Ahmad Shabsigh, MD, FACS
BASICS
DESCRIPTION
• T3 renal cell carcinoma (RCC) extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.
– T3a tumor grossly extends into the renal vein or its segmental (muscle containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota fascia.
– T3b tumor grossly extends into the vena cava below the diaphragm.
– T3c tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.
• T4 RCC invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).
EPIDEMIOLOGY
Incidence
• 63,920 new cases in USA in 2014 (39,140 in men and 24,780 in women)
• 13,860 deaths in USA in 2014
• 20% of patients present with locally advanced or node-positive RCC
• RCC with IVC involvement is seen in 4–10% of patients
Prevalence
8.3–12 new cases per 100,000 per year
RISK FACTORS
• Cigarette smoking results in a 1.4–2.5 increased risk of RCC; risk increases with higher pack/yr consumption, may not be as much of a factor for women as men.
• Obesity: 40% of RCC may be attributed to overweight or obesity.
• A positive family history of RCC in a 1st- or 2nd-degree relative carries a relative risk of 2.9 of developing RCC.
• HTN has a 1.4–2-fold increase in risk of RCC.
• Low socioeconomic status, urban background, and parity have been associated with an increased risk of RCC.
Genetics
• Nonhereditary clear cell RCC is associated with deletion of chromosome 3p and/or mutations of the VHL gene.
• VHL manifests clear cell RCC due to alterations of the VHL gene on chromosome 3p25–26.
• Nonhereditary papillary RCC has been linked with changes in both chromosome 7 and 17.
• Hereditary papillary renal cell carcinoma (HPRCC) arises from mutation of the MET protooncogene on chromosome 7p34.
• Chromophobe RCC: Loss of chromosome 17.
• Birt–Hogg–Dubé syndrome develops from changes in the BHD1 gene on chromosome 17p11.2.
• FH (fumarate hydratase) mutations on chromosome 1q42 in hereditary leiomyomatosis: Predispose to papillary Type 2 RCC.
• Mutations in the TSC1/2 genes predispose to tuberous sclerosis.
PATHOPHYSIOLOGY
• 20% of cases will have frank invasion of the capsule or collecting system.
• 10% will demonstrate venous involvement with tumor thrombus.
• Adjacent organs are usually compressed by growing tumor, whereas direct invasion of liver, spleen, colon, pancreas, diaphragm, and duodenum are rare but associated with very poor prognosis.
ASSOCIATED CONDITIONS
• Acquired renal cystic disease in conjunction with ESRD has a 1–2% risk of developing RCC, an overall 5–20-fold increase in risk of RCC for ESRD patients
• VHL-related RCC:
– Retinal angioma
– Cerebellar and spinal hemangioblastoma
– Pancreatic cysts
– Neuroendocrine tumors
• Facial fibrofolliculomas in the malar region, lung cysts, and spontaneous pneumothoraces are associated with BHD-related RCC
• Familial leiomyomatosis and RCC:
– Type 2 papillary RCC
– Cutaneous leiomyomas
– Uterine leiomyomas
• Birt–Hogg–Dubé syndrome:
– Chromophobe RCC
– Oncocytoma
– Occasional clear cell RCC
– Cutaneous fibrofolliculomas
– Lung cysts
– Spontaneous pneumothorax
• Possibly an increased risk of RCC in individuals with TS
GENERAL PREVENTION
• Smoking cessation
• Physical activity
• Weight loss
• Questionable association with certain foods and alcohol consumption
DIAGNOSIS
HISTORY
• The classic triad of symptoms: Flank pain, palpable flank mass, and hematuria are rarely seen since the advent of CT scanning.
• Associated symptoms are due to local tumor growth, hemorrhage, paraneoplastic syndromes (hypercalcemia, hypertension, polycythemia, Stauffer’s syndrome), or metastatic disease and generally indicate advanced disease.
• Locally invasive RCC causes pain from invasion of posterior abdominal wall, nerve roots, or paraspinous muscles.
• History of pulmonary embolism should increase index of suspicion for venous thrombus in patient with kidney mass.
• Caput medusa
• Early satiety or emesis
• Varicocele, lower-extremity edema
• Lower-extremities edema
PHYSICAL EXAM
• Palpable abdominal mass
• Flank or abdominal tenderness
• Bilateral lower-extremity edema
• Isolated right-sided varicocele, or one that does not decompress
• Caput medusa (dilated abdominal veins)
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• LFTs, creatinine, electrolytes, CBC, and urine analysis are standard initial evaluation, serum calcium
• Elevated ESR is present in 55.6%
• Abnormal liver function tests (LFT’s) are found in 14.4%, which is called Stauffer syndrome if elevation is due to paraneoplastic syndrome and not due to liver metastases
– Stauffer syndrome:
Elevated alkaline phosphatase
Increased PTT
Low albumin, and sometimes elevated bilirubin or transaminases
• Elevated serum calcium is seen in up to 13% overall and in 4.9% as a result of paraneoplastic syndromes
• Polycythemia can be detected in 3.5%
• Elevated C-reactive protein
Imaging
• CT scan with IV contrast if renal function is acceptable.
• MRI is generally considered best for IVC tumor thrombus evaluation, although multiplanar CT with contrast is similar in accuracy.
• Transabdominal US with color Duplex imaging can be used but may not be as accurate in evaluation of the extent of thrombus (85% accuracy).
• Transesophageal echocardiography (TEE) can be helpful pre-op and intraoperatively (1).
• Venacavography is only for those who cannot have an MRI or have an indeterminate MRI.
• Nonfunction of affected kidney may indicate extensive venous thrombus formation.
• Chest CT: Evaluate for pulmonary metastasis.
• CT or MRI of the brain if symptomatic.
Diagnostic Procedures/Surgery
Biopsy or FNA has a role in differentiating RCC from a renal metastasis of another primary and from renal lymphoma; rarely used for routine diagnosis except in cases of percutaneous ablation
Pathologic Findings
• Tumors with histologic necrosis are almost twice as likely to have lymph node metastases as those without necrosis.
• All RCC are adenocarcinomas, arising from renal tubular epithelial cells.
• Clear cell RCC is 70–80%.
• Higher Fuhrman nuclear grading is linked to worse outcome and more aggressive disease.
• Papillary RCC makes up 10–15% and has 2 subtypes:
– Type 1 associated with HPRCC: Basophilic cells with low-grade nuclei
– Type 2 very aggressive and associated with HLRCC: Eosinophilic cells with high-grade nuclei
– Immunohistochemistry (IHC): Low molecular weight cytokeratins (LMWCKs), CK7 (type 1 > type 2), alpha-methylacyl-CoA racemase (AMACR) positive in over 75%
• Chromophobe RCC is 3–5% of solid renal masses and may be less aggressive.
• Collecting duct RCC is rare (<1%) but very lethal.
• Medullary carcinoma associated with sickle cell trait in young African Americans, is often advanced and metastatic at the time of diagnosis; death occurs within a few months of diagnosis.
• Sarcomatoid variants of all subtypes have been described and are 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)
• Leiomyoma
• Metanephric adenoma
• Metastasis from other primary tumor
• Oncocytoma
• Renal lymphoma
• Urothelial carcinoma
• Wilms tumor (nephroblastoma)
TREATMENT
GENERAL MEASURES
• Preoperative renal artery embolization may cause the tumor thrombus to regress and reduce the morbidity of surgery as a result.
• Avoid IVC filter placement.
MEDICATION
The role of neoadjuvant targeted therapies (eg, sunitinib, sorafenib, others) for downsizing the primary tumor and the IVC thrombus is controversial: 5–10% reduction in primary site.
SURGERY/OTHER PROCEDURES
• Radical nephrectomy is standard of care.
• Nephron-sparing surgery is possible in selected patients with locally advanced RCC, with equivalent oncologic efficacy to radical nephrectomy (2).
• 45–70% of T3b patients can be cured with aggressive surgery.
• No clear survival benefit of extended lymph node dissection, except in HLRCC patients (3).
• In patients with single lymph node metastasis or micrometastasis, a regional lymphadenectomy may be beneficial.
• Open or minimally invasive surgery is acceptable.
ADDITIONAL TREATMENT
Radiation Therapy
• Role is limited; no survival benefit to preoperative treatment
• May slow growth if residual tumor left after surgery; rarely used
• May palliate symptomatic local recurrences in nonsurgical candidates
Additional Therapies
Targeted agents to growth factors are being evaluated in both an adjuvant and neoadjuvant setting for patients at high risk for recurrence (4).
Complementary & Alternative Therapies
None proven
ONGOING CARE
PROGNOSIS
• T3a: 60–80% 5-yr survival
• T3b/c: 40–60% 5-yr survival
• T4: 0–20% 5-yr survival
• Ipsilateral adrenal involvement has 0–40% 5-yr survival
• Node-positive RCC has 0–20% 5-yr survival
• For T4 tumors, the median time to recurrence is only 9.5 mo
COMPLICATIONS
• Surgical complications are bleeding, infection, injury to surrounding organs (liver, spleen, bowel, pancreas). Urine leak in partial nephrectomy.
• Pulmonary embolism from tumor thrombus
• Advanced tumors can bleed spontaneously either locally causing flank pain or into the urine resulting in hematuria and/or clot-induced urinary obstruction.
• Venous congestion resulting in bilateral lower-extremity edema, varicoceles, or portal HTN from tumor thrombi into the renal, caval, or hepatic vasculature.
FOLLOW-UP
Patient Monitoring
• T3: Every 6 mo for 2 yr then annually for 5 yr: H+P, comprehensive metabolic panel, LDH. Chest and abdomen imaging at 2–6 mo then as indicated.
• T4: Every 3 mo history and physical exam, CXR, labs; every 6 mo abdominal CT for 3 yr
Patient Resources
• Kidney Cancer Association www.kidneycancer.org
• National Cancer Institute, Kidney Cancer www.cancer.gov/cancertopics/types/kidney
REFERENCES
1. Glazer AA, Novick AC. Preoperative transesophageal echocardiography for assessment of resonance imaging. Urology. 1997;49:32–34.
2. Margulis V, Tamboli P, Jacobsohn KM, et al. Oncological efficacy and safety of nephron-sparing surgery for selected patients with locally advanced renal cell carcinoma. BJU Int. 2007;100(6):1235–1239.
3. Blute ML, Leibovich BC, Cheville JC, et al. A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol. 2004;172:465–469.
4. Cost NG, Delacroix SE Jr, Sleeper JP, et al. The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus. Eur Urol. 2011;59:912–918.
ADDITIONAL READING
• Hass NB, Uzzo RG. Targeted therapies for kidney cancer in urologic practice. Urol Oncol. 2007;25(5):420–432.
• Thillai K, Allan S, Powles T, et al. Neoadjuvant and adjuvant treatment of renal cell carcinoma. Expert Rev Anticancer Ther. 2012;12(6):765–776.
See Also (Topic, Algorithm, Media)
• Brit–Hogg–Dubé Syndrome
• Renal Cell Carcinoma, Localized (T1–T2)
• Renal Cell Carcinoma, Locally Advanced (T3–T4) Image 
• Renal Cell Carcinoma, General
• 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
• 198.89 Secondary malignant neoplasm of other specified sites
ICD10
• C64.1 Malignant neoplasm of right kidney, except renal pelvis
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
• C79.89 Secondary malignant neoplasm of other specified sites
CLINICAL/SURGICAL PEARLS
• Detailed evaluation of extent of the disease is critical.
• Consult vascular and/or cardiothoracic surgeon if needed.