Pathology of cancer



  • 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:


  • 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:


  • 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

DiagnosticsBenign tumorMalignant tumor
Clinical features
Growth rateSlowRapid
Paraneoplastic syndromes
Radiographic features
Peripheral demarcationWell demarcatedPoorly demarcated
Expansile masses
Floating teeth osteolysis
Histopathological features
Hyperchromatic nuclei
Mitotic indexLowHigh
Abnormal Ag secretionRarePresent
Nuclear-cytoplasmic ratioNormalIncreased
Desmosomal contact
Apoptotic bodiesNormalIncreased
Loss of cell polarity
Polymorphic nuclei
Prominent nucleoli
Cellular differentiationMature cellsImmature cells
Cellular pleomorphism
Benign tumor vs malignant tumor

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

  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 factorsDNA damageGenotypic changePhenotypic changeMalignancy
Virus, tobacco, genetic, UVB, alcohol, malnutrition1. 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
Pathology of cancer

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


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


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


  • 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


  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)


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