Hepatocellular carcinoma is the most likely diagnosis given the history of chronic alcoholism (a risk factor for cirrhosis and HCC) and elevated alpha-fetoprotein level (a marker for HCC).

1. Neoplasia -6
Chemical Carcinogenesis
Dr. Roopam Jain
Professor & Head, Pathology

2. Key words:
Carcinogenesis: Pathogenesis of cancer
Carcinogen - agent causing cancer.
Oncogen - agent causing neoplasm.
Mutagen - agent causing mutation.
Oncogenes – genes causing cancer
p-onc, v-onc – Proto/viral/ - naming of oncogenes.

3. Carcinogenesis or oncogenesis or tumorigenesis means
mechanism of induction of tumours (pathogenesis of cancer);
agents which can induce tumours are called carcinogens
(etiology of cancer).
Based on implicated causative agents, etiology and
pathogenesis of cancer can be discussed under 3 headings:
A. Chemical carcinogens and chemical carcinogenesis
B. Physical carcinogens and radiation carcinogenesis
C. Biologic carcinogens and viral oncogenesis.

4. How the tumor is initiated ?
1. Chemical carcinogenesis
2. Hormonal carcinogenesis
3. Viral carcinogenesis
4. Bacterial/parasitic carcinogenesis
5.Radiation
6. Chronic inflammation carcinogenesis
7. Hereditary- Genetic defects
as a sum of all things above

5. Carcinogenesis
Refers to the process by which a normal cell is transformed
into a malignant cell and repeatedly divides to become
a cancer.
A chemical which can initiate this process is called a chemical
carcinogen.
Some chemicals which are non-carcinogenic or only weakly
carcinogenic can greatly enhance the effectiveness of
carcinogenic chemicals. Such "helpers" are called
co-carcinogens.
They may act by altering uptake or metabolism of carcinogens
by cells.
Carcinogenesis may take as long as 15-25 years in humans
and in several animal models has been shown to involve
two stages, initiation and promotion.

6. Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion and metastasis
“Cancer genes” cause bad things in cells:

7. Basic concept of carcinogenesis
at molecular level

9. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion and metastasis
“Cancer genes” cause bad things in cells:

10. Genetic basis of cancer includes
major genetic properties
1. Excessive and autonomous growth:
Activation of Growth-promoting oncogenes.
2. Refractoriness to growth inhibition:
Inactivation of anti-oncogenes.
3. Escaping cell death by apoptosis:
Abnormal apoptosis regulatory genes.
4. Avoiding cellular ageing: Telomeres and
telomerase in cancer.
5. Continued perfusion of cancer: Cancer
angiogenesis

11. 6. Invasion and distant metastasis: Cancer
dissemination.
7. DNA damage and repair system: failure of
DNA repair genes, Mutator genes and cancer.
8. Cancer progression and tumour
heterogeneity: Clonal aggressiveness.
9. Cancer a sequential multistep molecular
phenomenon: Multistep theory.

12. Basic concept of
carcinogenesis at molecular
level

17. Chemical Carcinogenesis
Chemical carcinogens are highly reactive
electrophiles (electron-deficient atoms)
can react with nucleophilic sites
(electron-rich) in cells such as DNA, RNA
and protein.
-producing lethal damage to cell

18. Initiation –
Results from exposure of sufficient dose of carcinogenic
agent usually genetic, is introduced into a target cell.
(genotoxicity)=Interaction with DNA
Initiation:
(1) essentially irreversible & has memory
(2) occurs rapidly after carcinogen exposure
(3) alone does not result in tumor formation
Carcinogen altered cell must undergo atleast one cycle of
proliferation so that change in DNA becomes fixed or
permanent
Initiation of Carcinogenesis

19. Chemical carcinogens acting as initiators of
carcinogenesis can be grouped into 2 categories
I. Direct-acting carcinogens
II. Indirect-acting carcinogens or procarcinogens
steps are involved in transforming ‘the target
cell’ into ‘the initiated cell’
1. Metabolic activation
2. Reactive electrophiles
3. Target molecules
4. The initiated cell

20. Initiator Carcinogens
Direct-acting
i) Alkylating agents - cyclophosphamide,
chlorambucil, busulfan, melphalan, nitrosourea),
beta-propiolactone & epoxides.
ii) Acylating agents - acetyl imidazole & dimethyl
carbamyl chloride.

22. Indirect-acting carcinogens or procarcinogens
i) Polycyclic aromatic hydrocarbons- anthracenes (benza-,
dibenza-, dimethyl benza-), benzapyrene and
methylcholanthrene
ii) Aromatic amines and azo-dyes - b-naphthylamine,
Benzidine , Azo-dyes
iii) Naturally-occurring products - aflatoxin B1, actinomycin D,
mitomycin C, safrole and betel nuts.
iv) Miscellaneous -

24. Promotion is the process whereby an initiated tissue or organ
develop focal proliferations and it requires the presence of
continuous stimulation.
A promotor: is a substance which doesn't damage DNA but
enhance growth of tumor induced by genotoxic
carcinogens e.g.: skin cancer in mice can be induced by
application of benzo [α ] pyrene ( initiator) followed by
phorbol ester from cotton oil ( promoter).
Promotion
(1) reversible
(2) acts only after exposure to an initiating agent
(3) requires repeated administration of a promoter
(4) is not carcinogenic in itself
Promotion of Carcinogenesis

25. Promoter Carcinogens
phorbol esters,
phenols,
certain hormones and
drugs.

26. Contrasting features of initiator and
promoter carcinogens

27. Carcinogenesis
Initiation
 DNA damage
eg.Benzpyrene
Promotion
 Turpentine (co-
carcinogens)
Malignant transformation:
 Visible tumor formation –
further DNA damage.

28. Events in chemical carcinogenesis

29. Events in chemical carcinogenesis

30. Etiology and Pathogenesis of Neoplasia
Initiation and Promotion

31. Direct-Acting Alkylating Agents
Weak carcinogens
Therapeutic agents (cyclophosphamide,Chlorambucil,
Busulphan etc.) used as anticancer drugs but induce
lymphoid neoplasm, leukaemia & others
Cyclophosphamide also powerful immunosuppressive
agents used for Rheumatoid arthritis & others. Risk of
induce cancer is low.

32. Polycyclic Aromatic Hydrocarbons
Require metabolic activation
Painted on the skin – Skin cancer
Injected subcutaneously – sarcomas
Introduced into specific organ – cancer locally
Combustion of tobacco with cigarette smoking –
lung and bladder cancer
In process of broiling meats and smoked meats
produced Polycyclic aromatic hydrocarbons

33. Aromatic amines and azo dyes
“ultimate carcinogen” formed by action of cytochrome
P-450 oxygenase systems.
Cancer at the site of metabolism and NOT at the point
of entry or absorption. E .g., Azo dyes producing
Hepatocellluar CA and not gastric CA
Beta- naphthalamine after absorption, hydroxylated in
active form then detoxified by conjugation with
glucoronic acid in liver. when excreted in URINE,
nontoxic conjugate is split by urinary glucoronidase-
release of electrophilic reactant causing Bladder CA.
Food coloring Azo dyes i.e. butter yellow, scarlet red
dangerous to human

34. Naturally occurring carcinogens
Produced by plants and microorganisms
Mycotoxin produced by Aspergillus flavus
present on stored corn, rice and peanuts-
hepatocarcinogen producing hepatocellular
carcinoma in some parts of Africa and china
Aflatoxin and HBV collaborate in production of
HCC

35. Nitrosamines and Amides
Nitro stable amines and nitrate used as a food
preservative which is converted to nitrites by
bacteria in stomach producing gastric carcinoma

36. Professions and industries
associated with high risk of cancer
Aluminum industry polycyclic aromatic
hydrocarbons (PAHs)
Lung and bladder cancer
Coal industry polycyclic aromatic
hydrocarbons (PAHs)
Lung, bladder, skin,
scrotum cancer
Shoemaking Benzene Lymphomas, leukemias
Furniture making Wood dust Nasopharyngeal cancer
Fuchsin dye production Fuchsin, ortho-toluidine Bladder cancer
Rubber industry Aromatic amines,
solvents
Lung, colon, stomach,
bladder, prostatic cancer,
leukemia

37. Chemicals Generally Recognized as
Carcinogenic in Humans
Chemicals Generally Recognized as Carcinogenic in Humans
Industrial Exposures
Benzidine Urinary Bladder
Vinyl Chloride Liver
Certain tars Skin and
Asbestos Peritoneum (lungs when combined with cigarette smoking)
Benzene Lymphoid Tissue
Other Exposures
Diethylstilbestrol VaginaI
Arsenic Compounds Skin cancer
Cigarette Smoke Lungs, urinary tract
Betal Nut Buccal Mucosa

38. Cancer site Hormones Potentially important
genes
Breast Estrogen,
progesterone
ER, PRCYP17, CYP19,
HSD17B1,
Prostate Dihydrotestosterone CYP17, HSD17B3,
SRD5A2, AR
Ovary FSH,
progesterone
FSH, FSHR, PR
Endometrium Estrogen CYP17, HSD17B1,
HSD17B2, ER
Testis In utero estrogen CYP17, HSD17B1
Thyroid TSH, estrogen TSH, CYP17,
HSD17B1

39. Diet & nutrients protecting from cancer :
Fruits & vegetables
* High level of fibers
* Antioxidants which decrease damaging effects caused by
free radicals and reactive oxygen species on DNA
Examples:
a- Tocopherol & β- carotene ( carotenoids), vit C : decrease
tumor incidence.
b- Tomatos : contain lycopene protect against prostate
cancer .
c- Green tea : contain polyphenols which act as antioxidants.
d- Red grapes : contain resveratrol which acts an antioxidant.
Garlic & onions ( allylsulphide + diallylsulphide) :
* They inhibit Cyt P450 ( Phase I) which converts
percarcinogents to carcinogens
* They activate glutathione-s- transferase ( GSTs ) which help
conjugation of carcinogens with cellular GSH ( Phase II)

40. Cruciferous vegetables :
* E.g.: Cabbage - broccoli.
• They contain dithiol thiones & isothiocyanates
which activate phase II enzymes that help eliminating
the carcinogen.
Omega 3 fatty acids:
e.g. : fish oil
They crowd other fats replacing them inside the cells ,
thus preventing their promoter action.
Soy products:
* Contain weakly estrogenic isoflavonoids
* These isoflavonoids compete with estrogen for its
peripheral receptors on breast blocking them , Estrogen
– dependant breast cancer ( as tamoxifen ).

41. Red grapes :
* Red grapes contain resveratrol & turmeric
contains curcumin.
* tumor cells secrete factor that promotes
the development of new blood vessels
which are necessary for tumor growth ;
this process is know as angiogenesis.
Resveratrol & curcumin suppress the
release of growth factors by the tumor
inhibit angiogenesis.

42. Diets play important roles in the development of
tumors.
The following factors should be considered.
 Natural Foods May Contain Carcinogens:
Mushrooms»»Hydrazine
Betal Nut»»Hydrocarbons
 Food contaminants:
Aflatoxin B1»»Peanuts
Nitrosamines»»Beer, Wine, Pickled Vegetables
 Food Processing:
Barbecued Meat»»Polycyclic Hydrocarbons
Heat Processing of Protein-Rich Foods»»Heterocyclic
Aromatic compounds
 Dietary Fat:
Saturated Fatty Acids
Polyunsaturated Fatty Acids: Corn oil, Safflower oil
Natural Foods May Contain
Anticarcinogens»»Vitamins, Antioxidants

46. (A)
Lymphatic spread, especially to regional lymph nodes draining
from the primary site, is typical of a carcinoma.
Infection from a breast abscess – painful nodal enlargement.
Sarcomas uncommonly metastasize to lymph nodes.
CNS - malignancies rarely metastasize outside of the CNS.
Dysplasias do not metastasize because they are not
malignancies.

48. (G)
A teratoma is a neoplasm derived from totipotential germ cells that
differentiate into tissues that represent all three germ layers:
ectoderm, endoderm, and mesoderm.
When the elements all are well differentiated, the neoplasm is
“mature” (benign).
Adenocarcinomas have malignant-appearing glandular elements.
Fibroadenomas have a benign glandular and stromal component;
they are common in the breast.
Gliomas are found in the central nervous system.
Hamartomas contain a mixture of cell types common to a tissue
site; the lung is one site for this uncommon lesion.
A mesothelioma arises from the lining of thoracic and abdominal
body cavities.
A rhabdomyosarcoma comprises cells that poorly resemble
striated muscle; most arise in soft tissues.

50. F

51. Environmental carcinogens
51

53. (C)
Radiation is oncogenic. Cancers of thyroid and bone
often develop after radiation exposure; leukemias also
can occur.
Hepatocellular carcinomas can arise in cirrhosis caused
by chronic alcoholism.
Ataxia telangiectasia is an inherited syndrome that
carries an increased risk of development of leukemias
and lymphomas.
Trauma is not a risk factor for development of cancer
Arsenic exposure - leads to lung and skin cancers.

54. A 62-year-old man with a history of chronic
alcoholism has noted a 6-kg weight loss over
the past 5 months. Physical examination shows no
masses or palpable lymphadenopathy. Laboratory
studies include an elevated serum α-fetoprotein
level. A stool guaiac test result is negative. Which
of the following is the most likely diagnosis?
□ (A) Prostatic adenocarcinoma
□ (B) Pulmonary squamous cell carcinoma
□ (C) Multiple myeloma
□ (D) Pancreatic adenocarcinoma
□ (E) Hepatocellular carcinoma

55. (E)
α-Fetoprotein is a tumor marker for hepatocellular
carcinomas and some testicular carcinomas.
The PSA (prostate-specific antigen) is a helpful marker
for prostatic adenocarcinoma.
Squamous cell carcinomas - do not have useful specific
tumor markers.
A serum immunoglobulin level - myeloma.
Gastrointestinal tract adenocarcinomas, including those
arising in the pancreas, may be accompanied by
elevations in the serum CEA (carcinoembryonic
antigen level).