Pre-neoplastic Disorders Cancer Epidemiology Pre-neoplastic Disorders Carcinogenic Agents Neoplasia 7 Dr. Faten Ghazal Professor of Pathology

Intended Learning Outcomes (ILOs) By the end of this lecture YOU will be able to: Describe some geographic and environmental factors related to some types of cancer Identify some aspects of cancer incidence related to age & sex List some inherited cancer syndromes Relate some pre-neoplastic disorders to their specific type of cancer List important carcinogenic agents Define terms of initiation, promotion and progression

What is cancer epidemiology? What is its the importance? Distribution of cancer in population Its goal is to identify risk factors that may lead to early introduction of effective preventive measures.

The most common cancers in Developed Countries: Breast, Prostate, Lung, Colon/rectum Developing Countries: Lung, Stomach & Liver in men and Breast, Cervix & Lung in women About 1/3 of all cancers worldwide are attributed to the following modifiable life style factors: Tobacco use, low fiber diet, air pollutes, contaminated injections, alcohol consumption, physical inactivity, unprotected sex & indoor household smoke.

Cancer Incidence Men Women Children 1 Prostate Breast Leukemia 2 Lung Gliomas 3 Colorectal Bone Sarcoma 4 Urinary Bladder Endometrium Endocrine 5 Lymphoma Soft Tissue sarcoma ? ?

Cancer Incidence Why?? Death Rate in women as a result of Cervical Cancer has Death Rate in men as a result of Lung Cancer has The declining death rate from cervical cancer is directly related to (1) widespread use of cytological smear studies for early detection of the tumour and its precursor lesions and to (2) The development of human papilloma virus (HPV) vaccine may eliminate this cancer in the coming years. Due to screening tests of early cancer detection using cervical smear examination Extended Modular Program

Cancer Incidence Why?? Why?? Striking climb in rate of lung cancer in women Death Rate as a result of Cancer Stomach has The rise in cancer lung in women most probably due to increase smoking among women these days. While the decline in death rate for cancer stomach are obscure (?) however there have speculations about decreasing exposure to dietary carcinogens.

Epidemiologic Factors The role of some factors in the causation of cancer: well established still observational studies unknown. The pattern and incidence of cancer depends upon: Predisposing Epidemiologic Factors Pre-malignant (Chronic Non-neoplastic) Factors Role of Hormones in Cancer

Predisposing Epidemiologic Factors: Familial & Genetic Factors Racial & Geographic Factors Environmental & Cultural Factors Age Sex

A. Predisposing Factors Cancers with familial occurrence: colon, breast, ovary, brain and melanoma.

A. Predisposing Factors 1. Familial (Hereditary) & Genetic Factors: Hereditary forms of cancer are divided into 3 main categories based on their pattern of inheritance as: (a) autosomal dominant, (b) autosomal recessive & (c) uncertain pattern of inheritance

Autosomal Dominant Cancer Syndromes They include well defined cancers in which inheritance of a single mutant gene greatly increase the risk of developing a tumour. Retinoblastoma: 40% are familial & sporadic cases 60%. Inherited mutation in a tumour suppressor gene called retinoblastoma gene (RB gene).

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Retinoblastoma “Familial” Arising from: neuronal cell in the retina. Age: around 2 years. Type of mutation: loss of portion of chromosome 13 where retinoblastoma gene (tumour suppressor gene) is located. Inherited absence of a single copy of RB gene predisposes to retinoblastoma. The tumour develops when the other copy of the gene is also lost (one hit of mutation is needed) It can develop bilaterally and osteogenic sarcoma can also occur.

Inherited Predisposition to Cancer I. Inherited Autosomal Dominant Syndromes Retinoblastoma (40%): RB tumour suppressor gene Familial Adenomatous Polyposis/ Colonic Cancer: APC Breast & Ovarian Cancer: BRCA1 Breast Cancer: BRCA2 Neurofibromatosis type I & II: NF1 & NF2 Li Fraumeni syndrome (rhabdomyosarcoma, breast, leukemia & adrenal tumours) & various tumours: P53 II. Inherited Autosomal Recessive Syndrome Xeroderma Pigmentosum (damage by sunlight to DNA in epidermal cells resulting in multiple skin malignancies) (Children of the Night): Defective DNA Repair Gene III. Familial Cancer with still undetected defective inherited gene Breast (not linked to BRCA) Colon (not linked to APC) Ovary, brain, melanoma, & pancreatic tumours Defect in DNA Repair Gene

Predisposing Epidemiologic Factors: Familial & Genetic Factors Racial & Geographic Factors Environmental & Cultural Factors Age Sex

2. Racial & Geographic Factors Death rates from: Liver cancer is higher in African than American. Breast cancer is 4-5 times greater in United States than Japan Stomach cancer is about 7 times more in Japan than United States Cancer incidence in EGYPT (Aswan): Liver, Urinary Bladder & Lung (male) Breast, Liver & Brain (female) Back to Primary School

3. Environmental & Cultural Factors In your opinion which is more important environmental or hereditary factors? Environmental factors are more important (65%) than hereditary factors (35%). They are present in all the surroundings in: Personal practices: smoking even the passive one & alcohol Food: diet low in fiber & rich in fat Universe: sunlight Occupations exposed to: asbestos, arsenic, vinyl chloride & naphthalamine

Extended Modular Program Agent Cancer Site Use or Occurrence Arsenic Lung, skin, angiosarcoma Component of alloys, herbicides & fungicides Asbestos Lung, mesothelioma, colon Cables, roofing shipyard Benzene Leukemia Component of light oil Vinyl chloride Angiosarcoma in liver Adhesive for plastics Ethylene Oxide Ripening agent for fruits & nuts Nickel compounds Nose, lung Nickel plating Radon Lung From decay of minerals containing uranium Some Examples Extended Modular Program

4. Age Most cancers occur between 55- 75 years but the rate declines after 75 The frequency of cancer increases with age (why??): Accumulation of mutations. Decline in immune competence with aging. Cancer causes death in 10% in children ˂ 15yrs by leukemias, tumours of CNS (gliomas), bone sarcomas, soft tissue sarcomas & lymphomas

5. Sex Apart from the malignant tumours of organs specific to each sex, most tumours are generally more common in men than in women EXCEPT: cancer of breast, thyroid, gall bladder, & hypopharynx. Cancer breast is the commonest cancer in women throughout the whole world while cancer prostate is the commonest cancer occurring in men. Lung cancer is the second cancer common for both sexes.

Predisposing Epidemiologic Factors: Familial & Genetic Factors Racial & Geographic Factors Environmental & Cultural Factors Age Sex

Epidemiologic Factors The role of some factors in causation of cancer is established while that of other factors are still epidemiological and many others are still unknown. The pattern and incidence of cancer depends upon the following: Predisposing Epidemiologic Factors Pre-malignant (Chronic Non-neoplastic ) Factors Role of Hormones in Cancer

B. Chronic Non-neoplastic & Neoplastic (Premalignant) Conditions These are a group of conditions or lesions that can predispose to development of cancer. They arise as a result of: chronic tissue injury or inflammation It is important to recognize these lesions early: to prevent cancer development Why?

B. Chronic Non-neoplastic & Neoplastic (Premalignant) Conditions Barrette's esophagus (??) (columnar metaplasia) in gastro-esophageal reflux may lead to adenocarcinoma Chronic gastritis & helicobacter gastritis with (??) intestinal metaplasia can lead to carcinoma or lymphoma Adenoma of the colon is a risk of (??) colonic adenocarcinoma Ulcerative colitis (inflammatory bowel disease) can predispose to colonic adenocarcinoma Liver cirrhosis (??) predisposes to hepatocellular carcinoma

B. Chronic Non-neoplastic & Neoplastic (Premalignant) Conditions Squamous metaplasia, dysplasia & carcinoma in situ in bronchi of smokers is a risk of(??) Leukoplakia (white areas) (dysplasia) of the oral cavity is a risk for squamous cell carcinoma Chronic irritation from a ragged tooth leads to squamous dysplasia Old burn scar or chronic wound may lead to development of squamous cell carcinoma (Marjolin’s Ulcer) Neurofibromas (benign tumours) may lead to sarcoma Squamous cell carcinoma

Epidemiologic Factors The role of some factors in causation of cancer is established while that of other factors are still epidemiological and many others are still unknown. The pattern and incidence of cancer depends upon the following: Predisposing Epidemiologic Factors Chronic Non-neoplastic (Pre-malignant) Factors Role of Hormones in Cancer

C. Role of Hormones Unopposed estrogenic stimulation leads to: endometrial hyperplasia with atypia leads to increased risk of endometrial adenocarcinoma Contraceptive hormones maybe related to: breast cancer and benign liver cell adenoma Anabolic steroids used by athletes increase the risk of development of: benign & malignant liver tumours

To Summarize Epidemiologic Predisposing Factors Epidemiology Cancer Familial Cancers: autosomal dominant, autosomal recessive & unknown Racial or Geographic Factors: liver cancer, breast cancer, stomach cancer Environmental Factors: smoking, occupation related, universe & food Age: old (why?) Sex: male more than female To Summarize Epidemiology Cancer Premalignant Lesions: Squamous metaplasia Leukoplakia Barrette esophagus Chronic Gastritis Colonic adenoma Ulcerative colitis Liver cirrhosis NF Ragged tooth Marjolin Ulcer Role of Hormone: Unopposed Estrogen Contraceptive hormones Anabolic steroids

What are the carcinogenic agents you know? Chemical Carcinogens Physical Carcinogens Biological Carcinogens

Chemical Carcinogenesis It occurs after years, varies according to dose & mode of administration, individual susceptibility & predisposing factors. It occurs by induction of mutation in the proto-oncogenes & anti-oncogenes. The process involve 3 sequential (successive) stages: initiation, promotion & progression.

Radiation Carcinogenesis Mechanism of action of radiation: Chromosome breakage Translocations Point mutations (less frequent) Radiation is an established carcinogen (as UV rays, X-rays, nuclear fission, mines of radioactive substances): Skin cancers (melanoma, squamous cell and basal cell carcinomas) Papillary thyroid carcinoma (irradiation of the head and neck)  Lung cancers Leukemia

Biological Carcinogenesis Oncogenic Viruses: RNA Oncogenic Viruses (HTLV-1 & HCV): Human T cell Leukemia Virus type 1 (HTLV-1): Can induce T cell leukemia/lymphoma Hepatitis C Virus: can cause hepatocellular carcinoma

Biological Carcinogenesis Oncogenic Viruses: B. DNA Oncogenic Viruses (HPV, EBV, HHV-8 & HBV): Human Papilloma Virus (HPV) is associated with benign warts & cervical cancer Herpes Viruses (Epstein Barr Virus) (Burkitt Lymphoma & Hodgkin Lymphoma Human Herpes Virus 8: HHV-8 can cause Kaposi sarcoma (malignant neoplasm of blood vessels in AIDs infected persons) Hepatitis B Virus can cause hepatocellular carcinoma

Biological Carcinogenesis Oncogenic Bacteria: Helicobacter pylori bacilli: can produce Low grade malignant lymphoma & adenocarcinoma of the stomach Oncogenic Parasites: Schistosoma Hematobium can produce squamous cell carcinoma in urinary bladder on top of squamous metaplasia and transitional cell carcinoma Oncogenic Fungi: Asperigillus falvus liberates aflatoxin and is related to hepatocellular carcinoma

What is the importance of knowing the causative carcinogens? Diagnosis: by correlating the symptoms & signs with aetiologic factor (s) Treatment: Expect the type of cancer if the carcinogen is well known Preventive measures & follow up

Complete the following sentences: Quiz Complete the following sentences: The cervical cancer in women has declined due to ………………& …………………… Patients with familial retinoblastoma can develop …………… …………… and are at increased risk of developing …………………as a second cancer. Regarding the racial & geographic distribution, liver cancer is more prevalent in …………… population than…………. while breast cancer is present more in ………..and cancer stomach is more in……………………… In Xeroderma pigmentosum is an example of………… …………. inherited disease there is a defect in …………… gene

Complete the following sentences: Quiz Complete the following sentences: Contraceptive pills may predispose to ………………… Anabolic steroids may lead to ………… The most common cancers in men are ………….. & ………..while in women are …………….. & ………………. Benign tumours that may predispose to cancer are ………………….. & …………………………….. Some long standing inflammatory & hyperplastic conditions that may predispose to cancer include ………………… of colon, …………….in skin,……………..of liver, ………………..of stomach, ……………….of esophagus, ………………of oral mucosa