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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。
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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}
引用次数: 0
Histologic and Molecular Type Changes in Endometrial Cancer Recurrences in Comparison With Their Corresponding Primary Tumors. 子宫内膜癌复发的组织学和分子类型变化与相应原发肿瘤的比较
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-13 DOI: 10.1097/PAS.0000000000002308
Esther Moreno-Moreno, Tamara Caniego-Casas, Irene Carretero-Barrio, Alfonso Cortés, Alfonso Muriel, José Antonio Domínguez-Rullán, Carmen Martín-Gromaz, Gema Moreno-Bueno, Xavier Matías-Guiu, José Palacios, Belén Pérez-Mies

In this study, molecular alterations in endometrial carcinoma (EC) recurrences were analyzed. We aimed to identify genes implicated in tumor progression and to evaluate whether histologic and molecular type shifting occurs in recurrences. Thus, we analyzed 50 samples corresponding to 24 primary ECs (15 low-grade endometrioid endometrial carcinomas [LG-EECs] and 9 high-grade endometrial carcinomas) and their corresponding 26 recurrences. These were studied by immunohistochemistry, next-generation sequencing, and MLH1 promoter methylation. We observed shared mutations in all primary tumors and their recurrences, indicating a clonal relationship between both lesions. Most morphologic and molecular changes associated with progression were found in LG-EEC. In this group, 6 patients (40%) presented additional mutations in the recurrence. These mutations more frequently affected genes of the PI3K/AKT/PTEN pathway, implicating this pathway not only in tumor initiation but also in progression. In addition, 2 patients (13%) in which the primary tumor belonged to the nonspecific molecular profile subtype, shifted to the mismatch repair deficient (MMRd) subtype after the acquisition of MLH1 promoter methylation in the recurrence lesions. In 3 patients (20%) with MMRd, there was a change from LG-EEC to G3-EEC. One TP53-mutated LG-EEC transformed into an undifferentiated carcinoma in a mediastinal lymph node metastasis after losing the expression of SMARCA2 while preserving SMARCA4 and SMARCB1. Morphologic and molecular changes in EC recurrences, especially dedifferentiation and the acquisition of MMRd, should be considered for a correct diagnosis and treatment. MMRd should be tested in metastatic lesions, if available, in patients with primary tumors reported to be of a molecular subtype different from MMRd.

本研究分析了子宫内膜癌(EC)复发的分子改变。我们的目的是确定与肿瘤进展有关的基因,并评估复发中是否会发生组织学和分子类型的转变。因此,我们分析了 50 份样本,分别对应 24 例原发性子宫内膜癌(15 例低度子宫内膜样内膜癌 [LG-EECs] 和 9 例高级别子宫内膜癌)及其相应的 26 例复发。我们通过免疫组化、新一代测序和 MLH1 启动子甲基化对这些肿瘤进行了研究。我们在所有原发肿瘤及其复发瘤中都观察到了共同的突变,这表明这两种病变之间存在克隆关系。大多数与进展相关的形态学和分子变化都出现在 LG-EEC 中。在这组患者中,有6名患者(40%)的复发出现了额外的突变。这些突变更频繁地影响到 PI3K/AKT/PTEN 通路的基因,表明该通路不仅与肿瘤的发生有关,还与肿瘤的进展有关。此外,2 名患者(13%)的原发肿瘤属于非特异性分子特征亚型,在复发病灶中出现 MLH1 启动子甲基化后,转为错配修复缺陷(MMRd)亚型。3例(20%)MMRd患者从LG-EEC转变为G3-EEC。一名TP53突变的LG-EEC在失去SMARCA2的表达而保留SMARCA4和SMARCB1后,在纵隔淋巴结转移中转变为未分化癌。为了进行正确的诊断和治疗,应考虑EC复发的形态学和分子学变化,尤其是去分化和获得MMRd。据报道,原发肿瘤的分子亚型与 MMRd 不同,如有可能,应在转移病灶中检测 MMRd。
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引用次数: 0
Reassessment of Plurihormonal Pituitary Adenomas/PitNETs. 重新评估多激素垂体腺瘤/垂体网状细胞瘤。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-05 DOI: 10.1097/PAS.0000000000002306
B K Kleinschmidt-DeMasters, Christie G Turin

Plurihormonal pituitary adenomas/neuroendocrine tumors express multiple pituitary hormones and/or transcription factors, as determined by immunohistochemistry (IHC). Three types exist based on Endocrine WHO 2022 classification: mature plurihormonal PIT1 (pituitary-specific POU-class homeodomain factor-1), immature PIT1-lineage tumors, and a third type with unusual combinations of pituitary hormones and/or transcription factors. However, since then, "somatogonatotroph"/"multilineage" tumors with PIT1/SF1 (steroidogenic factor 1) co-expression have been described, possibly confounding this classification. We performed a database search, from 2018 to 2023, to identify and reclassify tumors, correlating with neuroimaging and endocrinological features at presentation. We identified 22 cases: M 9:F 13, mean age at surgery 51±16 years. The most common symptoms at initial presentation were headaches and/or vision changes (6/22) and acromegaly (5/22). All tumors were macroadenomas, mean diameter of 25±17mm; 11/22 (50%) had cavernous sinus invasion. More than 70% of tumors clinically secreted at least 1 hormone, and 27% tumors secreted at least 2 different hormones. Four patients underwent >1 surgical intervention. Reclassification by IHC yielded almost exclusively 2 types: immature PIT1-lineage (9/22) and "somatogonadotroph"/"multilineage tumors" with PIT1/SF1 co-expression (12/22), the latter replacing mature plurihormonal tumors. One true unusual plurihormonal tumor was identified. The extent of growth hormone, prolactin, thyroid stimulating hormone, PIT1, and SF1 IHC was variable, but immunopositivity for follicle-stimulating hormone and/or luteinizing hormone was nearly confined to co-expressors, distinguishing these from immature PIT1-lineage tumors. In conclusion, tumor size, invasiveness, and endocrinopathies do not distinguish PIT1/SF1 co-expressing tumors from immature PIT1-lineage tumors preoperatively; only full IHC pituitary workup allows distinction.

多激素垂体腺瘤/神经内分泌肿瘤表达多种垂体激素和/或转录因子,由免疫组化(IHC)确定。根据世界卫生组织 2022 年内分泌分类法,目前存在三种类型:成熟的多激素性垂体腺瘤 PIT1(垂体特异性 POU 类同源染色体因子-1)、未成熟的 PIT1 系肿瘤,以及第三种垂体激素和/或转录因子异常组合的类型。然而,从那时起,具有PIT1/SF1(类固醇生成因子1)共表达的 "体细胞营养"/"多线型 "肿瘤被描述出来,可能混淆了这一分类。我们对2018年至2023年的数据库进行了搜索,以识别和重新分类肿瘤,并与发病时的神经影像学和内分泌学特征相关联。我们确定了 22 个病例:男9:女13,手术时平均年龄(51±16)岁。初诊时最常见的症状是头痛和/或视力改变(6/22)和肢端肥大症(5/22)。所有肿瘤均为大腺瘤,平均直径(25±17)毫米;11/22(50%)有海绵窦侵犯。超过70%的肿瘤在临床上至少分泌一种激素,27%的肿瘤至少分泌两种不同的激素。四名患者接受了一次以上的手术治疗。通过IHC重新分类,几乎只发现两种类型:未成熟的PIT1系肿瘤(9/22)和PIT1/SF1共表达的 "嗜体细胞"/"多系肿瘤"(12/22),后者取代了成熟的多激素肿瘤。发现了一个真正不寻常的多荷尔蒙肿瘤。生长激素、催乳素、促甲状腺激素、PIT1和SF1 IHC的表达程度各不相同,但卵泡刺激素和/或黄体生成素的免疫阳性几乎仅限于共表达者,从而将这些肿瘤与未成熟的PIT1系肿瘤区分开来。总之,肿瘤大小、侵袭性和内分泌病变并不能在术前将PIT1/SF1共表达肿瘤与未成熟的PIT1系肿瘤区分开来;只有通过全面的IHC垂体检查才能将两者区分开来。
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引用次数: 0
Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma Beyond Fusions Between MYB/MYBL1 and NFIB Genes. 新型 TULP4/ACTN4/EWSR1/ACTB::MYB 和 ESRRG::DNM3 融合的发现扩展了腺样囊性癌的分子图谱,超越了 MYB/MYBL1 和 NFIB 基因之间的融合。
IF 4.5 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-04 DOI: 10.1097/PAS.0000000000002304
Alena Skálová, Natálie Klubíčková, Martina Bradová, Abbas Agaimy, Niels J Rupp, Ivan Damjanov, Georgina Kolnikova, Petr Martínek, Petr Šteiner, Petr Grossmann, Tomas Vaněček, Michal Michal, Ilmo Leivo

Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB, or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, MYB::TULP4, and ACTN4::MYB, each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB, ACTN4::MYB, and ACTB::MYB, in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.

腺样囊性癌(AdCC)是最常见的唾液腺恶性肿瘤之一,可发生于所有主要和次要唾液腺及血清粘液腺部位。长期以来,唾液腺来源的腺囊肿一直被归类为融合定义的癌,因为几乎一致存在融合基因 MYB::NFIB,或较少见的 MYBL1::NFIB。我们共收集了 95 例 AdCC,这些病例的主要特征是典型融合 MYB::NFIB (49 例)或 MYBL1::NFIB (9 例)。在另外 11 例 AdCC 中,通过 FISH 检测到了 MYB 或 NFIB 基因的重排。此外,NGS 还发现了新型非典型融合转录本 EWSR1::MYB、ACTB::MYB、ESRRG::DNM3、MYB::TULP4 和 ACTN4::MYB,各 1 例。出现非典型融合的肿瘤具有元典型 AdCC 的特征,包括多样化的结构、分叶状多结节生长模式、细胞核周边钙化(2 例)、管状嗜酸性细胞增多(2 例)和淡嗜酸性至空泡状(气泡状)胞质(3 例)。我们的研究记录了 3 例唾液腺 AdCC 病例,其中 1 例携带新型基因融合 TULP4::MYB、ACTN4::MYB 和 ACTB::MYB,这些基因融合以前从未报道过。有 1 例检测到罕见的 EWSR1::MYB 融合。此外,1 例鼻窦偏典型 AdCC 病例通过 FISH 检测到 EWSR1 重排。本研究还描述了1例意义不明的ESRRG::DNM3融合病例。这些发现说明了广泛的分子图谱分析将如何扩展对已知实体变化的理解。
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引用次数: 0
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American Journal of Surgical Pathology
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