The Natural History of Small Renal Masses

Summary and Introduction
Summary

The incidence of renal cell carcinoma is increasing, in part due to the growing use of cross-sectional imaging. Most renal tumors are now incidentally detected as small masses in asymptomatic patients. A minority of small renal masses, presumed to be renal cell carcinoma, grow significantly over time if managed conservatively, but the growth rate of the majority is slow or undetectable. In the absence of other prognostic factors, measurement of tumor growth rate can be helpful for initial conservative management of selected patients with small renal tumors. To date, there have been no reports of progression to metastatic disease occurring during active surveillance, but longer follow-up is needed to confirm this observation. The standard of care for small localized renal neoplasms is partial or radical nephrectomy. At the present time, active surveillance of small renal masses, with delayed therapy for patients whose disease progresses, is an experimental approach that can be considered for the elderly or patients with significant comorbidity. Renal core biopsy and fine-needle aspiration can provide essential information for treatment decision-making and should therefore be considered in the diagnostic work-up of all small renal masses. In future, the identification of prognostic indicators, with the use of new techniques including functional imaging and molecular or genomic characterization of tissue from needle biopsies, are expected to help clinicians differentiate between indolent and potentially aggressive small renal tumors.
Introduction

Malignant tumors of the kidney are responsible for about 2% of cancer incidence and mortality in the US, with an estimated 36,160 new cases and 12,660 deaths in 2005.[1] There has been an increase of 126% in the incidence of renal cell carcinoma (RCC) in the US since 1950.[2] This rising trend has been observed worldwide and is partially due to the growing use of new and improved noninvasive abdominal imaging modalities, such as ultrasonography, CT and MRI.[2,3,4,5]

The increasing incidence of RCC has occurred across all clinical stages, but the greatest increase has been observed in the incidence of localized tumors, with an average annual increase of 3.7% from 1973 to 1998 in the US.[3,4] In more recent years, 48 to 66% of RCCs have been detected incidentally as SMALL RENAL MASSES in asymptomatic patients, whereas historically most cases were diagnosed following investigations for flank pain or hematuria.[6,7,8] Tumor size at diagnosis has also decreased substantially over time. The Memorial Sloan-Kettering Cancer Center reported a drop in the mean size of resected renal tumors from a maximum diameter of 7.8 cm to 5.3 cm between 1989 and 1998.[9]

The largest increase in incidentally detected renal tumors has occurred among patients aged 70-89 years, presumably because these individuals are more likely to undergo radiologic examination for other medical issues.[3]

There are numerous reports suggesting that incidentally detected lesions are, on average, smaller and present at an earlier stage than those detected in symptomatic patients.[4,5,7,9,10,11,12,13] Compared to symptomatic renal masses, small asymptomatic masses are more frequently benign and those confirmed as RCCs are, on average, lower grade.[5,7,14,15,16] Frank et al. reviewed the pathology of 2,935 renal tumors at the Mayo Clinic. They observed that as tumor size decreases there is a significant increase in the likelihood of a benign histology, a papillary compared to a clear-cell histology and a low-grade compared to a high-grade malignancy. In their experience, 30% of tumors below 4 cm in their maximum dimension were benign and over 87% of those diagnosed as clear-cell RCCs were low-grade tumors.[15]

Finally, several authors have reported that small incidentally detected tumors are associated with better survival outcomes.[5,11,12,14,17] The 5-year disease-free survival rate for incidental renal tumors of <4 cm treated with radical or partial nephrectomy is 95-100%.[9,10] Bell was the first author to report an association between renal tumor size and prognosis, when he noted an increased rate of metastases in patients found to have RCCs >3 cm in maximum dimension at autopsy compared to those with RCCs of 3 cm.[18] Tumor size is a key component of the tumor-node-metastasis (TNM) staging system and remains the most important prognostic factor for RCC.

Natural history Of small renal masses The NATURAL HISTORY of small renal masses has not been extensively studied because most tumors are surgically removed soon after diagnosis; however, Table 1 lists the outcomes of some studies which have examined ACTIVE SURVEILLANCE of small renal masses.

In the landmark report of surveillance of kidney tumors, Bosniak et al. retrospectively reviewed the imaging of 40 incidentally detected <3.5 cm renal masses that had been followed up for a mean of 3.25 years (range 1.75-8.5 years). Of 26 tumors that were eventually removed after an average of 3.8 years (range 1.8-8.5 years), 22 (84.6%) were histologically confirmed as RCC. Variable tumor growth rates were observed, but the overall mean linear growth rate for all tumors was 0.36 cm/year (0-1.1 cm/year). Nineteen tumors grew at a rate of <0.35 cm/year and no patient developed metastatic disease.[19] More recently, Oda et al. observed 16 patients with incidentally diagnosed and histologically proven localized RCC. The tumor growth rate varied from 0.10 to 1.35 cm/year and was significantly lower than that of metastatic RCC lesions.[20]

In the first prospective study of watchful waiting for renal tumors, we reported a series of 13 patients incidentally diagnosed with a small <4 cm renal mass and followed expectantly because they were elderly or unfit for surgery. We hypothesized that the tumors that are destined to grow fast, and possibly metastasize, do so early, while most small tumors grow at a slow rate or not at all.[21] We have subsequently reported the Results of active surveillance of an expanded series of 32 renal masses in 29 patients. Of the 32 masses, 25 were solid masses and 7 were complex cysts (four were BOSNIAK CATEGORY III RENAL LESIONs and three were BOSNIAK CATEGORY IV RENAL LESIONs). The patients were prospectively followed up with serial abdominal imaging for a mean of 27.9 months (range 5.3-143 months), with at least three follow-up measurements carried out on each mass. Tumor volume, in addition to single and bidimensional diameters, was calculated from each follow-up image or report. After an average of 38 months of follow-up, nine masses in eight patients were surgically removed either because of the surgeon's concern or the patient's anxiety that the tumor was enlarging. All tumors were clear-cell RCCs, with the exception of one oncocytoma. The overall average growth rate was low and showed no correlation with either initial size or mass type. Seven masses (22%) reached 4 cm in diameter after 12 to 85 months of follow-up and eight (25%) doubled their volume within 12 months. Overall, 11 (34%) fulfilled one of these two criteria of rapid growth. No patient progressed to metastatic disease; two patients died of unrelated causes.[22]

Kassouf et al., who serially imaged 24 patients with small renal masses, have since reported a similar experience. Most of the tumors demonstrated no significant growth during the surveillance period and no metastases were documented, with a mean follow-up of 31.6 months.[23]

In another study, 29 small, incidentally detected, contrast-enhancing renal masses were followed with serial CT imaging. In 15 patients no tumor growth occurred during follow-up. Six patients were eventually treated for significant tumor growth or at the request of the patient. Pathology was obtained in five cases (four RCCs and one oncocytoma). No patients died of RCC or developed metastatic disease.[24]

Kato et al. reported on the natural history of 18 incidentally detected and histologically proven RCCs that were surgically removed after a median observation period of 22.5 months. The average annual growth rate was 0.42 cm, and FUHRMAN GRADE III tumors, which comprised 17% of the series, grew faster than FUHRMAN GRADE I-II tumors. The authors found a significant correlation between tumor growth rate and apoptotic activity measured with the TUNEL technique, but no correlation between tumor growth rate and proliferative activity measured by Ki-67 immunostaining.[25] Interestingly, Lamb et al. also observed a slow growth rate in larger renal tumors. They followed a series of 36 renal masses with an average size of 7.2 cm at diagnosis, in patients who were considered unsuitable for surgery or were unwilling to have surgery. Two-thirds of the masses were biopsied and the diagnosis of RCC was confirmed in all cases except one. The authors observed a growth rate of 0.0-1.76 cm/year, with 55% of patients showing no increase in tumor size. Only one patient, who had a high-grade tumor at biopsy, eventually developed metastases 132 months after the initial diagnosis.[26]

The studies on active surveillance that have been published to date are mostly retrospective, have a relatively short follow-up period and include a limited number of patients. Their Results are consistent, however, and clearly suggest that a large proportion of incidentally detected small renal masses have a slow growth rate and an indolent clinical behavior, if managed conservatively. Rare cases of small renal tumors presenting with distant metastases at diagnosis have been described in the literature, but, to date, we are unaware of a case in which a small renal mass that was either presumed or proven to be RCC has metastasized during the surveillance period.[27]

Compared to the large increase in the detected incidence of RCC in recent years, the mortality rate of RCC has increased only modestly. This could be due to a lead-time bias, or might further support the theory that many small renal tumors have a long natural history and are not destined to progress, while those likely to do so are probably resected too late despite their localized radiographic appearance.[1,2,3,4,28] Furthermore, reports from autopsy series performed before the widespread use of imaging show that 67-74% of RCCs remained undetected until death and that only 8.9-20% of undiagnosed RCCs were eventually responsible for the patient's death.[29,30]

The watchful-waiting series described above comprised mostly elderly patients. This population may not be entirely representative of all patients presenting with a small renal mass. The biology of small renal tumors may differ in younger patients. A report from the Mayo Clinic observed that patients aged 18-40 years were more likely to have chromophobe than clear-cell RCCs when compared to patients that are 60-70 years old. The tumors in the younger group were also more likely to be cystic and to present at a lower stage, all features that have been shown to be associated with a favorable prognosis.[31]

Imaging and biopsy of small renal masses Measurement error at imaging is a key concern in the management of patients with small renal tumors. Accurate edge detection of an irregular mass at imaging can be difficult, particularly in the presence of features such as hemorrhage, pyelonephritis, cysts or dilated calices adjacent to the tumor, multiple cysts within the kidney and localization near or invasion of the collecting system.[32] We have performed a study of interobserver and intraobserver variability in CT measurement of small renal masses, comparing volumes estimated on imaging with postoperative volumes. Although it is well known that differences between these measurements can occur as a result of decreased kidney and tumor blood volume in the surgical specimen caused by initial ligation of the arterial blood supply, we have demonstrated that measurement of the dimensions of a renal tumor based on CT scans and MRI offers an accurate means of assessing tumor growth.[33]

Renal masses with cystic components present a special problem because their growth rate can be easily overestimated or underestimated if the volume of cystic fluid grows at a different rate to the tumor cell volume. Some authors have observed that the prognosis for patients with cystic RCC is better than that for patients with solid tumors, but, as the tumors were all managed by surgery, these reports do not give us information about the natural history of this type of tumor.[34,35] In our experience, complex cystic renal masses have a comparable growth rate to that of solid tumors.[22]

Historically, needle-core biopsies of renal masses have been recommended to rule out the presence of metastatic disease to the kidney, renal abscess or lymphoma and to confirm the diagnosis of a renal-cell primary tumor in patients with disseminated metastases or unresectable tumors. Beyond these indications, renal needle biopsies have not been widely performed in North America because of concerns about complications, tumor seeding and sampling errors. However, the techniques and Results of needle biopsy of renal masses under imaging guidance have significantly improved over time and the associated risks have significantly decreased. Fine-needle aspiration and core biopsy of renal masses now appear to be safe and can be performed in an outpatient setting with a low morbidity rate.[36,37,38] A high degree of accuracy can now be achieved, both in obtaining tissue and interpreting it with routine pathologic techniques. The sensitivity and specificity of renal tumor biopsy reported in the literature are 70-92% and 100% respectively, with accuracy close to 90%.[39]

Neuzillet et al. reported the Results of helical CT-guided percutaneous fine-needle biopsy on 88 consecutive patients with solid, small (<4 cm in maximum dimension) renal masses. Adequate material for histologic examination was obtained from 96.6% of the patients. In 5.6% of cases pathology revealed only fibrosis and was considered inconclusive; 15.9% of the masses were found to be benign. Following diagnosis of RCC at biopsy, 62 patients underwent radical or partial nephrectomy. The sensitivity of the biopsy was 92% for diagnosis of malignancy and tumor subtype. There was a weaker correlation between the Fuhrman grade, as determined by biopsy, and the final tumor grade (70%); however, no tumor was erroneously graded by more than one point. There were no false-positive Results and no significant postbiopsy complications or track seeding were reported.[38] One of the major concerns with needle-core biopsies of renal tumors is the risk of misdiagnosing or undergrading tumors as a result of histologic heterogeneity. We recently reviewed our personal experience and observed that intratumoral heterogeneity does not represent a significant issue in small renal tumors (A Evans, A Saravannan, A Volpe and MA Jewett, unpublished data).

On the basis of their Results, Neuzillet et al. advocate the routine use of needle biopsies to better characterize the histology of small renal masses before surgical or conservative treatment. We believe that all patients who are incidentally diagnosed with a small renal mass should undergo a biopsy before being enrolled in an active-surveillance protocol.