Patient outcome and prognostic factors of renal cell carcinoma in clinical stage T1-3N1-2M0: a single-institution analysis

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1 211;31(5) J South Med Univ 749 Original Article atient outcome and prognostic factors of renal cell carcinoma in clinical stage T13N12M: a singleinstitution analysis CHEN Zhuangfei, WU eng, ZHENG Shaobin, ZHANG eng, TAN Wanlong, MAO Xiangming Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 51515, China Abstract: Objective To report our data of patients with clinical stage T 13N 12M renal cell carcinoma (RCC) and explore the biological behavior of this malignancy. Methods A total of 531 patients with no distant metastatic RCC underwent open radical nephrectomy at our institution between 1988 and 28, among whom 42 patients with histological nodal metastases had successful surgical tumor resection. The clinical data and outcomes of the 42 patients were analyzed. Results Of those 42 patients, 19.% had T1, 21.4% had T2, and 59.5% had T3 stage tumors; 42.9% had N1 and 57.1% had N2 stage tumors. Tumor recurred in 3 (71.4%) patients after the surgery, and death occurred in 26 (61.9%) cases at the last followup; among the recurrent cases, 83.3% (25/3) had multiple metastases at the initial recurrence. The median cancerspecific survival (CSS) and diseasefree survival (DFS) was 23 and 11 months in these cases, respectively. Multivariate analysis demonstrated that Fuhrman grade (=.5), N stage (=.14) and T stage (=.37) were the independent predictors of CSS; Eastern Cooperative Oncology Group (ECOG) performance status (S) (=.2), tumor size (=.7), Fuhrman grade (=.9) and N stage (=.19) were the independent predictors of DFS. Conclusion atients with T 13N 12M RCC have poor prognosis. N stage is an independent predictor of both CSS and DFS, suggesting that extended lymph node dissection should be performed when suspicious enlarged nodal disease is found during surgery. Key words: renal cell carcinoma; prognosis; multivariate analysis; lymph node dissection Introduction Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 85% of all primary malignant kidney tumors [1], and its incidence and mortality rate are still rising worldwide at a rate of approximately 2%3% per decade [2]. The overall risk of lymph node metastasis is approximately 2%, varying significantly in published literature [3] possibly due to patient selection, the extent of lymph node dissection (LND) and the presence or absence of distant metastasis. The rate of nodal metastasis in the absence of distant tumor metastasis is relatively low [45]. So far the documentation of the outcome of RCC patients with exclusive lymph node metastasis remains scarce. Lymph node involvement in RCC is often associated with a poor survival [67]. With a highly heterogeneous nature, RCC presents with marked variability in the disease behavior, histology and molecular biology [8]. An accurate prediction of the outcome and prognosis after surgical resection is valuable for adjuvant trial design, counseling, and effective scheduling followup visits and imaging studies [9]. The application of current prognosticators in patients with nodal metastasis in the absence of distant tumor metastasis is controversial. In this study, we report our Received: Accepted: Supported by the Key Discipline Development Foundation of the General Logistics Department of LA. Corresponding author: ZHENG Shaobin, MD & h.d, Tel: , nfykdxzsb@163.com clinical data of patients with T13N12M RCC and explore the outcome and clinical predictors of the malignancy. atients and Methods With Institutional Review Board approval, a retrospective study was performed based on a chart review of the demographic, clinical and pathological data of patients with RCC. A total of 531 patients without distant metastases underwent open radical nephrectomy (RN) at Nanfang Hospital between January 1988 and December 28. Of those patients, 45 had histological nodal metastases, including 42 receiving successful radical tumor resection with a negative margin during surgery and 3 without total resection of the primary tumor or/and nodal involvement. The clinical data of the 42 patients with successful total tumor resection were analyzed in this study. The tumor stage was determined according to the recommendations of the American Joint Committee on Cancer/ UICC TNM classification system (1997) [111]. T stage and N stage were defined by pathological examination, and M stage was defined by perioperative radiographic or pathological findings. Tumor grade was determined according to the 4tiered Fuhrman system. The Eastern Cooperative Oncology Group (ECOG) performance status (S) was determined preoperatively. All the 42 patients had radical nephrectomy (RN) in conjunction with extended LND for curative intent. For rightsided tumors, the dissection included the hilar,

2 75 J South Med Univ Vol.31 paracaval, precaval, postcaval, interaortocaval and preaortic lymph nodes, while for leftsided ones, the hilar, paraaortic, peraortic, retroaotic, interaortocaval and precaval nodes were dissected. All the surgeries were performed via an abdominal incision. All the nodal involvement was confined to the retroperitoneum as defined by perioperative radiographic imaging (CT or MRI) and pathological examinations. Regular followup examinations were schedualed in all the patients at the end of the first postoperative month, every 3 months in the first and the second years, every 6 months in the third year, and then on an annual basis thereafter. Each followup examination consisted of a general physical examination, laboratory examinations, and a chest Xray. The patients underwent CT scans at 3 months after the surgery, and then once every 6 to 12 months, with additional scans in cases of suspected tumor recurrence. Enhanced CT scan was performed in patients with suspicion of bone metastasis. Statistical analyses were carried out using SSS 13. statistical software package. The cancerspecific survival (CSS) and diseasefree survival (DFS) curves were plotted by the KaplanMeier method and compared by the logrank test. Univariate and multivariable Cox proportional hazard regression analyses were used to assess the effect factors of CSS and DFS in the 42 patients, including age, tumor size, histological subtype, Fuhrman grade, N stage, T stage, adjuvant therapy and ECOG S. Tumor necrosis was not taken into consideration as the majority of the patients (39/42, 92.9% ) showed necrotic foci in the tumor. Twotailed tests were used for all comparisons, and a value less than.5 was considered to denote a statistical significance. Results Clinical characteristics of the patients Tab.1 shows the clinical and pathological characteristics of the 42 patients with T13N12M RCC, who had a negative margin during surgery. The median tumor size was 9.5 cm (ranging from 5. to 2. cm). Most of the patients had T3 (59.5%) RCC, followed by T2 (21.4%) and T1 (19.%). N1 RCC and N2 RCC were found in similar proportions of the patients (42.9% vs 57.1%). Of the 42 patients, 32 were suspected to have positive nodes before or/and during surgery, and 1 showed no evidence of nodal metastases before and during surgery. Adjuvant therapy was administered in 17 cases after the surgery, which consisted of at least one treatment course of immunotherapy (IL2 and IFNα) or chemotherapy (5Fu, Gemicitabine). None of the patients received targeted therapy. Cancerspecific survival The median followup time was 15.5 months (ranging from 4 to 13 months). Death occurred in 26 Tab.1 Clinical and pathological data of the 42 patients with T13N12M RCC Variable Sex: female/male Age: median(range) Tumor size(cm): median(range) T stage T1 T2 T3a T3b N stage N1 N2 Histological type Conventional apillary Sarcomatoid Fuhrman grade G2 G3 G4 ECOG S 1 2 cases (61.9% ), and 16 (38.1% ) patients completed the last followup. The median CSS was 23 months with the 1, 3and 5year CSS rates of 72.3%, 32.%, and 22.4%, respectively (Fig.1a). The CSS did not show significant variations with the tumor size (=.81, Fig.1b), T stage (=.86, Fig.1c), histological subtype (=.593, Fig.1d), ECOG S (=.248, Fig. 1e) or adjuvant therapy (=.632, Fig.1f). Significant differences in CSS were found between patients with different Fuhrman grades (=.29, Fig.1g) and N stages (=.18, Fig.1h), and also between patients with multiple metastases and solitary metastases at the initial recurrence (=.1, Fig.2). Univariate analysis demonstrated that Fuhrman grade (=.36) and N stage (=.24) were significant predictors of CSS. Multivariate analysis showed that the Fuhrman grade (G4 vs G2/3, HR 3.4, =.5), N stage (N2 vs N1, HR 3.2, =.14) and T stage (T3 vs T1, HR 3.7, =.37) were independent predictors of CSS. Fuhrman grade was the strongest independent predictor, and patients with grade 4 was 3.4 times more likely to die of the disease than patients with grade 2/3 disease (=.5, Tab.2). Diseasefree survival n (%) 15(35.7)/27(64.3) 54.5(782) 9.5(5.2.) 8(19.) 9(21.4) 19(45.2) 6(14.3) 18(42.9) 24(57.1) 29(69.) 6(14.3) 7(16.7) 1(2.4) 24(57.1) 17(4.5) 18(42.9) 17(4.5) 7(16.7) Thirty (71.4% ) patients showed tumor recurrence and 12 (28.6%) had no evidence of recurrence at the last followup. In the recurrent patients, 25 (83.3% ) had multiple metastases and 5 (16.7% ) had solitary metastases at the initial recurrence; 14 had metastases involving more than one organ, including 7 with both lung and bone metastases and 3 with both lung and

3 No.5 Outcome and prognostic factors of T13N12M renal cell carcinoma a 1. b 1. c Median: 23 months (n=42).6.4 <9.5 cm (n=19, 29 months).6.4 T1 (n=8, 52 months) = cm (n=23, 18 months) d 1. e Sacomatiod (n=7, ).6.6 SO (n=13, 4 months) apillary (n=6, 28 months).4.4 = =.248 S1 (n=18, 23 months).2 Clear cell (n=29, 18 months) S2 (n=11, 16 months).. T2 (n=9, 19 months) =.86 T3 (n=25, 18 months) f Adjuvant therapy Yes(n=17, 23 months) no (n=25, 16 months) = g h.4.2. =.29 Grade 2/3 (n=25, 3 months) Grade 4 (n=17, 12 months).4.2. =.18 N1 (n=18, 29 months) N2 (n=24, 12 months) Fig.1 KaplanMeier curves of CSS (a) and CSS by tumor size (b), T stage (c), histological subtype (d), EOCG S (e), adjuvant therapy (f), Fuhrman grade (g) and N stage (h). Abscissa: months; vertical axis: cumulative survival. Cum survival =.1 Solitary metastases (n=5) mutiple metastases (n=5) Months Fig.2 Survival curves of the patients with multiple and solitary metastases at initial recurrence (median survival, 12 vs 52 months, =.1). retroperitoneal metastases. The most common site of metastases was the lung, occurring in 2 (66.7%) of the patients, followed by the bones (13 cases), retroperitoneum (9 cases, among which only 2 had renal fossa recurrence), brain (1 case), liver (1 case), colon (1 case), and chest wall (1 case). The median DFS of the patients was 11 months (Fig.3a). The DFS did not differ significant with the histological subtype (=.59, Fig.3b), T stage (=.56, Fig.3c) or the administration of adjuvant therapy (=.72, Fig.3d). The DFS varied significantly with the tumor size (=.33, Fig.3e), Fuhrman grade (=.41, Fig.3f), pn stage (=.33, Fig.3g) and ECOG S (=.12, Fig.3h). Univariate analysis indicated that the tumor size (=.44), N stage (=.43) and ECOG S (=.26) were significant predictors of DFS. ECOG S (=.5), Tumor size (=.7), Fuhrman grade (=.9) and N stage (=.19) were identified as the independent predictors of DFS by multivariate analysis. S1 (HR, 4.1, =.18) and S2 (HR, 7.5, =.2) were associated with greater likeliness of recurrence than S, and patients with a tumor size 9.5cm were 3.6 times more likely to have recurrence than those with a smaller tumor size (=.7, Tab.4). Discussion Exclusive nodal metastasis without distant

4 752 J South Med Univ Vol.31 Tab.2 Univariate and multivariate Cox proportional hazards model for CSS Variable Univariate Multivariate Age ( 55 vs <55yr) 1.2(.52.7).664 Tumor size ( 9.5vs <9.5cm) 2.1(.95.).91 Histology.61 apillary vs clear.5(.21.8).324 Sarcomatoid vs clear 1.(.33.5).995 Grade (G4 vs G2/3) 2.3(1.15.1) (1.58.1).5 T stage T2 vs T1 2.2(.67.6) (.45.1).66 T3 vs T1 3.6( ) ( ).37 N stage(n2 vs N1) 2.6(1.15.8) (1.37.9).14 Adjuvant therapy(yes vs no).8(.41.8).637 ECOG S 1 vs 2 vs 1.6(.64.4) 2.6(.88.1) a b 1. c.8 =.59.6 T1 (n=8, 31 months) Median: 11 months (n=42).4.4 apillary (n=6, 21 months) d Adjuvant therapy.4.2 Clear cell (n=29, 9 months) Sacomatiod (n=7, 5 months) e <9.5 cm (n=19, 11 months).4 Yes(n=17, 11 months) cm (n=23, 7 months) g N1 (n=18, 17 months) =.33 N2 (n=24, 6 months) Grade 2/3 (n=25, 17 months) =.41 2 Grade 4 (n=17, 8 mos) h =.12 S (n=13, 3 months) Fig.3 KaplanMeier curves of DFS (a).4 S1 (n=18, 11 months).2 S2 (n=11, 8 months) =.33 =.72 4 f no (n=25, 9 months) T3 (n=25 9 months) T2 (n=9, 11 months) = metastasis is rare in RCC patient, and only a few reports have been available to describe the results of this subset of patients 45. The incidence of TanyN12M RCC, according to the published reports, ranges from 1.8% to and DFS by histological subtype (b), T stage(c), adjuvant therapy (d), tumor size (e), Fuhrman grade (f), N stage (g) and EOCG S (h). Abscissa: Months; Vertical axis: Cumulative survival. 14.1% 4, 6, 1217, which is consistent with our data (8.5%). The rates of nodal metastases in M RCC in stage T1, T2 and T3 are 1.1%, 4.5% and 12.3%, respectively 12. TanyN12M RCC is often associated with a poor

5 No.5 Outcome and prognostic factors of T13N12M renal cell carcinoma 753 Tab.4 Univariate and multivariate Cox proportional hazards model for DFS Variable Univariate Multivariate Age ( 55 vs <55yr) 1.(.52.2).95 Tumor size ( 9.5 vs <9.5cm) 2.3(1.5.) (1.58.8).7 Histology.9 apillary vs Clear.4(.11.5).196 Sarcomatoid vs Clear 2.1(.85.6).119 Grade (G4 vs G2/3) 2.1(1.4.4) (1.37.6).9 T stage.82 T2 vs T1 2.4(.78.3).163 T3 vs T1 3.7( ).26 N stage(n2 vs N1) 2.1(1.4.5) (1.26.1).19 Adjuvant therapy(yes vs no).9(.41.8).728 ECOG S vs 2.5(.87.5) (1.313.).18 2 vs 4.9( ).8 7.5( ).2 prognosis, with a 5year survival rate ranging from 2.9% to 39.3% [4, 1215, 17] and a median survival of 2 to 27.6 months [46, 12]. In our cases, the median survival of the patients was 23 months with a 5year survival of 22.4%, similar to the reported data. Researchers have examined the survival predictors of these RCC patients. Canfield et al [5] reported that T stage and N stage were independent predictors of the overall survival, whereas the Fuhrman grade showed no significant predictive value. Karakiewicz et al [4] found that symptom classification contributed the most to the combined predictive accuracy of all the variables (+ 4.2%, <.1), followed by the Fuhrman grade (+ 2.3%) and histological subtype (+ 1.%), and suggested that patients presenting with systemic symptoms were expected to have an extremely poor survival. Their data showed that T stage was not an informative variable while histological subtype was a predictor of survival. In our study, we found that Fuhrman grade, N stage and T stage were independent predictors of CSS. The discrepancies in these results possibly results from a lack of standard extent of LND, absence of adjuvant therapy data and exclusion of N stage from analysis (as in the two other reports). Our data show that patients with T13N12M RCC had an early recurrence even a complete resection of the primary tumor and nodal involvement was performed. The median DFS was 11 months after the operation and the recurrent cases often had a high rate of multiple metastases (83.3% ) at initial recurrence. A low rate (6.7% ) of recurrence in the renal fossa was noted, suggesting the value of a radical tumor resection. This fact also suggested the potential presence of distant metastasis before the operation, as supported by the autopsy data reported by Johnsen et al [18], who found a low rate (5/554) of confined nodal metastases in comparison with a much higher rate of regional nodal involvement with additional metastases (75/554) [18]. To our knowledge, the recurrence data of T13N12M RCC were available only in the study by Canfield et al [5], who examined a cohort of 39 patients and found that pn stage (N2 vs N1, HR, 2.83, =.39) and Fuhrman grade (G4 vs G2/3, HR, 2.57, =.23) were the significant independent predictors of time to recurrence. But ECOG S and tumor size were not included in their analysis, and they failed to provided specific descriptions of the recurrence site and number of metastatic foci. In the current study, ECOG S, tumor size, Fuhrman grade and N stage were identified as the independent predictors of tumor recurrence, among which ECOG S and tumor size were more powerful predictors of recurrence of T13N12M RCC. ECOG S has also been identified as an independent predictor of survival and recurrence in RCC in a few studies [1921], and we further demonstrated its value as a powerful predictor of DFS in patients with T13N12M RCC. The therapeutic value of LND in patients with RCC have remained controversial since 1969, when Robson et al [22] advocated the need for lymphadenectomy for RCC. Some recent studies fail to show any benefit of LND in patients with RCC [6, 16]. However, patients undergoing LND at the time of cytoreductive RN for metastatic RCC had reportedly a better survival than those without LND [67]. Our data demonstrated that N stage was an independent predictor of both CSS and DFS in T13N12M RCC, and we recommend that extended LND be performed in cases of suspicious nodal enlargement during surgery. As this present study is based on the singlecenter data, and due to the rarity of T13N12M RCC, the sample size for analysis is relatively small in this study. But our findings may still provide important insight into the biological behavior of the malignancy. Acknowledgments We thank Dr. JIANG Yaodong for his valuable

6 754 J South Med Univ suggestions and critical reading of the manuscript. We are grateful to Dr. YANG Xukai for assistance in the data collection and statistical analysis. References 1 Dhote R, ellicercoeuret M, Thiounn N, et al. Risk factors for adult renal cell carcinoma: a systematic review and implications for prevention J. BJU Int, 2, 86(1): Gupta K, Miller JD, Li JZ, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mrcc): a literature review J. Cancer Treat Rev, 28, 34(3): Freedland SJ, dekernion JB. Role of Lymphadenectomy for atients Undergoing Radical Nephrectomy for Renal Cell Carcinoma J. Rev Urol, 23, 5(3): Karakiewicz I, Trinh QD, Bhojani N, et al. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease: prognostic indicators of diseasespecific survival J. Eur Urol, 27, 51(6): Canfield SE, Kamat AM, SánchezOrtiz RF, et al. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease (clinical stage TxN12M): the impact of aggressive surgical resection on patient outcome J. J Urol, 26, 175(3 t 1): antuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection J. J Urol, 23, 169(6): Vasselli JR, Yang JC, Linehan WM, et al. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma J. J Urol, 21, 166(1): Nelson EC, Evans C, Lara N Jr. Renal cell carcinoma: current status and emerging therapies J. Cancer Treat Rev, 27, 33(33): Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma J. J Urol, 25, 173(1): Sobin LH, Wittekind CH. International Union Against Cancer (UICC). TNM Classification of Malignant Tumours.5th edn M. New Vol.31 York: WileyLiss ublications, 1997: Fleming ID, Cooper JS, Henson DE, et al. AJCC Cancer Staging Manual. 5th ed M. hiladelphia: LippincotRaven ublishers, 1997: Capitanio U, Jeldres C, atard JJ, et al. Stagespecific effect of nodal metastases on survival in patients with nonmetastatic renal cell carcinoma J. BJU Int, 29, 13(1): Margulis V, Tamboli, Matin SF, et al. Analysis of clinicopathologic predictors of oncologic outcome provides insight into the natural history of surgically managed papillary renal cell carcinoma J. Cancer, 28, 112(7): Terrone C, Cracco C, orpiglia F, et al. Reassessing the current TNM lymph node staging for renal cell carcinoma J. Eur Urol, 26, 49 (2): Blute ML, Leibovich BC, Cheville JC, et al. A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma J. J Urol, 24, 172(2): Minervini A, Lilas L, Morelli G, et al. Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? J. BJU Int, 21, 88(3): Schafhauser W, Ebert A, Brod J, et al. Lymph node involvement in renal cell carcinoma and survival chance by systematic lymphadenectomy J. Anticancer Res, 1999, 19(2C): Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell carcinoma: an autopsy study J. J Urol, 1997, 157(2): Lara N Jr, Tangen CM, Conlon SJ, et al. redictors of survival of advanced renal cell carcinoma: longterm results from Southwest Oncology Group Trial S8949 J. J Urol, 29, 181(2): Shuch B, La Rochelle JC, Wu J, et al. erformance status and cytoreductive nephrectomy: redefining management in patients with poor performance J. Cancer, 28, 113(6): Shvarts O, Seligson D, Lam J, et al. p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma J. J Urol, 25, 173(3): Robson CJ, Churchill BM, Anderson W. The results of adical nephrectomy for renal cell carcinoma J. J Urol, 1969, 11(3): 临床分期 T13N12M 肾细胞癌患者临床分析 单中心研究 陈壮飞 吴 芃 郑少斌 张 鹏 谭万龙 毛向明 南方医科大学南方医院泌尿外科 广东 广州 摘要 分析临床分期为 T13N12M 肾癌的临床病理及预后资料 探讨其生物学行为特点 方法 1988 年至 28 年间我 院共收治无远处转移肾癌并行开放性肾癌根治术的患者 531 例 其中 42 例伴淋巴结转移患者顺利完成了手术 对其临床 病理及预后资料进行回顾性分析 结果 42 例患者中 19.%为 T1 期 21.4% 为 T2 期 59.5%为 T3 期 42.9%为 N1 期和 57.1%为 N2 期 末次随访 3 例 71.4% 出现肿瘤复发 26 例 61.9% 患者死亡 83.3% 25/3 初次复发即为多发性 42 例患者中位肿瘤特异生存期 CSS 和无病生存期 DFS 分别为 23 个月和 11 个月 多因素生存分析显示 病理分级 =.5 淋巴结分期 =.14 和T分期 =.37 是CSS的独立影响因素 术前状态 =.2 肿瘤大小 =.7 病理 分级 =.9 和淋巴结分期 =.19 是 DFS 的独立影响因素 结论 T13N12M 期肾癌患者预后较差 淋巴结分期 是T13N12M期肾癌CSS和DFS的独立影响因素 对术中出现可疑肿大淋巴结者应行扩大的淋巴结清扫术 关键词 肾细胞癌 预后 多因素分析 淋巴结清扫 中图分类号 R 文献标志码 A 文章编号 收稿日期 基金项目 总后勤部 重中之重 学科建设专项基金 作者简介 陈壮飞 博士研究生 医师 电话 chenzhuangfei@126.com 通讯作者 郑少斌 教授 博士生导师 主任医师 nfykdxzsb@163.com