PO.ET06.04 · 实验与分子治疗

PSMA在肿瘤细胞及肿瘤相关血管中的表达：一项评估来自135种不同肿瘤类型的12,409例癌症的组织芯片研究

PSMA expression in neoplastic cells and tumor-associated vasculature: A tissue microarray study evaluating 12,409 cancers from 135 different tumor types

编号 2990 展板 12 时间 4/20 02:00–05:00 区域 Section 13 主讲 Fiete Gehrisch

分会场 Molecular Targets 1

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作者与单位 Authors & Affiliations

Fiete Gehrisch¹, Alexandra Malinowski¹, Anne Menz¹, Florian Lutz¹, Viktoria Chirico¹, Florian Viehweger¹, David Dum¹, Ria Schlichter¹, Andrea Hinsch¹, Christoph Fraune¹, Christian Bernreuther¹, Seyma Büyücek¹, Martina Kluth¹, Claudia Hube-Magg¹, Georgia Makrypidi-Fraune¹, Nina Schraps¹, Katharina Möller¹, Andreas M. Luebke¹, Patrick Lebok¹, Guido Sauter¹, Maximilian Lennartz¹, Frank Jacobsen¹, Till S. Clauditz¹, Andreas H. Marx², Ronald Simon¹, Stefan Steurer¹, Eike Burandt¹, Nathalia Gorbokon¹, Maria C. Tsourlakis¹, Sarah Minner¹, Till Krech¹, Morton Freytag¹, Viktor Reiswich¹

¹Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,²Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany

摘要 Abstract

中文摘要

前列腺特异性膜抗原（PSMA）是一种跨膜糖蛋白，可作为前列腺癌的诊断和治疗靶点。除前列腺恶性肿瘤外，在多种其他恶性肿瘤中，PSMA表达也可在肿瘤细胞以及新生的肿瘤相关血管的内皮细胞（EC）中被检测到。为评估PSMA在肿瘤细胞和肿瘤相关新生血管中的表达流行率，采用免疫组织化学以组织芯片形式分析了来自135种不同肿瘤类型的12,409例肿瘤。在46种肿瘤实体中检测到肿瘤细胞PSMA阳性，其中13种至少有一例强阳性病例。肿瘤细胞PSMA阳性常见于前列腺腺癌（84.2-98.7%）、颗粒细胞瘤（76.5%）、涎腺基底细胞腺瘤（64.3%），以及子宫内膜癌（高达60.7%）和卵巢癌（高达13.8%）。在前列腺癌中，与Gleason 3+3癌（94.7%）相比，PSMA表达在Gleason 4+4和5+5癌中更高（96.4-98.7%），而在激素治疗后复发的癌症中最低（84.2%；p<0.0001）。在非特殊类型乳腺癌中，PSMA阳性与高级别（p=0.0451）、ER阴性（p=0.0279）和PR阴性（p=0.0135）相关。肿瘤相关血管EC的PSMA阳性发生在10,658例肿瘤中的4,888例（45.9%）。123种肿瘤实体至少有一例出现PSMA阳性EC，106种至少包含一份具有大量PSMA阳性血管的样本，102种至少有一例出现强血管阳性。EC PSMA阳性最常见于肾细胞癌（RCC）（88.7-88.9%）、子宫颈腺癌（82.4%）、子宫内膜样子宫内膜癌（76.7%）、结直肠腺癌（70.5%）、胆管癌（66.7%）、软骨肉瘤（63.5%）、HCC（62.5%）以及不同部位的鳞状细胞癌（高达88.2%）。阳性血管数量与其染色强度密切相关（<0.0001），且这两个参数常与癌症侵袭性特征相关。在浸润性乳腺癌中，血管PSMA染色数量和强度与肿瘤分期（p=0.0343）、肿瘤分级（p<0.0001）、ER阴性（p=0.0002）和PR阴性（p=0.0351）相关；在透明细胞RCC中与多种分级和分期系统相关（p=0.0022-0.0388）；在乳头状RCC中与Fuhrman分级（p=0.0091）和转移性疾病（p=0.0175）相关；在尿路上皮癌中与pT分期相关（p<0.0001）；在结直肠腺癌中与pT分期（p=0.0459）、淋巴结阳性（p=0.0089）、淋巴管浸润（p=0.0023）、错配修复（MMR）缺陷（p=0.0178）和BRAF突变（p=0.0026）相关；在胃腺癌中与MMR缺陷（p=0.0089）相关。结论认为，PSMA在肿瘤细胞中的表达主要局限于少数癌症实体，而EC阳性则在广泛的癌症类型中普遍存在。

查看英文原文 English abstract

Prostate-specific membrane antigen (PSMA) is a transmembraneous glycoprotein that serves as a diagnostic and therapeutic target in prostate cancer. Beyond prostate malignancies, PSMA expression can also be detected in tumor cells and in endothelial cells (ECs) of newly formed, tumor-associated blood vessels across various other malignancies. To evaluate the prevalence of PSMA expression in both tumor cells and tumor-associated neovasculature, 12,409 tumors from 135 different tumor types, were analyzed by immunohistochemistry in a tissue microarray format. PSMA positivity in tumor cells was detected in 46 tumor entities, including 13 with at least one strongly positive case. Tumor cell PSMA positivity was frequently observed in prostatic adenocarcinoma (84.2-98.7%), granular cell tumor (76.5%), basal cell adenoma of the salivary gland (64.3%), as well as in endometrial (up to 60.7%) and ovarian carcinomas (up to 13.8%). In prostate cancer, PSMA expression was higher in Gleason 4+4 and 5+5 cancers (96.4-98.7%) compared to Gleason 3+3 cancers (94.7%), while it was lowest in recurrent cancers after hormonal therapy (84.2%; p<0.0001). In breast cancer of no special type, PSMA positivity was linked to high grade (p=0.0451), ER- (p=0.0279), and PR-negativity (p=0.0135). PSMA positivity in ECs of tumor-associated vasculature occurred in 4,888 of 10,658 (45.9%) tumors. 123 tumor entities had at least one case with PSMA positive ECs, 106 included at least one sample with many PSMA-positive vessels and 102 had at least one case with strong vessel positivity. EC PSMA positivity was most frequent in renal cell carcinoma (RCC) (88.7-88.9%), adenocarcinoma of the uterine cervix (82.4%) endometrioid endometrial carcinoma (76.7%), colorectal adenocarcinoma (70.5%), cholangiocarcinoma (66.7%), chondrosarcoma (63.5%), HCC (62.5%), and squamous cell carcinomas from different sites (up to 88.2%). The number of positive vessels tightly correlated with their staining intensity (<0.0001) and both parameters were often associated with features of cancer aggressiveness. PSMA staining quantity and intensity in vessels were associated with tumor stage (p=0.0343), tumor grade (p<0.0001), ER- (p=0.0002) and PR-negativity (p=0.0351) in invasive breast carcinoma, multiple grading and staging systems (p=0.0022-0.0388) in clear cell RCC, Fuhrman grade (p=0.0091) and metastatic disease (p=0.0175) in papillary RCC, pT stage (p<0.0001) in urothelial carcinoma, pT stage (p=0.0459), nodal positivity (p=0.0089) and lymphatic invasion (p=0.0023), mismatch repair (MMR) deficiency (p=0.0178) and BRAF mutations (p=0.0026) in colorectal adenocarcinoma, and MMR deficiency (p=0.0089) in gastric adenocarcinoma. It is concluded that PSMA expression in tumor cells is largely limited to few cancer entities while EC positivity is common in a broad range of cancer types.

利益披露 Disclosure

F. Gehrisch, None.. A. Malinowski, None.. A. Menz, None.. F. Lutz, None.. V. Chirico, None.. F. Viehweger, None.. D. Dum, None.. R. Schlichter, None.. A. Hinsch, None.. C. Fraune, None.. C. Bernreuther, None.. S. Büyücek, None.. M. Kluth, None.. C. Hube-Magg, None.. G. Makrypidi-Fraune, None.. N. Schraps, None.. K. Möller, None.. A. M. Luebke, None.. P. Lebok, None. G. Sauter, MS Validated Antibodies GmbH Other, The PSMA antibody was provided from MS Validated Antibodies GmbH, Hamburg, Germany (owned by a family member of GS).. M. Lennartz, None.. F. Jacobsen, None.. T. S. Clauditz, None.. A. H. Marx, None.. R. Simon, None.. S. Steurer, None.. E. Burandt, None.. N. Gorbokon, None.. M. C. Tsourlakis, None.. S. Minner, None.. T. Krech, None.. M. Freytag, None.. V. Reiswich, None.

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