Correspondence: Atsushi Takahashi MD, Department of Urology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060–8543, Japan. Email: firstname.lastname@example.org
Abstract Background: The natural history and growth rate of renal cell carcinoma (RCC) have not yet been determined. The growth rates of primary lesions in incidentally found RCC were compared with those of metastatic lesions.
Methods: Sixteen patients who did not receive immediate surgical treatment for renal solid masses that were later proven to be RCC were reviewed retrospectively. All primary lesions of the 16 patients were found incidentally. For comparison, metastatic lesions were evaluated in another 16 patients with RCC. Of these, 11 underwent surgical treatment for the primary lesions.
Results: The growth rates of primary and metastatic lesions of RCC varied. They ranged from 0.10 to 1.35 cm/year for primary lesions and from 0.08 to 7.87 cm/year for metastatic lesions. The growth rate of primary lesions of incidentally found RCC was lower than that of metastatic lesions (P = 0.0159). The initial tumor diameter and pathological grade did not affect the growth rate of the primary lesion of incidentally found RCC. However, a close correlation was found between the growth rate of metastatic lesions and the pathological grade of the primary lesion in patients with metastasis.
Conclusions: The growth rate of incidentally found RCC varied. Some patients with the disease may be candidates for ‘watchful waiting’ when an immediate surgical treatment is not indicated, but they should be selected with great caution.
Recent progress in the use of computed tomography (CT) and ultrasonography (US) in diagnosis and their frequent use in daily clinical practice allow us to incidentally detect renal solid masses.1 These masses have a high probability of eventually being diagnosed as renal cell carcinoma (RCC); however, at the time of the initial diagnosis imaging modalities do not always allow a correct diagnosis to be made. Thus, follow up of some renal solid masses can provide a unique opportunity to observe the natural history of renal cell carcinoma.
In this study, we tried to determine the natural history of incidentally found RCC by reviewing 16 patients who had not received immediate surgical treatment for renal solid masses that were later histopathologically proven to be RCC. We compared the growth rates of primary lesions in these patients with the growth rates of metastatic lesions of RCC in another 16 patients.
Patients with incidentally found RCC
Twelve men and four women ranging in age from 28 to 78 years (median: 54 years) were studied. Their renal solid masses were incidentally found in other institutes. Eleven patients were diagnosed as having a benign mass and five as having a normal kidney. Patients were followed up for 1.0–6.0 years (median: 2.1 years) at Sapporo Medical University Hospital. All patients were finally treated surgically and were diagnosed as having RCC.
Patients with metastatic RCC
The study initially included 36 patients with RCC and metastatic lesions that were regularly studied with various imaging modalities. The patients were seen in Sapporo Medical University Hospital from 1989 to 1998. Patients were excluded from this study if they had an observation period of less than 3 months or a tumor that could not be evaluated in image diagnosis (< 1.0 cm at the largest diameter). Sixteen of these 36 patients were eligible for this study because growth of their metastatic lesions was regularly evaluated with CT. They were 13 men and three women ranging in age from 42 to 73 years (median: 60 years). All patients were diagnosed as having RCC and its metastasis (seven patients) or its metastasis with a previous history of surgically removed RCC (nine patients) at the time of this study. In all the latter patients, metastasis was found within 5 years after surgery for the primary lesion. Of these 16 patients, 11 were confirmed to have RCC in the primary lesion by histopathology. The remaining patients were diagnosed with RCC and its metastasis by clinical findings. Metastatic sites consisted of the lung in 14 patients, the retroperitoneum in one patient and the adrenal in one patient. All patients received systemic interferon therapy for at least 3 months. This achieved no apparent clinical response. The observation period for growth of metastatic lesions ranged from 3 months to 5.1 years (median: 1.0 years).
Measurement of the growth rates of primary and metastatic lesions
The size of the renal mass in the primary lesion was measured with CT at the time of initial diagnosis and just before the surgery. These measurements were used to determine the growth rate. Plain CT and CT enhanced by intravenous bolus injection of a contrast medium were performed with 10 mm sliced sections. The size of metastatic lesions was evaluated with CT in 16 patients during the follow-up period with the same procedures and sliced sections as for primary lesions. The first and last findings of image diagnosis were used to determine the growth rate of metastatic lesions. When multiple metastatic foci were found at the time of the initial evaluation, the largest one was followed thereafter.
Tumor grade and pathological stage of renal cell carcinoma
The tumors were classified grade 1–3, depending on the degree of nuclear anaplasia. This was done according to the International Union Against Cancer (UICC) TNM classification2 with minor modifications advocated by the Japanese Urological, Pathologic and Radiological Societies.3 The pathological stage was also determined according to this classification.
The Mann–Whitney U-test was used to compare two groups and the Kruskal–Wallis test for three groups or more. A P-value < 0.05 was considered to be statistically significant. The Kaplan–Meier method was used to determine the 5-year survival rates of patients.
Clinical and pathological characteristics of the patients
In patients with incidentally found RCC, all primary lesions were surgically removed. Fourteen RCC (88%) were localized in the kidney (pT1a or pT1b). Most of the RCC (94%) were low-grade (grade 1 or 2) carcinomas, with only one grade 3 carcinoma found. No patient had metastatic disease in regional lymph nodes or distant organs at the time of diagnosis or during the follow-up period. All patients were alive at the final follow up. Eleven of the 16 patients (69%) with metastatic RCC had the primary lesions surgically removed at the time of diagnosis. Of these, eight RCC (73%) were revealed to be low-grade (grade 1–2) carcinomas, with the remaining three (27%) having a grade 3 carcinoma. The 5-year survival rate was 31% in these 16 patients based on the interval from the time metastasis was initially found to time of death.
Growth rates of primary and metastatic lesions
In the 16 patients with incidentally found RCC, the largest tumor diameter of the primary lesion ranged from 1.0 to 4.5 cm (median: 2.0 cm) at the initial evaluation and from 1.5 to 6.2 cm (median: 3.4 cm) at the final evaluation (Table 1). The growth rates of primary lesions varied from 0.10 to 1.35 cm/year (median: 0.54 cm/year). The metastatic lesions in 16 patients were somewhat smaller at the initial evaluation than those of the primary lesions, with the largest tumor diameter ranging from 1.0 to 3.0 cm (median: 1.9 cm). However, their final diameters ranged from 1.6 to 6.0 cm (median: 3.9 cm). The growth rates of metastatic lesions ranged from 0.08 to 7.87 cm/year (median: 1.72 cm/year). Thus, the primary lesions in patients with incidentally found RCC grew more slowly than the metastatic lesions (Table 1; P = 0.0159 by Mann–Whitney U-test).
Table 1. Tumor diameter and growth rates of primary and metastatic lesions
Primary lesions of 16 patients with incidentally found renal cell carcinoma
Metastatic lesions of 16 patients with renal cell carcinoma
Years from the first to the last imaging examinations;
primary versus metastatic lesions: P = 0.0159 by Mann–Whitney U-test.
Growth rate, tumor diameter and pathological features of RCC
The largest diameter at the initial evaluation of the primary lesion was not related to the growth rate in 16 patients with incidentally found RCC (Fig. 1). Nor did the growth rate show a direct relation to the initial largest diameter of the metastatic lesion in patients having metastasis. The histopathological grade of carcinoma did not have a close correlation with the growth rate of the primary lesion (Table 2). However, in 11 patients with metastatic disease who received surgical treatment of the primary lesion, the pathological grade of the carcinoma of the primary lesion showed a significant correlation with the growth rate of the metastatic lesion (P = 0.0406 by Kruskal–Wallis test; Table 2). Indeed, the most rapid growth rate of the metastatic lesion was found in patients with a grade 3 carcinoma in the primary lesion.
Table 2. Pathological grade of the primary lesion surgically removed and growth rates of the primary and metastatic lesions
Pathological grade of the primary lesion
Growth rate (cm/year)
Grade 1 versus 2 by Mann–Whitney U-test;
Sixteen patients with incidentally found renal cell carcinoma
During the past 15 years, there has been a marked increase in the number of renal solid masses detected incidentally when patients are medically evaluated for diseases other than those in the kidney.4 This increase is due mostly to the widespread use of abdominal CT and US as screening modalities. Many of these incidentally detected solid renal masses are ultimately proven to be RCC. However, the characteristics of some small renal masses cannot be correctly diagnosed even with modern diagnostic imaging modalities. The clinical behavior of such masses should be carefully followed. Patients with RCC who are not indicated for surgical removal of the primary lesion because of poor general health status may sometimes provide an opportunity to observe a part of the natural history of RCC (i.e. the growth behavior of RCC). However, the growth rate of the primary lesion of RCC cannot easily be determined.
In this study, we used the increase of tumor diameter per year to determine growth rates of primary and metastatic lesions. While the doubling time of tumor volume is often used to evaluate tumor growth, it sometimes gives us an unrealistic clinical image of this growth, particularly when a tumor has a small diameter. For example, a tumor with a diameter of 1 cm doubles in volume when its diameter increases to 1.25 cm. Thus, a tumor with a small diameter can dramatically double in volume giving us a misleading impression in the clinical setting. In this context, we believe that evaluation of the increase of tumor diameter may be more appropriate for clinicians. Indeed, recent reports have indicated a preference for the use of tumor diameter in evaluating the growth rates of renal solid masses.5–7
Bosniak et al. demonstrated an overall growth rate for renal tumors of 0–1.10 cm/year (mean 0.36 cm/year).5–7 Many of these tumors had a slow growth rate and half showed a growth rate of less than 0.5 cm/year. In the present study the growth rate of incidentally found RCC ranged from 0.10 to 1.35 cm/year (median 0.54 cm/year). When compared with Bosniak’s series, the growth rate in our study tended to be rapid. This may have been due to the difference in the clinicopathological features of the patients. The study by Bosniak et al. included oncocytoma and unknown pathological findings of renal masses.5–7 In our study, all patients with incidentally found renal masses were eventually revealed to have a histopathologically proven RCC. This result may indicate that the growth rate of RCC in our study more precisely reflects the natural course of incidentally found RCC.
We found that the growth rate of primary lesions was slower than that of the metastatic lesions. The growth rate of metastatic lesions may be underestimated due to interferon therapy regardless of the apparent lack of clinical response. This finding is consistent with that of Fujimoto et al.,8 who demonstrated that the mean doubling time of pulmonary metastases was significantly shorter than that of primary lesions. When we converted the doubling time reported in their study into the growth rate (cm/year), the growth rate of pulmonary metastases ranged from 0.42 to 4.43 cm/year (median: 1.48 cm/year). In our study, the growth rates of metastatic lesions of RCC ranged from 0.08 to 7.87 cm/year (median: 1.72 cm/year). Our data were more variable than those of Fujimoto et al.8 This may have been due to the different proportions of histopathological grades of RCC in our study. For example, our study included four grade 1 carcinomas among 11 RCC (36%), but there were no grade 1 carcinomas in their study.
The growth rate of metastatic lesions in patients with grade 3 carcinoma of the primary lesion was significantly higher than in those with grade 1 and 2 carcinomas in our study as well as in Fujimoto’s.8 Therefore, the more rapid growth of metastatic lesions may simply reflect the aggressive behavior of the high-grade carcinoma of the primary lesion. Alternatively, it may be due to the behavior of the metastatic tumor itself independent of the primary one.
The prognosis for patients with incidentally discovered RCC has been reported to be better in terms of survival than for symptomatic cases because the former consist of RCC with small tumor size, low-stage and low-grade carcinoma.1,9–12 A recent review revealed that most incidentally found RCC had a grade 1 or 2 carcinoma,12 which was similar to our previous report.1 With regard to the relationship between the size of RCC and its influence on prognosis, a few studies have demonstrated a close association between tumor size and growth potential. Bell noted a direct correlation between tumor size and malignant potential, in which carcinomas less than 30 mm in diameter had the lowest incidence of metastasis (i.e. a low potential for growth).13 Thus, Birnbaum et al.7 suggested that management by ‘watchful waiting’ could be indicated for some small incidentally discovered RCC (i.e. those with poor surgical risks or with other significant diseases and well-marginated renal lesions less than 2.0 cm in size).7 We partly agree with them because none of our patients developed metastatic disease during the follow-up period. However, in principle, we should surgically treat healthy patients with even small renal tumors because we cannot determine definitely which patients will be good candidates for ‘watchful waiting’ due to the lack of association between pathological grade, initial tumor diameter and subsequent growth noted in our study. Therefore, we should follow up patients with incidentally discovered RCC with great caution when an immediate surgical treatment is not indicated for them.
The growth rates of primary and metastatic lesions of RCC were variable. The growth rate of primary lesions of incidentally found RCC was lower than that of metastatic lesions. The initial tumor diameter and pathological grade did not affect the growth of incidentally found RCC, while a close correlation was found between the growth rate of metastatic lesions and the pathological grade of the primary lesion. Initial clinical and pathological features can not always predict subsequent clinical behavior of incidentally found RCC, suggesting that candidates for ‘watchful waiting’ should be selected very carefully.