The Etiology and Incidence of Tumors

1. The Etiology and Incidence of Tumors Dr Eman MS Muhammad

2. Now medicine is moving from the field of treatment to that of prevention. • Cancer prophylaxis is now the aim of social and industrial medicine, by recognition of many exogenous agents. • Also precancerous lesions are being detected with great frequency and dealt with them early.

3. Theories of tumor origin • “Cell rest Cohnheium theory”: • It suggested that tumors arise from cell rests sequestered during embryonic life. • This theory may explain the development of the germ cell tumors and the embryonic tumors of infancy but not adult tumors.

4. “Single clone theory”: • It suggested that most tumors arise from a single clone of cells or only a few such clones that have undergone malignant transformation. • This evidence is derived from the following sources. In multiple myeloma there is a good evidence that a single clone of B. cells has become malignant giving local proliferation as well as metastatic spread.

5. These neoplastic cells produce only one type of immunoglobulin molecule and so can be easily identified. • This is applied to other tumors of B. cell origin as chronic lymphocytic leukemia which although not producing a circulating immunoglobulin, it has a specific cell-surface immunoglobulin.

6. “The field of growth theory”: • Many tumors tend to arise on a restricted area of tissue which is called a field of growth. • This theory based on the frequency of origin of multiple tumors on a restricted site and for apparently recurrent tumors to near the site of removal of a primary tumor. • Example of “multiple primary tumors” arising in a particular field are:

7. Transitional cell tumors of the urinary tract, from the pelvis and ureter to the bladder. • Polyposis coli. • In ulcerative colitis multiple malignancies are also the rule. • Squamous cell and basal cell carcinoma of the exposed skin and in xerodermapigmentosa. • Uterine leiomyomas.

8. Breast cancer is bilateral in 9% of cases especially “lobular” type carcinoma. • Sometimes there are multiple fibroadenomata of the breast. • Hepatoma of liver cirrhosis is often multicentric.

9. Sometimes there is a widespread malignancy in an epithelium with a common embryological derivation. e.g. • Gall bladder, bile ducts (extra and intra hepatic) and pancreatic ducts in a continuous wave. • Tumors arise in the epithelium of primitive cloacal origin “cloacogenic cancer” involving vagina, vulva and anus.

10. Causes of human cancer: • Most cancers in adults arise spontaneously in response to an unknown stimulus, but few can be attributed with certainty to some preceding cause as: • Chemical carcinogens • Physical carcinogenic agents • Viruses, bacteria, fungus and parasties • Hereditary predisposition • Hormonal imbalance • Cancer following chronic disease

11. Chemical Carcinogens • The “Chemical agents”: • The chemical agents incriminated in human cancer were derived from soot, coal tar and mineral oils. • The actual substances responsible for carcinogenesis in tar are a group of:

12. “Aromatic polycyclic hydrocarbons”: which include: • 1:2:5:6 dibenzanthracene • Methyl cholanthrene. • 3-4 benzpyrine • The last is the most significant carcinogen in human being present in coal tar and cigarette smoke. • The tumors these hydrocarbons produce appear at the site of application to the skin → leading to squamous cell carcinoma, while its subcutaneous injections induce sarcoma formation. • So, they are local carcinogens.

13. Aromatic amines: which include: • B-naphthylamine • 2. acetyl-amino-fluorene • This group affects persons working in rubber and cable manufacturing, pigment and paint manufacture, textile dyers and painters, gas workers, laboratory workers and rodent controllers. • These are remote carcinogens. • B- Naphcylamine is incriminated in inducing bladder cancer by its action on transitional epithelium.

14. The mode of its action: • An intermediary metabolic product is produced by oxidation in the liver, then detoxified by conjugation with glucuronic acid, and excreted in urine. • Bladder mucosa secretes the enzyme B glucuronidase which split the compound releasing its “ultimate carcinogen” by removing the glucuronic acid. • Its intermediary product produces tumors at its sites of excretion.

15. Acetyl aminofluorene was marketed as an insecticide. • It produces a wide rang of cancers including liver, lung, breast, intestine and bladder cancer in addition to carcinoma of the external auditory meats.

16. The azo compounds which includes: • 2:3 di-methlyl 4- amino-azobenzene in scarlet red. • 4- dimethy amino azobenzene in butter yellow. • These are used as dyes for leather and food stuffs. • They produce varieties of liver tumors e.ghepatomas, cholangiomas, usually without previous necrosis or cirrhosis. • This is facilitated by a diet deficiency. • They are a remote carcinogens.

17. Heavy metals e.g arsenic, iron: • Workers using arsenic are in danger of cancers of the skin of the limbs and face. • It may also cause, cancer lung. • Fowler’s solution used in recalcitrant psoriasis which contains the inorganic form of the metal may also develops cancer. • Iron produces hemochromatosis which may predispose to hepatoma.

18. Vinyl chloride: • A white solid plastic which is widely used and may lead to angiosarcoma of the liver. • Alkylating agents: • Mustard gas • Chloromethyl-ether • They increases the incidences of cancer lung, larynx, nasal sinuses and oropharynx.

19. VII. Hard wood furniture: • Makers in hard wood furniture are at an increased risk of developing adenocarcinoma of the nasal sinuses. • Leather workers are also at risk of cancer of nasal sinuses due to “isopropyl oil and nickel ore”.

20. The “carcinogens of natural origin”: • The natural food stuffs may have carcinogenic hazard. • This returns to the natural way of living. • The two important natural carcinogens are:

21. Aflatoxins: • It is produced by Aspergillus’sflavus and related fungi that contaminate food stuffs such ground nuts. • Aflatoxins fluoresce blue or green with ultraviolet light and accordingly named B or G. • B type is the most toxic and carcinogenic one of this family as it is a powerful liver carcinogens.

22. It is metabolized to its ultimate carcinogens by oxidase activity in the liver. • This explains that the prevalence of liver cancer in Africa and South East Asia is due to feeding them rather than to the effect of maturation.

23. Cycasine: • Which is glycoside isolated from a palm like tree “Cycascirciralis” which grows in the Far East. • It is carcinogenic only when given orally after hydrolysis of cycasine by intestinal bacteria and releasing its “ultimate carcinogen” called “methyl-azomethanol”. • It produces neoplasm at various sites especially the liver.

24. The bacterial metabolites: • The bacterial metabolites can produces carcinogens from many sources and “nitrosamines” are formed in the presence of nitrates or nitrites. • Nitrosamines can act locally in the stomach particularly if there is achlorohydria or at other sites after its absorption.

25. Initiation and promotion: • The application of a sub-threshold dose of carcinogen had “initiated” a group of cells, so that they become “latent” tumor cells, which were finally “promoted” to overt cancerous activity by a non specific-traumatizing agent. e.g.: hydrocarbon and croton oil. • The initial cells appear normal morphologically, but the action of a promoter causes them to divide so that papillomata “skin” or nodule “liver” appear.

26. These may be foci of apparent hyperplasia but can progress to areas of atypia, carcinoma in situ, invasive carcinoma and finally metastasizing carcinoma. • So, the development of a lethal tumor is a multi-step procedure. • Some of these steps appear to be reversible, but this becomes less as the lesions progress to greater malignancy.

27. The initiating agents have a dose dependant, irreversible, and additive effect which is transmissible to the cell’s progeny. • Cell proliferation occurs and after a number of divisions a cancer cell emerges. • Injury produced by a promoting agent speeds up this process. • Promoting agents are non specific and act slowly.

28. Initiation and promotion theory explains the long latent period between leaving employment and developing of tumor in cases of occupation cancers. • The damage on “promotion” may be produced by the carcinogen itself, toxic agent, infection or dietary deficiency, but in cases of unstable tissues (liver and kidney) a diseased organ may be more susceptible to the initiating action of a carcinogens than a normal tissue. • The nature of initiation is not known but the process is focal, and affects only a few cells in an organ.

29. Action of chemical carcinogens: • Chemical carcinogens can be placed into one of two groups: • Direct acting carcinogens: • These agents are in an active electrophilic form, and require no activation. • They are weak carcinogens. • This group includes cytotoxic drugs and immunosuppressant e.g. busulphan, melphalan, chlorambucil and cyclophosphamide.

30. Procarcinogens (indirect acting agents): • Most potent carcinogens fall in this group e.g. polycyclic aromatic hydrocarbons, aromatic amines, aflatoxin and nitrosamines. • They have little activity by themselves, but they can form strongly positive charged electrophilic reactants termed “ultimate carcinogens”. • This is effected by microsomal mixed function oxidase group of enzymes including the “cytochrome P450”.

31. They react with target molecules rich in electrons e.g. DNA causing their damage, derangement or mutation, e.g. mutation of RAS and p53. • The target may also be RNA, protein or polysaccharide. • Tissues vary very mush in their ability to form “ultimate carcinogens”. • The liver is the most important site for the metabolism of pro-carcinogens either by detoxification or activation.

32. The action of “mixed function oxidases enzymes” are affected by, diet, drugs and infection. In addition they are genetically controlled. • This explains individual, racial and species variation in response to particular carcinogens.

33. Physical Carcinogenic Agents • Ionizing radiations: • X-ray workers, radiotherapists, patients who have been treated with radioactive materials or x-rays, and the victims of nuclear fall-out have all developed malignant conditions particularly leukemia, bone tumor as osteosarcoma and squamous cell carcinoma of the skin or sometimes bronchogenic carcinoma.

34. Ultraviolet radiations: • Exert their harmful effects in the strong sunlight continually acting on the exposed skin of fair skinned people. • Those develop actinic (solar) keratoses later in life on their faces and hands. • They may develop into multiple squamous cell carcinomas, basal cell carcinomas, and malignant melanoma. • Ultraviolet light causes damage by giving rise to dimer formation between neighboring thymidine radicals in DNA. • When this DNA replicates the dimer causes mutation.

35. In normal cells there are enzymes that can excise the dimer and replace it by the correct nitrogen bases. • This repair mechanism protects the skin against actinic damage. • In xerodermapigmentosa; inherited as an autosomal recessive trait; one enzyme of the excision repair mechanism is defective and the patient’s skin is abnormally sensitive to the effects of sunlight.

36. Thermal radiation: • It probably acts as a “promoter” of cancer in area that has already been “initiated” by carcinogenic agents like ultraviolet light or the tar products from burning coals or tobacco. • This would account for the increased incidence of lip cancer in pipe-smokers.

37. Mechanism of action of radiation: • Chromosome breakage. • Translocation. • Point mutation (less frequent)

38. The latent period: • In all occupational and environmental cancers there is a long latent period that elapses from the time of application of the agent to the time of first appearance of the neoplasm. • E.g.: In x-ray workers there is 5 to 10 year’s latent period in order to develop leukemia.

39. Viruses and Neoplasia • Tumor producing (oncogenic) viruses may be DNA or RNA type. • All have the ability to integrate their DNA, or the provirus in case of RNA viruses, into the DNA of the host cell. • This transforms the cell to that capable of forming a tumor.

40. DNA oncogenic viruses: This group includes: A. Oncogenic herpes viruses: two (2) members of them can induce tumors. • The Epstein-Barr vivus (EB-virus): • This virus was first isolated from the cells of a patient with Burkett’s lymphoma.

41. Now this virus has been implicated in the pathogenesis of several human tumors as: • B. cell lymphoma • Subset of Hodgkin's lymphoma • Nasopharyngeal carcinoma. • Burkett's lymphoma • Its antibody is present in the serum of many normal individuals.

42. Infection of healthy people who have a little protective antibodies, causes infectious mononucleosis with positive Paul-Bunnel reaction. • The development of malignancy is not a complication.

43. Mechanism of EBV onchogenesis: • Certain EBV gene products stimulate normal B-cell proliferation. • Prevent apoptosis by activating BCl-2 • Activation of C-myconcogene.

44. Herpes simplex virus: • There is a definite association between herpes simplex virus type 2 (HSV-2) infections and carcinoma of the cervix uteri. • Patients with dysplasia, in situ carcinoma, and invasive tumor have a higher antibody titer of the virus. • Infection with HSV-8 can cause Kaposi’s sarcoma (vascular neoplasm common in AID patients).

45. Oncogenicpapova viruses: • Human Papilloma viruses (HPV): • They are responsible for various types of warts, laryngeal papillomas, and condylomataacuminata. • Malignant change is rare but it is encountered in renal transplant patients. • Laryngeal carcinoma may also occur on top of papilloma.

46. High risk HPVs (e.g., 16, 18 and 31), have been implicated in the genesis of several cancers, e.g., SCC of cervix uteri (sexual transmission), anal, vulvar and oropharyngeal cancers. • Mechanism of HPV oncogenesis: • Inactivates the p53 protein (loss of tumor suppresor gene). • Causes degranulation of Bax (a pro-apoptotic gene, inhibiting apoptosis.

47. Activates telomerase (competes cellular senescence) . • Inactivates CDKIs and activates cyclins.

48. Hepatitis B virus and hepatitis C virus: • Between 70% to 80% of hepatocellular carcinoma are due to chronic infection with HBV, or HCV. • Mechanism of action: • Immunologically mediated chronic inflammation, hepatocytic injury, stimulation of hepatocyte proliferation and production of reactive oxygen species can damage DNA.

49. HBx protein of HBV, and the HCV core can activate signal transduction pathways • Viral integration causes rearrangement of chromosomes, including multiple deletions (inactivation) of tumor suppressor genes.

50. The oncogenic RNA viruses (pocorna viruses): • They are associated with leukemia, lymphoma and sarcoma in birds, mice and cats. • The infecting virus carries an oncogene i.e. a gene capable of transforming a normal cell into a malignant cell. • RNA oncoviruses of human significance are: