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What is neoplasia ?
Tumor:
Dysplasia:
1st is hypercellularity .
A - Nuclear changes :
1-Nuclear enlargement ( increase N/C ratio ).
2-Pleomorphism ( variation in size & shape of nuclei).
3-Hyperchromatism &chromatin irregularity .
4-Multinucleation ( unequal size multiple nuclei ).
5-Irregularity of nuclear membrane .
6-Prominent & giant & multiple nucleoli ( differ in size &
shape) .
B Cytoplasmic changes :
1-Scanty cytoplasm .
2-Variation in size & shape .
3-Cytoplasmic staining :
Deep orange in keratinized squamous cell carcinoma.
Basophilic in poorely differentiated carcinoma.
4-Cytoplasmic inclusion :melanin in malignant melanoma
.
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Tunica adventitia
Consists of longitudinally oriented collagenous and
elastic fibers that become continuous with the
surrounded C.T.
Innervation of Blood vessels:
Hyperplasia:
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Hypertrophy:.
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.
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Metaplasia
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Benign tumor:
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Papilloma :
Term applied for benign tumor arising from surface
epithelium e.g skin or mucosal surface:
Grossly appear as finger like protrusion on surface or
warty projection on mucosa of hallow organ .
Microscopically :It is composed of finger-like
epithelial cell growing overlying fibrovascular core
(connective tissue with blood vessels) .
e.g Squamous papilloma of skin .
Squamous papilloma of larynx .
Transitional Papilloma of bladder.
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.
2-Malignant connective tissue tumors: ( Sarcoma ) :
Prefix (origin)+ suffix (sarcoma) .
e.g. Bone :Osteosarcoma ,
Adipose tissue : Liposarcoma,
Blood vessels : Angiosarcoma,
Smooth muscle :Leiomyosarcoma,
Skeletal muscle :Rhabdomyosarcoma .
Cartilage : Chondrosarcoma .
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.
Teratoma
pleomorphic adenoma
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2-Mixed tumors
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.
4-Distant metastases: development of secondary
implants in site that anatomically discontinous with
primary malignant tumor, possibly in remote tissue
(absolute feature of malignant tumor).
5-Gross features :
Benign : smooth , capsulated , uniform color.
Malignant: irregular , no capsule ,variegated color.
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1- Differentiation:
This indicates the degree of resemblance of the tumor
cell to its cell of origin,functionally &morphologically.
- In most benign tumors constituent cell closely
corresponding to normal cells :e.g - Cells of a lipoma
may look exactly like normal fat cells.
- Malignant tumors display a range of differentiation,
which form the basis of tumor grading (well , moderate
, poorly) :
-Malignant tumor can be extremely well differentiated e.g. a well differentiated liposarcoma or anaplastic in
which tumor cells lack of differentiation .
-
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Normal
Poorly differentiated
adenocarcinoma
adenoma
Well differentiated
adenocarcinoma
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Anaplastic carcinoma
8-Prominent nucleoli.
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Intraepithelial Neoplasia:
Dysplasia involving an epithelial surface
Low grade & High grade.
High grade dysplasia ,limited by intact epithelial
basement membrane CARCINOMA IN SITU.
Not all dysplasias progress to higher grade or
carcinoma in situ.
Not all carcinoma in situ progress to invasive CA.
Mild to moderate degrees of dysplasiacan be seen
in reactive & inflammatory lesions.
Dysplasia can regress.
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Intraepithelial Neoplasia
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2- Rate of growth:
3- Local invasion :
Second most important feature distinguishing
malignant tumors after metastases.
Benign tumors frequently have a capsule.
Not all benign tumor are encapsulated
(lieomyoma)
Malignant tumors progressively invade
(infiltrative ) & destroy surrounding normal
tissue: e.g. Breast cancer infiltrating
skin,muscle.
Basal cell carcinoma of skin infiltrating nerve
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4- Metastasis :
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1- Lymphatic Spread :
Invasion of lymphatic vessels followed by spread of
tumor to regional lymph nodes , ultimately to other
sites in the body.
More characteristic in Carcinoma than sarcoma.
Not all enlarged lymph nodes located at the sites of
drainage of a malignancy signifies a metastasis
(immune response in form of lymphoid hyperplasisa
Spread follows the anatomical route of drainage
e.g. : - Breast cancer in upper outer quadrant
axillary L.N.
- Lung Carcinoma - Peribronchial hilar
Paratracheal lymph nodes.
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2- Hematogenous spread :
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brain
lungs
liver
bone
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3- Transcelomic spread :
By seeding of surface of cavity :Tumor cells enter
the cavities & floate in the serous fluid to attached
on the surface of peritoneal cavity .
Within peritoneal or pleural cavity
e.g.: - CA of upper lobe of lung to lower lobe.
- CA of stomach to ovary (krukenburge tumor).
- CA of ovary spread widely through peritoneal
surface (mucinous adenocarcinoma spread to
peritoneal cavity to give pseudomyxoma peritoni )
- CA of colon across peritoneum to S.I.& colon
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Staging of Tumor :
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Tumor Therapy :
Staging, and to a less extent, grading, affect therapy :
1- Surgical excision .
2- Radiotherapy .
3- Chemotherapy .
4- Immunotherapy .
5- MULTIMODALITY of treatment .
Prognosis :
This indicates the final outcome of the disease in terms of
5year or 10 year survival.
This is influenced by :
Tumor Type e.g. Lung CA versus Lip CA
Tumor Grade & Stage.
Host reactions
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EPIDEMIOLOGY OF CANCER:
Cancer epidemiology deals with the occurrence of tumors in
human populations , by study the incidence , prevalence &
mortality .Epidemiologist are trying to identify
environmental , genetic causes of cancer , thus contribute to
better diagnosis ,treatment and prevention .Epidemiology
data may point to a cause & effect relationship between a
cancer and potential carcinogen .
In Iraq males the comments cancers are those of lung ,
bladder , larynx , non Hodgkin lymphoma & leukemias .
In Iraq females , breast cancer , non Hodgkin lymphoma ,
leukemias , CNS tumors , lung cancers.
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1- Geographic location :
Esophageal CA -- High in Iran &north of iraq.
Gastric CA -- High in Japan
Skin CA------ High in New Zealand
Hepatocellular CA --- High in China &south east Asia.
Breast CA , Prostatic CA ,Colorectal CA ---- High in USA
2- Environment factors :Significantly affect the occurrence
of specific forms of cancers in different parts of the world.
* Diet: e.g :gastric cancers in Japan & USA.
* Occupation :e.g : anyline dye with bladder cancer.
* Sunlight e.g : melanoma in Australia .
* Personal habits e.g : cigarette with lung cancer.
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3- Age :
In general , cancer incidence AGE : Cancers is most
common in those over 55 years of age( fact pointing that
cancer evolution requires multiple independent events,
apparently taking place over along period of time e.g.
prostatic carcinoma & lung carcinoma .
Certain cancers occur more in children less than 5years
Acute Leukemia ,Lymphoma , CNS Tumors
(retinoblastoma ,neuroblastoma),soft tissue Sarcomas
(rabdomyosarcoma).
Adolescence age tumors :Osteosarcoma , Ewing sarcoma
, Medulloblastoma .
Biphasic age incidence : Hodgkin lymphoma ( 20 & 60 ).
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4- Hereditery :
Hereditary play a role in the development of cancers even in the
presence of clearly defined environmental factor Usually well
defined inheritance & phenotype :
1-Inherited cancer syndromes:
- Familial Adenomatous Polyposis Coli & - MEN Syndrome
2- Autosomal recessive syndrome of defective DNA repair: - Xeroderma Pigmentos &- X linked immune deficiency:due to
genetic defect of nucleated excision enzyme lead to increase
susceptibility to UV irradiation .
3-Familial cancer :Familial clusters of specific forms of cancers,
but the transmission pattern is not clear (breast , colon ,brain &
ovary ). Younger age groups, multiple or bilateral, two or more
family members are affected. Some linked to inheritance of
mutant
genes e.g. BRCA-1
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Gross appearance of familial polyposis. Entire large bowel was involved. Note the
fact that practically all of the polyps are small and sessile.
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Function
Protooncogen Oncogen
Growth factor
PDGF
SIS
ERB-B2
Signal transduction
Tyrosine kinase
ABL
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1- Point mutation .
2- Chromosomal translocation.
3- Gene amplification.
4- Gene deletion .
Result : Change in structure or quantity of gene
product ( functional proteins).
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Most of these are located in the inner leaflet of plasma membrane where they
receive signals from outside the cell & transmit them to the nucleus.
RAS action: Active RAS in turn activates down-stream regulators of
proliferation (kinase mitogenic cascade) which flood the nucleus with signals
for cell proliferation.
Mutant RAS is trapped in its activated GTP bind form & cell
proliferation continue.
Active RAS
GDP
GTP
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1- Rb gene (Retinoblastoma ):
Example : Retinoblastoma :
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2-PT53
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Mode of Action of PT 53 :
Action of PT53
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3- Apoptosis Genes :
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5- Telomeres
(Cellular senescence)
TUMOR PROGRESSION :
Tumor Progression :
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BIOLOGY OF METASTASES
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Cathepsin D.
Protease .
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CARCINOGENIC AGENTS :
Chemical Mutagenes are detected & graded by the AMES TEST
Factors influencing carcinogenesis include :
- Genetic susceptibility
- Sex & hormonal status
- Diet
Chemical carcinogens act by inducing ras mutation
Some strong chemicals act as Initiator & Promoter
1- CHEMICAL CARCINOGENS :
Direct Carcinogens Directly produce damage without prior
Indirect Carcinogens- (Procarcinogen)
Metabolic conversion in liver by
cytochrome P-450 dependent monooxygenases ultimate carcinogen
metabolic conversion
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2- PHYSICAL CARCINOGENS :
1- U-V light : - Effect depends on intensity of exposure
& quantity of melanin
- Production of pyrimidine dimers in
DNA MUTATION in ras , p 53
- Failed repair Skin CA
- Skin cancer includes : Squamous Cell CA, Basal Cell CA, Melanoma .
2-Ionizing Radiation:
- Present in environment
- Explosions Leukemia after 7 yrs.
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3- VIRAL CARCINOGENESIS :
A - DNA Viruses :Virus have DNA transforming genes (E6,E7)
inactivate suppressor genes, activates cyclins, & inhibit
apoptosis.
1- HPV : Human Papilloma Virus
* Low risk groups (6, 11) Squamous Cell Papilloma
(wart ).
* High risk group ( 16, 18 ) Squamous Cell CA in cervix.
2- EBV : Ebstein Barr Virus
* BURKITTS LYMPHOMA , * B CELL LYMPHOMA
* HODGKINS LYMPHOMA, * NASOPHARYNGEAL CA
Mode of action :
Receptors for virus on B cells Activated B cells Polyclonal
Proliferation, under T cell control ,
- MONOCLONAL B proliferation due to deregulation of CMYC by translocation :
BURKITTS Lymphoma (t 8:14)
- In endemic cases Malaria & Malnutrition may play a role in
immunity ( Lost T cell control ).
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Helicobacter in carcinogenesis
CA LUNG Smoking.
CA CERVIX Sexual transmision of HPV.
CA BLADDER Rubber Industry.
CA LIVER Aflatoxin & HBV infection
CA THYROID Radiation.
ANGIOSARCOMA of Liver
Plastic(PVC).
MESOTHELIOMA Asbestose.
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TUMOR IMMUNOLOGY:
Tumor Antigens :
Tissue specific Ag (peptide of mutant gene),tissue associated
Ag (glycoprotein), viral, Oncofetal ( AFP , CEA)..etc
Anti tumor Host Mechanisms :
1- Sensitized Cytotoxic T lymphocytes (directed against TCell defined tumor Ag).
2- Natural Killer cells may kill tumor cells
without
previous sensitization lyse a wide range of tumors .
3- Macrophages activated by IFN- to secrete TNF- which
is lytic to
tumor cells.
4- Humoral mechanisms .
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Immune surveillance :
SELF POLICING IMMUNE SYSTEM
Supportive evidence :
1- Patients with congenital immune
deficiency have
200 timesrisk of cancer.
2- Immunosuppressed patients have
increased rates
of cancers , specially
LYMPHOMA
-Tumors may escape immune surveillance by :
1- Selection of antigen-negative variants .
2-Loss or reduced expresion of histocompatibility
antigens ,thus become less susceptible to cytotoxic TCell lysis .
3-Tumor induced immunosuppression.
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- Cancer Cachexia :
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4 - Paraneoplastic Syndrome :
Symptoms that not directly related to the primary tumor or
its metastasis or elaboration of hormones indigenous to the
tissue from which the tumor arose .
Syndrome that cant be explained by the effects of either
local or distant spread of tumor or by hormones indigenous
to cell of origin.
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PARANEOPLASTIC SYNDROMES:
1- Ectopic
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2- Oncofetal Antigens :
Carcinoembryonic Antigen ( CEA ) : in fetal tissue &
some malignancies - Colorectal CA & Pancreatic CA .
3- Isoenzymes :
2- Histological methods :
Biopsy of tissue: Needle Biopsy , Endoscopic Biopsy,
Open Biopsy.
Frozen Section (Rapid technique & rapid diagnosis during
operation): Define the lesion & surgical margins of
excision .
Paraffin Section ( 36-48 hrs. or longer ).
3-Immunocytochemistry
:Staining by use of monoclonal AB directed against various
components in cell
May help in diagnosis of undifferentiated cancers or help
in identifying source of a metastatic tumor.e.g.
Cytokeratin Carcinoma
Common leukocyte antigenLymphoma
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S 100 Melanoma
4- Electron microscopy :
For recognition of desmosomes (epithelial tumors ) , or
neurosecretory granules ( neuroendocrine tumors).etc.
5- Flow cytometry :
For measuring DNA content , detecting
diploid versus
aneuploid tumors.etc.
Correlates with rate of growth
&prognosis(aneuploidy=poor).
Useful in the diagnosis of Lymphoma (identification of cell
surface Ag).
DNA-probe analysis (molecular diagnosis):
diagnosis of malignant neoplasm by detection of polyclonal
(benign) B&T-Cell proliferation from monoclonal
(malignant).
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Specific procedures :
- Self examination of the breast .
- Mammography of breast .
- Serial PAP smears for the cervix.
- Serial sputum cytology in smokers.
- Serial urine cytology in some cases, e.g. bilharziasis,
workers in rubber.
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