CA9在透明细胞肾细胞癌预后评估中的价值

doi:10.16150/j.1671-2870.2023.01.006

摘要/Abstract

摘要：

目的: 评估CA9在预测透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）患者术后复发或转移以及生存预后中的价值。方法: 回顾分析上海交通大学医学院附属瑞金医院2017年1月1日至2020年12月31日期间收治的231例ccRCC患者，所有患者均接受了肾癌根治或部分切除术，分析其临床病理资料，并对患者进行随访，统计其肿瘤复发、转移和总生存期（overall survival, OS）、无病生存期(disease-free survival, DFS)情况。收集所有肿瘤组织切片及蜡块，制作组织微阵列，使用CA9多克隆抗体对组织微阵列进行免疫组织化学分析。采用Kaplan-Meier和多元Cox回归模型分析，评估组织微阵列CA9表达水平与患者临床病理特征及OS、DFS间的相关性。结果: 231例ccRCC患者的中位随访时间为37个月(13~54个月)，有8例患者死亡，38例（16.5%）患者术后出现肿瘤复发和（或）转移，其中3例出现肿瘤复发，29例发生肿瘤转移，另6例患者同时出现肿瘤复发和肿瘤转移。231例患者中，CA9的阳性表达率为94%(217/231)，其中153例(66%) CA9染色率≥85%，78例（34%)CA9染色率<85%。卡方分析显示，CA9的表达不仅与肿瘤T分期、国际泌尿病理学会（International Society of Urological Pathology，ISUP）核分级、肉瘤样或横纹肌样分化（坏死）、被膜侵犯、血管浸润等组织病理学参数相关（P均<0.01），且与肿瘤复发、转移及患者生存状态相关（P均<0.01），但与年龄、性别及肿瘤发生部位无关（P均>0.05）。卡方分析表明，CA9（<85%）低表达是ccRCC患者术后OS、DFS不良的预测因素，危险比分别为6.211(P=0.002)和8.980（P<0.001）。结论: ccRCC组织中CA9低表达与低OS、DFS相关，是ccRCC患者术后短OS和短DFS的独立危险因素，可作为评估ccRCC患者预后的分子标志物。

关键词: 透明细胞肾细胞癌, CA9, 免疫组化, 预后

Abstract:

Objective: To evaluate the prognostic value of CA9 in predicting postoperative recurrence， metastasis or survival in patients with clear cell renal cell carcinoma(ccRCC). Methods: The clinical pathological data from 231 patients with ccRCC who underwent radical or partial nephrectomy from January 1, 2017 to December 31, 2020 in Ruijin Hospital,Shanghai Jiao Tong University were retrospectively analyzed. The patients were followed up for the overall survival (OS),disease-free survival (DFS),and tumor recurrence or metastasis. All pathological sections and wax blocks of tumor issue were collected to make tissue microarray, and immunohistochemical analysis of tissue microarray was performed using CA9 polyclonal antibody. SPSS statistical software multivariate Cox and Kaplan-Meier were used to evaluate the correlation of CA9 expression with clinicopathological features, OS and DFS. Results: Of the 231 ccRCC patients had a median follow-up of 37 months (13-54 months). It revealed that postoperative recurrence and/or metastasis occurred in 38 cases, inclu-ding 6 cases with both recurrence and metastasis, 3 cases with only recurrence, 29 cases with only metastasis, and 8 deaths. Among 231 patients, CA9 positive expression rate was 94%(217/231), of which 153 (66%) were with cells stained with CA9 ≥85% and 78 (34%) were stained with CA9 <85%. Chi-square analysis showed that the expression of CA9 was not only correlated with T stage, ISUP nuclear grade, sarcomatoid or rhabdomyoid differentiation, necrosis, capsule invasion, vascular infiltration, but also correlated with tumor recurrence, metastasis and survival status. There was no relationship between CA9 expression and age, sex and tumor location (P>0.05). Univariate Kaplan-Meier analysis and multiva-riate Cox analysis showed that low expression of CA9 (<85%) was a poor prognostic factor for postoperative overall survival (OS) and disease-free survival (DFS) in patients with ccRCC, with hazard ratios of 6.211 (P=0.002) and 8.980 (P<0.001), respectively. Conclusions: In ccRCC, low expression of CA9 is associated with poor OS and DFS, and is an independent risk factor for OS and DFS in postoperative patients with ccRCC, which may serve as a useful prognostic indicator.

Key words: Clear cell renal cell carcinoma, Carbonic anhydrase 9, Immunohistochemistry, The prognosis

中图分类号:

R737.11

许建昆, 周露婷, 张文净, 许海敏, 王朝夫. CA9在透明细胞肾细胞癌预后评估中的价值[J]. 诊断学理论与实践, 2023, 22(01): 37-43.

XU Jiankun, ZHOU Luting, ZHANG Wenjing, XU Haimin, WANG Chaofu. The prognostic value of CA9 expression in clear cell renal cell carcinoma[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(01): 37-43.

图/表 7

图1

表1

表2

图2

表3

表4

图3

参考文献 26

[1]	HSIEH J J, PURDUE M P, SIGNORETTI S, et al. Renal cell carcinoma[J]. Nat Rev Dis Primers, 2017, 3:17009. doi: 10.1038/nrdp.2017.9 pmid: 28276433
[2]	SIEGEL R L, MILLER K D, JEMAL A. Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69(1):7-34. doi: 10.3322/caac.v69.1 URL
[3]	GRAY R E, HARRIS G T. Renal Cell Carcinoma: Diagnosis and Management[J]. Am Fam Physician, 2019, 99(3):179-184. pmid: 30702258
[4]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6):394-424. doi: 10.3322/caac.v68.6 URL
[5]	COHEN H T, MCGOVERN F J. Renal-cell carcinoma[J]. N Engl J Med, 2005, 353(23):2477-2490. doi: 10.1056/NEJMra043172 URL
[6]	KROEGER N, ZIMMERMANN U, BURCHARDT M, et al. Prognostication in localised renal cell carcinoma[J]. Lancet Oncol, 2015, 16(6):603-604. doi: 10.1016/S1470-2045(15)70227-5 pmid: 25979596
[7]	LEIBOVICH B C, HAN K R, BUI M H, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials[J]. Cancer, 2003, 98(12):2566-2575. pmid: 14669275
[8]	KLATTE T, ROSSI S H, STEWART G D. Prognostic factors and prognostic models for renal cell carcinoma: a lite-rature review[J]. World J Urol, 2018, 36(12):1943-1952. doi: 10.1007/s00345-018-2309-4
[9]	RENSHAW A A, CHEVILLE J C. Quantitative tumour necrosis is an independent predictor of overall survival in clear cell renal cell carcinoma[J]. Pathology, 2015, 47(1):34-37. doi: 10.1097/PAT.0000000000000193 URL
[10]	TSUI K H, SHVARTS O, SMITH R B, et al. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria[J]. J Urol, 2000, 163(4):1090-1095. doi: 10.1016/s0022-5347(05)67699-9 pmid: 10737472
[11]	LAM J S, LEPPERT J T, FIGLIN R A, et al. Role of molecular markers in the diagnosis and therapy of renal cell carcinoma[J]. Urology, 2005, 66(5 Suppl):1-9. doi: 10.1016/j.urology.2005.06.112 pmid: 16194700
[12]	BUI M H, ZISMAN A, PANTUCK A J, et al. Prognostic factors and molecular markers for renal cell carcinoma[J]. Expert Rev Anticancer Ther, 2001, 1(4):565-575. doi: 10.1586/14737140.1.4.565 URL
[13]	KIM H L, SELIGSON D, LIU X, et al. Using tumor mar-kers to predict the survival of patients with metastatic renal cell carcinoma[J]. J Urol, 2005, 173(5):1496-1501. doi: 10.1097/01.ju.0000154351.37249.f0 URL
[14]	IVANOV S, LIAO S Y, IVANOVA A, et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer[J]. Am J Pathol, 2001, 158(3):905-919. pmid: 11238039
[15]	MAXWELL P H, WIESENER M S, CHANG G W, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis[J]. Nature, 1999, 399(6733):271-275. doi: 10.1038/20459 URL
[16]	BUI M H, SELIGSON D, HAN K R, et al. Carbonic anhydrase Ⅸ is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy[J]. Clin Cancer Res, 2003, 9(2):802-811.
[17]	BENEJ M, PASTOREKOVA S, PASTOREK J. Carbonic anhydrase Ⅸ: regulation and role in cancer[J]. Subcell Biochem, 2014, 75:199-219.
[18]	TAFRESHI N K, LLOYD M C, BUI M M, et al. Carbonic anhydrase Ⅸ as an imaging and therapeutic target for tumors and metastases[J]. Subcell Biochem, 2014, 75:221-254.
[19]	ZATOVICOVA M, JELENSKA L, HULIKOVA A, et al. Carbonic anhydrase Ⅸ as an anticancer therapy target: preclinical evaluation of internalizing monoclonal antibody directed to catalytic domain[J]. Curr Pharm Des, 2010, 16(29):3255-3263. doi: 10.2174/138161210793429832 URL
[20]	ZHAO Z, LIAO G, LI Y, et al. Prognostic value of carbonic anhydrase Ⅸ immunohistochemical expression in renal cell carcinoma: a meta-analysis of the literature[J]. PLoS One, 2014, 9(11):e114096. doi: 10.1371/journal.pone.0114096 URL
[21]	LEIBOVICH B C, SHEININ Y, LOHSE C M, et al. Carbonic anhydrase Ⅸ is not an independent predictor of outcome for patients with clear cell renal cell carcinoma[J]. J Clin Oncol, 2007, 25(30):4757-4764. doi: 10.1200/JCO.2007.12.1087 URL
[22]	SANDLUND J, OOSTERWIJK E, GRANKVIST K, et al. Prognostic impact of carbonic anhydrase Ⅸ expression in human renal cell carcinoma[J]. BJU Int, 2007, 100(3):556-560. doi: 10.1111/bju.2007.100.issue-3 URL
[23]	PATARD J J, FERGELOT P, KARAKIEWICZ P I, et al. Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma[J]. Int J Cancer, 2008, 123(2):395-400. doi: 10.1002/ijc.23496 URL
[24]	SOYUPAK B, ERDOĞAN S, ERGIN M, et al. CA9 expression as a prognostic factor in renal clear cell carcinoma[J]. Urol Int, 2005, 74(1):68-73. pmid: 15711113
[25]	LAGUNA M P. Re: carbonic anhydrase IX (CAIX) is not an independent predictor of outcome in patients with clear cell renal cell carcinoma (ccRCC) after long-term follow-up[J]. J Urol, 2014, 191(1):54-55. doi: 10.1016/j.juro.2013.09.047 pmid: 24331469
[26]	ZERATI M, LEITE K R, PONTES-JUNIOR J, et al. Carbonic Anhydrase IX is not a predictor of outcomes in non-metastatic clear cell renal cell carcinoma-a digital analysis of tissue microarray[J]. Int Braz J Urol, 2013, 39(4):484-492. doi: 10.1590/S1677-5538.IBJU.2013.04.05 URL

Parameter	Number	Percentage（%）
Age (years)
Median	58
Range	20~91
Gender
Male	152	65.8
Female	79	34.2
Tumour site
Left	118	51.1
Right	113	48.9
Furman grade
1	8	3.5
2	148	64.0
3	42	18.2
4	33	14.3
T stage
Ⅰ	168	72.7
Ⅱ	22	9.5
Ⅲ	22	9.5
Ⅳ	19	8.3
Rhabdoid or sarcomatoid differentiation
No	206	89.2
Yes	25	10.8
Necrosis
No	182	78.8
Yes	49	21.2
Capsular invasion
No	206	89.2
Yes	25	10.5
Vascular invasion
No	211	91.3
Yes	20	8.7

Parameter	Amount	CA9 expression		P
Parameter	Amount	Negative	Positive	P
Age (years)
≤55	84	26（31.0%）	58（69.0%）	0.494
>55	147	52（35.4%）	95（64.6%）
Gender
Male	152	58（38.2%）	94（61.8%）	0.050
Female	79	20（25.3%）	59（74.7%）
Tumour site
Left	118	38（32.2%）	80（67.8%）	0.608
Right	113	40（35.4%）	73（64.6%）
Furman grade
1-2	156	38（24.4%）	118（75.6%）	<0.001
3-4	75	40（53.3%）	35（46.7%）
T stage
Ⅰ-Ⅱ	190	44（23.2%）	146（76.8%）	<0.001
Ⅲ-Ⅳ	41	34（82.9%）	7（17.1%）
Rhabdoid or sarcomatoid differentiation
No	206	58（28.2%）	148（71.8%）	<0.001
Yes	25	20（80.0%）	5（20.0%）
Necrosis
No	182	42（23.1%）	142（76.9%）	<0.001
Yes	49	36（73.5%）	13（26.5%）
Capsular invasion
No	206	59（28.6%）	147（71.4%）	<0.001
Yes	25	19（76.0%）	6（24.0%）
Vascular invasion
No	211	61（28.9%）	150（71.1%）	<0.001
Yes	20	17（85.0%）	3（15.0%）
Relapse or metastasis
No	193	45（23.3%）	148（76.7%）	<0.001
Yes	38	33（86.8%）	5（13.2%）

Parameter	Univariate analysis	multivariate analysis
Parameter	P	Risk ratio（95%CI）	P
Gender	<0.001	0.102（0.013-0.767）	0.027
Tumour site	0.235
Age（>55 years）	0.840
Furman Grade（3-4）	<0.001	0.534（0.165-1.724）	0.294
Rhabdoid differentiation	<0.001	1.106（0.375-3.261）	0.855
Necrosis	<0.001	0.725（0.210-2.500）	0.610
T Stage（Ⅲ-Ⅳ）	<0.001	1.131（0.223-5.730）	0.882
Capsular invasion	<0.001	0.503（0.130-1.944）	0.319
Vascular invasion	<0.001	0.491（0.141-1.710）	0.264
CA9 low expression	<0.001	6.211（1.908-20.00）	0.002

Parameter	Univariate analysis	Multivariate analysis
Parameter	P	Risk ratio（95%CI）	P
Gender	0.001	0.356（0.123-1.025）	0.056
Tumour site	0.483
Age（>55 years）	0.295
Furman Grade（3-4）	<0.001	0.404（0.159-1.026）	0.057
Rhabdoid differentiation	<0.001	1.040（0.458-2.359）	0.926
Necrosis	<0.001	0.746（0.290-1.920）	0.543
T Stage（Ⅲ-Ⅳ）	<0.001	1.591（0.460-5.511）	0.464
Capsular invasion	<0.001	0.350（0.121-1.011）	0.052
Vascular invasion	<0.001	0.616（0.229-1.658）	0.337
CA9 low expression	<0.001	8.980（3.219~25.057）	<0.001