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INTRODUCTION
Renal cell carcinoma is a type of kidney cancer in which the cancerous cells are found in the lining of very small tubes (tubules) in the kidney. Renal cell carcinoma is the most common renal cancer.
Renal cell carcinoma (RCC), an adenocarcinoma, accounts for 90 to 95% of primary malignant renal tumors. Less common primary renal tumors include transitional cell carcinoma, Wilms' tumor (most often in children), and sarcoma.
In the US, about 51,000 cases of RCC and 8,000 deaths occur each year. RCC occurs slightly more often in men (male: female incidence is about 3:2). People affected are usually between 50 and 70 yr. Risk factors include the following:
· Smoking, which doubles the risk (in 20 to 30% of patients)
· Obesity
· Excess use of phenacetin
· Acquired cystic kidney disease in dialysis patients
· Exposure to certain radiopaque dyes, asbestos, cadmium, and leather tanning and petroleum products
· Some familial syndromes, particularly von Hippel-Lindau disease
RCC can trigger thrombus formation in the renal vein, which occasionally propagates into the vena cava. Tumor invasion of the vein wall is uncommon. RCC metastasizes most often to the lymph nodes, lungs, adrenal glands, liver, and bone.
SYMPTOMS AND SIGNS
Symptoms usually do not appear until late, when the tumor may already be large and metastatic. Gross or microscopic hematuria is the most common manifestation, followed by flank pain, FUO, and a palpable mass. Sometimes hypertension results from segmental ischemia or pedicle compression. Paraneoplastic syndromes occur in 20% of patients. Polycythemia can result from increased erythropoietin activity. However, anemia may also occur. Hypercalcemia is common and may require. Thrombocytosis, cachexia, or secondary amyloidosis may develop.
DIAGNOSIS
· CT with contrast or MRI
Most often, a renal mass is detected incidentally during abdominal imaging (eg, CT, ultrasonography) done for other reasons. Otherwise, diagnosis is suggested by clinical findings and confirmed by abdominal CT before and after injection of a radiocontrast agent or by MRI. A renal mass that is enhanced by radiocontrast strongly suggests RCC. CT and MRI also provide information about local extension and nodal and venous involvement. MRI provides further information about extension into the renal vein and vena cava and has replaced inferior vena cavography. Ultrasonography and IVU may show a mass but provide less information about the characteristics of the mass and extent of disease than do CT or MRI. Often, nonmalignant and malignant masses can be distinguished radiographically, but sometimes surgery is needed for confirmation. Needle biopsy does not have sufficient sensitivity when findings are equivocal; it is recommended only when there is an infiltrative pattern instead of a discrete mass, when the renal mass may be a metastasis from another known cancer, or sometimes to confirm a diagnosis before chemotherapy for metastases.
Three-dimensional CT, CT angiography, or magnetic resonance angiography is used before surgery, particularly before nephron-sparing surgery, to define the nature of RCC, to more accurately determine the number of renal arteries present, and to delineate the vascular pattern. These imaging techniques have replaced aortography and selective renal artery angiography.
A chest x-ray and liver function tests are essential. If chest x-ray is abnormal, chest CT is done. If alkaline phosphatase is elevated, bone scanning is needed. Serum electrolytes, BUN, creatinine, and Ca are measured. BUN and creatinine are unaffected unless both kidneys are diseased.
STAGING
Information from the evaluation makes preliminary staging possible. Robson's system is still used in the US, but the TNM system is more precise and has almost completely replaced it. At diagnosis, RCC is localized in 45%, locally invasive in about 33%, and spread to distant organs in 25%.
PROGNOSIS
Five-year survival rates range from 95% for the AJCC stage grouping I (T1 N0 M0) to 20% for stage grouping IV (T4 with any N or M; or N2 with any T or M; or M1). Prognosis is poor for patients with metastatic or recurrent RCC because treatments are usually ineffective for cure, although they may be useful for palliation.
TREATMENT
· Surgical treatment (for early RCC)
· Palliative therapies or experimental protocols (for advanced RCC)
Curative Treatments: Radical nephrectomy (removal of kidney, adrenal gland, perirenal fat, and Gerota's fascia) is standard treatment for localized RCC and provides a reasonable chance for cure. Results with open or laparoscopic procedures are comparable. Nephron-sparing surgery (partial nephrectomy) is possible and appropriate for many patients, even in patients with a normal contralateral kidney if the tumor is < 4 cm. Nonsurgical destruction of renal tumors via freezing (cryosurgery) or thermal energy (radiofrequency ablation) is being done in highly selected patients, but long-term data about efficacy and indications are not yet available.
For tumors involving the renal vein and vena cava, surgery may be curative if no nodal or distant metastases exist.
If both kidneys are affected, partial nephrectomy of one or both kidneys is usually preferable to bilateral radical nephrectomy if technically feasible.
Radiation therapy is no longer combined with nephrectomy.
Palliative Treatments: Palliation can include nephrectomy, tumor embolization, and possibly external beam radiation therapy. Resection of metastases offers palliation and, if limited in number, prolongs life in some patients, particularly those with a long interval between initial treatment (nephrectomy) and development of metastases. Although metastatic RCC is traditionally characterized as radioresistant, radiation therapy can be palliative when metastatic in bone.
For some patients, drug therapy reduces tumor size and prolongs life. About 10 to 20% of patients respond to interferon alfa-2b Some Trade Names ROFERONor IL-2, although the response is long-lasting in < 5%. Three new targeted therapies have shown efficacy for advanced tumors: sunitinib and sorafenib (tyrosine kinase inhibitors) and temsirolimus, which inhibits the mammalian target of rapamycin (mTOR). Other treatments are experimental. They include stem cell transplantation, other interleukins, antiangiogenesis therapy (eg, bevacizumab Some Trade Names AVASTIN, thalidomide Some Trade Names
THALOMID , and vaccine therapy. Traditional chemotherapeutic drugs, alone or combined, and progestins are ineffective. Cytoreductive nephrectomy before systemic therapy, or as a delayed surgical procedure to remove the primary tumor after response in the metastases, is commonly performed in patients healthy enough to undergo it.
GENES RELATED TO RCC
1. VHL tumour suppressor gene (TSG): The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. 43 genes were methylated in >20% of primary RCC (range 20–45%) and most of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected, suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFß or ERK/Akt signalling.
2. Secreted Frizzled-Related Protein 3: The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. Level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, sFRP3 may play an important role in metastatic renal cancer. Few genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells.sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells.
3. Secreted Frizzled-Related Protein 1: The secreted Frizzled-related protein 1 (SFRP1) is a Wingless-type (Wnt) antagonist that has been associated with various malignancies, including renal cell carcinomas (RCC). SFRP1 is up-regulated in metastatic RCC. SFRP1 overexpression in metastatic RCC was confirmed by immunostaining in renal tissues. The molecular mechanisms underlying SFRP1 up-regulation by analyzing DNA methylation and histone modification patterns on SFRP1 promoter showed that this gene is unmethylated/hypomethylated and enriched in activating histone modifications in metastatic RCC. The overexpression of Wnt antagonist may be related to invasiveness and metastatic behavior in RCC. The molecular basis of the role of SFRP1 in invasion and metastasis and found that matrix metalloproteinase MMP10 is regulated by SFRP1.
4. S100A4: Increased metastatic activity is associated with acquisition of a myofibroblast-like signature. Some of the constituents of the mesenchymal signature, including the expression of the well-characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell.
5. STAT3: Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes that mediate cell survival, proliferation, and angiogenesis and is aberrantly activated in various types of malignancies, including renal cell carcinoma (RCC).
6. Succinate dehydrogenase B gene: Genetic analysis revealed a 141 G>A (exon 2) Trp47X mutation within the succinate dehydrogenase B gene in an abdominal paraganglioma and subsequently metastatic papillary cell renal cancer. Treatment with the novel multi-targeted tyrosine kinase inhibitor sunitinib resulted in a sustained partial response and reduced the level of the angiogenic marker PIGF.
7. Variants in Blood Pressure Genes: The risk of RCC in relation to 142 single nucleotide polymorphisms (SNPs) in 8 genes having a role in blood pressure control. Of the 8 genes, AGT (angiotensinogen) was most strongly associated with RCC. The effects of the AGT SNPs were statistically significant in participants with hypertension or high BMI (=25 kg/m2), but not in subjects without hypertension and with a normal BMI (<25 kg/m2). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared to the common haplotype in patients with hypertension or high BMI. The common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.
8. FOXO1 and TCF7L2 in metastasis of clear cell renal cell carcinoma (CRCC): Hemizygous deletions at 10q and 13q were found only in cases of metastatic disease. Homozygous deletion of TCF7L2 at 10q25.2 in an aggressive case that had hemizygous deletions at 10q. TCF7L2 mRNA levels in tumor is significantly lower in patients with metastasis when compared with those without metastasis. FOXO1 was identified as a down-regulated gene in the minimal overlapping region of the 13q hemizygous deletion in CRCC. Decreased FOXO1 expression was significantly correlated with metastasis and poor survival outcome. Knockdown of FOXO1 inhibited apoptosis after doxorubicin treatment in CRCC cells and reduced the expression of downstream genes involved in cell proliferation (CDKN1B) and survival (BCL2L11). Lower levels of FOXO1 expression were associated with decreased expression of CDKN1B and BCL2L11 in CRCC specimens. FOXO1 and TCF7L2 are involved in metastasis and that molecules in these signaling pathways may be targets for diagnostic procedures and therapies for CRCC.
9. HOXA5 and MSH2: The hypermethylation of two genes in clear cell renal cell carcinoma.
10. Tumour suppressor genes (TSGs): Genes that are frequently methylated and silenced in RCC such as KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse. |
