Matthew A. Meissner, MD
Ganesh V. Raj, MD, PhD, FACS
BASICS
DESCRIPTION
• Renal cell carcinomas (RCC’s) are malignant tumors of the kidney arising from different parts of the nephron
• Majority of renal neoplasms are RCC (80%)
• RCC is typically resistant to conventional chemotherapy and radiation, making it primarily a surgical disease
EPIDEMIOLOGY
Incidence
• 65,150 estimated new cases of RCC in 2014 in USA (39,140 in men and 24,780 in women); 12 new cases per 100,000/yr (1)[B]
• Male > Female, 3:2
• Increase in incidence since the 1970s of 3–4%/yr due to increased use of abdominal CT
• Estimated 13,860 deaths will occur in 2014 from RCC in USA (1)[B]
• Primarily occurs in 6th–7th decade of life
• 2–3% are familial; majority are sporadic
Prevalence
• 3rd most common GU malignancy in men (prostate, bladder); most common urinary tract malignancy in women
• RCC represents 2.3–6.6% of all pediatric renal tumors
RISK FACTORS
• Tobacco exposure: 1.4–2.5 times increased risk, this increases with duration, decreases after cessation (2)[C]
• Obesity
• Hypertension (HTN) has a 1.4–2-fold increase of RCC
• Family history in a 1st- or 2nd-degree relative associated with a relative risk of 2.9 of developing RCC
• Other potential environmental factors include viruses, lead compounds, and aromatic hydrocarbons
Genetics
• Clear-cell RCC is associated with chromosomal 3p deletion and/or mutations of VHL gene
• Alterations of chromosome 3p25–26 lead to clear-cell RCC in VHL syndrome (3)[A]
• Nonhereditary papillary RCC is linked to changes in chromosomes 7 and 17
• Hereditary pRCC typically involves type 1 pRCC and is due to missense mutations of the c-met proto-oncogene
• Chromophobe RCC is a result of allelic loss of chromosome 17
• Birt–Hogg–Dubé syndrome (BHD) includes cutaneous manifestations, spontaneous pneumothoraces, and chromophobe RCC, renal oncocytomas, or hybrid tumors consisting of both due to mutations in BHD gene on chromosome 17
• Translocation Xp11.2 Translocation carcinoma; predominantly younger patients
PATHOPHYSIOLOGY
• Clear cell and papillary RCC develop from the proximal convoluted tubules.
• Chromophobe and collecting-duct RCC develop from the distal convoluted tubule and collecting duct, respectively.
• VEGF and TNF-α are growth factors altered in development and progression of RCC.
• Local invasion is common; 20% of cases have invasion of the capsule or collecting system, and 10% have a tumor thrombus.
• Bilateral tumors occur 2–4% of the time with sporadic RCC, either at diagnosis or metachronously.
ASSOCIATED CONDITIONS
• For ESRD patients there is a 5–20-fold increase in risk of developing RCC, most commonly papillary subtype.
• Acquired renal cystic disease in conjunction with ESRD has a 1–2% risk of developing RCC.
• VHL-related RCC is associated with retinal angioma, pancreatic cysts, cerebellar and spinal hemangioblastomas, and neuroendocrine tumors.
• BHD-related RCC is associated with facial fibrofolliculomas in addition to lung cysts and spontaneous pneumothoraces.
GENERAL PREVENTION
• Smoking cessation reduces the relative risk of developing RCC by 20–50%
• Weight reduction: It is estimated that 40% of the cases of RCC in USA may be linked to obesity
DIAGNOSIS
HISTORY
• Most cases of localized RCC are asymptomatic and >50% of cases are detected incidentally during abdominal imaging for other reasons.
• Classic Triad: Flank pain, palpable flank mass, and hematuria. This is rarely seen except in advanced disease.
• Paraneoplastic symptoms found in 20% of patients. These include hypercalcemia (due to paraneoplastic phenomena or osteolytic bone involvement), HTN, polycythemia.
• Constitutional symptoms such as fever, weight loss, and anemia are thought to be due to paraneoplastic syndromes.
PHYSICAL EXAM
• Physical exam findings are usually absent, except in cases of advanced disease.
• Deep palpation for upper quadrant masses and auscultation for a renal artery bruit should be included in the abdominal exam.
• Assess for a varicocele with a careful testicular exam as venous outflow obstruction can occur due to a renal vein tumor thrombus. An epididymal mass may be seen in VHL-related disease.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Initial evaluation includes CBC, electrolytes, creatinine, LFTs, and UA
• Elevated ESR is present in 56% of patients
• Stauffer syndrome found in 14.4% of patients
– Characterized by abnormal LFTs from a paraneoplastic syndrome and not from liver metastases
– Also find elevated alkaline phosphatase, PTT, low albumin, elevated bilirubin, or transaminases
• Hypercalcemia seen in 13% overall, and in 4.9% resulting from paraneoplastic syndromes
• Anemia may be due to blood loss
Imaging
• Thin-slice renal CT scan with and without IV contrast is the best test for diagnosing renal masses
• Any enhancing lesion on CT or MRI is RCC until proven otherwise
– Enhancement generally defined as ≥20 HU increase between contrast and noncontrast phases
• R.E.N.A.L. Nephrometry score may provide a standardized system for radiologic comparison of renal masses (See RENAL Nephrometry in Section II)
• Any renal mass with a negative CT attenuation (<−20 HU) consistent with fat density is an AML
• Metastatic evaluation may include CT or MRI of the abdomen, chest x-ray for pulmonary lesions, and a bone scan in patients with elevated alkaline phosphatase or bone pain
Diagnostic Procedures/Surgery
• Biopsy of a renal mass is typically not included in the workup due to high false-negative rate, risk of bleeding, and remote possibility of seeding the biopsy tract
– Difficult to distinguish between oncocytoma and RCC on biopsy
– 83–90% of solid renal masses thought to be RCC are confirmed on final pathology
– Sensitivity and specificity of FNA biopsy is 80% and 95%, which is no better than imaging alone
• Biopsy helps differentiate primary renal neoplasms from metastasis or renal lymphoma
• Biopsy is now considered more frequently in patients being considered candidates for observation vs. surgical extirpation
– Biopsy is being used for surveillance in small RCC with >90% accuracy with adequate specimens
Pathologic Findings
• RCCs are adenocarcinomas, arising from renal tubular epithelial cells
• Clear cell RCC (formerly known as “conventional RCC”) 70–80% of RCC
• Papillary RCC accounts for 10–15%
– Type 1: Associated with Hereditary papillary renal cell carcinoma (HPRCC)
– Type 2: Aggressive, associated with Hereditary leiomyomatosis and renal cell cancer (HLRCC)
• Chromophobe 3–5% of solid renal masses, associated with a good prognosis
• Collecting duct (Bellini) RCC is rare (<1%), but associated with a very poor prognosis. Occurs in younger patients (3rd–5th decades of life).
• Renal medullary RCC found in African Americans with sickle cell trait, and is often metastatic at the time of diagnosis
• Furhman nuclear grading: Graded 1–4 according to nuclear aberrations in RCC. Independent prognostic indicator with higher grades portending worse outcomes (4)[B]
• Sarcomatoid differentiation: Reported as presence and extent found in the primary histologic subtype; not a distinct category. Associated with a worse prognosis
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)
• Renal cell carcinoma
• Renal lymphoma
• Renal medullary carcinoma (sickle cell trait)
• Renal sarcomas
• Reninoma (JG apparatus tumors)
• Urothelial carcinoma
• Wilms tumor (nephroblastoma)
TREATMENT
GENERAL MEASURES
• Surgical extirpation (radical or partial nephrectomy) is the primary treatment for solid renal masses
• Radical nephrectomy: Removal of the entire kidney, perinephric fascia, lymph nodes, and ipsilateral adrenal gland in upper pole tumors
MEDICATION
First Line
Systemic immunotherapy and targeted molecular therapies have no role in clinically localized RCC
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Partial nephrectomy is now the standard of care for clinical T1 renal masses (≤7 cm) in patients with a normal contralateral kidney who are surgical candidates. Oncologic outcomes equal to radical nephrectomy in selected patients. Renal function is preserved.
• Radical nephrectomy is the standard of care for large tumors, and for patients with metastases undergoing cytoreductive nephrectomy.
• Radiofrequency ablation/cryoablation minimally invasive; considered in selected small masses.
ADDITIONAL TREATMENT
Radiation Therapy
Radiation is limited to palliation of systemic metastases; no role in the management of clinically localized RCC
Additional Therapies
• Resection of solitary metastatic lesions (ie, lung) may be useful in selected cases
• No role for adjuvant systemic therapy in localized RCC
Complementary & Alternative Therapies
Renal masses <2 cm can be observed in many patients including those who are poor surgical candidates (∼30% benign).
ONGOING CARE
PROGNOSIS
• The single most important prognostic factor for RCC is pathologic stage (5):
– pT1a: 90–100% 5-yr survival
– pT1b: 80–90% 5-yr survival
– pT2: 70–80% 5-yr survival
– pT3: 45–69% 5-yr survival in the absence of nodal or systemic metastases
– pT4: 0–20% 5-yr survival in the absence of nodal or systemic metastases
• Direct invasion ipsilateral adrenal: 0–30% 5-yr survival; node-positive RCC: 0–20% 5-yr survival; metastatic RCC: 0–10% 5-yr survival
• Paraneoplastic syndromes, poor performance status, weight loss >10% worse outcome
• Other important prognostic factors include Fuhrman nuclear grade, histologic subtype, sarcomatoid features. Nomograms exist to predict risk of recurrence based on the above features.
COMPLICATIONS
• Surgical complications include bleeding, infection, urine leak, damage to surrounding structures including bowel, liver, spleen
• Large or locally invasive tumors may compromise GI or pulmonary function
• Bone metastases may result in pain and pathologic fractures
• Paraneoplastic syndromes causing cachexia, bleeding, HTN
FOLLOW-UP
Patient Monitoring
• See follow-up recommendations in “Renal Cell Carcinoma, Localized (T1–T2)”
• Incidence of local recurrence and the development of systemic metastases are directly associated with tumor stage (6)[B]:
– T1: 0% local; 4% metastatic
– T2: 2% local; 5.3% metastatic
• Surveillance is tailored to tumor stage
Patient Resources
• Kidney Cancer Association www.kidneycancer.org
• National Cancer Institute, Kidney Cancer www.cancer.gov/cancertopics/types/kidney
REFERENCES
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.
2. Parker AS, Cerhan JR, Janney CA, et al. Smoking cessation and renal cell carcinoma. Ann Epidemiol. 2003;13:245–251.
3. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170:2163–2172.
4. Pantuck AJ, Zisman A, Belldegrun A. Biology of renal cell carcinoma: Changing concepts in classification and staging. Semin Urol Oncol. 2001;19:72–79.
5. Campbell SC, Lane BR. Malignant renal tumors. Chapter 49. In: Wein AJ, ed. Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Saunders/Elsevier; 2011:1413–1474.
6. Eggener S, Reiher FK, Campbell SC. Surveillance for renal cell carcinoma after surgical management. Am Urol. 2001;20:202–207.
ADDITIONAL READING
• Kattan MW, Reuter V, Motzer RJ, et al. A postoperative prognostic nomogram for renal cell carcinoma. J Urol. 2001;166:63–67.
• Kutikov A, Uzzo RG. The R.E.N.A.L. Nephrometry Score: A comprehensive standardized system for quantitating renal tumor size, location, and depth. J Urol. 2009;182:844–853.
See Also (Topic, Algorithm, Media)
• Birt–Hogg–Dubé Syndrome
• Renal Cell Carcinoma, General Image 
• Renal Cell Carcinoma, Localized (T1–T2)
• 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
• 599.70 Hematuria, unspecified
• 789.09 Abdominal pain, other specified site
ICD10
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
• R10.9 Unspecified abdominal pain
• R31.9 Hematuria, unspecified
CLINICAL/SURGICAL PEARLS
• Most common solid renal mass is clear cell RCC.
• Most renal masses are detected incidentally.
• VHL syndrome is associated with chromosome 3p deletion and RCC, as well as other tumors.
• Surgical removal is the mainstay of treatment for RCC.
• Partial nephrectomy is increasingly utilized for larger, clinically localized tumors.