RENAL CELL CARCINOMA
Renal cell carcinomas (RCC) account for a vast majority of primary malignant renal tumors. Approximately 55,000 new cases are diagnosed in the United States each year, and about one third of patients have meta- static disease. Other, less common malignant renal tumors include transitional cell carcinomas of the renal pelvis (see Plate 9-9) and primary renal sarcomas. The kidneys may also contain metastases from extrarenal solid and hematologic tumors.
EPIDEMIOLOGY AND RISK FACTORS
RCC was once more than twice as common among men than among women, although this gap currently appears to be shrinking. The peak incidence is in the sixth to seventh decades of life. Environmental risk factors include cigarette smoking and exposure to cadmium, asbestos, or petroleum byproducts. Data suggest that cigarette smoking and cadmium exposure each double the risk, and that smoking alone is responsible for one third of total cases. In addition, genetic abnormalities in critical tumor suppressor genes and oncogenes are known to play a key role. Such mutations can be sporadic or part of a hereditary condition, such as von Hippel-Lindau disease, hereditary papillary RCC, and Birt-Hogg-Dube syndrome. Hypertension and obesity also increase the risk for RCC, although the mechanisms are not known. Although many tumors occur in patients without known risk factors, it is likely that a signiﬁcant number of “sporadic” cases will eventually be found to have a genetic basis.
PRESENTATION, DIAGNOSIS, AND STAGING
In the past, an RCC was typically not detected until it became symptomatic, usually as the classic triad of gross hematuria, ﬂank pain, and a palpable mass. In contemporary practice, however, the classic triad is seen in fewer than 10% of patients. Instead, the majority of renal masses are now incidentally detected during abdominal imaging.
Nonetheless, an RCC may also cause a variety of nonspeciﬁc symptoms, including weight loss, fever, night sweats, and lymphadenopathy. Some patients may also have dyspnea, cough, and bone pain, which are suggestive of metastatic disease. Finally, RCC can also be associated with a wide variety of paraneoplastic phenomena, including erythrocytosis, anemia, hypercalcemia, hypertension, and nonmetastatic hepatic dysfunction (Stauffer syndrome). Patients with any combination of these symptoms or syndromes require immediate evaluation for possible RCC.
The evaluation of a known or suspected RCC begins with a thorough history and physical examination, with careful attention to the symptoms listed previously. On laboratory assessment, possible abnormalities include abnormal hematocrit, elevated erythrocyte sedimentation rate, elevated serum calcium concentration, and abnormal liver function tests. Finally, a careful evaluation of kidney function is important because it may have a signiﬁcant impact on the type of management if RCC is diagnosed. A normal serum creatinine concentration is an acceptable assessment of renal function in patients with no comorbidities and normal-appearing kidneys on standard axial imaging. In patients with medical conditions that predispose to renal disease, such as hyper-tension and diabetes mellitus, assessing the function of each kidney with a nuclear scan may be helpful for deciding between radical and nephron-sparing approaches.
Several imaging techniques may be used to evaluate a suspected RCC, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), renal angiography, and radionuclide imaging (renography).
CT scan is the most frequently employed modality because it has a high sensitivity for detecting renal masses and is the most accurate. Any renal mass that enhances with contrast is potentially malignant. CT also provides excellent visualization of the adjacent structures into which the primary tumor can extend or metastasize—such as the renal vein, regional lymph nodes, inferior vena cava, and suprarenal (adrenal) glands—which enables accurate staging.
Ultrasound can help identify the presence of a renal mass. Although ultrasound evaluation does not require ionizing radiation and is less expensive than CT, it is less sensitive and is highly dependent on operator skill. MRI is as sensitive as CT and is the study of choice for patients who cannot receive iodinated contrast.
The most common sites for metastasis of renal cell carcinoma include the local and thoracic lymph nodes, lungs, liver, bone, brain, ipsilateral suprarenal gland, and contralateral kidney. Thus metastatic evaluation should include a chest radiograph/CT scan and liver function tests. Bone scans may be indicated if the patient complains of musculoskeletal pain, or if the serum calcium or alkaline phosphatase concentrations are elevated.
Renal tumors are generally not biopsied because of concerns regarding complications, the false-negative result rates, and the fact that an overwhelming majority (90%) of renal masses greater than 4 cm in diameter are malignant. In contemporary practice, with more small renal tumors (4 cm) being identiﬁed, the role of renal biopsy is actively being reevaluated, and it is likely that in the future renal biopsy will become a more common practice. Potential complications include bleeding, infection, needle track seeding, and pneumothorax. In addition, false negatives for malignancy do occur.
The optimal treatment of RCC depends largely on the tumor stage, size, and location, as well as the patient’s overall clinical condition.
Localized disease can be surgically treated with radical resection (see Plate 10-19), nephron-sparing surgery (such as partial nephrectomy [see Plate 10-22] or ablation [see Plate 10-24]), or observation with an active surveillance protocol. In contrast, unresectable or metastatic RCC in patients with good functional status is commonly managed with initial cytoreductive surgery followed by systemic medications, such as interleukin 2 and tyrosine kinase inhibitors. In patients with poor functional status, medical therapy alone is used.
Localized Disease. Radical nephrectomy was previously the initial standard of care for the treatment of all localized RCCs. The operation involves complete removal of the kidney and suprarenal (adrenal) gland within the renal fascia, as well as removal of regional lymph nodes from the crus of the diaphragm to the aortic bifurcation. The surgery can be performed using either an open or laparoscopic approach and results in an extremely low local recurrence rate (2% to 3%). Laparoscopic radical nephrectomy, however, has become increasingly popular in recent years because of shorter recovery times and equivalent oncologic outcomes when compared with the open approach. Thus it is now considered the treatment of choice for patients with localized tumors less than 10 cm in diameter with no local invasion, renal vein involvement, or lymph node metastasis.
Partial nephrectomy is an alternative to radical resection that preserves renal function in the affected kidney. The procedure can be performed using either an open or laparoscopic approach. In recent years, partial nephrectomy has become the standard of care for patients with tumors that are fewer than 4 cm in diameter. This option can be especially important in patients with decreased renal function, a solitary kidney, or a chronic disease that may affect long-term renal function. Careful preoperative and intraoperative imaging is required to adequately identify the tumor’s borders and its relationship to major intrarenal vessels and the collecting system.
Ablative procedures, including cryosurgery and radiofrequency ablation, are newer nephron-sparing techniques that have been studied as alternatives to partial nephrectomy. These techniques can be per- formed from either a percutaneous or laparoscopic approach, and they are associated with shorter recovery times and decreased morbidity. Successful treatment requires adequate intraoperative imaging to ensure optimal placement of the ablation probes, as well as repetitive ablative cycles to ensure complete tumor destruction. Although these procedures are safe and well-tolerated, long-term oncologic data are still relatively limited. The preliminary data, however, demonstrate that recurrence rates may be slightly higher than those following traditional surgery. Nonetheless, ablative techniques are useful options for many patients, including those with contraindications to conventional surgery, those with multiple lesions (in whom partial nephrectomy would be difﬁcult), or those with recurrent disease that requires focal salvage therapy.
In patients who are elderly or are poor candidates for surgery for other reasons, observation is a reasonable alternative. It is generally reserved for patients with small (3 cm) renal lesions. There is no established standardized protocol for active surveillance; however, most clinicians perform serial imaging every 6 to 12 months to assess for disease progression.
|HISTOPATHOLOGIC FINDINGS IN RENAL CELL CARCINOMA|
Metastatic Disease. In the past, patients with advanced RCC were not viewed as candidates for surgical resection, given their poor prognosis. Recently, however, advancements in adjuvant therapies have changed the role of surgery in the management of metastatic disease. In patients with good performance status and limited metastatic disease, the goal of surgical resection is to completely remove all affected tissue, including nearby organs and/or abdominal wall muscles. In addition, careful removal of solitary metastases has been shown to improve 5-year survival rates in some patients. Such interventions are cytoreductive and have been shown to improve outcomes if performed before the initiation of adjuvant therapy.
Several biologic agents have been recently developed and studied as treatment for disseminated clear cell RCC. Tyrosine kinase inhibitors, such as sorafenib and sunitinib, have been found to inhibit tumor growth and angiogenesis by blocking the vascular endothelial growth factor receptor (VEGF-R). Meanwhile, bevacizumab is an monoclonal antibody that has also been shown to be effective, and which acts by directly binding circulating VEGF. Additional agents with proven efﬁcacy include mTOR (mammalian target of rapamycin) inhibitors, such as temsirolimus and everolimus. Finally, high-dose interleukin 2 (IL-2) can activate an immune response against the tumor, with modest response rates. The effect of these various agents on the growth and overall prognosis of non–clear cell tumors is unclear and remains under active investigation.
There are several variants of RCC, which are distinguished based on histomorphology. In addition, there are cytogenetic abnormalities that correlate with the histologic ﬁndings. Renal cell carcinoma variants include clear cell (75% to 85%, arising from the proximal tubule), papillary (15%, also arising from the proximal tubule, sometimes termed chromophil), chromophobe (5%, arising from intercalated cells of the cortical collecting duct), unclassiﬁed (5%), multilocular clear cell (rare), renal medullary (rare), Xp11 translocation (rare), mucinous tubular, spindle cell (rare), and collecting duct (rare). The histologic features of the most common tumor types are shown in Plate 9-5.
For clear cell carcinomas, the Fuhrman nuclear grading system has prognostic signiﬁcance and should always be used; it grades these tumors from 1 to 4 based on nucleus size, nucleus shape, and nucleolus appearance. The use of this grading system in non–clear cell carcinomas is less well established.
The prognosis of treated RCC depends on numerous variables, including tumor stage, histopathologic ﬁndings, presence or absence of symptoms, laboratory values, and the patient’s overall performance status. The tumor stage is the most signiﬁcant factor, since the 5-year survival of a TNM stage I tumor has been found to be approximately 95%, whereas that of a stage IV tumor is less than 25%. Several scoring systems have been devised to calculate the overall prognosis based on various factors.
Although there is no standard recommendation for follow-up of patients who have undergone surgical resection of localized RCC, the frequency and intensity of the protocol are generally dictated by the clinical tumor stage, histopathology, and treatment strategy. Patients are at greatest risk for recurrence in the ﬁrst 5 years.
Many centers determine their follow-up schedule based on tumor stage. Patients with localized tumors that are less than 7 cm in diameter (T1) are at lowest risk for recurrence. Such patients should undergo annual evaluation that consists of a physical examination, chest radiograph, and laboratory testing of liver and kidney function. Some experts recommend measurement of serum alkaline phosphatase concentrations to monitor for bone metastases; however, the sensitivity and speciﬁcity of this laboratory marker are poor.
Patients with masses that are larger than 7 cm or extend into adjacent structures (T2-4) are at higher risk for recurrence and, in addition to the above, should also undergo annual CT scan. Finally, all patients who have undergone a nephron-sparing procedure require an additional CT scan 3 months after the procedure to evaluate the tumor resection site for local disease recurrence.