Management of Small Renal Masses (SRMs)

▪ 43A Natural History and Surveillance of Small Renal Masses

Daniel Canter

Alexander Kutikov

Stephen A. Boorjian

Robert G. Uzzo

INTRODUCTION

Statistically renal cell carcinoma (RCC) is the most lethal of all urologic cancers. In 2010, approximately 58,240 patients will be diagnosed with a renal malignancy and nearly 22.4% (˜13,000) will succumb to this disease (1). The advent of widespread cross-sectional imaging in the 1980s has led to a rise in the incidental diagnosis of a small renal mass (SRM). Early detection was initially heralded as an opportunity to cure an otherwise often lethal disease (2). However, despite a two-decade long rise in the incidental discovery of localized small renal tumors, there has not been a concurrent diminishment in death rates from RCC. Therefore, the benefits of early aggressive intervention for all localized renal tumors have been increasingly questioned (3). Specifically, the rising rate of surgery for incidentally detected SRMs is yet to translate into decreased mortality for patients confirmed to have RCC. For instance, when all-cause mortality of patients diagnosed with RCC is examined in the United States, there is a rise from 1.5 deaths per 100,000 individuals in 1983 to 6.5 in 2002 (4).

While large institutional series have demonstrated that approximately 25% to 30% of SRMs are potentially clinically aggressive, preoperative prediction of tumor behavior remains elusive (5). Furthermore, prospective identification of benign pathology, which is indistinguishable from RCC on imaging and can account for up to 15% to 20% of asymptomatic small renal tumors at resection, is still not reliable (5,6). Indeed, it is with this backdrop of clinical uncertainty and biological heterogeneity that one must interpret the benefits and shortcomings of various clinical approaches to SRM.

The management of small localized renal masses has continued to evolve along two basic themes—it has become less radical and less invasive. These changes are in part a reflection of an improved understanding that the biology of incidentally discovered RCC may be more indolent than previously thought. Moreover, despite a growing therapeutic armamentarium, whether excision, ablation, or observation is the best treatment strategy depends on a constellation of patient and tumor factors. Kunkle et al. demonstrated that patients who opt for surgical excision are statistically significantly younger and have larger tumors than patients who choose ablative therapy. Compared to patients who choose active surveillance (AS), patients undergoing surgery are younger but do not have a renal mass that is statistically significantly larger (7). Retrospective, large cohort surgical series evaluating excision by partial or radical nephrectomy (open or laparoscopic) consistently demonstrate excellent outcomes and 5-year survival rates that often exceed 95% (8). In fact, the recent AUA guidelines that reviewed the English-language literature for clinical stage T1 (<7.0 cm) renal masses showed that recurrence-free survival rates for all surgical therapies (open, laparoscopic, partial nephrectomy, or radical nephrectomy) were all >98.0% at 5 years for T1 tumors (9). Minimally invasive ablative technologies such as cryotherapy and radiofrequency ablation have entered the therapeutic arena with similar short and intermediate oncologic results that appear equally impressive (10). The AUA guidelines published recurrence-free survival rates for radiofrequency ablation and cryotherapy of 87% to 90.6%, respectively (9). Similar to other papers, the AUA panel found that patients who choose ablative therapies tend to be older with smaller tumors and shorter oncological follow-up. Given such high disease-specific survival rates, data on AS of localized renal tumors, primarily in the elderly or infirmed, have begun to accrue and cautiously appear oncologically sound (9).

The concept of AS or watchful waiting in urologic oncology has precedence. Increasing evidence has supported this approach in select patients with prostate cancer based on the belief that competing comorbidities pose a greater threat to life expectancy than the prostate cancer itself (11,12). A similar strategy has developed for select patients with SRMs, since emerging data suggest that some small renal masses may not significantly impact a patient’s mortality (7). Nevertheless, surgical resection, especially in young healthy patients with localized renal lesions continues to be the standard of care, since these individuals have a long life expectancy and salvage therapies for advanced RCC are noncurative (8). However, elderly patients with RCC present the urologist a unique set of challenges, since comorbidities of these individuals compete with RCC for life expectancy. In recent years, the growth kinetics and metastatic potential of SRMs under AS in selected patients have been studied (13). These data suggest that despite the fact that the majority of solid renal tumors prove to be malignant, the lesions exhibit predictable growth kinetics and early (within 3 years) metastases are unlikely. This chapter reviews existing data on the natural history of SRMs under AS.

INDICATIONS FOR ACTIVE SURVEILLANCE

When considering AS as a management strategy for the newly diagnosed renal mass, it is helpful to consider absolute, relative, and elective indications. Absolute indications include patients in whom surgery poses an immediate and unacceptable risk of mortality. In the series of AS published to date, the indications for observation are often omitted, but “significant” comorbidities have been listed as the primary reason for AS in 36% to 66% of patients (14,15). It is the responsibility of the treating physician to quantitate factors affecting life expectancy, including performance status and operative risk, and compare these factors to the known data regarding the morbidity and mortality of untreated localized RCC. Therefore, evaluation by the primary care physician, medical specialists, and often an anesthesiologist may be helpful. Chronic disease states that are unlikely to significantly improve despite
maximal medical therapy may preclude patients from ever becoming surgical candidates and, thus, the indication for observation is absolute.

Relative indications for observation include concomitant diseases, such as a second malignancy and/or significant but not overriding medical comorbidities. These conditions include renal, pulmonary, or cardiac disease as well as concurrent malignancies. In this regard, the potential need for postoperative renal replacement therapy must be strongly considered, particularly in the elderly. The need for chronic renal replacement in elderly patients is associated with an increased mortality rate and decreased transplantation rate compared to younger patients. The 3-year survival rate in patients requiring hemodialysis is significantly lower in patients 75 years old or older (45%) compared to those 50 to 60 years old (74%) (16). In such cases, we have found it particularly useful to determine creatinine clearance and chronic kidney disease (CKD) stage.

Finally, some patients may simply wish to undergo a period of AS despite being low-risk surgical candidates. This constitutes an elective indication for AS, and requires the treating physician to inform the patient of the available data on renal tumor growth kinetics, with limitations and the uncertain long-term risk of progression. No matter what the indication for AS of a renal mass, it must be understood that the patient and physician are both taking a calculated risk due to the heterogeneous and occasional unpredictable behavior of RCC.

ROLE OF PERCUTANEOUS BIOPSY

The presumed diagnosis of RCC is based on enhancement of the tumor on cross-sectional imaging and the diagnosis is ultimately confirmed following histopathological examination of the surgical specimen. The occurrence of benign disease in the pathological specimen ranges from 10% to 30% (17). Unfortunately, accurate prediction of benign pathology prior to resection is not currently possible (5). The knowledge of benign disease would prevent surgical intervention, and alleviate the anxiety and need for repeated imaging in patients undergoing AS. Percutaneous biopsy of renal lesions suspicious for malignancy could potentially clarify the diagnosis; however, the efficacy of percutaneous biopsy of renal masses has remained controversial. Nevertheless, the emerging data on AS have renewed interest in biopsy for the SRM.

TABLE 43A.1 MEAN GROWTH RATES OF CLINICALLY LOCALIZED ENHANCING RENAL LESIONS

Author	Year	N	Average Size on Presentation (cm)	Size Range (cm)	Duration of Follow-up (Average Months)	Growth Rate Average (cm/yr)	Growth Rate Range (cm/yr)
Oda	2003	16	2.0^a	1.0-4.5	25^a	0.54^a	0.1-1.35
Kato	2004	18	1.98	0.8-3.4	27	0.42	0.08-1.60
Volpe	2004	32	2.48	0.9-3.9	35	0.1	NA
Kassouf	2004	26	2.37	1.0-7.0	32	0.09	0-1.2
Bosniak	1995	40	1.73	0.2-3.5	39	0.47	0-1.1
Wehle	2004	29	1.83	0.4-3.5	32	0.12	NA
Lamb	2004	36	7.2	3.5-20.0	28	0.39^a	0-1.76
Sowery	2004	22	4.08	2.0-8.8	26	0.86	NA
Fujimoto	1995	6	2.47	1.8-3.4	29	0.47	0.05-0.73
Uzzo^b	2006	61	2.97	1.0-12.0	36	0.20	−1.64 to 1.80
Meta-analysis	2006	234	2.60	NA	34	0.28	NA
Siu	2007	47	2.00	0.8-5.0	29.5	0.27	−0.13 to 1.5
Kouba	2007	46	2.92	0.7-6.6	35.8	0.70	0.0-5.31
Crispen^b	2008	124	2.61	0.4-12.0	33.4	0.28	−1.4 to 2.47
Abouassaly	2008	110^c	2.5^a	0.9-11.2	24^a	0.26	NA
Crispen^b	2008	173	2.45	0.4-12.0	31	0.285	−1.4 to 2.47
^aMedian values. ^bIndicates single-institution series that have accrued more patients with time. Last paper represents totality from institution, whereas prior series represent portion of patients undergoing AS. ^cExpressed as number of patients, not number of tumors.
N, number of lesions observed in each series.

The overall sensitivity and specificity of biopsy specimens vary widely in published series. Furthermore, nondiagnostic specimens account for as many as 21% of biopsies (19). Tumor size was found to be a principal factor affecting the rate of a “nondiagnostic” biopsy, with tumors smaller than 3 cm having a 37% rate of insufficient tissue, compared to only 9% of tumors larger than 3 cm. The issue of percutaneous renal biopsy was recently readdressed in a comprehensive review (20). In this report, the authors demonstrated that in pooled data prior to 2001, renal biopsy exhibited an 81% accuracy rate with four out of five biopsies correctly predicting the tumor’s pathology. Pooled series after 2001 suggest that the accuracy rate has improved to >90%. This improvement may be attributed to improved technical considerations when performing the biopsies as well as the addition of immunohistochemical and molecular analyses of the tissue specimens.

As a result, while renal mass biopsy is as yet not accepted as part of the standard evaluation in a young or otherwise healthy individual in whom the mass can safely be excised, biopsy may be of value in the elderly patient with multiple comorbid conditions in whom AS is being considered.

GROWTH RATES OF SRMS

Several series to date have evaluated the growth rates of clinically localized enhancing renal lesions (Table 43A.1). The majority of these series represent small, single-institution retrospective reviews. Sample sizes have ranged from 6 to 40 lesions with mean follow-up ranging from 25 to 39 months
(13,14,15,18,22,23,24,25,26,27,28,29,30,31,32). Mean tumor size at presentation was <3 cm in all but two series with mean tumor sizes at presentation of 4.08 and 7.2 cm, respectively. The average linear growth rates observed in these individual series has ranged from 0.09 to 0.86 cm/year, and individual lesion linear growth rates varied widely within each series (13,14,15,18,22,23,24,25,26,27,28,29,30,31,32). These studies have concluded that most small enhancing clinically localized renal lesions demonstrate slow interval linear growth, and that a period of AS is feasible in patients who are medically unfit for surgery. It must be noted that growth rates in the individual series do not necessarily reflect that of RCC, as pathological evaluation was not performed in all lesions reported (Table 43A.2).

In a systematic review of all AS series published in 2006, which included 234 lesions, the median growth rate of all evaluable lesions was 0.28 cm/yr (13). A recent update of the largest of these series presented data on 173 lesions with at least 12 months of AS and demonstrated an average annual growth rate of 0.285 cm/yr at a follow-up of 31 months (32). The annual growth rate range was −1.4 to 2.47 cm/yr (31). Interestingly, most series have measured renal tumor growth based on the change in tumor diameter, and few have compared the change in tumor volume. In their series, Crispen et al. analyzed tumor growth both linearly and volumetrically and found that tumors appeared to exhibit Gompertzian growth kinetics, whereby a tumor grows initially in an exponential fashion and then decreases with increasing tumor size (32). Furthermore, Volpe et al. made volumetric observations in their cohort of 32 masses followed prospectively. They found that 28 masses (88%) had positive slopes of volume over time, whereas four masses (12%) had negative slopes. With longer follow-up, the slope decreases (23).

TABLE 43A.2 PATHOLOGY OF RENAL LESIONS UNDERGOING RESECTION AFTER A PERIOD OF AS

Author	N Lesions	Pathology Available (%)	Benign (%)	Positive for RCC (%)	Grade^a	Histology
Fujimoto	6	6 (100)	0	6 (100)	G2 = 5	Clear cell = 5
Bosniak	40	26 (65)	4 (15)	22 (85)	G1 = 18	NA
					G2 = 4
Oda	16	16 (100)	0	16 (100)	G1 = 6	NA
					G2 = 9
					G3 = 1
Kassouf	26	4 (15)	0	4 (100)	NA	Clear cell = 3
						Papillary = 1
Volpe	32	9 (28)	1 (11)	8 (89)	G2 = 4
					G3 = 2	Clear cell = 8
					G4 = 2
Wehle	29	5 (17)	1 (20)	4 (80)	NA	NA
Kato	18	18 (100)	0	18 (100)	G1 = 7	Clear cell = 15
					G2 = 8	Papillary = 3
					G3 = 3
Lamb^a	36	24 (67)	1 (4)	23 (96)	G1 = 3	Clear cell = 18
					G3 = 1	Papillary = 1
Sowery	22	2 (9)	0	2 (100)	NA	NA
Uzzo^b	61	21 (34)	4 (19)	17 (81)	G1 = 11	Clear cell = 9
					G2 = 5	Papillary = 7
					G3 = 1	Collecting duct = 1
Meta-analysis	286	131 (46)	11 (8)	120 (92)
Siu	47	16 (34)	6 (38)	10 (62)	NA	NA
Kouba	46	14 (30)	2 (14)	12 (86)	G1 = 2
					G2 = 8	NA
					G3 = 2
Crispen^b	124	39 (36)	4 (10)	35 (90)	NA	Clear cell = 24
						Papillary = 9
						Chromophobe = 1
						Collecting duct = 1
Abouassaly	110^c	4 (4)	2 (50)	2 (50)	G3 = 1	Clear cell = 1
						Papillary = 1
						Atypia = 1
Crispen^b	173	68 (39)	9 (13)	57 (84)	G1 = 19	Clear cell = 39
					G2 = 21	Papillary = 15
					G3 = 11	Chromophobe = 2
					G4 = 2	Collecting duct = 1
^aPathology presented in the Lamb et al. series represents pathologic assessment of percutaneous biopsies. ^bIndicates single-institution series that have accrued more patients with time. Last paper represents totality from institution, whereas prior series represent portion of patients undergoing AS. ^cExpressed as number of patients, not number of tumors.