Prognostic Benefit of Surgical Management of Renal Cell Carcinoma Invading the Inferior Vena Cava

Abstract

Renal cell carcinoma (RCC) accounts for approximately 3 % of adult malignancies and 90–95 % of neoplasms arising from the kidney. One of the unique features of RCC is the tumor thrombus formation that migrates into the venous system including renal vein (RV) and inferior vena cava (IVC). Only 10 % of patients with RCC present with the classic triad of flank pain, hematuria and defined mass, while 25–30 % of affected patients are asymptomatic. Signs of para-neoplastic syndrome such as hypercalcemia, hypertension, anemia, cachexia and increased erythrocyte sedimentation rate (ESR) are often apparent. Extension of tumor thrombus into the venous system is depicted by radiological examinations, such as contrast enhanced Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and vena cavography. The level of the thrombus is mostly determined according to the Mayo classification. Despite recent research on the therapeutic strategies against advanced RCC, surgical resection appears the only potentially curative approach. Aggressive surgical management including nephrectomy with thrombectomy is currently the standard therapeutic approach for RCC patients with tumor thrombus extending to the RV or the IVC. Pre-surgical down-staging with the use of molecular targeted therapy has also been proposed. Alternative therapies, such as radio- and chemotherapy proved insufficient. The aim of this review is to evaluate the results of surgical treatment for RCC invading IVC with special reference to the extent of its histological spread. Review of recent world literature was accomplished to provide an update on the current concepts of surgical management of the disease.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 3 % of adult malignancies and 90–95 % of neoplasms arising from the kidney [1–3]. One of the unique features of RCC is the tumor thrombus formation that migrates into the venous system including renal vein (RV) and inferior vena cava (IVC) with an incidence varying from 4 to 10 % among RCC cases [4–8]. RCC detection age ranges from 55 to 71 years [1]. Only 10 % of patients with RCC present with the classic triad of flank pain, hematuria and defined mass, while 25–30 % of affected patients are asymptomatic and RCC is diagnosed after incidental radiologic study. Signs of para-neoplastic syndrome such as hypercalcemia, hypertension, anemia, cachexia and increased erythrocyte sedimentation rate (ESR) are often apparent. Extension of tumor thrombus into the venous system is depicted by radiological examinations, such as contrast enhanced Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and vena cavography [9]. The level of the thrombus is mostly determined according to the Mayo classification [10, 11].

Despite recent research on the therapeutic strategies against advanced RCC, surgical resection appears the only potentially curative approach. Unfortunately, only a minority of patients is eligible to undergo surgical intervention. Even if surgical removal of the tumor is achieved long-term survival is uncertain [4, 12–15]. Furthermore, the prognostic factors and the efficacy of extended resection remain controversial. Aggressive surgical management including nephrectomy with thrombectomy is currently the standard therapeutic approach for RCC patients with tumor thrombus extending to the RV or the IVC [5, 9]. Pre-surgical down-staging with the use of molecular targeted therapy has also been proposed in patients with poor prognostic factors, extended tumor thrombus and distant metastases [16–18]. Alternative therapies, such as radio- and chemotherapy proved insufficient. The aim of this review is to evaluate the results of surgical treatment for RCC invading IVC with special reference to the extent of its histological spread. Review of recent world literature was accomplished to provide an update on the current concepts of surgical management of the disease.

Histopathology and Classification

RCC is not a single entity, but rather a collection of different types of tumors, deriving from the various parts of the nephron and possessing distinct histological features. Consequently, RCC is divided into 5 main histologic subtypes: clear cell, papillary, chromophobe, collecting duct and unclassified [19]. The most commonly described lesion (70–80 %) is Clear Cell RCC (CCRCC) which is originates from the proximal convoluted tubule. Generally neoplastic cells present a clear cytoplasm, are surrounded by a distinct cell membrane and contain round and uniform nuclei. RCC is also typically positive for vimentin, AE1/AE3 keratins, CD10, RCC marker and carbonic anydrase IX (G250) as well. In addition, Papillary RCC (PRCC) is detected in 14–17 % of RCC cases and is derived from the proximal convoluted tubule. Further division into two categories is implemented. Type 1 consists of papillae covered with a single or double layer of small cuboid cells with scanty cytoplasm. Type 2 PRCC is characterized by papillae covered by large eosinophilic cells arranged in an irregular or pseudostratified manner. Type 1 is often positive for vimentin, AE1/AE3 keratins, CK7, AMACR, and RCC marker, while Type 2 displays a quite variable immunoprofile. Papillary subtype is thought to be an independent prognostic factor for worse prognosis in patients with RCC and IVC thrombus [20]. Less common, the Chromophobe RCC (ChRCC) is documented in 4–8 % of RCC patients and originates from the cortical collecting duct and consists of tumor cells with abundant eosinophilic cytoplasm with mainly solid structure. It is positive for kidney-specific cadherin, parvalbumin, CD117, epithelial membrane antigen, AE1/AE3 keratin and CK7 respectively. Finally, collecting duct carcinoma remains the rarest RCC type (<1 %). Unclassified neoplasms include those that do not fulfil any of the above mentioned criteria either morphologically or cytogenetically. Moreover, 7 % of the kidney carcinomas are associated with urothelial disorders arising in the renal pelvis. Positivity for CK7, p63, CK5/6 as well as CK20 is apparent. Finally, approximately 10 % of renal tumors belong to one of the several benign entities including oncocytoma, angiomyolipoma and papillary adenoma.

According to the Mayo Staging system the level of tumor thrombus is classified as following: level 0 refers to thrombus extending only to the RV while level I is determined as thrombus invading the IVC up to no more than 2 cm above the RV. Level II includes thrombus extending into the IVC more than 2 cm above the RV but not the hepatic vein. Level III is characterized as thrombus extending into the IVC to above the hepatic vein but not to the diaphragm. Finally, level IV describes thrombus invading the supra-diaphragmatic IVC or right atrium [9–11].

Clinical Features and Outcome

RCC may remain asymptomatic for most of its course. The pathognomonic signs including pain, hematuria and well detected mass appears in the minority of the patients and is mainly indicative of advanced disease. It is estimated that 25–30 % of patients remain without particular symptoms and the carcinoma an incidental finding on imaging investigation. The majority of patients present with at least one feature of the classic triad, while other clinical indications include weight loss, fever, hypertension, night sweats, general malaise and a varicocele (usually left sided) due to obstruction of the left testicular vein. Apart from these, patients frequently appear with paraneoplastic syndromes, consisting of hypercalcemia, erythrocytosis or anemia, pyrexia of unknown origin (PUO) and non-metastatic liver dysfunction [21].

Patients with RCC and IVC invasion may present with a variety of symptoms. Clinical manifestation may be the same as mentioned above in which IVC involvement is defined after meticulous radiologic investigation. Patients may also remain asymptomatic or present with severe complications including pulmonary embolism. This entity is often described as an acute event including dyspnea, chest pain, hypoxemia and hemodynamic collapse. Micro-vessel tumor emboli are always apparent. Cases of dyspnea developing over weeks, sometimes together with thoracic pain, cough and hemoptysis have also been reported [22]. Finally, patients with IVC thrombus may appear with bilateral lower extremity edema associated with dilated, visible superficial abdominal veins.

Diagnostic Modalities

A substantial proportion of patients diagnosed with RCC are discovered incidentally on radiologic studies carried out for other reasons. A number of diagnostic modalities are available for evaluating renal masses, including ultrasonography (U/S), excretory urography, high-resolution CT, MRI and positron-emission tomography (PET) respectively. CT scanning remains the imaging procedure of choice, differentiating cystic lesions from solid masses [9]. According to the National Comprehensive Cancer Network (NCCN) version 2.2011 guidelines for kidney cancer, initial workup necessarily includes abdominal and pelvic CT with or without contrast and chest CT or radiography subsequently [12]. Given that RCC frequently appears with paraneoplastic disorders, standard laboratory evaluation includes a workup for hematological parameters, biochemical profile and ESR as well. Potential hypertension, anemia, cachexia, liver dysfunction and hypercalcemia should always be assessed [4]. Bone scintigraphy is implemented for patients with relevant pain. Tumor stage is usually determined according to the TNM classification [9].

Potential invasion of the IVC is most reliably established with CT scanning with intravenous (IV) contrast, MRI or vena cavography with the latter being invasive and therefore rarely preferred. The level of tumor thrombus is determined according to the Mayo Classification as previously mentioned. Contrast venography, also allows access for pulmonary angiography if indicated, given that IVC thrombus is commonly presented as pulmonary emboli. This can be also identified by a chest CT [21]. MRI is also warranted to estimate the age of the thrombus, while reconstructive imaging technology can create images similar to those provided with venography [23]. Furthermore, MRI scan can be performed to define caval wall invasion, so that a precise surgical plan can be formulated [24, 25]. Finally IVC thrombus may be diagnosed intraoperatively in patients treated with laparotomy, for their primary problem.

Surgical Strategies

Surgical resection remains the most effective approach for localized RCC, while it is also proposed for palliation in metastatic disease. Radical nephrectomy involves complete removal of Gerota’s fascia and its contents including kidney, perirenal fat and adrenal gland. Extended ipsilateral lymph node dissection is not always implemented. According to the 2011 NCCN guidelines, ipsilateral adrenal gland resection is indicated if adrenal glands appear abnormal on CT scanning or in patients with large upper-pole kidney tumors [12]. As far as locally extensive and invasive tumors, with no distant metastatic disease, are concerned adjacent structures such as bowel, spleen or psoas muscle may be excised en bloc as well during the initial procedure. Radical nephrectomy may be accomplished via transperitoneal, flank or thoracoabdominal approach, with the later giving the opportunity to resect solitary pulmonary metastases as well. Partial nephrectomy is strongly recommended for a T1a mass, while for T1b tumors radical nephrectomy is also accepted in case of difficulties in surgical manipulation of the kidney remnant. Moreover, patients with enlarged palpable or CT detected lymph nodes should undergo lymph node dissection [26].

When there is an IVC involvement, radical nephrectomy along with thrombectomy and lymph node dissection is strongly recommended. Defining the extent of IVC thrombus is necessary for staging and planning. Surgical procedure is performed mainly via a flank or midline abdominal incision depending on tumor characteristics and associated thrombus formation. In patients with supra- diaphragmatic IVC thrombus, the liver is mobilized to expose the retrohepatic vena cava with parallel incision of the falciform, triangular and coronary ligaments. When the tumor extends into hepatic or suprahepatic IVC, Pringle’s manoeuvre or median sternotomy may be occasionally recommended [4]. Finally, patients with thrombus extending to the right atrium may require cardiopulmonary bypass with hypothermic circulatory arrest and associated vascular cannulation [27, 28].

IVC wall invasion has been reported in 51 % of RCC with caval thrombus, indicating the need of either IVC ligation to achieve microscopically complete resection of the tumor or the establishment of IVC prosthetic replacement with anastomosis of the contralateral RV. In accordance with recent publications the use of polytetrafluoroethylene expanded prosthesis (PTFE) is preferred to a Dacron graft [5, 29, 30]. The reconstructive regimen depends on the affected caval segment, the availability of retroperitoneal collateral circulation and the invasion of adjacent structures. Nevertheless, the patency of PTFE prosthesis remains problematic with relevant IVC thrombosis occurring commonly during the first post-operative months. The use of anticoagulation therapy after vascular reconstruction is controversial with significant potential hazard of retroperitoneal hemorrhage. Additional techniques have been proposed to prevent the spread of embolic thrombosis, such as the ligature of IVC without replacement of continuity. Nevertheless, this surgical approach leads not only to edema and thrombosis of lower limbs, but also acute renal failure in case of absence or overestimation of the means of preoperative venous substitution. Potential advantages of IVC ligation refer to the elimination of operative time, graft infections, high output cardiac failure from creation of a fistula and the need for the long-term anticoagulation. Additional injury of the retroperitoneal lymphatic system should also be avoided. In case of patients presenting with pulmonary emboli, aggressive approach with all the above mentioned modalities together with embolectomy improves prognosis [21].

Current evidence in the literature demonstrates the potentially expanding role of preoperative targeted therapy with tyrosine kinase inhibitors in the management of locally advanced RCC [31]. Traditionally, systemic therapy has shown limited usefulness, and aggressive radical surgical resection with IVC thrombectomy remains the standard of care in appropriate candidates. Despite the curative intent of surgical management, the risks involved are not negligible [32]. Moreover, there is tremendous heterogeneity among related surveys with regard to a wide range of tumor stages and unstandardized evaluation and treatment protocols. Furthermore, the majority of the existing studies on the use of preoperative therapy in the setting of an IVC thrombus are single-center case reports. Therefore, while preoperative targeted therapy has been proposed to decrease primary tumor size, the overall body of literature would indicate that the same does not hold true for downstaging of IVC thrombi, as any decrease in the extent of the thrombus would have to be of such a magnitude to significantly affect the surgical approach in order to be clinically meaningful [33, 34]. Nevertheless, observations indicate that presurgical targeted therapy is safe and feasible and does not significantly increase overall postoperative complications rate despite the antiangiogenic effect of these agents and their involvement in tissue recovery.

In conclusion, IVC involvement in the RCC with tumor thrombus formation is not such a rare event and it should be taken into consideration when examining patients, especially given that IVC thrombus presence may not appear with further symptoms. Meticulous radiologic study is essential for determining the level of the thrombus, thus defining the surgical technique. The treatment accepted most, so far remains radical nephrectomy along with thrombectomy and prosthetic replacement of the IVC. Adjuvant therapy for RCC with IVC thrombus is still in evolving phase, but cost remains an important issue. Randomized trials of adjuvant radiation, hormonal therapy and, more recently, immunotherapy has shown no clinical benefit. Autologous tumor vaccines may decrease recurrence rates for patients with locally advanced RCC, but additional prospective, randomized studies need to be undertaken.

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Conflict of Interest

None.