Dr. med. Dirk Manski



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Etiology of Renal Cell Carcinoma

Pathogenesis of Renal Cell Carcinoma

Origin:

Clear cell renal cell carcinoma originates from cells of the proximal tubule. Other histological types arise from more distal parts of the nephron.

Carcinogenic substances.

Risk factors for RCC are smoking (RR 1.4–2.3 dose-dependent), chewing tobacco, cadmium, lead, petrochemical substances, Thorotrast, tar and wood preservatives.

Epidemiological risk factors for renal cell carcinoma:

Terminal renal insufficiency (RR 3–6), obesity (RR 2.7), arterial hypertension, low social status, urban origin, smoking (RR 1.4–2.3), increased consumption of fats and proteins in the diet. Protective factors are alcohol consumption and sportive activity.

Molecular biology:

Mutations of the VHL gene are detectable in the majority of sporadic renal cell carcinomasa (see below).

Familial renal cell carcinoma

The risk of renal cell cancer for first-degree relatives of affected patients is approximately doubled, this suggests a hereditary component. Several genetic variations for an increased risk with low penetrance are known, e.g. variations of HIF 2 alpha (hypoxia-inducible factor). Over all, familial renal cell cancer is rare (2–3%). Below mentioned rare genetic syndromes usually follow an autosomal dominant inheritance (Verine et al, 2010).

Hippel-Lindau disease and renal cell carcinoma:

Hippel-Lindau disease shows an autosomal dominant inheritance with a high risk for clear cell renal cell carcinoma, for a detailed presentation [please see section "von Hippel-Lindau syndrome" for details]. The responsible VHL gene mutation is located on chromosome 3. Different types of mutations result in different manifestations of the disease with up to 100% penetrance. The VHL protein is a tumor suppressor protein. The tumors develops according to the Knudson theory of two hits: one diseased gene is inherited on one chromosome, the second hit (change of DNA) is caused by a spontaneous mutation on the second chromosome. Tumors arise only when both VHL genes on both chromosomes are mutated. The probability of an occurrence (penetrance) of renal cell carcinoma in von Hippel-Lindau disease is 25–70%. In comparison to sporadic renal cell cancer, the RCC in von Hippel-Lindau patients occur earlier, often with multifocal lesions and present with changes in other organs (CNS, retina, adrenal glands, cystic changes in the parenchymatous organs).

Hereditary papillary renal cell carcinoma (HPRCC):

Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant disease which leads to papillary renal cell carcinoma with basophilic papillary histology (type 1). Mutations in the MET protooncogene have been described on chromosome 7, MET encodes the hepatocyte growth factor receptor (HGFR). Patients with HPRCC do not haven an increased risk for other tumor entities. Genetic diagnosis is possible.

Tuberous sclerosis:

Patients with tuberous sclerosis harbour an increased risk for renal cell carcinoma [see section "Tuberous sclerosis"].

Birt-Hogg-Dubé Syndrome:

Birt-Hogg-Dubé Syndrome is a genetic disorder causing benign skin tumors (fibrofolliculomas), renal tumors (chromophobe renal cell carcinoma, oncocytoma or seldom clear cell renal cell carcinoma) and pulmonary cysts with the risk of spontaneous pneumothorax. The responsible gene (FLCN) encodes a protein (Folliculin) with tumor suppressor function. The genetic defect is inherited autosomal dominant, genetic diagnosis is possible (Menko et al 2009).

Hereditary leiomyomatosis and renal cell carcinoma syndrome:

Hereditary leiomyomatosis and renal cell carcinoma syndrome was described in 2001: syndrome with cutaneous leiomyomas, uterine leiomyomas (in women) and a predisposition to particularly aggressive renal cell carcinoma (histology either type 2 papillary renal cell carcinoma or collecting duct carcinoma). The HLRCC syndrome is caused by mutations in the fumarate hydratase gene (FH) and is inherited autosomal dominant (Badeloe et al, 2009). A genetic diagnosis is possible. The exact connection between the enzyme of the citric acid cycle and the renal cell carcinoma is still unclear. Unlike in above-mentioned familial syndromes, renal tumors should be treated immediately since they metastasize early in HLRCC syndrome.

Tumor Biology of Renal Cell Carcinoma

Immunobiology:

Renal cell carcinoma induces a prominent immunological response of the patient, which may induce spontaneous regression of renal cell carcinoma metastases after cytoreductive radical nephrectomy (in 1–7%). The spontaneous remission of RCC may last a long time.

Resistance to chemotherapy:

The expression of multi-drug resistance protein-1 (MDR-1) has been made responsible for the lack of sensitivity to chemotherapy. MDR-1 (P-glycoprotein) is a transmembrane protein, which pumps many foreign substances out of the cell.

Tumor vascularization:

Rich neovascularization of renal cell carcinoma is caused by the overexpression of VEGF.

Regulation of proliferation:

Increased expression of TGF-α, EGF receptors, up-regulation of the Ras-Raf-MAPK signal transduction, up-regulation of the mTOR signal transduction, and increased expression of MET protooncogene (for the hepatocyte growth factor receptor) causes proliferation of tumor cells and is target for new substances for the treatment of advanced renal cell carcinoma.







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