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Clinico-pathological analysis of renal cell carcinoma demonstrates decreasing tumour grade over a 17-year period.

Introduction

Renal cell carcinoma (RCC) is the 12th most common cancer in Ireland, accounting for about 3% of adult malignancies; the median patient age at diagnosis is 65.[sup.1] There has been an increasing incidence of RCC reported internationally, in part due to the increase in incidentally diagnosed RCC[sup.2,3] as a result of the widespread use and accuracy of modern imaging techniques, such as computed tomography and magnetic resonance imaging.[sup.4,5]

Tumour-node-metastasis (TNM) staging, as well as pathological nuclear (Fuhrman) grading system, has been identified as a reliable and accurate prognosticator in RCC.[sup.6]-[sup.8] There have been reports of a shift towards smaller renal tumours with an associated downwards stage migration,[sup.9]-[sup.11] with an associated improved cancer-specific survival.[sup.12] This stage migration towards smaller lower stage tumours, however, was not observed in an Australian series; an upward histological migration was demonstrated.[sup.13]

We assess the clinico-pathological features and survival of patients with RCC in an Irish surgical cohort. Furthermore we evaluate whether a stage migration has developed in our series over the study period.

Methods

A retrospective review of all nephrectomies (radical and partial) performed in a single urology unit from 1995 to 2012 was conducted. Data recorded included patient demographics, size of tumour, TNM classification (adjusted according to the American Joint Committee on Cancer [AJCC] 2010 guidelines), operative details and final pathology. All specimens were analyzed in the same histopathology department by at least 2 consultant histopathologists. All oncology cases were discussed preoperatively and postoperatively at the departmental multidisciplinary (urology, radiology, histopathology, medical oncology, radiation oncology) conference. It is the policy of our ethics committee that no consent or prior ethical approval is required for a retrospective chart review.

The data was divided into 3 equal consecutive time periods for comparison purposes: Group 1 for 1995 to 2000, Group 2 for 2001 to 2006 and Group 3 for 2007 to 2012.

All statistical analyses were performed using Minitab version 16.0 (Minitab Inc., State College PA). Differences in patient characteristics between the 6 time periods were tested using Fisher's exact test and one-way analysis of variance (ANOVA). Overall and disease-specific survival was calculated using the Kaplan-Meier method. Time was calculated from date of diagnosis to date of death or to 31 December 2012 if alive at that time. The log-rank test was used to test differences in the disease-specific survival between the 6 periods. All deaths were cross-referenced with the National Cancer Registry of Ireland and the General Registry Office. A p value less than 0.05 was considered statistically significant.

Results

Between 1995 and 2012, 507 patients underwent nephrectomy for RCC in our unit. Overall, rates of nephrectomies increased over the study period (Fig. 1).

There were 105 patients in Group 1 (1995-2000), 146 in Group 2 (2001-2006) and 256 in Group 3 (2007-2012). The median age was 60.1 (range: 23-88). There were 198 females and 309 males. No difference in age (p = 0.275) or sex distribution (p = 0.871) was observed between the groups. The clinico-pathological parameters are summarised in Table 1.

The median tumour size was 5.8 cm (range: 1.2-20) and there was no statistical reduction in size observed over time (p=0.477). A total of 142 (28%) RCCs were classified as pT1a, 111 (21.9%) as pT1b, 67 (13.2%) as pT2, 103 (20.3%) as pT3a, 75 (14.8%) as pT3b and 9 (1.8%) as pT4. Organ-confined (pT1a, pT1b, pT2) tumours accounted for 63.1% of the series and there was no statistical T-stage migration observed (p = 0.213). 6.5% were Fuhrman nuclear grade 1, 43.6% were grade 2, 38.3% were grade 3 and 11.6% were grade 4. There was a significant grade reduction over time (p = 0.017), with an increased representation of grade 1 (from 1.9% to 6.3%) and grade 2 (from 35.2% to 55.6%) tumours and a decrease in grade 3 (51.9% to 24.6%). The histological subtypes remained consistent with time, with clear cell carcinomas being the most common (83%), followed by papillary carcinomas (9.3%) and chrombophobe carcinomas (5.9%).

There was a significant difference between overall and disease-specific survival over the study period (67.9% vs. 82.1%, respectively, p < 0.001). The overall 1-year, 3-year and 5-year survival rates were 90.5%, 70.7% and 57.2%, respectively. The disease-specific 1-year, 3-year, 5-year survival rates were 93.3%, 81.4% and 71.6%, respectively (Fig. 2). There was no difference between overall 1-year survival rates (83.8%, 88.4%, 91.1%, respectively), 3-year survival rates (72.4%, 78.1%, 81.2%, respectively) and 5-year survival rates (64.8%, 67.1%, 72.1%, respectively) between the 3 groups (p = 0.341). There was no difference between disease-specific 1-year survival rates (91.4%, 91.1%, 93.2%, respectively), 3-year survival rates (85.7%, 82.2%, 88.3%, respectively) and 5-year survival rates (81.9%, 74.7%, 83.1% respectively) between groups (p = 0.081) (Fig. 3).

Significant differences were noted in overall survival between the T-stages (p < 0.001), nuclear grades (p < 0.001) and histological subtypes (p = 0.022) (Fig. 4).

Discussion

In our Irish surgical series, we found an increase in the number of nephrectomies performed over the study period, with a threefold increase since 1995. Despite this, a migration towards lower T-stage tumours has not been observed and mean tumour size has remained stable (6.44 cm). We found that 63.1% represented organ-confined tumours (pT1a, pT1b, pT2) and this has remained constant. We observed a trend towards lower nuclear (Fuhrman) grade tumours, with an increasing representation of grade 1 tumours and grade 2 tumours, and a decrease in grade 3 tumours. The cause for a decreasing tumour grade is uncertain particularly given that tumour size has remained consistent in our series. One contributing factor may be that modern imaging is detecting tumours earlier. Also, it may be a change in pathological reporting, which would need to be tested by re-grading all specimens across the 3 groups - this is not practical.

Our findings are not consistent with previous international reports. A large analysis from the United States, reviewing 205 963 RCCs, demonstrated a stage migration pattern; clinical (radiological based) stage 1 RCC increased from about 43% to 57% in new patients between 1993 and 2004. A subset analysis of only surgically staged patients still observed an increase in pathological pT1 RCC patients from 51% to 60% between 1993 and 2004. There was a concomitant decrease in the proportion of all other stages of disease during the same time interval.[sup.9] Pathologic and clinical staging may yield different results because tumours tend to be larger on imaging than their ultimate size when measured pathologically.[sup.14] The size of stage 1 tumours also decreased from a mean of 4.1 cm in 1993 to a mean of 3.6 cm in 2004. The mean tumour size is smaller than our series and may reflect our purely surgically treated series (stage 1 tumour mean size 4.01 cm); smaller tumours undergoing surveillance were not included in our analysis.

Similarly, Pichler and colleagues reported a stage migration and decrease in tumour size in a sizable central European Caucasian series. The observed stage migration mainly consisted of an increasing number of resections of pT1a (12.5% to 32.6%) tumours and a decreasing number of pT3a (46.6% to 24.1%) tumours over the 25-year study period; there was also an associated decrease in mean tumour size from 6.7 cm to 4.8 cm.[sup.10] This stage migration was accompanied by an improved metastases free 5-year survival from 78.7% to 90.3%. This survival benefit was based upon a cohort in whom no adjuvant or neo-adjuvant therapies were used. This stage migration and shift towards smaller less severe tumours were echoed in findings by Lyrdal and colleagues who assessed Scandinavians from the Swedish Cancer Registry.[sup.11] Not only did the authors assess clinically significant RCCs, they also analyzed autopsy-detected RCCs. The frequency of autopsy-detected tumours decreased from 24% to 7% indicating more incidentally diagnosed RCCs. In contrast to these 3 large studies, Doeuk and colleagues reported a similar-sized Australian series to our study population (n = 499). They found an upward stage shift with an increasing proportion of stage 3 tumours from 13.9% to 21.5%. They also observed a trend towards more aggressive Fuhrman grade 3 tumours 17.6% to 30.8%. Furthermore, despite conventional (clear cell) carcinomas remaining the most common histological subtype, there was a significant increased representation of papillary carcinomas, which have a known poorer prognosis than clear cell[sup.15,16] or chrombophobe.[sup.17]

A large review of the National Cancer Database assessed the pathological characteristics of 47 909 RCCs. Most (66%) of these tumours were organ confined and the mean size was 6.49 cm - similar to our series. Pathological (AJCC) stage, nuclear (Fuhrman) grade and histological subtype are key prognosticators in RCC.[sup.7,18] Our data support the significant survival advantage with regard to T-stage, nuclear grade and histological subtype. Management and risk algorithms have been validated; these algorithms incorporate these parameters for the stratification of patients with RCC (Memorial Sloan-Kettering Cancer Centre RCC nomogram,[sup.19,20] The University of Los Angeles, (UCLA) Integrated Staging System[sup.21] and the Mayo Clinic (Rochester, MN) stage, size, grade and necrosis score (SSIGN).[sup.22]

The rising incidence of RCC, often accompanied by a fall in mortality, has been well-described and attributed to an increase in incidentally discovered renal tumours.[sup.23] Falebita and colleagues reported that the incidence of RCC from 1994 to 2004 rose and it was largely, but not entirely, due to an increase in incidentally diagnosed cancers.[sup.24] The improved cancer-specific survival of incidental cases has not, thus far, resulted in a decrease in overall mortality from kidney cancer, perhaps because of this lead-time bias.[sup.25]

The most important limitation of our retrospective single centre study was that we only reported patients who underwent nephrectomy. As a result, we were not able to report incidence or prevalence of RCC given that this was an analysis of a purely surgical series. In our study, patients who were undergoing radiological surveillance for small suspicious renal masses and those who underwent radiological intervention may influencing factors as to why we did not observe the reported migration towards smaller lower stage tumours. Furthermore the adjustment of tumour stage to the AJCC 2010 guidelines was based on histopathological reports. The number of patients in our series with metastatic disease is quite small reflecting our survival rates; therefore, many patients with metastatic disease would not have undergone surgery and were therefore not included in this series.

Conclusion

Despite a threefold increase in the number of nephrectomies performed over the study period, the previously reported stage migration towards smaller tumours was not observed in our series. There was, however, a significant grade reduction. Tumour stage, nuclear grade and histological subtype are significant prognosticators of relative survival in RCC.

The authors would like to acknowledge the help of the National Cancer Registry of Ireland and the General Registry Office.

Competing interests: Mr. Nason, Mr. McGuire, Mr. Kelly, Mr. Murphy, Ms. Looney, Mr. Bryne, Mr. Mulvin, Mr. Galvin, Mr. Quinlan and Mr. Lennon all declare no competing financial or personal interests.

This paper has been peer-reviewed.

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Figures and Table

Fig. 1.: Trends in the number of nephrectomies performed between 1995 and 2012. [Figure omitted]

Fig. 2a.: Overall survival for patients undergoing nephrectomy for renal cell carcinoma from 1995 to 2012. [Figure omitted]

Fig. 2b.: Disease-specific survival for patients undergoing nephrectomy for renal cell carcinoma from 1995 to 2012. [Figure omitted]

Fig. 3a.: Overall survival in Group 1. [Figure omitted]

Fig. 3b.: Disease specfic survival in Group 1. [Figure omitted]

Fig. 3c.: Overall survival in Group 2. [Figure omitted]

Fig. 3d.: Disease specfic survival in Group 2. [Figure omitted]

Fig. 3e.: Overall survival in Group 3. [Figure omitted]

Fig. 3f.: Disease specific survival in Group 3. [Figure omitted]

Fig. 4a.: Overall survival for patients undergoing nephrectomy for renal cell carcinoma from 1995 to 2012 based on T-stage. [Figure omitted]

Fig. 4b.: Overall survival for patients undergoing nephrectomy for renal cell carcinoma from 1995 to 2012 based on Fuhrman nuclear grade. [Figure omitted]

Fig. 4c.: Overall survival for patients undergoing nephrectomy for renal cell carcinoma from 1995 to 2012 based on histological subtype. [Figure omitted]

Table 1.: Patient demographics and tumour characteristics [Table omitted]

Author Affiliation(s):

[1] Department of Urology, St Vincent's University Hospital, Dublin 4, Ireland

Correspondence: Mr Gregory Nason, St. Vincent's University Hospital, Dublin 4, Ireland; nasong@tcd.ie
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Title Annotation:Original Research
Author:Nason, Gregory J.; McGuire, Barry B.; Kelly, Michael E.; Murphy, Theodore M.; Looney, Aisling T.; By
Publication:Canadian Urological Association Journal (CUAJ)
Article Type:Report
Geographic Code:4EUIR
Date:Mar 1, 2014
Words:3357
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