Neoplasia (4&5 of 6) Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

Carcinogenic agents 3 major classes: -Chemicals -Radiation -Microbes

Chemicals Direct-Acting or Indirect-Acting Chimney sweeps and chronic exposure to soot Direct-Acting or Indirect-Acting

Direct-Acting chemical carcinogens No metabolic conversion is needed Some are cancer chemotherapy drugs!!! …alkylating agents …used for Hodgkin lymphoma & others, & mainly causes leukemia …Such agents may be used for non-neoplastic conditions

Indirect-Acting chemical carcinogens Require metabolic conversion to an ultimate carcinogen …polycyclic hydrocarbons, present in fossil fuels benzo[a]pyrene and other carcinogens in cigarette smoking…lung cancer also in animal fat and smoked meat/fish epoxides are the active products…bind to nucleic acids and proteins

Indirect-Acting chemical carcinogens, cont’d …aromatic amines and azo dyes …β-naphthylamine and bladder cancer The cytochrome P-450–dependent monooxygenases are especially involved…polymorphism between people Some strains of Aspergillus, a mold that grows on improperly stored grains and nuts…Aflatoxin B1 aniline dye and rubber industries

Radiation carcinogenesis Hiroshima and Nagasaki: -Leukemia -Thyroid -Breast -Colon -Lung …etc.

Radiation carcinogenesis, cont’d Therapeutic irradiation of the head and neck…papillary thyroid carcinoma Double stranded DNA breaks seem to be the most important form of DNA damage caused by radiation Natural UV radiation derived from the sun …skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas) …at greatest risk are fair-skinned people who live in locales such as Australia and New Zealand that receive a great deal of sunlight

Radiation carcinogenesis, cont’d Non-melanoma skin cancers…total cumulative exposure to UV radiation Melanoma…intense intermittent exposure—as occurs with sunbathing UV light…pyrimidine dimers Patients with the inherited disease xeroderma pigmentosum have a defect in the nucleotide excision repair pathway Visit https://sites.google.com/site/uvdnadamagerepair/uv-effects-on-dna/cpd-s for references

Viral & microbial oncogenesis HTLV-1…CD4+ T cells EBV HPV HBV & HCV

HPV Cervix, anogenital & oropharyngeal (esp., tonsils) E6 & E7 gene products -binds RB and release E2F from it -also inactivates p21 & p27 (CDKIs) degrades p53

EBV B cell lymphoma Hodgkin lymphoma Nasopharyngeal carcinoma T cell lymphoma Gastric carcinoma NK cell lymphoma Visit https://en.wikipedia.org/wiki/Burkitt%27s_lymphoma for references

HBV & HCV HBV & HCV Helicobacter pylori

Clinical aspects Can benign tumors cause death? Complications: -mass effect -bleeding and infection…by ulceration of surfaces -rupture -secretion of hormones…etc. -cachexia

Cancer cachexia not starvation but due to mediators -TNF = progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia not starvation but due to mediators -TNF -proteolysis-inducing factor Visit https://www.medscape.com/viewarticle/854555 for references

Paraneoplastic syndromes = symptom complexes that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones not indigenous to the tissue of origin of the tumor 10-15% of cancers Hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis…of the most common ones …mainly lung, breast and hematologic malignancies

Paraneoplastic syndromes, cont’d Hypercalcemia resulting from skeletal metastases is not a paraneoplastic syndrome Bronchogenic carcinomas: Can secrete products identical to or having the effects of ACTH, antidiuretic hormone, parathyroid hormone, serotonin, human chorionic gonadotropin, and other bioactive substances Hypercoagulability: -venous thrombosis -nonbacterial thrombotic endocarditis Clubbing of the fingers and hypertrophic osteoarthropathy in patients with lung carcinomas Visit https://en.wikipedia.org/wiki/Nail_clubbing for references

Grading and staging What is the difference? What is TNM staging system?

Thank You