Radical Nephrectomy for Renal Cell Carcinoma Its Contemporary Role Related to Histologic Type, Tumor Size, and Nodal Status: A Retrospective Study

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1 AJCP /ORIGINAL ARTICLE Radical Nephrectomy for Renal Cell Carcinoma Its Contemporary Role Related to Histologic Type, Tumor Size, and Nodal Status: A Retrospective Study Kamran M. Mirza, MD, PhD, Jerome B. Taxy, MD, and Tatjana Antic, MD From the Department of Pathology, the University of Chicago Medicine, Chicago, IL. Key Words: Renal cell carcinoma; Lymph node dissection Am J Clin Pathol June 2016;145: DOI: /AJCP/AQW059 ABSTRACT Objectives: Staging for renal cell carcinoma (RCC) depends on tumor size and the status of the regional lymph nodes. Although lymph node involvement by tumor yields the most accurate staging and prognostic information in patients with carcinomas of various genitourinary organs, the role of lymph node sampling (LNS) in patients with RCC to definitively establish nodal metastases remains unsettled. Methods: In this retrospective study of 399 patients with RCC treated by total nephrectomy, 115 cases were subjected to lymph node dissection. Results: The corresponding primary tumors averaged larger than 8 cm. Twenty-nine showed positive lymph nodes (25%). The present review confirms that primary tumor size is a key indicator of nodal involvement. Clear cell and papillary tumors larger than 4 cm involve lymph nodes more commonly than other types of RCC. Sarcomatoid differentiation occurred in all major cell types and existed in numbers too few to predict the likelihood of nodal metastases. Conclusions: LNS in RCC for staging purposes may be warranted based on tumor size (>4 cm) as determined by imaging as well as histologic cell type, the latter suggesting a selective role for preoperative fine needle aspiration or core biopsy. The standard surgical therapy for renal cell carcinoma (RCC) has historically been the radical nephrectomy (RN). This approach predates the contemporary liberal use of body scanning for nonspecific abdominal complaints and the incidental discovery of renal tumors, their histologic subtyping and modern pathologic tumor staging including lymph node involvement. In considering postsurgical therapy for other urologic cancers, eg, bladder and prostate cancer, lymph node status has been shown to yield the most accurate staging and therefore useful prognostic information. 1,2 The value of lymph node sampling (LNS) to obtain this potential prognostic information in patients with RCC remains controversial. This may be, in part, related to partial nephrectomy (PN) becoming a standard procedure for smaller tumors. While PN has largely replaced RN for such lesions and is typically unaccompanied by LNS, RN may still have a clinical role for larger and more centrally placed tumors. Even in this narrower context, it may be unclear which RCCs are likely to demonstrate regional node involvement and might be optimal candidates for LNS. While some retrospective studies have demonstrated that nephrectomy with concurrent LNS imparts a survival benefit, other studies show no significant difference in mortality. 3-7 These studies notwithstanding, it must be acknowledged that, though RCC stage is the most important prognostic factor, lymph node status is a key American Joint Committee on Cancer staging parameter and lymph node involvement in some studies does portend a poor prognosis, with 5- and 10-year survival rates of 5% to 30% and 0% to 5%, respectively. 3 It is perhaps understandable that current actual practice regarding LNS in American Society for Clinical Pathology, All rights reserved. For permissions, please journals.permissions@oup.com 837 Am J Clin Pathol 2016;145: DOI: /ajcp/aqw059

2 Mirza et al /NODAL STATUS IN RADICAL NEPHRECTOMY Table 1 Radical Nephrectomy: RCC Subtype and Tumor Size RCC Type RCC varies. Lymph node status is a derived interpretation related to a presumed increased risk for lymph node involvement based on preoperative imaging, tumor grade 3 or 4, sarcomatoid histology, large tumor size (T3 or T4) or the presence of coagulative tumor necrosis These parameters primarily concern clear cell RCC (CCRCC), the most common histologic variant, and may imply a preoperative diagnosis. 9 The consistent and predictable influence of pathologic tumor variables of any type in the creation of a useful clinical algorithm related to the advisability of LNS in the management of RCC is just not known. The ultimate decision to sample lymph nodes may simply be one arrived at by the urologist in the operating room. This retrospective study reviews patients treated by total nephrectomy for RCC. The objective was to understand which tumor characteristics might warrant nodal sampling. Thus, in those subjected to LNS, positive or negative status is correlated with tumor type, size, stage and presence of sarcomatoid differentiation. These tumor parameters are also evaluated in those nephrectomies unaccompanied by LNS. To the extent that these data may be identified prior to definite surgery, by combinations of biopsy and imaging, prospective treatment plans may be modified. Materials and Methods No. of Cases (No. Sarcomatoid) With institutional review board approval, the pathology database was queried for all complete nephrectomies performed at the University of Chicago from January 1, 2005, to September 30, Clinical information was garnered from patients electronic medical records. Histologic subtypes of RCC were tabulated and further categorized according to size, presence of a sarcomatoid component and the number subjected to LNS. In the latter cases, the presence of nodal metastases was correlated with location (hilar or nonhilar) and primary tumor size. This was a retrospective study within a single institution. Nevertheless, the process of preoperative or intraoperative clinical decision-making related to nodal sampling or the possibility of preoperative tissue acquisition was unknown and is beyond the scope of the study. Results Size, cm (Average) No. of Cases 4 cm/ 7 cm(%/%) CRCC 257 (14) (7.27) 209/122 (81/47.2) MLCRCC (1.35) 0/0 (0/0) PRCC 67 (7) (7.5) 45/25 (67.1/37.3) CHRCC 36 (4) (9.8) 31/27 (86.1/75) Collecting duct (7.35) 1/2 (50/100) Medullary (4.5) 1/1 (50/50) MTSCRCC (5.56) 2/1 (66.6/33.3) CPRCC (3.68) 3/1 (25/8.3) ACDRCC (4.5) 1/1 (50/50) Translocation 7 (1) (10.6) 7/5 (100/71.4) Sarcomatoid /1 (100/100) Rhabdoid /1 (100/100) Unclassified (8.5) 5/2 (100/100) Summary 399 (26) (6.93) 306/189 (76.5/47.2) ACDRCC, acquired cystic disease-associated renal cell carcinoma; CHRCC, chromophobe renal cell carcinoma; CPRCC, clear cell tubulopapillary renal cell carcinoma; CRCC, clear cell renal cell carcinoma; MLCRCC, multilocular cystic renal cell carcinoma; MTSCRCC, mucinous tubular and spindle cell renal cell carcinoma; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma. RN A total of 399 RN cases were reviewed Table 1. There were 133 female and 267 male patients ranging between 21 and 88 years of age. All histologic subtypes are listed. The majority of specimens (64%) were CCRCC followed by papillary RCC (PRCC, 16%) and chromophobe RCC (CHRCC, 9%). The average tumor size approached 7 cm, with most tumors larger than 4 cm. Sarcomatoid transformation was identified in a total of 26 tumors, restricted to CRCC, PRCC, CHRCC, and translocation-associated RCC. Figure 1 shows the distribution of tumor size as reflected in tumor stage related to the three major cell types (CCRCC, PRCC, CHRCC). These histologic variants accounted for 89% of the tumors, as well as the dominant tumors among those of advanced stage (>T2). Table 2 relates RCC subtype with LND. In a total of 115 cases (29%), a broad range of tumor sizes across the RCC histologic spectrum is represented, with the average tumor size being larger than 8 cm and most larger than 4 cm. Table 3 represents lymph node involvement and sarcomatoid components related to tumor size and histologic type. Nodal metastases were identified in 29 cases (25%) 838 Am J Clin Pathol 2016;145: American Society for Clinical Pathology 838 DOI: /ajcp/aqw059

3 AJCP /ORIGINAL ARTICLE and nonhilar, were at risk and appear unrelated to cell type, tumor size or presence of sarcomatoid features. The following is a more detailed breakdown by cell type. No. of Patients T1a Rhabdoid Sarcomatoid Translocation ACDRCC T1b T2 Tumor Stage CPRCC MTSCRCC Medullary Collecting duct CHRCC over the entire RCC histologic spectrum, with most involving the major tumor subtypes. The rarer tumor subtypes were likely to have positive nodes. Thus, for example, of the collecting duct, medullary and translocation tumors subjected to LNS, nodal metastases were frequent. A substantial number (13/29) of those tumors with metastases demonstrated sarcomatoid components. The average overall tumor size was larger than 8 cm, and the average size of those tumors with sarcomatoid components was larger than 9 cm. The small case numbers specifically related to cell type and/or sarcomatoid features preclude a definitive statement regarding significance. Figure 2 further characterizes the location of the nodal metastases. Both locations, ie, hilar T3 T4 PRCC MLCRCC CRCC Figure 1 Radical nephrectomy: stage and renal cell carcinoma subtype. ACDRCC, acquired cystic disease-associated renal cell carcinoma; CHRCC, chromophobe renal cell carcinoma CRCC; CPRCC, clear cell tubulopapillary renal cell carcinoma; clear cell renal cell carcinoma; MLCRCC, multilocular cystic renal cell carcinoma; MTSCRCC: mucinous tubular and spindle cell renal cell carcinoma; PRCC, papillary renal cell carcinoma. CRCC Two hundred fifty-eight cases of CRCC were reviewed. Tumors ranged from 1.1 to 25.5 cm in greatest dimension (average, 7.27 cm). The majority of cases were over 4 cm in greatest dimension (81%) and many were over 7 cm (47%). The majority of tumors in this category demonstrated T3 disease (117 cases), followed by T1b (55 cases) and T1a (43 cases). Lymph node dissection was performed in 72 cases (28%). In this cohort, 94% of cases had a tumor size larger than 4 cm, and 72% were over 7 cm. Lymph node metastasis was identified in 12 cases (16%). In the cases with metastases, the original tumor size ranged from 2.5 to 22 cm (average, 11.8 cm). Seven of 12 cases with positive nodes demonstrated sarcomatoid differentiation and correlated with average tumor size of 10.5 cm (range, cm). In seven cases nodal positivity was perinephric, in eight cases it was nonhilar, and in three cases it was both hilar and nonhilar. PRCC The 67 PRCCs ranged from 0.5 to 33.2 cm in greatest dimension (average, 7.5 cm). There were 30 type I and 30 type II with seven of mixed type. The majority of cases were over 4 cm in greatest dimension (67%), and more than a third were over 7 cm (37%). The most frequent clinical stage for PRCC was T1a (22 cases), followed by T3 (16 cases) and T1b (14 cases) disease. Lymph node dissection was performed in 17 cases (25%). In this cohort, 88% of cases had a tumor size larger than 4 cm, and 59% were over 7 cm. Lymph node metastasis was identified in nine cases (53%); none of the seven mixed types metastasized. In the cases with metastases, the original tumor size ranged from 2.8 to 17 cm (average, 9.08 cm). Three of nine cases with positive nodes demonstrated sarcomatoid differentiation and correlated with a higher average tumor size of 9.76 cm (range, 6-12 cm). In three cases, nodal positivity was perinephric, in eight cases it was nonhilar, and in two cases it was both hilar and nonhilar. When stratified into type I and type II PRCC Table 4, the data show that type II is more likely to have metastatic involvement. The two cases of type I PRCC that had metastatic involvement both showed sarcomatoid differentiation. American Society for Clinical Pathology Am J Clin Pathol 2016;145: DOI: /ajcp/aqw059

4 Mirza et al /NODAL STATUS IN RADICAL NEPHRECTOMY Table 2 Radical Nephrectomy: LND and Correlation With RCC Subtype RCC Type No. of LNDs (%) Primary Tumor Size, cm (Average) No of Cases T1a and Larger 4 cm/7cm(%/%) CRCC 72 (27.9) (9.95) 68/52 (94.4/72.2) PRCC 17 (25.3) (9.32) 15/10 (88.3/58.8) CHRCC 10 (27.7) (10.9) 10/10 (100/100) Collecting duct 2 (100) (7.35) 2/2 (100/100) Medullary 2 (100) (4.5) 1/1 (50/50) MTSCRCC 2 (66.6) (5.5) 1/1 (50/50) Translocation 6 (85.7) (10.6) 6/4 (100/66.6) Rhabdoid 1 (100) 8.5 1/1 (100/100) Unclassified 3 (50) (7.76) 3/1 (100/33.3) Summary 115 (28.75) (8.26) 107/84 (92.2/72.4) CHRCC, chromophobe renal cell carcinoma; CRCC, clear cell renal cell carcinoma; MTSCRCC, mucinous tubular and spindle cell renal cell carcinoma; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma. Table 3 Radical Nephrectomy: Lymph Node Positivity by Tumor Type and Sarcomatoid Component Type No. Metastasis (%) Size, cm (Average) No. Sarcomatoid (%) CHRCC The 36 CHRCCs ranged from 1.9 to 23.3 cm in greatest dimension (average 9.8 cm). The majority of cases were over 4 cm in greatest dimension (86%), and many were over 7 cm (75%). This translated accordingly to the most frequent clinical stage being T2 (17 cases), followed by T3 (15 cases) disease. Lymph node dissection was performed in 10 cases (28%). In this cohort, 100% of cases had a tumor size >7 cm. Lymph node metastasis was identified in 1 case (10%). In this case, the original tumor size was 12 cm. Two of 10 cases with node dissection demonstrated sarcomatoid differentiation and correlated with a higher average tumor size of cm. The single case with the positive node status demonstrated a perinephric/hilar location. Interestingly, one patient demonstrated bilateral CHRCC (right side 23 cm, left side 21 cm) with a smaller focus of concurrent CRCC (2.7 cm) in the left kidney. This patient exhibited nodal metastasis in the left para-aortic chain from the left-sided CRCC. Despite the large size of both left- and right-sided CHRCCs, the smaller CRCC was the primary site of metastasis, even though it was much smaller. Remaining RCC Subtypes In these remaining groups, translocation-associated, sarcomatoid, rhabdoid and unclassified RCCs all presented with lesions over 4 cm (100% of cases), and the majority had tumors over 7 cm (the latter three subtypes had 100% cases >7 cm). Nodal involvement among those actually subjected to LNS was common. Discussion Sarcomatoid Tumor, cm (Average) No. STWM STWM Size, cm (Average) CRCC 12 (16.4) (11.79) 7 (9.72) (10.5) (13.37) PRCC 9 (52.9) (9.08) 3 (17.64) 6-12 (9.76) (9.76) CHRCC 1 (10) 12 2 (20) (11.95) 0 N/A Collecting duct 2 (100) (7.35) 0 N/A 0 N/A Medullary 2 (100) (4.5) 0 N/A 0 N/A Translocation 1 (16.6) (16.66) Unclassified 2 (66.6) (4.65) 0 N/A 0 N/A Summary 29 (25) (8.12) 13 (11.3) (9.92) (10.21) CHRCC, chromophobe renal cell carcinoma; CRCC, clear cell renal cell carcinoma; PRCC, papillary renal cell carcinoma; STWM, sarcomatoid tumor with metastasis. Unlike carcinomas in other genitourinary organs, there are no standard, reproducible guidelines for LNS in RCC. Albeit limited, current data suggest there is a low likelihood of nodal involvement in clinically negative lymph nodes. Therefore lymphadenectomy is understandably considered on a case-by-case basis. Data from the European Organization for Research and Treatment of Cancer (EORTC 30881) trial of 772 patients focus on survival outcomes in various arms, 7 but remain underpowered to demonstrate any benefit from lymphadenectomy among those patients (4%) with pathologically involved nodes. In a study involving over 9,500 patients (58% with node-positive disease), an increase of 10 lymph nodes retrieved for every one positive node identified was associated with a 10% absolute improvement in fiveyear disease-specific survival, 16 warranting further study to put forward guidelines for when to perform lymph node dissection in partial and complete nephrectomy cases for RCC. The present retrospective study of 399 RNs suggests that tumor size is a crucial factor in determining nodal spread. In a previous study of 491 PNs with an average size of 3.4 cm, a 840 Am J Clin Pathol 2016;145: American Society for Clinical Pathology 840 DOI: /ajcp/aqw059

5 AJCP /ORIGINAL ARTICLE No. of Patients Hilar Translocation Medullary Nonhilar Collecting dust CHRCC PRCC Table 4 Metastatic Disease in Type I vs Type II PRCC No. of Cases Both CRCC Figure 2 Location of positive nodes in different RCC types. CHRCC, chromophobe renal cell carcinoma; CRCC, clear cell renal cell carcinoma; PRCC, papillary renal cell carcinoma. No. of Cases With Lymph Node Dissection (%) LNS was done in only 14 cases, with only one being positive. 15 Among the present tabulation of 399 total nephrectomies, the average tumor size of almost 7 cm resulted in LNS in just under a third of cases, with metastases in about 25% of those. Most nodal metastases occurred in CRCC and PRCC, perhaps in keeping with the frequency of these cell types. Of the 27% CRCC with lymphadenectomy, 16.4% showed metastatic disease. In this group, the average tumor size was 10.5 cm. Four CRCCs with sarcomatoid differentiation and metastases had an average tumor size of cm. The 25.3% of PRCCs that had lymphadenectomy demonstrated metastatic disease in 52.9%. The average size of PRCCs with lymphadenectomy was 9.32 cm, and 9.08 cm in those with metastatic disease. PRCC exhibited sarcomatoid differentiation more often than CRCC (17.64% vs 9.72%, respectively), although there was no significant difference in size between metastatic PRCCs with or without sarcomatoid differentiation. Type II PRCC tumors showed more metastatic involvement. This observation may raise the question of whether a type II PRCC tumor, perhaps as seen on a preoperative core biopsy, is enough to justify a node sampling. An exception to the size parameter may be CHRCCs, which, in this series, were generally large tumors (average 9.8 cm). Almost 28% of CHRCC with an average size of 10.9 cm underwent LNS, but only one tumor (12 cm) had nodal disease. This data demonstrates the low rate of CHRCC metastasizing to lymph nodes, and, size notwithstanding, routine lymph node dissection may not be needed in CHRCC. Of the two cases (CHRCC) with sarcomatoid differentiation (average size of cm), neither demonstrated metastatic disease. Histologically high-grade tumors, represented in this series by collecting duct carcinoma and medullary carcinoma, were few. The average tumor sizes were 7.35 cm for collecting No. of Cases With Metastatic Disease (%) Tumor Size/Stage in Metastatic Cases PRCC type I 30 4 (13%) 2(7%) 11.3 cm, T3a, sarcomatoid 12.0 cm, T3b, sarcomatoid PRCC type II (33%) 7 (23%) 12.8 cm, T3a 6.0 cm T1b, sarcomatoid 6.0 cm, T3b 6.6 cm, T3a 7.6 cm, T3a 12.5 cm, T3a 17.0 cm, T3b PRCC mixed 7 3 (43%) 0 Summary PRCC, papillary renal cell carcinoma. American Society for Clinical Pathology Am J Clin Pathol 2016;145: DOI: /ajcp/aqw059

6 Mirza et al /NODAL STATUS IN RADICAL NEPHRECTOMY duct and 4.5 cm for medullary carcinoma, both types demonstrating metastatic disease. These are rare lesions with known clinically aggressive behavior for which the surgical management may best be individualized. LNS for known high-grade tumors may not be clinically indicated. However, if node sampling is to be influenced by the type of RCC or high tumor grade, a preoperative tissue diagnosis by fine needle aspiration or needle core biopsy would be required. Tumors less than 4 cm in greatest dimension also appear not to be candidates for routine lymph node dissection. In a previous report, of those patients treated by PN, only 14 underwent node dissection with only one positive. 15 It is a limitation of the retrospective nature of this study that even for small tumors, RN may be needed to actually determine T3 status, since beyond venous invasion, this determination involves extrarenal spread, which in many cases is a microscopic observation. However, the long-term outlook for patients undergoing PN is good and independent of cell type, and probably justifies foregoing an LNS. In the present study, smaller tumors treated by RN had a lower incidence of nodal metastases. In summary, the most important predictor of regional lymph node metastases in RCC is the size of the primary tumor followed by histologic tumor type. The number of metastatic tumors largely parallels the distribution of histologic tumor variants, with most occurring in CCRCC and PRCC. High histologic grade and sarcomatoid transformation are important co-factors. To the extent that histologic subtype may be important in determining the advisability of LNS, preoperative fine needle aspiration may be contributory; however, since immunohistochemical studies may be required and since fine needle aspiration may not reliably distinguish RCC types, or types 1 and 2 PRCC, a core needle biopsy should be seriously considered. Corresponding author: Tatjana Antic, 5841 S Maryland Ave, Chicago, IL 60637; tatjana.antic@uchospitals.edu. References 1. Stenzl A, Cowan NC, De Santis M, et al. The updated EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2009;55: Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer: part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59: Bassil B, Dosoretz DE, Prout GR Jr. Validation of the tumor, nodes and metastasis classification of renal cell carcinoma. J Urol. 1985;134: Crispen PL, Breau RH, Allmer C, et al. Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol. 2011;59: Mehta V, Mudaliar K, Ghai R, et al. Renal lymph nodes for tumor staging: appraisal of 871 nephrectomies with examination of hilar fat. Arch Pathol Lab Med. 2013;137: Capitanio U, Becker F, Blute ML, et al. Lymph node dissection in renal cell carcinoma. Eur Urol. 2011;60: Blom JH, van Poppel H, Maréchal JM, et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial Eur Urol. 2009;55: Capitanio U, Jeldres C, Patard JJ, et al. Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma. BJU Int. 2009;103: 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 Urol. 2004;172: Studer UE, Birkh auser FD. Lymphadenectomy combined with radical nephrectomy: to do or not to do? Eur Urol. 2009;55: Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2003;169: Vasselli JR, Yang JC, Linehan WM, et al. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol. 2001;166: Delacroix SE Jr, Wood CG. The role of lymphadenectomy in renal cell carcinoma. Curr Opin Urol. 2009;19: Hutterer GC, Patard JJ, Perrotte P, et al. Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram. Int J Cancer. 2007;121: Antic T, Taxy JB. Partial nephrectomy for renal tumors: lack of correlation between margin status and local recurrence. Am J Clin Pathol. 2015;143: Whitson JM, Harris CR, Reese AC, et al. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol. 2011;185: Am J Clin Pathol 2016;145: American Society for Clinical Pathology 842 DOI: /ajcp/aqw059