Strickland Sarah, Wasserman Jason K, Giassi Ana, Djordjevic Bojana, Parra-Herran Carlos
Department of Pathology and Laboratory Medicine (S.C., J.K.W., A.G., B.D., C.P.H.), University of OttawaThe Ottawa Hospital and Eastern Ontario Regional Laboratory Association (S.C., J.K.W., B.D., C.P.H.), Ottawa, ON, Canada.
Int J Gynecol Pathol. 2016 May;35(3):191-208. doi: 10.1097/PGP.0000000000000238.
Immunohistochemistry is frequently used to identify ovarian mucinous neoplasms as primary or metastatic; however, there is significant overlap in expression patterns. We compared traditional markers (CK7, CK20, CDX2, PAX8, estrogen receptor, β-catenin, MUC1, MUC2, and MUC5AC) to 2 novel proteins identified through mining of the Human Protein Atlas expression database: SATB2 and POF1B. The study cohort included 49 primary gastrointestinal (GI) mucinous adenocarcinomas (19 colorectal, 15 gastric, 15 pancreatobiliary), 60 primary ovarian mucinous neoplasms (19 cystadenomas, 21 borderline tumors, 20 adenocarcinomas), and 19 metastatic carcinomas to the ovary (14 lower and 5 upper GI primaries). Immunohistochemistry was performed on tissue microarrays, scored and interpreted as negative (absent or focal/weak) or positive. Metastatic tumors were frequently unilateral (42.8% of tumors from lower and 40% of tumors from upper tract) and ≥10 cm (85.7% of tumors from lower and 80% of tumors from upper tract). CK7 was positive in 88.5% upper GI and 88.3% primary ovarian compared with 24.3% lower GI neoplasms. CK20 and CDX2 were positive in 84.8% and 100% of lower GI tumors, respectively; however, expression was also common in upper GI (CK20 42.8%, CDX2 50%) and primary ovarian neoplasms (CK20 65.7%, CDX2 38.3%). Conversely, SATB2 was more specific for lower GI origin, being positive in 78.8% lower GI but only 11.5% upper GI and 1.7% primary ovarian neoplasms. PAX8 expression was common in primary ovarian neoplasms (75% of all neoplasms, 65% of carcinomas); only 1 (1.5%) GI tumor was positive. MUC2 and β-catenin were frequently positive in lower GI tumors (96.9% and 51.5%, respectively). Estrogen receptor expression was only seen in primary ovarian neoplasms (13.3%). Nuclear premature ovarian failure 1B (POF1B) expression was seen in malignant tumors regardless of their origin. A panel including CK7, SATB2, and PAX8 separated primary from secondary GI neoplasms with up to 77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and β-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts.
免疫组织化学常用于鉴别卵巢黏液性肿瘤是原发性还是转移性的；然而，其表达模式存在显著重叠。我们将传统标志物（细胞角蛋白7 [CK7]、细胞角蛋白20 [CK20]、尾型同源盒转录因子2 [CDX2]、配对盒基因8 [PAX8]、雌激素受体、β-连环蛋白、黏蛋白1 [MUC1]、黏蛋白2 [MUC2]和黏蛋白5AC [MUC5AC]）与通过挖掘人类蛋白质图谱表达数据库鉴定出的2种新蛋白：特殊AT富含序列结合蛋白2 [SATB2]和卵巢早衰蛋白1B [POF1B]进行了比较。研究队列包括49例原发性胃肠道（GI）黏液腺癌（19例结直肠癌、15例胃癌、15例胰胆管癌）、60例原发性卵巢黏液性肿瘤（19例囊腺瘤、21例交界性肿瘤、20例腺癌）以及19例卵巢转移性癌（14例下消化道和5例上消化道原发性肿瘤转移）。对组织芯片进行免疫组织化学检测，评分并解释为阴性（无或局灶性/弱阳性）或阳性。转移性肿瘤常为单侧（下消化道肿瘤的42.8%以及上消化道肿瘤的40%）且直径≥10 cm（下消化道肿瘤的85.7%以及上消化道肿瘤的80%）。CK7在上消化道肿瘤中的阳性率为88.5%，在原发性卵巢肿瘤中的阳性率为88.3%，而在下消化道肿瘤中的阳性率为24.3%。CK20和CDX2在下消化道肿瘤中的阳性率分别为84.8%和100%；然而，在上消化道肿瘤（CK20为42.8%，CDX2为50%）和原发性卵巢肿瘤（CK20为65.7%，CDX2为38.3%）中也常见表达。相反，SATB2对下消化道起源更具特异性，在下消化道肿瘤中的阳性率为78.8%，而在上消化道肿瘤中的阳性率仅为11.5%，在原发性卵巢肿瘤中的阳性率为1.7%。PAX8在原发性卵巢肿瘤中常见表达（所有肿瘤的75%，腺癌的65%）；仅1例（1.5%）胃肠道肿瘤呈阳性。MUC2和β-连环蛋白在下消化道肿瘤中常呈阳性（分别为96.9%和51.5%）。雌激素受体表达仅见于原发性卵巢肿瘤（13.3%）。核型卵巢早衰1B（POF1B）表达见于恶性肿瘤，无论其起源如何。一个包含CK7、SATB2和PAX8的组合可将原发性与继发性胃肠道肿瘤区分开来，敏感性高达77.1%，特异性为99%，优于肿瘤的侧别和大小。二线标志物如CDX2、MUC2、雌激素受体、MUC1和β-连环蛋白可提高免疫组织化学排除下消化道起源的敏感性。如SATB2所示，利用蛋白质组数据库进行生物标志物搜索在诊断病理学中具有价值；然而，如POF1B所示，这些数据库中的表达谱在更大的队列中并非总能重现。
