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Genitourinary Imaging |
1 From the Department of Radiology, Asan Medical Center, University of Ulsan, 388–1 Poongnap-dong, Songpa-gu, Seoul, 138–736, Korea. Received October 27, 2003; revision requested January 13, 2004; final revision received June 10; accepted June 23. Address correspondence to J.K.K. (e-mail: rialto@amc.seoul.kr).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: The institutional review board approved this study; patient informed consent was not required. There were 162 men (mean age, 54 years ± 13 [standard deviation]) and 32 women (mean age, 56 years ± 11) who had undergone complete surgical resection of RCC. Mean follow-up period was 45 months (range, 7–92 months). In consensus, two radiologists determined the presence or absence of tumor recurrence and recorded the time and sites of tumor recurrence. The relationships between tumor recurrence and tumor factors, including greatest diameter (
5 cm or <5 cm), T stage, N stage, stage group, histologic subtype, and nuclear grade, were evaluated by using Kaplan-Meier statistics.
RESULTS: Tumor recurred in 41 (21%) patients. The mean time of tumor recurrence was 17 months (range, 3–50 months). Tumor recurred within 2 years after surgery in 34 (83%) patients. Tumor recurrence sites included lung (n = 29), bone (n = 13), the nephrectomy site (n = 7), brain (n = 6), liver (n = 5), mediastinal lymph nodes (n = 5), the contralateral kidney (n = 4), and the neck muscles (n = 2). The recurrence rate was greater for tumors 5 cm or larger than for those smaller than 5 cm, greater for T3a or T3b tumors than for T1 tumors, greater for stage III tumors than for stage I tumors, and greater for tumors with a nuclear grade of 3 or 4 than for those with a nuclear grade of 1 or 2 (P < .05 for all).
CONCLUSION: RCC usually recurs within 2 years after surgery, with the lung being the most vulnerable site; greatest tumor diameter, T stage, stage group, and nuclear grade are important factors for recurrence.
© RSNA, 2004
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In monitoring patients who have undergone surgery for RCC, radiologic examinations such as computed tomography (CT), radiography, and scintigraphy play a major role because physical examinations and laboratory studies are not sensitive for surveying tumor recurrence. Therefore, it is necessary to establish proper follow-up imaging strategies. For this purpose, basic concepts or principles regarding the proper time and modality for follow-up examinations should be determined on the basis of knowledge about tumor recurrence patterns.
To our knowledge, in the radiology literature, there has been little, if any, information on the tumor recurrence pattern of RCC and the use of imaging studies. Although tumor recurrence patterns have been analyzed in previous reports in the urology and oncology literature, the follow-up protocol and the criteria for diagnosing tumor recurrence were not clearly provided.
Thus, the purpose of our study was to retrospectively analyze the recurrence pattern of RCC and the factors affecting tumor recurrence.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Protocol for Surveillance Imaging Studies after Surgery
Although the time of follow-up radiologic examinations may vary according to various factors such as patient status, tumor stage, or the results of physical examinations, the general principles for follow-up imaging studies at our institution are as follows: (a) The initial postoperative CT examination is performed within 12 months after surgery, and thereafter, sequential CT examinations are performed at 6–12-month intervals; (b) chest radiographs are obtained every 3 months during the first year after surgery and then at least twice annually; (c) bone scans are obtained at 6–12-month intervals; and (d) other examinations, such as radiography of the skeletal system, chest or brain CT, magnetic resonance (MR) imaging, and ultrasonography (US), are performed when the information from routine radiologic examinations is insufficient or when patients have abnormalities in other body parts that were not imaged at routine examinations.
Patient Population
A computerized search of the medical records at our institution from January 1992 to December 1999 generated a list of 444 patients who had undergone nephrectomy and had been given a histologic diagnosis of RCC.
Patient inclusion and exclusion criteria were applied as follows: (a) Patients who had no evidence of tumor recurrence but were lost to follow-up within 3 years after surgery were excluded; (b) patients who had tumor recurrence were included regardless of the follow-up duration; (c) patients who did not follow the time schedule of follow-up imaging examinations or who skipped any examinations were excluded; (d) patients with incomplete tumor resection were excluded; (e) patients with any foci of metastasis (M1) at the time of surgery were excluded, but those with regional lymph node metastasis (N1 or N2) were included; (f) patients with two or more renal tumors were excluded; and (g) patients who had malignant diseases other than RCC during the follow-up period were excluded.
Working together, two radiologists (E.J.C., J.K.K.) reviewed the radiology reports and medical records of the 444 patients and subsequently selected a total of 194 patients, including 162 men (mean age, 54 years ± 13 [standard deviation]; age range, 18–75 years) and 32 women (mean age, 56 years; age range, 32–77 years). Mean and median follow-up periods for these 194 patients were 45 and 79 months, respectively (range, 7–92 months). Of these patients, 175 (90%) underwent radical nephrectomy and 19 (10%) underwent partial nephrectomy.
CT Examinations
Contrast material–enhanced CT scans covering the area from the diaphragm to the ischial tuberosities were obtained with a 9800 Quick System scanner (GE Medical Systems, Milwaukee, Wis) or a Somatom Plus-S scanner (Siemens, Erlangen, Germany) and with a section thickness of 5–8 mm and a pitch of 1.5–1.7 at a 5- or 8-mm reconstruction interval. A dose of approximately 600–900 mL of contrast material (barium sulfate suspension, E-Z-CAT; E-Z-Em, Westbury, NY) was administered orally to all patients before scanning. A dose of 100–120 mL of contrast material (iopamidol, Iopamiro 300, Bracco, Milan, Italy; or iopromide, Ultravist 300, Schering, Berlin, Germany) was administered intravenously to all patients, with the injection beginning 80–100 seconds before the start of scanning.
Data Analysis
Two radiologists—including a staff radiologist (J.K.K.) with 8 years of experience in genitourinary imaging and a senior resident (E.J.C.)—reviewed all radiologic images in all of the 194 patients in a consensus fashion. Tumor recurrence was considered to have occurred when histologic confirmation was obtained or the extent of the lesions had increased on sequential follow-up images. The radiologists considered the lesions that decreased in size or were stable during follow-up to represent postoperative changes. On the basis of these criteria, the presence or absence of tumor recurrence was determined in each patient; the time and sites of tumor recurrence were then recorded in patients with tumor recurrence.
The two radiologists in consensus also evaluated the relationship between tumor recurrence and various tumor factors, including the greatest diameter (whether 5 cm or <5 cm), T stage, N stage, stage group, histologic subtype, and nuclear grade. T stage, N stage, and stage group were determined by using the 1997 TNM system proposed by the American Joint Committee on Cancer (6). According to this system, the stage group was divided into groups I–IV. In our study, which did not include patients who had distant metastasis at the time of initial diagnosis, stage group I included T1N0M0 cancer; stage group II, T2N0M0 cancer; stage group III, T1N1M0, T2N1M0, T3N0M0, and T3N1M0 cancers; and stage group IV, T4N0M0, T4N1M0, T1N2M0, T2N2M0, T3N2M0, and T4N2M0 cancers.
Histologic subtypes were determined according to the classification system of the First International Workshop on RCC held by the World Health Organization and included clear cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma, collecting duct renal carcinoma, and unclassified renal carcinoma (7). Patients (n = 24) whose tumor subtypes were categorized on the basis of the previously used classification system—that is, patients who were given a diagnosis of, for example, granular renal carcinoma or sarcomatoid carcinoma—were excluded from the statistical analysis of the relationship between subtype and tumor recurrence. The nuclear grade was classified from 1 to 4 according to the Fuhrman grading system, which is based on histopathologic features (8). Fifteen patients whose tumor nuclear grades were not listed in the charts were excluded from the statistical analysis of the relationship between nuclear grade and tumor recurrence.
Statistical Analysis
Patient age was compared between men and women by using the Student t test. To evaluate the relationship between tumor recurrence and various tumor factors, including greatest diameter (5 cm or <5 cm), T stage, N stage, stage group, histologic subtype, and nuclear grade, we used Kaplan-Meier statistics. A P value of less than .05 was considered to indicate a statistically significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Diagnosis of Tumor Recurrence
Among the 194 study patients, 41 (21%) were given a diagnosis of tumor recurrence. These patients had a total of 71 sites of tumor recurrence, and histologic confirmation was obtained for 33 (46%) sites, including lung (n = 19), bone (n = 3), the nephrectomy site (n = 3), mediastinal lymph nodes (n = 3), liver (n = 2), brain (n = 2), and the neck muscles (n = 1). The initial diagnosis of tumor recurrence was established with histologic confirmation in 23 (56%) patients. In another three (7%) patients, the initial tumor recurrence sites were identified on images, and, thereafter, histologic confirmation was obtained for additional sites of tumor recurrence. Therefore, 26 (63%) of 41 patients had histologically confirmed tumor recurrence. In the remaining 15 (47%) patients, tumor recurrence at all sites was diagnosed purely on the basis of image findings. Image findings of tumor recurrence in these 15 patients are summarized in Table 1.
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At the time of the first diagnosis of tumor recurrence, 34 (83%) of 41 patients had a single focus of disease. These foci included the lung (n = 21 [62%]), bone (n = 5 [15%]), liver (n = 4 [12%]), the nephrectomy site (n = 1 [3%]), the contralateral kidney (n = 1 [3%]), brain (n = 1 [3%]), and the soft tissue of the neck (n = 1 [3%]). The remaining seven (17%) of the 41 patients had two or more foci of recurrent disease at the initial diagnosis of tumor recurrence.
The initial site of tumor recurrence included lung in 23 (56%) patients, bone in 12 (29%) patients, the nephrectomy site in four (10%) patients, liver in three (7%) patients, brain in three (7%) patients, the contralateral kidney in one (2%) patient, and the soft tissue of the neck in one (2%) patient.
Image Findings of Tumor Recurrence
Lung.—All patients with tumor recurrence in the lung had undergone chest CT and radiography. At the time of the initial diagnosis of lung metastasis, CT and radiography showed well-defined round or ovoid nodules that were 0.5–2.0 cm in greatest diameter (Figs 1, 2). The number of lesions was variable and ranged from one to many.
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Nephrectomy site.—Imaging studies that revealed tumor recurrence at the nephrectomy site included contrast-enhanced CT in seven patients and US in two patients. At CT, tumor recurrences manifested as 3–6-cm enhancing solid masses with central necrosis in all (100%) patients (Fig 2). US images also showed 3- and 5-cm solid masses with central necrosis in both (100%) patients.
Brain.—Brain metastases were identified at MR imaging in four patients and at contrast-enhanced CT in four patients. At MR imaging, metastases appeared as multiple enhancing nodules or 1–4-cm masses with surrounding edema in all (100%) patients (Fig 3). CT images also showed multiple enhancing 1.0–3.5-cm nodules in all patients.
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Relationships between Various Tumor Factors and Tumor Recurrence
The relationships between the various tumor factors and tumor recurrence are shown in Table 3. Statistical analysis revealed that tumor recurrence was significantly related to the greatest diameter of the tumor and to T stage, stage group, and nuclear grade. Patients with tumors that were 5 cm or larger in greatest diameter had a greater frequency of tumor recurrence than those with tumors that were smaller than 5 cm in diameter (P = .01) (Fig 4). Tumor recurrence was significantly more common in patients with T3a or T3b tumors than in those with T1 tumors (P = .006 and P = .012, respectively) (Fig 5). Patients in stage group III had a greater frequency of tumor recurrence than those in stage group I (P < .001) (Fig 6). Patients with nuclear grade 3 or nuclear grade 4 tumors had a greater frequency of tumor recurrence than either those with grade 1 tumors (P = .048 and P = .039, respectively) or those with grade 2 tumors (P = .001 and P = .026, respectively) (Fig 7). Histologic subtype was not significantly related to the frequency of tumor recurrence (P > .05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In previous studies involving evaluation of follow-up imaging in patients who had undergone surgery for RCC, we observed that a variety of guidelines were used at institutions and even by clinicians. Montie (20) proposed a protocol that includes chest radiography every 6 months and abdominal and pelvic CT at 12, 24, and 48 months, regardless of the stage of the primary tumor. Levy et al (15) recommended that an annual chest radiograph be obtained beginning at 6 and 3 months for T2 and T3 diseases, respectively, then every 6 months for 3 years, and then annually. They also proposed that surveillance CT be performed at 24 and 60 months in patients with T2 and those with T3 disease. Ljungberg et al (2) concluded that there is no need for follow-up in patients with either diploid T1 or T2 tumors or aneuploid T1 tumors smaller than 5 cm in diameter. Despite the strengths of these studies, which involved the use of reasonable analytic methods, large patient populations, and long follow-up periods, they were limited in that they lacked a detailed description for determining tumor recurrence and included only a few risk factors for tumor recurrence. Therefore, in this study, we made efforts to clarify the criteria for determining tumor recurrence and to include as many tumor factors as possible.
In the present study, the mean time of tumor recurrence was 17 months, and 83% of recurrences occurred within 2 years after surgery; these results are similar to those of previous studies (13–18). In contrast to the high rate of recurrence within 2 years, our results show that the frequency of tumor recurrence more than 2 years after surgery was considerable, and several previous reports have also described late recurrences of RCC (2,15,21,22). Therefore, we suggest that follow-up imaging examinations should be intensively performed within 2 years after surgery and that short-term surveillance after that period may be ineffective.
In the present study, the lung was the most vulnerable site for RCC recurrence; this corresponds to the results of previous studies (14–18). On the basis of these data, the use of chest CT for early detection of pulmonary metastasis can be recommended, with the rationale that chest CT has higher sensitivity for lesion detection than radiography (23). Previous studies revealed that surgical removal of a single focus of lung metastasis from RCC could result in a long disease-free period (3,24); therefore, early detection of lung metastasis with CT seems to be useful for achieving better treatment results and greater patient survival rates. Therefore, we suggest that it may be most effective to perform chest CT examinations in patients with a high risk of tumor recurrence in the early postoperative period—that is, within 2 years after surgery.
Indications for bone scanning in patients who have undergone nephrectomy for RCC vary by institutions and even by clinicians. In a relatively recent report, Levy et al (15) recommended performing bone surveillance examinations when patients have specific signs such as elevated alkaline phosphatase levels. In contrast, at our institution, bone scanning is included in the routine postoperative imaging surveillance protocol. Our study results showed that 62% of bone metastases occurred within 1 year after surgery and that 77% occurred within 2 years. These data suggest that it is worthwhile to perform bone scanning regularly during the early postoperative period.
Our results show that, among the various tumor factors examined in this study, large diameter, high T stage, high stage group, and high nuclear grade are important risk factors for tumor recurrence. On the basis of relationships between tumor recurrence and these tumor factors evaluated individually or together in previous studies, the tumor factors have proved to be related to patient prognosis (8,9,15,16). Therefore, we suggest that patients with these risk factors be more intensively evaluated.
So that we could determine the presence or absence of tumor recurrence with sequential imaging studies, we did not regard lesions that did not show progression on follow-up images as representing tumor recurrence. Therefore, it is possible that true tumor recurrences that were stable in size during the follow-up period or regressed after immunotherapy might have been misinterpreted as postoperative changes.
In our study, the N stage and histologic subtype were not significantly related to the frequency of tumor recurrence. In previous studies, both of these factors have been found to be closely related to patient survival in that prognosis was worse in patients with advanced N stage disease than in patients with N0 stage disease and in patients with clear cell or collecting duct renal carcinoma than in patients with papillary or chromophobe renal carcinoma (7,14,25). We suggest that the lack of significance of these factors in this study was due to the small number of patients in the study who had positive lymph nodes, papillary renal carcinoma, or chromophobe renal carcinoma and that correlation of these factors with tumor recurrence should not be neglected.
The major limitation of this study was that not all recurrent or metastatic lesions were histologically confirmed. Although we had evident criteria for diagnosing tumor recurrence, there still remained a potential risk that the lesions considered to represent tumor recurrence on the basis of image findings might have represented another malignant disease process.
Another limitation of this study was that, despite the attempt to include as many risk factors for tumor recurrence as possible, we did not evaluate some important factors that have already been proved to be closely associated with patient prognosis, including patient performance status and genetic factors such as ploidy, nuclear morphometry, and molecular markers (19).
Last, the CT acquisition techniques used in this study were not cutting edge by today’s standards; therefore, some lesions, particularly hepatic metastases, which can be more accurately detected with three-phase CT scanning, may have been missed.
In summary, RCC usually recurs within 2 years after surgery, with the lung being the most vulnerable site; the greatest diameter of the tumor, T stage, stage group, and nuclear grade are important factors for tumor recurrence. In conclusion, intensive surveillance for RCC recurrence is necessary in the early postoperative period, and greater consideration should particularly be given to monitoring patients who are at high risk for tumor recurrence as pulmonary metastasis. We recommend that chest CT be included in the routine tumor surveillance protocol and that it be performed every 6 months during the first 2 years after surgery and then annually for 2 years in patients with a high risk for tumor recurrence.
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FOOTNOTES |
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Abbreviation: RCC = renal cell carcinoma
Authors stated no financial relationship to disclose.
Author contributions: Guarantor of integrity of entire study, J.K.K.; study concepts, K.S.C., J.K.K.; study design, J.K.K., E.J.C.; literature research, J.K.K., E.J.C.; clinical studies, E.J.C., S.H.K., J.K.K., S.J.B.; data acquisition and analysis/interpretation, E.J.C., J.K.K.; statistical analysis, J.K.K., E.J.C.; manuscript preparation, E.J.C., J.K.K., S.H.K., S.J.B.; manuscript definition of intellectual content and final version approval, J.K.K.; manuscript editing, E.J.C., J.K.K.; manuscript revision/review, J.K.K., K.S.C.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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