Prognostic Significance of Tumor Thrombus Level in Patients With Renal Cell Carcinoma and Venous Tumor Thrombus Extension. Is All T3b the Same?

0022-5347/04/1712-0598/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 171, 598 – 601, February 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000108842.27907.47

PROGNOSTIC SIGNIFICANCE OF TUMOR THROMBUS LEVEL IN PATIENTS WITH RENAL CELL CARCINOMA AND VENOUS TUMOR THROMBUS EXTENSION. IS ALL T3b THE SAME? ALIREZA MOINZADEH

AND

JOHN A. LIBERTINO

From the Department of Urology, Lahey Clinic, Burlington, Massachusetts

ABSTRACT

Purpose: We investigated the prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma with particular emphasis on 2 questions. Does the level of thrombus in the inferior vena cava (IVC) impact long-term survival? Is there a difference in long-term survival when tumor thrombus is in the renal vein versus the IVC for patients classified as T3b by 1997 TNM staging? Materials and Methods: Between July 1970 and July 2000, 153 patients underwent surgical resection. Cancer specific survival was determined for different tumor thrombus levels in a retrospective fashion. Results: Mean followup was 60 months with a range of 12 to 221. Level of tumor thrombus was renal vein (in 46), level I (in 68), level II (in 17) and level III (in 22). No demographic differences existed between the different levels including gender, age, perinephric extension, Fuhrman grade, percentage of metastatic disease and tumor size (Fisher’s exact test). Patients with evidence of nodal disease or metastasis at surgery were eliminated from cancer specific survival analysis. The overall 10-year cancer specific survival for patients was 30%, 19% and 29% for level I, II and III, respectively. Patient survival at 5 and 10 years was not significantly different between the 3 IVC levels (p ⫽ 0.48). Ten-year survival of patients with renal vein involvement (66%) versus level I (29%) was significantly different (p ⫽ 0.0001). Conclusions: The level of tumor thrombus in the IVC does not significantly effect long-term survival. Ten-year survival of patients classified as T3b is statistically different for patients having tumor thrombus in the renal vein compared to level I. Combining these 2 groups as T3b by the 1997 TNM staging may need to be reevaluated. KEY WORDS: kidney; carcinoma, renal cell; thrombosis, venal cavae

Tumors of the kidney account for approximately 31,900 new diagnoses per year and about 11,900 deaths in the United States.1 Of these cases 4% to 10% will have tumor thrombus extending into the inferior vena cava (IVC).2 When there is no evidence of metastatic disease at surgery, survival has been reported even when tumor thrombus extends to the right atrium.3–5 Although some series have indicated that the cephalad extent of the tumor thrombus may be a negative prognostic factor,6 –9 other series have not demonstrated decreased survival in patients with tumor thrombus in the IVC.4 More recently, the current TNM classification of malignant tumors published in 1997 by the International Union Against Cancer has been called into question with regard to the best cutoff size for T1 versus T2 disease.10 Analogous to these concerns, it has been our recent impression that a significantly greater number of patients with IVC tumor thrombus below the diaphragm have decreased survival compared to patients with renal vein thrombus. Interestingly, the 1997 TNM classification categorizes both of these groups as T3b. The objectives of this study were 2-fold. First, does the cephalad extent of tumor thrombus in the venous system affect long-term survival? Second, how does the survival of patients with tumor thrombus in the IVC below the diaphragm compare to patients with tumor thrombus in the

renal vein? To address these questions we retrospectively reviewed the long-term survival of patients with regard to the cephalad extent of IVC tumor thrombus. In addition, the survival of patients labeled T3b by the 1997 TNM classification is critically analyzed. MATERIALS AND METHODS

From July 1970 to July 2000, 153 patients who had renal cell carcinoma (RCC) with venous vascular extension were treated with radical nephrectomy and tumor thrombus extraction at our institution by primarily 1 surgeon (JAL). Venous extension was defined as gross involvement. The patients consisted of 101 males and 52 females with a median age 61 years (range 39 to 82). Median tumor size was 8 cm (range 2.2 to 20). For the purpose of this study tumor extension into the venous system was classified (see figure) as renal vein in 46, level I (tumor thrombus below the diaphragm) in 68, level II (thrombus above the diaphragm but below the atrium) in 17 and level III (thrombus into the atrium) in 22. Preoperative evaluation for these patients was not uniform, as the data span 30 years. All patients had preoperative chest x-rays and routine blood work. To define the extent of the tumor thrombus better or to rule out preoperative nodal disease, 87% had computerized tomography (CT), 57% venacavography and 26% had magnetic resonance imaging/ magnetic resonance angiography. As the imaging technology improved, there was less emphasis on venacavography and increased use of CT with 3-dimensional imaging and mag-

Accepted for publication August 1, 2003. Nothing to disclose. Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 854 and 855. 598

TUMOR THROMBUS LEVEL IN RENAL CELL CARCINOMA AND VENOUS TUMOR THROMBUS EXTENSION

599

Level of tumor thrombus classification

netic resonance imaging. Patients suspected of having atrial disease based on these studies had preoperative transesophageal echocardiogram. In the IVC group 13 patients had node positive disease, 11 with evidence of metastasis at the time of surgery. Of the patients with atrial extension 3 had node positive disease and 3 had evidence of metastasis. All patients underwent radical nephrectomy with complete resection of the tumor and thrombus. Regional lymphadenectomy was performed with the radical nephrectomy. In cases where mobilization of the vena cava was required, a more extensive lymphadenectomy was performed. In cases where patients were known to have a solitary lung metastasis, resection was performed at the time of surgery. Patients with tumor thrombus in the IVC (level I) had cavotomy and reconstruction. Extension of tumor thrombus above the diaphragm (level II) or to the atrium (level III) required circulatory arrest with cardiopulmonary bypass. Three patients (1 in each level) had invasion of the wall of the IVC at the ostium of the renal vein. In these cases the wall was resected with negative margins and reconstructed with synthetic graft or pericardial patch as appropriate. Details of the surgical technique have been described previously in Swierzewski et al.11 Postoperatively, patients were followed with blood test, chest x-rays and CT. Bone scans were obtained for patients when indicated. Hospital charts were retrospectively reviewed. Patient status was obtained via office visit or telephone call to the patient or the primary referring physician. Nonparametric estimates of survival were constructed with Kaplan-Meier curves. Survival curves were generated based on cancer-free survival representing patients still alive from time of surgery to date of death, or at the last followup. Log rank tests were used for statistical comparisons. Specifically, we analyzed the survival of level I vs level II vs level

III patients with IVC thrombus. In addition, we compared the renal vein vs level I classified patients. RESULTS

Pathological examination of the surgical specimen confirmed RCC with venous extension in all patients. One genitourinary pathologist reviewed all pathology slides. Mean followup was 60 months (range 12 to 221). There were no demographic differences seen for the 3 IVC tumor thrombus levels with regard to Fuhrman tumor grade, gender, mean age, mean tumor size and perinephric extension (Fisher’s exact test, table 1). The cephalad extent of tumor thrombus did not increase the likelihood of nodal disease, metastasis or perinephric fat invasion at the time of surgery as shown in table 2 (chi-square test). To evaluate survival for the 3 different IVC tumor thrombus levels, we compared only the patients with N0 M0 disease. Several studies previously shown that if nodal status or metastatic status is positive at the time of surgery, survival is dramatically decreased. The overall 5-year and 10-year cancer specific survival (CSS) for each level with N0 M0 status at the time of surgery was estimated using the Kaplan-Meier method for the cohort (table 3).12 The survival difference between each group was not statistically different (log rank test). To explore our impression that patients with tumor thrombus in the renal vein fared better than those with tumor thrombus in the IVC below the diaphragm, we looked at the long-term cancer specific survival in these patients. All patients were classified as T3b, ie no tumor extension beyond Gerota’s fascia and renal vein or vena cava involvement below the diaphragm. No difference existed among the groups in regard to Fuhrman tumor grade, gender, mean age,

TABLE 1. Demographic comparison of different tumor thrombus levels in patients with N0 and M0 disease Variable No. pts Mean age (range) Mean tumor size (range) % Males/% females No. perinephric fat (%) No. tumor grade (%): 1 2 3 4 n M0 is no evidence of metastasis at time

Renal Vein

Level I

Level II

Level III

p Value

38 62.0 (45–78) 8.0 (3.5–20) 76/24 14 (38)

46 62.1 (39–82) 7.2 (2.5–20) 61/39 15 (33)

14 64.5 (47–82) 9.9 (4–13) 57/43 8 (57)

17 63.6 (48–78) 9.8 (4.7–18.0) 58/41 7 (41)

0.8255 0.362 0.4137 0.4260

1 (6) 1 (3) 5 (29) 15 (47) 10 (59) 13 (41) 1 (6) 3 (9) 17 32 of surgery. N0 is no evidence of nodal involvement

0 (0) 1 (11) 8 (89) 0 (0) 9 at time of surgery.

0 4 2 0 6

(0) (67) (33) (0)

0.3558

600

TUMOR THROMBUS LEVEL IN RENAL CELL CARCINOMA AND VENOUS TUMOR THROMBUS EXTENSION

TABLE 2. Differences between proportion of metastasis and nodal disease for different IVC tumor thrombus levels No. Level I (%) Total pts N0 ⫹ M0 disease M0 disease N0 disease

No. Level II (%)

No. Level III (%)

68 46

17 14

22 17

57 (84) 54 (63)

15 (88) 14 (82)

19 (86) 18 (82)

p Value

0.5942 0.7481

TABLE 3. Cancer specific survival for levels I, II and III I II III p Value

5-Yr Survival ⫾ SE %

10-Yr Survival ⫾ SE %

52.7 ⫾ 8.5 38.9 ⫾ 17.3 29.0 ⫾ 16.2 0.4874

30.4 ⫾ 8.7 19.4 ⫾ 16.3 29.0 ⫾ 16.2 0.4874

mean tumor size and perinephric extension. In addition, the percent metastasis and perinephric fat extension was not different between the 2 groups. Survival analysis for patients with N0 M0 disease showed no statistically significant difference using log rank analysis. Patients with thrombus extension to the renal vein appear to live longer compared to patients with thrombus extension below the diaphragm (table 4). DISCUSSION

The treatment of RCC with vascular extension has historically been challenging and controversial. Various reported 5-year survival rates can be found in the literature ranging from 25% to 57%.2–12 In this retrospective analysis we looked at the long-term survival of patients with venous extension, placing emphasis on survival outcome of patients with different levels of tumor thrombus extension. Our experience with 84 IVC extensions and 22 atrial extensions represents 1 of the largest series to date. In addition, the long-term followup of these patients allows for better estimation of 10year survival. Some reports have demonstrated decreased survival in patients with tumor thrombus in the IVC, in particular, with higher cephalad extent.6 –9 Other studies have not identified IVC tumor thrombus level as a negative prognostic indicator.4, 12, 13 Most of the earlier studies are limited by the small number of patients in the series and a relatively short followup. In this study we retrospectively analyzed patients undergoing radical nephrectomy for RCC with disease extension into the renal vein, IVC or right atrium. To compare long-term survival of the different tumor thrombus extension groups we first had to show that demographic factors between the groups were the same (table 1). Next we demonstrated that with tumor thrombus ascent in the IVC, there is not increased spread of the tumor in lymph node or distant metastases (table 2). The CSS at 5 and 10 years for the 3 levels was then examined (table 3). No difference is seen in CSS as the tumor extends in a cephalad direction. There is a trend toward decreased survival, particularly noted at 5 years. However, this trend was not found to be statistically significant. Interestingly, patients who survived for 5 years continued to have CSS up to 10 years. It would therefore seem that most disease recurrence at distant sites occurs within 5 years. We also noted that patients with renal vein tumor throm-

TABLE 4. Long-term survival of renal vein group versus level I 5-Yr survival ⫾ SE% 10-Yr survival ⫾ SE%

Renal Vein

Level I

p Value

81.3 ⫾ 7.7 76.5 ⫾ 8.6

52.7 ⫾ 8.5 30.4 ⫾ 8.7

0.0006

bus appeared to have better survival compared to patients with tumor thrombus in the IVC. With the current 1997 TNM International Union Against Cancer classification, T3b includes venous extension into the renal vein or the vena cava below the diaphragm. To ensure metastatic potential was not a factor in this variance, we ruled out increased metastatic disease with a more cephalad extent by showing no difference in increased nodal or metastatic positivity at the time of surgery. We previously reported no significant difference in survival of patients with renal vein thrombus versus those with IVC extension.10 However, in this updated series, specifically comparing the renal vein versus patients at level I, the data show a significant decrease in survival in the latter group (table 4). This finding may, in part, be due to either increased number of patients included in this study or the longer followup available for these patients. It is unclear why patients with stage T3b disease with tumor thrombus in the renal vein had improved survival compared to T3b counterparts with tumor thrombus in the IVC below the diaphragm. Occult metastasis at the time of surgery may certainly be a plausible explanation for cancer recurrence in these patients. One may speculate that the results are related to the duration of tumor existence leading to an increased risk of metastasis. However, we cannot offer any conclusive evidence for this difference. One may postulate increased blood flow over the tumor thrombus in the IVC relative to the renal vein as a cause of potential seeding. It has been our experience that patients with tumor thrombus in the renal vein often have complete obstruction and collaterals develop. Thus, the tumor thrombus may obstruct blood flow and therefore decrease the likelihood of serving as a source for cancer cell germination. Others may argue that patients who have level I tumor thrombus may have an increased risk of invasion of the IVC wall. This possibility has previously been shown to be a negative prognostic indicator.14 However, in our review only 3 such patients were found to have IVC wall invasion. The IVC wall was resected with negative margins and the vena caval wall was reconstructed. Therefore, this condition would not account for the difference in survival between the 2 groups. We encourage other investigators at major referral institutions to look at T3b tumor thrombus data. If other investigations corroborate the data presented here, the prognostic value of the TNM staging with patients labeled T3b may be called into question. As the TNM committee plans future meetings to discuss the implications of tumor size as a criterion for change, perhaps further stratification of T3b may also be warranted based on the level of the tumor thrombus. CONCLUSIONS

Our results indicate that tumor thrombus level in the IVC does not predict a decreased survival outcome with cephalad extent. However, when looking at the 1997 TNM defined T3b patients, patients with tumor thrombus in the IVC below the level of the diaphragm have a significantly decreased survival compared to those with tumor thrombus in the renal vein. Based on our data the current definition of T3b may need to be reconsidered. REFERENCES

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