Neoplasia

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Helpful References for the
Students
 Robbins textbook of pathology
 http://www.pathguy.com/lectures/neo-1.htm
(Ed’s pathology notes)
 Webpath (General Pathology)

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Major topics of neoplasia
lectures (8 hours)
1. Introduction & Definitions
2. Biologic behaviour of neoplasms
3. Histogenesis
4. Nomenclature
5. Incidence & Distribution of Cancer
6. Oncogenesis
7. Grading and Staging of Cancer
8. Clinical findings related to neoplasms
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INTRODUCTION &
DEFINITIONS
 Neoplasia (Latin, new growth) is an abnormality of
cellular differentiation, maturation, and control of
growth.
 Neoplasms are commonly recognized by the
formation of masses of abnormal tissue (tumors).
 The term tumor can be applied to any swelling- and
in that context is one of the cardinal signs of
inflammation-but today it is used most commonly to
denote suspected neoplasm.

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 1 out of about every 5 persons in the US who
die this year will die of tumors (about 500,000
total).
 ‘Tumor’: literally any swelling. Galen
distinguished tumors that are:
• ‘natural’: pregnant uterus
• ‘unnatural’: pus, bony callus
• ‘contrary to nature’: what we now know as
neoplasms ("new growths")

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 Neoplasms are benign or malignant depending on
several features, chiefly the ability of malignant
neoplasms to spread from the site of origin.
 Benign neoplasms grow but remain localized.
 Cancer denotes a malignant neoplasm (the term is
thought to derive from the way in which the tumor
grips the surrounding tissues with claw-like
extensions, much like a crab). This feature led
Hippocrates to call such tumors karkinoma after
karkinos.

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 A neoplasm is an abnormal mass of
tissue, the growth of which exceeds and
is uncoordinated with that of the
surrounding normal tissues and persists
in the same excessive manner after
cessation of the stimuli that evoked the
change.
Rupert Willis

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 "Oncology" is the study of tumors. In current usage, an
oncologist is an internist or surgeon who specializes in the
administration of cancer chemotherapy.
 In modern usage, a tumor/neoplasm may be thought of as an
attempt by the body under some stimulus to make some new
sort of organ. (It develops in the wrong shape, in the wrong
place, and it persists after the initiating stimulus is removed.)
Tumors are like organs:
 All have parenchyma and stroma.

 Cells usually look similar to cells in the organ where the tumor
arose.
 Cells will continue to perform some of the functions of the parent
organ.
Tumors are different from organs:
 They don't contribute to the homeostasis of the body.

 They usually grow more rapidly than surrounding tissues.

 Some benign and all malignant tumors never cease to grow.

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BIOLOGIC BEHAVIOR OF
NEOPLASMS
 The biologic behavior of neoplasms constitutes a
spectrum with two extremes: Benign and Malignant.
 Benign: benign neoplasms grow slowly and do not
invade surrounding tissues or spread to distant sites
(ie, no metastasis).
 Benign neoplasms are rarely life-threatening but
may become so because of hormone secretion or
critical location, eg, a benign neoplasm can cause
death if it arises in a cranial nerve and compresses
the medulla spinalis.

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 Malignant: Malignant neoplasms grow
rapidly, infiltrate and destroy surrounding
tissues, and metastasize throughout the
body, often with lethal results.
 Between Benign and Malignant; is a smaller
third group of neoplasms that are locally
invasive but have low metastatic potential.
 Such neoplasms are borderline neoplasms or
locally aggressive neoplasms or low-grade
malignant neoplasms. An example is basal
cell carcinoma of the skin and serous
borderline neoplasm of the ovaries.
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Benign Malignant

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 1. Rate of Growth:

 Malignant neoplasms generally grow more rapidly

than benign ones, but there is no critical rate that
distinguishes malignant from benign.
 Assessment of the growth rate is based upon
clinical information (eg, change in size of the mass
in serial examinations).
 On microscopic examination, the number of mitotic
figures and the metabolically active appearance of
nuclei (enlarged, dispersed chromatin, large
nucleoli) correlate positively with the growth rate of
the neoplasm.

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 2. Size:

 The size of a neoplasm usually has no bearing

on its biologic behavior.
 Many benign neoplasms become very large;
conversely, highly malignant neoplasms may be
lethal by virtue of extensive dissemination even
though the original primary tumor is still small.
 In a few neoplasms (such as endocrine
neoplasms), however, size is the deciding factor
in distinguishing benign from malignant growths.

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 3. Degree of Differentiation:

 Denotes the degree to which a neoplastic cell

resembles the normal mature cells of the tissue in
question; this meaning is distinct from the more
general use of the word to describe passage of a cell
down a particular maturation pathway.
 Benign neoplasms are fully (well) differentiated, ie,
they closely resemble normal tissue.
 Malignant neoplasms, show variable degrees of
differentiation and frequently demonstrate little
resemblance to normal tissue (ie, they are poorly
differentiated).

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 In anaplasia, the neoplastic cells have no
morphologic resemblance whatsoever to
normal tissue.
 The importance of these individual criteria
varies with different neoplasms. For example,
the mitotic rate is the major factor
distinguishing benign from malignant smooth
muscle neoplasms in the uterus; in many other
neoplasms, the mitotic rate is of little
relevance.

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 Anaplastic
Carcinoma

Well-differentiated
SCC

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 4. Changes in Deoxyribonucleic Acid (DNA):

 Neoplasms are associated with abnormalities in their DNA

content; this abnormality increases with the degree of
malignancy.
 The degree of hyperchromatism (increased staining of the
nucleus) provides a crude assessment of DNA content on
microscopic examination; malignant cells are hyperchromatic.
 When measured precisely by flow cytometry, the DNA content of
malignant cells correlates well with the degree of malignancy in
malignant lymphoma, bladder neoplasms, and astrocytic
neoplasms.
 Cytogenetic studies demonstrating aneuploidy and polyploidy
also are indicative of malignancy.
 Molecular techniques that demonstrate clonal deletions,
translocations, or abnormalities of oncogene expression are of
increasing value.

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 One measure of malignancy is aneuploidy by
flow cytometry.
The worse the neoplasm, the greater the degree of
aneuploidy and the worse the prognosis.

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The malignant looking tumor
cell has;
 Increased nuclear DNA
 Increased nuclear/cytoplasmic ratio
 Hyperchromatic nucleus
 Coarsening of chromatin
 Wrinkled nuclear edges
 Multinucleation
 Macronucleoli
 Numerous and bizarre mitotic figures
 Failure to mature along normal functional lines
 Cells of widely varying sizes
 Loss of orientation of cells to one another

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 5. Infiltration and Invasion:

 Benign neoplasms are generally non-

infiltrative and are surrounded by a capsule of
compressed and fibrotic normal tissue.
 Malignant neoplasms, have infiltrating
margins. Some exceptions to this rule exist,
and some benign neoplasms (eg, granular
cell tumor, dermatofibroma, and carcinoid
tumors) lack a capsule and have an
infiltrative margin.

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Malignant Tumor

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 6. Metastasis:

 The occurrence of metastasis (noncontiguous or

distant growth of tumor) is absolute evidence of
malignancy.
 The major reason for distinguishing benign from
malignant neoplasms is to be able to predict their
ability to metastasize before they do so.
 Gross and microscopic examination of a neoplasm
usually enables a trained pathologist to classify
most neoplasms as benign or malignant.
 In some instances, however, this identification is
difficult, and the only reliable evidence of a
neoplasm's biologic behavior is the occurrence of
metastasis; about 90% of pheochromocytomas are
benign, but there are no reliable criteria for
identifying the 10% that will metastasize.
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 Neoplasms can spread by seeding along body cavities, and this
pattern is more typical for carcinomas than other neoplasms.
 Note the multitude of small tan tumor nodules seen over the
peritoneal surface of the mesentery shown here.
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 Both lymphatic and hematogenous spread of malignant
neoplasms is possible to distant sites.
 Here, a breast carcinoma has spread to a lymphatic in the lung.

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CELL OR TISSUE OF ORIGIN
(Histogenesis)
 Neoplasms are classified and named chiefly
on the basis of their presumed cell of origin.
These cells have different potentials for
further development into various cell types.

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1. Neoplasms of Totipotent Cells:

 The prototype of the totipotent cell-ie, a cell that is

capable of differentiating (maturing) into any cell
type in the body-is the zygote, which gives rise to
the embryo, and the eventual fetus. In postnatal life,
the only totipotent cells in the body are the germ
cells.
 These are most commonly found in the gonads but
also occur in the retroperitoneum, mediastinum, and
pineal region.
 Germ cell neoplasms
 Teratomas

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The microscopic appearance of a teratoma is seen here. The three
embryologic germ layers are represented by skin (ectoderm),
cartilage (mesoderm) and a colonic gland (endoderm)

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2. Neoplasms of Embryonic Pluripotent Cells:

 Pluripotent cells can mature into several different cell types,

and the corresponding neoplasms have the potential for
formation of diverse structural elements; neoplasms of the
renal anlage cells (nephroblastoma) commonly differentiate
into structures resembling renal tubules and less often into
rudiments of muscle, cartilage, and bone. These neoplasms
are generally called embryomas or blastomas.
 Embryonic pluripotent cells are found only in the fetal period
and during the first few years of postnatal life.
 The corresponding neoplasms usually occur in early
childhood and only rarely in adults.
 Blastomas may be completely undifferentiated -ie, are
composed of small, malignant, primitive- appearing,
hyperchromatic cells- or may show evidence of differentiation.
Evidence of differentiation generally signifies less malignant
biologic behavior. 36
 Wilm's tumor microscopically resembles the primitive
nephrogenic zone of the fetal kidney, with primitive glomeruloid
structures and a cellular stroma.

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3. Neoplasms of Differentiated Cells:

Differentiated, adult-type cells make up most

of the cells in the body in postnatal life. They
show a restricted potential for differentiation,
as seen when they undergo metaplasia. Most
human neoplasms are derived from
differentiated cells.

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Nomenclature of Neoplasms
of Differentiated Cells
 1. Epithelial neoplasms:

 A benign epithelial neoplasm is called an adenoma if it arises

within a gland (eg, thyroid adenoma, colonic adenoma) or a
papilloma (Latin, papilla = nipple) when arising from an epithelial
surface.
 Papillomas may arise from squamous, glandular, or transitional
epithelium (eg, squamous papilloma, intraductal papilloma of the
breast, and transitional cell papilloma, respectively).
 Not uncommonly, descriptive adjectives are incorporated in the
nomenclature; eg, colonic adenomas may be villous, tubular or
tubulovillous.

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 Malignant epithelial neoplasms are called
carcinomas
 Adenocarcinomas= if derived from glandular
epithelia;
 Squamous cell carcinoma & Transitional cell
carcinoma= if originating in those kinds of epithelia.
 Names may also include the organ of origin and
often an adjective as well.
 eg, clear cell adenocarcinoma of the kidney, Serous
papillary cystadenocarcinoma of ovary, papillary
adenocarcinoma of the thyroid, verrucous
squamous carcinoma of the larynx.

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 You can add adjectives as appropriate.
 papillary
 well-differentiated
 keratinizing
 moderately well-differentiated
 mucin-producing
 poorly differentiated
 follicular
 pleomorphic
 signet-ring cell
 cystic (cysto-)
 scirrhous
 desmoplastic
 medullary
 comedo-

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Papillary Carcinoma

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 2. Mesenchymal neoplasms:

 Benign mesenchymal neoplasms are named after the

cell of origin (a Greek or Latin word is used) followed by
the suffix -oma. The names of these tumors may contain
the organ of origin and an adjective, eg, cavernous
hemangioma of the liver.

 Malignant mesenchymal neoplasms are named after the

cell of origin, to which is added the suffix -sarcoma.
 Again, adjectives are commonly used; liposarcomas are
classified as sclerosing, myxoid, round cell, or
pleomorphic.

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fibro-: fibroblasts
myxo-: myxoid tissue (Wharton's jelly, etc.)
chondro-: cartilage
osteo-: osteoblasts
lipo-: fat
chordo-: notochord remnants
leiomyo-: smooth muscle
rhabdomyo-: striated muscle
schwanno- / neurilemmo- : nerve sheath
(perineurium)
neurofibro-: nerve sheath (endoneurium)
hemangio-: blood vessels
lymphangio-: lymphatics
glomangio-: glomus
synovio-: synovium
mesothelio-: mesothelium
meningio-: arachnoid granulation
lympho-: lymphocytes
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Osteosarco
ma

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Liposarcom
a
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 A handful of tumors that are thoroughly
malignant have "benign sounding" names.
You will just have to learn these!

 lymphoma
 mesothelioma
 myeloma ("multiple", plasma cell)
 astrocytoma
 carcinoid
 glioma (micro-, oligodendro-)
 ependymoma
 seminoma
 hepatoma (today, "hepatocellular carcinoma")
 melanoma
 dysgerminoma
 leukemia

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 3. Leukemias and Lymphomas
 Neoplasms of blood-forming organs are
called leukemias. These disorders are all
considered malignant, although some exhibit
a slower clinical course than others.
 Leukemias are classified on the basis of their
clinical course (acute or chronic) and cell of
origin (lymphocytic, granulocytic-myelocytic,
monocytic, etc).
 Leukemias are characterized by the presence
of neoplastic cells in bone marrow and
peripheral blood; they rarely produce
localized tumors.
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Myeloproliferative
syndromes: Pathogenesis

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 Lymphomas-Histologic types

Small Intermediate
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 Histologic types

Diffuse Follicular

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 4. Mixed tumors
 Neoplasms composed of more than one
neoplastic cell type are called mixed tumors.
 two epithelial components, as in
adenosquamous carcinoma;
 two mesenchymal components, as in malignant
fibrous histiocytoma; or
 an epithelial and a mesenchymal component, as
in carcinosarcoma of the lung and malignant
mixed müllerian tumor (MMMT) of the uterus.

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 MMMT

Slightly off center is a neoplastic gland with three lumena.

Surrounding the gland are cells with enlarged eosinophilic
cytoplasm admixed with smaller nuclei.
The cells with eosinophlic cytoplasm exhibit skeletal muscle
differentiation.
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 Neoplasms derived from two separate cell lines
that coincidentally became neoplastic at the
same time, or neoplasms of a single multipotent
cell type that then differentiates along more than
one pathway (Collusion tumors).
 In the case of benign mixed tumors such as
fibroadenoma of the breast, most investigators
believe that only the epithelial (adenoma)
component is neoplastic and that fibrous tissue
represents some form of reaction to the
adenoma cells.

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Fibroadenoma

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 5. Neoplasms those cell of origin is unknown.
 When the cell of origin is unknown, the name of the
person who first described the neoplasm is
commonly used to name the tumor.
 As the histogenesis of these neoplasms is clarified,
the name is often changed: Wilms' tumor is now
called nephroblastoma, and Grawitz's tumor is
better known as renal adenocarcinoma.
 Some neoplasms of uncertain histogenesis are
named descriptively, eg, granular cell tumor (from
Schwann cells?), alveolar soft part sarcoma (from
rhabdomyoblasts?).

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 A hamartoma is "not a tumor, but is a
developmental anomaly“, which contains the
same tissues as the organ in which it is
found, but in the wrong proportions.
 A choristoma ("ectopia") is a mass of normal
tissue in an abnormal location.
 A tumor which ends in blastoma is
composed of cells that resemble those seen
in a developing organ.
 Blastomas are generally malignant.

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Hamartoma
(LUNG)
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INCIDENCE &
DISTRIBUTION OF CANCER
IN
 HUMANS
Incidence & Mortality Rates
 Cancer is the second overall leading cause of death
(after ischemic heart disease) in the world. The
incidence continues to rise, probably reflecting the
increasing average age of the population.
 Major Factors Affecting Incidence
 The presence or absence of any of the many factors
influencing the incidence of cancer must be
established during history taking and physical
examination of a patient thought to have cancer.

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 Sex:
 Prostate cancer in men and uterine cancer
and breast cancer in women are obviously
sex-specific.
 In other types of cancer, the reasons for the
difference in incidence between the sexes
are less evident.
 For example, cancer of the oropharynx,
esophagus, and stomach is more than twice
as common in men, but cancers of the
gallbladder and thyroid and malignant
melanoma are more frequent in women.

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 Age:
 The frequency of occurrence of most types of
cancer varies greatly at different ages.
 Carcinoma is rare in children, but some
leukemias, primitive neoplasms (blastomas) of
the brain, kidney, and adrenal, malignant
lymphomas, and some types of connective
tissue tumors are relatively common. Most of
these childhood neoplasms grow rapidly and
are composed of small, very primitive cells with
large, hyperchromatic nuclei, scant cytoplasm,
and a high mitotic rate.

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 In adults, carcinomas make up the largest group of
malignant tumors; they result from neoplastic change
occurring in mature adult-type epithelial tissues.
Sarcomas occur in adults but are less common than
carcinomas.
 Neoplasms of the hematopoietic and lymphoid cells
(leukemias and lymphomas) occur at all ages. The
incidence of different types of these neoplasms varies
with age; acute lymphoblastic leukemia is common in
children, whereas chronic lymphocytic leukemia
occurs more often in the elderly.

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 Occupational, Social, and Geographic Factors:
 Occupational factors have been mentioned with
reference to an increased risk of bladder cancer in
workers in the dye industry and lung cancer in
certain miners.
 Because the risk is so high in certain industries, an
occupational history is an essential part of a full
medical examination.
 Similarly, such social habits as cigarette smoking
represent risk factors for development of several
types of cancer, and the physician must evaluate
the amount of exposure to these factors during
history taking.

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 Childbearing
 Circumcision

 Socioeconomic status

 Geographic area or country

 Eating and drinking habbits,

 Foodstufs...

are the other factors affecting the development

of specific types of cancer

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 Family History:

 A few cancers have a simple pattern of

genetic inheritance and those that do are so
striking that they warrant careful study of
relatives of known cases
 (eg, retinoblastoma, polyposis coli and
carcinoma of the colon, medullary carcinoma
of the thyroid, hereditary breast-ovary
carcinoma syndromes).

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 Inherited cancer
syndromes
 Li-Fraumeni syndrome - p53, breast,
bladder, sarcoma
 Familial retinoblastoma - Rb, retinoblastoma
 Xeroderma pigmentosum - XPAC, skin
cancer
 Hereditary Breast-Ovary Cancer (HBOC)-
BRCA1, BRCA2

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 History of Associated Diseases:

 Perhaps the most important finding in the

history of a patient with suspected cancer is a
record of diagnosis or treatment of previous
cancer.
 A positive history of cancer greatly increases
the chances that the current illness
represents either a metastasis (which may be
delayed many years) or a second primary
tumor.

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ETIOLOGY of NEOPLASIA

 Neoplasia is an abnormality of cell growth and

multiplication characterized by the following
features:
 (1) excessive cellular proliferation that typically
but not invariably produces an abnormal mass, or
tumor;
 (2) uncoordinated growth occurring without any
apparent purpose; and
 (3) persistence of excessive cell proliferation
and growth even after the inciting stimulus that
evoked the change has been removed -ie, neoplasia
is an irreversible process.

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 At a molecular level, neoplasia is a disorder
of growth regulatory genes (proto-oncogenes
and tumor suppressor genes).
 It develops in a multistep fashion, such that
different neoplasms, even of the same
histologic type, may show different genetic
changes.

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Monoclonal Origin

According to the concept of monoclonal origin, the

initial neoplastic change affects a single cell, which
then multiplies and gives rise to the neoplasm.

The monoclonal origin of neoplasms has been clearly

shown in neoplasms of B lymphocytes (B-cell
lymphomas and plasma-cell myelomas) that
produce immunoglobulin and in some other tumor
types by isoenzyme studies.

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Field Origin
A carcinogenic agent acting on a large number of similar cells may
produce a field of potentially neoplastic cells. Neoplasms may
then arise from one or more cells within this field. In many cases
the result is several discrete neoplasms, each of which derives
from a separate clonal precursor.
The field change may be regarded as the first of 2 or more
sequential steps that lead to overt cancer (multiple hits; see
below).
Multifocal (neoplastic field) neoplasms occur in skin, urothelium,
liver, breast, and colon.
Recognizing that a neoplasm is of field origin has practical
implications because one neoplasm in any of these sites should
alert the clinician to the possibility of a second similar neoplasm.
In the breast, for example, cancer in one breast carries a risk of
cancer in the opposite breast that is about 10 times higher than
that of the general population

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Multiple Hits & Multiple
Factors
 Carcinogenesis requires two hits. The first event is
initiation, and the carcinogen causing it is the
initiator.
 The second event, which induces neoplastic growth,
is promotion, and the agent is the promoter. It is
now believed that in fact multiple hits occur (five or
more), that multiple factors may cause these hits,
and that each hit produces a change in the genome
of the affectted cell that is transmitted to its progeny
(ie, the neoplastic clone).
 The period between the first hit and the
development of clinically apparent cancer is the lag
period.

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Lag period

 During the lag period, the altered cell may not

show any structural or functional abnormality;
 for example, an epidermal cell that has been
exposed to a carcinogen looks and functions
the same as surrounding cells.
 Subtle changes are present in such cells,
particularly in the genome, but these may not
be apparent morphologically

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Oncogenes & Tumor
Suppressor Genes
 There are two main categories of genes that
regulate cell growth, and the abnormal action of
either or both may lead to neoplasia.
 Proto-oncogenes (cellular oncogenes: c-onc)
code for a variety of growth factors, receptors,
and signal-relay or transcription factors, which
act in concert to control entry into the cell cycle
(eg, the growth promoter effect).

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 The action of these genes is opposed by the
action of tumor suppressor genes, which serve
to down-regulate the cell cycle. A net increase in
the production of stimulatory (promoter) factors,
a decrease in inhibitory (suppressor) growth
factors, or the production of functionally
abnormal factors may lead to uncontrolled cell
growth.

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Oncogene Associated Neoplasms
c-erb-B2 Breast and ovarian carcinomas

ras Many carcinomas and leukemias

c-sis Gliomas

c-abl Chronic myelogenous leukemia, acute lymphocytic leukemia

c-myc Lymphomas

BRCA-1 Breast and ovarian carcinomas

APC Colonic adenocarcinomas

NF-1 Neurofibromas and neurofibrosarcomas

Rb Retinoblastomas, osteosarcomas, small cell lung carcinomas

p53 Many carcinomas

bcl-2 Chronic lymphocytic leukemia, lymphomas 90

 example of c-erb-B2 positivity in a breast carcinoma.
 This oncogene acts via reduplication of the normal proto-oncogene
hundreds of times, leading to production of a protein product that
drives unregulated cell growth.
 This is detected here by immunoperoxidase staining with the brown
reaction product concentrated in a perimembranous pattern around
the cells. 91
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 an example of c-myc positivity in a carcinoma. This
oncogene acts via DNA transcriptional activation.
The nuclear binding is demonstrated here by
immunoperoxidase staining in which the brown
reaction product is localized to nuclei. 93
 Example of bcl-2 positivity in a lymphoma. The overexpression of
this oncogene results in an inhibition of apoptosis, and increased
numbers of lymphocytes. The immunoperoxidase stain here
highlights the lymphocytes in lymphoid follicles and interfollicular
areas.
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Neoplasia Associated With
Constant Genetic
Abnormalities
 As techniques for chromosomal analysis extend beyond
the gene to study of single nucleotides, so genetic
abnormalities are being uncovered in many tumors, and
the roles of the affected genes in normal growth and
tumorigenesis are being elucidated.
 Over 90% of patients with chronic granulocytic leukemia
show a reciprocal translocation of genetic material
between chromosome 22 and chromosome 9
(Philadelphia chromosome, Ph1).
 The translocation of the c-abl oncogene from chromo-
some 9 to 22 leads to production of a novel growth-
regulating protein and neoplastic proliferation of
granulocytes.

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Mechanisms of Gene
Activation & Inactivation
 It has been suggested that neoplastic transformation
occurs as a result of activation (or derepression) of
growth promoter genes (proto-oncogenes) or
inactivation or loss of suppressor genes.
 Activation is a functional concept whereby the
normal action of growth regulation is diverted into
oncogenesis. The resultant activated proto-
oncogene is referred to as an activated oncogene
(or a mutant oncogene, if structurally changed), or
simply as a cellular oncogene (c-onc). Activation
and inactivation may occur through several
mechanisms:

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 (1) mutation, including single nucleotide loss
(frameshift) or substitution (nonsense or missense
codon), codon loss, gene deletion or more major
chromosomal loss;
 (2) translocation to a different part of the genome
where regulatory influences may favor inappropriate
expression or repression;
 (3) insertion of an oncogenic virus at an
adjacent site;
 (4) amplification (production of multiple copies of
the proto-oncogenes), which appear as additional
chromosome bands or extra DNA fragments (double
minutes);
 (5) introduction of viral oncogenes or
 (6) derepression (loss of suppressor control)
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Viral Oncogene Hypothesis

 Certain RNA viruses contain nucleic acid

sequences that are complementary to a
protooncogene and can (by reverse
transcriptase) produce a viral DNA sequence
that is essentially identical, lacking only the
introns of the animal host cell.
 These sequences are termed viral
oncogenes (v-onc).

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Epigenetic hypothesis

 The main evidence for the role of epigenetic

mechanisms in neoplasia comes from
cancers produced by chemicals that have no
known effect on the genetic apparatus of the
cell.
 It is postulated that these chemicals may
serve as promoters by binding various growth
regulatory proteins, thus rendering them
inactive.

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Hypothesis of Failure of
Immune Surveillance
 (1) Neoplastic changes frequently occur in the cells
of the body.
 (2) As a result of alteration in their DNA, neoplastic
cells produce new molecules (neoantigens, tumor-
associated antigens).
 (3) The immune system of the body recognizes
these neoantigens as foreign and mounts a
cytotoxic immune response that destroys the
neoplastic cells.
 (4) Neoplastic cells produce clinically detectable
neoplasms only if they escape recognition and
destruction by the immune system

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AGENTS CAUSING
NEOPLASMS (Oncogenic
Agents;
 An agent thatCarcinogens)
causes neoplasms is an oncogenic
agent; an agent causing a malignant neoplasm
(cancer) is a carcinogenic agent.
 1) the cause of most common human cancers is
unknown;
 2) most cases of cancer are probably multifactorial
in origin; and
 3) except for cigarette smoking, the agents
discussed below have been implicated in only a
small percentage of cases.

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Carcinogen

 A cancer-causing agent
 Three classes:
 Chemical carcinogens (endogenous/exogenous)
 Physical carcinogens (UV, radiation, asbestos)
 Oncogenic microbes (mainly viruses)

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Human carcinogens -
environmental
 Aflatoxins  Creosote

 Asbestos  DDT
 Benzene  Polycyclic aromatic
 Cadmium hydrocarbons
 Coal tar  Radon
 Tobacco  Solar Radiation

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Chemical Carcinogens as
Mutagens
 Mutagen: an agent that can permanently
alter genetic constitution of a cell
 90% of known carcinogens are mutagenic
 Most mutagens are carcinogens

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Promoters in Human
Cancers
 Cigarettes
 UV
 High Fat Diet
 Hormones
 Viral Infections

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Human carcinogens

Drugs/therapeutic agents
 Adriamycin (doxorubicin)  Diethylstilbestrol
 Androgenic steroids  Ethylene oxide
 Chlorambucil  Melphalan
 Cisplatin  Tamoxifen
 Cyclophosphamide
 Cyclosporin A

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Direct-acting carcinogens

 Nitrogen mustard
 Nitrosomethylurea
 Benzyl chloride

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Nitrogen mustard
 Chlorambucil, melphalan
 Cancer chemotherapeutic agents
 Highly carcinogenic
 Increased risk of secondary cancers
(leukemias), 10-15 yrs. post-treatment

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Indirect-acting
carcinogens
 Polycyclic aromatic hydrocarbons (PAH)
 Produced by incomplete combustion of
organic materials
 Present in
 chimney soot,
 charcoal grilled meats,
 auto exhaust,
 cigarette smoke.

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Aflatoxins
 Another class of indirect-acting carcinogens
 Aflatoxin B1 is one of the most potent liver
carcinogens known
 A common contaminant of grains and peanuts
Africa and Asia
 A probable factor in the high incidence of
hepatocellular carcinoma in Africa and Asia
(along with Hepatitis B infection)
 Natural product of the mold Aspergillus
flavus

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Physical Carcinogens

 Ultraviolet light
 Asbestos
 Foreign body carcinogenesis
 Ionizing radiation (X-rays), radioisotopes,
nuclear bomb

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Cancers caused by UV
exposure
 Squamous cell carcinoma
 Basal cell carcinoma
 Malignant Melanoma

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Asbestos

 Widely used in construction, insulation, and

manufacturing
 Family of related fibrous silicates
 Chrysotile (serpentine form - flexible)
 Crocidolite (amphibole form - rigid rods)

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Ionizing radiation

 Death of pioneer radiation researchers from

neoplasms
 High incidence of leukemia among
radiologists recognized in 1940s
 Osteosarcoma incidence in radium dial
painters

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Viral Carcinogenesis

 Viral infections account for an estimated

one in seven human cancers worldwide
 Majority of these are due to infection with
two DNA viruses
 HBV – linked to hepatocellular carcinonoma
 HPV – linked to cervical carcinoma

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HPV

 HPV 6,11 – low risk viruses

 HPV – 16, 18, 31, 33, 35, 39, 45 – High risk
viruses
 85% of cervical carcinomas that are HPV-
positive contain a high risk HPV (70% have
HPV 16 or 18)

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EBV – involvement in human
tumors

 African Burkitt lymphoma

 B-cell lymphomas of immunosuppressed
patients
 Some cases of Hodgkin disease
 Nasopharyngeal carcinomas

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How do viruses like
HPV and HBV cause
cancer?
 Very small viruses
 Can integrate their viral DNA into host genome
 They code for viral proteins which block tumor
suppressor proteins in cell

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Helicobacter pylori

 Gastric infection linked to gastric lymphomas

and gastric carcinomas
 Detection of H. pylori in majority of cases of
gastric lymphomas
 Antibiotic treatment results in gastric
lymphoma regression in most cases

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Human Herpesvirus 8
 Kaposi sarcoma - a vascular neoplasm
originally described in eastern Europe
 KS is today most common neoplasm
associated with AIDS
 Cells contain HHV8 (also called KS-
associated herpesvirus) KSHV

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Factors Influencing
Chemical Carcinogenesis
 Metabolism
 Sex and Hormonal Status
 Diet

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Nutritional Oncogenesis

 A diet high in animal fat has been associated

statistically with an increased incidence of
cancer of the colon and with breast cancer;
this observation remains unexplained.

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Hormonal Oncogenesis
 Estrogens. causes endometrial hyperplasia, which is followed
first by cytologic dysplasia and then by neoplasia.
 Hormones and breast cancer. patients taking oral
contraceptives have shown that the risk of breast cancer is
minimally increased in patients taking preparations with high
estrogen content. The current low-estrogen contraceptives are
not thought to increase the risk of breast cancer.
 Diethylstilbestrol (DES). Female children who were exposed to
diethylstilbestrol in utero have a greatly increased incidence of
clear-cell adenocarcinoma, a rare vaginal cancer that develops in
young women between 15 and 30 years of age.
 Steroid hormones. Use of oral contraceptives and anabolic
steroids is rarely associated with development of benign liver
cell adenomas. A few cases of liver cell carcinoma have been
reported.

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Hormone dependent
neoplasms
 Prostate ca
 Breast ca
 Thyroid ca

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Genetic Oncogenesis
(The Role of Inheritance in
Oncogenesis)
 1. Neoplasms With Mendelian (Single-Gene) Inheritance

 Retinoblastoma. This uncommon malignant neoplasm of the

retina occurs in children, and 10% of cases are inherited. The
morphologic appearance of familial retinoblastoma is the same
as that of the non-inherited form. Familial form displays other
distinguishing features:
 (1) it is commonly bilateral;
 (2) chromosomal analysis consistently shows an abnormality of
the long arm of chromosome 13 (13q14, the retinoblastoma
[Rb1] gene);
 (3) spontaneous regression occurs in some cases.

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 Wilms' tumor (nephroblastoma)
 Nephroblastoma is a malignant neoplasm of the kidney
that occurs mainly in children.
 Many cases are associated with deletion of part of
chromosome 11. Both sporadic and familial cases occur
by mechanisms thought to resemble those described for
retinoblastoma.
 11p13 abnormalities are being identified in other tumor
types.
 WT-1 is also a tumor suppressor gene.

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 Several other neoplasms display a familial pattern.

 Neurofibromatosis (type 1 von Recklinghausen's disease)- This

tumor is characterized by multiple neurofibromas and pigmented
skin patches known as café au lait spots. In neurofibromatosis,
the NF-1 genes (chromosome 17q11) are absent or defective,
leading to loss of NF-1 suppressor protein. NF-1 protein is
thought to act by regulating the effect of the products (guanine-
binding G proteins) of the ras proto-oncogene.
 Multiple endocrine adenomatosis- This disorder is manifested
by benign neoplasms in the thyroid, parathyroid, pituitary, and
adrenal medulla.
 Familial polyposis coli- Polyposis coli is characterized by
innumerable adenomatous polyps in the colon. (There is loss of
heterozygosity on the long arm of chromosome 5, the APC-
adenomatous polyposis coli-gene).
 Gardner's syndrome
 Turcot's syndrome,

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 2. Neoplasms With Polygenic Inheritance:
 Many common human neoplasms are familial to a
much lesser degree- ie, they occur in related
individuals more often than would be expected on
the basis of chance alone.
 Breast cancer. First degree female relatives
(mother, sisters, daughters) of pre-menopausal
women with breast cancer have a risk of developing
breast cancer that is five times higher than that of
the general population.
 Colon cancer.

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 3. Neoplasms Occurring More Frequently in
Inherited Disease:
 (a) syndromes characterized by increased
chromosomal fragility
 (eg, xeroderma pigmentosum, Bloom's syndrome,
Fanconi's syndrome, and ataxia-telangiectasia), in
which neoplasia is due to frequent DNA
abnormalities; and
 (b) syndromes of immunodeficiency,
 in which failure of immune surveillance may
predispose to neoplasia. In these disorders, it is not
the neoplasm itself that is inherited but rather some
susceptibility to neoplasia.

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Grading and Staging of
Cancer

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Grading and Staging
 Methods to quantify the probable clinical
aggressiveness of a given neoplasm and its
apparent extent and spread in the individual patient
are necessary for making accurate prognosis and
for comparing end results of various treatment
protocols.
 For instance, the results of treating extremely small,
highly differentiated thyroid adenocarcinomas that
are localized to the thyroid gland are likely to be
different from those obtained from treating highly
anaplastic thyroid cancers that have invaded the
neck organs.

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Grading
 The grading of a cancer attempts to establish some estimate of
its aggressiveness or level of malignancy based on the cytologic
differentiation of tumor cells and the number of mitoses within the
tumor.
 The cancer may be classified as grade I, II, III, or IV, in order of
increasing anaplasia.
 Difficulties in establishing clear-cut criteria have led in some
instances to descriptive characterizations (e.g., "well-
differentiated adenocarcinoma with no evidence of vascular or
lymphatic invasion" or "highly anaplastic sarcoma with extensive
vascular invasion").

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Staging

 Staging of cancers is based on:

 the size of the primary lesion,
 its extent of spread to regional lymph nodes,
 the presence or absence of metastases.

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 This assessment is usually based on clinical
and radiographic examination (computed
tomography and magnetic resonance
imaging) and in some cases surgical
exploration.
 Two methods of staging are currently in use:
 TNM system (T, primary tumor; N, regional
lymph node involvement; M, metastases)
 AJC (American Joint Committee) system.
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 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.

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 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.
 It is worth noting that when compared with
grading, staging has proved to be of greater
clinical value!

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Biologic and Clinical Effects of
Neoplasms

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Tumor Cell Products

 The synthesis and secretion of various tumor

cell products are important for two reasons:
 (1) their presence may indicate the existence
of a neoplasm in the body (ie, they act as
tumor markers); and
 (2) they may produce clinical effects
(paraneoplastic syndromes) unrelated to
direct involvement of tissue by the tumor.

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Those tumor products are:

 Oncofetal antigens
 Enzymes
 Immungloblins
 Excessive Hormone production
 Ectopic Hormone Production

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Oncofetal antigens

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Ectopic Hormone production by the
neoplasms

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 PARANEOPLASTIC SYNDROMES (1)

 Fever (lymphomas, acute leukemias, sarcomas, renal cell

carcinomas (Grawitz tumors), and digestive malignancies
(including the liver).
 Leukemoid reactions (lymphomas or cancers of the lung,
breast, or stomach)
 Erythrocytosis or anemia, thrombocytosis (many types of
cancers)
 Disseminated intravascular coagulation (many types of
cancers)
 Cryoglobulinemia (lung cancer, pleural mesothelioma)
 Paraneoplastic arthropathies - rheumatic polyarthritis
(myelomas; lymphomas; acute leukemia; malignant histiocytosis;
and tumors of the colon, pancreas, prostate, CNS
 Hypertrophic osteoarthropathy (lung cancers)
 Scleroderma (breast, uterus, and lung)
 SLE (lung, breast, gonads)
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PARANEOPLASTIC SYNDROMES
(2)

 Amyloidosis (myeloma, renal carcinoma, and lymphomas)

 Nephrotic syndrome (Hodgkin lymphoma (HL); non-Hodgkin
lymphoma (NHL); leukemias; melanomas; or malignancies of
lung, thyroid, colon, breast, ovary, or pancreatic head)
 Watery diarrhea - electrolyte imbalance (medullary thyroid
carcinomas, proctosigmoid tumors, melanomas, myelomas,
ovarian tumors, pineal body tumors, and lung metastases)
 Acanthosis nigricans, dermic melanosis (metastatic
melanomas or pancreatic tumors
 Cushing syndrome (ectopic production of ACTH or ACTH-like
molecules from many tumors, eg, small cell cancer of the lung)
 Neuromuscular disorders (ovarian and pulmonary cancers)

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 Good luck for the exams
 Hope to see all of you next year!
 Thank you...

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