Download Neoplasia - ISpatula

Khairat battah, MD
University of jordan
Faculty of medicine, pathology department.
- Neoplasia literally means "new growth“
- In medicine it is referred to as a tumor,
- The study of tumors is called oncology.
fundamental and shared characteristics of
cancers:
 Cancer is a genetic disorder caused by DNA
mutations that are (for the most part)
acquired spontaneously or induced by
environmental insults.
 Genetic alterations are heritable
 Accumulation of mutations gives rise to a set
of properties that have been called hallmarks
of cancer.
- Neoplastic cells are transformed because they continue
to replicate, independent of normal regulatory
mechanisms, so enjoy a certain degree of autonomy.
- But their autonomy is not complete, because they
depend on the host for their nutrition and blood supply.
- Neoplasms are either benign or malignant.
- All tumors, benign and malignant, have two basic
components:
1. The neoplastic cells (the parenchyma) which
determines its biologic behavior,
2. The non-neoplastic connective tissue stroma, is
important to the growth of the neoplasm
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In general, benign tumors are designated by attaching
the suffix -oma to the cell type from which the tumor
arises.
I. Benign mesenchymal Tumors:
a. A benign bone tumor is called osteoma
b. A benign smooth muscle tumor is leiomyoma
II. Benign epithelial tumors
1. Adenomas : Are benign epithelial neoplasms producing
glands or derived from glands such as renal adenomas and
adenomas derived from adrenal cortex.
2. Polyp : Is a mass projects above a mucosal surface, as in gut.
Most polyps are benign adenomas but a few are
malignant.
3. Cystadenomas : like cystic tumors that arise in the ovary
4. Papillomas are benign epithelial neoplasms, growing on any
surface, that produce microscopic or macroscopic finger-like
fronds.
Teratoma :
Is a tumor contains tissues (either mature or immature)
from more than one germ cell layer and sometimes all
three layers, and present in ovaries and testes.
Contain bone, epithelium, muscle, fat, nerve.
III. Malignant mesenchymal neoplasms
- Malignant neoplasms arising in “solid” mesenchymal
tissues or its derivatives are called sarcomas
- Malignant neoplasms arising from the mesenchymal
cells of the blood are called leukemias or
lymphomas-
IV. Malignant tumors of epithelium are carcinomas
- Those arise from glands adenocarcinomas
- Those produce squamous cells called squamous cell
carcinomas
- Poorly differentiated or undifferentiated carcinoma
Choristoma called (heterotopia)
- Is a congenital anomaly not a neoplasm.
- Means presence of normal tissue in an abnormal location
such as presence of normal pancreatic tissue in stomach.
Hamartoma is a malformation that presents as a mass
of disorganized tissue native to the particular site.
 Not a neoplasm.
- Example : hamartomatous nodule in the lung
containing islands of cartilage, bronchi, and blood
vessels
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A. Differentiation and anaplasia
Diffrentiation means how much neoplastic cells resemble their
normal forebears morphologicaly and functionaly
1. Benign neoplasms :
Composed of well-differentiated cells that resemble their normal
counterparts.
Example: Lipoma and chondroma.
2. Malignant neoplasms: Characterized by a wide range of
differentiation, from well differentiated to poorly
differentiated. .
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The better the differentiation of the cell, the more
completely it retains the functional capabilities found in
its normal counterparts.
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Benign neoplasms and even well-differentiated cancers
of endocrine glands frequently elaborate the hormones
characteristic of their origin.
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Well-differentiated squamous cell carcinomas elaborate
keratin.
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Anaplasia means lack of differentiation, is considered a
hallmark of malignancy.
Anaplastic cells display:
Marked pleomorphism (i.e., marked variation in size and shape)
Nuclei are extremely hyperchromatic (darkly stained) and large..
The nuclear-to-cytoplasmic ratio is high.
Giant cells .
Anaplastic nuclei are variable and bizarre in size and shape.
nucleoli may be of astounding size.
Mitoses are often numerous and distinctly atypical
B. Rate of Growth
- Most benign tumors grow slowly and most cancers
grow faster
- The rate of growth of malignant tumors correlates with
their level of differentiation
- Poorly differentiated tumors grow more rapidly than
well-differentiated tumors.
- The more rapidly growing and the more anaplastic a
tumor, the less likely it is to have specialized functional
activity.
C. Local Invasion:
1- Benign neoplasms: Usually encapsulated and do not
have the capacity to invade the normal tissue.
However, not all benign neoplasms are encapsulated.
2- Cancers grow by progressive invasion, and
penetration of the surrounding tissue
- It is necessary to remove a wide margin of surrounding
normal tissue after excision of a malignant tumor
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Next to the development of metastases, local
invasiveness is the most reliable feature that
distinguishes malignant from benign tumors.
D. Metastasis :
- Are secondary implants of a tumor, discontinuous from
the primary tumor and located in remote tissues
- However, not all cancers have ability to metastasize
such as basal cell carcinomas of the skin and the majority
of malignant central nervous system tumors.
- Approximately 30% of newly diagnosed patients with
solid tumors present with clinically evident metastases.
- Dissemination strongly may prevent, the possibility of
curing the disease.
1-Spread by seeding :
Occurs when neoplasms invade a natural body cavity.
Examples:
1-Ovarian cancer, which spread to the peritoneal surfaces.
2-Central nervous system tumors such as
medulloblastoma or ependymoma, may penetrate the
cerebral ventricles and be carried by the cerebrospinal
fluid to reimplant on the meningeal surfaces.
2. Lymphatic spread :
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Is more typical of carcinomas.
 Enlargement of lymph nodes near primary neoplasm should
arouse concern for metastatic spread. However , it does not
always imply metastasis.
 Depends on lymphatic drainage of the organ.
 Sentinel lymph node is the first regional lymph node
that receives lymph flow from a primary tumor.
3. Hematogenous spread :
- Is the favored pathway for sarcomas
- Arteries are penetrated less than veins.
- Liver and lungs are the most common site for
hematogenous metastasis.
- The skeletal muscles are rarely the site of metastatic
deposits
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However, there are numerous interconnections,
between the lymphatic and vascular systems, and so all
forms of cancer may disseminate through either or both
systems
- It contribute to knowledge about the origin of cancer.
For example the association between smoking and lung
cancer arose from epidemiologic studies
- There is association between high dietry fat and low
fiber with colon cancer.
1- Age:
The cancer frequency increases with age.
- This is due to accumulation of somatic mutations and the
decline in immune competence with age .
- Cancer occurs also among children
The major lethal cancers in children are leukemias, tumors of
the central nervous system, and bone sarcomas..
2- Geographic and Environmental Variables .
3- Heredity :
Only 10% of cancers are familial
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4-Acquired Preneoplastic Lesions
- Increase the likelihood of malignancy, but most do not
progress to cancer and their removal may prevent the
development of a cancer.
- Examples.
a. Endometrial hyperplasia.
b. Cirrhosis .
c. villous adenoma of colon.
Are benign tumors precancerous?
In general the answer is no, but there are exceptions,
and it is better to say that each benign tumor is
associated with a particular risk, ranging from high to
virtually nonexistent.
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- For example, large colon villous adenoma can undergo
malignant transformation. However, leiomyomata of
uterus do not transform to malignany.
Biology of tumor growth,
invasion and metastasis
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The tumor cell develop self sufficiency in growth signals as
they use a number of strategies to drive their proliferation and
become insensitive to normal growth regulators.
The tumor cell become insensitivity to growth inhibitory
signals
The tumor cell can evade cell death (apoptosis)
The tumor cell have limitless replicative potential
The tumor develop sustained angiogenesis
Development of neovascularization
- Tumors cannot enlarge beyond 1 to 2 mm in
diameter unless they are vascularized.
- The 1 to 2 mm zone represents the maximal
distance across which oxygen and nutrients can
diffuse from blood vessels.
Importance of vascularization:
1. It supplies needed nutrients and oxygen,
2. Is required for tumor metastasis
3. Growth factors for tumor growth
The metastatic cascade can be subdivided into two
phases:
1- Invasion of extracellular matrix (ECM) and vascular
dissemination.
2- Homing of tumor cells.
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A carcinoma first must breach the underlying basement
membrane, then traverse the interstitial connective
tissue, and ultimately gain access to the circulation by
penetrating the vascular basement membrane.
a. Detachment of tumor cells.: due to loss of inter-cellular
E-cadherin function that keeps the cells together;
b. Local degradation of the basement membrane and
connective tissue.
c. Attachment of tumor cells to ECM.
d. Migration of tumor cells: propelling tumor cells
through degraded basement membranes and the interstitial
connective tissue.
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Tumor cells in the circulation are prone to destruction
by immune cells .
In the bloodstream, some tumor cells form emboli by
aggregating with platelets; thus aggregated tumor cells
are afforded some protection from antitumor cells.
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Extravasation of free tumor cells or tumor emboli
involves adhesion to the vascular endothelium,
followed by egress through the basement membrane
into the organ parenchyma by mechanisms similar to
those involved in invasion.
The site of extravasation and the organ distribution of
metastases generally can be predicted by the location
of the primary tumor and its vascular or lymphatic
drainage
1. Chemical Carcinogens
A-Diret-Acting Agents:
 Direct-acting agents require no metabolic conversion to
become carcinogenic
 Weak carcinogens.
Are important because some are cancer chemotherapy
drugs (Alkylating agents) used to cure certain
lymphoma but can evoke a subsequent, second form of
cancer, usually leukemia.
b. Indirect-Acting Agents:
chemicals that require metabolic conversion to
an ultimate carcinogen.
1- Benzo[a]pyrene present in cigarette smoking cause
lung cancer.
2- Polycyclic hydrocarbons which are produced from
smoked meats and fish and fossil fuels.
3- Aromatic amines and azo dyes associated with urinary
bladder cancer.
4. Aflatoxin B1 produced by Aspergillus, that grows on
improperly stored grains and can cause hepatocellular
carcinoma.
2. Radiation Carcinogenesis
A- Therapeutic irradiation of the head and neck can give
rise to thyroid cancers years later.
B- Natural UV radiation derived from the sun can cause skin
cancers .
Cumulative DNA damage is the mechanism of carcinogenesis.
Note: patients with the inherited disease xeroderma
pigmentosum (defective DNA repair), there is a increased
predisposition to skin cancers .
3.Viral and Microbial Oncogenesis
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Oncogenic DNA Viruses:
1. Human Papillomavirus (HPV) causes:
a. Skin warts.
b. Genital warts caused by low risk HPV (6 and 11)
c. Squamous cell carcinoma of the uterina cervix caused
by high-risk HPVs (16 and 18)
2. Epstein-Barr Virus (EBV) :
a. Burkitt lymphoma
b. Lymphomas in patients with AIDS
c. Nasopharyngeal carcinoma.
d. Hodgkins lymphoma.
3. HBV and HCV :
- Hepatocellular carcinoma.
Bacterial agents
- H. pylori bacteria may cause
1. Adenocarcinoma of stomach.
2. Gastric lymphoma (MALT) and early eradication of H.
pylori "cures" the lymphoma.
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There is an initial development of chronic
inflammation/gastritis, followed by gastric atrophy, intestinal
metaplasia of the lining cells, dysplasia, and cancer. This
sequence takes decades to complete and occurs in only 3% of
infected patients.
1 - Oncofetal Antigens:
- Such as carcino-embryonic antigen (CEA) and alpha
fetoprotein.
- Are expressed during embryogenesis but not in normal adult.
- Although, they are not tumor-specific, they can serve as
serum markers for cancer. For example , serum CEA is high in
cases of colon cancer.
2. Cell Type-Specific Differentiation Antigens
- Tumors express molecules that normally are present
on the cells of origin and these antigens are called
differentiation antigens.
- Such as PSA (prostate specific antigen) in prostate
cancer.
Both malignant and benign tumors may cause
problems because of
(1) location and impingement on adjacent
structures,
(2) functional activity such as hormone synthesis or
the development of paraneoplastic syndromes,
(3) bleeding and infections when the tumor
ulcerates through adjacent surfaces,
(4) symptoms that result from rupture or infarction
(5) cachexia or wasting.
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1- Location is crucial in both benign and malignant
tumors,
a. A small pituitary adenoma can destroy the surrounding
normal gland, giving rise to hypopituitarism.
b. Benign and malignant colon tumors can ulcerate and
cause hemorrhage and in addition can cause
obstruction.
2. Cancer Cachexia
 Progressive loss of body fat and lean body mass,
accompanied by weakness, anorexia, and anemia.
 There is correlation between the size of the tumor and
severity of cachexia
 Cachexia is not caused by the nutritional demands of
the tumor.
 Although patients with cancer are anorexic, but
cachexia results from the action of soluble factors
rather than reduced food intake; TNF is implicated.
3- Paraneoplastic Syndromes
 It is the symptom complexes that cannot be explained by
local or distant spread of the tumor or by the elaboration of
hormones native to the tissue of origin of the tumor.
 Most common syndromes are:
Hypercalcemia (PTHrP)
Cushing syndrome(ACTH)
Nonbacterial thrombotic endocarditis.
 Occurs in lung, pancreatic and breast cancers and
hematologic malignancies.
 It should be noted that hypercalcemia resulting from bone
metastases is not a paraneoplastic syndrome.
The grading of a cancer
Establish some estimate of tumor aggressiveness or
level of malignancy based on the resemblance of the
tumor to the normal tissue (cytologic
differentiation) and the number of mitosis.
Staging of cancers is based on :
a. The size of the primary lesion,
b. The spread to regional lymph nodes,
c. The presence or absence of metastases.