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Renal cell carcinoma with inferior vena cava thrombus: The Hacettepe experience
Urologic Oncology: Seminars and Original Investigations 28 (2010) 603– 609
Original article
Renal cell carcinoma with inferior vena cava thrombus: The Hacettepe experience Sertac Yazici, M.D.a, Kubilay Inci, M.D.a, Cenk Yucel Bilen, M.D.a, Ahmet Gudeloglu, M.D.a, Bulent Akdogan, M.D.a, Dilek Ertoy, M.D.b, Volkan Kaynaroglu, M.D.c, Metin Demircin, M.D.d, Haluk Ozen, M.D.a,* a
Department of Urology, Hacettepe University School of Medicine, Ankara, Turkey Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey c Department of General Surgery, Hacettepe University School of Medicine, Ankara, Turkey d Department of Cardiovascular Surgery, Hacettepe University School of Medicine, Ankara, Turkey b
Received 27 August 2008; received in revised form 20 November 2008; accepted 21 November 2008
Abstract Objectives: We evaluated the clinical outcome and factors affecting survival in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC). Methods: Between 1990 and 2007, 28 patients with RCC and tumor thrombus extending into IVC underwent radical nephrectomy and thrombectomy. Patient data were reviewed retrospectively to evaluate the demographics, clinical presentation, surgical approach, pathological features, clinical outcomes, and survival. Results: Twenty-eight patients with a mean age of 52.7 years were operated. Thrombus level was infrahepatic in 15 patients (54%), intrahepatic in 3 patients (10%), suprahepatic in 3 patients (10%), supradiaphragmatic in 2 patients (8%), and intracardiac in 5 patients (18%). All patients with intracardiac thrombi underwent cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). The mean tumor size was 98.21 mm. Four patients had distant metastases and 3 patients had lymph node involvement. Pathological examination revealed RCC of clear cell type in 26 patients, papillary in 1 and chromophobe in 1 patient. At a mean follow-up of 36.4 months, 16 patients were still alive while 8 patients died due to disease progression and 2 patients died of other causes. Two patients died of pulmonary emboli in the early postoperative period. Lymph node involvement, distant metastases, hypercalcemia, and sarcomatoid component were found to be factors affecting overall survival significantly. Level of tumor thrombus and Fuhrman grade did not affect survival. Conclusions: Radical nephrectomy and tumor thrombectomy is currently known to be the most effective method in patients with RCC and tumor thrombus extending into IVC. Factors affecting survival are the ones related to tumor biology. Tumor thrombus level does not affect the prognosis. © 2010 Elsevier Inc. All rights reserved. Keywords: Renal cell cancer; Inferior vena cava thrombus; Survival
1. Introduction Renal cell carcinoma (RCC) has a tendency for invasion of renal vein or inferior vena cava (IVC) in 4% to 10% of cases [1]. An aggressive approach with radical nephrectomy and thrombectomy is the mainstay of the treatment in these patients [2]. Patients with RCC and tumor thrombus usually present with severe symptoms requiring palliation even in
the presence of metastatic disease [3]. The prognostic significance of cephalad extension of tumor thrombus have been evaluated in several studies [4 – 8]. In the present study, we retrospectively analyzed the surgical approaches, clinical outcome, and clinicopathological factors affecting survival in patients with RCC involving IVC.
2. Patients and Methods * Corresponding author. Tel.: ⫹90-312-305-1969; fax: ⫹90-312311-2262. E-mail address: [email protected] (H. Ozen). 1078-1439/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2008.11.017
A total of 612 patients with renal cell carcinoma underwent partial or radical nephrectomy at the Hacettepe Uni-
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versity Hospital between 1990 and September 2007. Of these patients, 28 (4.5%) had tumor thrombus extending into inferior vena cava (IVC). Patients with bilateral tumor, Von Hippel-Lindau disease, or tuberous sclerosis were excluded. Patient data were reviewed retrospectively to evaluate the demographics, clinical presentation, surgical approach, pathological features, clinical outcomes, and survival. Performance status for each patient was measured by the Eastern Cooperative Oncology Group performance score (ECOG PS) [9]. All patients were examined preoperatively with chest X-ray and computerized tomography (CT) of the abdomen, pelvis, and lungs. Magnetic resonance imaging (MRI) and transesophageal echocardiography were performed to assess the level of thrombus and to examine any possible intracardiac extension. Operative variables included surgical incision, duration of surgery, level of thrombus, need for cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), estimated blood loss, and hospital stay. The 2002 American Joint Committee on Cancer TNM classification was used for tumor staging [10]. Patients with tumor thrombus in the renal vein were not included. Therefore, according to our experience, the definition of vena cava thrombus level was modified as infrahepatic, intrahepatic, suprahepatic (infradiaphragmatic), supradiaphragmatic, and intracardiac. All pathology slides were reviewed by the central pathologist for tumor histological type and nuclear grade, which were determined according to the 1997 WHO classification [11] and Fuhrman’s grading scheme [12]. Histological tumor necrosis was defined as presence of microscopic tumor necrosis. 2.1. Surgical management All patients had undergone radical nephrectomy and thrombectomy. No preoperative arterial embolization was performed. In all cases, renal artery was ligated early during the course of the surgery to decrease venous bleeding and to reduce the cephalad extension of vena cava thrombus. Surgical approach and technique depended on the level of tumor thrombus. For infrahepatic thrombi, a subcostal approach was preferred. After the mobilization of the kidney, clamps were placed consecutively on infrarenal vena cava, contralateral renal vein, and suprarenal vena cava. Following the accomplishment of vascular control, vena cavotomy and extraction of tumor thrombus was performed together with nephrectomy. The lumen was flushed and the cavotomy was closed with running 5-0 Prolene sutures. The clamps were removed orderly beginning from the distal vena cava and proceeding to the contralateral renal vein and proximal vena cava. For intrahepatic and suprahepatic thrombi below the diaphragm, satisfactory exposure of the retrohepatic inferior vena cava is important; therefore a midline abdominal incision was our favorite. First, the liver was mobilized to the left using techniques described for liver transplantation
[13]. For exposure and control of the major hepatic veins, the Pringle maneuver was used when necessary. After the separation of IVC from the posterior abdominal wall, the suprahepatic infradiaphragmatic vena cava, the infrarenal vena cava, the contralateral renal vein, and hepatic vein were clamped consecutively. IVC was dissected extensively, tumor thrombus was removed, and the vena cava reconstruction was performed as previously described for infrahepatic thrombi. No veno-venous bypass was required in any of the patients. A midline abdominal approach with median sternotomy was performed in patients with supradiaphragmatic and intracardiac thrombi. All patients with intracardiac thrombi underwent cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Tumor thrombi were removed as described previously [14]. Renal tumor and vena cava thrombus were removed completely in all cases, with regional lymphadenectomy for enlarged or suspicious lymph nodes. Vena cava reconstruction using synthetic grafts was required in 4 patients. Patients were followed up at 6-month intervals postoperatively with physical examination, imaging studies (chest X-ray and computed tomography of the abdomen), complete blood count, and serum chemistry evaluation. Progression was defined as the development of new tumor, either local or distant, in a patient after nephrectomy. Survival was calculated from the date of surgery to the date of last follow-up visit for surviving patients or to death. 2.2. Statistics Overall survival and progression-free survival were estimated using Kaplan-Meier curves. Subgroup differences were tested using the log-rank test. Multivariate Cox proportional survival analysis was done using clinical presentation, patient age, ECOG PS, distant metastasis (M⫹), lymph node metastasis (N⫹), Fuhrman grade, tumor stage, tumor size, histological type, presence of necrosis, preoperative calcium level, and thrombus level as possible independent variables. 2.3. Limitations of the study The main disadvantage of the study was the low number of population and a relatively high number of variables. Although the computer medium made it very “easy” to run very complicated statistical methods for even such low numbers, basic explanatory statistics such as the rates, ratios, and univariate analysis results would be more reliable in such a work.
3. Results Patient characteristics are summarized in Table 1. Twenty male and 8 female patients with a mean age of 52.7
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vasion of IVC wall documented histologically. Tumor invaded beyond Gerota’s fascia in 1 patient (stage T4).
Table 1 Patient characteristics Age (years) Mean Median Sex (n) Male Female Tumor and thrombus site Left Right Mean Follow-up (months) Presentation (n) Incidental Hematuria Abdominal pain Palpable mass Combination ECOG performance status 0 1 2 3
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52.7 54.5
3.2. Survival and progression
20 (71%) 8 (29%)
The mean follow-up was 36.4 months (range 6 to 164 months). A total of 12 patients were still alive with no evidence of disease, 4 patients were alive with disease, 8 patients had died due to disease progression, and 2 patients had died of other causes. Overall 3-year survival in patients with inferior vena cava thrombus was 60.2% (mean overall survival 104.3 ⫾ 16.5 months). Independent variables that were significantly associated with overall survival were lymph node metastasis, distant metastasis, presence of sarcomatoid component, and preoperative hypercalcemia (serum calcium level ⬎ 10.2 mg/dl) (Fig. 1). Level of tumor thrombus and Fuhrman grade were not found to affect survival significantly. Although significant in univariate analysis, lymph node metastasis and hypercalcemia were not retained in multivariate analysis. Distant metastasis and presence of sarcomatoid component remained significant
7 (25%) 21 (75%) 36.4 5 (18%) 9 (32%) 8 (29%) 2 (7%) 4 (14%) 19 (68%) 8 (29%) 1 (3%) 0
years had undergone radical nephrectomy and thrombectomy. A predominance of right-sided tumors was present (75%). Hematuria was the most common symptom (32%) followed by abdominal pain (29%). Mean operation time was 230.35 minutes (range 110 to 480 minutes). Mean blood loss and hospital stay were 1935 ml (range 280 to 5000 ml) and 10.8 days (range 4 to 45 days) respectively. The level of thrombus did not affect the operative time, blood loss, and hospital stay significantly, although a trend toward a longer operative time and increased estimated blood loss was observed with the higher levels of thrombus. None of the patients required re-exploration after the surgery. 3.1. Clinical and pathological findings Table 2 lists the clinical and pathological characteristics. Level of thrombus was infrahepatic in 15 patients (54%), intrahepatic in 3 patients (10%), suprahepatic in 3 patients (10%), supradiaphragmatic in 2 patients (8%), and intracardiac in 5 patients (18%). A subcostal incision was preferred in 8 patients (28%). All patients with intracardiac thrombi underwent CPB with DHCA. Venous wall resection and grafting was required in 4 patients due to tumoral involvement of the IVC wall. Renal tumor and the tumor thrombus were removed in all cases. Two patients died in the early postoperative period (postoperative sixth hour and eleventh day) due to pulmonary emboli and cardiac arrhythmia. Of the 28 patients, 4 (14%) had distant metastases (lung), and 3 (11%) had lymph node involvement (Table 2). Pathological evaluation revealed clear cell RCC in 26 patients (92%), papillary RCC in 1 patient (4%), and chromophobe RCC in 1 patient (4%). Three patients (10%) had direct tumor in-
Table 2 Clinical and pathological characteristics Mean tumor size (⫾SD) Incision Subcostal Chevron Median sternotomy Midline abdominal Flank RCC histological type Clear Cell Papillary Chromophobe Sarcomatoid component Histological tumor necrosis Yes No Fuhrman nuclear grade 1 2 3 4 Thrombus Level Infrahepatic Intrahepatic Suprahepatic Supradiaphragmatic Intracardiac Pathological stage pT3b pT3c pT4 Lymph node involvement pNx/pN0 pN1/pN2 Distant metastasis pM0 pM1
98.21 ⫾ 35.09 mm 8 (28%) 7 (25%) 7 (25%) 4 (14%) 2 (8%) 26 (92%) 1 (4%) 1 (4%) 4 (14%) 13 (46%) 15 (54%) 0 5 (18%) 12 (43%) 11 (39%) 15 (54%) 3 (10%) 3 (10%) 2 (8%) 5 (18%) 20 (71%) 7 (25%) 1 (4%) 25 (89%) 3 (11%) 24 (86%) 4 (14%)
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Fig. 1. Kaplan-Meier overall survival estimates based on (A) distant metastasis; (B) lymph node metastasis; (C) preoperative serum calcium level; and (D) sarcomatoid tumor component.
for predicting survival in multivariate analysis (P ⬍ 0.005). Mean survival of patients with lymph node metastasis and distant metastasis were 14.3 and 12.1 months respectively (Table 3). Among patients with lymph node or distant metastasis, 6 had died of disease and 1 patient has the disease receiving immunotherapy for bone metastases. Mean survival of patients with no lymph node or distant metastasis was 137.13 months (median 164 months). The KaplanMeier cumulative estimate of overall 3-year survival was 81% in patients without lymph node or distant metastasis and 0% in patients with lymph node or distant metastasis (log rank P ⬍ 0.001). In patients with no metastatic disease (M0), univariate survival analysis revealed that lymph node metastasis (P ⫽ 0.0001), presence of sarcomatoid component (P ⬍ 0.0001), preoperative serum calcium level (P ⫽ 0.012), and ECOG performance status (P ⫽ 0.014) were significant predictors of overall survival. On multivariate analysis, sarcomatoid component was the only variable to significantly affect overall survival (P ⬍ 0.0001). Tumor size, Fuhrman grade, pathological stage, and thrombus level did not affect the
outcome. Overall survival rate in patients without metastatic disease was 68.5% at 3 years (mean overall survival 117.4 ⫾ 17.1 months). Table 3 Overall survival (OS) rates and mean survival time according to distant metastasis, lymph node involvement, sarcomatoid component status, and preoperative serum calcium levels
Distant metastasis pM0 pM1 Lymph node involvement pNx/N0 pN1/N2 Sarcomatoid component Absent Present Preoperative serum Ca ⬍10.2 mg/dL ⱖ10.2 mg/dL
1-year OS rate
3-year OS rate
Mean survival (month)
90.1% 50%
68.5% 0%
117.4 12.1
81.5% 66.6%
70.2% 0%
119.4 14.3
85.9% 66.6%
69.4% 0%
118.5 11
84.8% 66.6%
75% 0%
115.4 17.3
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Tumor recurrence occurred in 10 patients (36%) after the surgery. Recurrence was only in the lungs in 4 patients, only in the bones in 2 patients, in the lungs and other organs in 2 patients, and local in 2 patients. Two patients with local recurrence at the renal bed underwent surgical exploration and removal of the tumor, which was histologically proven to be RCC. Other patients with visceral or bony tumor recurrence received cytokine-based immunotherapy. Of the 10 patients with recurrence, 6 had died due to disease progression (median survival after recurrence 7 months, range 1 to 27). Two patients who had undergone surgical exploration for local recurrence are still alive. One patient with lung metastases responded partially to immunotherapy and is still alive receiving sorafenib. Another patient with bone metastases is still on immunotherapy. On univariate analysis, distant metastasis and preoperative hypercalcemia were found to be significant predictors of progression-free survival (P values 0.036 and 0.008, respectively). Univariate analysis also revealed that the level of thrombus was not an independent factor affecting progression-free survival. On multivariate analysis, distant metastasis and preoperative hypercalcemia were independent co-variables of progression-free survival (P ⬍ 0.005). The Kaplan-Meier cumulative estimate of 3-year progression-free survival was 54.7% (mean progression-free survival 92.2 ⫾ 17 months).
4. Discussion Radical nephrectomy and tumor thrombectomy are known to be the most effective treatment methods in patients with RCC and tumor thrombus extending into IVC [1– 8,15]. Patients with IVC thrombus usually present with large tumors causing severe symptoms that require surgical palliation [6]. In our study, majority of the patients were symptomatic and hematuria was the most common one (32%). None of the patients had clinical evidence of complete IVC obstruction. Surgery is usually for palliation in patients with metastatic disease but it is performed with curative purpose for those with no evidence of distant metastasis [3,7,8,16,17]. The cephalad extension of tumor thrombus in RCC was first defined by Neves and Zincke [16] as thrombus of the renal vein (level 1), thrombus extending into the infrahepatic IVC (level 2), thrombus extending into the retrohepatic IVC (level 3), and intra-atrial thrombus (level 4). We used a modified classification for definition of the thrombus level according to our experience: infrahepatic, intrahepatic, suprahepatic (infradiaphragmatic), supradiaphragmatic, and intracardiac. In both situations, the extent of the vena cava thrombus did not have a significant impact on survival. Large series have also shown that decreased survival is not associated with the level of tumor thrombus [4,6 – 8,15,18]. Actually, Lambert et al. reported that survival for patients with IVC thrombus did not differ from that for patients with
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tumor thrombus confined to the renal vein [4] but tumor size, tumor grade and nodal involvement significantly affected survival in patients without distant metastases. However, tumor thrombus level is an important factor in deciding the type of surgical approach and technique. It is important to acquire the control of IVC above the thrombus before manipulating the thrombus to prevent tumor embolization preoperatively. Most of the IVC thrombi located infrahepatically can be managed via subcostal incision which enables the surgeon to control the proximal and distal parts of IVC and bilateral renal veins. Nevertheless, excision of intrahepatic and suprahepatic thrombi below the diaphragm requires adequate exposure of the retrohepatic inferior vena cava. We performed liver transplantation techniques for mobilization of liver to the left which was described by Ciancio et al. [13]. We performed sternotomy in 5 patients with tumor thrombi extending into the right atrium. Cardiopulmonary bypass with deep hypothermic circulatory arrest did not result in any severe morbidity. In our study, pathological examination revealed that RCC of clear cell type was the most common histological subtype in patients with IVC thrombus. Pathological tumor stage and Fuhrman grade were not found to be affecting survival significantly on univariate analysis. However, Parekh et al. reported that these 2 factors have a significant influence on survival [6]. Our findings suggest that factors affecting survival significantly are the ones related to tumor biology in terms of lymph node metastases, distant metastases, and presence of sarcomatoid component. RCC with sarcomatoid differentiation are aggressive neoplasms with poor prognosis with a median survival of less than 1 year [19]. In the present study, the presence of sarcomatoid component in RCC resulted in a significantly shorter overall and progression-free survival rates. It was found as an independent prognostic factor for survival in multivariate analysis in both metastatic and nonmetastatic patients. None of the patients with sarcomatoid differentiation survived beyond 16 months with a mean survival of 11 ⫾ 4.04 months. Similarly, patients with lymph node metastasis and distant metastasis have significantly poor prognosis, which is supported by other studies although some series reported no effect of nodal metastasis on survival [20 –22]. In a series of 100 patients with RCC extending into the renal vein and vena cava, 5-year survival rates in metastatic and nonmetastatic patients after nephrectomy and thrombectomy were found as 20% and 64%, respectively [15]. In our series, the overall 3-year survival of 60.2% and progression-free survival of 54.7% in patients with IVC thrombus were similar to those in previously reported studies [4 – 8,21,22]. These findings show that tumors with different levels of thrombus extending into renal vein or vena cava have similar biological behavior and thus tumor biology rather than the level of thrombus is more important in determining survival. RCC is unique among the genitourinary malignancies in that 10% to 40% of patients with this disease develop paraneoplastic syndromes, and hypercalcemia is the most
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common one occurring in 10% to 20% of patients [23,24]. Hypercalcemia of RCC can be secondary to bone metastases (metastatic hypercalcemia) or due to elaboration of hormonal peptides by tumor cells (nonmetastatic hypercalcemia). Studies have shown that renal tumor cells can produce parathyroid hormone-related peptide (PTHrP), which in turn results in increased bone resorption and decreased renal clearance of calcium [25,26]. Other specific mediators such as transforming growth factor alpha (TGF-␣), interleukin-1 (IL-1), osteoclast activating factor (OAF), and tumor necrosis factor (TNF) are also related to cancer-associated hypercalcemia [27]. Although 75% of those with hypercalcemia and RCC have advanced disease, neither the presence nor the degree of hypercalcemia has been shown to have a significant effect on disease recurrence or survival [28,29]. In a retrospective study of patients with RCCinduced hypercalcemia, Chasan et al. failed to show a significant correlation between the degree of calcium elevation and survival [30]. In our study, 14% of the patients were found to have tumor induced hypercalcemia, which was resolved completely after nephrectomy. None of the patients with hypercalcemia had evidence of bone metastases but interestingly pathological examination showed clear cell carcinoma with sarcomatoid differentiation in 2 of these patients. Kaplan-Meier analysis demonstrated a better survival rate in eucalcemic patients. More importantly, univariate analysis revealed that hypercalcemia is a significant indicator of progression-free survival and overall survival. It also has an independent impact on disease progression under multivariate analysis. Based on our findings, hypercalcemia may serve as a guide in predicting disease progression and survival outcome in patients with RCC and IVC thrombus. 5. Conclusions Cephalad extension of RCC is not a sign of aggressive type of tumor, especially in the absence of distant metastases. Metastatic behavior of the tumor rather than the level of thrombus is more important in determining the prognosis. Therefore, we believe that an aggressive approach towards total resection of renal tumor and IVC thrombus provides the best chance of cure and long-term survival in this group of patients. References [1] Marshall FF, Dietrick DD, Baumgartner WA, et al. Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol 1988;139:1166 –72. [2] Kaplan S, Ekici S, Dogan R, et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 2002; 183:292–9. [3] Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: The rationale for aggressive surgical management. J Urol 1972;107:711– 6.
[4] Lambert EH, Pierorazio PM, Shabsigh A, et al. Prognostic risk stratification and clinical outcomes in patients undergoing surgical treatment for renal cell carcinoma with vascular tumor thrombus. Urology 2007;69:1054 – 8. [5] Haferkamp A, Bastian PJ, Jakobi H, et al. Renal cell carcinoma with tumor thrombus extension into the vena cava: Prospective long-term followup. J Urol 2007;177:1703– 8. [6] Parekh DJ, Cookson MS, Chapman W, et al. Renal cell carcinoma with renal vein and inferior vena caval involvement: Clinicopathological features, surgical techniques, and outcomes. J Urol 2005;173: 1897–902. [7] Glazer AA, Novick AC. Long-term follow-up after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 1996;155:448 –50. [8] Kim HL, Zisman A, Han KR, et al. Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different? J Urol 2004;171:588 –91. [9] Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649 –55. [10] Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag, 2002. [11] Störkel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80:987–9. [12] Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655– 63. [13] Ciancio G, Livingstone AS, Soloway M. Surgical management of renal cell carcinoma with tumor thrombus in the renal and inferior vena cava: The University of Miami experience in using liver transplantation techniques. Eur Urol 2007;51:988 –94. [14] Klein EA, Kaye MC, Novick AC. Management of renal cell carcinoma with vena caval thrombi via cardiopulmonary bypass and deep hypothermic circulatory arrest. Urol Clin North Am 1991;18:445–7. [15] Swierzewski DJ, Swierzewski MJ, Libertino JA. Radical nephrectomy in patients with renal cell carcinoma with venous, vena caval, and atrial extension. Am J Surg 1994;168:205–9. [16] Neves RJ, Zincke H. Surgical treatment of renal cancer with vena cava extension. Br J Urol 1987;59:390 –5. [17] Hatcher PA, Anderson EE, Paulson DF, et al. Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 1991;145:20 –3. [18] Libertino JA, Zinman L, Watkins E Jr. Long-term results of resection of renal cell cancer with extension into inferior vena cava. J Urol 1987;137:21– 4. [19] Kwak C, Park YH, Jeong CW, et al. Sarcomatoid differentiation as a prognostic factor for immunotherapy in metastatic renal cell carcinoma. J Surg Oncol 2007;95:317–23. [20] Staehler G, Brkovic D. The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 2000;163: 1671–5. [21] Montie JE, el Ammar R, Pontes JE, et al. Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 1991;173: 107–15. [22] Skinner DG, Pritchett TR, Lieskovsky G, et al. Vena caval involvement by renal cell carcinoma. Surgical resection provides meaningful long-term survival. Ann Surg 1989;210:387–92. [23] Bedke J, Buse S, Kurosch M, et al. Paraneoplastic syndrome in renal cell carcinoma. Urologe A 2007;46:45– 8. [24] Muggia FM. Overview of cancer-related hypercalcemia: Epidemiology and etiology. Semin Oncol 1990;17:3–9.
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Original article
Renal cell carcinoma with inferior vena cava thrombus: The Hacettepe experience Sertac Yazici, M.D.a, Kubilay Inci, M.D.a, Cenk Yucel Bilen, M.D.a, Ahmet Gudeloglu, M.D.a, Bulent Akdogan, M.D.a, Dilek Ertoy, M.D.b, Volkan Kaynaroglu, M.D.c, Metin Demircin, M.D.d, Haluk Ozen, M.D.a,* a
Department of Urology, Hacettepe University School of Medicine, Ankara, Turkey Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey c Department of General Surgery, Hacettepe University School of Medicine, Ankara, Turkey d Department of Cardiovascular Surgery, Hacettepe University School of Medicine, Ankara, Turkey b
Received 27 August 2008; received in revised form 20 November 2008; accepted 21 November 2008
Abstract Objectives: We evaluated the clinical outcome and factors affecting survival in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC). Methods: Between 1990 and 2007, 28 patients with RCC and tumor thrombus extending into IVC underwent radical nephrectomy and thrombectomy. Patient data were reviewed retrospectively to evaluate the demographics, clinical presentation, surgical approach, pathological features, clinical outcomes, and survival. Results: Twenty-eight patients with a mean age of 52.7 years were operated. Thrombus level was infrahepatic in 15 patients (54%), intrahepatic in 3 patients (10%), suprahepatic in 3 patients (10%), supradiaphragmatic in 2 patients (8%), and intracardiac in 5 patients (18%). All patients with intracardiac thrombi underwent cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). The mean tumor size was 98.21 mm. Four patients had distant metastases and 3 patients had lymph node involvement. Pathological examination revealed RCC of clear cell type in 26 patients, papillary in 1 and chromophobe in 1 patient. At a mean follow-up of 36.4 months, 16 patients were still alive while 8 patients died due to disease progression and 2 patients died of other causes. Two patients died of pulmonary emboli in the early postoperative period. Lymph node involvement, distant metastases, hypercalcemia, and sarcomatoid component were found to be factors affecting overall survival significantly. Level of tumor thrombus and Fuhrman grade did not affect survival. Conclusions: Radical nephrectomy and tumor thrombectomy is currently known to be the most effective method in patients with RCC and tumor thrombus extending into IVC. Factors affecting survival are the ones related to tumor biology. Tumor thrombus level does not affect the prognosis. © 2010 Elsevier Inc. All rights reserved. Keywords: Renal cell cancer; Inferior vena cava thrombus; Survival
1. Introduction Renal cell carcinoma (RCC) has a tendency for invasion of renal vein or inferior vena cava (IVC) in 4% to 10% of cases [1]. An aggressive approach with radical nephrectomy and thrombectomy is the mainstay of the treatment in these patients [2]. Patients with RCC and tumor thrombus usually present with severe symptoms requiring palliation even in
the presence of metastatic disease [3]. The prognostic significance of cephalad extension of tumor thrombus have been evaluated in several studies [4 – 8]. In the present study, we retrospectively analyzed the surgical approaches, clinical outcome, and clinicopathological factors affecting survival in patients with RCC involving IVC.
2. Patients and Methods * Corresponding author. Tel.: ⫹90-312-305-1969; fax: ⫹90-312311-2262. E-mail address: [email protected] (H. Ozen). 1078-1439/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2008.11.017
A total of 612 patients with renal cell carcinoma underwent partial or radical nephrectomy at the Hacettepe Uni-
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versity Hospital between 1990 and September 2007. Of these patients, 28 (4.5%) had tumor thrombus extending into inferior vena cava (IVC). Patients with bilateral tumor, Von Hippel-Lindau disease, or tuberous sclerosis were excluded. Patient data were reviewed retrospectively to evaluate the demographics, clinical presentation, surgical approach, pathological features, clinical outcomes, and survival. Performance status for each patient was measured by the Eastern Cooperative Oncology Group performance score (ECOG PS) [9]. All patients were examined preoperatively with chest X-ray and computerized tomography (CT) of the abdomen, pelvis, and lungs. Magnetic resonance imaging (MRI) and transesophageal echocardiography were performed to assess the level of thrombus and to examine any possible intracardiac extension. Operative variables included surgical incision, duration of surgery, level of thrombus, need for cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), estimated blood loss, and hospital stay. The 2002 American Joint Committee on Cancer TNM classification was used for tumor staging [10]. Patients with tumor thrombus in the renal vein were not included. Therefore, according to our experience, the definition of vena cava thrombus level was modified as infrahepatic, intrahepatic, suprahepatic (infradiaphragmatic), supradiaphragmatic, and intracardiac. All pathology slides were reviewed by the central pathologist for tumor histological type and nuclear grade, which were determined according to the 1997 WHO classification [11] and Fuhrman’s grading scheme [12]. Histological tumor necrosis was defined as presence of microscopic tumor necrosis. 2.1. Surgical management All patients had undergone radical nephrectomy and thrombectomy. No preoperative arterial embolization was performed. In all cases, renal artery was ligated early during the course of the surgery to decrease venous bleeding and to reduce the cephalad extension of vena cava thrombus. Surgical approach and technique depended on the level of tumor thrombus. For infrahepatic thrombi, a subcostal approach was preferred. After the mobilization of the kidney, clamps were placed consecutively on infrarenal vena cava, contralateral renal vein, and suprarenal vena cava. Following the accomplishment of vascular control, vena cavotomy and extraction of tumor thrombus was performed together with nephrectomy. The lumen was flushed and the cavotomy was closed with running 5-0 Prolene sutures. The clamps were removed orderly beginning from the distal vena cava and proceeding to the contralateral renal vein and proximal vena cava. For intrahepatic and suprahepatic thrombi below the diaphragm, satisfactory exposure of the retrohepatic inferior vena cava is important; therefore a midline abdominal incision was our favorite. First, the liver was mobilized to the left using techniques described for liver transplantation
[13]. For exposure and control of the major hepatic veins, the Pringle maneuver was used when necessary. After the separation of IVC from the posterior abdominal wall, the suprahepatic infradiaphragmatic vena cava, the infrarenal vena cava, the contralateral renal vein, and hepatic vein were clamped consecutively. IVC was dissected extensively, tumor thrombus was removed, and the vena cava reconstruction was performed as previously described for infrahepatic thrombi. No veno-venous bypass was required in any of the patients. A midline abdominal approach with median sternotomy was performed in patients with supradiaphragmatic and intracardiac thrombi. All patients with intracardiac thrombi underwent cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Tumor thrombi were removed as described previously [14]. Renal tumor and vena cava thrombus were removed completely in all cases, with regional lymphadenectomy for enlarged or suspicious lymph nodes. Vena cava reconstruction using synthetic grafts was required in 4 patients. Patients were followed up at 6-month intervals postoperatively with physical examination, imaging studies (chest X-ray and computed tomography of the abdomen), complete blood count, and serum chemistry evaluation. Progression was defined as the development of new tumor, either local or distant, in a patient after nephrectomy. Survival was calculated from the date of surgery to the date of last follow-up visit for surviving patients or to death. 2.2. Statistics Overall survival and progression-free survival were estimated using Kaplan-Meier curves. Subgroup differences were tested using the log-rank test. Multivariate Cox proportional survival analysis was done using clinical presentation, patient age, ECOG PS, distant metastasis (M⫹), lymph node metastasis (N⫹), Fuhrman grade, tumor stage, tumor size, histological type, presence of necrosis, preoperative calcium level, and thrombus level as possible independent variables. 2.3. Limitations of the study The main disadvantage of the study was the low number of population and a relatively high number of variables. Although the computer medium made it very “easy” to run very complicated statistical methods for even such low numbers, basic explanatory statistics such as the rates, ratios, and univariate analysis results would be more reliable in such a work.
3. Results Patient characteristics are summarized in Table 1. Twenty male and 8 female patients with a mean age of 52.7
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vasion of IVC wall documented histologically. Tumor invaded beyond Gerota’s fascia in 1 patient (stage T4).
Table 1 Patient characteristics Age (years) Mean Median Sex (n) Male Female Tumor and thrombus site Left Right Mean Follow-up (months) Presentation (n) Incidental Hematuria Abdominal pain Palpable mass Combination ECOG performance status 0 1 2 3
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52.7 54.5
3.2. Survival and progression
20 (71%) 8 (29%)
The mean follow-up was 36.4 months (range 6 to 164 months). A total of 12 patients were still alive with no evidence of disease, 4 patients were alive with disease, 8 patients had died due to disease progression, and 2 patients had died of other causes. Overall 3-year survival in patients with inferior vena cava thrombus was 60.2% (mean overall survival 104.3 ⫾ 16.5 months). Independent variables that were significantly associated with overall survival were lymph node metastasis, distant metastasis, presence of sarcomatoid component, and preoperative hypercalcemia (serum calcium level ⬎ 10.2 mg/dl) (Fig. 1). Level of tumor thrombus and Fuhrman grade were not found to affect survival significantly. Although significant in univariate analysis, lymph node metastasis and hypercalcemia were not retained in multivariate analysis. Distant metastasis and presence of sarcomatoid component remained significant
7 (25%) 21 (75%) 36.4 5 (18%) 9 (32%) 8 (29%) 2 (7%) 4 (14%) 19 (68%) 8 (29%) 1 (3%) 0
years had undergone radical nephrectomy and thrombectomy. A predominance of right-sided tumors was present (75%). Hematuria was the most common symptom (32%) followed by abdominal pain (29%). Mean operation time was 230.35 minutes (range 110 to 480 minutes). Mean blood loss and hospital stay were 1935 ml (range 280 to 5000 ml) and 10.8 days (range 4 to 45 days) respectively. The level of thrombus did not affect the operative time, blood loss, and hospital stay significantly, although a trend toward a longer operative time and increased estimated blood loss was observed with the higher levels of thrombus. None of the patients required re-exploration after the surgery. 3.1. Clinical and pathological findings Table 2 lists the clinical and pathological characteristics. Level of thrombus was infrahepatic in 15 patients (54%), intrahepatic in 3 patients (10%), suprahepatic in 3 patients (10%), supradiaphragmatic in 2 patients (8%), and intracardiac in 5 patients (18%). A subcostal incision was preferred in 8 patients (28%). All patients with intracardiac thrombi underwent CPB with DHCA. Venous wall resection and grafting was required in 4 patients due to tumoral involvement of the IVC wall. Renal tumor and the tumor thrombus were removed in all cases. Two patients died in the early postoperative period (postoperative sixth hour and eleventh day) due to pulmonary emboli and cardiac arrhythmia. Of the 28 patients, 4 (14%) had distant metastases (lung), and 3 (11%) had lymph node involvement (Table 2). Pathological evaluation revealed clear cell RCC in 26 patients (92%), papillary RCC in 1 patient (4%), and chromophobe RCC in 1 patient (4%). Three patients (10%) had direct tumor in-
Table 2 Clinical and pathological characteristics Mean tumor size (⫾SD) Incision Subcostal Chevron Median sternotomy Midline abdominal Flank RCC histological type Clear Cell Papillary Chromophobe Sarcomatoid component Histological tumor necrosis Yes No Fuhrman nuclear grade 1 2 3 4 Thrombus Level Infrahepatic Intrahepatic Suprahepatic Supradiaphragmatic Intracardiac Pathological stage pT3b pT3c pT4 Lymph node involvement pNx/pN0 pN1/pN2 Distant metastasis pM0 pM1
98.21 ⫾ 35.09 mm 8 (28%) 7 (25%) 7 (25%) 4 (14%) 2 (8%) 26 (92%) 1 (4%) 1 (4%) 4 (14%) 13 (46%) 15 (54%) 0 5 (18%) 12 (43%) 11 (39%) 15 (54%) 3 (10%) 3 (10%) 2 (8%) 5 (18%) 20 (71%) 7 (25%) 1 (4%) 25 (89%) 3 (11%) 24 (86%) 4 (14%)
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Fig. 1. Kaplan-Meier overall survival estimates based on (A) distant metastasis; (B) lymph node metastasis; (C) preoperative serum calcium level; and (D) sarcomatoid tumor component.
for predicting survival in multivariate analysis (P ⬍ 0.005). Mean survival of patients with lymph node metastasis and distant metastasis were 14.3 and 12.1 months respectively (Table 3). Among patients with lymph node or distant metastasis, 6 had died of disease and 1 patient has the disease receiving immunotherapy for bone metastases. Mean survival of patients with no lymph node or distant metastasis was 137.13 months (median 164 months). The KaplanMeier cumulative estimate of overall 3-year survival was 81% in patients without lymph node or distant metastasis and 0% in patients with lymph node or distant metastasis (log rank P ⬍ 0.001). In patients with no metastatic disease (M0), univariate survival analysis revealed that lymph node metastasis (P ⫽ 0.0001), presence of sarcomatoid component (P ⬍ 0.0001), preoperative serum calcium level (P ⫽ 0.012), and ECOG performance status (P ⫽ 0.014) were significant predictors of overall survival. On multivariate analysis, sarcomatoid component was the only variable to significantly affect overall survival (P ⬍ 0.0001). Tumor size, Fuhrman grade, pathological stage, and thrombus level did not affect the
outcome. Overall survival rate in patients without metastatic disease was 68.5% at 3 years (mean overall survival 117.4 ⫾ 17.1 months). Table 3 Overall survival (OS) rates and mean survival time according to distant metastasis, lymph node involvement, sarcomatoid component status, and preoperative serum calcium levels
Distant metastasis pM0 pM1 Lymph node involvement pNx/N0 pN1/N2 Sarcomatoid component Absent Present Preoperative serum Ca ⬍10.2 mg/dL ⱖ10.2 mg/dL
1-year OS rate
3-year OS rate
Mean survival (month)
90.1% 50%
68.5% 0%
117.4 12.1
81.5% 66.6%
70.2% 0%
119.4 14.3
85.9% 66.6%
69.4% 0%
118.5 11
84.8% 66.6%
75% 0%
115.4 17.3
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Tumor recurrence occurred in 10 patients (36%) after the surgery. Recurrence was only in the lungs in 4 patients, only in the bones in 2 patients, in the lungs and other organs in 2 patients, and local in 2 patients. Two patients with local recurrence at the renal bed underwent surgical exploration and removal of the tumor, which was histologically proven to be RCC. Other patients with visceral or bony tumor recurrence received cytokine-based immunotherapy. Of the 10 patients with recurrence, 6 had died due to disease progression (median survival after recurrence 7 months, range 1 to 27). Two patients who had undergone surgical exploration for local recurrence are still alive. One patient with lung metastases responded partially to immunotherapy and is still alive receiving sorafenib. Another patient with bone metastases is still on immunotherapy. On univariate analysis, distant metastasis and preoperative hypercalcemia were found to be significant predictors of progression-free survival (P values 0.036 and 0.008, respectively). Univariate analysis also revealed that the level of thrombus was not an independent factor affecting progression-free survival. On multivariate analysis, distant metastasis and preoperative hypercalcemia were independent co-variables of progression-free survival (P ⬍ 0.005). The Kaplan-Meier cumulative estimate of 3-year progression-free survival was 54.7% (mean progression-free survival 92.2 ⫾ 17 months).
4. Discussion Radical nephrectomy and tumor thrombectomy are known to be the most effective treatment methods in patients with RCC and tumor thrombus extending into IVC [1– 8,15]. Patients with IVC thrombus usually present with large tumors causing severe symptoms that require surgical palliation [6]. In our study, majority of the patients were symptomatic and hematuria was the most common one (32%). None of the patients had clinical evidence of complete IVC obstruction. Surgery is usually for palliation in patients with metastatic disease but it is performed with curative purpose for those with no evidence of distant metastasis [3,7,8,16,17]. The cephalad extension of tumor thrombus in RCC was first defined by Neves and Zincke [16] as thrombus of the renal vein (level 1), thrombus extending into the infrahepatic IVC (level 2), thrombus extending into the retrohepatic IVC (level 3), and intra-atrial thrombus (level 4). We used a modified classification for definition of the thrombus level according to our experience: infrahepatic, intrahepatic, suprahepatic (infradiaphragmatic), supradiaphragmatic, and intracardiac. In both situations, the extent of the vena cava thrombus did not have a significant impact on survival. Large series have also shown that decreased survival is not associated with the level of tumor thrombus [4,6 – 8,15,18]. Actually, Lambert et al. reported that survival for patients with IVC thrombus did not differ from that for patients with
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tumor thrombus confined to the renal vein [4] but tumor size, tumor grade and nodal involvement significantly affected survival in patients without distant metastases. However, tumor thrombus level is an important factor in deciding the type of surgical approach and technique. It is important to acquire the control of IVC above the thrombus before manipulating the thrombus to prevent tumor embolization preoperatively. Most of the IVC thrombi located infrahepatically can be managed via subcostal incision which enables the surgeon to control the proximal and distal parts of IVC and bilateral renal veins. Nevertheless, excision of intrahepatic and suprahepatic thrombi below the diaphragm requires adequate exposure of the retrohepatic inferior vena cava. We performed liver transplantation techniques for mobilization of liver to the left which was described by Ciancio et al. [13]. We performed sternotomy in 5 patients with tumor thrombi extending into the right atrium. Cardiopulmonary bypass with deep hypothermic circulatory arrest did not result in any severe morbidity. In our study, pathological examination revealed that RCC of clear cell type was the most common histological subtype in patients with IVC thrombus. Pathological tumor stage and Fuhrman grade were not found to be affecting survival significantly on univariate analysis. However, Parekh et al. reported that these 2 factors have a significant influence on survival [6]. Our findings suggest that factors affecting survival significantly are the ones related to tumor biology in terms of lymph node metastases, distant metastases, and presence of sarcomatoid component. RCC with sarcomatoid differentiation are aggressive neoplasms with poor prognosis with a median survival of less than 1 year [19]. In the present study, the presence of sarcomatoid component in RCC resulted in a significantly shorter overall and progression-free survival rates. It was found as an independent prognostic factor for survival in multivariate analysis in both metastatic and nonmetastatic patients. None of the patients with sarcomatoid differentiation survived beyond 16 months with a mean survival of 11 ⫾ 4.04 months. Similarly, patients with lymph node metastasis and distant metastasis have significantly poor prognosis, which is supported by other studies although some series reported no effect of nodal metastasis on survival [20 –22]. In a series of 100 patients with RCC extending into the renal vein and vena cava, 5-year survival rates in metastatic and nonmetastatic patients after nephrectomy and thrombectomy were found as 20% and 64%, respectively [15]. In our series, the overall 3-year survival of 60.2% and progression-free survival of 54.7% in patients with IVC thrombus were similar to those in previously reported studies [4 – 8,21,22]. These findings show that tumors with different levels of thrombus extending into renal vein or vena cava have similar biological behavior and thus tumor biology rather than the level of thrombus is more important in determining survival. RCC is unique among the genitourinary malignancies in that 10% to 40% of patients with this disease develop paraneoplastic syndromes, and hypercalcemia is the most
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common one occurring in 10% to 20% of patients [23,24]. Hypercalcemia of RCC can be secondary to bone metastases (metastatic hypercalcemia) or due to elaboration of hormonal peptides by tumor cells (nonmetastatic hypercalcemia). Studies have shown that renal tumor cells can produce parathyroid hormone-related peptide (PTHrP), which in turn results in increased bone resorption and decreased renal clearance of calcium [25,26]. Other specific mediators such as transforming growth factor alpha (TGF-␣), interleukin-1 (IL-1), osteoclast activating factor (OAF), and tumor necrosis factor (TNF) are also related to cancer-associated hypercalcemia [27]. Although 75% of those with hypercalcemia and RCC have advanced disease, neither the presence nor the degree of hypercalcemia has been shown to have a significant effect on disease recurrence or survival [28,29]. In a retrospective study of patients with RCCinduced hypercalcemia, Chasan et al. failed to show a significant correlation between the degree of calcium elevation and survival [30]. In our study, 14% of the patients were found to have tumor induced hypercalcemia, which was resolved completely after nephrectomy. None of the patients with hypercalcemia had evidence of bone metastases but interestingly pathological examination showed clear cell carcinoma with sarcomatoid differentiation in 2 of these patients. Kaplan-Meier analysis demonstrated a better survival rate in eucalcemic patients. More importantly, univariate analysis revealed that hypercalcemia is a significant indicator of progression-free survival and overall survival. It also has an independent impact on disease progression under multivariate analysis. Based on our findings, hypercalcemia may serve as a guide in predicting disease progression and survival outcome in patients with RCC and IVC thrombus. 5. Conclusions Cephalad extension of RCC is not a sign of aggressive type of tumor, especially in the absence of distant metastases. Metastatic behavior of the tumor rather than the level of thrombus is more important in determining the prognosis. Therefore, we believe that an aggressive approach towards total resection of renal tumor and IVC thrombus provides the best chance of cure and long-term survival in this group of patients. References [1] Marshall FF, Dietrick DD, Baumgartner WA, et al. Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol 1988;139:1166 –72. [2] Kaplan S, Ekici S, Dogan R, et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 2002; 183:292–9. [3] Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: The rationale for aggressive surgical management. J Urol 1972;107:711– 6.
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