Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma – A multicentre study

doi:10.1016/j.ejca.2012.05.002

European Journal of Cancer

Volume 48, Issue 15, October 2012, Pages 2347-2352

https://doi.org/10.1016/j.ejca.2012.05.002 Get rights and content

Abstract

Aim of the study

Papillary renal cell carcinoma (pRCC) is the second most common subtype of RCC after the conventional clear cell type (cRCC). However, its characteristics and prognosis have been less intensively investigated. The aim of our study was to examine the tumour characteristics and long-term prognosis of pRCC compared to clear cell RCC (cRCC).

Methods

In total, 4941 evaluable patients were subjected to either radical nephrectomy or nephron-sparing surgery for pRCC or cRCC at five centres in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm and Marburg) between 1990 and 2010.

Results

pRCC (n = 565) and cRCC (n = 4376) patients were comparable with regard to mean age, clinical symptoms, tumour differentiation and regional lymph node metastases. Patients with pRCC had a significantly higher rate of organ confined tumours (pT1-2, N/M0; 74.9% versus 62.9%), less synchronic visceral metastases (9.6% versus 15.2%), and a higher 5-year CSS rate than those with cRCC (85.1% versus 76.9%). Multivariate analysis identified the papillary subtype as a significant positive prognostic factor in localised (HR, 0.45) but as a negative prognostic factor in metastatic tumour stages (HR, 1.37).

Conclusion

pRCC can apparently be differentiated into two subgroups: an organ-confined/localised subgroup with a significantly better prognosis and an advanced/metastatic subgroup with a worse prognosis compared to cRCC.

Introduction

Clear cell renal carcinoma (cRCC) is the most common histopathological subtype of malignant kidney tumours and accounts for approximately 75–80% of all cases. As most clinical studies and guidelines focus on patients with this subtype, those with less common tumour entities such as papillary, chromophobe or collecting duct tumours have often been excluded.¹ Papillary renal cell carcinoma (pRCC), the second common subtype after cRCC accounting for 10–15% of all cases, is morphologically and cytogenetically subclassified as type 1 and type 2; it can occur sporadically or as part of a hereditary syndrome.2, 3, 4 Up to now, it has been widely assumed that papillary tumours generally have a more favourable prognosis than cRCC.

The prognostic significance of histological subtypes has been investigated in several studies with patient populations of to up to 4063 individuals.⁵ Regardless of these in part large study cohorts, results are not consistent. Some authors identified histologic subtype as a prognostic factor,6, 7 while others were not able to show a survival advantage for pRCC.3, 8 Particularly multivariate analysis failed to reveal any significant differences between histological subtypes when tumour stage and differentiation were included.3, 5, 9, 10, 11

Therefore, the aim of this large retrospective multicentre study was to compare incidence, tumour characteristics and long-term prognosis of papillary and clear cell RCC.

Section snippets

Patients and tumour characteristics

This retrospective study included 4941 patients who underwent renal tumour surgery 1990–2010 for pRCC (n = 565) or cRCC (n = 4376) at Hannover, Homburg, Mainz, Ulm (1995–2010), or Marburg (1990–2005) University Medical Centers. The histological tumour subtype was determined according to the 1997 UICC Classification¹² by pathologists dedicated to GU pathology. Staging was based on the 2002 TNM Classification. Information on patients’ and tumour characteristics, such as age, sex, stage, presence of

Results

Our patient population of 3208 (64.9%) men and 1733 (35.1%) women had a mean age of 62.3 (range, 19–93) years. The median/mean follow-up was 46.7/60.3 months (IQR: 18.0–91.9). By the last day of data acquisition, 954 (22.3%) had died from their tumour disease and 381 (8.9%) from other causes. Detailed tumour and patients’ characteristics are summarised in Table 1.

Discussion

The prognostic significance of the tumour subtype has been investigated in a series of large inter-institutional and collaborative national and international studies with patient populations of up to 4063 individuals.⁵ Despite these large numbers of cases, study results are not consistent. Some authors identified the histologic subtype as a prognostic factor,6, 7 while others saw no survival advantage for a histological subtype of RCC.3, 8 Particularly multivariate analysis failed to reveal any

Conclusion – practical implications

The pRCC group can apparently be differentiated into two prognostically divergent subgroups: an organ-confined/localised subgroup with a significantly better prognosis and a metastatic subgroup with a worse prognosis than the clear cell reference group. The question of whether they correspond to the classical pRCC subtypes 1 and 2 or are characterised by other genetic alterations has to be further evaluated.

Conflict of interest statement

This work had no specific funding. There are no financial disclosures from any authors.

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The prognostic role of histomorphological subtyping in nonmetastatic papillary renal cell carcinoma after curative surgery: is subtype really irrelevant? A propensity score matching analysis of a multi-institutional real life data
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The role of histomorphological subtyping is an issue of debate in papillary renal cell carcinoma (papRCC). This multi-institutional study investigated the prognostic role of histomorphological subtyping in patients undergoing curative surgery for nonmetastatic papRCC.
A total of 1,086 patients undergoing curative surgery were included from a retrospectively collected multi-institutional nonmetastatic papRCC database. The patients were divided into 2 groups based on histomorphological subtyping (type 1, n = 669 and type 2, n = 417). Furthermore, a propensity score-matching (PSM) cohort in 1:1 ratio (n = 317 for each subtype) was created to reduce the effect of potential confounding variables. The primary outcome of the study, the predictive role of histomorphological subtyping on the prognosis (recurrence free survival [RFS], cancer specific survival [CSS] and overall survival [OS]) in nonmetastatic papRCC after curative surgery, was investigated in both overall and PSM cohorts.
In overall cohort, type 2 group were older (66 vs. 63 years, P = 0.015) and more frequently underwent radical nephrectomy (37.4% vs. 25.6%, P < 0.001) and lymphadenectomy (22.3% vs. 15.1%, P = 0.003). Tumor size (4.5 vs. 3.8 cm, P < 0.001) was greater, and nuclear grade (P < 0.001), pT stage (P < 0.001), pN stage (P < 0.001), VENUSS score (P < 0.001) and VENUSS high risk (P < 0.001) were significantly higher in type 2 group. 5-year RFS (89.6% vs. 74.2%, P < 0.001), CSS (93.9% vs. 84.2%, P < 0.001) and OS (88.5% vs. 78.5%, P < 0.001) were significantly lower in type 2 group. On multivariable analyses, type 2 was a significant predictor for RFS (HR:1.86 [95%CI:1.33–2.61], P < 0.001) and CSS (HR:1.91 [95%CI:1.20–3.04], P = 0.006), but not for OS (HR:1.27 [95%CI:0.92–1.76], P = 0.150). In PSM cohort balanced with age, gender, symptoms at diagnosis, pT and pN stages, tumor grade, surgical margin status, sarcomatoid features, rhabdoid features, and presence of necrosis, type 2 increased recurrence risk (HR:1.75 [95%CI: 1.16–2.65]; P = 0.008), but not cancer specific mortality (HR: 1.57 [95%CI: 0.91–2.68]; P = 0.102) and overall mortality (HR: 1.01 [95%CI: 0.68–1.48]; P = 0.981)
This multiinstitutional study suggested that type 2 was associated with adverse histopathologic outcomes, and predictor of RFS and CSS after surgical treatment of nonmetastatic papRCC, in overall cohort. In propensity score-matching cohort, type 2 remained the predictor of RFS. Eventhough 5th WHO classification for renal tumors eliminated histomorphological subtyping, these findings suggest that subtyping is relevant from the point of prognostic view.
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Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.
Race/Ethnicity Determines Life Expectancy in Surgically Treated T1aN0M0 Renal Cell Carcinoma Patients
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Life expectancy (LE) is an important consideration in the clinical decision-making for T1aN0M0 renal cell cancer (RCC) patients.
To test the effect of race/ethnicity (Caucasian, African American, Hispanic/Latino, and Asian) on LE predictions from Social Security Administration (SSA) life tables in male and female T1aN0M0 RCC patients.
We relied on the Surveillance, Epidemiology, and End Results database.
Radical nephrectomy (RN) and partial nephrectomy (PN).
Five-year and 10-yr observed overall survival (OS) of pT1aN0M0 RCC patients treated between 2004 and 2006 were compared with the LE predicted from SSA life tables. We repeated the comparison in a more contemporary cohort (2009–2011), with 5-yr follow-up and higher PN rates.
In the 2004–2006 cohort, PN rate was 40.7%. OS followed the predicted LE in Caucasians, Hispanics/Latinos, and Asians, but not in African Americans, in whom 5-yr OS rates were 5.0% (male) and 8.7% (female) and 10-yr rates were 4.2% (male) and 11.1% (female) lower than predicted. In the 2009–2011 cohort, PN rate was 59.4%. Same observations were made for OS versus predicted LE in Caucasians, Hispanics/Latinos, and Asians. In African Americans, 5-yr OS rates were 1.5% (male) and 4.9% (female) lower than predicted.
In RN- or PN-treated pT1aN0M0 RCC patients, LE predictions closely approximated OS of Caucasians, Hispanics/Latinos, and Asians. In African-American patients, SSA life tables overestimated LE, more in females than in males. The limitations of our study are its retrospective nature, its validity for US patients only, and the under-representation of racial/ethnic minorities.
Social Security Administration life tables can be used to estimate long-term life expectancy in patients who are surgically treated for renal cancer (≤4 cm). However, while for Caucasians, Hispanics/Latinos, and Asians, the prediction performs well, life expectancy of African Americans is generally overestimated by life table predictions.
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Expression of the CXCR4 and CXCR7 in renal cancers; can “the orphan receptor” predict the mortality?
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Citation Excerpt :
Our study group included 13 pRCC patients out of which 7 had advanced metastatic disease. Mortality was associated with well-known parameters of aggressiveness such as: tumour size, higher grade, pTNM stage and stadium, as well as the presence of necrosis and sarcomatoid differentiation [16,17]. In our study overall survival (OS) decreased 1.2 times with every cm of tumour growth.
CXCR4 and CXCR7 are chemokine receptors that bind with chemokine CXCL12 and influence various physiological and pathological processes. In renal cell carcinoma, their expression has been mostly associated with tumour aggressiveness. However, there are some contradictory results regarding the localization of immunohistochemical staining and predictive potential of these markers. The expression of CXCR4 and CXCR7 was immunohistochemicaly analyzed in 98 tumour samples, including 85 clear cell type (ccRCC) and 13 papillary type (pRCC). Depending on the staining localization (cytoplasmatic or membranous), intensity and percentage of stained cells, histoscores were calculated, and their association with clinicopathological parameters was analyzed. PRCC was associated with both CXCR7 and CXCR4 cytoplasmatic expression. We have also found that higher CXCR7 expression can be expected in tumours of greater size. In our study, mortality could be predicted by membranous CXCR7 histoscore, tumour size and pRCC type. With each centimetre in tumour size, survival decreases 1.2 times. CXCR7M histoscore higher by 50 units was associated with 1.5 greater risk of mortality. Neither membranous nor cytoplasmatic CXCR4 histoscore was found to be mortality predictor. Our data showed that CXCR7 could be considered as a valid prognostic marker regarding survival of RCC patients.
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View all citing articles on Scopus

ⁱ: For the German Renal Cell Cancer Network.

^j: These authors contributed equally.

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Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma – A multicentre study

Abstract

Aim of the study

Methods

Results

Conclusion

Introduction

Section snippets

Patients and tumour characteristics

Results

Discussion

Conclusion – practical implications

Conflict of interest statement

J Urol

Hum Pathol

Eur Urol

J Urol

Urology

Pathology

Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches

J Cancer Res Clin Oncol

Incidence and long-term prognosis of papillary renal cell carcinoma

J Cancer Res Clin Oncol

Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience

J Clin Oncol

Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma

Am J Surg Pathol

Papillary renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases

Cancer

Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases

Am J Surg Pathol