Neoplasia

Neoplasms (tumors) result due

to excessive and unregulated
proliferation that is independent
of physiologic growth-regulatory
stimuli
• In common medical usage, a neoplasm is
often referred to as a tumor
• the study of tumors is called oncology (from
oncos, "tumor," and logos, "study of").
• In oncology, the division of neoplasms into
benign and malignant categories is important.
Tumors are either
benign or malignant
 A tumor is said to be Benign when its
microscopic & gross characteristics are
considered to be relatively innocent ie :
It will remain localized
It cannot spread to other sites
It is amenable to local surgical removal
Malignant tumors are
collectively referred to as
cancer(latin word for crab)
 A tumor is said to be Malignant
when it can :
-invade & destroy adjacent
structures
-spread to distant sites(metastasize)
to cause death
 NOMENCLATURE
• Neoplasia literally means "new growth”
• an abnormal mass of tissue the growth of
which exceeds and is uncoordinated with that
of the normal tissues and persists in the same
excessive manner after the cessation of the
stimuli which evoked the change
• Neoplastic cells are said to be transformed
because they continue to replicate,despite
the regulatory influences that control normal
cell growth.
• Neoplasms therefore enjoy a certain degree
of autonomy and more or less steadily
increase in size regardless of their local
environment and the nutritional status of the
host.
• All neoplasms depend on the host for their
nutrition and blood supply.
• All tumors, benign and malignant, have two
basic components:
• (1) the parenchyma, made up of transformed
or neoplastic cells.
• (2) the supporting, host-derived, non-
neoplastic stroma, made up of connective
tissue, blood vessels, and host-derived
inflammatory cells.
• The parenchyma of the neoplasm largely
determines its biologic behavior, and it is this
component from which the tumor derives its
name.
• The stroma is crucial to the growth of the
neoplasm, since it carries the blood supply
and provides support for the growth of
parenchymal cells.
 Benign Tumors
• benign tumors of non-epithelial origin are
designated by attaching the suffix -oma to
the cell type from which the tumor arises.
• E.g
-A benign tumor arising in fibrous tissue is a
fibroma
-A benign cartilaginous tumor is a
chondroma.
• The nomenclature of benign epithelial tumors
is more complex.
• They are classified on the basis of :
• 1-their microscopic pattern
• 2-on the basis of their macroscopic pattern.
• 3-by their cells of origin.
• Adenoma is applied to benign epithelial
neoplasms producing gland patterns and to
neoplasms derived from glands but not
necessarily exhibiting gland patterns.
• A benign epithelial neoplasm arising from
renal tubule cells and growing in glandlike
patterns would be termed an adenoma
• Papillomas are benign epithelial neoplasms,
growing on any surface, that produce microscopic
or macroscopic finger-like fronds.
• A polyp is a mass that projects above a mucosal
surface, as in the gut, to form a macroscopically
visible structure
• Although this term is commonly used for benign
tumors, some malignant tumors also may appear as
polyps
Colonic polyps
Colonic polyps
(adenoma)
• Cystadenomas are hollow cystic masses;
typically they are seen in the ovary.
• Tumor cells may undergo divergent differentiation,
creating so-called mixed tumors.
• Examples :
• 1- mixed tumor of salivary gland (pleomorphic
adenoma) .
- These tumors have obvious epithelial components
dispersed throughout a fibromyxoid stroma,
sometimes harboring islands of cartilage or bone .
- All of these diverse elements are thought to derive
from epithelial cells, myoepithelial cells, or both in
the salivary glands
Pleomorphic adenoma
Pleomorphic adenoma
(high magnification)
• 2-Fibroadenoma of the female breast
This benign tumor contains a mixture of
proliferated ductal elements (adenoma)
embedded in a loose fibrous tissue
(fibroma).
Fibroadenoma
Fibroadenoma
• Teratoma
• contains recognizable mature or immature cells or tissues
representative of more than one germ-cell layer and
sometimes all three.
• Teratomas originate from totipotential stem cells such as
those normally present in the ovary and testis and
sometimes abnormally present in sequestered midline
embryonic rests.
• Such cells have the capacity to differentiate into any of the
cell types found in the adult body
• It may give rise to neoplasms that mimic bone, epithelium,
muscle, fat, nerve, and other tissues
Mature teratoma
 Exceptions to the general rules of
terminology
Lymphoma Mesothelioma
Melanoma Seminoma
Dysgerminoma Ependymoma
Astrocytoma Neurocytoma
-All are used for malignant neoplasms
-All tumors that end with “blastoma” are
malignent e.g nephroblastoma
medulloblastoma
• Hamartoma
• is a malformation that presents as a mass of
disorganized tissue indigenous to the particular site.
• Examples
• 1-liver hamartoma
disorganized hepatic cells, blood vessels, and
possibly bile ducts within the liver
• 2-lung hamartoma
islands of cartilage, bronchi, and blood vessels
• choristoma.
congenital anomaly composed of heterotopic
rest of cells.
• E.g
Pancreatic or adrenal rest
• a small nodule of well-developed and
normally organized pancreatic tissue may be
found in the submucosa of the stomach,
duodenum, or small intestine.
 Malignant Tumors
• 1-Carcinoma
• 2-Sarcoma
 Malignant Tumors
• Carcinomas
• Malignant neoplasms of epithelial cell origin
• Carcinomas that grow in a glandular pattern
are called adenocarcinomas.
• Carcinomas that produce squamous cells are
called squamous cell carcinomas.
• Sometimes the tissue or organ of origin can
be identified
• E.g renal cell adenocarcinoma
cholangiocarcinoma (bile duct
origin)
• Sarcomas
• Malignant neoplasms arising in mesenchymal
(non-epithelial) tissue or its derivatives
• E.g
Malignant tumor of fibrous tissue origin is a
fibrosarcoma
Malignant tumor of chondrocytes is a
chondrosarcoma
 Non-epithelial tumors
Tissue of origin Benign Malignent

Fibrous Fibroma Fibrosarcoma

Adipose Lipoma Liposarcoma

Cartilage Chondroma Chondrosarcoma

Bone Osteoma Osteosarcoma

Blood vessels Hemangioma Hemangio-

sarcoma
Lymph vessels Lymphangioma Lymphangio-
sarcoma
Synovium --- Synovial sarcoma

Mesothelium Mesothelioma Malignent

Mesothelioma
Meninges Meningioma Invasive
Meningioma
Smooth muscles leiomyoma leiomyosarcoma

Skeletal muscles Rhabdomyoma Rhabdomyo-

sarcoma
 Epithelial tumors
Type of origin Benign Malignent
Stratified squamous Squamous cell Squamous cell or
papilloma epidermoid carcinoma
Epithelial lining of Adenoma Adenocarcinoma
glands or ducts Papilloma Papillary carcinomas
cystadenoma Cystadenocarcinoma

Respiratory passages Bronchial adenoma

Bronchogenic carcinoma
Renal epithelium Renal tubular adenoma
Renal cell carcinoma
Liver cells Liver cell adenoma Hepatocellular carcinoma

Urinary tract epithelium (transitional)Urothelial Urothelial (Trasitional cell)

papilloma carcinoma
Tissue of origin Benign Malignent

Placental epithelium Hydatidiform mole Choriocarcinoma

Testicular epithelium - Seminoma

(germ cells) Embryonal carcinoma
 Others
Tissue of origin Benign Malignent

Tumors of melanocytes nevus Malignent melanoma

Hematopoietic cells --- leukemia

Lymphoid tissue --- lymphoma

 More Than One Neoplastic Cell Type-Mixed Tumors,
Usually Derived from One Germ Cell

Tissue of origin Benign Malignent

Salivary glands Pleomorphic Malignant mixed

adenoma (mixed tumor of salivary
tumor of salivary gland
gland)
Renal --- Wilms tumor
(nephroblastoma)
breast Fibroadenoma carcinosarcoma
 More Than One Neoplastic Cell Type Derived from
More Than One Germ Cell Layer-Teratogenous

Tissue of origin Benign Malignent

Totipotential Mature teratoma Immature teratoma

cells in gonads or (dermoid cyst) (teratocarcinoma)
in embryonic
rests
 Epidemiology
Major insight into the causes of
cancer can be obtained by
epidemiologic studies that relate
particular environmental , racial and
cultural influences to the occurrence
of specific neoplasms
• cancer incidence can be gained from national
incidence and mortality data.
• Over several decades, the death rates of
many forms of malignant neoplasia have
changed.
 Ten most common cancers among
Jordanian males(JCR-2007)
rank cancer %
1 colorectal 13.7
2 lung 11.9
3 prostate 7.7
4 Urinary bladder 7.7
5 leukemia 6.0
6 NHL 5.5
7 Stomach 4.7
8 Brain &CNS 4.0
9 Hodgkin lymphoma 3.9
10 larynx 3.5
 Ten most common cancers among
Jordanian females(JCR-2007)
rank cancer %
1 Breast 35.8
2 Colorectal 10.6
3 Corpus uteri 5.5
4 Leukemia 5.1
5 Thyroid 4.7
6 NHL 3.9
7 Ovary 3.5
8 Brain & CNS 2.6
9 Cervix 2.5
10 stomach 2.4
 Geographic & environmental
variables

Environmental factors that give rise

to somatic mutations are the
predominant cause of the most
common sporadic cancers
• This notion is supported by the geographic
differences in death rates from specific forms
of cancer.
• E.g
• death rates from breast cancer are about 4-
5X higher in the United States and Europe
compared with Japan.
• Conversely, the death rate for stomach
carcinoma in men and women is about 7X
higher in Japan than in the United States.
• Liver cell carcinoma is relatively infrequent in
the United States but is the most lethal
cancer among many African populations.
• Nearly all the evidence indicates that these
geographic differences are environmental
rather than genetic in origin.
• Nisei (second-generation Japanese living in
the United States) have mortality rates for
certain forms of cancer that are intermediate
between those of natives of Japan and of
Americans who have lived in the United
States for many generations. The two rates
come closer with each passing generation.
 Agents or groups of Agents Human cancer, Site and type for which
Reasonable evidence is available
Arsenic and arsenic compounds Lung, Skin, Hemagiosarcoma

Asbestos Lung, mesothelima; gastrointestinal

tract (esophagus, stomach, large
intestine)

Benzene Leukemia, Hodgkin lymphoma

Beryllium and beryllium compounds Lung

Cadmium and cadmium compounds Prostate

Chromium compounds Lung

Ethylene Oxide Leukemia
Nickel compounds Nose, Lung
Radon and its decay products Lung
Vinyl chloride Angiosarcoma, liver
 Age
-In general the frequency of cancer increases with
age
-Most cancer mortality occurs betweens ages
55 – 75
-The raising incidence may be explained by :
• Accumulation of somatic mutation associated
with malignant neoplasm
• Decline in immune competence that
accompany aging.
• Cancer causes slightly more than 10% of all
deaths among children younger than 15 years
• The major lethal cancers in children are:
1-Leukemia
2-Central nervous system tumors
3-Lymphomas
4-Soft tissue sarcomas
5-Bone sarcomas
Cancer incidence
 Heredity

• Hereditary predisposition for

cancer is well documented
• The inheritance of a single
mutant gene greatly increases
the risk of developing a tumor
• The influence of hereditary factors
is subtle and indirect.
• The genotype may influence the
likehood of one’s developing
environmentally induced cancers
Inherited predisposition to cancer
• 5% to 10% of all human cancers
• Modes of inheritance:
• 1-autosomal dominant
• 2-autosomal recessive of defective repair
genes
• 3-familial cancers
 Autosomal dominant
Gene Inherited predisposion
RB Retinoblastoma
p53 Li-Fraumeni syndrome
p16 Melanoma
APC Familial adenomatous
polyposis/colon cancer

NF1& NF2 Neurofibramatosis 1&2

BRCA 1 &BRCA 2 Breast & ovarian cancer
MEN 1 & RET Multiple endocrine
neoplasia 1 & 2

MSH 2 , MLH 1, MSH 6 Hereditary nonpolyposis colon

cancer

PATCH Nevoid basal cell carcinoma

syndrome
• Inherited Autosomal Recessive Syndromes of
Defective DNA Repair:
• Xeroderma pigmentosum
• Ataxia-telangiectasia
• Bloom syndrome
• Fanconi anemia
• autosomal recessive disorders is collectively
characterized by chromosomal or DNA
instability.
• E.g xeroderma pigmentosum, in which DNA
repair enzymes are defective icreasing the risk
for skin cancers.
 Familial cancers
• Virtually all the common types of cancers
that occur sporadically have been reported to
occur in familial forms.
• Examples :
• Breast cancer.
• Ovarian cancer.
• Pancreatic cancer.
• Colon cancer.
• Features that characterize familial cancers
include :
• 1-early age at onset.
• 2-tumors arising in two or more close
relatives of the index case.
• 3-multiple or bilateral tumors.
• Familial cancers are not associated with
specific marker phenotypes.
• E.g in contrast to the familial adenomatous
polyposis syndrome, familial colonic cancers
do not arise in preexisting benign polyps.
• In general, siblings have a relative risk
between 2-3X.
• The transmission pattern of familial cancers is
not clear.
• Segregation analysis of large families usually
reveals that predisposition to the tumors is
dominant, but multifactorial inheritance
cannot be easily ruled out.
• certain familial cancers can be linked to the
inheritance of mutant genes
 Acquired preneoplasic disorder
• certain clinical conditions are well recognized
to the development of malignant neoplasm
• Examples :
1. Persistent regenerative cell replication e.g:
Squamous cell carcinoma in the margins of
chronic skin fistula, long-unhealed skin wound
HCC in cirrhosis
2. Hyperplasic and dysplastic proliferation e.g :
Atypical endometrial hyperplasia
Bronchial dysplasia in chronic smokers
3. Chronic atrophic gastritis
- gastric carcinoma in pernicious anemia or following
long-standing Helicobacter pylori infection
4. Chronic ulcerative colitis
increased incidence of colorectal carcinoma
5. Leukoplakia of the oral cavity, vulva,--etc
increased risk of squamous cell carcinoma
6. Villous adenoma of the colon
high risk of transformation to colorectal carcinoma
 CHARACTERISTICS OF BENIGN AND
MALIGNANT NEOPLASMS
• The four fundamental features by which
benign and malignant tumors can be
distinguished are:
• 1- differentiation and anaplasia
• 2- rate of growth
• 3- local invasion
• 4- metastasis.
 Differentiation and Anaplasia
• The extent to which they resemble their normal
tissues(the parenchymal cells that constitute the
transformed elements of neoplasms )
morphologically and functionall
• The stroma does not aid in the separation of benign
from malignant tumors.
• The amount of stromal connective tissue
determines the consistency of a neoplasm.
• Certain cancers induce a dense, abundant fibrous
stroma (desmoplasia), making them hard, so-called
scirrhous tumors.
• Benign neoplasms are composed of well-
differentiated cells that closely resemble their
normal counterparts morphologically &
functionally.
• The better the differentiation of the cell, the more
completely it retains the functional capabilities
found in its normal counterparts
• In well-differentiated benign tumors, mitoses are
extremely scant in number and are of normal
configuration
Lipoma
Lipoma
Mature adipose tissue
(lipoma)
Leiomyoma
 Leiomyoma
smooth muscle bundles
• Malignant neoplasms are characterized by a
wide range of parenchymal cell
differentiation ranging from well
differentiated to completely undifferentiated.
• Between the two extremes lie tumors loosely
referred to as moderately differentiated.
• Benign neoplasms and even well-
differentiated cancers of endocrine glands
frequently elaborate the hormones
characteristic of their origin.
• Well-differentiated squamous cell carcinomas
elaborate keratin
• well-differentiated hepatocellular carcinomas
elaborate bile.
 Well differentiated squamous cell
carcinoma (keratin formation-arrow)
Normal colonic mucosa vs adenoma
Moderately differentiated
adenocarcinoma
Moderately differentiated
Liposarcoma
• Malignant neoplasms that are composed of
undifferentiated cells are said to be anaplastic.
• Lack of differentiation, or anaplasia, is considered a
hallmark of malignancy.
• The term anaplasia literally means "to form
backward." It implies dedifferentiation, or loss of
the structural and functional differentiation of
normal cells.
• At least some cancers arise from stem cells in
tissues; in these tumors failure of differentiation,
rather than dedifferentiation of specialized cells,
accounts for undifferentiated tumors.
• Malignent cells display :
• 1-marked pleomorphism (i.e., marked variation in size and
shape).
• 2-Nuclear hyperchromatic (darkly stained) and large.
• 3-increased nuclear-to-cytoplasmic(N/C) ratio
it may approach 1 : 1 instead of the normal 1 : 4 or 1 : 6.
• 4--Giant cells that are considerably larger than their
neighbors may be formed and possess either one enormous
nucleus or several nuclei. Anaplastic nuclei are variable and
bizarre in size and shape.
• 5-The chromatin is coarse and clumped, and nucleoli may be
of oustanding size.
• 6-mitoses are often numerous and distinctly
atypical; sometimes appear as tripolar or
quadripolar forms
• 7-anaplastic cells usually lose normal polarity
- cells fail to develop recognizable patterns of
orientation to one another
- cells may grow in sheets with total loss of
communal structures such as gland formations or
stratified squamous architecture.
Anaplasia
Anaplasia
Anaplastic tumor with abnormal
mitosis
Abnormal mitotic figures highly
suggestive of malignancy
• Dysplasia, a term used to describe disorderly but non-neoplastic
proliferation.
• Dysplasia is encountered principally in the epithelia.
• It is a loss in the uniformity of individual cells and in their architectural
orientation.
• Dysplastic cells exhibit considerable pleomorphism and often possess
hyperchromatic nuclei that are abnormally large for the size of the cell.
• Mitotic figures are more abundant than usual.
• Frequently the mitoses appear in abnormal locations within the
epithelium.
• In dysplastic stratified squamous epithelium, mitoses are not confined to
the basal layers, where they normally occur, but may appear at all levels
and even in surface cells.
• The usual progressive maturation of tall cells in the basal layer to
flattened squames on the surface may be lost and replaced by a
disordered scrambling of dark basal-appearing cells
• When dysplastic changes are marked and involve
the entire thickness of the epithelium, the lesion is
referred to as carcinoma in situ, a pre-invasive stage
of cancer
• the term dysplasia without qualifications does not
indicate cancer, and dysplasias do not necessarily
progress to cancer.
• Mild-to-moderate changes that do not involve the
entire thickness of epithelium may be reversible,
and with removal of the putative inciting causes,
the epithelium may revert to normal.
Carcinoma in situ. A Low-power view shows the entire thickness of the epithelium is replaced by
atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement
membrane is intact, and there is no tumor in the subepithelial stroma. B, High-power view shows
failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous
mitotic figures extending toward the surface.
 Rate of Growth
• Most benign tumors grow slowly & increase in size slowly over the span
of months to years.

• most cancers grow much faster

• exceptions do occur
• E.g
• the rate of growth of leiomyomas (benign smooth muscle tumors) of the
uterus is influenced by the circulating levels of estrogens.
• They may increase rapidly in size during pregnancy then cease growing,
becoming largely fibrocalcific, after menopause.
• Other influences, such as adequacy of blood supply or pressure
constraints, also may affect the growth rate of benign tumors.
• Adenomas of the pituitary gland locked into the sella turcica have been
observed to shrink suddenly.
• The rate of growth of malignant tumors correlates in
general with the level of differentiation.
• Rpidly growing tumors tend to be poorly
differentiated.
• Most cancers progressively enlarge over time, some
slowly, others rapidly.
• Rapidly growing malignant tumors often contain
central areas of ischemic necrosis because the tumor
blood supply, derived from the host, fails to keep
pace with the oxygen needs of the expanding mass
of cells.
 Local Invasion
• A benign neoplasm remains localized at its site of origin.
• It does not have the capacity to infiltrate, invade, or
metastasize to distant sites, as do malignant neoplasms.
• Benign tumors are well encapsulated.
• E.g
• fibromas and adenomas slowly expand & develop an
enclosing fibrous capsule that separates them from the host
tissue.
• This capsule probably is derived from the stroma of the host
tissue as the parenchymal cells atrophy under the pressure
of the expanding tumor. The stroma of the tumor itself also
may contribute to the capsule
Well encapsulated schwannoma
Hepatic adenoma(encapsulated)
Liver adenoma(encapsulated)
low magnification
Liver adenoma(encapsulated)
higher magnification
 Fibroadenoma of breast
encapsulated small tumor is sharply demarcated from the whiter breast tissue.
• Not all benign neoplasms are encapsulated.
• E.g the leiomyoma of the uterus is discretely demarcated
from the surrounding smooth muscle by a zone of
compressed and attenuated normal myometrium, but there
is no well-developed capsule.
• A well-defined cleavage plane exists around these lesions.
• A few benign tumors are neither encapsulated nor discretely
defined e.g vascular benign neoplasms of the dermis or liver
(hemangioma).
• Although encapsulation is the rule in benign tumors, the lack
of a capsule does not imply that a tumor is malignant.
 Uterine leiomyoma
well-defined but not encapsulated
Liver Hemangioma
Hemangioma of skin
• Malignent tumors do not develop well-
defined capsules
• They grow by progressive infiltration,
invasion, destruction, and penetration of the
surrounding tissue
• The infiltrative mode of growth makes it
necessary to remove a wide margin of
surrounding normal tissue when surgical
excision of a malignant tumor is attempted.
Infiltrating breast carcinoma
 Metastasis
• The term metastasis connotes the development of
secondary implants (metastases) discontinuous
with the primary tumor, in remote tissues
• The properties of invasiveness and metastasis
identify a neoplasm as malignant than any of the
other attributes of a tumor.
• Not all cancers have equivalent ability to
metastasize.
• At one extreme are basal cell carcinomas of the skin
and most primary tumors of the CNS that are highly
invasive in their primary sites of origin but rarely
metastasize.
• At the other extreme are osteogenic
sarcomas, which usually have metastasized
to the lungs at the time of initial discovery.
• Approximately 30% of newly diagnosed
patients with solid tumors (excluding skin
cancers other than melanomas) present with
clinically evident metastases.
• An additional 20% have occult (hidden)
metastases at the time of diagnosis.
• Tendency of metastasis is more with:
• 1-anaplasia
• 2-the larger the primary neoplasm
• Exceptions:
-Extremely small cancers have been known to
metastasize e.g choriocarcinoma
and, conversely, some large and ominous-
looking lesions may not spread.
 Pathways of Metastasis :
• (1) seeding within body cavities.
• (2) lymphatic spread.
• (3) hematogenous spread .
• Spread by seeding occurs when neoplasms invade a natural
body cavity.
• This mode of dissemination is particularly characteristic of
cancers of the ovary, which often cover the peritoneal
surfaces widely.
• The implants literally may glaze all peritoneal surfaces and
yet not invade the underlying parenchyma of the abdominal
organs.
• Neoplasms of the CNS, such as a medulloblastoma or
ependymoma, may penetrate the cerebral ventricles and be
carried by the cerebrospinal fluid to reimplant on the
meningeal surfaces, either within the brain or in the spinal
cord.
• Lymphatic spread is more typical of carcinomas,
• hematogenous spread is favored by sarcomas.
• There are numerous interconnections between the
lymphatic and vascular systems, and so all forms of cancer
may disseminate through either or both systems.
• The pattern of lymph node involvement depends principally
on the site of the primary neoplasm and the natural
pathways of lymphatic drainage of the site.
• Lung carcinomas arising in the respiratory passages
metastasize first to the regional bronchial lymph nodes, then
to the tracheobronchial and hilar nodes.
• Carcinoma of the breast usually arises in the upper outer
quadrant and first spreads to the axillary nodes.
• Medial breast lesions may drain through the chest wall to
the nodes along the internal mammary artery.
• In both instances, the supraclavicular and infraclavicular
nodes may be seeded.
• In some cases, the cancer cells seem to traverse the
lymphatic channels within the immediately proximate nodes
to be trapped in subsequent lymph nodes, producing so-
called skip metastases.
• The cells may traverse all of the lymph nodes ultimately to
reach the vascular compartment via the thoracic duct.
• A "sentinal lymph node" is defined as the first
lymph node in a regional lymphatic basin that
receives lymph flow from a primary tumor.
• It can be delineated by injection of blue dyes
or radiolabelled tracers.
• Biopsy of sentinal lymph nodes allows
determination of the extent of spread of
tumor and can be used to plan treatment
• Hematogenous spread is the most feared consequence of a
cancer.
• It is the favored pathway for sarcomas, but carcinomas use it
as well.
• Arteries are penetrated less readily than are veins.
• With venous invasion the blood-borne cells follow the
venous flow draining the site of the neoplasm with tumor
cells often stopping in the first capillary bed they encounter.
• Since all portal area drainage flows to the liver, and
all caval blood flows to the lungs, the liver and lungs
are the most frequently involved secondary sites in
hematogenous dissemination.
• Cancers arising near the vertebral column often
embolize through the paravertebral plexus
• this pathway probably is involved in the frequent
vertebral metastases of carcinomas of the thyroid
and prostate.
• Certain carcinomas have a propensity to
invade veins.
• Renal cell carcinoma often invades the renal
vein to grow in a snakelike fashion up the
inferior vena cava, sometimes reaching the
right side of the heart.
• Hepatocellular carcinomas often penetrate
portal and hepatic radicles to grow within
them into the main venous channels.
 Etiology of cancer
Carcinogenic agents
There are three classes of cancriogenic agents
1. Chemicals
2. Radiant energy
3. Microbial agents
 Chemical Carcinogens
• Hundreds of chemicals have been shown to
be carcinogenic in animals.
• Chemical carcinogens are divided into:
1. Direct- acting agents
2. Indirect- acting agents
 Direct acting chemicals
• In general weak carcinogens

• Require no metabolic conversion to become

carcinogenic
 Indirect acting chemicals
• These chemicals require metabolic
conversion to an ultimate carcinogen before
they become active.
Direct- acting Type of cancer
carcinogens
Alkylating Agents leukemia
β- Propiolactone lymphoma
Dimethyl sulfate Hodgkins
lymphoma
Diepoxybutane
Anticancer drugs Ovarian tumors
(cyclophosphami
de, chlorambucil,
nitrosoureas,
and others)
Acylating agents
1-Acetyl-
imidazole
Dimethylcarbam
yl chloride
Indirectly-acting agents source Type & site of cancer

Polycyclic and hetercyclic Smoked meats & fish

armotic hydrocarbons
Benz(a)anthracene
Benzo(a)pyrene Combustion of tobacco Lung cancer
Dibenzanthracene
3-Methylcholanthrene
dimethylbenz(a)anthracen
e
Aromatic amines, amides,
amides, azo dyes
2- Napththylamine (β- Aniline dye Bladder cancer
naphthylamine) Rubber industry
Benzidine
2- Acetylaminofluorene
 source Type & site of cancer

Aflatoxin B1 Aspergillus Hepatocellular carcinoma

Betel nuts chewing Oral carcinoma

benzene Paint,rubber,dry cleaning Leukemia,lymphoma

Arsenic compounds Electrical Lung,skin angiosarcoma

devices,herbicides,fungici
des
asbestos Floor tiles,roofing Mesothelioma
paper,brakes lining Lung carcinoma
Cadmium compounds Batteries,metal coating Prostate cancer

Nitrosamine and amides Food preservatives

Vinyl chloride Adhesive for plastics Liver angiosarcoma

nickel Nickelplating,ceramics, Nose & lung cancer
Batteries
Chromium compounds Paints,preservatives, Lung cancer
pigments
Insecticides, fungicides
 Mechanism of action of chemical
carcinogens
• Chemicals that have electrophile groups form
chemical adducts with DNA,cellular proteins
and RNA
• RAS and p53 genes are important targets of
chemical carcinogens
• Carcinogenicity of some chemical can be
augmented by subsequent adminstration of
promoters(hormones,drugs,phenols---)
 Radiation carcinogenesis
• 1-ultraviolet light of sun rays
• 2-x-rays
• 3-nuclear fission
• 4-radionuclides
• Risk factors :
• 1-fair-skin
• 2-increased exposure to sun light
cumulative exposure
intense intermittent exposure
• 3-efficiency of DNA repair system
 Viral & microbial oncogenesis
• RNA & DNA viruses have been linked with
human cancer.
• The study of oncogenic retroviruses in animals
has provided spectacular insight into the
genetic basis of cancer.
• HTLV-1 is associated with a form of T-cell
Leukemia/lymphoma that is endemic in
certain parts of Japan & Caribbeans.
 Oncogenic DNA Viruses
• 1-Human papilloma virus (HPV)
• 2-Epstein Barr virus (EBV)
• 3-Kaposi sarcoma herpes virus (KSHV)
Human herpes virus 8
• 4-Hepatitis B virus(HBV)
 1-Human papilloma virus (HPV)

• HPV has been associated with:

• 1- benign squamous
papilloma(warts)(HPV1,2,4,7).
• 2- genital warts(HPV 6,11).
• 2- cervical cancer (HPV 16 & 18).
• 3- oropharyngeal cancer.
• The oncogenic ability of HPV is related to the
expression of two viral oncoproteins, E6 and
E7.
• 1-they bind to RB and p53
• 2-inhibit CDKIs p21 &27.
• E6 and E7 from high- risk HPV also activate
cyclins E & A.
 2-Epstein Barr virus (EBV)
• EBV has been implicated in the
pathogenesis of :
• 1-Burkitt lymphomas
• 2- lymphomas in immunosuppressed
individuals with HIV infection or organ
transplantation
• 3- some forms of Hodgkin lymphoma
• 4- Nasopharyngeal carcinoma
• EBV gene(LMP-1) products contribute to
oncogenesis by stimulating a normal B-cell
proliferation pathway.
• LMP-1 prevents apoptosis through BCL-2
• EBV gene EBNA-2 activates cyclin D.
• vIL-10 prevents macrophages & monocytes
from activating T-cells & killing the infected
cells.
• Concomitant compromise of immune
competence allows sustained B-cell
proliferation and eventually development of
lymphoma with occurrence of additional
mutations such as t(8,14) leading to activation
of the MYC gene.
 3-Hepatitis B & Hepatitis C viruses
• 70%-85% of hepatocellular carcinomas worldwide are
due to infection with HBV or HCV.
• The oncogenic effects of HBV and HCV are
multifactorial but the dominant effect seems to be
immunologically mediated chronic inflammation,
hepatocellular injury, stimulation of hepatocyte
proliferation, and production of reactive oxygen
species that can damage DNA.
• The HBx protein of HBV and the HCV core protein can
activate a variety of signal transduction pathways that
may also contribute to carcinogenesis.
 4-Helicobacter Pylori
• H. pylori infection has been implicated in both
1-Gastric adenocarcinoma
2-MALT lymphoma.
• The mechanism of H. pylori-induced gastric cancers is
multifactorial, including Immunologically mediated
chronic inflammation, stimulation of gastric cell
proliferation, and production of reactive oxygen
species that damage DNA.
• H.pylori pathogenicity genes, such as CagA, may also
contribute by stimulating growth factor pathway
• It is thought that H.pylori infection leads to polyclonal
B-cell proliferations and that eventually a monoclonal
B-cell tumor (MALT lymphoma) emerges as a result of
accumulation of mutations.
 Grading of Cancer
• The grading of a cancer attempts to establish
some estimate of its aggressiveness or level
of malignancy.
• It is based on :
• 1-the cytologic differentiation of tumor cells.
• 2-the number of mitoses within the tumor.

• The cancer may be classified as grade I, II, III,

or IV, in order of increasing anaplasia.
• Criteria for the individual grades vary with
each form of neoplasia .
• Difficulties in establishing clear-cut criteria
have led in some instances to descriptive
characterizations as :
• Well-differentiated
• Moderately-differentiated.
• Poorly-differentiated.
• Highly anaplastic.
 Staging of cancer
• Staging of cancers is based on :
• 1-the size of the primary lesion.
• 2-its extent of spread to regional lymph
nodes.
• 3-the presence or absence of metastases.
• This assessment is usually based on clinical
and radiographic examination (CTscan & MRI)
and in some cases surgical exploration.
• Two methods of staging are currently in use:
• 1-the TNM system (T, primary tumor; N,
regional lymph node involvement; M,
metastases)
• 2-the AJC (American Joint Committee)
system..
• In the TNM system, T1, T2, T3, and T4
describe the increasing size of the primary
lesion;
• N0, N1, N2, and N3 indicate progressively
advancing node involvement;
• M0 and M1 reflect the absence or presence
of distant metastases.
• In the AJC method, the cancers are divided
into stages 0 to IV, incorporating the size of
primary lesions and the presence of nodal
spread and of distant metastases.
• Staging has proved to be of greater clinical
value.
 Staging of breast carcinoma
stage Tumor Lymph Nodes Metastasis Prognosis
5-yr survival

0 DCIS or LCIS 0 M0 92%

I Invasive 0 M0 87%
carcinoma 2
cm or less in
diameter
< or = 5cm < or 3 M0 75%
II
> 5cm 0 M0
III < or = 5 cm 4 or more Skin or chest 46%
>5 cm Any number wall
Any size 10 or more involvement

IV Any size Any number M1 13%

 TNM Staging of Colon Cancers
• Tumor
• T0 none evident
• Tis = in situ (limited to mucosa)
• T1 = invasion of lamina propria or submucosa
• T2 = invasion of muscularis propria
• T3 = invasion through muscularis propria into subserosa or
nonperitonealized perimuscular tissue
• T4 = invasion of other organs or structures
• Lymph Nodes (N)
• 0 = none evident
• 1 = 1 to 3 positive pericolic nodes
• 2 = 4 or more positive pericolic nodes
• 3 = any positive node along a named blood vessel
• Distant Metastases (M)
• 0 = none evident
• 1 = any distant metastasis
• 5-Year Survival Rates
• T1 = 97%
• T2 = 90%
• T3 = 78%
• T4 = 63%
• Any T; N1; M0 = 66%
• Any T; N2; M0 = 37%
• Any T; N3; M0 = data not available
• Any M1 = 4%
 Laboratory Diagnosis of Cancer
• 1-Morphologic Methods :
• H&E stain
• A-excision or biopsy.
• B-fine-needle aspiration.
• C-cytologic smears (Papanicolaou) .
• D-Frozen sections.
• Immunocytochemistry:
• Cytokeratin
• prostate-specific antigen (PSA) =prostate
carcinoma.
• estrogen receptors =breast cancers.
• Flow cytometry
• is used routinely in the classification of
leukemias and lymphomas.
• Fluorescent antibodies against cell surface
molecules and differentiation antigens are
used to obtain the phenotype of malignant
cells.
• 2-Tumor Markers :
• A-PSA
• Prostatic carcinoma can be suspected when
elevated levels of PSA are found in the blood.
• Although PSA levels are often elevated in
cancer, PSA levels also may be elevated in
benign prostatic hyperplasia
• PSA test suffers from both low sensitivity and
low specificity.
• B-carcinoembryonic antigen (CEA).
• carcinomas of the colon, pancreas, stomach, and breast.
• C-α-fetoprotein.
• produced by :
• 1- hepatocellular carcinomas,
• 2-yolk sac remnants in the gonads,
• 3-teratocarcinomas
• 4-embryonal cell carcinomas.
• 5-neural tube defect of the fetus
• CEA and α-fetoprotein assays lack both specificity and
sensitivity