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

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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

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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	–	✓

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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

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Phases of cancer

1. Transformation
2. Growth of transformed cells
3. Local invasion
4. 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:

1. VEGF
2. Basic FGF
3. PDGF
4. GM-CSF
5. IL-1
6. Insulin like GF

c) Tumor heterogeneity

Step wise acquisition of mutations to produce phenotypes that:

1. Confer invasivness
2. Non-antigenicity
3. High growth rates
4. Metastatic potential
5. Apoptosis evasion
6. 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

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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

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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

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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

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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

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Cancer cachexia

• Marked weight loss in patient with cancer, cannot be reversed by normal nutritional support
• Anorexia + cachexia

Clinical:

1. Involuntary weight loss
2. Muscular wasting
3. Loss of appetite – poor overall quality of life
4. Pain
5. Fatigue
6. 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:

1. Clinical features
2. BMI
3. Lab markers:
   • Albumin
   • Prealbumin
   • C reactive protein
   • Hemoglobin
4. Biomarkers: IL-6, IL-1b, TNFα, IL-8, INFγ
5. Imaging (muscle mass):
   • CT, MRI
   • Bioelectrical impedance analysis
   • Dual energy x-ray absorptiometry (DEXA)

Management:

1. Exercise
2. Nutrition
3. Supplements
4. Anti-inflammatory drugs
5. Psychotherapeutic intervention
6. Medication – glucocorticoids, progestins, antiemetics