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Risk Factors of Lymph Node Metastasis and Prognosis in 891 Chinese Patients With Submucosal Early Gastric Carcinoma, Emphasizing Differences Between Gastric Cardiac and Noncardiac Origins. 891例中国黏膜下早期胃癌患者淋巴结转移的风险因素和预后,强调胃癌心源性和非心源性的差异
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-19 DOI: 10.1097/PAS.0000000000002282
Yuqing Cheng, Mingzhan Du, Yaohui Wang, Ting Li, Chongfang He, Xiaoli Zhou, Min Lin, Qin Huang

Differences in risk factors (RF) of lymph node metastasis (LNM) and prognosis between submucosal early gastric cardiac (SEGCC) and noncardiac (SEGNCC) carcinomas remain unclear. In this study, we investigated and compared RF of LNM and prognosis in 891 patients with radical gastrectomy for SEGCC (n=217) or SEGNCC (n=674). Compared with SEGNCC, SEGCC displayed significantly higher proportion of elderly patients (70 y or above), the elevated macroscopic type, well/moderately differentiated tubular and low-grade papillary adenocarcinomas, as well as low-grade tumor budding, but lower prevalence of the depressed macroscopic type, poorly differentiated tubular adenocarcinoma, mixed adenocarcinoma, poorly cohesive carcinoma, lymphovascular invasion (LVI), perineural invasion, and high-grade tumor budding. By univariate analysis, significant RF for LNM of the cohort included female sex, poor differentiation, SM2 invasion, LVI, intermediate-grade and high-grade tumor budding, whereas tumor size, histology type, and perineural invasion were the significant RF for LNM in SEGNCC. By multivariate analysis, significant independent RF for LNM included female sex and LVI in SEGCC but were female sex, mixed adenocarcinoma, LVI, and high-grade tumor budding in SEGNCC. The 5-year overall survival was significantly worse in SEGCC than in SEGNCC for patients with LNM, but not for those without. For overall survival, LNM was the only significant independent RF in SEGCC, whereas age 70 years or above and LNM were independent RF in SEGNCC. The results of our study provided the clinicopathologic evidence for individualized clinical management strategies for these 2 groups of patients and suggested different pathogenesis mechanisms between SEGCC and SEGNCC.

粘膜下早期胃心性癌(SEGCC)和非心性癌(SEGNCC)的淋巴结转移(LNM)风险因素(RF)和预后的差异仍不清楚。在这项研究中,我们调查并比较了891例因SEGCC(217例)或SEGNCC(674例)而接受根治性胃切除术的患者的LNM射频和预后。与 SEGNCC 相比,SEGCC 的老年患者(70 岁或以上)比例明显较高、宏观类型升高、分化良好/中等的管状腺癌和低级别乳头状腺癌以及低级别肿瘤出芽的比例明显较高、但宏观类型低沉、分化差的管状腺癌、混合型腺癌、内聚性差的腺癌、淋巴管侵犯(LVI)、神经周围侵犯和高级别肿瘤萌芽的发病率较低。单变量分析显示,女性性别、分化不良、SM2侵犯、LVI、中级和高级别肿瘤萌芽是队列中LNM的显著RF,而肿瘤大小、组织学类型和神经周围侵犯是SEGNCC中LNM的显著RF。通过多变量分析,在SEGCC中,女性性别和LVI是导致LNM的重要独立因素,而在SEGNCC中,女性性别、混合腺癌、LVI和高级别肿瘤出芽是导致LNM的重要独立因素。在有LNM的患者中,SEGCC的5年总生存率明显低于SEGNCC,但在没有LNM的患者中则没有明显差异。就总生存率而言,LNM是SEGCC中唯一显著的独立RF,而年龄在70岁或以上和LNM则是SEGNCC中的独立RF。我们的研究结果为这两类患者的个体化临床治疗策略提供了临床病理学证据,并提示了SEGCC和SEGNCC的不同发病机制。
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引用次数: 0
Inflammatory Giant Cell Carcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Next-generation Sequencing Study of 14 Cases. 肺部炎性巨细胞癌:14例临床病理学、免疫组织化学和新一代测序研究。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-11 DOI: 10.1097/PAS.0000000000002285
David I Suster, A Craig Mackinnon, Natali Ronen, Haider A Mejbel, Shuko Harada, Michael Michal, Saul Suster

A distinctive histological variant of poorly differentiated, sarcomatoid, non-small cell lung carcinoma characterized by a discohesive population of giant tumor cells associated with prominent interstitial inflammatory cell infiltrates is described. The tumors occurred in 7 women and 7 men, 42 to 72 years of age (mean: 56 y). They predominantly affected the upper lobes and measured 1.3 to 9 cm in greatest diameter (mean: 4.6 cm). The tumor cells were characterized by large pleomorphic nuclei with prominent nucleoli, ample cytoplasm, and frequent abnormal mitoses, and were surrounded by a dense inflammatory cell infiltrate, often associated with emperipolesis. Immunohistochemical stains were positive in the tumor cells for cytokeratin AE1/AE3 and CK8/18 and negative for TTF1, napsin A, p40, and CK5/6. Next-generation sequencing was performed in all cases using the Oncomine Precision Assay; the most common abnormalities found included TP53 mutations (9 cases) and AKT1 amplification (8 cases), followed by KRAS mutations (4 cases) and MAP2K1/2 mutations (4 cases). Clinical follow-up was available in 13 patients. Three patients presented with metastases as the initial manifestation of disease; 8 patients died of their tumors from 6 months to 8 years (mean: 2.7 y); 3 patients were alive and well from 4 to 6 years; and 2 patients had metastases when last seen but were lost to follow-up thereafter. The importance of recognizing this distinctive and aggressive variant of non-small cell lung carcinoma lies in avoiding confusion with a sarcoma or other types of malignancy.

本文描述了分化不良、肉瘤样、非小细胞肺癌的一种独特的组织学变异,其特征是巨大肿瘤细胞的盘状群体伴有突出的间质炎性细胞浸润。这些肿瘤发生在 7 名女性和 7 名男性身上,年龄在 42 岁至 72 岁之间(平均 56 岁)。肿瘤主要累及上叶,最大直径为 1.3 至 9 厘米(平均 4.6 厘米)。肿瘤细胞的特点是核大、多形性、核仁突出、胞浆丰富、有丝分裂异常,周围有密集的炎性细胞浸润,常伴有包膜增生。免疫组化染色显示,肿瘤细胞的细胞角蛋白AE1/AE3和CK8/18呈阳性,TTF1、napsin A、p40和CK5/6呈阴性。使用 Oncomine Precision Assay 对所有病例进行了新一代测序;发现的最常见异常包括 TP53 突变(9 例)和 AKT1 扩增(8 例),其次是 KRAS 突变(4 例)和 MAP2K1/2 突变(4 例)。13 例患者接受了临床随访。其中,3 名患者最初表现为转移灶;8 名患者在 6 个月至 8 年(平均 2.7 年)期间死于肿瘤;3 名患者在 4 至 6 年期间存活良好;2 名患者最后一次就诊时有转移灶,但此后失去了随访机会。识别非小细胞肺癌这种独特的侵袭性变异的重要性在于避免与肉瘤或其他类型的恶性肿瘤相混淆。
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引用次数: 0
The Pathology of Pulmonary Disease After Pediatric Hematopoietic Stem Cell Transplantation. 小儿造血干细胞移植后肺部疾病的病理学。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-29 DOI: 10.1097/PAS.0000000000002267
Nahir Cortes-Santiago, Gail Deutsch, Kalyani R Patel, Manuel Silva-Carmona, Carolyn Henderson, Sarah E Sartain, Saleh Bhar, Jennifer Pogoriler

Pulmonary complications continue to cause significant morbidity and mortality in posthematopoietic stem cell transplantation (HSCT) settings. The histopathology of pulmonary diseases in the post-HSCT context is poorly characterized, especially in the pediatric population. We sought to characterize the pathologic spectrum of pulmonary disease post-HSCT in a pediatric cohort. Fifty-six specimens, including 53 biopsy specimens, corresponding to 53 patients, were identified. Biopsy slides were reviewed and assigned to diagnostic categories (infectious, graft-versus-host disease, vasculopathy, indeterminate, and others) by consensus among 3 pediatric pulmonary pathologists, taking into consideration pathologic, clinical, radiologic, and laboratory findings. The most common diagnostic category was infection (n=20). Vasculopathy, mostly in the form of fibromyxoid intimal expansion, was very common in the entire cohort (n=26) and was the sole finding in a small subset of patients (n=5), with particularly poor outcomes. A subset of biopsies remained indeterminate (n=10), and the findings in this cohort were dominated by acute lung injury. The latter group had a poor prognosis, with a short biopsy-to-death interval. The overall clinicopathologic concordance was 40%, most commonly agreeing in the infectious category. Finally, wedge biopsies led to a change in management in 69% of cases versus 23% of limited procedures (i.e., core needle biopsies). Our results suggest that while infectious complications continue to be common post-HSCT, other findings such as vasculopathy and acute lung injury portend a particularly poor prognosis and should be actively sought and reported.

在造血干细胞移植(HSCT)后,肺部并发症继续导致严重的发病率和死亡率。造血干细胞移植后肺部疾病的组织病理学特征尚不明确,尤其是在儿科人群中。我们试图在儿科人群中描述造血干细胞移植后肺部疾病的病理范围。我们鉴定了 53 名患者的 56 份标本,包括 53 份活检标本。三名儿科肺病病理学家对活检切片进行了审查,并在考虑病理、临床、放射和实验室检查结果的基础上达成共识,将活检切片归入诊断类别(感染性、移植物抗宿主疾病、血管病变、不确定及其他)。最常见的诊断类别是感染(20 人)。血管病变主要表现为纤维瘤样内膜扩张,在整个组别中非常常见(26 例),也是一小部分患者(5 例)的唯一发现,这些患者的预后特别差。有一部分活检结果仍不确定(10 人),这部分患者的检查结果以急性肺损伤为主。后一组患者的预后较差,从活检到死亡的间隔时间较短。总体临床病理一致率为40%,最常见的是感染性类别。最后,楔形活检导致改变治疗方案的病例占 69%,而有限手术(即核心针活检)占 23%。我们的研究结果表明,虽然感染性并发症在 HSCT 术后仍很常见,但血管病变和急性肺损伤等其他发现预示着预后特别差,因此应积极寻找并报告。
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引用次数: 0
A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1 -altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1 - amplified Versus GLI1- rearranged Tumors. 对GLI1改变的间质肿瘤进行全面的临床病理学和分子再评估,结果显示GLI1扩增肿瘤的生存率低于GLI1重组肿瘤。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-27 DOI: 10.1097/PAS.0000000000002272
Carla Saoud, Abbas Agaimy, Josephine K Dermawan, Jie-Fu Chen, Marc K Rosenblum, Brendan C Dickson, Nooshin Dashti, Michael Michal, Kemal Kosemehmetoglu, Nasir Ud Din, Karen Albritton, Narasimhan P Agaram, Cristina R Antonescu

GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors.

GLI1改变的间质瘤是最近描述的一种独特病理实体,具有既定的恶性风险,其分子定义为GLI1基因融合或扩增。这两种看似不同的 GLI1 激活机制导致的肿瘤的临床病理重叠仍在不断出现。在此,我们报告了迄今为止经分子证实的最大规模的GLI1改变间叶肿瘤系列,包括23例GLI1扩增和15例GLI1重排新病例,并进行了临床病理学、基因组学和生存率的比较研究。GLI1重组肿瘤发生在较年轻的患者中(42岁对52岁),与GLI1扩增肿瘤相比体积更大(分别为5.6厘米对1.5厘米)。两组患者的组织学特征总体相似,均表现为多结节型和上皮样细胞(较少见的是纺锤形细胞)巢状结构,周围有丰富的毛细血管网。在 3 个 GLI1 扩增的肿瘤中发现了明显的轮状模式。两组肿瘤中都很少见到散在的多形性巨细胞。免疫图谱显示 CD56 表达一致,S100、CD10 和 SMA 表达不一。从基因组学来看,两组肿瘤的基因突变负担总体较低,只有在GLI1扩增的肿瘤中出现罕见的TP53突变。GLI1扩增的间质瘤大多在12q13-15位点表现出单个扩增子,相比之下,去分化脂肪肉瘤则表现出以CDK4(12q14.1)和MDM2(12q15)为中心的双峰扩增。与GLI1重组肿瘤相比,GLI1扩增肿瘤的GLI1 mRNA表达量明显更高。对现有病例和已发表病例(n=83)进行的生存期汇总分析表明,GLI1扩增患者的总生存期较差,16%的患者死于疾病,而GLI1重组组仅为1.7%。尽管进展率相当,但与GLI1重组肿瘤相比,GLI1扩增肿瘤的中位无进展生存期更短(25个月对77个月)。单变量分析表明,传统的恶性肿瘤组织学预测指标(有丝分裂计数≥4/10个高倍视野、出现坏死、肿瘤大小≥5厘米)与GLI1改变间质肿瘤的较差预后有关。
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引用次数: 0
Reply to Letter by Cyrta et al, Entitled "Additional Considerations on Aberrant BRG1 (SMARCA4) Expression in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT)". 回复 Cyrta 等人题为 "关于卵巢高钙型小细胞癌 (SCCOHT) 中 BRG1 (SMARCA4) 异常表达的其他考虑 "的信件。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1097/PAS.0000000000002295
Jasenka Mazibrada, Sabrina Croce, William D Foulkes, W Glenn McCluggage
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引用次数: 0
Additional Considerations on Aberrant BRG1 (SMARCA4) Expression in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT). 关于卵巢高钙型小细胞癌 (SCCOHT) 中 BRG1 (SMARCA4) 表达异常的更多考虑。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-02 DOI: 10.1097/PAS.0000000000002296
Joanna Cyrta, Riwan Brillet, Enora Laas, Pierre-Alexandre Just, Mamy Andrianteranagna, Alexandra Leary, Anne Vincent-Salomon, Franck Bourdeaut, Julien Masliah-Planchon
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引用次数: 0
Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types. 人类癌症中 S-甲基-5'-硫代腺苷磷酸酶 (MTAP) 缺乏的流行率:对来自 149 种不同肿瘤类型的 13,067 例肿瘤进行的组织芯片研究。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1097/PAS.0000000000002297
Natalia Gorbokon, Niklas Wößner, Maximilian Lennartz, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Florian Lutz, Christoph Fraune, Andreas M Luebke, Claudia Hube-Magg, Anne Menz, Ria Schlichter, Till Krech, Andrea Hinsch, Eike Burandt, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H Marx, Patrick Lebok, David Dum, Sarah Minner, Frank Jacobsen, Till S Clauditz, Thilo Hackert, Faik G Uzunoǧlu, Lukas Bubendorf, Christian Bernreuther, Martina Kluth

Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8 + lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.

S-甲基-5'-硫代腺苷磷酸化酶(MTAP)表达缺失是癌症中的常见现象,会导致癌细胞极易受到抗癌药物的伤害。同基因 MTAP 缺失会导致完全表达缺失,可通过免疫组织化学(IHC)检测到。本研究通过 IHC 分析了包含来自 149 个不同肿瘤实体的 17,078 个样本的组织芯片,并通过荧光原位杂交验证了 MTAP 的完全缺失。在 149 种肿瘤中,有 83 种观察到 MTAP 缺失,包括神经内分泌肿瘤(高达 80%)、霍奇金淋巴瘤(50.0%)、间皮瘤(32.0% 至 36.8%)、胃肠道腺癌(4.0%至 40.5%)、尿路肿瘤(10.5%至 36.7%)、鳞状细胞癌(高达 38%)以及各种肉瘤(高达 20%)和非霍奇金淋巴瘤(高达 14%)。在大多数肿瘤类别中,90%至100%的病例发现了同基因MTAP缺失,MTAP表达缺失。然而,神经内分泌肿瘤、霍奇金淋巴瘤和其他淋巴瘤缺乏MTAP缺失。MTAP缺失与某些肿瘤实体的不良肿瘤表型、肿瘤细胞上的PD-L1表达、免疫细胞上的PD-L1表达缺失以及CD8+淋巴细胞的低密度密切相关。总之,MTAP 缺乏可发生在各种肿瘤实体中,与不利的肿瘤表型和非炎症性肿瘤微环境有关,但并不总是与缺失有关。MTAP IHC 在多种不同应用中检测肿瘤转化具有相当高的诊断价值。
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引用次数: 0
Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK-rearranged Myxoid Spindle Cell Neoplasm: A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions. 上皮样纤维组织细胞瘤与浅表ALK排列肌样纺锤细胞肿瘤之间的关系:35例临床病理系列,包括RET和NTRK3交替融合。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-27 DOI: 10.1097/PAS.0000000000002315
Mia S DeSimone, Igor Odintsov, Harrison K Tsai, Brendan C Dickson, Ahmed K Alomari, Jason L Hornick, Christopher D M Fletcher, David J Papke
<p><p>Anaplastic lymphoma kinase (ALK) rearrangements drive most examples of epithelioid fibrous histiocytoma (EFH) and have been reported in an emerging family of receptor tyrosine kinase (RTK) fusion-positive mesenchymal neoplasms, including superficial ones described under the rubric of "superficial ALK-rearranged myxoid spindle cell neoplasm" (SAMS). Here, we describe 35 superficial tumors with SAMS morphology, which occurred in 18 females (51%) and 17 males at a median age at presentation of 39 years (range: 6 to 82 y). Most tumors occurred on the lower extremity (25 tumors; 71%), followed by upper extremity (5; 14%), trunk (3; 9%), and face (2; 6%). Nine tumors were reported to have grown slowly before presentation, including >10 years in 2 cases. Tumors occurred primarily in the dermis (32 tumors; 91%) or subcutis (3; 9%); 8 dermal tumors extended into the subcutis. Median tumor size was 1.3 cm (range: 0.5 to 8.0 cm). Clinical follow-up was available for 12 patients (34%; range: 2 mo to 21 y; median: 2.7 y), none of whom experienced metastasis. One incompletely resected tumor recurred locally at 19 months, and no other patients experienced recurrence. Histologically, tumors were characterized by bland spindle-to-ovoid cells showing whorled growth and myxoid-to-collagenous stroma. Recurrent features included an epidermal collarette (19/30; 63%), perivascular hyalinization (20/35; 57%), amianthoid collagen (14/35; 40%), and metaplastic ossification (2/35; 6%). Immunohistochemistry (IHC) demonstrated expression of ALK (24/31; 77%), CD34 (15/21; 71%), EMA (17/28; 61%), and S-100 (9/32; 28%). Eleven tumors showed hybrid morphologic features between EFH and SAMS; 9 of them (82%) showed cytomorphology typical of EFH but with whorled growth, myxoid stroma, and/or regions of spindle cell morphology. Two hybrid tumors showed sharp transitions between a region characteristic of EFH and a region characteristic of SAMS, with a concomitant sharp transition in EMA, CD34, and S-100 expression by IHC. Sequencing revealed ALK fusions in 15 of 19 tumors: 2 each with fusion partners FLNA, SQSTM1, and VCL, and 1 each with COL1A2, DCTN1, EML4, FXR1, MPRIP, PLEKHH2, PRKAR1A, SPECC1L, and TLN2. Thirteen of 14 ALK-rearranged tumors expressed ALK by IHC. Three tumors negative for ALK fusions instead harbored alternate RTK fusions (NCOA4::RET, TRIM27::RET, and VIM::NTRK3), and 1 tumor was negative for RTK alterations. CDKN2A/B deletions were found in 2 tumors with ALK fusions and both tumors with RET fusions. SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologi
无性淋巴瘤激酶(ALK)重排是大多数上皮样纤维组织细胞瘤(EFH)的驱动因素,据报道,在新出现的受体酪氨酸激酶(RTK)融合阳性间充质肿瘤家族中也存在无性淋巴瘤激酶(ALK)重排,其中包括以 "浅表ALK重排肌样纺锤形细胞瘤"(SAMS)为名的浅表肿瘤。在此,我们描述了35例具有SAMS形态的表浅肿瘤,其中18例为女性(51%),17例为男性,发病年龄中位数为39岁(6至82岁)。大多数肿瘤发生在下肢(25 例;71%),其次是上肢(5 例;14%)、躯干(3 例;9%)和面部(2 例;6%)。据报道,9例肿瘤在发病前生长缓慢,其中2例生长时间超过10年。肿瘤主要发生在真皮(32 例;91%)或皮下(3 例;9%);8 例真皮肿瘤延伸至皮下。肿瘤大小中位数为 1.3 厘米(范围:0.5 至 8.0 厘米)。12名患者(34%;范围:2个月至21年;中位数:2.7年)接受了临床随访,其中无一发生转移。一名未完全切除的肿瘤患者在 19 个月时局部复发,其他患者均未复发。从组织学上看,肿瘤的特征是平滑的纺锤形至卵圆形细胞呈轮状生长,基质为肌层至胶原层。复发特征包括表皮领带(19/30;63%)、血管周围透明化(20/35;57%)、淀粉样胶原(14/35;40%)和移行骨化(2/35;6%)。免疫组化(IHC)显示了ALK(24/31;77%)、CD34(15/21;71%)、EMA(17/28;61%)和S-100(9/32;28%)的表达。11例肿瘤表现出EFH和SAMS的混合形态特征;其中9例(82%)表现出典型的EFH细胞形态,但有轮状生长、肌样基质和/或纺锤形细胞形态区域。两个混合瘤在EFH特征区域和SAMS特征区域之间出现急剧转变,同时IHC显示EMA、CD34和S-100表达也出现急剧转变。测序结果显示,19 例肿瘤中有 15 例存在 ALK 融合:与 FLNA、SQSTM1 和 VCL 融合的各 2 例,与 COL1A2、DCTN1、EML4、FXR1、MPRIP、PLEKHH2、PRKAR1A、SPECC1L 和 TLN2 融合的各 1 例。通过 IHC 检测,14 例 ALK 重组肿瘤中有 13 例表达 ALK。3个ALK融合阴性的肿瘤携带交替RTK融合(NCOA4::RET、TRIM27::RET和VIM::NTRK3),1个肿瘤RTK改变阴性。在2个ALK融合的肿瘤和2个RET融合的肿瘤中发现了CDKN2A/B缺失。SAMS与EFH在形态学和分子遗传学上具有相同的谱系,分布在相似的身体部位,临床上常表现为外生性皮肤肿瘤,而且无一例外都是良性结果;我们的结论是,SAMS应被视为EFH的一种组织学变异。一些形态上的典型病例存在交替的 RET 和 NTRK3 融合,因此 SAMS 并不是这一形态类别的恰当名称;相反,为了突出与 EFH 在临床病理上的相似性,我们提出了 "上皮样纤维组织细胞瘤的肌样纺锤细胞变异型 "这一诊断术语。
{"title":"Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK-rearranged Myxoid Spindle Cell Neoplasm: A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions.","authors":"Mia S DeSimone, Igor Odintsov, Harrison K Tsai, Brendan C Dickson, Ahmed K Alomari, Jason L Hornick, Christopher D M Fletcher, David J Papke","doi":"10.1097/PAS.0000000000002315","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002315","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Anaplastic lymphoma kinase (ALK) rearrangements drive most examples of epithelioid fibrous histiocytoma (EFH) and have been reported in an emerging family of receptor tyrosine kinase (RTK) fusion-positive mesenchymal neoplasms, including superficial ones described under the rubric of \"superficial ALK-rearranged myxoid spindle cell neoplasm\" (SAMS). Here, we describe 35 superficial tumors with SAMS morphology, which occurred in 18 females (51%) and 17 males at a median age at presentation of 39 years (range: 6 to 82 y). Most tumors occurred on the lower extremity (25 tumors; 71%), followed by upper extremity (5; 14%), trunk (3; 9%), and face (2; 6%). Nine tumors were reported to have grown slowly before presentation, including &gt;10 years in 2 cases. Tumors occurred primarily in the dermis (32 tumors; 91%) or subcutis (3; 9%); 8 dermal tumors extended into the subcutis. Median tumor size was 1.3 cm (range: 0.5 to 8.0 cm). Clinical follow-up was available for 12 patients (34%; range: 2 mo to 21 y; median: 2.7 y), none of whom experienced metastasis. One incompletely resected tumor recurred locally at 19 months, and no other patients experienced recurrence. Histologically, tumors were characterized by bland spindle-to-ovoid cells showing whorled growth and myxoid-to-collagenous stroma. Recurrent features included an epidermal collarette (19/30; 63%), perivascular hyalinization (20/35; 57%), amianthoid collagen (14/35; 40%), and metaplastic ossification (2/35; 6%). Immunohistochemistry (IHC) demonstrated expression of ALK (24/31; 77%), CD34 (15/21; 71%), EMA (17/28; 61%), and S-100 (9/32; 28%). Eleven tumors showed hybrid morphologic features between EFH and SAMS; 9 of them (82%) showed cytomorphology typical of EFH but with whorled growth, myxoid stroma, and/or regions of spindle cell morphology. Two hybrid tumors showed sharp transitions between a region characteristic of EFH and a region characteristic of SAMS, with a concomitant sharp transition in EMA, CD34, and S-100 expression by IHC. Sequencing revealed ALK fusions in 15 of 19 tumors: 2 each with fusion partners FLNA, SQSTM1, and VCL, and 1 each with COL1A2, DCTN1, EML4, FXR1, MPRIP, PLEKHH2, PRKAR1A, SPECC1L, and TLN2. Thirteen of 14 ALK-rearranged tumors expressed ALK by IHC. Three tumors negative for ALK fusions instead harbored alternate RTK fusions (NCOA4::RET, TRIM27::RET, and VIM::NTRK3), and 1 tumor was negative for RTK alterations. CDKN2A/B deletions were found in 2 tumors with ALK fusions and both tumors with RET fusions. SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologi","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expanding the Molecular Spectrum of Carcinoma Ex Pleomorphic Adenoma: An Analysis of 84 Cases With a Novel HMGA2::LINC02389 Fusion. 扩展癌外多形性腺瘤的分子谱:对84例新型HMGA2::LINC02389融合病例的分析
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-26 DOI: 10.1097/PAS.0000000000002307
Reydson Alcides de Lima-Souza, Albina Altemani, Michal Michal, Fernanda Viviane Mariano, Ilmo Leivo, Alena Skálová

Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications.

多形性腺瘤癌(CXPA)是一种侵袭性上皮和/或肌上皮肿瘤,与多形性腺瘤(PA)同时发生。其发病机理目前仍不十分清楚,但据认为,这种肿瘤的发生是由于 PA 中基因、蛋白质、代谢和表观遗传学改变的累积所致。通过对比尔森唾液腺肿瘤登记处进行回顾性研究,发现了 84 例 CXPA,即 25/84 例唾液腺导管癌 (SDC)、15/84 例肌上皮癌 (MC)、1/84 例上皮-肌上皮癌 (EMC) 和 1/84 例腺样囊性癌 (AdCC)。对所有 84 例 CXPA 病例进行了新一代测序(NGS)和/或荧光原位杂交(FISH)分析。最初诊断为 CXPA 的 43 例肿瘤(43/84,51.2%)出现了一些分子改变。在 12/16 例(75%)CXPA 中发现了融合转录本,包括 LIFR::PLAG1、CTNNB1::PLAG1、FGFR1::PLAG1 和一种新型融合 HMGA2::LINC02389。大多数融合都通过使用 PLAG1(6/11)和 HMGA2(1/1)基因断裂探针进行 FISH 验证。FISH 鉴定出 PLAG1(12/17)、HMGA2(3/4)、EWSR1(7/22)和 MYB(2/7)的基因断裂分裂信号。关于致病基因突变,只有上皮分化的CXPA(SDC)出现了这些改变,包括HRAS突变(2/4)、TP53(1/4)、PTEN(1/4)和ATK1(1/4)。此外,还检测到ERBB2(17/35)、MDM2(1/4)和EWSR1(1/7)的扩增。一项新发现是在一名EMC ex-PA患者中发现了HMGA2::LINC02389融合。本研究结果表明,肌上皮分化型(MC)CXPA 的分子图谱分析倾向于揭示染色体融合事件,而上皮分化型(SDC)CXPA 的致病突变和基因扩增频率更高。
{"title":"Expanding the Molecular Spectrum of Carcinoma Ex Pleomorphic Adenoma: An Analysis of 84 Cases With a Novel HMGA2::LINC02389 Fusion.","authors":"Reydson Alcides de Lima-Souza, Albina Altemani, Michal Michal, Fernanda Viviane Mariano, Ilmo Leivo, Alena Skálová","doi":"10.1097/PAS.0000000000002307","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002307","url":null,"abstract":"<p><p>Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
D2-40 and CK17 Immunohistochemistry as a Diagnostic Adjunct for HPV-Independent Squamous Lesions in the Vulva and Their Role in Defining Atypical Lichen Sclerosus. D2-40和CK17免疫组化作为外阴HPV依赖性鳞状病变的诊断辅助手段及其在确定非典型苔藓样硬化症中的作用。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-17 DOI: 10.1097/PAS.0000000000002310
Emily M Hartsough, Jaclyn Watkins, Rosalynn M Nazarian

Vulvar lichen sclerosus (LS) is a common, chronic inflammatory disorder with a subset of cases progressing to differentiated vulvar intraepithelial neoplasia (dVIN) and/or squamous cell carcinoma (SCC). Histopathologic diagnosis of LS and dVIN can be challenging, and it is difficult to predict the subset of LS cases that progress. Immunohistochemistry (IHC) may be a useful diagnostic aid in this setting. CK17 has been shown to be overexpressed in invasive SCC and dVIN, and less commonly in LS. Similar to CK17, D2-40 has been correlated with cutaneous SCC prognosis but has not been evaluated in vulvar lesions. We identified a total of 13 patients with HPV-independent vulvar SCC that had precursor LS or dVIN. CK17 and D2-40 IHC stain intensity and pattern was scored in foci of LS, dVIN, and SCC. An increase in basal layer D2-40 expression was observed with progression from LS to dVIN with strong and diffuse staining in SCC. CK17 maintained similar stain intensity among squamous lesions, but displayed different patterns of staining, with superficial staining in LS, suprabasal staining in dVIN, and diffuse staining in SCC. A subset of LS cases displayed an intermediate (suprabasal) CK17 IHC profile, wild-type p53 expression, and cytomorphologic and architectural features intermediate between LS and dVIN; we defined such cases as "atypical LS." We found that a panel of D2-40/CK17 can serve as a diagnostic adjunct to differentiate LS, dVIN, and invasive SCC. Additional studies with larger patient cohorts are needed to validate these findings and determine their prognostic significance.

外阴硬皮病(LS)是一种常见的慢性炎症性疾病,部分病例会发展为分化型外阴上皮内瘤变(dVIN)和/或鳞状细胞癌(SCC)。LS和dVIN的组织病理学诊断具有挑战性,而且很难预测哪些LS病例会恶化。在这种情况下,免疫组化(IHC)可能是一种有用的辅助诊断方法。研究表明,CK17在浸润性SCC和dVIN中过度表达,而在LS中较少见。与 CK17 相似,D2-40 也与皮肤 SCC 的预后相关,但尚未对外阴病变进行评估。我们共发现了 13 例有前驱 LS 或 dVIN 的 HPV 非依赖性外阴 SCC 患者。我们对LS、dVIN和SCC病灶的CK17和D2-40 IHC染色强度和模式进行了评分。观察到基底层 D2-40 的表达随着从 LS 到 dVIN 的进展而增加,在 SCC 中则有强烈的弥漫性染色。在鳞状病变中,CK17保持了相似的染色强度,但显示出不同的染色模式,在LS中为表层染色,在dVIN中为基底层上染色,而在SCC中为弥漫性染色。LS病例中有一部分显示出中间(基底膜上)CK17 IHC图谱、野生型p53表达以及介于LS和dVIN之间的细胞形态学和结构特征;我们将这类病例定义为 "非典型LS"。我们发现,D2-40/CK17 检测面板可作为诊断辅助工具,用于区分 LS、dVIN 和侵袭性 SCC。要验证这些发现并确定其预后意义,还需要对更大的患者群体进行更多的研究。
{"title":"D2-40 and CK17 Immunohistochemistry as a Diagnostic Adjunct for HPV-Independent Squamous Lesions in the Vulva and Their Role in Defining Atypical Lichen Sclerosus.","authors":"Emily M Hartsough, Jaclyn Watkins, Rosalynn M Nazarian","doi":"10.1097/PAS.0000000000002310","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002310","url":null,"abstract":"<p><p>Vulvar lichen sclerosus (LS) is a common, chronic inflammatory disorder with a subset of cases progressing to differentiated vulvar intraepithelial neoplasia (dVIN) and/or squamous cell carcinoma (SCC). Histopathologic diagnosis of LS and dVIN can be challenging, and it is difficult to predict the subset of LS cases that progress. Immunohistochemistry (IHC) may be a useful diagnostic aid in this setting. CK17 has been shown to be overexpressed in invasive SCC and dVIN, and less commonly in LS. Similar to CK17, D2-40 has been correlated with cutaneous SCC prognosis but has not been evaluated in vulvar lesions. We identified a total of 13 patients with HPV-independent vulvar SCC that had precursor LS or dVIN. CK17 and D2-40 IHC stain intensity and pattern was scored in foci of LS, dVIN, and SCC. An increase in basal layer D2-40 expression was observed with progression from LS to dVIN with strong and diffuse staining in SCC. CK17 maintained similar stain intensity among squamous lesions, but displayed different patterns of staining, with superficial staining in LS, suprabasal staining in dVIN, and diffuse staining in SCC. A subset of LS cases displayed an intermediate (suprabasal) CK17 IHC profile, wild-type p53 expression, and cytomorphologic and architectural features intermediate between LS and dVIN; we defined such cases as \"atypical LS.\" We found that a panel of D2-40/CK17 can serve as a diagnostic adjunct to differentiate LS, dVIN, and invasive SCC. Additional studies with larger patient cohorts are needed to validate these findings and determine their prognostic significance.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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American Journal of Surgical Pathology
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