Renal cortical tumors: a diversity of tumors and potential threats

Renal cortical tumors (RCTs) are members of a complex family with unique histologies, cytogenetic defects, and variable metastatic potentials ranging from the benign oncocytoma, to the indolent papillary and chromophobe carcinomas, to the more malignant conventional clear carcinoma. At our center, Memorial Sloan Kettering Cancer Center (MSKCC), the conventional clear cell tumor accounts for 90% of all metastatic RCTs but only 54% of the renal tumors undergoing resection. Two groups of patients with RCTs currently exist. The first group consists of patients with symptomatic, large, locally advanced tumors often presenting with regional adenopathy, adrenal invasion, and extension into the renal vein or inferior vena cava. Despite radical nephrectomy in conjunction with regional lymphadenectomy and adrenalectomy, progression to distant metastasis and death from disease occurs in approximately 30% of these patients. For patients presenting with isolated metastatic disease, metastasectomy in carefully selected patients has been associated with long-term survival. For patients with diffuse metastatic disease and an acceptable performance status, cytoreductive nephrectomy, compared to cytokine therapy alone, may add several additional months of survival. Cytoreductive nephrectomy also prepares patients for integrated treatment, now in neoadjuvant and adjuvant clinic trials, with the new multitargeted tyrosine kinase inhibitors (sunitinib, sorafenib) and mammalian target of rapamycin inhibitors (temsirolimus, RAD001).

The second group of RCTs consists of small renal tumors (median tumor size <4 cm, T1a) often incidentally discovered in asymptomatic patients during imaging for nonspecific abdominal or musculoskeletal complaints or during unrelated cancer care. A greater than 90% survival rate, depending on the tumor histology, is expected following partial or radical nephrectomy. Despite vast improvements in modern CT, ultrasound, and MRI imaging of the kidney, these studies are nonspecific and between 16.4% and 23% of patients undergoing tumor resection are ultimately found to have a benign lesion, including angiomyolipoma, oncocytoma, metanephric adenoma, or hemorrhagic cyst. Although CT-guided percutanous renal biopsy can easily be performed, the differentiation between a benign and malignant tumor and the determination of tumor histologic subtypes by current radiological and biopsy techniques alone or in combination is only 70% accurate. Active research to determine if immunohistochemical and cytogenetic techniques can substantially improve the accuracy of RCT percutaneous biopsy is ongoing. An alternative strategy to image the more malignant clear cell carcinoma with a specific radio-labeled antibody that reacts to carbonic anhydrase 9 124I-cG250 is under active investigation and has shown a high sensitivity and specificity in preliminary studies. This immuno–positron emission tomographic scan may play an important role in the future for planning surgeries, selecting for active surveillance, determining the response to novel local and systemic therapies, and evaluating extent of disease.

Partial nephrectomy is as effective as radical nephrectomy for T1 tumors

Contemporary surgical oncology (eg, for breast cancer, soft tissue sarcoma) now favors surgical approaches that preserve organs and limbs whenever possible, and is often used in conjunction with adjuvant therapies, with resulting local tumor control and long-term survival equivalent to their more radical counterparts. Partial nephrectomy, once used only for the essential indications, is now considered a preferred alternative to radical nephrectomy for patients with T1 tumors, normal renal function, and two intact kidneys. Studies from the United States and abroad have shown that partial nephrectomy for tumors of 4 cm or less provides equivalent tumor control compared with radical nephrectomy. Previous deterrents to partial nephrectomy, including proximity to collecting system or major segmental vessels, endophytic tumor location, concern for tumor multifocality, and the desire for a 1-cm surgical margin, are now routinely managed effectively in the operating room. Tumor localization using intraoperative ultrasound for endophytic and multifocal tumors, suture repair of the collecting system and blood vessels, and closed suction retroperitoneal drainage, has made open partial nephrectomy a highly effective operation. Complication rates are less than 10% and mostly relate to prolonged urinary fistula with only the rare need for reoperation or endoscopic interventions. Renoprotective measures of ice slush and mannitol seem effective in limiting damage to the kidney with normalization of renal function by 12 months postoperatively. Prolonged ischemia time, increasing blood loss, and partial nephrectomy in a solitary kidney, all indicators of a more challenging operation, are associated with early declines in glomerular filtration rate (GFR) but not long-term damage. It is our practice to perform partial nephrectomy with no ischemia (no renal artery cross-clamping) whenever possible to limit potential glomerular damage, which may not be detectable by serum markers or formulas that estimate kidney function. If renal artery clamping is required to limit blood loss during the resection of a large tumor or an endophytic tumor, mannitol (12.5 gm/250 mL of saline) and ice slush are routinely used with every attempt to limit cold ischemia to less than 30 minutes. In addition, careful visual inspection of the kidney and the use of intraoperative ultrasound address the small likelihood (<5%) of a previously unrecognized tumor satellite, which can also be excised at the same operation.

Recent studies have demonstrated that gross resection of all tumors, as assessed by the operating surgeon, even in the presence of only microscopically negative surgical margins, provides excellent local tumor control without an increased risk of local tumor recurrence and without the need for a 1-cm margin of surrounding renal parenchyma. One-centimeter margins are easily achievable goal for an exophytic tumor, but often not technically feasible for a renal sinus tumor, a juxtahilar tumor, or an intraparenchymal tumor. Complete resection of RCTs in these less-accessible locations increases the percentage of patients eligible for kidney-sparing operations and renders an excellent prognosis with a high likelihood (>90%) of freedom from local, regional, and metastatic recurrence, particularly because a significant percentage of patients with central tumors have indolent or benign histology (30.2%). In the event of a positive microscopic surgical margin on final pathology, previous recommendations for a “completion” radical nephrectomy appear unnecessary. In recently published study of 1344 partial nephrectomies from MSKCC and the Mayo Clinic, 77 patients (5.5%) were found to have positive surgical margins on final pathology. This was more likely to occur during the resection of a tumor in a solitary kidney or one in a technically challenging location. Although the surgeon should make every effort to achieve a complete resection at the time of a partial nephrectomy, a final pathologic positive surgical margin was not associated with an increased likelihood of local tumor recurrence or metastatic disease.

Partial nephrectomy has been safely extended to tumors of 7 cm or less, when technically feasible, with disease-free intervals equivalent to those in similar patients treated with radical nephrectomy across all histologic subtypes. MSKCC investigators compared the results of 45 patients undergoing partial nephrectomy to 151 patients undergoing radical nephrectomy (22 of whom were originally slated to have a partial nephrectomy but were converted to radical nephrectomy) for T1b (4–7 cm) conventional clear cell carcinomas. Disease-free survival between the groups were no different, but the serum creatinine levels, a relatively crude indicator of overall renal function, were substantially better in patients undergoing partial nephrectomy at 3, 6, and 12 months.

Clinical local recurrence in the partial nephrectomy bed is a rare event (<1%) and is often associated with a grossly positive surgical margin at the time of the initial resection, which is more likely to occur in patients with multifocal tumors or a large tumor in a solitary kidney. A recent publication from Pahernik and colleagues from Mainz, Germany, confirmed the oncological efficacy of partial nephrectomy in tumors larger than 4 cm. New tumor formation in the operated kidney is an uncommon event, occurring at a lifetime risk, in the absence of familial or hereditary syndromes, in less than 5% of patients. Following either partial nephrectomy or radical nephrectomy, the contralateral kidney also retains a lifetime risk of approximately 5% for the development of new tumor formation necessitating lifelong surveillance. At some finite point, likely measured in years, the risk of a new ipsilateral or contralateral tumor formation exceeds the risk of metastatic disease development from the index tumor. In any case, long-term surveillance with a yearly renal imaging study (CT, ultrasonography, or MRI) and chest radiograph (for clear cell, chromophobe, papillary renal cancer, but not benign oncocytoma or metanephric adenoma) to assess local or systemic recurrence is recommended. With this approach, disease-free survival rates of greater than 90% are achieved using partial nephrectomy for T1 RCTs across all histologic subtypes.

Partial nephrectomy is as effective as radical nephrectomy for T1 tumors

Contemporary surgical oncology (eg, for breast cancer, soft tissue sarcoma) now favors surgical approaches that preserve organs and limbs whenever possible, and is often used in conjunction with adjuvant therapies, with resulting local tumor control and long-term survival equivalent to their more radical counterparts. Partial nephrectomy, once used only for the essential indications, is now considered a preferred alternative to radical nephrectomy for patients with T1 tumors, normal renal function, and two intact kidneys. Studies from the United States and abroad have shown that partial nephrectomy for tumors of 4 cm or less provides equivalent tumor control compared with radical nephrectomy. Previous deterrents to partial nephrectomy, including proximity to collecting system or major segmental vessels, endophytic tumor location, concern for tumor multifocality, and the desire for a 1-cm surgical margin, are now routinely managed effectively in the operating room. Tumor localization using intraoperative ultrasound for endophytic and multifocal tumors, suture repair of the collecting system and blood vessels, and closed suction retroperitoneal drainage, has made open partial nephrectomy a highly effective operation. Complication rates are less than 10% and mostly relate to prolonged urinary fistula with only the rare need for reoperation or endoscopic interventions. Renoprotective measures of ice slush and mannitol seem effective in limiting damage to the kidney with normalization of renal function by 12 months postoperatively. Prolonged ischemia time, increasing blood loss, and partial nephrectomy in a solitary kidney, all indicators of a more challenging operation, are associated with early declines in glomerular filtration rate (GFR) but not long-term damage. It is our practice to perform partial nephrectomy with no ischemia (no renal artery cross-clamping) whenever possible to limit potential glomerular damage, which may not be detectable by serum markers or formulas that estimate kidney function. If renal artery clamping is required to limit blood loss during the resection of a large tumor or an endophytic tumor, mannitol (12.5 gm/250 mL of saline) and ice slush are routinely used with every attempt to limit cold ischemia to less than 30 minutes. In addition, careful visual inspection of the kidney and the use of intraoperative ultrasound address the small likelihood (<5%) of a previously unrecognized tumor satellite, which can also be excised at the same operation.

Recent studies have demonstrated that gross resection of all tumors, as assessed by the operating surgeon, even in the presence of only microscopically negative surgical margins, provides excellent local tumor control without an increased risk of local tumor recurrence and without the need for a 1-cm margin of surrounding renal parenchyma. One-centimeter margins are easily achievable goal for an exophytic tumor, but often not technically feasible for a renal sinus tumor, a juxtahilar tumor, or an intraparenchymal tumor. Complete resection of RCTs in these less-accessible locations increases the percentage of patients eligible for kidney-sparing operations and renders an excellent prognosis with a high likelihood (>90%) of freedom from local, regional, and metastatic recurrence, particularly because a significant percentage of patients with central tumors have indolent or benign histology (30.2%). In the event of a positive microscopic surgical margin on final pathology, previous recommendations for a “completion” radical nephrectomy appear unnecessary. In recently published study of 1344 partial nephrectomies from MSKCC and the Mayo Clinic, 77 patients (5.5%) were found to have positive surgical margins on final pathology. This was more likely to occur during the resection of a tumor in a solitary kidney or one in a technically challenging location. Although the surgeon should make every effort to achieve a complete resection at the time of a partial nephrectomy, a final pathologic positive surgical margin was not associated with an increased likelihood of local tumor recurrence or metastatic disease.

Partial nephrectomy has been safely extended to tumors of 7 cm or less, when technically feasible, with disease-free intervals equivalent to those in similar patients treated with radical nephrectomy across all histologic subtypes. MSKCC investigators compared the results of 45 patients undergoing partial nephrectomy to 151 patients undergoing radical nephrectomy (22 of whom were originally slated to have a partial nephrectomy but were converted to radical nephrectomy) for T1b (4–7 cm) conventional clear cell carcinomas. Disease-free survival between the groups were no different, but the serum creatinine levels, a relatively crude indicator of overall renal function, were substantially better in patients undergoing partial nephrectomy at 3, 6, and 12 months.

Clinical local recurrence in the partial nephrectomy bed is a rare event (<1%) and is often associated with a grossly positive surgical margin at the time of the initial resection, which is more likely to occur in patients with multifocal tumors or a large tumor in a solitary kidney. A recent publication from Pahernik and colleagues from Mainz, Germany, confirmed the oncological efficacy of partial nephrectomy in tumors larger than 4 cm. New tumor formation in the operated kidney is an uncommon event, occurring at a lifetime risk, in the absence of familial or hereditary syndromes, in less than 5% of patients. Following either partial nephrectomy or radical nephrectomy, the contralateral kidney also retains a lifetime risk of approximately 5% for the development of new tumor formation necessitating lifelong surveillance. At some finite point, likely measured in years, the risk of a new ipsilateral or contralateral tumor formation exceeds the risk of metastatic disease development from the index tumor. In any case, long-term surveillance with a yearly renal imaging study (CT, ultrasonography, or MRI) and chest radiograph (for clear cell, chromophobe, papillary renal cancer, but not benign oncocytoma or metanephric adenoma) to assess local or systemic recurrence is recommended. With this approach, disease-free survival rates of greater than 90% are achieved using partial nephrectomy for T1 RCTs across all histologic subtypes.

Kidney tumor patients and unrecognized medical renal disease

A historical misconception is that radical nephrectomy, although likely to cause a detectable and permanent rise in serum creatinine because of the sacrifice of normal renal parenchyma not involved by tumor, will not cause serious long-term side effects as long as the patient has a normal contralateral kidney. The renal transplant literature is often cited as the clinical evidence to support this view since patients undergoing donor nephrectomy have not been reported to have higher rates of kidney failure requiring dialysis or resulting in death. However, distinct differences between renal donors and renal tumor patients exist. Donors tend to be carefully selected, screened for medical comorbidities, and are generally young (age 40 or less). In contrast, renal tumor patients are not screened, are older (mean age 61 years), and often have significant comorbidities that can affect kidney function, including metabolic syndrome, hypertension, obesity, vascular disease, and diabetes, alone or in combination. As patients age, particularly beyond the age of 60, nephrons atrophy and GFRs progressively decreases.

A recent clinical and pathologic study from the Harvard Medical School examined the non–tumor-bearing kidney of patients undergoing resection of RCTs and demonstrated a far greater degree of unsuspected underlying renal disease in kidney tumor patients than previously appreciated. The nonneoplastic renal tissue in 110 nephrectomy specimens, including 67 clear cell carcinomas of which 39 were less than 5 cm, were correlated to the patient’s clinical history. Only 10% of patients had completely normal adjacent renal tissue and 28% were found to have vascular sclerotic changes. In the remaining 62% of cases, evidence of significant intrinsic renal abnormalities, including diabetic nephropathy, glomerular hypertrophy, mesangial expansion, and diffuse glomerosclerosis, was noted. In this study, 91 patients (83%) underwent radical nephrectomy for the treatment of their tumors. This study indicates that the loss of functional nephrons during radical nephrectomy, coupled with pre-existing renal diseases, which may or may not be clinically apparent but is present at the pathologic level in the vast majority of patients, causes the worsening of overall renal function.

Chronic kidney disease is an independent risk factor for cardiovascular disease

CKD is increasingly viewed as a major public health problem in the United States. Currently it is estimated that there are 19 million adults in the United States in the early stages of CKD and that by the year 2030, 2 million will be in need of chronic dialysis or renal transplantation. CKD is defined as a GFR of less than 60 mL/min/1.73m ² . Traditional risk factors for CKD include age greater than 60, hypertension, diabetes, cardiovascular disease, and family history of renal disease. The prevalence and incidence of kidney failure requiring either dialysis or renal transplantation have increased from 1988 to 2004. Also, a significant trend has been a 10% increase in the prevalance of earlier stages of CKD, as indicated by decreased GFR, increased proteinuria, or both. These findings were determined by the National Health and Nutrition Examination Surveys, which compared 15,488 adults from 1988 to 1994 to 13,233 adults from 1999 to 2004. A higher rate of diabetes and hypertension during a later time frame in the United States is thought to be responsible for the increase in earlier stages of CKD.

Recommendations for assessing patients at increased risk for CKD include measurement of urine albumin and estimation of GFR using equations based on the level of serum creatinine. In 2003, the National Kidney Foundation; the American Heart Association; and the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classified CKD as an independent cardiovascular risk factor. Certain serum factors, including elevated inflammatory and prothrombotic factors (C-reactive protein, fibrinogen, IL-6, and IL-8) and decreased hemoglobin levels and lipoprotein A may mechanistically contribute to the elevated cardiovascular risk. Therefore, medical interventions designed to modify well-known traditional risk factors, such as systolic blood pressure greater than 140 mm Hg, diabetes, cigarette smoking, high-density lipoprotein less than 40, low-density lipoprotein more than 130, body mass index over 30, physical inactivity, and left ventricular hypertrophy, may be effective in reducing the cardiovascular mortality risk in CKD.

Two widely used formulas, the Modification in Diet and Renal Disease (MDRD) equation and the Cockcroft-Gault equation, are superior to serum creatinine alone in estimating the GFR. These formulas have been extensively evaluated in populations of patients, including blacks, whites, and Asians; people with and without diabetes or kidney disease; and transplant donors. Both equations are more accurate in evaluating kidney function in patients with CKD, as opposed to younger patients, those with type 1 diabetes without microalbuminuria, or healthy potential kidney donors.

An estimated GFR of less than 60 mL/min/1.73 m ² , stage 3 CKD, is associated with a graded increase in the risk of progression to end-stage kidney disease and premature death caused by cardiovascular disease. A clinician can quickly calculate the estimated GFR using a Web site that only requires patient age, sex, race, and serum creatinine ( http://www.nephron.com/MDRD_GFR.cgi ). In our practice, the routine use of the MDRD equation to estimate GFR has become an essential part of the initial evaluation of the renal tumor patient and is critical for surgical planning and counseling.

The adverse clinical impact of a decline in estimated GFR was reported by investigators at Kaiser Permanente in California who estimated the longitudinal GFR in 1,120,295 patients between 1996 and 2000 who had not undergone dialysis or kidney transplantation. The investigators examined the multivariable association between estimated GFR and the risks of death, cardiovascular events, and hospitalization. The median patient age was 52 years, 55% of the patients were women, and median follow-up was 2.84 years. The risk of death increased as the estimated GFR decreased below 60 mL/min/1.73 m ² with the adjusted hazard ratios of 1.2 (GFR 45–59 mL/min/1.73 m ² ), 1.8 (GFR 30–44 mL/min/1.73 m ² ), 3.2 (GFR 15–29 mL/min/1.73 m ² ), and 5.9 (GFR <15 mL/min/1.73 m ² ) respectively. The adjusted risk of hospitalization followed a similar pattern. The link between CKD and cardiovascular risk factors was also reported by Foley and colleagues, who analyzed data from 15,837 noninstitutionalized adults from 1988 to 1994 in the Third National Health and Nutrition Examination Survey. Data were gathered on nine cardiovascular risk factors (smoking, obesity, hypertension, high total cholesterol, C-reactive protein, glycosylated hemoglobin, homocysteine levels, low hemoglobin, high urinary albumin to creatinine ratio) and estimated GFR. Estimated GFR was greater than 60 mL/min/1.73 m ² in 93.3% of patients, between 30 and 59 mL/min/1.73 m ² (stage 3 CKD) in 6.2%, and less than 30 mL/min/1.73 m ² (stage 4 and 5 CKD) in 0.5%. As kidney function deteriorated, the percentage of subjects with two associated cardiovascular risk factors increased from 34.7% (stage 1 and 2 CKD), to 83.6% (for stage 3), to 100% for stage 4 and 5 subjects. Patients with CKD were far more likely to require medical interventions to treat cardiovascular disease than those with normal renal function. The low prevalence of patients with stage 4 or 5 CKD is attributable to their 5-year survival rates of only 30%.