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Available online at www.sciencedirect.com

www.elsevier.com/locate/semdp

Outcome prediction for patients with renal cell carcinoma Christine M. Lohse, MSa, Sounak Gupta, MDb, John C. Cheville, MDb,n a

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St, Southwest Rochester, Minnesota 55905

b

article info

abstract Outcome assessment for renal cell carcinoma is somewhat controversial. Despite numerous studies, a very limited variety of features have been recognized as having prognostic significance in clinical practice. In this review, tumor features considered to be of importance in outcome prediction for surgically treated patients with the 3 most commonly encountered morphotypes of renal cell carcinoma (clear cell, papillary, and chromophobe renal cell carcinoma) are evaluated. In particular, we have focused upon histologic subtype, sarcomatoid and rhabdoid differentiation, TNM staging, primary tumor size, tumor grade, and the presence of histologic coagulative tumor necrosis. We have also examined the importance of these prognostic features in a variety of postoperative or outcome prediction models developed by several institutions. & 2015 Elsevier Inc. All rights reserved.

Introduction Renal cell carcinoma (RCC) was diagnosed in an estimated 32,000 patients in the United States in 2014, with approximately 11,000 estimated deaths.1 Of note, the incidence and mortality rates for RCC have risen steadily over the past several decades between both genders, trends that are not explained by the increased use of abdominal imaging alone.2,3 Prognosis for patients with RCC is known to be related to a number of pathologic features, including the TNM classification and grade, which have been incorporated into prognostic models by Memorial Sloan-Kettering Cancer Center, University of California Los Angeles (UCLA), and our own institution. Herein, pathologic features important in outcome prediction for patients treated surgically for the 3 most common subtypes of RCC are reviewed, including histologic subtype, sarcomatoid and rhabdoid differentiation, the TNM n

Corresponding author. E-mail address: [email protected] (J.C. Cheville).

http://dx.doi.org/10.1053/j.semdp.2015.02.008 0740-2570/& 2015 Elsevier Inc. All rights reserved.

classification, primary tumor size, grade, and histologic coagulative tumor necrosis. We then examine how these features have been incorporated into postoperative prognostic or outcome prediction models developed by several institutions and used in clinical practice. Throughout, the distributions of pathologic features and their impact on patient outcome are summarized using data from 4380 patients in the Mayo Clinic Nephrectomy Registry treated with radical or partial nephrectomy for clear cell (n ¼ 3521), papillary (n ¼ 627), and chromophobe (n ¼ 232) RCC between 1970 and 2009.

Pathologic features used in outcome prediction models Histologic subtype In 1997, an international consensus conference on RCC sponsored by the Union Internationale Contre le Cancer

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Papillary RCC

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Clear cell RCC

40

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Fig. 1 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 74% (73–76; 2101), 91% (89–93; 448), and 89% (85–93; 157) for patients with clear cell, papillary, and chromophobe RCC, respectively. There are significant differences in outcome among the 3 subtypes (p o 0.001) but not between patients with papillary and chromophobe RCC (p ¼ 0.54). (UICC) and the American Joint Committee on Cancer (AJCC) outlined recommendations for the classification of RCC.4 The UICC/AJCC adopted the classification system originally proposed at the Heidelberg conference in 1996.5 The participants at both the conferences proposed that RCC be categorized as clear cell, papillary, chromophobe, and collecting duct RCC subtypes. In addition, RCC that does not fall into one of these 4 groups is classified as RCC, not otherwise specified. Since that time, a number of additional less common histologic subtypes have been recognized, yet the 3 most common subtypes of clear cell, papillary, and chromophobe RCC continue to comprise over 90% of RCCs.6 Significant differences in pathologic features exist among the 3 most common histologic subtypes. Specifically, patients with clear cell RCC present with higher grade and stage tumors than patients with papillary and chromophobe RCC. In addition, papillary RCC is significantly more likely to be multifocal and exhibit tumor necrosis compared with the other subtypes. There are also significant differences in outcome among the histologic subtypes.7–13 The cancer-specific survival rates at 5 years following surgery for patients with clear cell, papillary, and chromophobe RCC in our registry are 74%, 91%, and 89%, respectively (Fig. 1; p o 0.001). Patients with clear cell RCC have a worse prognosis compared with patients with papillary and chromophobe RCC, and there is not a statistically significant difference in outcome between patients with papillary and chromophobe RCC (p ¼ 0.54). In our experience, clear cell RCC is a significant predictor of metastases and cancer-specific death in multivariable analyses that adjust for tumor size, stage, and grade.7,8 However, cystic clear cell RCC, which accounts for 4% of clear cell RCC in our registry, is invariably associated with an excellent outcome regardless of the type of surgical intervention.14 Given the predominance of clear cell RCC in previous surgical series and the lack of central pathologic review in some contemporary studies, differences in outcome among the histologic subtypes stratified by tumor stage and grade

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have not been apparent. With larger numbers and standardized pathologic review, significant differences in outcome are evident even after stratifying by stage and grade.7,8 For example, in our registry, the 5-year cancer-specific survival rates for grade 3 clear cell and papillary RCC are 61% and 84%, respectively (p o 0.001), indicating that grade 3 papillary RCC does not follow the same clinical course as grade 3 clear cell RCC. Furthermore, the impact of other prognostic features such as tumor necrosis differs among the histologic subtypes. For example, in our registry, the hazard ratios for the associations of tumor necrosis with death from RCC among patients with clear cell and chromophobe RCC are 5.8 (p o 0.001) and 5.0 (p o 0.001), respectively, whereas the hazard ratio among patients with papillary RCC is 2.2 (p ¼ 0.001), demonstrating that the magnitude of the effect of tumor necrosis on outcome varies by histologic subtype.

Sarcomatoid and rhabdoid differentiation Sarcomatoid RCC was first described by Farrow et al.15 as an RCC containing enlarged pleomorphic or malignant spindle cells reminiscent of a sarcoma. In the past, sarcomatoid RCC was considered a distinct subtype; however, this was dropped from the 1997 UICC/AJCC and Heidelberg classification since sarcomatoid differentiation can arise among all histologic subtypes.4,5 Previous studies indicate that the presence of sarcomatoid differentiation in RCC is associated with a dismal prognosis, with a median survival following diagnosis of less than 1 year.16–24 As a result of the small number of patients with sarcomatoid differentiation and the aggressive nature of these tumors, few studies have identified prognostic factors for patients with sarcomatoid differentiation, although TNM stage, performance status, tumor size, tumor necrosis, and presence of metastases have been associated with outcome in various studies.16–24 The incidence of sarcomatoid differentiation in RCC in our registry is 4%. Cancer-specific survival rates at 2 years following surgery for patients with clear cell, papillary, and chromophobe RCC with sarcomatoid differentiation are 28%, 56%, and 42%, respectively, compared with 86%, 95%, and 96%, respectively, for patients with clear cell, papillary, and chromophobe RCC without sarcomatoid differentiation. In studies by Ro et al.,17 de Peralta-Venturina et al.,21 Mian et al.,22 and Cheville et al.,23 the underlying histologic subtype was not significantly associated with outcome among patients with sarcomatoid differentiation, in contrast to the effect of subtype on outcome among patients without sarcomatoid differentiation. Several studies have shown that metastases at the time of surgery and tumor necrosis are significantly associated with outcome among patients with sarcomatoid differentiation.17,22,23 Shuch et al.24 reported that Eastern Cooperative Oncology Group performance status, tumor size, and metastases were independent predictors of outcome in 104 patients with sarcomatoid differentiation; microvascular invasion, percentage of sarcomatoid differentiation, and percentage of tumor necrosis were strongly associated with outcome but were not independent predictors. Similarly, other studies have found a significant association between

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the amount of sarcomatoid differentiation and outcome in a univariate setting, but not after adjusting for stage.16,20 Other investigators have not identified a significant association between the amount of sarcomatoid differentiation and outcome even in a univariate setting.19 The most recent data from over 200 patients treated surgically for RCC with sarcomatoid differentiation at Mayo Clinic show that the amount of sarcomatoid differentiation is an independent predictor of cancer-specific death after multivariable adjustment for the TNM classification and tumor necrosis.25 Specifically, each 10% increase in the amount of sarcomatoid differentiation is associated with a 6% increased risk of death from RCC; patients whose tumors contained 30% or more sarcomatoid differentiation have a 50% increased risk of death from RCC. Therefore, we believe that it is critical to report both the presence of and percentage of sarcomatoid differentiation in RCC. Rhabdoid differentiation in RCC is characterized by the presence of tumor cells that resemble rhabdomyoblasts with eccentric large nuclei, with prominent nucleoli, and abundant eosinophilic cytoplasm with central inclusion. Like sarcomatoid differentiation, rhabdoid differentiation can occur in association with any histologic subtype, and patients typically present with higher stage tumors and experience poor outcomes.26–30 Currently, the International Society of Urological Pathology (ISUP) recommends the reporting of rhabdoid differentiation in RCC, with the presence of rhabdoid differentiation indicating a grade 4 RCC.31 However, to date, there is little evidence to support quantifying the amount of rhabdoid differentiation.

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100

2010 TNM I

80

II

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40

20 IV

0

0

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Fig. 2 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 97% (96–98; 1807), 84% (81–87; 414), 59% (55–62; 409), and 16% (13–19; 76) for patients with 2010 TNM stage group I, II, III, and IV, respectively (p o 0.001). tumor 4 cm or less in greatest dimension, and the pT1b classification is defined as a tumor more than 4 cm but not more than 7 cm in greatest dimension. The subclassification is supported by outcome data from multiple institutions.35–37 In 2010, pT2 tumors confined to the kidney were also subclassified into 2 categories: the pT2a classification is defined as a tumor more than 7 cm but not more than 10 cm in greatest dimension, and the pT2b classification is defined as a tumor more than 10 cm.33 Among patients with pT2 RCC in our registry, the 5-year cancer-specific survival rate for patients with pT2a tumors is 75% compared with 69%

TNM classification The primary tumor (T), regional lymph nodes (N), and distant metastases (M) classification for RCC is critical to outcome prediction in patients with RCC and is a component of all postoperative algorithms for primary RCC. The classification standardizes the description of tumor extent, improves communication between pathologists and clinicians, and guides postoperative follow-up. For simplification, the TNM classification can be divided into 4 stage groups.32,33 The association of the TNM stage groups with cancer-specific survival for patients in our registry is illustrated in Fig. 2. Although recognized as an excellent prognostic factor for patients with RCC since its introduction in 1978, the TNM classification has undergone multiple modifications, most recently in 2010.33 The AJCC has published the criteria for the continuous improvement of the TNM classification, which include the following: (1) clinical relevance for assessment, treatment, and outcome; (2) presence of evidence for improved prognostic ability; and (3) acceptance by the members of the AJCC TNM committee.34 The distributions of the 2010 TNM classification and stage groups by histologic subtype for patients in our registry are summarized in Table 1. Each component of the classification is explored in greater detail below.

Primary tumor (T) In 2002, the AJCC subclassified pT1 tumors confined to the kidney into 2 categories: the pT1a classification is defined as a

Table 1 – The 2010 TNM classification and stage groups for 4380 patients with clear cell, papillary, and chromophobe RCC in the Mayo Clinic Nephrectomy Registry, n (%). Clear cell n ¼ 3521

Papillary n ¼ 627

Chromophobe n ¼ 232

Primary tumor pT1a 1069 (30) pT1b 809 (23) pT2a 373 (11) pT2b 168 (5) pT3a 795 (23) pT3b 205 (6) pT3c 30 (1) pT4 72 (2)

314 157 49 38 54 10 2 3

71 (31) 50 (22) 37 (16) 42 (18) 26 (11) 3 (1) 0 3 (1)

Regional lymph nodes pNX 2693 (76) pN0 645 (18) pN1 183 (5)

554 (88) 41 (7) 32 (5)

180 (78) 44 (19) 8 (3)

Distant metastases M0 3060 (87) M1 461 (13)

606 (97) 21 (3)

223 (96) 9 (4)

Stage group I II III IV

464 81 60 22

120 (52) 74 (32) 28 (12) 10 (4)

1801 437 787 496

(51) (12) (22) (14)

(50) (25) (8) (6) (9) (2) (o1) (o1)

(74) (13) (10) (4)

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sinus.40 The ISUP Consensus Conference defined renal sinus fat invasion as tumor involving renal sinus fat, loose connective tissue, or any sinus-based endothelial-lined space.43

2010 pT1a

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Regional lymph nodes (N) pT3a

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pT4

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Fig. 3 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 98% (97–99; 1108), 89% (87–91; 722), 75% (71–80; 107), 69% (63–75; 140), 53% (50–56; 373), 31% (26–39; 56), 36% (22–59; 10), and 10% (5–20; 7) for patients with 2010 primary tumor classifications of pT1a, pT1b, pT2a, pT2b, pT3a, pT3b, pT3c, and pT4 RCC, respectively (p o 0.001). for patients with pT2b tumors, supporting the pT2 subclassification. Several other important changes were made in the classification of pT3 tumors from 2002 to 2010. The 2010 pT3a classification includes tumors that grossly extend into the renal vein or its segmental (muscle-containing) branches (previously 2002 pT3b) or invade the perinephric or renal sinus fat. The 2010 pT3b classification encompasses tumors that extend into the inferior vena cava below the diaphragm, while pT3c classification includes tumors that involve the vena cava above the diaphragm or invade the wall of the vena cava. A pT4 tumor invades beyond Gerota's fascia, including direct extension to the ipsilateral adrenal gland. The association of the pT classification with cancer-specific survival for patients in our registry is illustrated in Fig. 3. Although the pT classification provides important prognostic information, its definition continues to evolve. In the 2010 pT classification, there is no distinction made between tumors with isolated renal vein involvement and tumors that exhibit both renal vein involvement and perinephric/renal sinus fat invasion— both are classified as pT3a. In our experience, patients with renal vein involvement and perinephric/renal sinus fat invasion are nearly twice as likely to die from RCC compared with patients with only renal vein involvement (hazard ratio ¼ 1.87; p o 0.001). Over the past several years, the prognostic importance of renal sinus invasion has been established.38–42 The renal sinus encompasses the hilar fat and draining vessels and lymphatics between the kidney proper and pelvicalyceal system. Patients whose tumors invade the renal sinus have a significantly worse cancer-specific survival than patients with confined tumors, and although reviewed retrospectively, patients treated at Mayo Clinic with tumors classified as pT3a because of renal sinus fat invasion have a worse prognosis compared with patients with tumors classified as pT3a because of perinephric fat invasion only (hazard ratio ¼ 1.65; p ¼ 0.017).41 Involvement of the renal sinus increases with increasing tumor size such that greater than 90% of tumors that are 7 cm or larger have involvement of the renal

The 2010 regional lymph node classification for RCC is based on the number of positive renal hilar, caval (paracaval, precaval, and retrocaval), interaortocaval, and aortic (paraaortic, preaortic, and retroaortic) lymph nodes identified during lymphadenectomy. The pNX classification indicates that no regional lymph nodes were resected; pN0 indicates that one or more regional lymph nodes were resected, but none contained metastases; and pN1 indicates the presence of metastases in one or more lymph nodes.33 The initial spread of tumor occurs through the interaortocaval lymph nodes for left-sided tumors and the aortic lymph nodes for right-sided tumors. Positive lymph nodes outside of the hilar, caval, interaortocaval, and aortic regions are considered a distant metastasis (pM1). It has been shown in multiple series that regional lymph node involvement is associated with poor outcome among patients with RCC.37,44–46 The role of lymphadenectomy in the treatment of RCC is unclear, largely because of the low frequency of identified lymph node metastases and the lack of a standardized protocol for lymphadenectomy. Blute et al.47 and Crispen et al.48 identified that grade 3 or 4 RCC, presence of sarcomatoid differentiation, tumor size of 10 cm or greater, 2002 tumor stage pT3 or pT4, and tumor necrosis were significantly associated with regional lymph node involvement in a multivariable analysis. These features can be determined by pathologic gross and frozen section histologic examination to identify candidates for extended lymph node dissection at the time of nephrectomy. Mayo Clinic urologic oncologists advocate the following template for an extended lymph node dissection: for right-sided tumors, the precaval, paracaval, retrocaval, and interaortocaval nodes from the crus of the diaphragm to the bifurcation of the great vessels and for left-sided tumors, the preaortic, paraaortic, and retroaortic nodes from the crus to the bifurcation. A properly performed standardized dissection for patients with high-risk features will improve staging, provide greater prognostic information, and improve clinical trial design for these high-risk patients. While it is clear that determination of regional lymph node involvement provides important staging and prognostic information, there are limited data regarding the association of pathologic features of the lymph node metastases with patient outcome. Data from our institution indicate that outcome is not significantly different between patients with one and multiple involved lymph nodes. Patients are more accurately stratified by the presence of tumor extension outside the capsule of the lymph node rather than the number of regional lymph nodes that are positive.49 We believe that a regional lymph node classification based on the presence or absence of lymph node metastases (pNX, pN0, and pN1) with a notation regarding the presence or absence of extranodal extension would improve the prognostic accuracy of the current regional lymph node classification.

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Distant metastasis (M) The proportion of patients with widely disseminated disease at the time of surgery can range from 11% currently at Mayo Clinic to as high as 56% at UCLA.37 Distant metastatic disease at the time of surgery portends a poor prognosis for all histologic subtypes of RCC.43 The median cancer-specific survival (i.e., the point in time at which the estimated cancer-specific survival rate reaches 50%) for patients with metastatic clear cell, papillary, and chromophobe RCC in our registry occurs at 1.2, 1.0, and 0.5 years, respectively. To our knowledge, no studies have investigated the association of pathologic features of the distant metastases with patient outcome. Such an evaluation would require resection of the metastatic disease, but it is well documented that complete resection of all metastatic lesions has been shown to result in improved patient outcome.50–52

Primary tumor size Although primary tumor size is incorporated into the TNM classification,33 studies from our institution have shown that size is an independent prognostic factor for patients treated surgically for RCC, even after accounting for both the TNM classification and grade.44–46 The impact of tumor size on patient outcome assessed as part of the TNM classification or assessed independently is well documented. However, contemporary literature on the relationship of tumor size to other pathologic features, including histologic subtype and grade, has been limited. Frank et al.53 showed that as the size of a malignant tumor increases, the likelihood that it is clear cell and high-grade increases. For example, among patients with tumors less than 5 cm in our registry, 75% have clear cell, 20% have papillary, and 5% have chromophobe RCC. In contrast, among patients with tumors more than 10 cm, 83% have clear cell, 8% have papillary, and 9% have chromophobe RCC. Only 23% of clear cell RCC tumors less than 5 cm are high-grade compared with 80% of tumors more than 10 cm. The incidence of tumor necrosis also increases as tumor size increases, regardless of histologic subtype. The proportion of necrotic clear cell RCC increases from 7% for tumors less than 5 cm to 58% for tumors more than 10 cm, while the proportion of necrotic papillary RCC similarly increases from 32% to 64%.

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that the classification and pathology of RCC were poorly understood. They reported a significant association of the 4 grades with survival. In 1982, Fuhrman, using a grading system very similar to that by Skinner et al., reported on 85 patients with at least 5 years of follow-up and showed an association of grade with patient outcome; however, unlike Skinner et al. who found a significant difference in outcome between each grade, Fuhrman et al.56 reported a significant difference between grade 1 and grade 2/3 and between grade 2/3 and 4. There was no statistically significant difference in outcome between patients with grade 2 and 3 tumors. Despite this limitation and the relatively small sample studied, the Fuhrman grade became the universally accepted grading system for RCC. Over time, as our knowledge of the pathology of RCC grew, including our understanding of histologic subtypes, and larger, more comprehensive analyses of patient cohorts were reported, it became clear that there were several limitations to the Fuhrman grading system.57 The assessment of nuclear features of the Fuhrman grading system show significant interobserver variation, and the size of the highest-grade area that determines grade was not well defined. In addition, the Fuhrman grade is not appropriate for chromophobe RCC, a tumor that in most instances would be considered high Fuhrman grade despite relatively indolent behavior.58 In 2012, the ISUP Consensus Conference defined a grading system based on nucleolar features to be applied to clear cell and papillary RCC.31 In this system, ISUP grade 1 tumors are defined as having inconspicuous or absent nucleoli at 400  magnification; ISUP grade 2 tumors have visible nucleoli at 200  ; ISUP grade 3 tumors have distinct visible nucleoli at 100  ; and ISUP grade 4 tumors show marked nuclear atypia, contain tumor giant cells, or exhibit sarcomatoid or rhabdoid differentiation. There was no consensus on the size of the highest-grade area to be used to grade RCC, so this issue remains unresolved. The distribution of ISUP grade for patients with clear cell and papillary RCC in our registry is summarized in Table 2. Cancer-specific survival by ISUP grade for patients with clear cell and papillary RCC is illustrated in Figs. 4 and 5, respectively. In our analyses, the highest-grade area had to encompass at least one power field (400  ). It was the consensus decision of the ISUP not to grade chromophobe RCC until more data are accumulated.

Histologic coagulative tumor necrosis Grade The earliest studies of grading in RCC were performed in 1932 by Hand and Broder54 at the Mayo Clinic. This study along with several subsequent reports showed an association of grade assessed by nuclear features with patient outcome. A landmark article was published in 1971 by Skinner et al.55 that defined several features of grading RCC, which remain in use today. The study was composed of 309 patients treated by nephrectomy and followed up for at least 6 years. The grading system was a 4-tier system that relied solely on nuclear features, assessed the highest-grade area in a tumor, and reported the association of grade and outcome by RCC morphotypes. Skinner et al. defined 3 morphotypes (clear cell, spindle cell, and granular) but recognized at the time

Histologically, coagulative tumor necrosis is characterized by homogenous clusters and sheets of degenerating and dead cells with an abrupt transition to viable tumor. The pattern of Table 2 – ISUP grade for patients with clear cell and papillary RCC in the Mayo Clinic Nephrectomy Registry, n (%). ISUP grade

Clear cell n ¼ 3521

Papillary n ¼ 627

1 2 3 4

360 1496 1344 321

12 356 246 13

(10) (42) (38) (9)

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Fig. 4 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 96% (94–98; 286), 92% (91–94; 1084), 61% (58–64; 669), and 25% (20–30; 62) for patients with ISUP grades 1, 2, 3, and 4 clear cell RCC, respectively (p o 0.001). necrosis may be focal, with small islands of necrosis in the tumor or confluent with larger areas of interconnecting necrotic areas. In our registry, tumor necrosis is present in 28%, 42%, and 19% of clear cell, papillary, and chromophobe RCC, respectively. The viable tumor adjacent to either focal or confluent necrosis in clear cell and chromophobe RCC is typically high-grade, although this is not necessarily true for papillary RCC. For example, 94% of necrotic clear cell RCC and 77% of necrotic chromophobe RCC tumors in our registry have grade 3 or 4 components, compared with 54% of necrotic papillary RCC. Microscopic coagulative tumor necrosis in clear cell RCC has been shown to correlate with patient outcome in almost all studies in which it was assessed.7,10,11,59–62 In studies where necrosis was not associated with outcome, tumors were extensively necrotic, suggesting a different mechanism of cell death such as infarction that does not have the same association with outcome as coagulative tumor necrosis.63,64 Our studies have focused on histologic coagulative tumor

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necrosis, not gross tumor necrosis. The evaluation of gross tumor necrosis may not be reliable since RCC tumors tend to be grossly heterogeneous due to degenerative features such as hemorrhage, fibrosis, and edema. In addition, in our experience, coagulative tumor necrosis is often a focal or multifocal process that cannot be seen grossly, and by definition, the process of coagulative tumor necrosis can only be assessed microscopically. Therefore, if coagulative tumor necrosis is suspected grossly, it should be confirmed with microscopic evaluation. Likewise, tumor necrosis identified by radiological examination should be confirmed microscopically, as many of the radiological features of RCC considered “necrotic” may in fact be degenerative in nature. There are several degenerative features of RCC that need to be distinguished from histologic coagulative tumor necrosis. Edema is a common feature of low-grade clear cell RCC and is characterized by loose edematous fibrous tissue devoid of tumor cells. Hemorrhage or the presence of extravasated red blood cells is another common feature of RCC and is characterized by red blood cells in the tumor interstitium and can be associated with hyalinization. Dense eosinophilic fibrous tissue or hyalinized connective tissue is one of the most common degenerative features of clear cell RCC, but it should not be mistaken for histologic coagulative tumor necrosis. Recently, a novel grading system was reported that combined coagulative tumor necrosis and ISUP grade.65 In clear cell RCC, this novel grading system outperformed the ISUP grading system when cases were stratified according to the TNM classification. The definition of this novel grade for clear cell RCC patients currently in our registry is shown in Table 3, and its association with cancer-specific survival is illustrated in Fig. 6. The combination of tumor necrosis and ISUP grade did not improve upon the ISUP grading system for papillary RCC. It is important to note that studies report a wide variance in the frequency of necrosis in clear cell RCC, ranging from 27% to 60%. In the report that identified necrosis in 60% of tumors,66 the presence of necrosis was not a significant predictor of survival; therefore, a standardized definition of coagulative tumor necrosis is necessary so that the appropriate prognostic information is gained from its assessment.

ISUP Grade 1 in Papillary RCC

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Prognostic algorithms and nomograms

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Fig. 5 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 100% (100–100; 8), 97% (96–99; 281), 84% (80–89; 158), and 27% (11–69; 1) for patients with ISUP grades 1, 2, 3, and 4 papillary RCC, respectively (p o 0.001).

Several groups have sought to improve the ability to accurately predict outcome for patients treated surgically for RCC by combining known prognostic factors into a single system (Table 4).37,44–46,67–69 Prognostic algorithms and nomograms can be used to counsel patients, determine the need for adjuvant therapy, stratify patients for clinical trials, and develop appropriate postoperative surveillance programs tailored to a patient's risk for disease progression. These outcome prediction models utilize a combination of pathologic features including histologic subtype, the TNM classification, tumor size, grade, and histologic coagulative tumor necrosis to predict recurrence, metastases, or death from RCC. We highlight the most commonly clinically applied algorithms and nomograms that are based primarily on pathologic features.

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Table 3 – Novel grade incorporating ISUP grade and tumor necrosis for 3521 patients with clear cell RCC in the Mayo Clinic Nephrectomy Registry. ISUP grade

Necrosis

Sarcomatoid or rhabdoid

Novel grade

n (%)

1 1 2 2 3 3 4 4 4 4

No Yes No Yes No Yes No No Yes Yes

No No No No No No No Yes No Yes

1 1 1 2 2 3 3 4 4 4

359 1 1442 54 708 636 13 19 94 195

Memorial Sloan-Kettering Cancer Center Kattan et al.67 were part of an early effort to develop a nomogram to predict treatment failure (clinical evidence of recurrence or death from RCC) using a cohort of 601 patients treated with radical or partial nephrectomy for clinically localized clear cell, papillary, and chromophobe RCC between 1989 and 1998. There was recurrence in 64 patients and 2 patients died from RCC; the median follow-up for the remaining 535 patients was 40 months. Their nomogram includes symptoms at presentation (incidental, local, or systemic), histologic subtype, tumor size, and the 1997 primary tumor classification.31 Each feature is assigned points ranging from 0 to 100, which are then totaled and used to obtain the probability of remaining free of recurrence or death from RCC at 5 years following surgery. For example, a patient with a 5cm (þ25), 1997 pT3b (þ30), clear cell tumor (þ40) with systemic symptoms at presentation (þ30) would have a total score of 125 and an associated 5-year recurrence-free survival rate of 60%. In contrast, a patient with a 5-cm (þ25), 1997 pT1 (þ0), papillary tumor (þ10) discovered incidentally (þ0) would have a total score of only 35 and an associated recurrencefree survival rate of 96%.

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80

2 60

3

40

4

20

0 0

2

4

6

8

10

Years

Fig. 6 – Cancer-specific survival rates (95% CI, number still at risk) at 5 years following surgery are 94% (92–95; 1334), 77% (74–81; 477), 43% (39–47; 231), and 24% (19–29; 59) for patients with novel grades 1, 2, 3, and 4 clear cell RCC, respectively (p o 0.001). p-values for comparisons of cancerspecific survival between novel grades 1 and 2, between 2 and 3, and between 3 and 4 are all o0.001.

(10) (o1) (41) (2) (20) (18) (o1) (1) (3) (6)

One advantage of the nomogram developed by Kattan et al. is that it recognizes the importance of stratifying patient outcome by histologic subtype, and therefore, it can be used for all patients with localized RCC treated surgically. However, there are limitations. First, only histologic subtype and tumor size were statistically significantly associated with recurrence in a multivariable setting. Kattan et al. did not remove symptoms at presentation and primary tumor classification from the nomogram, since they believed these exclusions would diminish the predictive accuracy of the model. However, the presence of systemic symptoms adds 30 points to a patient's total, on par with a 6-cm tumor, even though symptoms were not found to be significantly associated with recurrence. In addition, a patient with a pT2 tumor is assigned 20 points, while a patient with a pT3a tumor is assigned only 10 points, despite the recognized importance of fat invasion in RCC.38–42 Second, grade is not a component of the nomogram, as papillary RCC was not assigned a grade; therefore, this feature could not be assessed in their analysis, despite their finding that grade is an important prognostic factor among patients with both papillary and clear cell RCC. Their rationale at the time for not grading papillary RCC was based on the lack of a significant association with outcome in some studies. However, as previously discussed, multiple large studies have shown an association of grade and outcome in patients with papillary RCC, including a recent study of nearly 400 patients treated surgically for papillary RCC.70 In 2005, Sorbellini et al.68 introduced a nomogram to predict disease recurrence using 701 patients with clear cell RCC, of whom 72 developed recurrence. The nomogram was based on tumor size, the 2002 primary tumor classification, Fuhrman grade, necrosis, vascular invasion, and symptoms at presentation, and it was externally validated and appeared accurate in predicting disease recurrence with a concordance index of 0.82. However, in the development of the nomogram, only Fuhrman grade and microvascular invasion were significantly associated with recurrence, while the other features in the nomogram (tumor size, necrosis, primary tumor classification, and symptoms) were not. However, these statistically insignificant features were included in the nomogram with the rationale that excluding insignificant features exaggerates the effects of the remaining variables. Potential limitations with the development of this nomogram include that most patients (63%) had pT1 tumors; necrosis was

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Table 4 – Outcome prediction algorithms and nomograms in clinical practice. Institution

Year

Extent of disease

Histologic subtype

Features in nomogram/algorithm

MSKCC66 MSKCC67 UCLA37

2001 2005 2001

All Clear cell All

Stage, tumor size, subtype, and symptoms Stage, tumor size, grade, necrosis, microvascular invasion, and symptoms Stage, grade, and performance status

UCLA69

2002

All

Stage, grade, and performance status

Mayo Clinic44 Mayo Clinic46

2002

Localized Localized Localized, metastatic Localized, metastatic Localized, metastatic Metastatic

Clear cell

Stage, tumor size, grade, and necrosis

Clear cell

Symptoms, location of, number of, and completeness of resection of metastases, tumor thrombus level, grade, and necrosis

2005

reported in only 3% of tumors; the absence of necrosis, as opposed to its presence, was assigned points towards an increased risk of recurrence; and relatively few patients experienced the outcome of interest. In addition, the external validation was limited to 200 patients, of whom only 26 developed recurrence.

et al. did not identify differences in outcome between patients with clear cell and chromophobe RCC, contrary to published reports from multiple institutions.5,8,10,11 In fact, the numbers of patients with clear cell and chromophobe RCC are not delineated in their report. Second, sarcomatoid RCC was analyzed as a distinct histologic subtype, even though sarcomatoid changes have been found among all histologic subtypes of RCC. Despite these discrepancies, histologic subtype remained a significant predictor of survival among patients with metastatic RCC even after adjusting for the UISS, as were a number of other features including the number of symptoms, weight loss, and inferior vena cava involvement. The inclusion of these features, at least for metastatic patients, would likely improve the prognostic ability of the UISS. Over half (56%) of the patients in the UCLA series presented with metastatic RCC, resulting in a high percentage of patients in the UISS IV category (46%). In contrast, only 11% of patients currently in our registry have distant metastases at the time of surgery, and accordingly, only 8% of patients fall into the UISS IV category. The majority (53%) of Mayo Clinic patients are placed in the UISS II category, a category that encompasses a broad range of patients with varied pathologic features. For example, the 5-year overall survival rates for UISS II patients with TNM stage group II disease and

UCLA Zisman et al.37 proposed an algorithm to predict overall survival using a cohort of 477 patients treated with radical or partial nephrectomy for RCC between 1989 and 1999. The majority (76%) of patients with metastatic RCC were treated with recombinant interleukin 2-based immunotherapy. At the conclusion of their study, 242 patients had died; the median follow-up for the remaining 235 patients was 37 months. The UCLA Integrated Staging System (UISS) uses the 1997 TNM stage groups,31 Fuhrman grade,68 and Eastern Cooperative Oncology Group (ECOG) patient performance status to classify patients into 5 groups. The combinations of the features that comprise the 5 groups of the UISS, as well as estimated 2-year and 5-year overall survival rates, are summarized in Table 5. One limitation of the algorithm by Zisman et al. is that their tumors were not assigned a histologic subtype. First, Zisman Table 5 – Overall survival by the UISS classification. UISS

1997 TNM stage

Fuhrman grade

ECOG

2-Year survival

5-Year survival

%

SE

%

SE

I

I

1 and 2

0

96

2.5

94

2.5

II

I I II III III

1 and 2 3 and 4 Any Any 1

1 or more Any Any 0 1 or more

89

3.8

67

6.4

III

III IV IV IV

2–4 1 and 2 3 and 4 1–3

1 or more 0 0 1 or more

66

6.5

39

2.8

42

3.5

23

3.1

IV

4

1 or more

9

6.2

0

4.0

IV

V

Adopted with permission from Zisman et al.37

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Table 6 – The Mayo Clinic SSIGN score. Feature

Score

1997 Primary tumor classification pT1 pT2 pT3a, pT3b, and pT3c pT4

0 1 2 0

1997 Regional lymph nodes pNX and pN0 pN1 and pN2 Distant Metastases pM0 pM1

0 2 0 4

Primary tumor size o5 cm 5 cm or more

0 2

Grade 1 and 2 3 4

0 1 3

Histologic coagulative tumor necrosis Absent Present

0 2

Adapted with permission from Frank et al.44

grade 1, 2, 3, and 4 tumors are 87%, 84%, 70%, and 25%, respectively (p o 0.001). Similarly, the 5-year overall survival rates for UISS II patients with TNM stage group III disease and grade 1, 2, 3, and 4 tumors are 84%, 69%, 55%, and 31%, respectively (p o 0.001). Therefore, Mayo Clinic patients classified in the UISS II category can have 5-year overall survival rates ranging from 25% to 87%. As a result, the UISS may be more generalizable to institutions that treat patients with more advanced disease. In 2002, Zisman et al.,69 using a cohort of patients with similar characteristics as the one used to develop the UISS scoring system, condensed the 5 UISS groups into low-, intermediate-, and high-risk categories.

Mayo Clinic Frank et al.44 developed an algorithm to predict cancerspecific survival using a cohort of 1801 patients treated with radical nephrectomy for clear cell RCC between 1970 and 1998. At the conclusion of the study, 1152 patients had died, including 652 deaths from RCC; the median follow-up for the remaining 649 patients was 8 years. The Mayo Clinic SSIGN (Stage, Size, Grade, and Necrosis) score incorporates the 1997 TNM classification,31 primary tumor size, grade, and histologic coagulative tumor necrosis, all the features that were found to be significantly associated with death from RCC on multivariable analysis. The score is calculated as 1 (pT2) þ 2 (pT3a, pT3b, and pT3c) þ 2 (pN1 and pN2) þ 4 (pM1) þ 2 (tumor size of 5 cm or more) þ 1 (grade 3) þ 3 (grade 4) þ 2 (necrosis), and 0 otherwise (Table 6). For example, a patient with pT1, pN0, pM0 clear cell RCC who has a grade 1 tumor less than 5 cm that shows no evidence of necrosis has a score of 0. A patient with pT3b, pN0, pM0 clear cell RCC with a

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Table 7 – Cancer-specific survival rates (%) by the SSIGN Score for 2671 patients treated with radical nephrectomy for clear cell RCC in the Mayo Clinic Nephrectomy Registry. SSIGN score

Year

0–1 2 3 4 5 6 7 8 9 10þ

1

3

5

7

10

100 100 98 97 92 89 80 66 72 49

100 97 92 89 77 71 52 40 38 22

99 95 91 81 98 61 42 25 28 10

97 92 87 72 61 55 34 16 23 6

96 89 79 68 54 46 29 13 18 5

grade 3 tumor 5 cm or greater with necrosis has a score of 7. To illustrate the effect of distant metastases, a patient with pT3b, pN0, pM1 disease with a necrotic grade 3 tumor 5 cm or greater has a score of 11. The cancer-specific survival rates at 1, 3, 5, 7, and 10 years following radical nephrectomy for patients with clear cell RCC currently in our registry are summarized in Table 7 and illustrated in Fig. 7. At 5 years following radical nephrectomy, patients with scores of 0, 7, and 11 have estimated cancer-specific survival rates of 96%, 42%, and 13%, respectively. The SSIGN score has limitations as well. First, the SSIGN score only applies to patients with clear cell RCC. Creating a single algorithm for all histologic subtypes would have to account for the interaction between histologic subtype and tumor necrosis, and potentially between histologic subtype and other pathologic features as well, resulting in a complex algorithm. Given this, and the observation that papillary and chromophobe RCCs represent less-aggressive tumors compared to the more aggressive clear cell RCC, we believe it is inappropriate to use a single prognostic algorithm for all histologic subtypes. Rather, separate algorithms for these less common subtypes should be developed and published. Second, the SSIGN score could be improved by incorporating recent changes to the TNM classification. 100

0-1 2

Cancer-specific Survival, %

180

80

3 4

60 5 6 40 7 20

9 8 10+

0 0

2

4

6

8

10

Years

Fig. 7 – Cancer-specific survival for patients treated with radical nephrectomy for clear cell RCC by the Mayo Clinic SSIGN Score. The estimated cancer-specific survival rates are summarized in Table 7.

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In 2005, Leibovich et al.46 from the Mayo Clinic introduced a scoring algorithm to predict outcome for patients with metastatic clear cell RCC. The study consisted of 727 patients treated with radical nephrectomy for clear cell RCC between 1970 and 2000 who had metastases at nephrectomy (n ¼ 285) or subsequently developed metastases (n ¼ 442). The algorithm is based on a number of pathologic features of the primary tumor including grade, coagulative tumor necrosis, and tumor thrombus level. In addition, constitutional symptoms at presentation, metastatic site, number of metastases, years from nephrectomy to metastases, and complete resection of metastases were included in the algorithm. Like the SSIGN score, the Leibovich score is based on all features found to be predictive of outcome on multivariable analysis, and each feature in the algorithm is given a score that is totaled to provide an estimated cancer-specific survival rate. This algorithm is a useful tool for managing patients with metastatic clear cell RCC and for patient stratification in clinical trials.

Conclusion Accurate histologic subtyping of RCC is critically important and should be considered in algorithms and nomograms developed as prognostic tools for the patient and clinician. The TNM classification, already a powerful prognostic factor, will continue to evolve. We recommend that each component of the classification be assessed and reported during pathologic examination so that the impact of each component on patient outcome can be studied and to more easily accommodate future modifications to the TNM classification. Our review also highlights the importance of assigning a grade based on standardized and reproducible criteria that reflect the nucleolar features within RCC as recommended by the ISUP. Lastly, it is increasingly evident that coagulative tumor necrosis and sarcomatoid differentiation are compelling prognostic factors, on par with grade, and should be routinely assessed.

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