Clinicopathological Features and Epidermal Growth Factor Receptor Gene Status of Adrenocortical Oncocytic Carcinoma
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摘要:
目的 探讨肾上腺嗜酸细胞型皮质癌临床病理特征及其表皮生长因子受体(epidermal growth factor receptor, EGFR)蛋白表达、基因突变和基因拷贝数改变情况。 方法 回顾性分析2000年1月至2009年12月在北京协和医院手术切除的9例肾上腺嗜酸细胞型皮质癌的临床特点、组织形态学特征, 并以9例肾上腺嗜酸细胞型皮质腺瘤为对照, 应用免疫组织化学、Scorpion ARMS突变系统及荧光原位杂交(fluorescence in situ hybridization, FISH)的方法分析EGFR在二者中的蛋白表达、基因突变和基因拷贝数改变的情况。 结果 9例肾上腺嗜酸细胞型皮质癌中, Cushing综合征2例, 无功能性皮质癌7例。病例随访时间6~56个月, 皮质癌患者失访2例, 死亡6例。肾上腺嗜酸细胞型皮质癌中EGFR蛋白过表达率为77.8%(7/9), EGFR FISH阳性率为55.6%(5/9);仅有22.2%(2/9)皮质腺瘤存在EGFR蛋白的表达, 且EGFR FISH均为阴性。肾上腺嗜酸细胞型皮质腺瘤及皮质癌中均未检测出EGFR基因扩增及基因突变。 结论 肾上腺嗜酸细胞型皮质癌非常罕见, 其诊断依据病理学及免疫表型, EGFR蛋白过表达和7号染色体的高多体性较腺瘤更常见, 可能有助于与后者的鉴别诊断, 也有可能成为今后临床分子靶向治疗的潜在方向。 -
关键词:
- 肾上腺嗜酸细胞型皮质癌 /
- 表皮生长因子受体 /
- 免疫组化 /
- 荧光原位杂交 /
- 基因突变
Abstract:Objective To explore the clinicopathological features of adrenocortical oncocytic carcinoma and protein expression, gene mutation, and gene copy number alteration of epidermal growth factor receptor (EGFR) in this carcinoma. Methods We reviewed the clinical and histomorphological features of 9 adrenocortical oncocytic carcinoma cases who received surgical resection in the period of January 2000 to December 2009 in Peking Union Medical College Hospital, and 9 adenoma cases were included as control. EGFR protein expression, EGFR gene mutation and EGFR gene copy number alteration in both groups were detected by immunohistochemistry, Scorpion Amplification Refractory Mutation System (ARMS), and fluorescence in situ hybridization (FISH), respectively. Results The 9 cases of adrenocortical oncocytic carcinomas included 2 cases of Cushing's syndrome and 7 cases of nonfunctional cortical carcinoma. All cases were followed up for 6 to 56 months, and 2 patients with adrenocortical oncocytic carcinomas lost to follow-up, and 6 died. In the adrenocortical oncocytic carcinoma patients, EGFR overexpression was found in 77.8% (7/9), and EGFR FISH was positive in 55.6% (5/9). In contrast, only 22.2% (2/9) of the adrenocortical adenoma patients showed EGFR weak expression and none had positive FISH result. No EGFR gene amplification or mutation was found in the 2 groups of patients. Conclusions Adrenocortical oncocytic carcinoma is rare. EGFR overexpression and chromosome 7 polysomy are frequent abnormality in the adrenocortical oncocytic carcinomas, which may be used in the differential diagnosis. Also, an investigation of the gene status of EGFR should facilitate the identification of a target therapeutic regimen for carcinoma patients. -
表 1 9例肾上腺嗜酸细胞型皮质癌临床特点
病例 性别 年龄(岁) 病变位置 肿瘤有无功能 有无转移 TNM分期 随访结果 1 女 48 右侧 无功能 无 Ⅱ 术后6个月失访 2 男 59 右侧 无功能 有,右侧腹壁转移 Ⅳ 术后48个月死于肿瘤 3 男 46 右侧 无功能 无 Ⅱ 术后12个月死于肿瘤 4 女 46 右侧 无功能 无 Ⅱ 术后23个月死于肿瘤 5 男 20 右侧 无功能 无 Ⅱ 术后失访 6 女 34 右侧 Cushing综合征 有,下腔静脉癌栓 Ⅳ 术后35个月死于肿瘤 7 女 25 右侧 Cushing综合征 有,肾脏转移 Ⅳ 术后28个月死于肿瘤 8 女 51 左侧 无功能 有,肾脏、脾脏、胰腺转移 Ⅳ 术后15个月死于肿瘤 9 女 75 右侧 无功能 无 Ⅲ 术后32个月尚存活 表 2 9例肾上腺嗜酸细胞型皮质癌病理组织学特征
病例 肿瘤最大径
(cm)重量
(g)核异
型性病理性核分裂象
>6/50高倍视野病理性
核分裂嗜酸细胞
≥75%瘤细胞弥漫
分布≥33%坏死/
出血静脉
侵犯窦隙
浸润包膜
浸润1 7 100 + + + + + - - - - 2 6.6 95 + + + + + - - + - 3 21 2000 + + + + + + - - - 4 9 350 + + + + + + + - + 5 8.5 285 + + + + + - - - - 6 4 16 + + + + + + + + + 7 8 40 + + + + + + - + + 8 16.5 2000 + + + + + + + + + 9 12 420 + + + + + + - - - 表 3 表皮生长因子受体在肾上腺嗜酸细胞型皮质癌及腺瘤中蛋白表达、基因突变和基因拷贝数改变情况
肿瘤类型 免疫组织化学 荧光原位杂交 突变 - + ++ +++ - + 肾上腺嗜酸细胞型
皮质癌(n=9)2 0 2 5 4 5 0 肾上腺嗜酸细胞型
皮质腺瘤(n=9)7 2 0 0 9 0 0 -
[1] Wong DD, Spagnolo DV, Bisceglia M, et al. Oncocytic adrenocortical neoplasms-a clinicopathologic study of 13 new cases emphasizing the importance of their recognition[J]. Hum Pathol, 2011, 42:489-499. doi: 10.1016/j.humpath.2010.08.010 [2] Ohtake H, Kawamura H, Matsuzaki M, et al. Oncocytic adrenocortical carcinoma[J]. Ann Diagn Pathol, 2010, 14:204-208. doi: 10.1016/j.anndiagpath.2009.06.006 [3] Thway K, Olmos D, Shah C, et al. Oncocytic adrenal cortical carcinosarcoma with pleomorphic rhabdomyosarcomatous metastases[J]. Am J Surg Pathol, 2012, 36:470-477. doi: 10.1097/PAS.0b013e31824517d9 [4] Bisceglia M, Ludovico O, Di Mattia A, et al. Adrenocortical oncocytic tumors:report of 10 cases and review of the literature[J]. Int J Surg Pathol, 2004, 12:231-243. doi: 10.1177/106689690401200304 [5] Song SY, Park S, Kim SR, et al. Oncocytic adrenocortical carcinomas:a pathological and immunohistochemical study of four cases in comparison with conventional adrenocortical carcinomas[J]. Pathol Int, 2004, 54:603-610. doi: 10.1111/j.1440-1827.2004.01669.x [6] Hoang MP, Ayala AG, Albores-Saavedra J. Oncocytic adrenocortical carcinoma:a morphologic, immunohistochemical and ultrastructural study of four cases[J]. Mod Pathol, 2002, 15:973-978. doi: 10.1038/modpathol.3880638 [7] Mearini L, Del Sordo R, Costantini E, et al. Adrenal oncocytic neoplasm:a systematic review[J]. Urol Int, 2013, 91:125-133. doi: 10.1159/000345141 [8] Erickson LA, Rivera M, Zhang J. Adrenocortical carcinoma:review and update[J]. Adv Anat Pathol, 2014, 21:151-159. doi: 10.1097/PAP.0000000000000019 [9] 许敬平, 吴大为, 黄江梅, 等.肾上腺皮质嗜酸细胞癌7例临床病理分析[J].临床与实验病理学杂志, 2013, 29:765-767. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lcysyblxzz201307016 [10] 潘敏鸿, 张新华, 马恒辉, 等.肾上腺嗜酸细胞型皮质癌临床病理观察[J].诊断病理学杂志, 2007, 14:423-426. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zdblxzz200706006 [11] Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer[J]. Gene, 2006, 366:2-16. doi: 10.1016/j.gene.2005.10.018 [12] Sibilia M, Kroismayr R, Lichtenberger BM, et al. The epidermal growth factor receptor:from development to tumorigenesis[J]. Differentiation, 2007, 75:770-787. doi: 10.1111/j.1432-0436.2007.00238.x [13] Adam P, Hahner S, Hartmann M, et al. Epidermal growth factor receptor in adrenocortical tumors:analysis of gene sequence, protein expression and correlation with clinical outcome[J]. Mod Pathol, 2010, 23:1596-1604. doi: 10.1038/modpathol.2010.153 [14] Zhang J, Wang C, Liang Z, et al. Adrenal cortical neoplasms:a study of clinicopathological features related to epidermal growth factor receptor gene status[J]. Diagn Pathol, 2014, 9:19. doi: 10.1186/1746-1596-9-19 [15] Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer[J]. J Natl Cancer Inst, 2005, 97:643-655. doi: 10.1093/jnci/dji112 [16] Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma[J]. Am J Surg Pathol, 1989, 13:202-206. doi: 10.1097/00000478-198903000-00004 [17] Kamio T, Shigematsu K, Sou H, et al. Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma[J]. Hum Pathol, 1990, 21:277-282. doi: 10.1016/0046-8177(90)90227-V [18] Nakamura M, Miki Y, Akahira J, et al. An analysis of potential surrogate markers of target-specific therapy in archival materials of adrenocortical carcinoma[J]. Endocr Pathol, 2009, 20:17-23. doi: 10.1007/s12022-009-9058-2 [19] Kotoula V, Sozopoulos E, Litsiou H, et al. Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas[J]. Endocr Relat Cancer, 2009, 16:565-572. doi: 10.1677/ERC-08-0101