2. CARCINOGENESIS
1. Cell Rest Theory of Conheim – during development of
an individual, some embryonic cells did not develop into
mature cells. They become activated later on, grow
rapidly into cancer.
2. Clone Theory – single cell has become abnormal and
become the starting point of the tumor.
3. Group of Cell Theory – several cells become abnormal
and become cancer cells.
4. Irritation Theory – some cells are damaged and
become cancer cells.
5. Microbial Theory – begin to grow because of
microorganisms , i.e., Epstein Barr Virus (EPV) and
Ewing’s sarcoma
4. 1. Molecular Basis of Tumor
• Nonlethal genetic damage lies at the
core of carcinogenesis
• Four classes of regulatory genes,
protooncogene, cancer suppressor
gene, regulated apoptosis gene, and
DNA repair gene, are the principal
targets of genetic damage.
• Carcinogenesis is a multistep process
at both the phenotypic and genetic
levels.
5. (1) Oncogenes and cancer
① Protein products of oncogenes
a. Growth factors
b. Growth factors receptors
c. Signal transducing proteins
d. Nuclear transcription proteins
e. Cyclones and cyclic-dependent kinases
6. ② Activation of oncogenes
a. Point mutations
b. Chromosome rearrangements
Translocations
Inversions
c. Amplification
8. Table Selected oncogenes their mode of
activation and associated human tumors
Category Protooncogene Mechanism Associated
Human
Tumor
Growth Factors
Sis Overexpression Astrocytoma
PDGF-β chain Osteosarcoma
Hst-1 Overexpression Stomach cancer
Fibroblast growth factors Int-2 Amplification Bladder cancer
Breast cancer
Melanoma
9. (2) Cancer suppressor genes
① Molecules that regulated nuclear
transcription and cell cycle
Rb gene: 13q14, G1 × S
P53 gene: 17p13.1, related to 50% of
human tumors
BRCA- l gene: 17q12-21,
BRCA-2 gene: 13q12-13
10. Molecules that regulated signal
transduction
NF-1 gene: 17q11.2
APC gene: 5q21
12. (4) Genes that regulate DNA repair
Humans literally swim in a sea
of environmental carcinogens. Although
exposure to naturally occurring DNA-
damaging agents, such as ionizing
radiation, sunlight, and dietary
carcinogens, is common, cancer is a
relatively rare outcome of such
encounters.
13. This happy state of affairs results from
the ability of normal cells to repair DNA damages
and thus prevent mutations in genes that
regulate cell growth and apoptosis.
In addition to possible DNA damage
from environmental agents, the DNA of normal
dividing cells is also susceptible to alterations
resulting from errors that occur spontaneously
during DNA replication.
Such mistakes, if not repaired promptly,
can also push the cells along the slippery slope
of neoplastic transformation.
14. The importance of DNA repair in
maintaining the integrity of the genome is
highlighted by several inherited disorders
in which genes that encode proteins
involved in DNA repair are defective.
Those born with such inherited
mutations of DNA repair proteins are at a
greatly increased risk of developing
cancer. Several examples are discussed
next.
15. (5) Telomere and tumor
telomerase activity increased
in majority of human tumors.
17. 2. Carcinogenic agents
A large number of agents cause genetic
damage and inchece neoplastic
transformation of cells
(1) Chemical carcinogens
Chemical carcinogenesis is also a
multistep process.
18. ① Initiation of carcinogenesis
Chemical carcinogens are diverse in structure,
but they fall into one of two categories:
a. Direct-acting chemical carcinogenes
b. Indirect-acting chemical carcinogens
(procarcinogenes),
Which require metabolic conversion in vivo to
produce.
Ultimate carcinogens capable of transforming
cells.
HP Solution Center.lnk
19. Both of them are highly reactive
electrophiles that can react with
nucleophilic (electron-rich) sites in the
cells.
These reactions are nonenzymatic and
result in the formation of covalent
adducts between the chemical
carcinogen and nucleotide in DNA.
20. The carcinogenic potency of a chemical
is determined not only by the inherent
reactivity of its electrophilic derivative,
but also by the balance between
metabolic activation and inactivation
reactions.
If initiation occurs, carcinogen-altered
cells could be heritable.
21. ② Promotion of carcinogenesis
Promoters earn induce tumors in initiated
cells, but they are nontumorigenic by them
selves.
Prompters render cells susceptible to
additional mutations by causing cellular
proliferation.
22. CARCINOGEN
Metabolic activation
Excretion
Electrophilic
intermediates
DNA
INITIATION
repair
Binding to DNA:
Normal cell
Adduct formation
Cell death
Permanent DNA lesion:
Initiated cell
Cell proliferaion:
Altered differentiation
PROMOTION
PRENEOPLASTIC CLONE
Additional
mutations
Proliferation
MALIGNANT NEOPLASM (Quoted from Robbins
《 Pathology Basis of disease 》 )
23. STAGES OF CANCER
1. First Stage – intraepithelial, primary,
carcinoma-in-situ
2. Second Stage – infiltrative, invasive,
beyond the basement membrane
3. Third Stage – metastasis present, with
secondary growth
24. Nomenclature
• Although parenchymal cells determine their nature, the growth
and evolution of neoplasms are critically dependent on their
stroma.
• Sometimes the parenchymal cells stimulate the formation of
an abundant collagenous stroma referred to as desmoplasia.
• Papillomas are benign epitjelial neoplasms producing visible
warty projections
• Syringomas are tumors of sweat glands
• Trichoepithelioma are tumors arising from hair follicles
• Hemartoma is a disorganized, benign tumor-like nodule that
contains differentiated cells and one cell type often
predominates
• Carcinoma-in-situ is an epithelial tumor that has not yet
penetrated the basement membrane and thus has no current
chance of metastasis
• Choristoma is the presence of normal tissue in an abnormal
location
• Hidradenomas are tumors arising from the vulva.
25. Basic Components of Tumor
There are 2 basic components of a tumor:
1. Parenchyma – made up of proliferating
neoplastic cells. It is the component from
which the tumor derives its name. It
determines the biologic behavior of the
tumor.
2. Stroma – is the supporting tissue of the
tumor made u of CT, blood vessels and
possibly lymphatics.
27. Choristoma
• An ectopic rest of normal tissue is called a
choristoma.
• Example is a rest of adrenal cells under the
kidney capsule
• Analogously, aberrant differentiation may
produce a mass of disorganized mature
specialized cells or tissue indigenous to the
particular site, referred to as hamartoma.
• Types are: Salivary gland chorsitoma,
cartilaginous choristoma,oral osseous
choristoma, lingual thyroid choristoma, lingual
sebaceous chorsitoma, and glial choristoma
29. HAMARTOMA
• Hamartoma is a developmental
abnormality, tumor-like but non-
neoplastic malformation consisting of a
mixture of tissues normally found at a
particular site.
• The commonest forms are those
composed of blood vessels and those
involving cells of the skin.
31. Fibroma
• A benign neoplasm arising from fibroblast
• The tumor is discrete, encapsulated, spherical
ovoid nodules; about 15-20 cm particularly in the
ovary, CT sheaths of nerves, and of muscles
• They are soft, rubbery, pliable masses.
• They occur at any age, the cut surface discloses
a firm, white glistening surface
• Microscopically, typical spindle cell fibrocytes
and fibroblasts are present.
• Scant to large amounts of collages are found
between the fibroblasts
33. Leiomyoma
• Also called “myoma” or “fibroid”.
• Tumor is composed on intertwining bundles of
smooth muscle cells that more or less resemble
of uninvolved myometrium.
• They are sharply circumscribed, unencapsulated
but discrete, firm, gray-white masses with a
characteristic whorled appearance on cut
surface.
• This tumor may have an increase of the CT with
dense hyalinization of the stroma
37. Types of Nevus
• Intradermal nevus – is the common, flat or elevated
type composed of sheets of nevus cells, many of
which contain melanin pigment.
• Compound nevus – exhibit features of both the
intradermal and junctional nevus
• Blue nevus – is a smooth blue to blue-black lesion
located in the CT and composed of spindle-shaped
melanoblasts.
• Juvenile nevus – found in children that is
histologically similar to malignant melanoma but is
clinically benign
• Junctional nevus – appears to be dropping off from
the overlying epithelium. It is of particular clinical
significance, since it may undergo malignant
transformation to malignant melanoma.
44. Adenoma
• Adenoma is the term applied to the benign
epithelial neoplasm that forms glandular patterns
• Cystadenoma- those that form large cystic
masses in the ovary
• Papillary cystadenoma – protrude into cystic
spaces
• Papilloma – finger-like or warty projections from
epithelial surfaces
• Desmoplasia – result when parenchymal cells
stimulate the formation of an abundant stroma.
49. Question
A tumor composed of tissues
representing all three embryonic germ
layers commonly seen either in the
ovary or in the testis is called
A. adenocarcinoma
B. choristoma
C. hamartoma
D. teratoma
E. mixed mesodermal tumor
50. ADENOMATOUS POLYPS COLI
APC is an inherited
disorder characterized
by the development of
myriad polyps in the
colon beginning in
late adolescence or
early childhood.
If untreated, the
condition may lead to
colon cancer.
The gene is located on
chromosome 5.
51. HODGKIN’S LYMPHOMA
• Also called benign
lymphoblastoma
• Affects the lymph
nodes, spleen, liver
and bone marrow
• Diagnostic feature
in the RS giant cell
(Reed-Sternberg
giant cell)
53. Question
• On Southern Blot examination the DNA of a
malignant tumor is found to have a clonal
immunoglobulin gene rearrangement. From
what type of cell is the tumor derived?
A. fibroblast
B. T lymphocyte
C. squamous epithelial cell
D. smooth muscle cell
E. B lymphocyte
54. FIBROADENOMA - FEMALE BREAST
Fibroadenoma is the most coomon benign
Tumor of the breast. It developed as a
result of
increased sensitivity to estrogen.
Types of fibroadenoma:
1. Intracanalicular fibroadenoma – the
proliferating comonents into the
parenchymal channels are large
polysoid masses
2. Pericanalicular fibroadenoma – the
proliferating components are both the
epithelium and CT stroma.
Varieties of fibroadenocarcinoma:
1. Scirrhous and medullary carcinomas
2. Adenocarcinomas
3. Intraductal carcinomas
4. Paget’s disease of the nipple
57. Giant cell Tumor or Osteoclastoma
or Codmon’s Tumor
• This is a tumor of the epiphyses of long bones
• Males and females are equally affected.
• It involves the proximal tibia, distal femur and
distal radius.
• It consists of destruction and replacement of
original bone matrix
• Extensive production of new bone trabeculae
• Filling of all cancellous bone spaces with
proliferating bone forming tumor cells.
• It recur after curettage.
61. Clinical Differences Between
Benign and Malignant Neoplasms
Grow slowly Grow rapidly
Expansive growth Invasive growth
Usually encapsulated Not capsulated
Do not recur after careful Recur after removal
removal
Do not metastasize Often metastasize
Do not kill unless they Do kill
compress vital organs
Rarely show metastasis Often show necrosis and
ulceration
No cachexia Cachexia and anemia
62. Histological Differences between Benign and Malignant
Neoplasms
Benign Malignant
Consist of well-differentiated cells Consist of poorly-differentiated
anaplastic cells
Cells are rather uniform in size and Pleomorphism of cells
shape
Nuclei take up stain normally Hyperchromatic nuclei
Few mitosis Numerous multipolar mitosis
Cells do not infiltrate Cells do infiltrate
Fairly good imitation of the Unsuccessful imitation of the
arrangement of the tissue from tissue of the origin
which they are derived
64. Differences Between Carcinoma and Sarcoma
Points of Differences Carcinoma Sarcoma
Cell origin Epithelial Mesenchymal
Cellular arrangement Alveolar or glandular Singly
Size Less in size More
Blood vessels Less More
Hemorrhages Less More
Necrosis Less More
Age incidence Older (may also occur in the Younger (may also affect
young) the older)
Mode of metastases Commonly through the Commonly through the
lymphatics blood but may also involve
the lymphatics
Site of first metastasis Regional lymph nodes Lungs
66. ROUTES OF METASTASIS
• LOCAL INVASION
• LYMPHATIC SPREAD
• BLOOD OR HEMATOGENOUS SPREAD
• TRANSCOELOMIC SPREAD
• PERINEURAL SPREAD
• INTRAEPITHELIAL SPREAD
67. Pathways of Spread (Metastasis)
• Direct seeding of body cavities – most often
involve the peritoneal cavity
• Transplantation – refers to the mechanical
transport of tumor fragments by instruments of
gloved hands during surgical procedures.
• Lymphatic spread – is the transport through the
lymphatics and it is the most common pathway
for the initial dissemination of carcinomas but
sarcomas may also use these routes.
• Hematogenous spread – this pathway is typical
with sarcomas but may also found in
carcinomas.
68. Mechanisms of Cancer
Invasiveness
• Physical pressure
• Reduced adhesiveness and cohesiveness
of tumor cells
• Increased motility of tumor cells
• Loss of contact inhibition
• Release of destructive enzymes
• Reduced immune response inducing
inflammatory reaction
79. SCC or Epidermoid carcinoma
• Account for 90% of all malignant oral tumors
• Arise at any site normally covered by stratified
squamous epithelium – skin, mouth, esophagus
• Develop following conditions like leukoplakia, senile
keratosis, arsenic keratosis, burns, scar or foci of
radiodermatitis
• Two Macroscopic types:
1. Papillary or exophytic types- appears as a
warty outgrowth with an infiltrating base
2. Nodular or endophytic types – produces a
hard, nodular mass beneath the surface and shows
more raid infiltration and dissemination
82. MULTIPLE MYELOMA
• Multiple myeloma is a malignant
neoplasm of the bone marrow. The tumor,
composed of plasma cells destroys
osseous tissue, especially in flat bones,
causing pain, fractures, hypercalcemia
and skeletal deformities.
• Characteristically, there is
hyperglobulinemia, Bence Jones
proteinuria, anemia, weight loss,
pulmonary complications secondary to rib
fractures and kidney failures are present.
84. Bone Lesions in MM
• The tumor cells produce lytic lesions in bone,
especially in the skull and axial skeleton,
• Bone lesions:
- appear lucent on X-ray exam, with
characteristic sharp borders, referred to as
punched out lesions
- diffuse demineralization of bone (osteopenia)
- severe bone pain and spontaneous fractures
86. Ameloblastoma
• A highly destructive, malignant, rapidly
growing tumor of the jaw.
• Also called adamantinoma.
• The histologic pattern is quite variable and
recapitulates the enamel organ of the
tooth.
• Microscopically, nests or cords of stratified
squamous or columnar epithelium are
embedded in a loose fibrous stroma.
89. Arrhenoblastoma
• An ovarian neoplasm whose cells mimic
those in testicular tubules and secrete
male sex hormome, causing virilization in
females.
• Also called andreoblastoma or Sertoli-
Leydig cell tumor
94. TNM
• GRADING of cancer is a system for
describing the size and extent of spread of
a malignant tumor, used to plan treatment
and predict prognosis.
• T is used to represent the tumor size
• N denotes the regional lymph node
involvement
• M indicates distant metastases
• Numeric subscripts-in each category
indicates the degree of dissemination
95. TNM
• T1N0M0 - is a small, localized tumor
• T2N1M0 - is larger primary tumor that has
extended to regional nodes
• T4N3M3 – is a very large lesion involving
regional nodes and distant sites
