具有中度核不典型性和高有丝分裂活性的未定级浆液性癌，但缺乏广泛的染色体不稳定性（2例），以及低分化癌（2例，包括1例高级别穆勒氏癌和1例具有肉瘤特征的未分化癌）。总之，同步和近同步的低级别浆液性肿瘤和高级别癌是克隆相关的。早期遗传分化在 TP53 突变的病例中最为明显，这表明高级别转化可能是一个相对较早的分子事件。

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引用次数: 0

POU4F3 Is a Sensitive and Specific Marker of Merkel Cell Carcinoma POU4F3 是梅克尔细胞癌敏感而特异的标记物

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-26 DOI: 10.1016/j.modpat.2024.100627

Although of therapeutic importance, a single sensitive and specific immunostain to distinguish Merkel cell carcinoma (MCC) from mimics is not currently available. In addition, single tumor cells are difficult to detect in sentinel lymph node biopsy. Leveraging publicly available data sets of 9264 solid tumors and >600,000 single-cell transcriptomes, we identified POU4F3 to be a specific marker of MCC. Analyses of Pan-Cancer RNA bulk sequencing data of 24 tumor types from Tumor Cancer Genomic Atlas data sets as well as non-Tumor Cancer Genomic Atlas small cell lung carcinoma and MCC data sets confirmed POU4F3 specificity for MCC. Single-cell RNA-sequencing analyses also confirmed the lack of POU4F3 expression in lung small cell carcinoma as well as a variety of normal tissues. Nuclear POU4F3 immunohistochemical expression was noted in 98.7% of 153 MCCs and in only 1.7% of mimics (3 of 180 cases, including 95 small cell carcinomas, of which 55 were from lungs and the remainder from other sites). Three POU4F3-positive non-MCC cases were from lungs (2 cases) and vagina (1 case). All 153 tested MCC cases were negative for ASCL1, a key transcriptional regulator highly expressed in small cell lung carcinoma. NeuroD1 was seen in a subset of MCC cases (20.9%, 32/153). POU4F3 immunostain was performed on 29 sentinel lymph nodes, and strong POU4F3 nuclear expression facilitated the ease of metastasis detection, even single tumor cells. Our study built on prior works shows that POU4F3 is a sensitive and specific clinical marker of MCC.

梅克尔细胞癌（Merkel cell carcinoma，MCC）虽然具有重要的治疗意义，但目前还没有一种灵敏而特异的免疫印迹可用于区分梅克尔细胞癌（MCC）和拟态梅克尔细胞癌（MCC）。此外，前哨淋巴结活检也很难检测到单个肿瘤细胞。利用公开的 9264 个实体瘤数据集和超过 60 万个单细胞转录组，我们发现 POU4F3 是 MCC 的特异性标记物。对来自肿瘤癌症基因组图谱（TCGA）数据集以及非TCGA SCLC和MCC数据集的24种肿瘤类型的泛癌症RNA批量测序数据的分析证实了POU4F3对MCC的特异性。单细胞 RNA 测序分析也证实肺小细胞癌和各种正常组织中缺乏 POU4F3 表达。在153例MCC中，98.7%有核POU4F3免疫组化表达，只有1.7%的拟态MCC（180例中有3例，包括95例小细胞癌，其中55例来自肺部，其余来自其他部位）有核POU4F3免疫组化表达。3例POU4F3阳性的非MCC病例分别来自肺部（2例）和阴道（1例）。所有153例接受检测的MCC病例的ASCL1均为阴性，而ASCL1是一种在SCLC中高度表达的关键转录调节因子。NeuroD1可见于一部分MCC病例（20.9%，32/153）。对29个前哨淋巴结进行了POU4F3免疫染色，即使是单个肿瘤细胞，POU4F3的强核表达也有助于转移瘤的检测。我们的研究在先前研究的基础上表明，POU4F3是MCC的一个敏感而特异的临床标记物。

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引用次数: 0

A Comparative Genomic Study of Conventional and Undifferentiated Melanoma 传统和未分化黑色素瘤基因组对比研究

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-25 DOI: 10.1016/j.modpat.2024.100626

Undifferentiated melanoma, defined as melanoma that has lost all usual phenotypic and immunohistochemical characteristics of conventional melanoma, can pose significant diagnostic challenges. Molecular studies have advanced our understanding of undifferentiated melanoma by demonstrating that a subset of these tumors harbors known melanoma driver alterations in genes such as BRAF, NRAS, and NF1. However, there is a paucity of data describing genetic alterations that may distinguish undifferentiated melanoma from conventional melanoma. In this study, we directly compared the genomic profiles of undifferentiated melanoma to a cohort of conventional melanomas, including 14 undifferentiated melanoma cases (comprised of 2 primary cases, 2 cutaneous recurrences, and 10 metastases) and a cohort of 127 conventional melanomas including primary, recurrent, and metastatic cases. Targeted sequencing of 447 cancer-associated genes was performed, including identification of mutations and copy number alterations. NRAS was the most frequent melanoma driver in undifferentiated melanoma (8/14 cases, 57%), although notably, only 1 undifferentiated melanoma harbored an NRAS Q61R mutation. Compared with the conventional melanoma cohort, undifferentiated melanoma demonstrated statistically significant enrichment of pathogenic activating RAC1 mutations (6/14 total cases, 43%), including P29S (4/6 cases), P29L (1/6 cases), and D11E (1/6 cases). In addition to providing insight into the molecular pathogenesis of undifferentiated melanoma, these findings also suggest that RAS Q61R immunohistochemistry may have limited utility for its diagnosis. The presence of recurrent RAC1 mutations in undifferentiated melanoma is also notable as these alterations may contribute to mitogen-activated protein kinase pathway–targeted therapy resistance. Furthermore, the RAC1 alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.

未分化黑色素瘤是指失去了传统黑色素瘤所有常见表型和免疫组化特征的黑色素瘤，它可能给诊断带来重大挑战。分子研究表明，未分化黑色素瘤中的一部分存在已知的黑色素瘤驱动基因改变，如 BRAF、NRAS 和 NF1，从而加深了我们对未分化黑色素瘤的了解。然而，描述可将未分化黑色素瘤与传统黑色素瘤区分开来的基因改变的数据还很少。在这项研究中，我们直接比较了未分化黑色素瘤与传统黑色素瘤的基因组图谱，包括14例未分化黑色素瘤（包括2例原发病例、2例皮肤复发病例和10例转移病例）和127例传统黑色素瘤（包括原发、复发和转移病例）。研究人员对 447 个癌症相关基因进行了靶向测序，包括突变和拷贝数改变（CNA）的鉴定。在未分化黑色素瘤中，NRAS是最常见的黑色素瘤驱动基因（8/14例，57%），但值得注意的是，只有一个未分化黑色素瘤携带NRAS Q61R突变。与常规黑色素瘤队列相比，未分化黑色素瘤在统计学上明显富含致病性活化RAC1突变（共6/14例，43%），包括P29S（4/6例）、P29L（1/6例）和D11E（1/6例）。这些发现不仅有助于深入了解未分化黑色素瘤的分子发病机制，而且还表明，RAS Q61R 免疫组化在诊断未分化黑色素瘤方面的作用可能有限。未分化黑色素瘤中反复出现的RAC1突变也值得注意，因为这些改变可能会导致丝裂原活化蛋白（MAP）激酶通路靶向治疗耐药。此外，在这组患者中发现的RAC1基因突变已被证明能促使黑色素细胞向间质细胞转变，从而为这些黑色素瘤的未分化表型提供了可能的解释。

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引用次数: 0

DNA Methylation Profiling of Salivary Gland Tumors Supports and Expands Conventional Classification 唾液腺肿瘤的 DNA 甲基化分析支持并扩展了传统分类。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-25 DOI: 10.1016/j.modpat.2024.100625

Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.

大唾液腺和小唾液腺肿瘤在组织学上包括多种多样且部分重叠的肿瘤，在诊断上经常具有挑战性。尽管最近在分子检测和肿瘤特异性突变或基因融合的鉴定方面取得了进展，但对于缺乏特异性改变的实体来说，鉴定其他诊断生物标志物的需求仍未得到满足。在这项研究中，我们收集了一个包含 20 种不同唾液腺肿瘤实体的 363 个病例的综合队列，并探索了 DNA 甲基化对这些肿瘤进行分类的潜力。我们能够证明大多数实体都显示出特定的表观遗传特征，并提出了一种机器学习算法，其平均平衡准确率达到了 0.991。值得注意的是，我们发现楔形腺癌在表观遗传学上有别于经典的多形性腺癌，这有助于对这些肿瘤进行风险分层。肌上皮瘤和多形性腺瘤形成了一个统一的表观遗传学类别，支持了具有广泛但连续形态谱的单一实体的理论。此外，我们还发现了一个组织形态异质但表观遗传学上不同的类别，它可能代表了一个新的肿瘤实体。总之，我们的研究提供了唾液腺肿瘤 DNA 甲基化图谱的全面资源。我们的数据提供了对有争议实体的新见解，并显示了 DNA 甲基化在识别新肿瘤类别方面的潜力。此外，我们的机器学习分类器将来还能支持涎腺肿瘤的组织病理学诊断。

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引用次数: 0

Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma 空间癌症--免疫表型预测了NSMP分子亚型子宫内膜癌较短的无复发生存期。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-24 DOI: 10.1016/j.modpat.2024.100624

Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.

免疫反应分为三大空间癌症免疫表型（SCI）--炎症型、排斥型和荒漠型--已被认为是预测实体瘤对免疫检查点抑制剂反应的主要指标。本研究的目的是通过将SCI与分子亚型、临床病理特征和预后相关联来定义和描述连续213例子宫内膜癌（EC）的SCI。免疫组化（IHC）和下一代测序（NGS）被用来确定代用的分子亚型：POLE突变型（POLE）、错配修复缺陷型（MMRd）、TP53突变型（p53abn）和无特异性分子特征型（NSMP）。通过全切片 IHC 评估免疫细胞标记物（CD20、CD3、CD8、CD68、PD-L1），并通过数字图像分析进行量化，以确定三种 SCI。心肌细胞被分为四种分子亚型：17个（8.0%）POLE亚型、68个（31.9%）MMRd亚型、42个（19.7%）p53abn亚型和86个（40.4%）NSMP亚型。SCI 测定结果显示，105 例（49.3%）为炎性肿瘤，62 例（29.1%）为荒漠性肿瘤，46 例（25.6%）为排除性肿瘤。与NSMP（45.3%）和p53abn（21.4%）相比，炎症表型在MMRd（64.7%）和POLE（76.5%）亚型中更为普遍。SCI与NSMP肿瘤的DFS密切相关：炎症96.2%，荒漠83.2%，除外40.5%。在接受辅助治疗的NSMP病例中，SCI对预后的影响也保持不变，这导致炎性表型和除外表型之间的复发率存在显著差异。为了简化SCI的判定，研究人员选择了合适的免疫细胞标记物子集来定义三种SCI模式：上皮内CD8高的为炎症表型；CD68、CD20和PD-L1用于区分荒漠型和排除型肿瘤。将 SCI 纳入分子分类可能是改善患者预后风险分层的大好机会，并可指导治疗方法，尤其是在 NSMP 亚型中。因此，不同的免疫反应模式是NSMP亚型的一个新的预后参数。

{"title":"Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma","authors":"","doi":"10.1016/j.modpat.2024.100624","DOIUrl":"10.1016/j.modpat.2024.100624","url":null,"abstract":"<div><div>Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: <em>POLE</em> mutant (<em>POLE</em>), mismatch repair deficient (MMRd), <em>TP53</em> mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) <em>POLE</em>, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and <em>POLE</em> (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma IDH 突变前列腺腺癌的组织病理学和分子特征。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-24 DOI: 10.1016/j.modpat.2024.100616

Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications have suggested that psammomatous calcifications in PCa are associated with IDH1 mutations. In this retrospective study, we queried our institutional clinical sequencing database (cohort 1), and previously published PCa data sets in cBioPortal (cohort 2). Samples were stratified based on oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other nonhotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa cases in cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N = 15, 1 of which was subclonal) or IDH2 (N = 2) mutations, and 20 (0.5%) cases had nonhotspot IDH1/2 mutations. A histologic review of 13 cases with IDH1 hotspot mutations and available material showed grade group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutations when possible and showed AR, PSA, PSMA, and NKX3.1 positive in all the 4 cases stained. In cohort 2, 9 cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and 9 cases carried nonhotspot IDH1/2 mutations. The combined cohorts of 23 PCa cases with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, and somatic or germline alterations in BRCA1/2, ATM, RB1, or AR; 19 cases with successful microsatellite instability testing were all microsatellite stable. Conversely, among 29 cases with nonhotspot IDH mutations, there were 4 with TMPRSS2::ERG fusions, 6 with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; 8 were microsatellite instability high. Notably, two cases with IDH1 hotspot mutations had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

功能增益型异柠檬酸脱氢酶（IDH）突变在许多肿瘤类型中都具有重要的致病性，在胆管癌、低级别胶质瘤和急性髓性白血病中具有可操作性。前列腺腺癌（PCa）中也出现了罕见的 IDH 突变。最近有文献指出，PCa 中的炎性钙化与 IDH1 突变有关。在这项回顾性研究中，我们查询了本机构的临床测序数据库（队列 1）和之前在 cBioPortal 上发表的 PCa 数据集（队列 2）。样本按IDH1 R132和IDH2 R140/R172的致癌热点IDH突变以及其他非热点IDH突变进行了分层。在队列1的4033例PCa中，发现17例（0.4%）携带相互排斥的致癌热点IDH1（15例，其中1例为亚克隆）或IDH2（2例）突变，20例（0.5%）携带非热点IDH1/2突变。对13例IDH1热点突变病例的组织学检查和现有材料显示，病变为3级或3级以上。在可能的情况下，对有IDH1热点突变的病例进行了免疫组化，结果显示所有4例染色病例的AR、PSA、PSMA和NKX3.1均为阳性。在队列 2 中，从 2749 例患者中发现了 9 例（0.3%）携带 IDH1 热点突变的病例，另有 9 例携带 IDH1/2 非热点突变。23例IDH1热点突变的PCa患者中没有ETS融合、SPOP热点突变、BRCA1/2、ATM、RB1或AR的体细胞或种系改变；19例成功通过微卫星不稳定性（MSI）检测的病例均为微卫星稳定型。相反，在29例非热点IDH突变病例中，4例有TMPRSS2::ERG融合，6例有SPOP热点突变，10例有AR扩增/热点突变；8例为MSI-高。值得注意的是，只有两例IDH1热点突变病例出现了炎性钙化。我们的研究结果提供了证据，证明IDH1热点突变是这种罕见但独特的PCa分子亚群的驱动性改变。还需要进一步研究雄激素剥夺和IDH抑制剂的相关反应。

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引用次数: 0

Contemporary Approach to the Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes—Recommendations From the International Consortium for Myelodysplastic Neoplasms/Syndromes (MDS [icMDS]) 骨髓增生异常肿瘤/综合征的当代诊断和分类方法--国际骨髓增生异常综合征联盟（icMDS）的建议。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-23 DOI: 10.1016/j.modpat.2024.100615

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, 2 classification systems (the 5th edition of the World Health Organization Classification of Haematolymphoid tTumours and the International Consensus Classification) further subcharacterized MDS into morphologically and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification.

骨髓增生异常肿瘤/综合征（MDS）是一组生物学上不同的异质性实体，其特征是不同程度的无效造血。最近，两个分类系统（第五版世界卫生组织分类和国际共识分类）将 MDS 进一步细分为形态学组和基因组。MDS 的准确诊断和亚分类需要多步骤的系统方法。MDS 国际联盟（icMDS）总结了一种现代、实用和多模式的 MDS 诊断和分类方法。

引用次数: 0

RNA Sequencing May Call CEP170::RAD51B Fusion Because of Alignment Artifacts RNA 测序可能会因对齐误差而误判 CEP170::RAD51B 融合

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-13 DOI: 10.1016/j.modpat.2024.100597

引用次数: 0

Regulatory Aspects of Artificial Intelligence and Machine Learning 人工智能-ML 的监管问题。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-12 DOI: 10.1016/j.modpat.2024.100609

In the realm of health care, numerous generative and nongenerative artificial intelligence and machine learning (AI-ML) tools have been developed and deployed. Simultaneously, manufacturers of medical devices are leveraging AI-ML. However, the adoption of AI in health care raises several concerns, including safety, security, ethical biases, accountability, trust, economic impact, and environmental effects. Effective regulation can mitigate some of these risks, promote fairness, establish standards, and advocate for more sustainable AI practices. Regulating AI tools not only ensures their safe and effective adoption but also fosters public trust. It is important that regulations remain flexible to accommodate rapid advances in this field to support innovation and also not to add additional burden to some of our preexisting and well-established frameworks. This study covers regional and global regulatory aspects of AI-ML including data privacy, software as a medical device, agency approval and clearance pathways, reimbursement, and laboratory-developed tests.

在医疗保健领域，已经开发和部署了大量生成式和非生成式人工智能和机器学习（AI-ML）工具。与此同时，医疗设备制造商也在利用 AI-ML。然而，在医疗保健领域采用人工智能会引发一些问题，包括安全、安保、道德偏见、问责、信任、经济影响和环境影响。有效的监管可以降低其中一些风险，促进公平，建立标准，并倡导更可持续的人工智能实践。对人工智能工具进行监管不仅能确保其安全有效地应用，还能促进公众信任。重要的是，监管应保持灵活性，以适应该领域的快速发展，从而支持创新，同时也不给我们现有的一些完善框架增加额外负担。本文涉及人工智能医疗的地区和全球监管方面，包括数据隐私、软件即医疗设备（SaMD）、机构审批和许可途径、报销和实验室开发测试（LDTs）。

引用次数: 0

p53 Abnormal Oral Epithelial Dysplasias are Associated With High Risks of Progression and Local Recurrence—A Retrospective Study in a Longitudinal Cohort p53异常口腔上皮增生异常与病情恶化和局部复发的高风险有关--一项纵向队列的回顾性研究。

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2024-09-10 DOI: 10.1016/j.modpat.2024.100613

Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by 2 pathologists (Y.C.K.K., C.F.P.) blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (P < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence–free survival compared with p53 wild-type OED (P = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade.

口腔上皮发育不良（OED）的分级具有挑战性，观察者内部和观察者之间的差异很大。最近的研究表明，肿瘤抑制蛋白 p53 的异常免疫组化染色模式可能与 OED 的进展有关。我们回顾性地鉴定了 2001 年至 2008 年间一项纵向研究招募的 203 名患者的 214 份口腔活检样本，诊断为反应性、非增生性病变、低级别病变（LGLs；轻度 OED、中度 OED）和高级别病变（HGLs；重度 OED/原位癌）。组织微阵列（TMA）由最具代表性的病理区域构建而成。对三个连续切片进行切片，并进行苏木精和伊红染色、p53 免疫组化和 p16 免疫组化。染色结果由两名对临床结果保密的病理学家进行审核。采用之前发表的基于模式的方法，将样本分为p53-异常OED（n = 46）、p53-常规OED（n = 118）和p53-HPV（HPV相关）OED（n = 12）。所有p53-HPV（HPV相关）OED病例都是在HGLs中发现的。相比之下，p53异常的OED病例出现在轻度OED（9.5%）、中度OED（23%）和重度OED/原位癌（51%）中。27个反应性或非增生性病变中没有一个显示出异常的p53染色模式。在135例LGL中，23例（17.0%；2例轻度OED和21例中度OED）进展为HGL或鳞癌，其中11例在最初3年内出现进展。值得注意的是，在这些进展较快的病例中，82%（9/11）的病例显示出异常的 p53 模式。生存期分析表明，p53异常的OED的无进展概率明显较低（p

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引用次数: 0