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10.1245/ASO.2004.06.016
Annals of Surgical Oncology 11:71-77 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Effect of Papillary and Chromophobe Cell Type on Disease-Free Survival After Nephrectomy for Renal Cell Carcinoma

Stephen D. W. Beck, MD, Manish I. Patel, MD, Mark E. Snyder, BA, Michael W. Kattan, MD, Robert J. Motzer, MD, Victor E. Reuter, MD and Paul Russo, MD

From the Departments of Urology (SDWB, MIP, MES, PR), Epidemiology and Biostatistics (MWK), Medicine (RJM), and Pathology (VER), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Paul Russo, MD, Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-988-0760; E-mail: russop{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: The clinical staging of renal cortical tumors traditionally has not evaluated the potential effect of histological subtypes on survival. Evidence suggests that conventional clear cell renal cell carcinoma (RCC) and nonconventional clear cell RCC (chromophobe and papillary) have different metastatic potential. Using a large renal tumor database, we examined the effect of tumor histology on the pattern of metastasis and patient survival.

Methods: All patients with nonmetastatic renal cortical tumors undergoing partial or radical nephrectomy were identified from a renal tumor database between July 1989 and July 2002. Kaplan-Meier and Cox regression tests were used for statistical analysis.

Results: Analysis revealed 1057 patients: 794 with conventional clear cell RCC, 157 with papillary RCC, and 106 with chromophobe RCC. Metastasis occurred in 95 conventional clear cell RCC, 9 papillary RCC, and 6 chromophobe RCC with a median follow-up of 34.6, 43.0, and 33.2 months, respectively. Using log-rank analysis, chromophobe and papillary RCC were associated with an improved disease-free survival at 5 years (P = .009 and .015, respectively). Multivariate analysis revealed tumor size, stage, and chromophobe histology as significant variables for disease progression.

Conclusions: Renal cortical tumors have distinct histological subtypes with varying degrees of metastatic potential. Conventional clear cell RCC, which comprises two thirds of renal cortical tumors presenting with localized disease, has a less favorable outcome when compared with papillary and chromophobe RCC. Controlling for size and stage, chromophobe, and not papillary, RCC was a significant variable for disease progression compared with conventional clear cell RCC. Knowledge of renal cortical tumor histological subtype is critical for projecting prognosis, tailoring follow-up strategies, and designing clinical trials.

Key Words: Kidney cancer • Histology • Metastases • Staging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
In 1997, an international consensus was reached concerning the histological classification of renal cortical epithelial tumors.1 This Heidelberg classification identified distinct malignant histological subtypes: conventional clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, collecting duct RCC, and RCC unclassified. Oncocytoma and metanephric adenoma were classified as benign tumors.2,3 Of the histological subtypes, the three most common are conventional clear cell RCC, papillary RCC, and chromophobe RCC, with an incidence of 60% to 62%, 7% to 14%, and 6% to 11%, respectively.4

These histological subtypes of renal cortical tumors are associated with distinct chromosomal abnormalities. Conventional clear cell RCC, which originates from the proximal convoluted tubule, possesses the von Hippel–Lindau gene mutation and a deletion or partial deletion of chromosome 3p.5–9 Papillary RCC, which probably originates from the distal convoluted tubule, is characterized by trisomy of chromosomes 7, 16, and 17 and loss of chromosome Y.10–14 Chromophobe RCC, which arises from intercalated cells similar to oncocytoma, is associated with loss of chromosomes 1 and Y and by combined chromosomal losses that usually affect chromosomes 1, 6, 10, 13, 17, and 21.15–18

Despite recent evidence that these genetically distinct histological subtypes of renal cortical tumors seem to display differing degrees of metastatic potential in the clinical setting, the integration of the Heidelberg classification and the TNM staging system has not been extensively evaluated, and renal cortical tumors continue to be grouped under generic titles such as RCC or hypernephroma. The purpose of this study was to determine the effect of tumor histology on the pattern of metastases and disease-free survival for patients undergoing curative surgery for renal cortical neoplasms.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
A retrospective review was performed on all patients at our center who were undergoing partial or radical nephrectomy for cure from July 1, 1989, to July 1, 2002. Excluded from analysis were those patients with bilateral renal tumors (n = 59), metastatic tumors (n = 115), multiple tumor histologies (n = 52), or benign tumors (n = 140) and those with uncommon pathologic variants, including collecting duct carcinoma, medullary carcinoma, and unclassified carcinoma (n = 23). After these exclusions, 1057 patients were analyzed. The following pathologic features were recorded for each specimen: (1) histological subtype in accordance with the Heidelberg classification; (2) tumor size; and (3) pathologic stage, reported in accordance with the 2002 version of the tumor, node, metastasis staging system.19

Patients were followed up after surgery with physical examination, chest radiography, and serum creatinine determination every 6 months and with abdominal computed tomography scan annually. Survival time was calculated from the time of partial or radical nephrectomy to the last known follow-up.

The {chi}2 test was used to evaluate the difference in means between categorical groups, and the Kruskal-Wallis test was used to evaluate the difference in means between continuous groups. The Kaplan-Meier method was used to compare the cumulative survival of patients and the effect of histology on survival. The Cox proportional hazards regression model was used to determine the relative importance of pathology and clinical parameters on recurrence. Disease-free survival (DFS) was defined as alive without disease, and an event included any recurrence (local or distant) or any death. To determine the effect of histology on predicting outcome, the concordance index was calculated from a model that contained established markers (pathologic stage and tumor size) with and without histology.20


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
A total of 1057 tumors were classified as malignant: 794 conventional clear cell RCC (75%), 157 papillary RCC (15%), and 106 (10%) chromophobe RCC. The clinicopathologic features and prognostic information regarding the different subtypes are listed in Table 1.


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  		TABLE 1. Patient demographics and tumor characteristics (n = 1057)
 
Conventional (Clear Cell) RCC
The mean and median tumor diameter was 5.6 and 4.8 cm, respectively. Sixty percent of patients had stage pT1 tumors, and 8.4% had stage pT2 tumors. Metastasis occurred in 95 patients at a median follow-up of 34.6 months. The 5- and 10-year actuarial DFS for conventional cell RCC was 73.3% and 50.8%, respectively (Fig. 1).



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  		FIG. 1. Disease-free survival and histological subtype in renal cell carcinoma.

 
Papillary RCC
There were 157 papillary tumors with a mean and median tumor size of 4.8 and 4.0 cm, respectively. Three quarters of the patients were male, which was significantly different (P = .003) from either conventional clear cell RCC or chromophobe RCC. More tumors tended to be organ confined when compared with conventional clear cell RCC: 85% of papillary RCC were stages I and II, versus 68% for conventional clear cell RCC. At a median follow-up of 43.0 months, metastases were identified in nine patients. DFS for papillary RCC at 5 and 10 years was 81.7% and 67.6%, respectively.

Chromophobe RCC
Chromophobe RCC was the least common malignant tumor (10%). Patients presented at a younger age (mean age, 57.5 years; P < .003) than with either conventional or papillary subtypes. The mean and median tumor size of 7.1 and 6.0 cm, respectively, for chromophobe RCC was larger compared with the other histological subtypes (P < .001). Organ-confined disease (stage T2 or less) was observed in 74% of patients. There were six metastatic events at a median follow-up of 33.2 months. Five- and 10-year DFS for chromophobe RCC was 80.1% (Fig. 1).

Metastatic Site and Time to Recurrence
Lung and retroperitoneal lymph nodes were the most common sites of metastases for all three histological subtypes: 62% and 23% for conventional clear cell RCC, respectively; 44% and 22.2% for papillary RCC, respectively; and 50% and 33.3% for chromophobe RCC, respectively. Seventy-eight percent of conventional clear cell RCC and 77.7% of papillary RCC had only one metastatic site. For chromophobe RCC, two thirds of patients (four of six) had more than one site of metastasis. Bone metastasis was similar in all groups, ranging from 11% to 17%, and brain metastases were identified in both conventional clear cell RCC (7.4%) and papillary RCC (11.1%) tumors. The median time from nephrectomy to metastasis (32.4 months) and the time from metastasis to death (33.2 months) for chromophobe RCC was twice that for either conventional clear cell RCC (14.9 and 16.3 months, respectively) or papillary RCC (15.6 and 8.9 months, respectively).

Survival Analysis
By univariate analysis, chromophobe (P = .013) and papillary (P = .015) RCC had a significantly greater DFS compared with conventional clear cell RCC (Fig. 1). The 5- and 10-year DFS for conventional clear cell RCC was 73.3% and 65.6.7%, respectively. For nonconventional clear cell RCC, the 5- and 10-year DFS was 80.1% for chromophobe RCC and was 81.7% and 76.7%, respectively, for papillary RCC.

The multivariate Cox proportional hazard regression analysis was used to evaluate the combined effect of the study variables on freedom from disease progression (Table 2). Statistically significant results included tumor size, tumor stage, and chromophobe versus conventional clear cell histology. Despite papillary RCC being statistically significant compared with conventional clear cell RCC for DFS by univariate analysis, papillary cell type was not significant by multivariate analysis (P = .16). The concordance index, a measure of the predictive accuracy of a prognostic model, was .81 for the model that contained pathologic stage and size and was .82 with the addition of histology (95% confidence interval for improvement, .001–.02).


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  		TABLE 2. Results of multivariate Cox proportional hazards regression analysis for predictors of recurrence
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
With the introduction of the Heidelberg classification, the generic term RCC is considered obsolete. Prognosis for stage pT1/pT2 tumors varies according to each histological subtype, ranging from 73% to 97%.21 Recognizing this, multiple institutions have validated the varied clinicopathologic characteristics of both papillary22–28 and chromophobe29–35 tumors. Contemporary reports are now incorporating the Heidelberg classification into the statistical analysis when determining factors that influence outcome for renal cortical tumors.36–38 Three large studies, collectively evaluating 1782 patients, reported a significantly improved 5- and 10-year DFS for nonconventional clear cell RCC compared with conventional clear cell RCC.39–41 Although it was significant by log-rank test, only Amin,40 in a study of 405 patients, evaluated histology as a variable by multivariate analysis (controlling for size and stage) and did not find it to be a significant prognostic factor for either disease-specific survival (P = .54) or freedom from progression (P = .22). These studies concluded that histological subtypes have independent prognostic significance that should be included with pathologic stage to assist in stratifying patients to individual risk groups.

In this series, there was a significant difference in 5-year DFS by log-rank test among the three histological subtypes. By Cox regression analysis, tumor size, stage, and conventional clear cell RCC compared with chromophobe RCC were significant predictors of recurrence (Table 2). To our knowledge, this is the first study to demonstrate histological subtype, specifically, chromophobe RCC, as a significant factor for disease progression by multivariate analysis. Although significant by log-rank test, papillary RCC was not a significant predictor of relapse (P = .16) by multivariate analysis. This may be explained by (1) a greater proportion of pathologic stage T1/T2 tumors for papillary RCC compared with conventional clear cell RCC or (2) a disproportionate number of type 2 versus type 1 papillary RCC. Delahunt and Eble42 proposed dividing papillary RCC into two morphological types. Type 1 is characterized by small cuboidal cells with a single line of uniform nuclei and small nucleoli, and type 2 is characterized by papillae covered by large eosinophilic cells with pleomorphic nuclei, prominent nucleoli, and nuclear pseudostratification. In a study of 66 cases, type 2 papillary RCC was associated with a significantly higher Furman grade and a poorer prognosis.43 In the current study, papillary RCC was not further classified into subtypes. A higher proportion of the type 2 papillary subtype would negatively influence outcome after controlling for stage and size and could explain the lack of significance of papillary cell type on outcome by multivariate analysis.

The collective data from this study, along with previously published reports, indicate that disease progression and survival are significantly influenced by tumor histology. When controlling for stage and size, chromophobe cell type, and not papillary RCC, was a significant predictor of progression-free relapse compared with conventional clear cell RCC. For tumors of similar stage and size, these data suggest that only chromophobe RCC will have a significantly improved nonprogression rate; papillary and conventional clear cell RCC have similar clinical outcomes.

The concordance index is the probability that, given two randomly selected patients, the patient with the worse outcome is, in fact, predicted to have a worse outcome.44 This measure, similar to an area under the receiver operating characteristic curve, ranges from .5 (i.e., chance or a coin flip) to 1.0 (perfect ability to rank patients). In this study, the concordance index of the model containing established markers (pathologic stage and size) was .81. When histology was added to the predictive model, chromophobe cell type was statistically significant (P = .02), and papillary cell type was not (P = .16), although the concordance index improved to .82 (P < .05), indicating the usefulness of histology in predicting outcome. Markers (e.g., histology) should be judged on their ability to improve an already optimized prediction model, rather than on their P value in a multivariate analysis.

Despite the statistical significance of chromophobe RCC by log-rank test and multivariate analysis for disease-free recurrence, these patients presented at a younger age with larger tumors (mean tumor size of 7.1 cm) compared with papillary (4.8 cm) and conventional clear cell (5.6 cm) RCC. Amin et al.40 also reported a larger mean tumor size (7.2 cm) for chromophobe RCC, with no patient developing recurrence at 5 years. These observations further support the more indolent nature of chromophobe RCC.

The lung and retroperitoneal nodes were the most common sites of disease recurrence for all three tumor subtypes. Conventional clear cell RCC and papillary RCC were more likely to have a solitary site of metastatic disease, whereas chromophobe RCC relapsed in two sites in 66.7% of patients (four of six). Other institutions have reported a greater propensity for conventional clear cell RCC to metastasize to the lung, a greater propensity for chromophobe RCC to metastasize to the liver, and a greater propensity of papillary RCC for locoregional invasion with lymphatic spread.45,46

Motzer et al.47 from Memorial Sloan-Kettering Cancer Center reported outcome data for patients with metastatic nonconventional clear cell RCC. The median survival for patients with chromophobe RCC was 29 months, compared with 5.5 months for papillary RCC. In the current series, the median time from nephrectomy to metastasis (32.4 months) and metastasis to death (33.2 months) for chromophobe RCC was twice that of the other tumor subtypes, again supporting a more indolent metastatic potential of the chromophobe subtype and the similar clinical behavior for papillary and conventional clear cell RCC.

The significance of a working knowledge of the clinical outcomes of the various histological subtypes of renal cortical tumors is 6-fold: (1) to define a more rational follow-up, imaging, and visit schedule and (2) provide patient counseling regarding prognosis by using a postoperative nomogram38 that predicts disease-free probability. (3) Although bilateral nonfamilial renal tumors are uncommon, the histological concordance rate for synchronous and/or metachronous renal lesions is 75% to 80%,48 which may affect surgical treatment decisions. (4) Future analyses evaluating novel techniques in managing renal cortical tumors, as well as selection for clinical trials, should include histology because this variable is a significant predictor of metastasis. (5) Immunotherapy is a mainstay treatment for metastatic RCC as a group, though recent reports suggest that both chromophobe RCC and papillary RCC are nonresponders,47 and alternative clinical trials should be considered for such patients. (6) With increased focus on determining the histology of a renal mass before surgery by either invasive or noninvasive techniques, an accurate identification of the histological subtype will allow surgeons to better tailor treatment for the individual, possibly extending the boundaries for partial nephrectomy, as well as possibly allowing a more liberal policy for careful observation of small indolent tumors.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Renal cortical tumors are a heterogenous group of histological subtypes with varying clinical outcomes. Conventional clear cell RCC, comprising two thirds of all renal masses, portends a less favorable outcome with a significantly shorter 5-year DFS compared with papillary RCC and chromophobe RCC. Controlling for size and stage, compared with conventional clear cell RCC, only the chromophobe cell type significantly influenced outcome. Directing management, patient counseling, follow-up strategies, systemic therapies for metastatic disease, and analysis of investigational modalities for renal cortical tumors must incorporate histological subtypes into the decision algorithm.


   FOOTNOTES
 
Presented at the 56th Annual Cancer Symposium, Society of Surgical Oncology, San Diego, CA, March 5–9, 2003.

Renal cortical tumors have distinct histological subtypes with varying degrees of metastatic potential. Conventional clear cell renal cell carcinoma (RCC), which comprises two thirds of renal cortical tumors that present with localized disease, has a less favorable outcome when compared with papillary and chromophobe RCC.

Received for publication June 13, 2003. Accepted for publication August 21, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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