Neoplasia 6: Dr. Eman Krieshan, M.D. 5-1-2022

Neoplasia 6
DR. EMAN KRIESHAN, M.D.

5-1-2022
ETIOLOGY OF CANCER: CARCINOGENIC
AGENTS
 Carcinogenic agents inflict genetic damage,
which lies at the heart of carcinogenesis.
 Three classes of carcinogenic agents have

been identified:
 (1) chemicals.
 (2) radiant energy.
 (3) microbial products.
1. Chemical Carcinogens
 Chemical Carcinogens are subdivided into:

 A. Direct-Acting Agents:
 Direct-acting agents require no metabolic
conversion to become carcinogenic. e.g., alkylating
agents).
 B. Indirect-Acting Agents :
 chemicals that require metabolic conversion to an
ultimate carcinogen, e.g benzo[a]pyrene formed
during the combustion of tobacco .
 Polycyclic hydrocarbons that are present in smoked
meats and fish
Another important examples of
indirect-acting carcinogens.
 The aromatic amines and azo dyes with
bladder cancer.
 Aflatoxin B1 from Aspergillus with
hepatocellular carcinoma .
 nitrites used as food preservatives are
suspected to be carcinogenic.
Mechanisms of Action of Chemical
Carcinogens
 Most chemical carcinogens are mutagenic.
2. Radiation Carcinogenesis
 Radiation, whatever its source (UV rays of sunlight,

radiographs, nuclear fission, radionuclides), is an
established carcinogen.
 Biologically, doublestranded DNA breaks seem to be the

most important form of DNA damage caused by
radiation
 A follow-up study of survivors of Hiroshima and
Nagasaki disclosed a markedly increased
incidence of leukemia, thyroid, breast, colon,
and lung carcinomas.
 Therapeutic irradiation of the head and neck can

give rise to papillary thyroid cancers years later.
3. Viral and Microbial Oncogenesis
 Many DNA and RNA viruses have proved to be
oncogenic and its include:
 A. Oncogenic RNA Viruses.

 B. Oncogenic DNA Viruses.
 c. Helicobacter pylori.
A. Oncogenic RNA Viruses:
 Human T-cell leukemia virus type 1 (HTLV-1).

 It cause adult T-cell leukemia/lymphoma (ATLL) .
 HTLV-1 has tropism for CD4+ T cells, and hence
this subset of T cells is the major target for
neoplastic transformation.
 Leukemia develops in only 3% to 5% of the
infected individuals, typically after a long latent
period of 40 to 60 years
b. Oncogenic DNA Viruses
 Five DNA viruses are strongly associated

with human cancer:
 HPV.
 Epstein-Barr virus (EBV).
 Kaposi sarcoma herpes virus [HHV-8]).
 polyoma virus called Merkel cell virus.
 hepatitis B virus (HBV)
1. Human Papilloma virus(HPV)
 They are subdivided into:

 low-risk HPVs (type 6,11):
• cause genital warts have, it low malignant potential
 high-risk HPVs (types 16 and 18):

• cause squamous cell carcinoma of the cervix and
anogenital region and oropharyngeal cancers.
 The oncogenic potential of HPV can be related to
products of two early viral genes, E6 and E7:
 Oncogenic activities of E6:

 the E6 protein binds to and mediates the
degradation of p53
 Oncogenic activities of E7:

 It binds to the RB protein promoting
progression through the cell cycle
2. Epstein-Barr Virus
 EBV, a member of the herpesvirus family, was

the first virus linked to a human tumor, Burkitt
lymphoma.
 EBV is implicated in the pathogenesis of :

 lymphomas in immunosuppressed patients.
 Hodgkin lymphoma.
 uncommon T-cell and NK-cell tumors
 nasopharyngeal carcinoma
 a subset of gastric carcinoma.
pathogenesis
 EBV uses the complement receptor CD21

 to attach to and infect B cells
 That leads to polyclonal B cell proliferation
 generation of immortal B lymphoblastoid cell
lines
3. Hepatitis B and Hepatitis C
Viruses
 The epidemiologic evidence linking chronic
HBV and hepatitis C virus (HCV) infection
with hepatocellular carcinoma is strong .
 the dominant effect seems to be

immunologically mediated chronic
inflammation with hepatocyte death, leading
to regeneration and genomic damage.
 Although the immune system generally is
thought to be protective, recent work has
demonstrated that in the setting of unresolved
chronic inflammation, as occurs in viral hepatitis
or chronic gastritis caused by H. pylori , the
immune response may become maladaptive,
promoting tumorigenesis.
4. Helicobacter pylori
 H. pylori infection is implicated in the genesis

of both gastric adenocarcinomas and gastric
lymphomas (MALT lymphoma).
 The scenario for the development of gastric
adenocarcinoma is involves increased
epithelial cell proliferation on a background
of chronic inflammation.
CLINICAL ASPECTS OF NEOPLASIA
 The importance of neoplasms ultimately lies in their

effects on patients.
 both malignant and benign tumors may cause
problems because of :
 (1) location and impingement on adjacent
structures.
 (2) functional activity such as hormone synthesis or
the development of paraneoplastic syndromes.
 (3) bleeding and infections when the tumor
ulcerates through adjacent surfaces.
 (4) symptoms that result from rupture or infarction.
 (5) cachexia or wasting
Effects of Tumor on Host
 1. location:
 A small (1-cm) pituitary adenoma can compress and
destroy the surrounding normal gland, giving rise to
hypopituitarism.
 A 0.5-cm leiomyoma in the wall of the renal artery may
encroach on the blood supply, leading to renal ischemia
and hypertension.
 2. Signs and symptoms related to hormone
production , e.g;
 Neoplasm arising in the beta cells of the
pancreatic islets of Langerhans can produce
hyperinsulinism.
 3. A tumor may ulcerate through a surface,

with consequent bleeding or secondary
infection.
Cancer Cachexia
 Many cancer patients suffer progressive loss

of body fat and lean body mass, accompanied
by profound weakness, anorexia, and
anemia—a condition referred to as cachexia.
 current evidence indicates that cachexia

results from the action of soluble factors such
as cytokines produced by the tumor and the
host, rather than reduced food intake
 In patients with cancer, calorie expenditure
remains high, and basal metabolic rate is
increased, despite reduced food intake.
 It is suspected that TNF produced by
macrophages mediate cachexia
Paraneoplastic Syndromes
 Symptom complexes that occur in patients with
cancer and that cannot be readily explained by local or
distant spread of the tumor or by the elaboration of
hormones indigenous to the tissue of origin of the
tumor.
 The neoplasms most often associated with

Paraneoplastic Syndromes are:
 lung .
 breast cancers .
 hematologic malignancies
 The most common paraneoplastic syndromes
are :
 Hypercalcemia.
 Cushing syndrome.
 nonbacterial thrombotic endocarditis.
Grading and Staging of Cancer
 Systems have been developed to express, the

level of differentiation, or grade, and extent
of spread of a cancer within the patient, or
stage, as parameters of the clinical gravity of
the disease and clinical aggressiveness .
 Grading of a cancer is based on the degree of
differentiation of the tumor cells, and generally
range from two categories (low grade and high
grade).
 The major staging system currently in use is
the American Joint Committee on Cancer
Staging, TNM system
 The staging of solid cancers is based on:
 the size of the primary lesion (T for primary
tumor)
 its extent of spread to regional lymph
nodes(N for regional lymph node).
 presence or absence of blood borne
metastases (M for metastases).
Laboratory Diagnosis of Cancer
 Tumor Markers:
 Biochemical assays for tumor-associated
enzymes, hormones, and other tumor markers in
the blood cannot be utilized for definitive
diagnosis of cancer; however, they are used as:
 screening tests.
 monitoring the response to therapy
 detecting disease recurrence.
examples
 PSA, used to screen for prostatic

adenocarcinoma.
 CEA which is elaborated by carcinomas of the
colon, pancreas, stomach, and breast.
 AFP which is produced by hepatocellular
carcinomas.
Molecular Diagnosis
 An increasing number of molecular

techniques are being used for the diagnosis of
tumors and for predicting their behavior.
 1. Diagnosis of malignancy:
 E.g PCR-based detection of BCR-ABL
transcripts can confirm the diagnosis of
chronic myeloid leukemia .
 2. Prognosis and behavior:
 Certain genetic alterations are associated
with a poor prognosis, e.g HER2 and NMYC,
expression breast cancers and
neuroblastomas, respectively.
 3. Diagnosis of hereditary predisposition to

cancer, e.g BRCA1

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Neoplasia 6

DR. EMAN KRIESHAN, M.D.

 Three classes of carcinogenic agents have

 Chemical Carcinogens are subdivided into:

 Radiation, whatever its source (UV rays of sunlight,

 Biologically, doublestranded DNA breaks seem to be the

 Therapeutic irradiation of the head and neck can

 A. Oncogenic RNA Viruses.

 Human T-cell leukemia virus type 1 (HTLV-1).

 Five DNA viruses are strongly associated

 They are subdivided into:

 high-risk HPVs (types 16 and 18):

 Oncogenic activities of E6:

 Oncogenic activities of E7:

 EBV, a member of the herpesvirus family, was

 EBV is implicated in the pathogenesis of :

 EBV uses the complement receptor CD21

 the dominant effect seems to be

 H. pylori infection is implicated in the genesis

 The importance of neoplasms ultimately lies in their

 3. A tumor may ulcerate through a surface,

 Many cancer patients suffer progressive loss

 current evidence indicates that cachexia

 The neoplasms most often associated with

 Systems have been developed to express, the

 PSA, used to screen for prostatic

 An increasing number of molecular

 3. Diagnosis of hereditary predisposition to

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