NEOPLASM (Dr - Angelfire
NEOPLASM (Dr. Lena)
growth
- progressive increase in the size of the individual
1. multiplication of cells
2. increase intracellular substances
development
- increase in size of the cells (low ( higher state)
differentiation
- increase in complexity of function fo cells & their organizational structure
hamartroma
- disorganized mass of normal tissues
- "hemangioma" - considered as a form of hamartroma
choristoma
- tumor-like mass of normal displaced tissues
dysplasia
- disordered development
- same cell size at all levels
anaplasia (reversionary atrophy)
- change from well-differentiated to embryonic
- "carcinoma in situ" - earliest form of cancer of basement membrane which is not penetrated by anaplastic cells (invasive cancer if penetrated)
heterotopia
- deviation from the natural position
- heterotrophic tissue - thymus
neoplasia
- new growth
neoplasm
- mass composing the new growth
- uncoordinated, purposeless growth that exceeds that of normal tissue, persisting after the cessation of stimuli, preys on the host & competes for energy & nutrition causing wasting of the individual
cancer
- tumor where the cells adhere to the adjacent or any part of the tissue in an obstinate manner
tumor
a. benign: not life threatening
b. malignant: life-threatening
BASIC COMPONENTS OF TUMOR
1. parenchyma - proliferating neoplastic cells
2. supporting stroma - CT with blood vessel & lymphatic
abundant - soft mass depending on the
scanty - firm mass supporting stroma
SPREAD OF CANCER
← adjacent tissue
← lymphatics malignant cells can penetrate
← blood vesels organs or adjacent tissues
← body cavities (natural open field)
← transplantation (iatrogenic)
BENIGN vs. MALIGNANT NEOPLASM
characteristic BENIGN MALIGNANT
differentiation well differentiated (adult-type; well differentiated to anaplastic/embryonic
typical of its tissue origin) (primitive, stem or undifferentiated cells;
pleomorphism with giant tumor cells,
increased N/C ratio, loss of polarity)
rate of growth slow & progressive; standstill or faster (( mitoses; starts as an in situ;
regress (normal mitosis & rare) unpredictable)
- growth can't be tremendous,
regress, stay in same size
local invasion expantile, pushing, cohesive, non- usually infiltrative or erosive (rarely cohesive)
invasive, encapsulated or defined invasiveness = less cohesiveness & ( calcium
cleavage
metastasis absent frequent
(except H-mole & leiomyoma) (aggressive, large & rapidly growing types
except basal cell carcinoma & glioma)
course usually non-fatal fatal in general
(except: neuroblastoma in infants ( ganglio-
neuroma or regress)
can impinge & cause hemorrhage
occasionally that becomes
malignant long standing types
of neurons
BASIS OF DIFFERENTIATION OF TUMOR
1. differentiation 3. mode of growth 5. course
2. rate of growth 4. metastasis
The spread of cancer is due to organ trophism of cancer cells which may be due to:
← adhesion molecules (specificity for endothelial cells of the organ)
← chemoattractants liberated by the organs
← favorable soil of growth
e.g. prostatic cancer (bones)
bronchiogenic carcinoma (adrenals)
neuroblastoma (liver & bones)
GRADING OF CANCER
- estimate the "aggressiveness" or "degree of malignancy" based on:
1. cytologic differentiation (poorly differentiated squamous cell carcinoma)
2. number of mitoses (smooth muscle & connective tissue tumor)
STAGING OF CANCER
- determines the outcome based on:
1. size
2. lymph node spread
3. distant metastasis
- TNM staging (accepted staging)
a. tumor
To - in situ
T4 - extreme tumor with invasion
b. node
No - lymph node involvement
N1 - mild
N2
N3
( higher number, higher involvement
c. metastasis
Mo - no metastasis
M1 - distant metastasis
NOMENCLATURE OF TUMORS
I. BENIGN: tissue + "oma" (fibrous, fat, skeletal, etc)
(exception: seminoma, melanoma, lympoma, hepatoma)
II. BENIGN EPITHELIAL TISSUE
1. glandular - adenoma (liver, pancreas, kidney, etc.)
2. finger-like - papilloma/polyp
3. large cystic mass, glandular - cystadenoma
4. optic mass with finger-like projection - papillary cystadenoma
5. cystic mass with mucin producing gland - mucinous cystadenoma
III. MALIGNANT EPITHELIAL TISSUE
- carcinoma (adenocarcinoma, papillary carcinoma, squamous cell carcinoma, etc.)
IV. MALIGNANT TUMOR FROM MESENCHYMAL TISSUE
- sarcoma
V. MORE THAN ONE NEOPLASTIC CELL (relate tissues)
e.g. mixed tumor of salivary gland
malignant mixed mulllerian tumor
VI. TUMOR OF MORE THAN ONE GERM CELL - teratoma
VII. UNDIFFERENTIATED MALIGNANT EPITHELIAL TUMOR
- poorly differentiated or undifferentiated carcinoma
teratoma
← benign
← malignant
← solid
squamous cell carcinoma
← stratified cells
← loss of polarity
← cells are hyperchromatic
papillary tumor
← arising from parotid gland & forms a cyst
9 WARNING SIGNS OF CANCER
1. change in bowel habits
2. sore that does not heal
3. unusual bleeding or discharges
4. lump in breast or elsewhere
5. indigestion or difficulty of swallowing
6. change in wart or mole
7. nagging cough or hoarseness
8. sudden unexplained weight loss
9. unexplained anemia
PREDISPOSITION TO CANCER
I. adults
MALE FEMALE
prostate breast
lungs colorectum colorectum lungs
urinary tract uterus
lymphomas lymphomas
II. children (less than 15 years old)
MALE FEMALE
leukemia leukemia
brain & other NS brain & other NS lymphomas bone
connective tissue bladder
bone lymphoma
FACTORS IN THE CAUSATION OF CANCER
A. GEOGRAPHIC/RACIAL FACTORS
e.g. gastric cancer - more on Japan than America
lung cancer - more on America than Japan
B. ENVIRONMENTAL FACTORS
1. cardiogenic substances
coal tar (hydrocarbon) - scrotal cancer (chimney sweepers)
aflatoxin - liver cancer (Aspergillus flavus)
nitrosamine (preserved food) - stomach cancer
betel nuts - oral cavity cancer
UV rays - skin cancer
alcohol - cancer in oropharynx, esophagus, larynx, liver
cigarette smoking - cancer of lungs, mouth, pharynx, esophagus, pancreas, bladder
asbestos - mesothelioma
arsenic (fungicides, herbicides, metals) - cancer of lungs & skin hemangiosarcoma
benzene (light oil, rubber, detergents) - leukemia, lymphoma
cadmium (batteries, metal platings) - prostatic cancer
diethylstilbestrol - vaginal adenocarcinoma
ethylene oxide (ripening agents for fruits &
nuts) - leukemia
vinyl chloride (refrigerant, plastics) - angiosarcoma, liver cell carcinoma
nickel (ceramics, batteries) - cancer of nose and lungs
2. practices
sexual practices: many partners, early age of
marriage
exposure = cervical cancer
circumcision
3. viruses
HTLV - leukemia (human T-cell leukemia virus)
HSV - cervical cancer (herpes simplex virus)
HPV - warts (human papilloma virus)
EBV-NP - lymphoma (epstein barr/Burkitt's lymphoma)
4. bacteria (Helicobacter pylori : gastric)
- gastric cancer, gastritis, lymphoma
(mucosa associated type)
C. AGE
D. HEREDITY
1. inherited cancer syndrome: inheritance of a single mutant gene increases risk of cancer (related to cancer suppressor gene)
characteristics:
← autosomal dominant pattern of inheritance
← involve specific sites or tissues
← associated with specific marker phenotype
← with incomplete penetrance & variable expressibility
example:
← retinoblastoma - most frequent
← familial adenomatous polyposis
← neurofibromatosis
2. familial cancer
characteristics:
← early age of onset
← 2 or more close relatives
← multiple or bilateral
← no specific marker phenotype
← nuclear transmission pattern
example:
← breast cancer
← ovarian cancer
← colonic cancer
3. autosomal recessive syndrome of defective DNA repair
- associated with chromosomal or DNA instability
e.g. xerodermal pigmentosum
E. ACQUIRED PRE-NEOPLASTIC DISORDER
condition example
hyperplasia endomethelial cancer
bronchial dysplasia bronchogenic
cirrhosis liver cell cancer
chronic atrophic gastritis gastric cancer
leukoplasia mucosal cancer
borderline tumor
- tumors of low malignant potential
- compared to an angel with horn or tail
CHEMICAL CARCINOGENS
1. direct acting (e.g. cyclophorphoride)
2. indirect acting (procarcinogens)
- should be activated
- e.g. aflatoxin, nitrosamine, insecticides
TARGETS OF CHEMICAL CARCINOGEN
DNA (mutagenic)
mutagenic effects:
1. oncogenes - causes cancer
2. for apoptosis
3. cancer suppressor gene
I. INITIATION PHASE (rapid & irreversible)
metabolic activation - CARCINOGEN
1. cytocchrome P450
2. peroxidase oxidation
3. reduction reaction
4. glutathione conjugation
CARCINOGEN
electrophilic intermediate detoxification
EXCRETION
binding to DNA: detoxification
ADDUCT FORMATION
DNA repair
Normal cell
permanent DNA lesion: Cell death
INITIATED CELL
II. PROMOTION PHASE
(reversible & dose-dependent)
promoters:
hormones cell proliferation
drugs altered differentiation
phenols
phosphoesters preneoplastic clone
artificial sweetener
(saccharin) neoplastic cells
RADIATION
I. UV rays (UVB & UVC)
- depends on quantity & intensity
mechanism:
pyrimidine dimer formation on DNA
transcriptional error ( cancer formation
example:
skin cancer (UVB)
II. IONIZING RADIATION
Types:
electromagnetic (X-ray, gamma ray)
particulate ((, (, protons, neutrons)
Mechanism:
chromosomal damage
protein alteration
enzyme inactivation
cell membrane damage
Example:
Skin cancer, leukemia, etc.
VULNERABLE TO DEVELOP CANCER WITH RADIATION
1. infants
2. children
3. with DNA repair defects seen in:
a. xeroderma pigmentosum
- degradation of skin, skin tumors
b. bloom's syndrome
- mental retardation, causes several types of cancer
c. ataxia-telangiectasia
- lymphomas, uculocutaneous type
d. fanconi's anemia
- leukemia
- ( RBC, ( patelet
BIOLOGY OF TUMOR GROWTHS
4 PHASES:
1. transformation
2. growth of transformed cells
3. local invasion/infiltration
4. metastasis (distant spread of tumor)
OBSERVATIONS
1. A 10 ( should at least has 30 population doubling to attain 1 gram (smallest detectable size).
2. A 1 gram tumor needs 10 doubling to attain 1 kilo (maximum size compatible with life for malignancy).
3. Progressive growth of tumors & its rate of growth determined by excessive cell production over cell loss.
4. Rapidly dividing cells are targets of most anti-cancer reaction but not those in the replicating pool (cell that lack nutrients = in Go-G1 phase).
5. Doubling time is unpredictable (1 month to years).
6. Even if monoclonal in origin, cells in the tumor are of several variants (polyclonal) - due to genetic instability?
a. non-antigenic clone
b. invasive
c. metastatic
d. clone that requires few growth factors
ANGIOGENESIS
- caused by tumor associated angiogenic factors (produced by tumor cells/inflammatory cells)
- e.g 1. vascular endothelial growth factor (VEGF)
2. basic fibroblast growh factor (bFGF)
OBSERVATION:
Tumors cannot be more than 1-2 mm if without blood vessel:
hypoxia ( apoptosis (p53 influence)
ANGIOGENESIS is a result of influence of the:
a. angiogenic factors
b. anti-angiogenic factors: thrombospondin 1, angiostantis, etc.
CHANGES IN CANCER CELLS
I. TRANSFORMATION
- cell & nuclear size
- transplantability
- invasion
metastasis:
1. penetration of vessel
2. release/embolization
3. arrest & adherence
4. development of blood vessel & stroma ( secondary tumor
Figure 1: Metastatic cascade
STEP: Should be able to loosen & detach itself brought by down-regulation.
"Cadherin" - bind cells together
EXTRCELLULAR MATRIX INVASION
1. detachment ("loosening up") of cell
2. attachment to extracellular matrix (integrin)
3. degradation of ECM (proteolytic enzyme or proteases - destroy components)
4. migration (locomotion)
- autocrine motility factor (a cytokine)
- bind to receptor for motility
II. CHANGES IN MEMBRANE
← decreased adhesiveness & cohesiveness
← loss of intracellular junctions
← increased transport of sugar & amino acid
III. ANTIGENIC CHANGES
← fetal antigen (liver, ovarian & testicular tumor)
← common tumor associated antigen
• seen in normal tissues which elicits rejection response to tumors
← soluble (shed) antigen
• blocks antibody of cell-mediated response
IV. CHANGES IN KARYOTYPE
- deletion
- gene amplification
- balanced translocation
V. BIOCHEMICAL CHANGES
- alkaline phosphatase (placental type - lung cancer)
- aldolase (hepatoma)
- insulin (fibrosarcoma)
FUNDAMETAL PRINCIPLES IN CARCINOGENESIS
(Molecular Point of View)
1. Cancer is due to "non-lethal damage".
2. Three targets of genetic damage:
a. growth promoting protooncogenes
b. growth inhibiting cancer-suppressor genes
c. genes regulating apoptosis
3. Damaged gene is regulated by DNA repair genes
• 4th regulating gene
• "caretakers"
• 2abc - considered as "gate-keeper"
4. Carcinogenensis is a multi-step process with genetic & phenotypic attributes (excessive growth, local invasiveness & distant metastasis)
ACTIVATION OF PROTOONCOGENES
- change in structure of gene ( change in regulation of gene expression ( increased growth promoting proteins ( increase in number of cells
1. POINT MUTATION
• involvement of a specific point
• e.g. RAS oncogene - pancreatic adenocarcinoma
2. CHROMOSOMAL REARRANGEMENT
• translocaton results to:
a. overexpression of protooncogenes (in Burkett's lymphoma - Cr 8 & 14))
b. hybrid gene formed that promotes growth promoting proteins (as in Philadelphia chromosome - Cr 9 & 22)
3. GENE AMPLIFICATION
• 2 patterns:
a. double minutes (chromosome like structure - small rounded, oval)
b. homogeneous staining region
(HSP within chromosome)
ONCOGENES (cancer causing genes)
e.g. 1. V-oncogene (viral oncogene) - in transforming viruses
2. C-oncogene (cellular oncogene) - result to insertional mutagenesis
ONCOPROTEINS: protein products of oncogenes
TYPES OF GROWTH FACTORS
1. PLATELET DERIVED GROWTH FACTOR
← osteosa & fibrosarcoma
← fibroblast of cancer of the breast, stomach, etc.
2. GROWTH FACTOR RECEPTOR
← deliver oncogenic signals
← activated by mutation, overexpression or gene rearrangement
← e.g. epidermal growth factor receptor - SCC of lung
3. SIGNAL TRANSDUCING PROTEINS
← at inner leaflet of plasma membrane
← e.g. RAS GTP binding protein which regulates cell cycle through control of kinases
4. NUCLEAR TRANSCRIPTION PROTEIN
← contain specific amino acid sequences that bind to DNA
5. CYCLINS & CYCLIN-DEPENDENT KINASES
← modulators of cell cycle
← allow quiescent cells to enter the cell cycle
← mutation that dysregrate their activity favor cell proliferation
TUMOR SUPPRESSOR GENES
- basic characteristics: regulate cell growth, do not prevent tumor formation
- loss of these genes ( tumor
- products of tumor & suppressor genes (nuclear)
a. Rb Gene
▪ "brake" from G1 to S phase (inactivated)
▪ by phosphorylation ( brake release ( cells to S phase
b. p53 Gene
▪ single most common target for genetic alteration in human tumor
▪ "guardian of the genome"; "molecular policeman" - prevents cancer: control in transcription of their genes
▪ specific functions:
1. recognizes DNA damage ( arrest G1 phase for DNA repair
2. direct cells with unrepaired DNA to undergo apoptosis
c. BRCA - ? DNA repair
▪ transcriptional regulation; mutation (
1. female: cancer of ovary & breast
2. male & female breast cancer
- outside the nucleus:
a. genes that regulate signal transduction
e.g. adenomatous?C in cytosol-inihibitor - degrades B catanin which promotes cell proliferation
b. cell surface receptor
e.g. epithelial cadherin gene ( cell adherence; "glue gene"
loss of cell's ability to invade & metastasize
GENES that regulate APOPTOSIS
Characteristics:
1. starts with letter "b"
2. with 2 types:
a. inhibition of apoptosis (if overexpressed)
e.g. bcl 2 - in lymphoma
- regulates exit of cytochrome C which help in activating caspase g
b. favors apoptosis
e.g. bad, bax, bcl-xs
← ratio of death antagonists to agonist = determine occurrence of apoptosis
DNA REPAIRS GENE
facts:
1. defective DNA repair - reduction error
2. repair is done by the mismatched gene
e.g. during replication, instead of the normal A=T pair, it may be G=T pair
( allows mutation in other
genes
if there is loss of the normal repair, genes = cancer
TUMOR GROWTH
telomere
← specialized structure at the end of the chromosome, the shortening of which serves as a clock for cell division, shortening beyond certain point = cell death
telomerase
← increased activity in cancer
TUMOR ANTIGENS
I. tumor specific antigen (TSA)
- in tumor cells
- source:
1. mutation of normal cell
- associated with major histocompatibility Ag, class I); recognized by CD8T cell
2. product of oncogene & anti-oncogene
II. tumor associated antigen (TTA)
- normal & tumor cells
- e.g. 1. TA carbohydrate Ag (as mucin assoc. Ag)
2. oncofetal Ag (as CEA, AFP)
3. differentiation - specific Ag (CD10-B cell type)
III. semi-tumor specific antigen
- e.g. overexpressed Ag in tumors
- between tumor-associated & specific
PARANEOPLASTIC SYNDROME
- characteristics:
can't be explained by:
local spread
distant spread
hormone production
- e.g. 1. Cushing's syndrome (ACTH)
2. hyperthyroidism (TSH) - bronchogenic
& prostatic cancer
3. hypoglycemia (insulin) - fibrosarcoma
& hepatoma
4. polycythemia (erythropoeitin)
- facts:
1. No single oncogene cvan transform cells in vitro but combination is needed.
2. Every human cancer has several genetic alterations: activation of several oncogenes & loss of 2 or more suppressor gene.
3. Usually a gene is present in cancer that influences mutations.
EFFECTS OF TUMOR ON THE HOST
1. LOCAL & HORMONAL
e.g. pituitary adenoma ( pituitary destruction ( endocrinopathy
B cell adenoma ( insulin production
2. CACHEXIA
← cachectin-mediated (TNF alpha, IL-1, etc.)
← loss of body fat, wasting, & profound weakness
← loss of appetite
← reduced synthesis & storage of fat & increased mobilization of fatty acids from adipocytes
3. PARANEOPLASTIC SYNDROME
- symptoms not directly related to the spread of the tumor or elaboration of hormones indigenous to the tissue from which the tumor arose
- may be the earliest clinical manifestations of a neoplasm & may mimic distant spread
HOST DEFENSES VIA TUMOR
1. cytotoxic cells
- vs. membrane associated tumor Ag
2. NK cells (natural killing cells)
- no sensitization needed
3. complement activation
4. macrophages
- with cytotoxic product; Ab dependent
a. produce reactive O2 metabolites
b. secrete TNF ( (tumor necrosis factor)
immunosurveillance - cancer cells acted on by host effector
cells/host immune responses
MECHANISMS TO INVADE IMMUNOSURVEILLANCE
1. outgrowth of Ag-negative variant
2. loss or decreases expression of class I - histocompatibility Ag (ALA)
3. lack of co-stimulatory molecules to sensitized T-lymphocyte
4. immunosuppression by oncogenic agents (chemical & radiation)
5. apoptosis of cytotoxic T cells (e.g. in melanoma & hepatomas with Fas ligand)
DIAGNOSIS OF TUMORS
1. histology & cytology (biopsy, FNAB, smears)
2. immunocytochemisry stain (keratin-carcinoma, mesothelioma; desmin)
3. DNA flow cytometry
4. molecular diagnosis
5. tumor markers
a. carcinoembyonic
b. ( - feto protein
c. prostatic specific antigen
d. prostatic acid phosphatase
e. ( - HCG
f. thyroglobin
g. Ca 15.3 (breast)
h. Ca 1.25 (ovary)
i. Ca 19.9 (pancreatic)
j. Ca 72 (GIT cancer)
IMMUNOTHERAPY
1. adoptive cellular Tx
2. cytokine Tx
3. Ab-based Tx: Ab + potent toxin
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