Kidney Cancer
David M.J. Hoffman
Rekha A. Kumbla
Robert A. Figlin
I. RENAL CELL CARCINOMA (RCC)
Known as “the internist’s tumor” for its diverse clinical manifestations, advances in the understanding of the biology of renal carcinoma have led to a revolution in the medical management and a refinement of surgical approaches and other local modalities. With seven new therapeutic medications approved for the treatment of advanced disease since December 2005, novel agents targeting angiogenesis, intracellular signaling, and host immune activation have provided a model that may be applied across the spectrum of solid tumor malignancies.1,2
A. Histopathology
Clear cell carcinoma, an adenocarcinoma that arises from the proximal convoluted tubule, is the most common histologic subtype, representing 75% to 85% of primary renal neoplasms.3,4 Papillary carcinomas comprise 10% to 15% of renal malignancies. More likely to be multifocal, there are two primary subtypes: types I and II. Type I typically are lower grade, may be hereditary, and have a more indolent biology. Type II have a more aggressive behavior and a poorer prognosis.5 Chromophobe carcinomas are composed of sheets of darker cells lacking in lipid and glycogen. They have a more favorable prognosis. Oncocytomas are made of large well-differentiated cells with granular eosinophilic cytoplasm due to a rich population of mitochondria. They originate from intercalated cells of the collecting ducts. Multiple and bilateral oncocytomas are associated with tuberous sclerosis complex (TSC) and Birt-Hogg-Dube (BHD) syndrome. These tumors generally exhibit benign behavior. Collecting duct carcinomas are rare and tend to affect younger patients. They tend to have an aggressive behavior and frequently show sarcomatoid differentiation. Unclassified carcinomas are less than 5% of renal neoplasms and have an unfavorable prognosis when compared with clear cell carcinomas.6
B. Genetic alterations
Loss of 3p is commonly seen in sporadic clear cell carcinoma. Genes included in this region include Von Hippel-Lindau (VHL), BRCA1 Associated Protein-1 (Ubiquitin Carboxy-Terminal Hydrolase) (BAP1), and Polybromo 1 (PBRM1). Diseases associated with PBRM1 include clear cell renal cell carcinoma and renal cell carcinoma.
VHL gene (3p25-26) is altered in more than 90% of patients with clear cell carcinoma. Inactivation or deletion of VHL is associated
with increased production of vascular endothelial growth factor (VEGF), a key regulator of tumor angiogenesis.7,8
with increased production of vascular endothelial growth factor (VEGF), a key regulator of tumor angiogenesis.7,8
Hereditary RCCs and their genetic abnormalities are outlined in Table 13.1.
C. Epidemiology
In the United States in 2015, about 61,560 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,080 deaths. The incidence is rising, attributed in part to an increase in incidental diagnoses from the widespread use of advanced imaging studies.
This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.
TABLE 13.1 Hereditary Renal Cell Carcinoma Syndromes | ||||||||||||||||||||||||||||||||
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D. Risk factors
Tobacco smoking doubles the risk of developing kidney cancer, with a direct correlation to pack-years. Exposure to industrial toxins including cadmium, asbestos, and petroleum by-products, along with the use of certain analgesics (phenacetin and aspirin) confer an increased risk. Other factors implicated include hypertension, obesity, polycystic renal disease (hereditary and acquired), childhood exposure to cytotoxic chemotherapy, and chronic hepatitis C infection. Of interest, sickle cell trait (more so than hemoglobin SS disease) raises the risk of renal medullary carcinoma. Hereditary syndromes, including VHL and BHD, are associated with renal neoplasms.10
E. Clinical characteristics
Many renal cancers are asymptomatic and diagnosed incidentally.11 While the classic triad of hematuria, a palpable abdominal mass, and flank pain is seen in only 9% of patients at diagnosis, individually these are common presenting complaints.12 Also reported are weight loss and fever. Typically, signs and symptoms are frequently a reflection of a site of metastatic involvement. At diagnosis, 25% of patients are symptom-free. The diversity of initial signs of a renal neoplasm mirrors the complex heterogeneity of its biology.
Nearly one-third of patients present with metastatic disease, most frequently involving lungs, soft tissue, bone, and liver. Paraneoplastic syndromes include humoral hypercalcemia, erythrocytosis, hypertension, hyperglycemia, and hepatic dysfunction in the absence of liver metastases (Stauffer syndrome).13
F. Staging
1. TNM staging. Renal carcinoma is staged using the AJCC TNM system.14
2. Prognostic systems. University of California Los Angeles (UCLA) Integrated Staging System, first published in 2001, improves upon the AJCC staging system by taking into account a person’s performance status and the Fuhrman grade of the tumor (see Table 13.2). The Fuhrman nuclear grading system is best applied to clear cell carcinomas and takes into account nuclear size, shape, and prominence of nucleoli. This grading system plays a significant role in survival outcomes for renal cancers. Thus, these factors are combined to divide people into low-, intermediate-, and high-risk groups.14
Factors other than stage contribute to overall survival. Certain findings correlate with shorter survival times in patients with metastatic (stage IV) disease using the Memorial Sloan Kettering Cancer Center (MSKCC) criteria first published in 1999. Table 13.3 presents the risk stratification system for metastatic RCC per MSKCC.
High blood lactate dehydrogenase (LDH) level
High blood calcium level
Anemia (low red blood cell count)
Cancer spread to two or more distant sites
Less than a year from diagnosis to the need for systemic treatment (targeted therapy or chemotherapy)
Poor performance status (a measure of how well a person can do normal daily activities)
TABLE 13.2 UISS Staging for Patients With Localized Disease | ||||||||||||||||||||||||||||||
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TABLE 13.3 MSKCC Risk Stratification for Metastatic Disease | |||||||||||||||||||||
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People with none of the above factors are considered to have a good prognosis; one or two factors are considered intermediate prognosis, and three or more of these factors are considered to have a poor prognosis and may be more or less likely to benefit from certain treatments.
G. Treatment considerations
1. Localized disease
Laparoscopic- and robotic-assisted nephrectomy, associated with less pain and a faster recovery, has supplanted open radical nephrectomy as the optimal technical approach. When possible, nephron-sparing surgery is preferred.15 Risk of recurrence after nephrectomy is stratified per TNM staging, and there are multiple guidelines for surveillance including those from the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN). The recommendation is to
perform a computed tomography scan of the chest and abdomen more frequently in the intermediate- and high-risk groups.16
perform a computed tomography scan of the chest and abdomen more frequently in the intermediate- and high-risk groups.16
For elderly or frail patients, ablative therapy (cryoablation, radiofrequency, microwave) is a surgical alternative.17,18 Active surveillance appears to be a safe strategy for patients with small (<4 cm), incidentally discovered lesions, especially those with comorbidities or a limited life span.19
2. Metastatic disease
Cytoreductive nephrectomy offers a survival benefit for patients with favorable features who then go on to treatment with immunotherapy. Likewise, there is a clear role for surgical metastatectomy, either with oligometastatic disease at presentation or at relapse that may result in a durable remission.20,21
Radiation therapy, utilizing both conventional external-beam and stereotactic approaches, is reserved for the palliation of painful bone metastases, recurrence in the renal fossa, or involvement of the central nervous system (CNS).22
3. Systemic therapy
a. Immunotherapy
First approved by the FDA in 1992, high-dose interleukin-2 results in long-term remission in 10% to 20% of patients. A cytokine resulting in the expansion of cytotoxic T lymphocytes, IL-2 has no direct antitumor effect.23 Recently studied in the SELECT trial, 120 patients with clear cell RCC and history of nephrectomy with good performance status (ECOG 0 to 1 and good organ function—serum creatinine less than 1.5) were administered IL-2. The tumor specimens were separated into good and poor risk on the basis of histologic features. Both groups benefited from high-dose IL-2 with durable remissions and prolonged survival. The overall response rate was 25%, which was higher than historical overall response rates. It was noted that 11% of these patients were progression free at 3 years and median overall survival was around 42.8 months. There was no significant difference in response between good- and poor-risk groups. The trial proved to highlight the need for biomarkers with the use of IL-2 and introduced the possible use of programmed death ligand 1 (PDL1) as a predictor of response to immunotherapy.24
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