Renal cell carcinoma

Renal cell carcinoma (RCC, also known as hypernephroma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases. It is also known to be the most lethal of all the genitourinary tumors. Initial treatment is most commonly a radical or partial nephrectomy and remains the mainstay of curative treatment. Where the tumour is confined to the renal parenchyma, the 5-year survival rate is 60-70%, but this is lowered considerably where metastases have spread. It is resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib, temsirolimus, bevacizumab, interferon-alpha, and possibly sorafenib have improved the outlook for RCC (progression-free survival), although they have not yet demonstrated improved survival.
Signs and symptoms
A wide range of symptoms can be present with renal carcinoma depending on which areas of the body have been affected. The classic triad is hematuria (blood in the urine), flank pain and an abdominal mass. This triad only occurs in 10-15% of cases, and is generally indicative of more advanced disease. Today, the majority of renal tumors are asymptomatic and are detected incidentally on imaging, usually for an unrelated cause.
Signs may include:
• Abnormal urine color (dark, rusty, or brown) due to blood in the urine (found in 60% of cases)
• Loin pain (found in 40% of cases)
• Abdominal mass (25% of cases)
• Malaise, weight loss or anorexia (30% of cases)
• Polycythemia (5% of cases)
• Anaemia resulting from depression of erythropoietin (30% of cases)[4] Also, there may be erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion.
• The presenting symptom may be due to metastatic disease, such as a pathologic fracture of the hip due to a metastasis to the bone
• Varicocele, the enlargement of one testicle, usually on the left (2% of cases). This is due to blockage of the left testicular vein by tumor invasion of the left renal vein; this typically does not occur on the right as the right gonadal vein drains directly into the inferior vena cava.
• Vision abnormalities
• Pallor or plethora
• Hirsutism - Excessive hair growth (females)
• Constipation
• Hypertension (high blood pressure) resulting from secretion of renin by the tumour (30% of cases)
• Elevated calcium levels (Hypercalcemia)
• Stauffer syndrome - paraneoplastic, non-metastatic liver disease
• Night Sweats
• Severe Weight Loss
Patients may also experience the following symptoms:
• Recurrent fevers  which occur in 9% of the patients
• Cold intolerance
• Back pain
• Chronic fatigue
• Leg and ankle swelling
• Loss of appetite
Classification
• Clear cell renal cell carcinoma (VHL and others on chromosome
• Papillary renal cell carcinoma (MET, PRCC)
• Chromophobe renal cell carcinoma
• Collecting duct carcinoma
Renal epithelial neoplasms have characteristic cytogenetic aberrations that can aid in classification.[13] Sealso Atlas of Genetics and Cytogenetics in Oncology and Haematology.
• Clear cell carcinoma: loss of 3p
• Papillary carcinoma: trisomy
• Chromophobe carcinoma: hypodiploid with loss of chromosomes
Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology.  Array-based karyotyping performs well on paraffin embedded tumors and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumors.
Other associated genes include TRC8, OGG1, HNF1A, HNF1B, TFE3, RCCP3, and RCC17.
Treatment
If it is only in the kidneys, which is about 40% of cases, it can be cured roughly 90% of the time with surgery. If it has spread outside of the kidneys, often into the lymph nodes or the main vein of the kidney, then it must be treated with adjunctive therapy, including cytoreductive surgery. RCC is resistant to chemotherapy and radiotherapy in most cases, but does respond well to immunotherapy with interleukin-2 or interferon-alpha, biologic, or targeted therapy. In early stage cases, cryotherapy and surgery are the preferred options..
Medications for advanced or metastatic cases
RCC "elicits an immune response, which occasionally results in dramatic spontaneous remissions." This has encouraged a strategy of using immunomodulating therapies, such as cancer vaccines and interleukin-2 (IL-2), to reproduce this response. IL-2 has produced "durable remissions" in a small number of patients, but with substantial toxicity. Another strategy is to restore the function of the VHL gene, which is to destroy proteins that promote inappropriate vascularization. Bevacizumab, an antibody to VEGF, has significantly prolonged time to progression, but As of 2008 phase 3 trials have not been published. Sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus, which are small-molecule inhibitors of proteins, have been approved by the U.S. F.D.A.
Treatment with tyrosine kinase inhibitors including Nexavar, pazopanib, and rapamycin have shown promise in improving the prognosis for advanced RCC since 2004.
Sorafenib (Nexavar), a protein kinase inhibitor, was FDA approved in December 2005 for treatment of advanced renal cell cancer.
A month later, Sunitinib (Sutent) was approved as well. Sunitinib (an oral, small-molecule, multi-targeted (RTK) inhibitor) and sorafenib both interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation. Sunitinib appears to offer greater potency against advanced RCC, perhaps because it inhibits more receptors than sorafenib.
Chemotherapy
Most of the currently available cytostatics are ineffective for the treatment of RCC. Their use can not be recommended for the treatment of patients with metastasized RCC,as response rates are very low,often just 5-15%,and most responses are short lived. The use of Tyrosine Kinase (TK) inhibitors, such as Sunitinib and Sorafenib, and Temsirolimus are described in a different section
Vaccine
Cancer vaccines, such as TroVax, have shown promising results in phase 2 trials for treatment of renal cell carcinoma. However, issues of tumor immunosuppression and lack of identified tumor-associated antigens must be addressed before vaccine therapy can be applied successfully in advanced renal cell cancer.
Metastatic renal cell carcinoma
The metastatic stage of the renal cell carcinoma occurs when the disease invades and spreads to other organs. It is most likely to spread to neighboring lymph nodes, the lungs, the liver, the bones, or the brain.  Metastatic renal cell carcinoma presents a special challenge to oncologists, as about 70% of patients with renal cell carcinoma develop metastases during the course of their disease, and 5 year survival for patients with metastatic renal cell carcinoma is between 5-15%,though it is much improved if metastatectomy and nephrectomy to remove all visible disease is performed. even if metastases are not removed,cytoreductive nephrectomy is sometimes used in the treatment of metastatic renal cell carcinoma,and at least 1 study has supported the use of cytoreductive nephrectomy in "some cases" of metastatic renal cell carcinoma,citing improved response rates to interleukin-2 immunotherapy and modestly prolonged survival.
Radiotherapy and chemotherapy have less of a role in therapy of renal cell carcinoma then in other malignancies; but they are still sometimes used in treatment of metastatic renal cell carcinoma. Radiotherapy is used in bone metastases from renal cell carcinoma to reduce pain and lower the risk of pathologic fracture, in patients with brain metastases, and to palliate symptoms of metastatic disease to the liver, adrenals, or lungs from renal cell carcinoma. Interleukin-2, has been the standard of care since the 1990s in metastatic renal cell carcinoma, as although response rates are low [7-16%], about half of patients that respond have long term disease free survival, and some of these patients may be cured of their disease. However,the side effects of interleukin-2 are very severe, including decreased neutrophil function, increased risk of dissemenated infection, including central venous catheter infections, septicaemia, and bacterial endocarditis, capillary leak syndrome, which can result in myocardial infarction, renal failure, angina, hypotension, reduced organ perfusion, altered mental status, pulmonary failure requiring intubation, cardiac arrhythmias, edema, and gastrointestinal bleeding. Proleukin also can result in lethargy and somnolence; if interleukin-2 therapy is not discontinued lethargy may progress to coma. Interleukin-2 can also worsen pre-existing autoimmune diseases.exacerbation of scleroderma, diabetes mellitus, thyroiditis, inflammatory bowel disease, myesthinisa gravis, nephritis, and other autoimmune diseases have been reported. Neurological side effects can also occur, and include ataxia, cortical blindness, hallucinations, psychosis, speech problems, and coma. Other side effects include abdominal pain, rigors, fever, malaise, asthenia, acidosis, tachycardia, vasodialation, diarrhea, vomiting, mouth sores, loss of appetite, dermatitis, dyspnea, thrombocytopenia, and anaemia. Also, patients must be in good health with normal cardiovascular, hepatic, pulmanary,and neurological function to be treated with interleukin-2.
Recently, targeted therapies including torisel, nexavar, sutent, and bevacizumab have been developed, and all are now approved for the treatment of metastatic renal cell carcinoma. Also, votrient [pazopanib] was approved for the treatment of metastatic renal cell carcinoma in October 2009. This is the sixth drug to be approved for metastatic renal cell carcinoma since 2005. The last 3–5 years have seen dramatic improvements in treatment for those with metastatic renal cell carcinoma, Richard Pazdur, MD, director of the office of oncology drugs at the U.S. Food and Drug Administration (FDA). However, despite these improvements in therapy, overall survival in metastatic renal cell carcinoma remains quite poor.
Currently, tumor vaccines and chemotheraputic, biologic, and immunologic agents are being researched in the treatment of metastatic renal cell carcinoma, and some appear promising. It is not known whether or not detecting metastatic renal cell carcinoma earliar improves survival or response to treatment. Symptoms of metastatic renal cell carcinoma are often mistaken for other, less severe illness,and include: for bone metastases, pain, stiffness, bruit, and pathologic fracture; for liver metastases, abdominal pain, jaundice, elevations in AST and ALT, and vomiting, for lung metastases, cough, dyspnea, and abnormal chest radiograph. Brain metastases produce diplopia, personality changes, headache, ataxia, vertigo, and seizures. Systemic symptoms occur in some people with metastatic renal cell carcinoma, and include anorexia, fatigue, fever of unknown origin, weight loss, and malaise. Given that many diseases can cause these symptoms, extensive testing is typically required to diagnose metastatic renal cell carcinoma. Differential diagnoses include leukaemia, arthritis, any other neoplastic disease, locomotor ataxia, Lyme disease [in the case of unexplained malaise, fatigue, and bone pain], and other chronic infections.