Renal Cell Carcinoma: Etiology


Many different factors are involved in the development of Renal Cell Carcinoma. Some of these factors have been demonstrated in experimental models in vitro, but it is still not possible to fully accept all of them as etiologic factor.

For more information about the etiology and epidemiology of Renal Cell Carcinoma, you can read:
Epidemiology of Kidney Cancer


Smoking

It is known that the risk of Renal Cell Carcinoma increases by 2.3-fold in smokers. [1]

This risk increase is directly related to number of cigarettes and inversely proportional to the age of starting smoking.

According to some studies, it is stated that the former smokers will have the same risk of Renal Cell Carcinoma with the non-smokers, after 10 years after they quit smoking. [2]

Another study confirmed that tobacco use which is the most important etiologic factor in this malignancy, detected nearly in 20% of all Renal Cell Carcinoma cases. [3]

Chemical Carcinogens

According to the information in the literature, some chemical carcinogens have been reported in the etiology of renal cell carcinoma.

Although substances such as Cycasin which is a radiological contrast and Cadmium have been reported, there are 3 main substances known to be in the etiology of this malignancy today. [4]

a. Asbestos

Asbestos has been considered to significantly increase the mortality rate in kidney cancer, as a result of researches on insulation workers and asbestos production workers. Besides, some studies indicate the deposition of asbest fibers in the kidney. [5]

b. Organic solvents

When prolonged exposure is discussed, pesticides, copper sulphate, benzidine, benzene herbicides, and vinyl chloride are known as risk factors of renal cell carcinoma. Dose-dependent effect is seen only in organic solvents and copper sulphate. [6]

The risk of developing Renal Cell Carcinoma in people exposed to gasoline and gasoline products is considered to be minimal, although controversial. [7]

c. Polycyclic aromatic hydrocarbons

Coke and coal oven workers, tar and asphalt workers and firefighters, who are exposed to high doses of aromatic hydrocarbons are under higher risk rates of developing renal cell carcinoma.

Radiation

In particular, in patients with ankylosing spondylitis and cervical cancer, ionizing radiation slightly increases the risk of having Renal Cell Carcinoma.
Increased risk has also been reported in patients who received high doses of radium 224 for bone tuberculosis and ankylosing spondylitis. [8]

Viruses

The prevalence of Renal Cell Carcinoma development in an HIV-infected population is 8.5 – fold higher than in an uninfected population.

With the experimental studies, it is also claim that polyomavirus SV 40 and adenovirus 7 have an effect. [9]

In a recent study, although the proteins of the herpes virus have been found in the Renal Cell Carcinoma tumor, this is the information to be confronted with yet.

Drugs and Hormones

Some drugs and hormones also involved in the etiology of renal cell carcinoma.

a. Diuretics

Diuretics that inhibit water absorption from renal tubule cells increased the risk of formation of cancer in the etiology of Renal Cell Carcinoma.

However, it has been shown that the treatment of hypertension with diuretics has got ahead the risk of these drugs. Because hypertension is much more powerful etiologic factor than diuretics. [10]

b. Analgesics

Although some studies reported that there is an increased risk of renal cell carcinoma with the use of analgesics such as paracetamol, salicylates, or phenacetin, yet in some studies neither these drugs and nor their doses or time of consumptions are present in the etiology of this malignancy.

c. Oestrogens

Although oestrogen has been shown to induce Renal Cell Carcinoma in animal experiments, there is no scientific basis for this as a definite in humans. [11]

Inheritance

Most cases of the Renal Cell Carcinoma are sporadic; but still, some types of this malignancy also have a hereditary pattern.

a. Von Hippel-Lindau (VHL) disease

This syndrome caused by a germline mutation on chromosome 3p25-26, which named as VHL tumor suppressor gene. Normally VHL protein takes function in the cell cycle and angiogenesis, and regulates these processes. However, when there is mutation in VHL gene, patients have capillary hemangioblastomas especially in the retina and central nervous system. Also, these patients have clear cell carcinoma, pheochromocytoma, pancreatic and inner ear tumors

40% to 60% patients with the Von Hippel Lindau syndrome, present with the Renal Cell Carcinoma.  But these tumors are generally low-grade and their rate of metastasis is around 30%. If patient is carrier of VHL gene mutation, then typically multifocal and bilateral cysts or clear cell type of Renal Cell Carcinoma are seen.

b. Hereditary papillary renal carcinoma

This type of renal carcinoma is late onset and has autosomal dominant inheritance pattern. Hereditary papillary renal carcinoma is seen with type 1 bilateral papillary renal cell tumor in the kidney following mutations that activate MET oncogene.

c. Hereditary leiomyomatosis and renal cell carcinoma

This tumor seen after the autosomal dominant germline mutations in the chromosome lq42.3–q43 (FH gene). Actually, these patients typically have tendency to benign leiomyomas, but still type 2 Renal Cell Carcinoma can also be seen.

d. Birt-Hogg-Dube syndrome

Birt-Hogg-Dube syndrome occurs as a result of mutation in the gene encoded in chromosome 17p11.2 and characterized by benign skin tumors such as fibrofolliculomas, trichodiscomas, and acrochordons. Folliculin protein which involved in sporadic Renal Cell Carcinoma, is also encoded in the chromosome where the mutation takes place. Because of that multiple renal tumors also can be seen in this syndrome. [12]

e. Familial clear cell renal cell carcinoma

As a result of various translocations in Chromosom 8, 6, 2, 1, and 4, there are hereditary, bilateral and multiple clear cell type renal tumors in these families without any clinical evidence of von Hippel-Lindau syndrome. [13]

Acquired Cystic Disease and Chronic Dialysis

Approximately 35% to 47% of patients with chronic dialysis have acquired cystic kidney disease. In 5% to %9 of these patients, papillary hyperplasia may develop in the epithelium of the cysts, which may be the starting point of the Renal Cell Carcinoma. Therefore, in patients with a long history of chronic dialysis, the risk of Renal Cell Carcinoma is increased and because of that close follow-up is recommended. [14]

Lifestyle

Risk factors related to lifestyle are also defined in the etiology of Renal Cell Carcinoma. These are very important for the prevention of renal cell carcinoma because they are changeable.

a. Diet and Obesity

Studies have shown that the incidence of obesity in renal cancers is approximately 30%, so high-caloric diet is a very important risk factor.

In addition, the incidence of Renal Cell Carcinoma is 3.3 times higher in females and 2.3 in males with high body mass index

The mechanism underlying the increased risk of Renal Cell Carcinoma in high body mass index patients has not been fully elucidated. This mechanism is thought to depend in elevated levels of hormones such as endogenous estrogens, arterionephrosclerosis, elevated cortisol levels and low vitamin D levels. [15]

b. Coffee, alcohol and other beverages

Case-control studies have not established a clear relationship between coffee consumption and kidney cancer. According to one study in the literature, while the 2-fold risk increase in both genders was shown as a result of decafeinnated coffee consumption, in another study it is stated as this was only the case for females. None of the studies reported that the increase in risk was dose-dependent.

On the other hand, as a result of a study conducted in Norway, it is stated that the risk of Renal Cell Carcinoma in patients consuming 7 or more cups of coffee per day is relatively decreased. [16]

The relationship between alcohol and kidney cancer mortality is also controversial. Even in one of the case-control studies, it was shown that there is an inverse relationship between the risk of Renal Cell Carcinoma and alcohol consumption. [17]

c. Physical activity

Although the mechanism is not clear, it is thought to be related to the reduction of obesity incidence, a moderate physical activity is known to reduce the risk of kidney cancer.

Hypertension

Hypertension is a very strong factor in the etiology of kidney cancer. Because the incidence is reduced by the use of antihypertensive and diuretic drugs.
However, the relationship between these two components is not clearly understood.
It is not clear whether this decrease is due to the treatment of hypertension or with some effects of anti-hypertensive drugs. [18]

Alterations in Development of the Kidney

Abnormal development of the kidneys in the fetal life may act as a teratogenic factor.

The isthmus region of the horseshoe kidneys is sensitive to tumor development. This is thought to be due to the abnormal migration of cells into this region.

However, although the most common tumor is Renal Cell Carcinoma in horseshoe kidney malformation, the incidence is similar to the general population and there is also no difference in prognosis or evolution. [19]


References(Show/Hide)

1. Vogelzang NJ, Stadler WM. Kidney cancer. The Lancet. 1998;352(9141):1691–1696

2. Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. International Journal of Cancer. 2005;114(1):101–108.

3. McLaughlin JK, Lipworth L. Epidemiologic aspects of renal cell cancer. Seminars in Oncology. 2000;27(2):115–123.

4. Bannayan GA, Lamm DL. Renal cell tumors. Pathology Annual. 1980;15, part 2:271–308.

5. Selikoff IJ, Hammond EC, Seidman H. Mortality experience of insulation workers in the United States and Canada, 1943–1976. Annals of the New York Academy of Sciences. 1979;330:91–116.

6. Buzio L, Tondel M, De Palma G, et al. Occupational risk factors for renal cell cancer. An Italian case-control study. Medicina del Lavoro. 2002;93(4):303–309.

7. Redmond CK, Ciocco A, Lloyd JW, Rush HW. Long-term mortality study of steelworkers. VI. Mortality from malignant neoplasms among coke oven workers. Journal of Occupational Medicine. 1972;14(8):621–629

8. Boice JD, Jr., Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiation Research. 1988;116(1):3–55.

9. Murai M, Oya M. Renal cell carcinoma: etiology, incidence and epidemiology. Current Opinion in Urology. 2004;14(4):229–233.

10. Yuan J-M, Castelao JE, Gago-Domínguez M, Ross RK, Yu MC. Hypertension, obesity and their medications in relation to renal cell carcinoma. British Journal of Cancer. 1998;77(9):1508–1513.

11. McLaughlin JK, Schuman LM. Epidemiology of renal cell carcinoma. In: Lilienfeld AM, editor. Reviews in Cancer Epidemiology. Vol. 2. New York, NY, USA: Elsevier/North Holland; 1983. pp. 170–210.

12. Khoo SK, Kahnoski K, Sugimura J, et al. Inactivation of BHD in sporadic renal tumors. Cancer Research. 2003;63(15):4583–4587.

13. Cohen AJ, Li FP, Berg S, et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. The New England Journal of Medicine. 1979;301(11):592–595.

14. Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: implications for the urologist. British Journal of Urology. 1991;67(4):342–348.

15. Shapiro JA, Williams MA, Weiss NS. Body mass index and risk of renal cell carcinoma. Epidemiology. 1999;10(2):188–191.

16. Jacobsen BK, Bjelke E, Kvale G, Heuch I. Coffee drinking, mortality, and cancer incidence: results from a Norwegian prospective study. Journal of the National Cancer Institute. 1986;76(5):823–831.

17. Brownson RC. A case-control study of renal cell carcinoma in relation to occupation, smoking, and alcohol consumption. Archives of Environmental Health. 1988;43(3):238–241.

18. Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. American Journal of Epidemiology. 1999;149(6):521–530.

19. Rubio Briones J, Regalado R, Sánchez F. Incidencia de patología tumoral en los riñones en herradura. European Urology. 1999;6(4):306–310.

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