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Japanese Journal of Clinical Oncology Advance Access published online on July 8, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyp075
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© The Author (2009). Published by Oxford University Press. All rights reserved

Is there a Role of the Histologic Subtypes of Papillary Renal Cell Carcinoma as a Prognostic Factor?

Ja Hyeon Ku1, Kyung Chul Moon2, Cheol Kwak1, Hyeon Hoe Kim1 and Sang Eun Lee1

1 Department of Urology, Seoul National University College of Medicine
2 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea

For reprints and all correspondence: Cheol Kwak, Department of Urology, Seoul National University Hospital, 28, Yongon Dong, Jongno Ku, Seoul 110-744, Korea. E-mail: mdrafael{at}snu.ac.kr

Received March 30, 2009; accepted June 7, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Objective: The aim of this study was to compare type 1 and type 2 papillary renal cell carcinoma (RCC) for validating this subclassification as a prognostic factor.

Methods: A total of 70 patients with chromophobe RCC were included in the analysis. Patients with papillary RCC were categorized into type 1 (n = 33) and type 2 (n = 37).

Results: The median progression-free survival was 31.0 months for the type 1 group and 12.0 months for the type 2 group (P = 0.001). The median cancer-specific survival was 41.1 months for the type 1 group and 24.0 months for the type 2 group (P = 0.097). Multivariate Cox proportional hazards model for patients with papillary RCC showed that no variables including histologic subtyping were independent predictors of progression-free and cancer-specific survival.

Conclusions: In the present study, the type of papillary RCC does not reach independent prognostic significance.

Key Words: kidney neoplasm • papillary renal cell carcinoma • prognosis • survival


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Renal cell carcinoma (RCC) is a heterogenous disease consisting of various subtypes with diverse genetic, biochemical and morphologic features. Papillary RCCs represent ~10–20% of all RCCs and are the second most frequent histologic form after clear cell RCC (1,2). Papillary RCCs are histologically characterized by the presence of fibrovascular cores with tumor cells arranged in a papillary configuration. The majority of papillary RCC tumors show indolent behavior and have a limited risk of progression and mortality, but a distinct subset displays highly aggressive behavior (3). Thus, papillary RCC seems to constitute clinically, histologically and even genetically highly heterogenous groups, suggesting the necessity for characterizing their subtypes.

In 1997, Delahunt and Eble (3) found two papillary RCC histologic subtypes, type 1 and type 2. Type 1 is characterized by the presence of small cuboidal cells covering thin papillae, with a single line of small uniform nuclei and basophilic cytoplasm. Type 2 is characterized by the presence of large tumor cells with eosinophilic cytoplasm and pseudo-stratification. Despite the small number of studies analyzing prognosis of papillary RCC based on this morphologic classification, it has been generally accepted that type 1 papillary RCC has a more favorable survival than type 2 papillary RCC (4–10). However, the morphologic classification remains controversial, and there is limited molecular and biochemical evidence to support this morphologic classification. The relatively high incidence of mixed type 1 and 2 tumors poses additional difficulties for such a method of classification. Furthermore, published series have shown conflicting results regarding the clinical implication of papillary RCC subtyping (11).

In the present study, to analyze the clinical behavior of papillary RCC further, we reviewed 70 consecutive cases of papillary RCC and performed a survival analysis comparing type 1 and type 2 papillary RCCs to validate this subclassification as a prognostic factor.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Approval of the study was obtained from the Institutional Review Board. We reviewed the medical records of patients treated by surgical treatment for a suspected RCC between January 1995 and December 2005 at the Seoul National University Hospital, Seoul, Korea, and at the Seoul National Bundang Hospital, Seongnam, Korea. Of total patients, 70 with papillary RCC were included in the analysis. The patient population consisted of 52 males and 18 females, with an age range of 21.3–86.0 years (median, 50.8). Pathological stage and tumor grade were diagnosed according to 2002 TNM classification (12) and Fuhrman et al.'s (13) nuclear grading system, respectively. The histologic classification was determined according to the Union Internationale Contre le Cancer (14). The T stage was T1 in 47, T2 in 10 and T3 in 13 patients, with Fuhrman's grade 2 in 27, grade 3 in 37 and grade 4 in 1 patient.

The patients were evaluated with office visits, laboratory workups and chest X-ray every 6 months for 5 years and yearly thereafter. Computed tomography and bone scans were performed yearly and on request until disease progression. Median follow-up duration of total patients was 29.0 months [95% confidence interval (CI), 7.6–115.7]. Deaths were determined by reviewing medical records and/or confirmed by interview with the patient's family.

The microscopic slides from all tumor specimens were reviewed by a urologic pathologist (K.C.M) without the knowledge of patient outcome. The histologic subtype and Fuhrman's nuclear grade were determined. The presence of tumor necrosis was evaluated based on macroscopic description of tumor, and tumors were considered necrotic only if they exhibited >10% macroscopic necrosis which would be apparent to experienced pathologists on gross examination of specimen. Lymphovascular invasion was defined as the unequivocal presence of tumor cells within the endothelial linings of lymphatic and/or vascular channels.

For statistical analysis, patients with papillary RCC were categorized into type 1 (n = 33) and type 2 (n = 37). The characteristics of subject groups were compared using the {chi}2 test. The statistical endpoint in our analysis was progression-free and cancer-specific survival of patients. Kaplan–Meier survival curves were generated from the life table analysis, and survival was compared using log-rank tests. Prognostic implications of selected variables were evaluated using the Cox proportional hazards model. The statistical software package SPSS 13.0 (SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses, with P < 0.05 indicating statistical significance.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Conflict of interest statement
 References
 
Characteristics of the patient population are shown in Table 1. Patients with type 1 papillary RCC differed significantly from those with type 2 papillary RCC for the following parameters: smaller tumor diameter (P = 0.009), less advanced TNM stage (P = 0.004), lower Fuhrman nuclear grade (P < 0.001), less tumor necrosis (P < 0.001) and less lymphovascular invasion (P = 0.011). There was no statistical difference with regard to age and tumor diameter.


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  		Table 1. Demographic and tumor characteristics according to tumor subtype in papillary renal cell carcinoma (RCC)

 
During the follow-up periods, disease progression occurred in 11 patients (15.7%) with papillary RCC and 8 (11.4%) died related to their tumor disease with a median follow-up of 29.0 months. The 1-, 3- and 5-year progression-free survival rates were calculated at 91.3%, 82.5% and 82.5%, respectively. The 1-, 3- and 5-year cancer-specific survival rates were 92.5%, 88.8% and 83.5%, respectively. The median progression-free survival was 31.0 months (95% CI, 4.0–123.7) for the type 1 group and 12.0 months (95% CI, 0.0–72.8) for the type 2 group, respectively (P = 0.001) (Fig. 1A). Progression-free survival rates at 1 year were 96.4% and 73.8%, at 3 year 96.4% and 62.7%, and at 5 year 87.7% and 62.7%, respectively. The median cancer-specific survival was 41.1 months (95% CI, 7.7–143.3) for the type 1 group and 24.0 months (95% CI, 5.0–91.0) for the type 2 group, respectively (P = 0.097) (Fig. 1B). Cancer-specific rates at 1 year were 96.6% and 89.0%, at 3 year 96.6% and 80.3%, and at 5 year 89.7% and 80.3%, respectively.


Figure 1
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  		Figure 1. (A) Progression-free survival in patients with type 1 and type 2 papillary renal cell carcinoma (RCC) (log-rank test for trend, P = 0.001). (B) Cancer-specific survival in patients with type 1 and type 2 papillary RCC (log-rank test for trend, P = 0.097).

 
Univariate associations of the clinical and pathologic features studied with death from RCC are summarized in Table 2. The TNM stage (P = 0.005 and P = 0.015), and the presence of tumor necrosis (P = 0.014 and P = 0.034) and lymphovascular invasion (P < 0.001 and P = 0.004) were significantly associated with progression-free and cancer-specific survival for papillary RCC, respectively. Although mode of presentation (P = 0.011) and histologic subtype (P = 0.007) were significantly associated with progression-free survival, there was not a statistically significant association with death from papillary RCC.


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  		Table 2. Univariate analysis of survival prognostic parameters in papillary RCC

 
Multivariate Cox proportional hazards model analysis using the variables of mode of presentation, TNM stage, tumor necrosis, lymphovascular invasion and histologic type showed that no variables were independent predictors of progression-free survival; additionally, using the variables including the TNM stage, necrosis and lymphovascular invasion, all variables were not independent prognostic predictors of cancer-specific survival and lost statistical significance (Table 3).


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  		Table 3. Association of various factors with overall survival on multivariate Cox proportional hazard regression analysis in papillary RCC

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Conflict of interest statement
 References
 
The identification of valid histologic prognostic parameters for renal parenchymal malignancies has, to date, proved to be somewhat elusive. Although large monocentric series with expert pathologic review have been published (1,5,15–17), no consensus has been reached on the independent prognostic value of histologic type. In 1999, Ljungberg et al. (18) were the first to observe significantly different cancer-specific survivals in the three main RCC histotypes. In that series, patients with papillary RCC had significantly longer survival, compared with those with clear cell RCC, as did patients with chromophobe RCC. Beck et al. (17) also reported that when multivariate analysis was performed, histologic type did retain significance when tumor stage and grade were included in the analysis. In a large series of 2528 patients from Mayo Clinic, Cheville et al. (15) showed that patients with clear RCC had significantly lower cancer-specific survival probabilities, compared with those with papillary or chromophobe RCC, even after stratification by pathologic stage and nuclear grading. Also, in that series, no survival difference was observed between papillary and chromophobe RCC. However, in most series where multivariate analysis was performed, histologic type did not retain significance when tumor stage and grade were included in the analysis (1,2,16,19).

In our series, type 2 papillary RCC was larger, advanced and poorer differentiated, and more frequently showed tumor necrosis and lymphovascular invasion compared with type 1 papillary RCC. However, we could not found statistically significant difference in cancer-specific survival probability, although progression-free survival rates in type 1 papillary RCC was higher than in type 2 papillary RCC. Fuhrman et al. (13) noted that nuclear grading was applicable to all tumors of any size, pattern and cell type; however, Sika-Paotonu et al. (20) suggested that this grading system was not applicable to papillary RCC. Ficarra et al. (21) reported that the 2002 TNM staging system did not appropriately stratify the cancer-related outcome of the patients with papillary RCC. In that subgroup of patients, the disease-specific survival rates of patients with pT1a tumors overlapped those reported for patients with pT1b tumors, although a close to statistical significance was found when comparing the outcome both of patients with pT1a and pT2 (P = 0.05) and patients with pT1b and pT2 (P = 0.06) papillary RCC.

Table 4 summarizes the survival difference of type 1 and 2 papillary RCC in the published series (4–11). The poorer outcome of type 2 tumors on univariate analysis (4,5,7–10) was also shown in a multivariate analysis of overall survival in a series by Delahunt et al. (6) and Allory et al. (8). In series of Pignot et al. (10), type 2 papillary RCC was an independent prognostic factor of disease-free survival. However, Yamanaka et al. (11) reported that there were no significant differences in overall and cause-specific survival. Furthermore, other series could not confirm that survival rates in type 1 papillary RCC was higher than those in type 2 papillary RCC in the multivariate analysis (5,9). These findings suggest that the discrepancy among reports might be a result of the small number of patients with short follow-up period. Therefore, data regarding the prognostic significance of histologic subtyping papillary RCC are limited, largely due to the small numbers of cases in most series and the apparent favorable prognosis of this tumor type, with relatively few tumor-related deaths being reported.


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  		Table 4. Survival difference of type 1 and 2 papillary RCCs in the published series

 
Our study has several weaknesses. First of all, our study is a retrospective one and included a small number of patients with a relatively short follow-up. Delahunt et al. (22) demonstrated that the risk of death as a result of RCC is continuous for increasing size if sample sizes are large enough. Therefore, our findings will have to be validated by additional studies in a larger series.

In the present study, the type of papillary RCC did not reach independent prognostic significance in multivariate analysis, possibly due to the correlation between the histologic subtype and the histologic grade or stage. Further investigations of the clinicopathological characteristics of papillary RCC are needed to fully characterize this neoplasm of the kidney.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
1 Amin MB, Tamboli P, Javidan J, Stricker H, de-Peralta Venturina M, Deshpande A, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol (2002) 26:281–91.[CrossRef][Web of Science][Medline]

2 Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol (2005) 23:2763–71.[Abstract/Free Full Text]

3 Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinopathologic and immunohistochemical study of 105 tumors. Mol Pathol (1997) 10:537–44.

4 Jiang F, Richter J, Schraml P, Bubendorf L, Gasser T, Sauter G, et al. Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol (1998) 153:1467–73.[Abstract/Free Full Text]

5 Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer (2000) 89:604–14.[CrossRef][Web of Science][Medline]

6 Delahunt B, Eble JN, McCredie MR, Bethwaite PB, Stewart JH, Bilous AM. Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol (2001) 32:590–5.[CrossRef][Web of Science][Medline]

7 Leroy X, Zini L, Leteurtre E, Zerimech F, Porchet N, Aubert JP, et al. Morphologic subtyping of papillary renal cell carcinoma: correlation with prognosis and differential expression of MUC1 between the two subtypes. Mod Pathol (2002) 15:1126–30.[CrossRef][Web of Science][Medline]

8 Allory Y, Ouazana D, Boucher E, Thiounn N, Vieillefond A. Papillary renal cell carcinoma: prognostic value of morphological subtypes in a clinicopathologic study of 43 cases. Virchows Arch (2003) 442:336–42.[Web of Science][Medline]

9 Mejean A, Hopirtean V, Bazin JP, Larousserie F, Benoit H, Chretien Y, et al. Prognostic factors for the survival of patients with papillary renal cell carcinoma: meaning of histological typing and multifocality. J Urol (2003) 170:764–7.[CrossRef][Web of Science][Medline]

10 Pignot G, Elie C, Conguy S, Vieillefond A, Flam T, Zerbib M, et al. Survival analysis of 130 patients with papillary renal cell carcinoma: prognostic utility of type 1 type 2 subclassification. Urology (2007) 69:230–5.[CrossRef][Web of Science][Medline]

11 Yamanaka K, Miyake H, Hara I, Inoue TA, Hanioka K, Fujisawa M. Papillary renal cell carcinoma: a clinicopathological study of 35 cases. Int J Urol (2006) 13:1049–52.[Web of Science][Medline]

12 Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. (2002) 6th edn. New York: Wiley-Liss Inc.

13 Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol (1982) 6:655–63.[Web of Science][Medline]

14 Storkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bostwick DG, et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer (1997) 80:987–9.[CrossRef][Web of Science][Medline]

15 Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol (2003) 27:612–24.[CrossRef][Web of Science][Medline]

16 Gudbjartsson T, Hardarson S, Petursdottir V, Thoroddsen A, Magnusson J, Einarsson GV. Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nationwide study of 629 patients. Eur Urol (2005) 48:593–600.[CrossRef][Web of Science][Medline]

17 Beck SD, Patel MI, Snyder ME, Kattan MW, Motzer RJ, Reuter VE, et al. Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol (2004) 11:71–7.[CrossRef][Web of Science][Medline]

18 Ljungberg B, Alamdari FI, Stenling R, Roos G. Prognostic significance of the Heidelberg classification of renal cell carcinoma. Eur Urol (1999) 36:565–9.[CrossRef][Web of Science][Medline]

19 Kim H, Cho NH, Kim DS, Kwon YM, Kim EK, Rha SH, et al. Renal cell carcinoma in South Korea: a multicenter study. Hum Pathol (2004) 35:1556–63.[CrossRef][Web of Science][Medline]

20 Sika-Paotonu D, Bethwaite PB, McCredie MR, William Jordan T, Delahunt B. Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg Pathol (2006) 30:1091–6.[Web of Science][Medline]

21 Ficarra V, Schips L, Guille F, Li G, De La Taille A, Praver Galetti T, et al. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer (2005) 104:968–74.[CrossRef][Web of Science][Medline]

22 Delahunt B, Kittelson JM, McCredie MR, Reeve AE, Stewart JH, Bilous AM. Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters. Cancer (2002) 94:659–64.


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This Article
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hyp075v1
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