RENAL CELL CARCINOMA

WHAT IS RENAL CELL CARCINOMA?

Renal cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney.

Renal cell cancer (also called kidney cancer or renal adenocarcinoma) is a disease in which malignant (cancer) cells are found in the lining of tubules (very small tubes) in the kidney. There are 2 kidneys, one on each side of the backbone, above the waist. The tiny tubules in the kidneys filter and clean the blood, taking out waste products and making urine. The urine passes from each kidney into the bladder through a long tube called a ureter. The bladder stores the urine until it is passed from the body.

The incidence of renal cell carcinoma is 31,200 cases per year, representing 2–3% of new cancers. Men are affected approximately twice as often as are women, and the mean age at diagnosis is approximately 60 years. Some 4,500 patients died of renal cancer in 1998.



WHAT ARE ETIOLOGIC FACTORS OF RENAL CANCER?

Little is known about the causes of renal cancer. Risk factors that have been proved or implicated include:

Smoking, obesity, analgesic abuse, and occupational exposure to cadmium or aromatic hydrocarbons.
Approximately 1% of renal cancers cluster in families, most of whose members have abnormalities on the short arm of chromosome 3 and on the p53 gene on chromosome 17. Features suggestive of familial renal cell cancer include a history of two or more first-degree relatives with the same cancer, multicentric cancer, bilateral cancer, and early-onset cancer.
Patients with acquired renal cystic disease are nearly 100 times more likely to develop renal cell carcinoma than is the general population, and the risk is particularly high in men who have large kidneys and are receiving hemodialysis.
More than 80% of patients with von Hippel-Lindau (VHL) disease have an inactivated VHL gene (chromosome 3p25), and renal cancer is the most common cause of death.


HOW TO DETECT RENAL CANCER?

Early Detection

Screening may be useful in high-risk patients, such as those with VHL disease, dialysis-dependent acquired renal cystic disease, autosomal dominant polycystic kidney disease, tuberous sclerosis, familial renal cell cancer, and symptoms suggestive of cancer. Genetic counseling also is indicated for many of the individuals in these groups.

Possible signs of renal cell cancer include blood in the urine and a lump in the abdomen.

These and other symptoms may be caused by renal cell cancer or by other conditions. There may be no symptoms in the early stages. Symptoms may appear as the tumor grows. A doctor should be consulted if any of the following problems occur:

Blood in the urine.
A lump in the abdomen.
A pain in the side that doesn't go away.
Loss of appetite.
Weight loss for no known reason.
Anemia.
Tests that examine the abdomen and kidneys are used to detect (find) and diagnose renal cell cancer.

The following tests and procedures may be used:

Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.
Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, and bacteria.
Liver function test: A procedure in which a sample of blood is checked to measure the amounts of enzymes released into it by the liver. An abnormal amount of an enzyme can be a sign that cancer has spread to the liver. Certain conditions that are not cancer may also increase liver enzyme levels.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.

Case 1. Small left renal cell carcinoma is subtle on this intravenous urographic image Case 1. Small renal cell carcinoma. Tomogram

Case 1. Small renal cell carcinoma. Contrast-enhanced CT scan


Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.

Case 2. Large renal cell carcinoma. Delayed tomogram Case 2. Large renal cell carcinoma. Sonogram
Case 2. Large renal cell carcinoma. Contrast-enhanced CT scan

CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Renal cell carcinoma. Computed tomography demonstrates a large infiltrating mass in the right kidney, extending into the right renal vein



MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Case 3. Left renal cell carcinoma in patient who underwent prior right nephrectomy for renal cell carcinoma. T1-weighted axial MRI Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. T2-weighted axial MRI with renal vein invasion and extension of tumor into the inferior vena cava
Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. Tumor extends into the intrahepatic inferior vena cava


Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. A thin needle is inserted into the tumor and a sample of tissue is withdrawn. A pathologist then views the tissue under a microscope to check for cancer cells.
The histologic classification was based chiefly on light-microscopical tumor appearance but is consistent with the prevailing genetic understanding of tumors.

Conventional (clear-cell) renal carcinoma is the most common cancer of the renal cortex, accounting for approximately 70% of cases.
Papillary renal cell carcinoma accounts for approximately 15% of renal cell cancers.
Papillary renal cell carcinoma. The well-differentiated neoplastic cells cover delicate stalks of benign fibrovascular tissue

Chromophobe renal carcinoma accounts for 5% or so of cases of renal cell carcinoma.
Collecting-duct carcinoma is a rare renal cell carcinoma, representing fewer than 1% of cases.
Staging

The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney. Involvement of blood vessels may not be a poor prognostic sign if the tumor is otherwise confined to the substance of the kidney. Abnormal liver function test results may be due to a paraneoplastic syndrome that is reversible with tumor removal and do not necessarily represent metastatic disease. Except when computed tomography (CT) examination is equivocal or when iodinated contrast material is contraindicated, CT scanning is as good as or better than magnetic resonance imaging (MRI) for detecting renal masses.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.





HOW TO TREAT RENAL CELL CANCER?

TRADITIONAL TREATMENT
Surgery

Surgery is the preferred treatment for resectable renal cancer .Radical nephrectomy consists of removal of the kidney, perinephric fat, Gerota’s capsule, and lymph nodes and is useful for localized cancer and for palliation of intractable bleeding and pain. Most surgeons prefer an open approach to nephrectomy, but several investigators have advocated laparoscopic nephrectomy for cancers measuring less than 6 cm in diameter. Partial nephrectomy, also known as nephron-sparing surgery, is increasingly popular, owing to improved surgical methods and outcome. Partial nephrectomy is adequate treatment for small localized cancer and also offers some value for bilateral synchronous cancer, cancer in a functionally or anatomically solitary kidney, cancer in a patient with compromised renal function, and cancer in a patient with VHL disease. Bench surgery is a variation of partial nephrectomy and consists of removal of the kidney, resection of the tumor or tumors, and autotransplantation of the residual kidney.

Cancer-specific survival after nephrectomy varies by stage and grade. Five-year survival rates are 60–80%, 50–80%, 15–35%, and less than 15% for stages I, II, III, and IV, respectively. Solitary metastases also are cured occasionally by resection, especially in such soft tissues as the lung. Venous invasion can be treated successfully with surgery in some cases; five-year cancerspecific survival rates were 50–60% and 3–50% for renal vein and vena caval involvement, respectively.

Embolectomy may be useful for management of disease in some patients, despite massive pulmonary involvement.

Chemotherapy

Adjuvant chemotherapy or radiation have not been shown to prevent or decrease relapse rates. A review of 155 trials including 80 single agents showed a median response rate of only 4%.The overall response rates for vinblastine, and 5-FU or FUDR were 6% to 9%,and 5% to 8%,respectively. A trial combining gemcitabine with infusional 5-FU reported a 17% response rate.

Radiotherapy

The propensity for irradiation nephritis precludes routine use of radiotherapy for primary treatment of renal cancer. Sometimes, postoperative irradiation is used and may be useful for patients with residual local cancer, extension of cancer into perinephric fat, regional lymph node involvement, renal vein invasion, and cancer spillage or transection during surgery. It is used also after surgical excision of metastases. Palliative radiotherapy for metastatic renal cancer is particularly effective for bone pain, with a response rate of up to 86%

NOVAL THERAPIES

Immunotherapy

Biological therapy or immunotherapy that exploits the host immune system has generated considerable interest in recent years, owing to preliminary favorable results with cytokines for patients with metastatic renal cancer. The results with interferon-α now are considered generally modest, and this agent as monotherapy has little long-term efficacy for treatment of metastases. Interleukin-2 augments natural killer cell function, and monotherapy has resulted in complete or partial responses in up to 70% of patients; however, severe renal, cardiopulmonary, and other toxicities are limiting.

Combination therapy consisting of interleukin-2 and tumor-infiltrating lymphocytes or interferon-α has provided promising results, and trials continue to optimize this therapy. Autolymphocyte therapy, consisting of reinfusing autologous lymphocytes after activation in culture and irradiation to inactivate suppressor T lymphocytes, has shown definitive responses in previously refractory disease .

The future of immunotherapy rests on cancer vaccines, gene therapy, and adoptive immunotherapy. Approaches under investigation include combinations of cytokine therapy, use of new cytokines, combinations of cytokine modulation and autologous cancer vaccination, and use of genetically engineered cancer cells to augment endogenous immune system responses. Activation of cytotoxic T lymphocytes may be the common mechanism of action of many of these disparate treatments, including gene therapy. Adoptive immunotherapy that exploits dendritic cells as effectors is actively being investigated.

Interleukin-2(IL-2)therapy

High-dose regimen: High-dose IL-2 is only agent approved by FDA, U.S. for treatment of metastatic RCC. A group of patients treated with high-dose IL-2 showed durable response, being CR of 7%,PR of 8%,with a median response duration of 54 months for all responses. The schedule is
IL-2 600 000 to 720 000 U/kg i.v. infused over 15 minutes every 8 hours until toxicity or 14 doses for 5 days. Repeat the cycle once after a 7-to 10-day rest, with one or two additional courses repeated every 6 to 12 weeks if there is evidence of tumor stabilization or regression.

Low dose(i.v.) regimen:72 000 U/kg i.v. bolus every 8 hours to a maximum of 15 doses every 7 to 10 days for two cycles(one course),with an additional course if there is evidence of tumor stabilization or regression. One or two additional courses may be given if further regression is observed.
Low dose(SQ) regimen: First 5-day cycle:18 million U/day s.c., for 5 days(week 1).Subsequent 5-day cycles:9 million U/day s.c., for 2 days, and then 18 million U/day s.c.,3 days/week(weeks 2 through 6).
Interferon-atherapy

Interferon-a(IFN-a)can produce response rates of 12% to 15% for RCC patients; complete response (2% to 5%) are generally observed in patients with lung metastases .Usual regimen is 5 million to 10 million U/m2 s.c., three to five times per week, or daily.

Interleukin-2 (IL-2) plus Interferon-atherapy

Some trials reported response rates and overall survival of combination similar or superior to that of high dose IL-2 alone.

IL-2 20 million U/m2 s.c., days 3 to 5,weeks 1 and 4;5 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5,and 6.
IFN-a:6 million U/m2 s.c., day 1,weeks 1 and 4;6 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5 and 6.Repeat cycle every 8 weeks.
Hormonal Therapy

Progesterone has been used for treatment of metastatic cancer. However, its efficacy has not been proved.

Percutaneous mini-invasional ablation

Cryoablation and radiofrequency ablation may be used for unresectable cancer of kidneys and matastatic masses in other organs such as liver and lungs.