The cause of renal adenocarcinoma is unknown. Occupational exposures, chromosomal aberrations, and tumor suppressor genes have been implicated. Cigarette smoking is the only risk factor consistently linked to RCC by both epidemiologic case-control and cohort studies (La Vecchia et al, 1990), with most investigations demonstrating at least a twofold increase in risk for the development of RCC in smokers (Yu et al, 1986). Exposure to asbestos, solvents, and cadmium has also been associated with an increased incidence of RCC (Mandel et al, 1995).
RCC occurs in two forms, inherited and sporadic. In 1979, Cohen and colleagues described a pedigree with hereditary RCC in which the pattern of inheritance was consistent with an autosomal dominant gene with a balanced reciprocal translocation between the short arm of chromosome 3 and the long arm of chromosome 8. Subsequent work has documented that both the hereditary and sporadic forms of RCC are associated with structural changes in chromosome 3p (Erlandsson, 1998; Kovacs et al, 1988; Noordzij and Mickisch, 2004).
Other hereditary forms of RCC have been described. Von Hippel-Lindau disease is a familial cancer syndrome in which affected individuals have a mutation of chromosome 3p predisposition to develop tumors in multiple organs, including cerebellar hemangioblastoma, retinal angiomata, and bilateral clear cell RCC. In 1993, Latif and colleagues identified the von Hippel–Lindau gene, leading to the detection of a germ line mutation in approximately 75% of families affected by von Hippel–Lindau disease (Chen et al, 1995). It has also been recognized that at least 50% of cases of sporadic clear cell RCC has mutations in the Von Hippel–Lindau (VHL) gene (Gnarra et al, 1994).
Hereditary papillary renal carcinoma was described in 1994 and is characterized by a predisposition to develop multiple bilateral renal tumors with a papillary histologic appearance (Zbar et al, 1994). In contrast to von Hippel–Lindau patients, the major neoplastic manifestations appear to be confined to the kidney.
Acquired cystic disease of the kidneys is a well-recognized entity of multiple bilateral cysts in the native kidneys of uremic patients (Reichard et al, 1998). The risk of developing RCC has been estimated to be >30 times higher in patients receiving dialysis who have cystic changes in their kidney than in the general population (Brennan et al, 1991). Several series reported in the literature suggest that RCC occurs in 3–9% of patients with acquired cystic disease of the kidneys (Gulanikar et al, 1998). Most RCC cases have been described in patients undergoing hemodialysis, but RCC has been reported in association with peritoneal dialysis (Smith et al, 1987) and successful renal transplants (Vaziri et al, 1984) and in patients with long-term renal insufficiency not requiring dialysis (Bretan et al, 1986; Fallon and Williams, 1989).
RCC originates from the proximal renal tubular epithelium, as evidenced by electron microscopy (Makay et al, 1987) and immunohistochemical analysis (Holthöfer, 1990). These tumors occur with equal frequency in either kidney and are randomly distributed in the upper and lower poles. RCCs originate in the cortex and tend to grow out into perinephric tissue, causing the characteristic bulge or mass effect that aids in their detection by diagnostic imaging studies. Grossly, the tumor is characteristically yellow to orange because of the abundance of lipids, particularly in the clear cell type. RCCs do not have true capsules but may have a pseudocapsule of compressed renal parenchyma, fibrous tissue, and inflammatory cells.
Histologically, RCC is most often a mixed adenocarcinoma containing clear cells, granular cells, and, occasionally, sarcomatoid-appearing cells. The classifications of the subtypes of RCC are based on morphology and cytogenetic characteristics. Most RCCs are classified into one of the following histologic subtypes: conventional clear cell, papillary (chromophilic), chromophobe, collecting duct, neuroendocrine, and unclassified (Mostofi and Davis, 1998). Benign renal tumors are papillary adenoma, renal oncocytoma, and metanephric adenoma. Clear cells are rounded or polygonal with abundant cytoplasm, which contains cholesterol, triglycerides, glycogen, and lipids (Figure 22–3).
Photomicrograph of clear cell renal adenocarcinoma (original magnification, ×125).
The cells present in the papillary (chromophilic) type contain less glycogen and lipids, and electron microscopy reveals that the granular cytoplasm contains many mitochondria and cytosomes. Chromophobe-type carcinomas contain large polygonal cells with distinct cell borders and reticulated cytoplasm, which can stain diffusely with Hale's colloidal iron (Theones et al, 1988). Oncocytic RCC or oncocytomas tend to have cytoplasm packed with mitochondria, giving it a granular appearance. Collecting duct tumors tend to have irregular borders and a basophilic cytoplasm with extensive anaplasia and are likely to invade blood vessels and cause infarction of tissue. Sarcomatoid cells are spindle shaped and form sheets or bundles. This later cell type rarely occurs as a pure form and is most commonly a small component of either the clear cell or papillary cell type (or both).
Tumor Staging and Grading
The ultimate goal of staging is to select appropriate therapy and obtain prognostic information. Appropriate studies for a complete clinical staging evaluation include history and physical examination, complete blood count, serum chemistries (renal and hepatic function), urinalysis, chest x-ray (chest CT scan for an equivocal exam), CT scan of abdomen and pelvis, and a radionuclide bone scan (with x-rays of abnormal areas).
The original staging system described by Robson (1963) is easy to use, but it does not relate directly to prognosis and hence it is no longer commonly used. The tumor-node-metastasis (TNM) system more accurately classifies the extent of tumor involvement and is currently most often used. The TNM classification system for RCC has undergone multiple revisions with the most recent edition being the 2010 version (Table 22–1). In the most recent American Joint Committee on Cancer TNM staging, stage T1 disease is further divided into T1a (tumor size <4 cm) and T1b (size 4–7 cm) as there is a difference in long-term survival between stage T1a and T1b (Ficarra et al, 2005).
Table 22–1. TNM Classification System for Renal Cell Carcinoma.a ||Download (.pdf)
Table 22–1. TNM Classification System for Renal Cell Carcinoma.a
Primary tumor cannot be assessed
No evidence of primary tumor
Tumor 7.0 cm or less in greatest dimension, limited to the kidney
Tumor less than 4.0 cm in greatest dimension, limited to the kidney
Tumor 4.0–7.0 cm in greatest dimension, limited to the kidney
Tumor more than 7.0 cm in greatest dimension, limited to the kidney
Tumor >7 cm but ≤10 cm in greatest dimension, limited to kidney
Tumor >10 cm in greatest dimension, limited to kidney
Tumor extends into major veins or perinephric tissues but not into ipsilateral adrenal gland or beyond Gerota's fascia
Tumor invades renal vein or its segmental branches or perirenal fat or renal sinus fat but not beyond Gerota's fascia
Tumor grossly extends into vena cava below the diaphragm
Tumor grossly extends into vena cava above diaphragm or into the wall of the vena cava
Tumor invades beyond Gerota's fascia including contiguous extension into ipsilateral adrenal gland
N—Regional lymph nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in regional lymph nodes
Distant metastasis cannot be assessed
No distant metastasis
Fuhrman grading has become commonly used by pathologists in North America (Fuhrman et al, 1982; Goldstein, 1997). The system uses four grades based on nuclear size and irregularity and nucleolar prominence. The system is most effective in predicting metastasis (50% of high-grade tumors within 5 years). When high-grade, predominantly granular tumors are corrected for grade and stage, there is no apparent difference between clear cell and granular cell tumor prognosis (McNichols et al, 1981). However, patients presenting with advanced disease do poorly irrespective of tumor grade.
The classically described triad of gross hematuria, flank pain, and a palpable mass occurs in only 7–10% of patients and is frequently a manifestation of advanced disease. Patients may also present with hematuria, dyspnea, cough, and bone pain that are typically symptoms secondary to metastases. With the routine use of CT scanning for evaluation of nonspecific findings, asymptomatic renal tumors are increasingly detected incidentally (>50%).
RCC is associated with a wide spectrum of paraneoplastic syndromes including erythrocytosis, hypercalcemia, hypertension, and nonmetastatic hepatic dysfunction. Overall, these manifestations can occur in 10–40% of patients with RCC.
RCC is the most common cause of paraneoplastic erythrocytosis, which is reported to occur in 3–10% of patients with this tumor (Sufrin et al, 1989). In patients with RCC, the elevated erythrocyte mass is physiologically inappropriate and may result either from enhanced production of erythropoietin from the tumor or as a consequence of regional renal hypoxia promoting erythropoietin production from nonneoplastic renal tissue (Hocking, 1987).
Hypercalcemia has been reported to occur in up to 20% of patients with RCC (Muggia, 1990). Hypercalcemia may be due to production of a parathyroid hormone-related peptide that mimics the function of parathyroid hormone (Strewler et al, 1987) or other humoral factors such as osteoclast-activating factor, tumor necrosis factor, and transforming growth factor-alpha (Muggia, 1990).
Hypertension associated with RCC has been reported in up to 40% of patients (Sufrin et al, 1989), and renin production by the neoplasm has been documented in 37%. The excess renin and hypertension associated with RCC are typically refractory to antihypertensive therapy but may respond after nephrectomy (Gold et al, 1996).
In 1961, Stauffer described a reversible syndrome of hepatic dysfunction in the absence of hepatic metastases associated with RCC. Hepatic function abnormalities include elevation of alkaline phosphatase and bilirubin, hypoalbuminemia, prolonged prothrombin time, and hypergammaglobulinemia. Stauffer's syndrome tends to occur in association with fever, fatigue, and weight loss and typically resolves after nephrectomy. The reported incidence of Stauffer's syndrome varies from 3% to 20% (Gold et al, 1996). It may be due to overproduction of granulocyte-macrophage colony stimulating factor by the tumor (Chang et al, 1992).
RCC is known to produce a multitude of other biologically active products that result in clinically significant syndromes, including adrenocorticotropic hormone (Cushing's syndrome), enteroglucagon (protein enteropathy), prolactin (galactorrhea), insulin (hypoglycemia), and gonadotropins (gynecomastia and decreased libido; or hirsutism, amenorrhea, and male pattern balding) (Sufrin et al, 1986).
A paraneoplastic syndrome present at the time of disease diagnosis does not, in and of itself, confer a poor prognosis. However, patients whose paraneoplastic metabolic disturbances fail to normalize after nephrectomy (suggesting the presence of clinically undetectable metastatic disease) have very poor prognoses (Hanash, 1982).
In addition to the laboratory abnormalities associated with the various RCC paraneoplastic syndromes, anemia, hematuria, and an elevated sedimentation rate are frequently observed.
Anemia occurs in about 30% of RCC patients. The anemia typically is not secondary to blood loss or hemolysis and is commonly normochromic. The serum iron and total iron-binding capacity are usually low, as in the anemia of chronic disease. Iron therapy is usually ineffective; however, surgical removal of early-stage tumors usually leads to physiologic correction of the anemia. The potential role of recombinant erythropoietin for patients with unresectable disease represents a potential, but untested, option.
Gross or microscopic hematuria can be seen in up to 60% of patients presenting with RCC. An elevated erythrocyte sedimentation rate is also commonly seen, with a reported incidence as high as 75%. These findings are nonspecific, and normal findings do not rule out a diagnosis of RCC.
Although many radiologic techniques are available to aid in the detection and diagnosis of renal masses, CT scanning remains the primary technique with which others must be compared. Other radiologic techniques used include US and MRI.
US examination is a noninvasive, relatively inexpensive technique able to further delineate a renal mass. It is approximately 98% accurate in distinguishing simple cysts from solid lesions. Strict ultrasonographic criteria for a simple cyst include through transmission, a well-circumscribed mass without internal echoes, and adequate visualization of a strong posterior wall (Figure 22–4).
A: Ultrasound image of a simple renal cyst showing renal parenchyma (long arrows), cyst wall (arrowheads), and a strong posterior wall (short arrows). B: Ultrasound image of a solid renal mass (arrows).
CT scanning is more sensitive than US for detection of renal masses. A typical finding of RCC on CT is a mass that becomes enhanced with the use of intravenous contrast media. In general, RCC exhibits an overall decreased density in Hounsfield units compared with normal renal parenchyma but shows either a homogeneous or heterogeneous pattern of enhancement (increase in density of >10 Hounsfield units) following contrast administration (Figure 22–5). In addition to defining the primary lesion, CT scanning is also the method of choice in staging the patient by visualizing the renal hilum, perinephric space, renal vein and vena cava, adrenals, regional lymphatics, and adjacent organs. In patients with equivocal chest x-ray findings, a CT scan of the chest is indicated. Patients who present with symptoms consistent with brain metastases should be evaluated with either head CT or MRI. Spiral CT with 3-dimensional reconstruction has become useful for evaluating tumors before nephron-sparing surgery to delineate the 3-dimensional extent of the tumor and precisely outline the vasculature, which can aid the surgeon in preventing positive surgical margins (Holmes et al, 1997). Intraoperative ultrasonography is also often used to confirm the extent and number of masses in the kidney at the time of performing a partial nephrectomy.
Computed tomogram (contrast enhancement) of a renal cell carcinoma (arrows).
With the widespread availability of CT scanners, the role of renal angiography in the diagnostic evaluation of RCC has markedly diminished and is now very limited. There remain a very few specific clinical situations in which angiography may be useful; for example, guiding the operative approach in a patient with an RCC in a solitary kidney when attempting to perform a partial nephrectomy may be indicated (Figure 22–6). However, CT angiography or MR angiography can give better information with less risk to the patient.
Right renal angiogram showing typical neovascularity (arrows) in a large lower pole renal cell cancer.
Determination of metastases to bones is most accurate by radionuclide bone scan, although the study is nonspecific and requires confirmation with bone x-rays of identified abnormalities to verify the presence of the typical osteolytic lesions. There is evidence that patients without bone pain and with a normal alkaline phosphatase level have a very low incidence of bone metastases (Henriksson et al, 1992), and thus a routine bone scan is not necessary in such patients.
Magnetic Resonance Imaging
MRI is equivalent to CT for staging of RCC (Hricak et al, 1988). Its primary advantage is in the evaluation of patients with suspected vascular extension (Figure 22–7). Prospective trials have demonstrated that MRI is superior to CT in assessing inferior vena caval involvement (Kabala et al, 1991) and is at least as accurate as venacavography (Horan et al, 1989). In contrast to both CT and cavography, MRI evaluation does not require either iodinated contrast material or ionizing radiation. Recent studies using MRI angiography with gadolinium or CT angiography have improved vascular evaluation of renal neoplasms (Bluemke and Chambers, 1995). MR angiography can also be used to delineate the vascular supply before planned nephron-sparing surgery.
Transaxial magnetic resonance image (T2) of a renal cell carcinoma (long arrows) with vena caval tumor thrombus (short arrows).
Positron Emission Tomography (PET) and Targeted Imaging
This technique allows the measurement of systemically administered biochemical agents such as 18-fluoro-2-deoxyglucose (FDG), which can accumulate in the kidney. Although FDG-PET scanning can yield false-positive results in some patients with RCC (Bachor et al, 1996), it may be useful in monitoring response to systemic therapy in those with metastatic disease (Hoh et al, 1998). FDG-PET may also be more accurate than routine CT scanning in detecting disease recurrence or progression, which may alter treatment decisions in up to 50% of cases (Ramdave et al, 2001). However, most recent studies suggest that FDG-PET is of insufficient sensitivity to be useful for staging RCC.
The enzyme carbonic anhydrase IX (CA IX) is expressed at high levels in clear cell RCC. CA IX is regulated by the VHL gene through HIF1α and with loss of the VHL tumor suppressor gene being very common in clear cell RCC, there is loss of regulation of CA IX expression which is significantly increased. It is expressed at low levels in the gastrointestinal, mucosa, and biliary tract but not in other normal tissues. This characteristic can be exploited to detect clear cell RCC using a radiolabeled monoclonal antibody scan using the antibody G250 which targets carbonic anhydrase IX (Stillebroer et al, 2010). Up to 80% of clear cell RCC are found to express G250 antigen and in nearly imaging studies (Oosterwijnk et al, 1993). Other renal tumors such as chromophobe and papillary RCC demonstrate very little CA IX expression. More recently an immuno-PET approach has been used combining the monoclonal antibody to CA IX and a PET scan to better visualize renal lesions. In early studies, 94% of renal tumors were correctly identified using this approach (Divgi et al, 2007).
Fine-needle aspiration of renal lesions is the diagnostic approach of choice in those patients with clinically apparent metastatic disease who may be candidates for nonsurgical therapy. Other settings in which fine-needle aspiration may be appropriate include establishing a diagnosis in patients who are not surgical candidates, differentiating a primary RCC from a renal metastasis in patients with known primary cancers of nonrenal origin, and evaluating some radiographically indeterminate lesions. Fine needle aspiration is being increasingly used to confirm the diagnosis of a neoplasm particularly in patients who may undergo observation or percutaneous ablative therapy (Shah et al, 2005). While core needle biopsies may be able to accurately diagnose malignancy in up to 100% of cases >4 cm and 95% of cases <4 cm, this may require multiple cores for accuracy (Wunderlich et al, 2005). Rare reports of seeding of the needle tract have been reported but the risk of seeding is reported to be <0.01% (Volpe et al, 2007). Recently, core biopsies of the primary renal mass have been more commonly utilized in patients with metastatic disease (when biopsying a metastatic site is not feasible), in order to guide appropriate targeted systemic therapy (prior to or instead of cytoreductive nephrectomy), since the choice of systemic therapy can be influenced by the specific RCC histology. The accuracy of needle core biopsies is reported to be >90% with sensitivity ranging between 70–100% and specificity of 100% (Volpe et al, 2007). The accuracy of fine needle aspiration cytology of renal masses is reported to be slightly lower mainly because of lower sensitivity. Specificity can still be high and close to 100%.
Instrumental and Cytologic Examination
Patients presenting with hematuria should also be evaluated with cystoscopy. Blood effluxing from the ureteral orifice identifies the origin of bleeding from the upper tract. Most renal pelvis tumors can be distinguished radiographically from RCC; however, endoscopic evaluation of the bladder, ureters, and renal pelvis is occasionally helpful in making a diagnosis. In addition, although urine cytologic study is rarely helpful in the diagnosis of RCC, cytologic study of urine with renal pelvis washing is frequently diagnostic in renal pelvis tumors.
When a patient presents with clinical findings consistent with metastatic disease and is found to have a renal mass, a diagnosis of RCC can be straightforward. Most patients present with a renal mass discovered after an evaluation of hematuria or pain or as an incidental finding during an imaging workup of an unrelated problem. The differential diagnosis of RCC includes other solid renal lesions. The great majority of renal masses are simple cysts. Once the diagnosis of a cyst is confirmed by US, no additional evaluation is required if the patient is asymptomatic. Equivocal findings or the presence of calcification within the mass warrant further evaluation by CT. A wide variety of pathologic entities appear as solid masses on CT scans, and differentiation of benign from malignant lesions is frequently difficult. Findings on CT scan that suggest malignancy include amputation of a portion of the collecting system, presence of calcification, a poorly defined interface between the renal parenchyma and the lesion, invasion into perinephric fat or adjacent structures, and the presence of abnormal periaortic adenopathy or distant metastatic disease. The frequency of benign lesions among renal masses <7 cm in size is as high as 16–20% (Duchene et al, 2003; Snyder et al, 2006). Masses >7 cm are rarely benign.
Some characteristic lesions can be defined using CT criteria in combination with clinical findings. Angiomyolipomas (with large fat components) can easily be identified by the low-attenuation areas classically produced by substantial fat content. A renal abscess may be strongly suspected in a patient presenting with fever, flank pain, pyuria, and leukocytosis, and an early needle aspiration and culture should be performed. Other benign renal masses (in addition to those previously described) include granulomas and arteriovenous malformations. Renal lymphoma (both Hodgkin's disease and non-Hodgkin's disease), transitional cell carcinoma of the renal pelvis, adrenal cancer, and metastatic disease (most commonly from a lung or breast cancer primary) are additional diagnostic possibilities that may be suspected based on CT and clinical findings.
Surgical removal of the early-stage lesion remains the only potentially curative therapy available for RCC patients. Appropriate therapy depends almost entirely on the stage of tumor at presentation and therefore requires a thorough staging evaluation. The prognoses of patients with stages T1–T3a disease are similar following radical nephrectomy.
Radical or partial nephrectomies are the primary treatments for localized RCC. The goal is to achieve the removal of tumor and to take a wide margin of normal tissue. Radical nephrectomy entails en bloc removal of the kidney and its enveloping fascia (Gerota's) including the ipsilateral adrenal, proximal one-half of the ureter, and lymph nodes up to the area of transection of the renal vessels (Figure 22–8).
Boundaries of a left radical nephrectomy. Dotted line represents both the surgical margin and Gerota's fascia.
Various open incisions provide optimal access for the radical nephrectomy, including an anterior subcostal (unilateral chevron) or thoracoabdominal incision, and, occasionally, a midline incision or the classic flank incision.
The likelihood of local recurrence after radical nephrectomy is 2–3% (Itano et al, 2000). Repeat resection of isolated local recurrence can be curative and yield a survival benefit (Itano et al, 2000; Tanguay et al, 1996). The role of regional lymphadenectomy in RCC remains controversial. Between 18% and 33% of patients undergoing radical nephrectomy with lymph node dissection for RCC have metastatic disease identified (Skinner et al, 1988). Although several retrospective studies (Thrasher and Paulson, 1993) and a prospective, nonrandomized study (Herrlinger et al, 1991) suggest that regional lymphadenectomy can improve survival in patients with T1–T2 RCC. More recent studies including a randomized prospective study as well as a population-based study failed to show any survival benefit that could be obtained by routinely performing regional lymphadenectomy especially in patients with organ-confined disease (Blom et al, 1999; Joslyn et al, 2005). Removal of the adrenal is unnecessary if the tumor is not in the upper pole, because adrenal involvement is uncommon in this instance.
Preoperative renal artery embolization (angioinfarction) has been used in the past as a surgical adjunct to facilitate radical nephrectomy, but because there is no conclusive evidence that preoperative embolization actually decreases blood loss or facilitates surgery, its use should be limited to patients with very large tumors in which the renal artery may be difficult to reach early in the procedure. In addition, this technique may be useful to palliate patients with nonresectable tumors and significant symptoms such as hemorrhage, flank pain, or paraneoplastic syndromes.
Radiation therapy has been advocated as a neoadjuvant (preoperative) or adjuvant method to radical nephrectomy, but there is no evidence that postsurgical radiation therapy to the renal bed, whether or not residual tumor is present, contributes to prolonged survival.
RCC may invade renal vascular spaces and produce tumor thrombi extending into renal veins, inferior vena cava, hepatic veins, and, occasionally, the right atrium. Between 5% and 10% of patients presenting with RCC have some degree of vena caval involvement (Figure 22–9) (Skinner et al, 1988). Patients presenting with involvement of the vena cava below the hepatic veins (T3bN0M0) but without evidence of regional or distant metastases have a prognosis similar to patients with stage T2 disease when treated by radical excision. The surgical approach to the removal of caval thrombi depends entirely on the level of cephalad extension. In general, these thrombi do not invade the wall of the cava and therefore can be removed without resection of the caval wall. For tumor thrombi that have reached the level of the right atrium, the use of cardiopulmonary bypass is typically required.
Coronal magnetic image (T1) of a large vena caval tumor thrombus (long arrows) in a patient with renal cell carcinoma. Thrombus extends just to entrance of hepatic veins (short arrows).
Laparoscopic or robotic radical nephrectomy and partial nephrectomy can also be accomplished successfully and safely. Laparoscopic/robotic radical nephrectomy is being used increasingly for patients with localized renal tumors. This approach results in quicker recovery with efficacy comparable to that of open radical nephrectomy and is now the approach of choice in appropriate patients with <10 cm tumors and without local extension or a renal vein or caval thrombus (Gill et al, 2001; Portis et al, 2002).
The approach to the patient with either bilateral RCC or disease in a solitary kidney differs from the standard approach of radical nephrectomy. Bilateral RCC occurs with a frequency as high as 3% (Smith, 1986). Radical nephrectomy in these patients or in those with solitary kidneys obviously commits patients to long-term dialysis or renal transplantation and the morbidities of these conditions. Staging these patients is essentially the same as previously outlined, with the notable exception that either MR or CT angiography is often used to assess the extent of tumor within the kidney and the renal artery anatomy. Surgical alternatives to radical nephrectomy include open or laparoscopic/robotic partial nephrectomy, ex vivo partial nephrectomy (bench surgery followed by autotransplantation) (Novick et al, 1980), and enucleation of multiple lesions (Marshall et al, 1986). Given the lack of curative adjuvant therapy, the risk of inadequate excision, and subsequent recurrence from various renal-sparing approaches, partial nephrectomy with an adequate parenchymal margin remains the preferred treatment.
Partial nephrectomy and wedge resection with an adequate margin of normal parenchyma is considered standard primary surgical therapy for patients with tumors <4 cm in size, even in the presence of a normal contralateral kidney. Local recurrence of tumor in the same kidney ranges from 0% to 10%, and it is between 0% and 3% for tumors <4 cm in size (Hafez et al, 1997; Morgan and Zincke, 1990; Uzzo and Novick, 2001). In patients with multiple small tumors, such as those with von Hippel–Lindau disease, enucleation of the tumor(s) is also an acceptable approach. Long-term follow-up demonstrates that partial nephrectomy has a similar outcome as radical nephrectomy (Herr, 1999). Laparoscopic or robotic partial nephrectomy for these small tumors is recently gaining in use. The main advantages of the laparoscopic/robotic approach to partial nephrectomy are lower blood loss, less pain, and faster recovery.
Additional therapeutic approaches being increasingly applied for the treatment of small, incidentally discovered renal lesions include the use of cryoablation, high-intensity focused US, and radiofrequency ablation (Murphy and Gill, 2001). Cryoablation with liquid nitrogen or argon gas, either percutaneously using MRI guidance or via laparoscopic probes, has proved to be feasible and effective in selected patients (Gill et al, 2000; Shingleton and Sewell, 2002). Radiofrequency ablation has also been accomplished via the percutaneous approach with minimal morbidity in small groups of patients (Pavlovich et al, 2002). These approaches are particularly attractive in patients with single or multiple small lesions or older individuals with many comorbidities. The long-term effectiveness of both radiofrequency ablation as well as cryoablation appears to be acceptable (Kimura et al, 2010). It appears that cryoablation is superior to radiofrequency ablation in terms of long-term cancer control. Bleeding, scarring of renal pelvis, and urine leak are among the commonly reported complications with the ablative therapies.
Observation as treatment can also be considered an acceptable management approach for small (<3.0 cm) lesions, particularly in elderly patients. One recent study noted a growth rate of 0–1.3 cm/year in 40 patients followed up for a mean of 3.5 years (Bosniak, 1995), indicating that with careful follow-up, watchful waiting may be appropriate in selected patients. Only one-third of small (<4 cm) renal masses are observed to increase in size over 2 years with none experiencing disease progression (Volpe et al, 2004). This further suggests that at least initially observation is a reasonable option particularly for older patients with comorbidities who may not be amenable to surgery.
Approximately 30% of patients with RCC will present with advanced disease. Metastatic RCC has a variable natural history, with 5-year survival rates typically <10% (Motzer et al, 1996). Infrequently, the disease may have a more protracted course. The biological diversity of RCC is illustrated by the 6.6% response rate (including 3% complete responders) in the placebo arm of a phase III trial of interferon-gamma (IFN-γ) in advanced RCC (Gleave et al, 1998).
Role of stratification factors: The experience with IFN has led to the understanding that patients can be grouped into three different risk categories, which predicts their overall survival from metastatic RCC. The so-called Motzer criteria, or Memorial Sloan-Kettering Cancer Center risk group, stratify patients into good, intermediate and poor risk based on performance status, prior nephrectomy, hemoglobin, lactate dehydrogenase (LDH), and calcium level (Motzer et al, 1999). Importantly, even though IFN is currently no longer used in the treatment of RCC, these risk groups were utilized to select different patient populations in the development of currently available targeted therapies (below).
The role of radical nephrectomy in the management of patients with advanced disease has been reevaluated based on the results of randomized clinical trials. Historically, radical nephrectomy was primarily used as a palliative procedure in the setting of metastatic disease for managing patients with severe hemorrhage or unremitting pain. Over the past 20 years, retrospective observations of the potential for nephrectomy to improve the outcome of patients receiving biologic response modifier therapy prompted a prospective evaluation of this effect. The Southwest Oncology Group performed a randomized phase III trial, randomizing patients with advanced RCC to nephrectomy followed by interferon-alpha (IFN-α) 2b versus interferon alone. The median survival of patients undergoing nephrectomy followed by interferon was 3 months longer compared to those receiving only interferon (Flanigan et al, 2001). A similar, smaller, randomized trial conducted in Europe demonstrated similar findings (Mickisch et al, 2001). These two studies have prompted a shift in the standard of care for patients with metastatic RCC and good performance status who desire systemic therapy to include a nephrectomy prior to systemic therapy. Nephrectomy in the presence of metastatic disease (cytoreductive nephrectomy) can be performed via the open approach or laparoscopically. Patients who undergo the nephrectomy laparoscopically may have shorter hospital stay, less blood loss, and obtain adjuvant therapy earlier (Rabets et al, 2004)
The continued role of cytoreductive nephrectomy prior to systemic therapy has undergone considerable scrutiny after 2004, with the availability of new targeted systemic therapy (anti-vascular endothelial growth factor (anti-VEGF) tyrosine kinase inhibitors (TKIs) and mTOR inhibitors). While a majority of patients who received these drugs in clinical trials (and in current medical practice in 2010) have had prior cytoreductive nephrectomy, no randomized comparison regarding the role of cytoreductive nephrectomy in prolonging survival in the targeted therapy era is yet available. An ongoing clinical trial in Europe is examining this question. Trials are also examining the role of neoadjuvant-targeted therapy prior to cytoreductive nephrectomy.
Patients presenting with a solitary metastatic site particularly in the lung that is amenable to surgical resection may be candidates for combined nephrectomy and removal of the metastatic foci (Hoffman et al, 2005). This approach can result in 5-year survival rates of 30–40% with patients developing metachronous solitary lung metastases having a better prognosis (Hoffman et al, 2005). In patients who are destined to receive adjuvant therapy, even limited resection of metastases can yield improved survival further emphasizing the potential benefit of tumor debulking (Vogl et al, 2006).
The important role of surgical resection of solitary brain metastases has been highlighted by several randomized trials demonstrating an improvement in survival in patients with solitary brain metastases who undergo both surgical resection and whole-brain radiotherapy compared with patients who receive only radiation therapy (Patchell et al, 1990; Vecht et al, 1993).
Radiation therapy is an important method in the palliation of patients with metastatic RCC. Despite the belief that RCC is a relatively radioresistant tumor, effective palliation of metastatic disease to the brain, bone, and lungs is reported in up to two-thirds of patients (Fossa et al, 1982; Onufrey and Mohiuddin, 1985).
Biologic Response Modifiers
The use of metastatic RCC as a model for the investigation of various biologic response modifiers was a consequence of both the lack of effective chemotherapy and the long-recognized biologic “eccentricities” of this tumor. Spontaneous regression of metastatic RCC is a well-recognized, albeit rare, event (Kavoussi et al, 1986; Vogelzang et al, 1992). Although no specific evidence exists, many believe this phenomenon to be immunologically mediated.
Studies using partially purified human leukocyte interferon in renal cancer were first reported in 1983, with subsequent studies using human lymphoblastoid interferon and, subsequently, recombinant interferon-alpha (r-IFN-α). Various doses and schedules of r-IFN-α have demonstrated reproducible overall response rates of 10–15% in advanced renal cancer (Pastore et al, 2001). A modest impact on survival has been demonstrated in some randomized trials of IFN-α. The Medical Research Council compared IFN-α to medroxyprogesterone acetate and demonstrated a 2.5-month median survival improvement favoring the IFN-α arm (Medical Research Council Renal Cancer Collaborators, 1999). Other large randomized studies have failed to demonstrate a survival advantage of IFN-α compared to other biologic response modifiers (Motzer et al, 2000; Negrier et al, 1998). IFN-α is commonly administered 3–5 days/week as a subcutaneous injection. Patients most likely to have a clinical benefit from interferon therapy are those who have minimal tumor burden (ie, primary kidney tumor removed), lung or nodal metastases only, and an excellent performance status. Given the modest activity of interferon in patients with advanced disease, trials of interferon administered in the adjuvant setting to patients at high risk of recurrence have been conducted but have not demonstrated clinical benefit (Pizzocaro et al, 2001; Trump et al, 1996). The experience with beta and gamma interferons has been less extensive. In 1989, Aulitzky and colleagues reported a 30% response rate in a trial of low-dose IFN-γ (Aulitzky et al, 1989). Unfortunately, subsequent trials, including a phase III trial, have demonstrated response rates of <10% (Gleave et al, 1998).
Interleukin-2 (IL-2), a T-cell growth factor, was first identified in 1976. Recombinant IL-2 was for a long time the only agent approved by the US Food and Drug Administration for patients with advanced renal carcinoma. The approval was based on several nonrandomized trials showing overall response rates for high-dose IL-2 in the 15% range and a complete response rate of 5%, resulting in some long-term survivors being seen with this treatment. The wide variability in response rates to IL-2 is likely a function of patient selection. Fyfe and colleagues (1995) reported a retrospective evaluation of 255 patients treated with high-dose IL-2 and found that an Eastern Cooperative Oncology Group performance score of 0 was a significant predictor of clinical response. More recently, the Cytokine Working Group presented the results of the SELECT trial, which was designed to prospectively evaluate predictive factors for response to high-dose IL-2. This trial showed that in optimally selected patients, response rates could be as high as 30%, with optimal criteria being clear cell histology and good or intermediate UCLA SANI score (which takes into account number of metastatic sites, thyroid function, lymph node status, constitutional symptoms, and histology). (McDermott et al, 2001).
Randomized trials comparing IFN-α, IL-2, and IL-2 plus INF-α have demonstrated higher objective response rates to the combination therapy, with no difference in survival and significantly higher toxicity associated with the combination (Negrier et al, 1998). Biochemotherapy regimens have been evaluated with a phase III trial demonstrating no advantage to the combination of IL-2, IFN-α, and fluorouracil versus IL-2 and IFN (Negrier et al, 2000).
With the advent of the targeted therapy era for RCC (forthcoming section), and given the low response rates to IFN, and the significant toxicities of high-dose IL-2 (despite it being the only treatment to date with potential for durable responses), immunotherapy treatments are currently offered to a minority of carefully selected patients and in centers with expertise.
There has been significant progress in the development of several antiangiogenic agents and inhibitors of tyrosine kinase and other cell cycle activators in RCC, with currently six drugs having FDA approval for treatment of metastatic RCC in different settings and routinely used in clinical practice. Both inherited and sporadic RCCs appear to have mutations of the VHL gene resulting in loss of the gene product. This causes increased levels of hypoxia-inducible factor-alpha that in turn promotes increased expression of VEGF and promotes angiogenesis.
Bevacizumab is a monoclonal antibody that binds and inactivates VEGF A. It has shown the ability to yield partial responses, delay disease progression, and improve survival in patients with advanced renal cancer (Yang et al, 2003). Randomized trials comparing IFN with the IFN and bevacizumab combination have shown the superiority of the combination in terms of progression-free survival (Escudier et al, 2010; Rini et al, 2010).
Anti-VEGF TKIs are small molecules that are orally bioavailable. Currently FDA approved are sorafenib, sunitinib, and pazopanib. Sunitinib and pazopanib were shown to have significant activity in the first-line setting with higher response rates and longer progression-free survival compared to IFN or placebo (Motzer et al, 2007; Sternberg et al, 2010). Sorafenib was shown to have activity in patients who had previously received cytokine immunotherapy. (Escudier et al, 2009). Anti-VEGF TKI administration requires significant expertise in managing toxicities, which for instance include hypertension, diarrhea, rash, hand-foot skin reactions, cardiac abnormalities, and many others. Not all drugs in this class exhibit the same toxicities or frequency thereof. Most patients who entered clinical trials with TKIs had clear cell histology and prior cytoreductive nephrectomy.
mTOR inhibitors are another important class of agents with activity against RCC. The mTOR pathway interacts with the VEGF pathway at the molecular level and is another contributor of angiogenesis in RCC. Temsirolimus was the first mTOR inhibitor to be FDA approved and has been demonstrated to prolong survival in patients with advanced renal cancer who present with poor risk or multiple sites of metastases (Hudes et al, 2007). The phase III trial that demonstrated the efficacy of temsirolimus also notably included several patients with nonclear cell histology, a rare finding in the trials of TKIs. Everolimus was subsequently FDA-approved based on its ability to prolong progression-free survival as second-line therapy for patients with metastatic clear-cell RCC (Motzer et al, 2010). mTOR inhibitors can cause mouth sores, fatigue, pneumonitis, and hypertriglyceridemia among other side effects.
Given all the drugs available for metastatic RCC in 2010, there are many challenges ahead of us in understanding what is the best sequence of therapies to treat patients suffering from advanced RCC today. The sequential nature of the treatments also makes it difficult to prove overall survival benefits with each individually used drug in a clinical trial. The current belief is that the overall survival of patients with metastatic RCC has increased over time, approaching a median overall survival of 2 years (as opposed to 1 year in the interferon era). It is also to be highlighted that much of the clinical benefit seen with the targeted agents is not evidenced by tumor shrinkage (response rates, which are generally modest), but instead from increased duration of tumor control (progression-free survival and projected overall survival) benefits. Finally, in making decisions about which systemic therapy to use for a specific patient, many factors are taken into consideration including performance status, histology, sites and number of metastases, mode of administration, anticipated tolerance to each individual drug, line of therapy, and socioeconomic and clinical trial considerations.
There is no universal agreement on the frequency or studies required in the follow-up care of patients with RCC. A stage-specific follow-up schedule is recommended for patients who have undergone radical or partial nephrectomy (Levy et al, 1998; Hafez et al, 1997). Patients with stage T1 disease need less stringent follow-up with yearly chest x-rays and liver and renal function tests. Those with stage T2 or T3 disease require more frequent follow-up of at least 3-month or 6-month intervals in the early postoperative period. Repeat CT scans of the abdomen should also be obtained, especially in those who have undergone partial nephrectomy, to rule out local recurrence. Patients with metastatic disease who are not undergoing therapy need continued follow-up to provide appropriate supportive care.