Reza Mehrazin, MD
Robert G. Uzzo, MD
BASICS
DESCRIPTION
• Renal cell carcinoma (RCC) refers to an adenocarcinoma and is the most common type of renal neoplasm. Stage T1 and T2 differ by size and are localized to the parenchyma with no extension outside the capsule.
• Stage T1 is further classified as T1a (tumor <4 cm) or T1b tumor (4–7 cm). Stage T2 is confined to the kidney and further classified as T2a (tumor 7–10 cm) and T2b (>10 cm).
EPIDEMIOLOGY
Incidence
• 63,920 new cases; 13,570 deaths in USA in 2014
– Most lethal of all GU neoplasms (21% of those diagnosed will ultimately die of disease)
• Male > Female (∼1.7:1)
– 7th most frequent tumor in men (lifetime risk 1:61 in men and 1:103 in women)
• Peak incidence: 6th and 7th decades of life
• 10–20% higher incidence in African Americans
• 96% of cases are sporadic, whereas 4% are associated with familial syndromes
RISK FACTORS
• Only accepted environmental risk factor is tobacco exposure: Increases relative risk by 1.4–2.5. All forms of tobacco implicated; Risk increases with cumulative exposure
• Family history, obesity, hypertension, end stage renal disease (ESRD), autosomal dominant polycystic kideny disease (ADPCKD) and horseshoe kidney have all been implicated but not proven to be genetic or acquired risk factors
Genetics
• 3p25 (VHL gene) (tumor suppressor) implicated in >70% of all acquired (somatic mutations) cases of clear cell RCC. In cases of germ line Von Hippel-Lindau syndrome (VHL) mutation, additional manifestations include retinal angiomas, CNS hemangioblastomas, epididymal cystadenomas, endolymphatic sac tumors, pancreatic cysts, islet cell tumors, and pheochromocytomas.
• 7q31 (cMet gene) (oncogene) implicated in papillary type I RCC. With germ line mutations there are no known extrarenal manifestations.
• 17p11 (Birt–Hogg–Dubé/folliculin gene) (tumor suppressor) implicated in cases of chromophobe/oncocytoma. With germ line mutations can see: Cutaneous fibrofolliculomas, nevus, PTH adenomas, colonic polyps/tumors and pneumothorax.
• 1q42 (HLRCC gene) (Tumor suppressor) HLRCC syndrome (type II papillary RCC) manifestations include painful cutaneous leiomyomas, and uterine fibroids
PATHOPHYSIOLOGY
• RCC arises from the proximal convoluted tubule. Chromophobe, oncocytoma, and papillary tumors, believed to arise from the distal tubule.
• Tumors may grow locally and/or systemically concurrently. Local symptoms occur late and renal insufficiency is rare even with large tumors.
• Histology, grade, and stage are independent factors that correlate with survival
– Lower risk: Low-grade (type I) papillary, chromophobe, and oncocytic carcinomas
– Intermediate risk: Clear cell tumors
– High risk: Collecting duct carcinomas, sarcomatoid clear cell carcinomas, renal medullary carcinomas associated with sickle cell
• Lesions <4 cm: Up to 20–30% can be benign. Progression to metastasis appears to be a late event although up to 3–5% of small renal masses can present with synchronous metastases.
• In highly selected series, median radiographic growth rate during a period of active surveillance for a small renal mass is 0.08–0.58 cm/yr with mean growth rate of ∼0.28 cm/yr (1)
ASSOCIATED CONDITIONS
• Extrarenal manifestations associated with RCC typically part of hereditary syndromes (such as Von Hippel-Lindau syndrome [VHL], Hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt–Hogg–Dubé [BHD])
• Renal medullary carcinomas associated with sickle cell trait are highly aggressive (mean survival: 12–15 mo) and present during 3rd decade of life
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Most stage T1/T2 lesions are asymptomatic, incidentally discovered on cross-sectional imaging for unrelated reasons
• Symptoms of more advanced disease include hematuria, flank pain, fever, weight loss (>10% of total body weight), bone pain
PHYSICAL EXAM
• In stage T1/T2 disease, typically few physical findings. Larger tumors may be palpable or symptomatically compressing on adjacent organs.
• Palpable abdominal mass, lymphadenopathy, nonreducing or rapid onset of varicocele may suggest advanced disease (renal vein or IVC involvement)
• Absence of symptoms or findings on physical exam does not rule out advanced disease
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• CBC: Anemia may suggest worse prognosis, polycythemia may suggest paraneoplastic state
• Serum creatinine: eGFR clearance better estimate of renal function. Calculate CKD stage.
• Liver function tests: If abnormal consider Stauffer syndrome (reversible hepatitis), metastasis, or biliary duct obstruction
• Calcium: Elevated in paraneoplastic syndromes due to PTH-like substances
• Alkaline phosphatase: Elevation suggests bone or liver involvement
Imaging
• Pre- and postcontrast-based CT or MRI is essential (>20 Hounsfield units enhancement on CT of >20% increase in postcontrast region of interest (ROI) on MR)
• US can usually distinguish cystic from solid masses. Hyperdense cyst which may look solid and exhibit pseudoenhancement. CT or MRI (not US) is used to assign Bosniak grade.
• Extent of disease evaluation includes CXR or CT chest. Bone scan and CNS imaging performed if symptoms/signs mandate.
• FDG-PET not useful in evaluation of T1/T2 RCC due to low sensitivity and specificity
Pathologic Findings
• Staging (see “TNM Staging” section)
• Needle biopsy:
– Appropriate if wide range of options are under consideration (focal therapy vs. observation)
– Needle-tract seeding very uncommon
– Good at distinguishing cancer and histologic type. Unreliable for tumor grade.
DIFFERENTIAL DIAGNOSIS
• Adrenal mass
• Angiomyolipoma (fat poor)
• Collecting duct tumor (Bellini)
• Cystic nephromas (multilocular cystic nephroma)
• Cysts (hemorrhagic, infected)
• Focal pyelonephritis
• Hemangioma
• Inflammatory masses (xanthogranulomatous pyelonephritis, abscess, infected calyceal diverticulum)
• Leiomyoma
• Metanephric adenoma
• Metastasis from other primary tumor
• Oncocytoma
• Pseudotumors (hypertrophied column of Bertin, or fet al lobulations: Can mimic a central tumor, particularly in congenitally solitary kidneys)
• RCC
• Renal lymphoma
• Renal medullary carcinoma (sickle cell trait)
• Renal sarcomas
• Reninoma (JG apparatus tumors)
• Urothelial carcinoma
• Wilms tumor (nephroblastoma)
TREATMENT
GENERAL MEASURES
• To avoid future renal insufficiency and metabolic disturbances, assess global renal function (eGFR) and consider nephron-sparing approaches, especially in those patients with low-to-intermediate complex renal masses and reasonable life expectancy
• For T1/T2 lesions, depending on pathology, surgery by radical or partial nephrectomy is highly likely to result in a long-term cure
• For T1 tumors radical and partial nephrectomy appear cancer equivalent. For T2 tumors partial is emerging as oncologically equivalent option (2).
MEDICATION
First Line
• Localized RCC is a surgical disease. Limited role for tyrosine kinase inhibitors and antiangiogenic therapy in localized RCC.
• Control of blood pressure, diabetes, lipids and minimization of atherosclerotic risk factors (smoking) are all important to subsequent renal function mandating physician involvement and patient counseling
• Use of ACE inhibitors or angiotensin receptor blockers may slow hyperfiltration injury
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Approach is dictated by many factors (3) including patient risks (comorbidities, underlying renal function, prior surgeries, trade-offs), tumor risk (size/location of the tumor, complexity of the mass [ie, nephrometry score—www.nephrometry.com], number of lesions), hospital and physician factors
• Excision: Partial or radical nephrectomy via open, laparoscopic, or robotic techniques
• Nephron-sparing surgery:
– Partial nephrectomy is the standard of care for masses T1 in young otherwise healthy individuals for absolute, relative, and elective indications. Removal of mass with a small rim of normal parenchyma.
– Other indications for partial nephrectomy: Absolute indications (patients with bilateral renal masses, a tumor in a solitary kidney) and relative indications (existing or comorbidities with potential for future renal insufficiency)
– Enucleation (removal of mass by dissection between normal parenchyma and pseudocapsule of the tumor) is acceptable for small and/or multiple renal masses as long as negative margins are achieved
• Bilateral (synchronous) RCC: ∼1–6%. Stage surgeries (Nephron sparing surgery (NSS) on easier side 1st as it provides more options for the difficult side). Can alter if there is a large discrepancy between complexity, size, and risks of the two sides.
• Ablation: Cryoablation or radio frequency ablation (RFA) by minimally invasive surgery (MIS) or percutaneous (preferred) technique:
– Best with advanced age, significant comorbidities, and potentially amenable recurrence after prior NSS
– Best: <3.5 cm, peripheral, solid, exophytic, remote from vessels/collecting system
– Survival data are short term and there are no definitive data to date proving that ablation impacts tumor biologic potential
• Active surveillance: Elderly or with significant medical risks. Serial radiographic surveillance with assessment of the growth kinetics of the untreated mass and continued reassessment.
ADDITIONAL TREATMENT
Radiation Therapy
• No role in localized RCC outside of clinical trials of focal radiotherapy (CyberKnife) or HIFU
• Used for painful bony metastases and CNS metastasis in advanced RCC
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Related to stage, grade, histology. Nomograms available to calculate risk at www.cancernomograms.com.
• Local recurrence after resection is ∼2–3% after radical nephrectomy and 4–6% after partial depending on pathology
• 5-yr risks of recurrence for local or regional RCC fully excised are approximately:
– 5–9% low-risk disease
– 20–25% intermediate-risk disease
– 60–80% high-risk disease
• Prognosis for partial nephrectomy with a positive margin is less clear. Related to pathology and biology. Every attempt should be made intraoperatively to avoid a positive surgical margin; with focal positive margin, close observation is often indicated.
COMPLICATIONS
• Acute surgical/medical risks depend on treatments, techniques, comorbidities, and complexity of the mass. Overall perioperative death rate <0.5%. Risk of major Clavien grade 3–5 complications: 6.4%, 11.1%, 21.9% for low-, intermediate-, and high-complexity lesions (4).
• Risks after partial nephrectomy: Urinary leak/fistulas, AVF, bleeding, transient or permanent decline in renal function (5)
• Increased risk of Nephrogenic systemic fibrosis (NSF), with gadolinium (eGFR <30 mL/min per 1.73 m2) and/or risk of contrast-induced nephropathy following use of iodinated contrast for radiographic surveillance
FOLLOW-UP
Patient Monitoring
• Periodic history, physical (including BP monitoring), and selected lab studies (calcium, hemoglobin, liver, renal profiles, urine analysis) at least yearly
• Radiographic stage/grade/histology-specific surveillance mandatory based on clinical stage and mode of treatment. Surveillance may be adjusted for other risk factors (grade/histology).
• Following ablation, initial radiographic follow-up requires lack of enhancement on pre-/postcontrast-based CT or MRI at 3–6 mo after procedure. Biopsy confirmation of successful ablation is recommended. Occasionally after cryotherapy, an area of rim enhancement can be seen that should resolve within 1st 3 mo.
• NCCN (National Comprehensive Cacner Network) guidelines (level of evidence 2B—lower level but consensus recommended)
– Every 6 mo for 2 yr, then annually for 5 yr: History, physical, metabolic panel
– At 2 yr (based on recurrence risk) chest and abdominal ± pelvic imaging then risk based
Patient Resources
• Kidney Cancer Association www.kidneycancer.org
• National Cancer Institute, Kidney Cancer www.cancer.gov/cancertopics/types/kidney
REFERENCES
1. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: A systematic review and pooled analysis. Cancer. 2012;118:997–1006.
2. Long CJ, Canter DJ, Kutikov A, et al. Partial nephrectomy for renal masses ≥7 cm: Technical, oncological and functional outcomes. BJU Int. 2012;109(10):1450–1456.
3. Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: Indications, techniques and outcomes. J Urol. 2001;166:6–18.
4. Simhan J, Smaldone MC, Tsai KJ, et al. Objective measures of renal mass anatomic complexity predict rates of major complications following partial nephrectomy. Eur Urol. 2011;60(4):724–730.
5. Mehrazin R, Palazzi KL, Kopp RP, et al. Impact of tumor morphology on renal functional decline after partial nephrectomy. BJU Int. 2013;111(8):E374–E382.
ADDITIONAL READING
• AUA Guideline for Management of the Clinical Stage 1 Renal Mass, 2009: http://www.auanet.org/content/media/renalmass09.pdf
• NCCN Guidelines: www.NCCN.org
See Also (Topic, Algorithm, Media)
• Birt–Hogg–Dubé Syndrome
• Renal Cell Carcinoma, General
• Renal Cell Carcinoma, Localized (T1–T2) Image 
• Renal Cell Carcinoma, Locally Advanced (T3–T4)
• Renal Cell Carcinoma, Metastatic (N+, M+)
• Renal Cell Carcinoma, Pediatric
• Renal Mass
• Reference Tables: TNM: Kidney Cancer
• Von Hippel–Lindau Disease/Syndrome
CODES
ICD9
189.0 Malignant neoplasm of kidney, except pelvis
ICD10
• C64.1 Malignant neoplasm of right kidney, except renal pelvis
• C64.2 Malignant neoplasm of left kidney, except renal pelvis
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
CLINICAL/SURGICAL PEARLS
• Always review the images and carefully assess the presence of the contralateral kidney and the adrenal glands.
• Do not overtreat or undertreat renal mass.