NEOPLASM (Dr



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

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download