Definitions
Neoplasm:
- Abnormal mass of tissue
- Where growth is excessive and uncoordinated than normal tissues
- Persists in same excessive manner after cessation of stimulus
The following are pathological growths but not neoplasms:
Teratoma:
- A mass consisting of all 3 germ layers
- Totipotent cells differentiate – form cystic tumor lined with skin, hair, sebaceous glands and tooth structure
- Eg. Ovarian cystic teratoma
Choristoma: Ectopic rest of normal tissue
Hamartoma: Disorganized + mature differentiated cells of a different site eg. Hemangioma
The following may occur physiologically:
Hyperplasia:
- Increased number of cells
- Hormonal – pregnancy
- Compensatory – partial hepatectomy
Hypertrophy: Increased size of cell eg. muscular hypertrophy
Etiopathogenesis of cancer
1. Chemical carcinogens
a) Direct acting compounds
- These do not need chemical transformation for their carcinogenicity
- Eg. Alkylating agents, acylating agents
b)Indirect acting compounds (procarcinogens)
- Need metabolic conversion to activate them
- Eg. Polycyclic aromatics, asbestos, silica, benzene, aflatoxin (hepatocellular carcinoma), nitrosamines (tobacco)
c) Promoters
- Compounds that are not in themselves tumorigenic but enhance the effects of the direct and indirect acting agents
- Eg. Hormones – estrogen
2. Radiation energy
a) Ultraviolet rays – Formation of pyrimidine dimers due to UVB (280-320nm) damage
b) Ionizing radiation
- Cause DNA damage (by producing free radicals/peroxides)
- Eg. X-rays, gamma rays, α & β particles, protons and neutrons
3. Oncogenic microbes
a) DNA viruses
- HPV – Producers of E6 and E7 proteins which inactivate p53 and Rb
- Hepatitis B – Producers of HBx – a p53 deactivating protein that contributes to hepatocellular carcinoma
- EBV:
- Switches of Bcl-2
- Selective binder to CD21 B-lymphocyte receptor, causing immortalization
- 100% associated with – Nasopharyngeal cancers, Hodgkin’s disease
b) RNA viruses
- HTLV-1 – has selective tropism for CD4+ T cells and contains Tax gene responsible for immortalization
- HIV – indirectly
c) Helicobacter pylori – Uncontrolled proliferation, particularly of B cells in response to chronic infection – causes gastric carcinoma
d) Endoparasites – Schistosoma spp.
4. Genetics
Clinicopathological characteristics of benign and malignant tumors
| Diagnostics | Benign tumor | Malignant tumor |
| Clinical features | ||
| Growth rate | Slow | Rapid |
| Ulceration | – | ✓ |
| Indentation | – | ✓ |
| Metastases | – | ✓ |
| Paraneoplastic syndromes | – | ✓ |
| Radiographic features | ||
| Peripheral demarcation | Well demarcated | Poorly demarcated |
| Expansile masses | ✓ | – |
| Floating teeth osteolysis | – | ✓ |
| Histopathological features | ||
| Hyperchromatic nuclei | – | ✓ |
| Invasiveness | – | ✓ |
| Mitotic index | Low | High |
| Abnormal Ag secretion | Rare | Present |
| Nuclear-cytoplasmic ratio | Normal | Increased |
| Desmosomal contact | ✓ | – |
| Apoptotic bodies | Normal | Increased |
| Loss of cell polarity | – | ✓ |
| Aneuploidy | – | ✓ |
| Polymorphic nuclei | – | ✓ |
| Prominent nucleoli | – | ✓ |
| Cellular differentiation | Mature cells | Immature cells |
| Cellular pleomorphism | – | ✓ |
Principles of carcinogenesis
1. Multistep process – acquisition of genotypic changes – results in phenotypic attributes – necessary for tumor progression
2. These changes induced in a cell by – mutations in genes of DNA – and are non lethal genetic damage
3. Mutations are hereditary or environmental (chemical, virus, radiation)
4. Modes of mutation:
- Chromosomal rearrangement
- Deletions, insertions, point mutations, translocation
- Gene amplification or silencing
5. Damaged progenitor cells proliferate in clonal manner – therefore excessive growth and local invasiveness – promote tumor progression
6. Principle targets of genetic cell damage:
a) Proto-oncogenes:
- Growth promoters – mutate – form oncogenes
- Proto-oncogenes – regulators of normal growth and differentiation
- Oncogenes – encode oncoproteins – lack regulatory elements, don’t function normally
b) Anti-oncogenes/ tumor suppressor genes:
- Regulate cell growth
- Prevent abnormal proliferation
- Therefore regulate:
- Nuclear transcription
- Cell cycle
- Cell surface receptors -of growth promoting and apoptotic pathway
- Genes lose heterozygosity – neoplastic proliferation occurs
c) Apoptosis regulatory genes:
- Regulate programmed cell death
- Caspases (cysteine aspartic proteases) – exist as inactive zymogens in cytosol – activated by proteolytic cleavage
- Mutations interfere with the function of the apoptotic cascade eg. Bax (pro apoptotic agent) & TFF-b (apoptosis receptor) mutations
d) DNA repair genes:
- Hereditary defects of DNA repair genes – multiple malignancies
- Normally damaged DNA – apoptosis or DNA repair
- Therefore malfunction of DNA repair genes + silenced tumor genes – mutations persist
e) Decreased telomerase activity:
- Telomerase regulates number of cell divisions by shortening telomers
- Therefore decreased activity – cannot regulate cell division
Phases of cancer
- Transformation
- Growth of transformed cells
- Local invasion
- Distant metastases
Factors that contribute to these are:
- Cell proliferation
- Angiogenesis
- Tumor heterogeneity
a) Cell proliferation
- Doubling time is shorter (therefore immature cells)
- Increased fraction of cells in the replicative pool
- Lower rate of apoptosis
b) Angiogenesis
- Physiologic angiogenesis – embryogenesis, ovulation, wound healing
- Pathologic angiogenesis – Inflammation, tumor growth, metastasis
Angiogenic cytokines:
c) Tumor heterogeneity
Step wise acquisition of mutations to produce phenotypes that:
- Confer invasivness
- Non-antigenicity
- High growth rates
- Metastatic potential
- Apoptosis evasion
- Resistance to antineoplastic agents
| Environmental factors → | DNA damage → | Genotypic change → | Phenotypic change → | Malignancy |
| Virus, tobacco, genetic, UVB, alcohol, malnutrition | 1. Direct 2. Chronic oxidative stress (ROS) | 1. Cell growth + 2. Neoangiogenesis + 3. Immune evasion + 4. Metastasis + 5. Apoptosis -ve 6. DNA repair -ve | Potentially malignant lesions (Red and white lesions) | Oral carcinoma |
The metastatic process
1. Destruction of cell-cell contact within the tumor
- Down regulation of cadherins and catenins (cytoskeletal binding agent)
2. Attachment to matrix components
- Development of high affinity receptors for basement membrane (lamin and integrins)
- For fibronectin, collagen, laminin and vitronectin
3. Degradation of extracellular matrix
- Tumor secrete proteases:
- Serines
- Cystines
- Matric metalloproteins (MMPs)
4. Migration of tumor cells
- Tumor cell derived motility factors – beta thymosin
- Growth promoting, angiogenic and chemotactic cleavage products of matrix components (collagen, proteoglycans) – used for motility
Escape of immune surveillance
1. Eliminate immunogenic subclones + selective outgrowth of antigen negative variants
2. Low expression of histocompatibility antigens (HLA class 1) – to escape T cell cytotoxicity – more susceptible to NK cells
3. Lack co-stimulatory molecules eg. B7
- T cell activity needs: foreign signal binding + co-stimulatory molecule binding
4. Secrete immunosuppressive agents eg. TGF beta
5. Kill T cells: melanomas and hepatocellular carcinomas express Fas-ligand – selectively kill T cells by apoptosis – when they come into contact
Field cancerization
- Stepwise accumulation of genetic changes in an area exposed to carcinogens
- Phenotypic change – a result of genetic changes – due to exposure of mucosa to carcinogens
Steps:
1. Acquiring genetic mutations and epigenetic changes – occur over a widespread multifocal field – leads to molecular lesions
2. Progress to cytologically recognizable premalignant foci of dysplasia
Histological changes in epithelial dysplasia:
- Loss of polarity of basal cells
- Loss of intercellular adherence
- Cellular pleomorphism
- Keratinization of single cells/cell groups
- Enlarged nuleoli
- Drop-shaped rete pegs/ridges
- Presence of > 1 layer having basaloid appearance
- Irregular epithelial stratification
- Increased nuclear – cytoplasmic ratio
- Nuclear pleomorphism
- Nuclear hyperchromatism
- Mitotic figures:
- Abnormal in form
- Present in superficial 1/2 of epithelium
- Increase in number
Architectural changes:
- Bulbous rete pegs
- Basilar hyperplasia
- Hypercellularity
- Altered maturation pattern of keratinocytes
3. Progress to carcinoma in-situ
- Entire thickness from basal level to mucosal surface affected
- Dysplastic cells breach basement membrane – invade underlying CT
4. Progress to carcinoma
Multistep hypothesis
- States that cancer occurs due to a step wise accumulation of mutations:
Normal cells —Initiation→ Initiated cells —Promotion→ Preneoplastic cells —Progression→ Neoplastic cells
- Acquire several mutations in a proper sequence
- Targets genetic cell regulators
Procarcinogen —Metabolic activation→ Genotoxic carcinogen → DNA damage —Proliferation→ DNA mutations —Proliferation→ Activate oncogene, inactivate tumor suppressors —Proliferation→ Tumor
Cancer cachexia
- Marked weight loss in patient with cancer, cannot be reversed by normal nutritional support
- Anorexia + cachexia
Clinical:
- Involuntary weight loss
- Muscular wasting
- Loss of appetite – poor overall quality of life
- Pain
- Fatigue
- Nausea
Mechanism:
- Poorly understood
- Multifactorial
- Inflammatory cytokines – TNFα, INFγ & IL-6
- Catabolic effect on skeletal muscle and adipose tissue – cause proteolysis
- Increased levels of leptin (secreted by adipocytes) – block release of neuropeptide Y – decrease energy intake despite high demand
Diagnosis:
- Clinical features
- BMI
- Lab markers:
- Albumin
- Prealbumin
- C reactive protein
- Hemoglobin
- Biomarkers: IL-6, IL-1b, TNFα, IL-8, INFγ
- Imaging (muscle mass):
- CT, MRI
- Bioelectrical impedance analysis
- Dual energy x-ray absorptiometry (DEXA)
Management:
- Exercise
- Nutrition
- Supplements
- Anti-inflammatory drugs
- Psychotherapeutic intervention
- Medication – glucocorticoids, progestins, antiemetics
