Under-grading of <4 cm renal masses on renal biopsy
Catherine R. Harris, Department of Urology, University of California, San Francisco, 400 Parnassus Avenue A633, San Francisco, CA 94143-0738, USA. e-mail: HarrisCR@urology.ucsf.edu
Study Type – Prognosis (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
It is well documented that biopsy of small renal masses is inaccurate and tends to under-estimate tumour grade compared with surgical specimens. To our knowledge there has not been a study showing grading discrepancy between biopsy and surgical excision in a large population-based cohort.
- • To determine whether differences exist in tumour grade between patients who undergo partial nephrectomy (PN) and those who undergo ablation for renal tumours.
PATIENTS AND METHODS
- • Data was obtained using the Surveillance, Epidemiology and End Results database. Patients with solitary renal tumours of <4 cm treated with ablation or PN and with renal cell carcinoma (RCC) histopathology were identified.
- • Tissue diagnosis in the ablation specimens was obtained from biopsy reports, whereas tissue from PN specimens was determined from surgical pathology.
- • Variables analysed included: year of diagnosis, age, sex, race/ethnicity, marital status, population density, education, poverty level, and tumour size.
- • Stacked bar graphs were created to compare the distributions of grade and histology between the groups. Multinomial logistic regression was used to determine factors independently associated with grade.
- • In all, 7704 (87.4%) patients underwent PN and 1114 (12.6%) underwent either radiofrequency ablation or cryoablation.
- • The PN patients were younger at diagnosis (59 vs 68 years, P < 0.001), more likely to be married (70% vs 64%, P < 0.001), and had smaller tumours (2.4 vs 2.6 cm, P < 0.001).
- • There were no differences in the distribution of histology between the PN and ablation groups.
- • Tumour grade was significantly lower in tumours treated with ablation.
- • Compared with grade 1 disease, those undergoing ablation were 30% less likely to have grade 2 (P < 0.001), 30% less likely to have grade 3 (P < 0.001), and 92% less likely to have grade 4 disease (P < 0.01) than those having PN.
- • There is a strong association between grade and treatment type in patients with small renal masses after controlling for baseline characteristics.
- • As grade is determined by different methods, we think that this shows systematic under-grading in biopsy of small renal masses.
Surveillance, Epidemiology and End Results
The incidence of RCC is rising in the USA . This can be largely attributed to increased detection of small renal masses from more widespread use of abdominal imaging [2,3]. Although surgical excision of renal masses remains the standard for small, localised tumours, ablative techniques have emerged as a less invasive option and have reported short- and intermediate-term oncological outcomes comparable with partial nephrectomy (PN) , although randomised trials have yet to be performed. In this setting, observational studies can be used to compare effectiveness, provided differences in baseline characteristics between treatment groups are measured and can be adjusted for in analyses.
It is known that patients who undergo ablation are older and have more medical comorbidities compared with those who undergo surgery . In addition, ablation patients often have other high-risk features including prior nephrectomy for more advanced tumours, multiple lesions, and hereditary RCC syndromes [6–8]. Conversely, these patients tend to have smaller tumours [5,9]. Tumour grade is known to be a strong predictor of cancer-specific outcomes in RCC [10,11] and is associated with tumour size, pathological stage, venous invasion, lymph node involvement, and distant metastasis . It is unknown whether there is a difference in grade between patients who undergo PN, where grade is determined from the pathological specimen, and those who undergo ablation, where grade is determined from biopsy material.
Using data from the Surveillance, Epidemiology and End Results (SEER) database, we sought to determine whether there is a difference in RCC tumour grade between patients undergoing PN or ablation for renal masses of <4 cm in diameter.
PATIENTS AND METHODS
Data was obtained using the SEER database, a USA population-based cancer registry managed by the National Cancer Institute. The SEER database includes incident cancer cases from 18 individual cancer registries, which mirror the demographic population of the USA, and accounts for ≈26% of the population. An exemption for this project in lieu of formal review was obtained from the Institutional Review Board.
We identified patients in SEER with solitary renal tumours of <4 cm treated with ablation or PN who had histopathology consistent with RCC. Histology was identified using the following codes: clear cell (8310), papillary (8050, 8260, 8342), chromophobe (8270, 8290, 8317), collecting duct (8319), medullary (8510), granular (8320), sarcomatoid (8318), and RCC not otherwise specified (8312). The grade for patients undergoing PN is determined from the pathology report. In contrast, the grade for patients undergoing ablation is determined from a fine needle aspiration or core biopsy report, although coding does not exist to distinguish the two.
Predictor variables included: year of diagnosis, age at diagnosis, sex, race/ethnicity, marital status, population density, education, poverty level, and tumour size.
‘Rx Surgery Primary Site 1998+’ was used to identify the type of surgery as follows: no surgery (0), ablation (10–25), PN (26–39), radical nephrectomy (40–89), nephrectomy not otherwise specified (90), and unknown (99). Only subjects coded as ablation or PN were included in the analysis.
Race/ethnicity was categorised as White, Black, Hispanic, or other (Asian, American Indian/Alaska Native, and Native Hawaiian/Pacific Islanders). Marital status was classified as married or not married. The proportion of people per county with less than a high school education and living below the poverty line were recorded. Tumour histologies of medullary, collecting duct, and sarcomatoid were combined to simplify the analysis.
Stacked bar graphs were created to compare the distributions of grade and histology between those patients who underwent renal biopsy before ablation and those who underwent PN. Because of a violation of proportional odds, multinomial logistic regression rather than ordered logistic regression was used to determine factors that were independently associated with grade. Significant variables on univariable analysis were placed in the multivariable model. The α value was set at 0.05 and 95% CIs were determined.
Between 1998 and 2006, 8818 patients in the SEER database met the inclusion criteria, with 7704 (87.4%) undergoing PN and 1114 (12.6%) undergoing ablation. Of the patients who underwent ablation, 662 (59%) had cryotherapy, 213 (19%) had radiofrequency ablation, and 239 (21%) were not specified.
The demographics of the groups are shown in Table 1. More patients underwent PN in the earlier years compared with ablation (median year 2004 vs 2006, P < 0.001). PN patients were younger at the time of diagnosis (median age 59 vs 68 years, P < 0.001), more likely to be married (70% vs 64%, P < 0.001), and had smaller tumours (2.4 vs 2.6 cm, P < 0.001). There were no differences with respect to gender, ethnicity, population density, education or poverty level.
Table 1. The patients' characteristics
|Number of patients||7704||1114|| |
|Median (IQR) year of diagnosis,||2004 (2002–2006)||2006 (2004–2007)||<0.001|
|Mean (sd) age at diagnosis, years||59 (13)||68 (12)||<0.001|
|N (%):|| || || |
| Male||4770 (62)||687 (62)||0.87|
| Race:|| || ||0.77|
| White||5816 (76)||858 (77)|| |
| Black||696 (9)||98 (9)|| |
| Hispanic||730 (10)||103 (9)|| |
| Asian/Other||386 (5)||49 (4)|| |
| Married||5177 (70)||683 (64)||<0.001|
| Metropolitan area||6904 (90)||995 (90)||0.63|
|Median (IQR):|| || || |
| below poverty line, %||9 (6–13)||9 (6–13)||0.61|
| <H.S. education, %||14 (10–20)||14 (10–20)||0.99|
|Mean (sd) tumour size, cm||2.4 (0.8)||2.6 (0.8)||<0.001|
For the pathological findings, there were no differences in the distribution of histology between PN and ablation patients, with clear cell, papillary, chromophobe, and sarcomatoid RCC identified in order of decreasing frequency (Fig. 1). However, tumour grade was significantly lower in tumours treated with ablation compared with tumours that were resected (Fig. 2). Furthermore, when comparing grade as a dichotomous variable, i.e. low-grade (I, II) and high-grade (III, IV), patients undergoing ablation had 58% lower odds of high-grade disease (95% CI 0.31–0.58, P < 0.001).
The difference in grade between those undergoing ablation and those undergoing PN persisted after multinomial logistic regression, adjusting for baseline differences between the groups (Table 2). Referenced to the risk of grade 1 RCC, those undergoing ablation compared with PN were 30% less likely to have grade 2 (P < 0.001), 30% less likely to have grade 3 (P < 0.001), and 92% less likely to have grade 4 RCC (P < 0.01).
Table 2. Multinomial logistic regression of factors associated with grade*
|Ablation (vs PN)||0.7 (0.5–0.8), <0.001||0.3 (0.2–0.5), <0.001||0.08 (0.0–0.6), <0.01|
|Year (vs 1998–2001)|| || || |
| 2002–2003||1.1 (0.9–1.3), 0.50||0.9 (0.7–1.2), 0.48||1.0 (0.5–2.2), 0.95|
| 2004–2005||1.2 (1.0–1.4), <0.05||1.3 (1.0–1.7), 0.04||1.4 (0.7–2.6), 0.36|
| 2006–2006||1.3 (1.1–1.6), 0.001||1.6 (1.3–2.1), <0.001||1.1 (0.6–2.1), 0.78|
|Age (per 10 year inc.)||1.0 (1.0–1.1), 0.21||1.2 (1.1–1.2), <0.001||1.2 (1.0–1.4), 0.04|
|Married (vs other)||1.1 (1.0–1.2), 0.15||1.0 (0.8–1.2), 0.79||1.2 (0.7–1.9), 0.48|
|Tumour size (per cm inc.)||1.2 (1.2–1.3), <0.001||1.4 (1.3–1.5), <0.001||2.0 (1.5–2.6), <0.001|
The increasing incidence and detection of small renal masses has led to a predicament in their optimal management. The treatment strategy for the incidental small renal mass is complex, as these lesions are often asymptomatic and less likely to be malignant compared with larger masses. Furthermore, treatment-related morbidity, renal function, and patient preferences must be considered [2,13]. These observations define the dilemma in the treatment of small renal masses, particularly in the elderly patient or those with significant medical comorbidities. Given the absence of prospective clinical trials, a careful comparison of the various methods used is needed to better understand the relevant issues and differences amongst treatments.
In the present population-based study, there was a strong association between RCC grade and treatment type in patients undergoing either PN or ablation; tumours in the ablation group were significantly less likely to be grade 3–4. We do not think there is evidence that selection bias resulted in this observation. Given the overall similarities between the treatment groups, it is unlikely that clinical parameters alone could have been used for preferential selection of low-grade tumours for ablation. These findings were consistent after multivariable adjustment for numerous factors, including tumour size.
It is important to note that pathological assessment is made differently in the two groups, with the entire specimen available for review after surgical resection. We propose that the present findings are the result of systematic under-grading of RCC on renal mass biopsy.
The present results are supported by studies of patients who have undergone biopsy of the tumour before PN. The accuracy of identifying Fuhrman grade in biopsy material ranges from 46–70% [14–17]. In these reports, the discrepancy in grade between biopsy and final pathology is usually one grade difference, and under-grading rather than over-grading is usually observed. Although significantly less discrepancy is noted if the grading system was condensed to low-grade (Fuhrman I-II) and high-grade (Fuhrman III-IV), one study found a grade change of >2 points in 17% of patients, and sarcomatoid features were identified in only 12% of the preoperative renal biopsies . However, the present results did not change when grouping by high and low grade.
Despite tumour under-grading, the proportion of various RCC histologies is similar in those undergoing PN and ablation. Published data have shown excellent accuracy of biopsy in the determination of histological type of small renal masses, with concordance of biopsy and surgical pathology ranging from 86% to 100%.
Although grade is a significant predictor of outcome [10–12,14], it is unlikely to be a confounder when comparing outcomes between PN and ablation. By definition, a confounder must be causally associated with both the predictor and outcome . Presumably renal mass biopsy is performed at the same time as ablation in most patients, and results are unknown before treatment. Therefore, it cannot be causally associated with treatment type and adjustment for grade is probably inappropriate. Furthermore, because of the current findings of significant measurement error, adjustment for grade would actually induce bias, rather than limit confounding as intended.
Moreover, systematic under-grading on renal mass biopsy poses a potential significant problem for those who would seek to use biopsy information in selecting low-risk patients for surveillance or ablation, based on the idea that higher grade tumours may require more aggressive intervention. The inability to identify other adverse pathological characteristics, such as sarcomatoid features and necrosis, further limits the utility of biopsy findings. The introduction of newer biopsy techniques that allow for multiple core biopsies to be taken safely, may greatly improve the diagnostic yield and accuracy. It is also possible that molecular profiling of biopsy specimens may be used to better risk-stratify tumours.
Although one limitation of the present study is the inability to test agreement of biopsy and excision on the same specimen, the large sample size and population-based nature represent important strengths. It is also assumed that biopsy was done at the time of ablation and that biopsy results did not dictate treatment method. However, we cannot exclude that in a population-based study derived from patients largely treated in the community setting, practice patterns may differ from the published literature.
In conclusion, in the present study there was a strong association between grade and treatment type in patients with small renal masses after controlling for baseline characteristics. As grade is determined by different methods, we think that this shows systematic under-grading in biopsy of small renal masses. Further refinements in biopsy technique, imaging, or molecular profiling are needed to increase accuracy of grade on biopsy to better select patients for treatment method or surveillance.
CONFLICT OF INTEREST