Transcript Neoplasia

Neoplasia
What is a “neoplasm”?
• Lay term of “tumor” conveys usual connotations – ie a new
growth or mass
• Definition revolves around these features:
• Monoclonal proliferation of cells with specific mutations
• Excessive and unregulated growth of these cells, often at
the expense of surrounding normal tissue
• Tumor is an abnormal mass of tissue, the growth of which is
virtually autonomous and exceeds that of normal tissue.
• The growth of tumor persist after cessation of the stimuli
that initiated the changes.
• Tumor classified into two categories; benign and malignant.
• All tumors have two basic component:
1. The transformed neoplastic cells.
2. The supporting stroma composed of non transformed
elements such as connective tissue and blood vessels.
Benign tumors.
• In general benign tumors end with suffix oma .
• Examples lipoma, fibroma, angioma and leiomyoma (mesenchymal
tumor).
• The nomenclature of benign epithelial tumors is somewhat
complex and is based on both histogenesis and architecture.
• Adenoma-arise from glands or forming glandular pattern.
• Cystadenoma- adenoma producing large cystic masses.
• Papilloma- epithelial tumor forming microscopic or macroscopic
finger like projections.
Malignant tumors
• Often called cancers and divided into two categories.
1. Carcinoma- arising from epithelial cells.
2. Sarcoma- arising from mesenchymal cells.
• Nomenclature based on their appearance and presumed
histogenetic origin.
• Malignant epithelial tumor with glandular growth termed
adenocarcinoma.
• Sarcoma of smooth muscle cells called leimomyosarcoma.
Classification continued
• Tumors of lymphocytes are always malignant – called
lymphoma
• Tumors of melanocytes
• Benign – nevus
• Malignant - melanoma
• Some tumors have more than one parenchymal cell type,
two important members:
1. Mixed tumors: derived from one germ cell layer that
differentiate into more than one parenchymal type, as
mixed salivary gland tumor contain epithelial cells as well
as myxoid stroma and cartilage like tissue, all elements
arise from altered differentiation of ductal epithelial cells.
2. Teratomas: made up of variety of parenchymal cell types
represented of more than one germ cell layer, usually all
three endodermal, ectodermal and mesenchymal, such
tumor present principally in ovary and testis.
Characteristic of benign and malignant
neoplasms.
• Based on appearance (morphology) and ultimately on
behavior (clinical course) using four criteria.
1. Differentiation and neoplasia.
2. Rate of growth.
3. Local invasion.
4. Metastasis.
Differentiation and neoplasia
• Differentiation is the extent to which tumor cells resemble
comparable normal cells.
• Cells within most benign tumors closely mimic corresponding
normal cells.
• Thyroid adenoma composed of normal looking thyroid acini
and cells in lipoma mimic normal adipose tissue.
• Malignant tumors in general less well differentiated than
their benign counterparts.
• Malignant tumors display pattern of differentiation ranging
from well differentiated to poorly differentiated.
• Lack of differentiation called also anaplasia.
• Cytological features of poorly differentiated or anaplastic
tumors.
1. Nuclear and cellular pleomorphism-wide variation in shape
and size of cells and nuclei.
2. Hyperchromasia- darkly stained nuclei that frequently
contain prominent nucleoli.
3. Nuclear/cytoplasmic ratio-approach 1:1 instead of 1:4 or
1:6 reflecting nuclear enlargement.
Microscopic features of tumors
• Pleomorphism – variation in size and shape of cells
within the neoplasm
4. Abnormal mitosis- reflect proliferative activity, mitotic
figures may be abnormal.
5. Tumor giant cells- contain a single large polypoid nucleus or
multiple nuclei.
• Poorly differentiated anaplastic tumor demonstrate also
total disarray of tissue architecture.
• Well differentiated tumor whether benign or malignant tend
to retain the functional characteristics of their normal
counterparts such as production of hormones.
Microscopic features of tumors
• Mitotic activity - Increased in more malignant tumors
and often abnormal in shape
Here are three abnormal mitoses. Mitoses by themselves are not
indicators of malignancy. However, abnormal mitoses are highly
indicative of malignancy. The marked pleomorphism and
hyperchromatism of surrounding cells also favors malignancy.
Dysplasia
• Refer to disorderly but non neoplastic growth.
• Characterized by pleomorphism, Hyperchromasia and loss of
normal orientation.
• Usually encountered in epithelia, especially in uterine cervix.
• When changes are marked and involve entire thickness of
epithelium, the lesion considered a preinvasive neoplasm
and referred to as carcinoma insitu.
• Mild dysplasia do not always lead to cancer and are often
reversible when inciting cause removed.
Rate of growth
• Most malignant tumors grow more rapidly than benign tumors.
• Some cancers grow slowly for years, however, and then enter a
phase of rapid growth, others expand rapidly from the onset.
• Growth of cancer arising from hormone sensitive tissue, such as
the uterus, may be affected by variation in hormones level
associated with pregnancy and menopause.
• Rapidly growing malignant tumor often contain central areas of
ischemic necrosis because of blood supply fail to pace with O2
needed for expanding cells.
Local invasion; characterized by
• Most benign tumors grow as cohesive expansible masses
that develop a rim of condensed connective tissue or capsule
at periphery.
• They do not penetrate capsule or surrounding normal tissue.
• The plane of cleavage between capsule and surrounding
tissue facilitate surgical enucleation.
• Malignant tumors are invasive infiltrating and destroying
normal surrounding tissue.
• Well defined capsule and plane of cleavage are lacking ,
making enucleation difficult or impossible.
• Surgical treatment of such tumors require removal of
considerable margin of healthy tissue.
Gross (macroscopic) features of
two breast neoplasms
Benign – circumscribed, often
encapsulated, pushes normal
tissue aside
Malignant – infiltrative growth,
no capsule, destructive of
normal tissues
Metastasis
• Involve invasion of the lymphatics, blood vessels and body
cavities by the tumor.
• Follow by transport and growth of secondary tumor cell
masses that are discontinuous with the primary tumor.
• This distinguish benign from malignant tumors.
• Distant metastasis occur by three routes.
1. Spread into body cavities: occur by seeding of surfaces in
peritoneal, pleural, pericardial and subarachnoid spaces.
2. Invasion of the lymphatics: follow by transport of tumor cells
to regional lymph nodes and ultimately other parts of the
body.
3. Hematogenous spread: this is typical of all sarcoma but also
is the favor routes of certain carcinoma such as kidney
originating tumor.
• 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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Benign
Malignant
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Epidemiology :
1. Geographic and environmental factors:
• In USA cancer responsible for approximately 23% of all deaths
annually.
• In men lung, colon and prostate cancer are leading cause of death.
• In women lung, breast and colon cancer are leading cause of death.
• increase risk of certain cancers with exposure to asbestos and vinylchloride.
• Association of oropharynx, larynx and lung cancer with cigarette
smoking.
2. Age.
• Cancer is most common in those older than 55 y of age.
• Certain tumors are particular common in children younger
than 15 y old as leukemia, neuroblastoma, wilm’s tumor,
retinoblastoma and bone sarcoma.
3. Hereditary.
• Play a role in the development of cancer even in the
presence of clearly defined environmental factors.
• Hereditary form can be classified into three categories:-
1. Inherited cancer syndrome:
• Inheritance of single mutant gene that greatly increase the risk
of developing a certain type of tumors.
• The predisposing to tumor is thus autosomal dominant trait as
familial retinoblastoma.
• These tumors associated with inheritance of single mutant allel
of cancer suppression gene.
2. Familial cancer:
• Characterized by familial clustering of specific forms of cancer,
but the transformation pattern is not clear in an individual
case.
• Familial form of common cancers for examples, breast, ovary,
colon are recorded.
3. Autosomal recessive syndromes of defective DNA repair:
• are characterized by chromosome or DNA instability that
greatly increase the predisposition to environmental
carcinogens.
4. Acquired preneoplastic disorders
• Certain clinical conditions are associated with the increase risk of
developing cancer.
a. Cirrhosis of liver-hepatocellular carcinoma.
b. Atrophic gastritis-stomach cancer.
c. Chronic ulcerative colitis- colon carcinoma.
d. Leukoplakia of oral cavity and genital mucosa- squamous cell
carcinoma.
• Certain benign tumors associated with subsequent development of
cancer-villous adenoma of colon often develop in to cancer
Molecular basis of cancer
• Cancer is a genetic disease; genetic injury may be acquired in
somatic cells by environmental agents or inherited in germ line.
• Tumors develop as clonal progeny of single genetically damaged
progenitor cell.
• Four classes of genes are the target of genetic damage.
1. Growth promoting proto-oncogenes.
2. Growth inhibiting tumor suppressor gene.
3. Gene that regulate apoptosis.
4. Gene that regulate DNA repair.
• carcinogenesis is a multistep process
Oncogene and cancer
Oncogenes and proto-oncogenes are defined as follows:
• Oncogenes are gene whose products are associated with neoplastic
transformation.
• Protooncogenes are normal cellular gene that affect growth and
differentiation. They can be transformed into oncogenes by
1. Transduction into retrovirus (v-onc)- most human tumors not
caused by this type.
2. Change insitu that affect their expression, function or both there
by converting them into c-onc.
Protein products of oncogenes
• Growth factor: some Protooncogenes (c-sis) code for growth
factor as PDGF, many tumors that produce growth factors are
also responsive to growth promoting effect of secreted
growth factors and hence autocrine stimulation.
• Growth factor receptor: several oncogenes encode for
growth factor receptors, both structural alteration
(mutation) and over expression of receptor gene has been
found in association with malignant transformation.
• Signals transducing proteins: these proteins are biochemically
heterogeneous and grouped into two major categories.
1. Guanosine triphosphate (GTP) binding protein- e.g: colonic
carcinoma.
2. Non receptor associated tyrosine kinase- e.g: chronic myeloid
leukemia.
• Nuclear transcription protein: the product of myc and myb
oncogenes are nuclear proteins, expressed highly in normal cell
proliferation, their oncogene version associated with persistent
expression, e.g; Burkett's lymphoma.
• Cyclins and cyclin dependent kinase (CDK): these regulate
progression of cells through cell cycle.
Activation of oncogenes
• Protooncogenes can be transformed into oncogenes by one
of three mechanism.
1. Point mutation.
2. Chromosomal rearrangement.
3. Gene amplification.
Point mutation.
• The ras Protooncogenes activated by point mutation.
• Approximately 15 % of human tumors associated with mutated H-ras
or K-ras oncogenes.
• One possible mechanism of these mutation is exposure to cancer
causing chemicals.
•
Chromosomal rearrangement.
1. Placement of gene next to strong promoter/enhancer
elements of Ig or T-cell receptor loci in lymphoid cellsBurkitt lymphoma t(8;14).
2. Fusion of the gene with new genetic sequences, in CML
t(9;22).
Gene amplification
• Reduplication of proto-oncogenes can lead to increase
expression or activity.
• Example-N-myc
amplification
in
neuroblastoma,
amplification of
c-erb-2 gene in 30-40% of breast cancer.
Cancer suppressor genes
• Cancer may arise not only by activation of growth promoting
oncogenes, but also by inactivation of gene that normally
suppress cell proliferation (antioncogenes).
• The Rb gene is prototypic cancer suppressor gene.
Protein products of tumor suppressor genes
• P53: is mutated in greater than 50% of all human cancers,
those who inherit mutant copy of P53 gene are at high risk of
developing malignant tumor by inactivation of the second
normal allel in somatic cells,the normal function of P53 gene
is to prevent propagation of genetically damage cells.
• BRCA-1&BRCA-2: mutation in these can account for 80% of
breast cancers.
• APC gene: those with one mutant allel of this gene develop
hundreds of adenomatous polyps in the colon.
Gene that regulate apoptosis
• The prototypic gene in this group, bcl-2 prevent apoptosis.
• Over expression of bcl-2 extend cell survival , and if the cells
are genetically damaged, the continue to suffer additional
mutations in oncogenes and cancer suppressor gene.
• Most common example B- cell lymphoma of follicular type.
Gene that regulate DNA repair.
• The DNA repair gene do not contribute directly to cell
growth or proliferation.
• They act indirectly by correcting error in DNA that occur
spontaneously during cell division or those that follows
exposure to mutagenic chemicals or irradiation.
• Patient with hereditary non polyposis colon cancer are born
with one defective copy of one of several DNA repair gene.
Biology of tumor growth