Dr.Sunil Shroff
Prof. & HOD – Urology and Renal Transplantation
Sri Ramachandra Medical College & Research Institution, Chennai
www.srmcurology.com
Synonyms and Related Terms: Grawitz Tumor, Hypernephroma,
Nephrocarcinoma, RCC, Renal Adenocarcinoma, von Hippel-Lindau syndrome, VHL syndrome, VHL disease, hereditary papillary renal carcinoma, familial renal oncocytoma
ICD Codes - ICD-10 C64 , ICD-9 189.0
Synopsis of Renal Cell Carcinoma (RCC)
All tumours of the kidney diagnosed clinically should be regarded as malignant as benign disease is rare. Renal cell carcinomas originate from the cells of proximal tubules of the nephron.
Disease Prevalence – The incidence of renal cell carcinoma is on the increase. Rare in young, it usually affects adults between 50 and 70 years old. Male to female ratio is 2:1.
Key Risk factors - include – diet high in fat, being on long term dialysis, taking pain killers, exposure to cadmium or asbestos, suffering from inherited gene mutation - Von Hippel-Lindau syndrome or Tuberous sclerosis.
Pathology - Malignant cells contain glycogen – hence on staining appears clear under the microscope (called clear cell carcinoma). TCC in the renal pelvis due to transitional epithelium and constitute 4% of renal neoplasms.It may extend into renal vein and IVC or vena cava and blood-borne spread can result in 'cannon ball' pulmonary seconadries.
Symptoms and Signs - Usually asymptomatic till in advanced stage. Symptoms include – hematuria, loss of weight, fatigue, loss of appetite and sometimes lump or mass in the abdomen.
Staging – TNM and Robson staging is popular. Staging helps in deciding treatment and giving the prognosis of RCC. Stage I and II are early disease with better prognosis as the disease is confined to kidney or its surrounding tissues whereas in stage 3 and 4 the disease spreads beyond the fascia of Gerota or into the renal vein or IVC.
Metastasis – Metastasis occurs through lymphatic channels into regional and mediastinal nodes or by hematogenous routes primarily to the lungs, bone, and brain.
Diagnosis – Ultrasound of abdomen can pick up an early asymptomatic RCC (incidentaloma) and almost 50% of early RCC are now picked up on routine ultrasound for some other reason. Neo-vascularisation of tumor tissue leads to its enhancement on injection of contrast. CT with and without contrast is very sensitive for diagnosis of the tumor and also helps in its staging. CT allows assessment of renal vein and spread into IVC .
Treatment Options - Radical Nephrectomy- The most common treatment for renal cell cancer. Renal vein ligated early to reduce tumor propagation and adjacent tissue - adrenal, perinephric fat removed with kidney.
RCC resistant to Radiation and chemotherapy agents. More recently Sinitinab given orally seems to give better results than interferon and interleukin treatment in metastatic tumors.
Prognosis - depends on pathological stage, tumor size, nuclear grade and histological type.
Introduction
Renal cell carcinoma on early detection has a high cure rate after a nephrectomy, however in our country most of the tumours present late and then the tumour cure rate is low as it is highly radio and chemo-resistant. The use of ultrasound has helped in the diagnosis of early RCC; the pickup rate of such incidentaloma is as high as 50% in some series. Some advanced cases may respond to immunotherapy. More recently there has been advent of targeted cancer therapies such as sunitinib that has vastly improved the outlook for treatment of RCC. Sunitinib has become the new standard of care in the first-line treatment of metastatic RCC and was approved by FDA in 2006.
Incidence and Global Burden
Renal cell Carcinoma (RCC) are mostly adenocarcinomas of the kidney and are responsible for over 100,000 deaths worldwide in year. In the USA ( from where stats are more accurate) there were 38,890 new cases of Renal Cell carcinoma (RCC) diagnosed and 12,840 people died from the cancer in 2006. Majority of cases that are diagnosed are in adults between 50 and 70 years old and it is rare in younger age groups(1).
RCC Third most common genitourinary cancer after prostate and bladder[2]
5-year survival has improved - 20.0% in 1974-1976; 63.9% in 1995
Types of Renal Tumors
| Oxygenated Free Radicals |
| RCC | 85% |
| Metastatic Tumors | 10% |
| TCC of Renal Pelvis | 3-4% |
| SCC | |
| Lymphomas | |
| 1. Conventional (clear cell) | 70 – 80 % |
| 2. Papillary | 10 – 15 % |
| 3. Chromophobic | 4 – 5 % |
| 4. Collecting duct | < 1 % |
| 5. Medullary cell | < 1 % |
Malignant Renal Tumors, Frequency and Oncogene
VHL Tumour Suppressor Gene – Gatekeeper Gene – Its mutation causes Clear Cell RCC
Clear cell variant of RCC arises from proximal tubule,
Chromophobic and Papillary type are derived from distal tubule.
Only accepted environmental risk is tobacco use
Familial renal cell carcinoma: Tumor suppressor genes and oncogenes have been characterized for development of sporadic and familial form of this malignancy. Knudson and Strong 1971 hypothesized the mutation or inactivation of tumor suppressor gene for tumorigenesis to occur.
Von Hippel – Lindau Disease (Familial RCC) - It is a rare autosomal dominant disorder with an incidence of 1 per 36,000 population. RCC develops in 50% of patients with VHL, often has early age onset, and is bilateral and multifocal. VHL tumor suppressor gene is located at chromosome 3p25-26. There is an increased incidence of pancreatic tumors with VHL.
SCREENING FOR RCC: TARGET POPULATION
- Patients with end stage renal failure – Screen patients with long life expectancy by periodic ultrasound or CT , starting from 3rd year of dialysis.
- Patients with known VHL Syndrome: Biannual CT or Ultrasound beginning at 15-20 yrs, periodic radiographic screening for non renal manifestations
- Relatives of patients with VHL: Obtain genetic analysis, if positive, follow screening for patients with VHL syndrome.
- Relatives of patients with other form of familial RCC: Periodic ultrasound and genetic analysis
- Patient with Tuberous sclerosis: Periodic screening with ultrasound or CT.
- Patients with autosomal polycystic kidney disease: Screening not justified
Tuberous sclerosis: An autosomal dominant disorder in which patients develop 1 .Adenoma sebaceum 2. Distinctive skin lesions 3. Epilepsy 4. Mental retardation
5. Renal cysts 6. Angiomyolipoma
Increased incidence of RCC in TS is debatable.
PATHOLOGY
RCC has no true histologic capsule but has a pseudo capsule of compressed parenchyma.
RCC are adenocarcinoma derived from renal tubular epithelial cells. They are not grossly infiltrative except sarcomatoid variant. On bivalving, the tumor consists of yellow, tan or brown tumor interspersed with fibrotic, necrotic or hemorrhagic areas. Calcification is seen in 10- 20% of RCC.
Fuhrman’s grading system is adopted to demonstrate prognostic significance.
Fuhrman system is based on nuclear size, shape and presence or absence of prominent nucleoli.
Spread of RCC precluded by Gerota’s fascia. Unique feature of RCC is its predilection of venous system involvement which is seen in 10% of cases. Sporadic RCC are unilateral and unifocal. 2-4% of sporadic forms are bilateral. Papillary subtype is seen in patients with end stage renal disease and acquired renal cystic disease. Papillary RCC is mostly hypo vascular. Sarcomatoid variants of almost all histologic subtypes are described; they have infiltrative growth pattern, aggressive behavior and a poor prognosis
Sarcomatoid differentiation is found in 1-5 % of RCC.
Characteristics for identification of the subtypes -
Clear Cell Type - Long microvilli, Glycogen, Lipid droplets
Oncocytoma - Pleomorphic mitochondria, Lamelliform (plate like) mitochondrial cristae, dense bodies in mitochondria
Chromophobe Type - Microvesicles, Hale’s colloidal iron positive
Papillary (chromophil) Type - Abundant mitochondria
Renal Cell Carcinoma – occupying the lower pole
CLINICAL FEATURES
50 % of RCC are now detected incidentally -‘Radiologist’s tumor’
Triad of presentation:
- Pain (40%),
- Hematuria (40%)
- And palpable mass (25%)
Stauffer’s syndrome: Non metastatic hepatic dysfunction reported in 3-20% of cases
Hepatic function normalizes in 60 to 70% of cases after nephrectomy.
Other signs and symptoms
- Weight loss (33%)
- Fever (20%)
- Hypertension (20%)
- Hypercalcemia (5%)
- Night sweats
- Malaise
- Varicocele usually left sided, due to obstruction of the testicular vein (2% of males)
Paraneoplastic syndromes are found in 20% of patients with RCC
- Elevated E.S.R.
- Hypertension
- Anemia
- Cachexia
- Pyrexia
- Abnormal liver function
- Hypercalcemia
- Polycythemia
- Neuromyopathy
Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass if bruit is present in abdomen.
Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.
Physical Examination
Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease and signs of metastasis in other organs.
Careers