1.11 CARCINOGENESIS

• DEFINE NEOPLASIA

  
  

  • Neoplastic transformation due to multiple genetic (e.g., mutations, deletions, translocations, amplifications) and epigenetic (e.g., promoter methylation) alterations in cells
  • mutation in 1 cell= abnormal proliferation= neoplasm
  • abnormal growth and formation of new tissue AKA TUMOUR / NEOPLASM
• Describe the growth that is exhibited in neoplastic transformation?

  
  

  • Autonomic
  • uncontrolled
  • abnormal
• What does neoplastic transformation result in?

  Development of new but useless tissue (mass) that variably simulates the tissue of origin

  
  

  • stimulating tissue of origin= it can either inhibit (destroy tissue of origin) or stimulate (cause tissue of origin to proliferate and aid in growth of tumour)
• what follows new mutations and epigenetic events?

  New clones of neoplastic cells with new biological characteristics evolve
• 2 types of neoplastic tissue?

  
  

  • benign
  • malignant
• neoplasia is: More common with increased age - often age peaks

  • most malignancy occurs in older adults
  • peadiatric tumours: blastomas, leukemia, CNS, embryonal rhabdomyosarcoma
• Typical paediatric tumours

  • blastomas
  • leukemia
  • CNS
  • embryonal rhabdomyosarcoma
• Common cancers in men

  • Prostate
  • lung
  • colon
• Common cancers in women

  • Breast
  • colon
  • cervix (in SA)
• Geographic factors(where people live)

  Hepatocellular carcinoma in Eastern-Cape
• Genetic factors

  Familial adenomatous polyposis and colon carcinoma
• Immune-suppressed patients

  More prone to certain neoplasia e.g., HIV (Kaposi sarcoma, lymphomas)
• Environmental factors (carcinogens)

  Smoking and lung carcinoma
• Environmental factors + genetic predisposition

  Sun light + defect in DNA repair = skin cancer

  • EG albinism
• what 2 parts make up the tumours structure?

  
  

  • PARENCHYMA: Transformed neoplastic cells (aka tumour cells)
  • STROMA: supportive connective tissue and blood vessels
• Describe what the parenchyma and stroma determine for the tumour?

  
  

  • parenchyma: biological potential of tumour (aggressiveness, response to treatment)
  • stroma: tumour growth and proliferation
• describe how the stroma can vary in characteristics:

  • consistency: soft to firm
  • desmoplasia: fibrous and hard
  • inflammation: absent to abundant
  • DIC
• Describe what the parenchyma influences:

  
  

  • tumour nomenclature
  • differentiation of tumour
  • function of the tumour
• Tumour cells induce angiogenic and other growth factors (VEGF)
• Stroma enables transport of nutrients to neoplastic cells, intercellular signalling
• Tumour angiogenesis: formation of new blood vessels inside a tumour for 02 and nutrients= growth. Describe the process.

  1. Neoplastic transformation of a single cell results in the growth of a tumour nodule, limited by the ability of nutrients to diffuse into it, to a diameter of 1-2 mm

  2. Production of angiogenic factors (AF) stimulates the proliferation and ingrowth of blood vessels, enabling tumour growth to be supported by perfusion

  3. Eventually, the tumour outgrows its blood supply, and areas of necrosis appear, resulting in slower growth

  
• describe the macroscopic (clinical) appearance/ shape of a tumour

  
  

  • sometimes the appearance correlates with clinical behaviour of the tumour
  • sessile
  • polypoid- benign
  • papillary- benign/ malignant
  • exophytic/fungating- malignant
  • ulcerated- malignant
  • annular- malignant
• Macroscopic appearance and clinical behaviour

  • Polypoid: generally localized without invasion of adjacent tissue = benign neoplasia
  • Ulcerated, fungating, annular: more commonly show destructive invasive behaviour = malignant neoplasia
  • Papillary often benign but may be malignant

  
• Macroscopic appearance does not always correlate with a neoplasm, and other clinical, macroscopic and microscopic features are necessary for a specific diagnosis
• Examples of non-neoplastic macroscopic appearances

  • Ulcerated - peptic ulcers in the stomach; infectious e.g. intestinal typhoid; ischaemic e.g. skin ulcer due to underlying arterial insufficiency
  • Annular – tuberculosis of the small bowel
• Connective tissue neoplasms are often well-circumscribed but still malignant. A biopsy is essential to establish a diagnosis.
• Cut surfaces of tumours may correlate with benign or malignant behaviour
• what do Malignant tumour cut surfaces show

  • Necrosis
  • Haemorrhage
  • Fibrosis
  • Degeneration
• Some malignant tumours, such as lymphomas and seminomas, appear uniformly bland, mimicking benign tumours
• Neoplasms differ histologically from their corresponding normal tissue bywhich features?

  
  

  • Loss/reduction of differentiation including function of the malignant cells- less specialized
  • Loss/reduction of cellular cohesion- disorganized structure
  • Nuclear: enlargement, pleomorphism and hyperchromasia(intensity of staining)
  • Increased mitotic activity
  • NB: these features vary in severity and the degree of the features= aggressiveness and prognosis
• define Anaplasia

  Most severe changes associated with malignancy

  • state of extreme loss of cellular differentiation where cells lose their features (of tissue of origin) and return to primitive and undifferentiated state
  • A MALIGNANT TUMOUR THAT shows no immediately recognisable differentiated features, loss of cellular cohesion, increased nuclear size and mitotic acitivty
• Cytological features of anaplasia

  • Pleomorphism
  • High nuclear:cytoplasmic
  • Large nucleoli
  • Abnormal mitoses
  • Hyperchromatic nuclei
  • Loss of cellular cohesion
• Architecture of anaplastic tumour?

  
  

  No recognisable structures
• Functional and Biology of anaplastic tumour:

  
  

  • function: No or abnormal, inappropriate function
  • biology: aggressive
• describe the 2 types of classification of tumours:

  • Biological behaviour: benign, malignant, uncertain
  • Histogenesis (origin of tumour from a specific cell type/ ability to simulates the cell of origin): morphological differentiation (extent to which they resemble morphology of origin cell) OR functional differentiation (extent to which they exhibit same function as origin cell)
• Precise classification of individual tumours is important for planning effective treatment
• WHEN DO BENIGN TUMOURS CAUSE CLINCAL PROBLEMS? PHOMA

  
  

  • pressure on adjacent tissues (e.g. benign meningeal tumour causing epilepsy)
  • obstruction to the flow of fluid (e.g. benign epithelial tumour blocking a duct)
  • production of a hormone (e.g. benign thyroid tumour causing thyrotoxicosis)
  • transformation into a malignant neoplasm (e.g. adenomatous polyp progressing to an adenocarcinoma)
  • anxiety (because the patient fears that the lesion may be something more sinister).
  • Local pressure effects, Obstruction, Rarely poorly circumscribed
• when do Malignant tumours cause clinical problems? PHOMA

  
  

  • pressure on and destruction of adjacent tissue
  • formation of secondary tumours (metastases)
  • blood loss from ulcerated surfaces / vascular impairment (ischaemia necrosis)
  • obstruction of flow (e.g. malignant tumour of the colon causing intestinal obstruction)
  • production of a hormone (e.g. adrenocorticotropic hormone [ACTH] and vasopressin [ADH] from some lung tumours)
  • other paraneoplastic effects causing weight loss and debility
  • anxiety and pain.
• Factors influencing malignant tumour growth rate

  • Grade of differentiation
  • Hormonal effect- oestrogen and endometrial carcinoma
  • Vascular impairment- eg ischaemic necrosis - reduced growth
  • Immunity: tumour regression
• Malignant tumour effects

  Local destructive infiltration, Invade adjacent structures/organs/lymphatics/blood vessels, Ulceration/necrosis/bleeding, Obstruction