1. EPIDEMIOLOGY OF CANCER and GENERAL RISK FACTORS OF CANCER Hanggoro Tri Rinonce, MD, PhD Department of Anatomical Pathology Faculty of Medicine, Gadjah Mada University

2. INTRODUCTION Cancer epidemiology  knowledge about the origin of cancer. – Cigarette smoking  lung cancer – Dietary fat and fiber content  colon cancer Causes of cancer?  epidemiology studies – Environmental factor – Racial (hereditary) factor – Cultural factor Preneoplastic disorders  clues to the pathogenesis of cancer

3. CANCER INCIDENCE US, 2011 – ± 1.5 million new cancer cases – 569,000 people died of cancer Over several decades, the death rates for many forms of cancer have changed. – Men: Death rate for lung cancer    – Women: Overall death rate   death rates for cancers of the uterine cervix, stomach, and large bowel . Lung cancer   death rate from cervical cancer  use of cytologic smear Human papillomavirus (HPV) vaccine  eliminate cervical cancer?  death rates for stomach cencer   exposure to dietary carcinogens

4. Cancer incidence and mortality by site and sex (US, 2010)

5. Geographic and Environmental Variables Environmental factors are the predominant cause of the most common sporadic cancers. – Geographic differences in death rates from specific forms of cancer. Death rates from breast cancer are about four to five times higher in the United States and Europe than in Japan. Death rate for stomach carcinoma in men and women is about seven times higher in Japan than in the United States. Liver cell carcinoma is relatively infrequent in the United States but is the most lethal cancer among many African populations. Nearly all the evidence indicates that these geographic differences are environmental rather than genetic in origin. – Nisei (second-generation Japanese living in the United States) have mortality rates for certain forms of cancer that are intermediate between those in natives of Japan and in Americans who have lived in the United States for many generations.

6. Environmental carcinogens – Ambient environment – Workplace – Food – Personal practices  cigarette smoking and chronic alcohol consumption – Sunlight – In urban settings  asbestos – Limited to a certain occupation – Age at first intercourse and the number of sex partners

7. Occupational Cancers

8. AGE Cancer  increases with age. – Most cancer deaths: 55 and 75 The rising incidence with age ? – the accumulation of somatic mutations – the decline in immune competence that accompanies aging Cancer causes slightly more than 10% of all deaths among children younger than 15 years. The major lethal cancers in children – leukemias – tumors of the central nervous system – Lymphomas – soft tissue and bone sarcomas.

9. HEREDITY Many types of cancer  hereditary predispositions. Hereditary forms of cancer – Autosomal dominant cancer syndromes – Autosomal Recessive Syndromes of Defective DNA Repair – Familial cancers of uncertain inheritance

10. Inherited Predisposition to Cancer

11. Autosomal Dominant Cancer Syndromes Retinoblastoma – 40% are familial – Inherited disabling mutations in a tumor suppressor gene – Carriers of this gene have a 10,000-fold increased risk – Familial retinoblastoma Bilateral tumors Increased risk of developing a second cancer, particularly osteosarcoma. Often ssociated with a specific marker phenotype. May be multiple benign tumors in the affected tissue  familial polyposis of the colon and in multiple endocrine neoplasia. Abnormalities in tissue that are not the target of transformation  Lisch nodules and cafe-au-lait spots in neurofibromatosis type 1.

12. Autosomal Recessive Syndromes of Defective DNA Repair A group of rare autosomal recessive disorders is collectively characterized by chromosomal or DNA instability and high rates of certain cancers. Xeroderma pigmentosum  DNA repair is defective.

13. Familial Cancers of Uncertain Inheritance Virtually all the common types of cancers that occur sporadically have been reported to occur in familial forms where the pattern of inheritance is unclear  carcinomas of colon, breast, ovary, and brain. Features that characterize familial cancers – Early age at onset – Tumors arising in two or more close relatives of the index case – Multiple or bilateral tumors Familial cancers are not associated with specific marker phenotypes.

14. What can be said about the influence of heredity in the large preponderance of malignant tumors? There is emerging evidence that the influence of hereditary factors is subtle and sometimes indirect. The genotype may influence the likelihood of developing environmentally induced cancers. – Polymorphisms in drug-metabolizing enzymes confer genetic predisposition to lung cancer in people who smoke cigarettes. – Genomewide association studies (GWAS) in lung cancer, which sought to identify common genetic variants that increase risk for developing cancer, identified variants in a nicotinic acid receptor as being associated with development of lung cancer. – These variants were strongly associated with the number of cigarettes smoked, suggesting that they indirectly increase lung cancer risk by enhancing the addictiveness of cigarettes.

15. ACQUIRED PRENEOPLASTIC LESIONS In many instances, precursor lesions arise in the setting of chronic tissue injury or inflammation, which may increase the likelihood of malignancy by stimulating continuing regenerative proliferation or by exposing cells to byproducts of inflammation, both of which can lead to somatic mutations. Molecular analyses have shown that many precursor lesions possess some of the genetic lesions found in their associated cancers. Precursor lesions are important to recognize  their removal or reversal may prevent the development of a cancer.

16. Precursor lesions: – Squamous metaplasia and dysplasia of the bronchial mucosa, seen in habitual smokers  lung cancer – Endometrial hyperplasia and dysplasia (in women with unopposed estrogenic stimulation)  endometrial carcinoma – Leukoplakia of the oral cavity, vulva, or penis  squamous cell carcinoma – Villous adenomas of the colon  colorectal carcinoma

17. What is the risk of malignant change in a benign neoplasm? Are benign tumors precancerous? In general the answer is no, but inevitably there are exceptions, and perhaps it is better to say that each type of benign tumor is associated with a particular level of risk, ranging from high to virtually nonexistent. – Adenomas of the colon as they enlarge can undergo malignant transformation in 50% of cases – Malignant change is extremely rare in leiomyomas of the uterus.

18. SUMMARY The incidence of cancer varies with age, race, geographic factors, and genetic backgrounds. – Cancers are most common at the two extremes of age. – The geographic variation results mostly from different environmental exposures. Most cancers are sporadic, but some are familial. – Autosomal dominant  inheritance of a germ line mutation of cancer suppressor genes – Autosomal recessive  associated with inherited defects in DNA repair. Familial cancers – Bilateral – Arise earlier in life Some acquired diseases (preneoplastic disorders)  increased risk for development of cancer.

19. TOBACCO AS RISK FACTOR OF LUNG CARCINOMA

20. Annual incidence risks of lung cancer per 100,000 people in 2012 ( International Agency for Research on Cancer)

21. Estimated causes of lung cancer in Britain, 2014.

22. US National Cancer Institute, Surveillance, Epidemiology, and End Results Program Cancer Statistics Review 1975– 2011

23. Smoking-related carcinomas of the lung arise by a stepwise accumulation of a multitude of genetic abnormalities  transformation of benign progenitor cells in the lung into neoplastic cells. The sequence of molecular changes is not random but follows a predictable sequence that parallels the histologic progression toward cancer. – Inactivation of the putative tumor suppressor genes located on the short arm of chromosome 3 (3p) is a very early event, whereas TP53 mutations or activation of the KRAS oncogene occurs relatively late. It seems that certain genetic changes, such as loss of chromosomal material on 3p, can be found even in benign bronchial epithelium of persons with lung cancer, as well as in the respiratory epithelium of smokers without lung cancer, suggesting that large areas of the respiratory mucosa are mutagenized after exposure to carcinogens (“field effect”). On this fertile soil, those cells that accumulate additional mutations ultimately develop into cancer.

24. About 90% of lung cancers occur in active smokers or those who stopped recently. A nearly linear correlation has been recognized between the frequency of lung cancer and pack-years of cigarette smoking. – The increased risk becomes 60 times greater among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers. Since only 11% of heavy smokers develop lung cancer, however, other predisposing factors must be operative in the pathogenesis of this deadly disease. For reasons not entirely clear, women have a higher susceptibility to carcinogens in tobacco than men. Although cessation of smoking decreases the risk of developing lung cancer over time, it may never return to baseline levels. In fact, genetic changes that predate lung cancer can persist for many years in the bronchial epithelium of former smokers. Passive smoking (proximity to cigarette smokers) increases the risk of developing lung cancer to approximately twice that of nonsmokers. The smoking of pipes and cigars also increases the risk, but only modestly.

25. Precursor lesions of squamous cell carcinomas that may antedate the appearance of invasive tumor by years. A–C, Some of the earliest (and “mild”) changes in smoking-damaged respiratory epithelium include goblet cell hyperplasia (A), basal cell (or reserve cell) hyperplasia (B), and squamous metaplasia (C). D, More ominous changes include the appearance of squamous dysplasia, characterized by the presence of disordered squamous epithelium, with loss of nuclear polarity, nuclear hyperchromasia, pleomorphism, and mitotic figures. E and F, Squamous dysplasia may, in turn, progress through the stages of mild, moderate, and severe dysplasia. Carcinoma in situ (CIS) (E) is the stage that immediately precedes invasive squamous carcinoma (F). Apart from the lack of basement membrane disruption in CIS, the cytologic features of CIS are similar to those in frank carcinoma. Unless treated, CIS eventually progresses to invasive cancer.

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