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Dysfunction > Carcinogenesis > Flashcards

Carcinogenesis Flashcards

1
Q

Define NEOPLASIA

A
  • Neoplastic transformations due to multiple genetic (e.g. mutations, deletions, translocations, amplification) and epigenetic (e.g. promoter methylation) alterations in cells.
  • Autonomic, uncontrolled cell growth
  • Development of new but useless tissue that variably simulates the tissue of origin
  • New clones of neoplastic cells with new biological characteristics evolve following new mutations and epigenetic events.
  • Benign or malignant (cancer)
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2
Q

Incidence of neoplasia

A
  • About 25% of people develop a malignant neoplasm
  • More common with increased age
  • Immune-suppressed patients more prone to certain neoplasia
  • Typical paediatric tumours: blastomas, leukemia, CNS, embryonal rhabdomyosarcoma

GENDER
- prostate, lung and colon in men
- breat and colon in women

GEOGRAPHIC
- hepatocellular carcinoma in EC

GENETIC
- familial adenomatous polyposis and colon carcinoma

ENVIRONMENTAL
- smoking and lung carcinoma

ENVIRO + GENETIC PREDISPOSITION
- e.g. sunlight and defect in DNA repair = skin cancer

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3
Q

Tumour shape (macroscopic pathology) and correlation with clinical behaviour

A

Macroscopic appearance of tumour on a surface
- may be sessile, polypoid, papillary, exophytic/fungating, ulcerated or annular
- often correlates with clinical behaviour of the tumour:
- polypoid: generally localized without invasion of adjacent tissue= benign neoplasia
- ulcerated, fungular or annular: more commonly show destructive invasive behaviour = malignant neoplasia
- papillary: often benign but may be malignant

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4
Q

Adenamatous polyp

A

Adenomatous polyp of the colon with a stalk. Usually benign but may be precursors of adenocarcinoma of the colon. Histology necessary for specific diagnosis.

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5
Q

Squamous cell carcinoma cervix

A

Carcinoma invades and destroys the cervix, extending into the adjacent lower segment of the uterus. Leiomyoma is a benign neoplasm of smooth muscle.

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6
Q

Tumour histology

A
  • Neoplasms differ histologically from their corresponding normal tissue by various features:
    - loss/reduction of differentiation including function of the malignant cells
    - loss/reduction of cellular cohesion
    - nuclear enlargement, pleomorphism and hyperchromasia
    - increased mitotic activity
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7
Q

Define ANAPLASIA

A
  • is a malignant neoplasm showing no immediately recognisable differentiated features, loss of cohesion and increased nuclear size and mitotic activity

Cytology:
- pleomorphism
- high nuclear: cytoplasmic
- large nucleoli
- abnormal mitoses
- hyperchromatic nuclei
- loss of cellular cohesion

Architectural:
- no recognisable structures

Function:
- no or abnormal, inappropriate function

Biological:
- aggressive

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8
Q

BENIGN tumours

A
  • grow slowly – mitoses few
  • exophytic growth
  • well-differentiated
  • cytology mimics benign cells
  • localized and non-invasive; sometimes a capsule
  • ulceration, necrosis rare
  • no metastases
  • usually not fatal
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9
Q

MALIGNANT tumours

A
  • rapid growth - many mitoses
  • endophytic growth
  • less differentiation
  • cytology is malignant to anaplastic
  • invasive and destructive; poorly circumscribed
  • ulceration, necrosis common
  • metastases often
  • often fatal
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10
Q

LIPOMA

A
  • benign tumour of fat with well- circumscribed margins
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11
Q

NEUROFIBROMA

A
  • benign tumour of peripheral nerve with well-circumscribed margins
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12
Q

FIBROADENOMA

A
  • benign tumour of the breast with well-circumscribed margins
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13
Q

INTRADUCT PAPILLOMA

A

-benign tumour of the breast with a stalk and well-circumscribed margins without invasion

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14
Q

Benign tumours cause clinical problems due to:

A
  • pressure on adjacent tissues (e.g. benign meningeal tumour causing epilepsy)
  • obstruction to the flow of fluid (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)
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15
Q

Malignant tumours - invasive, destructive, rapid growth rate, metastasise

A
  • Grade of differentiation correlates with growth rate
  • Hormonal effect on neoplastic cells e.g. estrogen and endometrial carcinoma
  • vascular impairment
  • immunity - tumour regression occurs
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16
Q

SARCOMA

A
  • malignant connective tissue tumour - poorly circumscribed and destructive invasion—> of adjacent skeletal muscle
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17
Q

Tumour differentiation - the extent to which the tumour resembles histologically and or functionally its cell or tissue of origin determines the tumour grade or degree of differentiation

A

Benign - almost always well-differentiated
Lipoma - tumour cells appear like normal fat cells
Liver cell adenoma - mimics normal liver with bile production, but without portal tracts
Insulinoma - hyperinsulinemia = fetal hypoglycemia
Gastrinoma - hypergastrinemia = peptic ulcer

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18
Q

LIPOSARCOMA

A

Tumour cells mimic lipoblasts with alrge, hyperchromatic, pleomorphic nuclei and irregular-sized fat gloubules with scalloping of nuclei

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19
Q

MELANOMA

A

(Malignant neoplasm of melanocytes)

Tumour cells show marked cytological features of malignancy (poorly differentiated) but with pigment production by tumour cells (good functional differentiation) allowing histogenetic classification of the tumour

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20
Q

Histological grading of differentiation

A

Well-differentiated adenocarcinoma of colon: glandualr structures similar to those in normal mucosa
Poorly-differentiated adenocarcinoma of colon: More solid growth pattern with little evidence of gland formation

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21
Q

OSTEOCHONDROMA

A
  • benign tumour of cartilage with a stalk of mature bone
  • tumour cells appear like normal cartilage and produce cartilage - well-differentiated as expected in a benign tumour
22
Q

OSTEOSARCOMA

A

Malignant bone tumour with malignant bone formation and variable cartilaginous differentiation

23
Q

Tumour nomenclature

A
  • most suffixed with ‘-oma’
  • benign epithelial tumours either: papillomas or adenomas
  • benign connective tissue tumours have a prefix denoting the cell of origin
    -malignant epithelial tumours: carcinomas
  • malignant connective tissue tumours: sarcomas
24
Q

Benign mesenchymal tumours are named after the cell or tissue of origin suffixed by ‘-oma,’ as follows:

A

LIPOMA - benign tumour of the lipocytes of adipose tissue
RHABDOMYOMA - benign tumour of striated muscle
LEIOMYOMA - benign tumour of smooth muscle cells
CHONDROMA - benign tumour of cartilage
OSTEOMA - benign tumour of bone
ANGIOMA - benign vascular tumour

Carcinomas and sarcomas may be well- to poorly-differentiated

25
Q

MIXED TUMOURS

A
  • Non-organoid combinations of mature tissue types of one germ cell layer: pleomorphic adenoma
  • mesenchymal elements e.g. cartilage combined with epithelial elements (myothelium; glandular structures; ducts)
26
Q

ENDOCRINE TUMOURS

A

Derive from: diffuse endocrine system (hormone secreting epithelial cells) e.g. medullary carcinoma - C-cell thyroid: calcitonin + Beta-cell tumour - islets of Langerhans (insulinoma): insulin

Neuronal or paraneuronal cells e.g. adrenal paragangliomas (phaeochromocytoma) and extra- adrenal paragangliomas
- often functionally active with characteristic clinical manifestations - often manifest as syndromes and may befatal
- biological behaviour sometimes unpredictable
- may occur as hereditary or familial conditions
- nomenclature often based on name of secreted hormone

27
Q

POLYP

A
  • any microscopic projection above an epithelial surface: non-neoplastic; neoplastic (benign or malignant)
  • thus, not a diagnosis per se!
28
Q

HAMARTOMA

A

Tumour-like lesion - not neoplastic

  • the growth is co-ordinated with the individual; it lacks the autonomy of a true neoplasm
  • always benign and usually consists of two or more mature cell types normally found in the organ in which the lesion arises, e.g. pulmonary hamartoma: lobules of cartilage with entrapped respiratory epitheliu and often other mesenchymal tissues such as: fat, smooth muscle, myxoid stroma
29
Q

CYSTS

A

Epithelium-lined structure or space
- Non-neoplastic e.g.
= parasitic cyst - hydatid due to Echinococcus granulosus
= congenital cyst due to embryological defects - branchial cyst
= retention cyst - mucous cyst in the oral cavity
= implantation cyst due to traumatic implantation or displacement of e.g. epidermis = epidermoid cyst

  • Neoplastic (benign or malignant)
    = cystic teratoma
    = cystadenoma
    = cystadenocarcinoma
30
Q

BIOLOGY OF TUMOUR CELLS

A
  • no single biological feature is unique to neoplastic cells
  • neoplastic cells are relatively or absolutely autonomous, unresponsive to extracellular growth control, showing self-sufficiency in growth signalling and evading apoptosis
  • neoplastic cells often have genomic instability
  • tumour products include foetal substances and unexpected hormones
  • neoplastic transformation follows a mutation in the genes of a normal cell with subsequent formation of new cell clones and development of divergent and new tumour properties that can influence the biological nature and behaviour of the tumour
  • genetic mutation may be due to a known environmental carcinogen; predisposing condition or spontaneous (unknown)
  • interaction between features of neoplastic cells and host factors dtermine development to a macroscopic neoplasm
31
Q

INVASION AND METASTASIS

A
  • Invasion is the most important sole criterion for malignancy
  • Invasion is due to reduced cellular cohesion, production of proteolytic enzymes and abnormal cell motility
  • Metastasis is the process of formation of distant secondary tumours
  • Common routes metastasis include: lymphatice channels, blood vessels and through body cavities
32
Q

Invasiveness of malignant neoplasms is determined by the properties of neoplastic cells. Neoplastic cells show:

A

Neoplastic cells show:

  • decreased cellular adhesion between tumour cells due to loss of adhesion molecules e.g. E-cadherin
  • secretion of proteolytic enzymes degrades various types of collagen allowing easier stromal invasion by tumour cells
  • abnormal or increased cellular motility: cells are more mobile
  • loss of the normal mechanism that arrests or reverses normal cellular migration: contact inhibition of migration
  • invasion often follows routes of least resistance e.g. perineural or lymphatics
  • other tissues resist neoplastic invasion e.g. cartilage, intervertebral discs
33
Q

METASTASES

A

– process whereby malignant tumours spread from their site of origin (primary tumour) to form other tumours (secondary tumours) at distant sites
- metastases can be the presenting clinical feature e.g. bone pain or fractures due to skeletal metastases from a clinically occult internal malignancy, such as: renal cell carcinoma, lung carcinoma, melanoma
- palpable lymph nodes (lymphadenopathy), e.g. occult nasopharyngeal carcinoma or papillary carcinoma of the thyroid presenting cervical lymph node metastases

34
Q

HEMATOGENOUS METASTASES

A
  • usuall via veins
    -systemic veins to lungs e.g. typical sarcomas
    -portal vein to the liver e.g. carcinomas of the GIT
  • via paravertebral veins to the vertebrae e.g. prostate carcinoma
  • probably due to affinity between antigen expression on surfaces of tumour cells and endothelial cells in the preferred tissue types
  • tumour emboli- fragment tumour emobilises to another organ without progressive growth as observed in true metastases
35
Q

LATROGENIC

A
  • transfer of tumour cells during a procedure
  • biopsies from fine-needle aspiration or biopsy - very rare
  • intra-operative rupture of tumour - nephroblastoma of child; ovarian carcinoma
36
Q

CLINICAL EFFECTS OF TUMOURS

A
  • local effects due to compression, invasion, ulceration or destruction of adjacent structures
  • metabolic effects due to appropriate or unexpected neoplastic cell products
  • effects due to metastases, if tumour is malignant
  • local effect - macroscopic appearance of tumour
  • ulceration with haemorrhage: anaemia; shock
  • infection
  • intussusception
  • stenosis with obstruction
  • pressure on critical structures e.g. brain stem
  • infarction e.g. torsion of a polypoid tumour or ovarian tumour
37
Q

CACHEXIA

A
  • a catabolic clinical state of cancer patient with severe weight loss and debility
  • may be the presenting clinical feature of an underlying occult malignant tumour e.g. lung carcinoma
  • mediated by tumour-derived humoral factors that interfere with protein metabolism causing muscle loss (sarcopenia)
38
Q

PROGNOSIS OF TUMOURS

A

Determined by:
- tumour type and sub-type
- grade or tumour differentiation often correlates with its biological aggression - grading is typically based on mitotic index, differentiation and nuclear features (nuclear size, hyperchromasia and pleomorphism)
- stage or extent of spread of tumour
- molecular pathology tests for specific or multiple molecular changes in selected tumours
- distinction between primary and metastatic tumours, which can be challenging
- accurate histopathological diagnosis of the tumour type is essential to determine these features for therapeutic planning and prognosis

STAGING
- dissemination of a tumour
- TNM system is based on the features of a primary tumour (T), the extent of lymph node metastases (N) and absence or presence of distant metastases
- there is a specific TNM for each tumour type

39
Q

TUMOUR DORMANCY

A
  • after surgical removal, radiotherapy and/or chemotherapy there may be no clinically detectable tumour remaining in a patient
  • minute deposits may survive and evade detection by even the most sophisticated imaging techniques
  • these occult tumour foci can remain clinically dormant for several years before their regrowth causes signs and symptoms
40
Q

CARCINOGENESIS

A
  • process that leads to transformation of normal cells to neoplastic cells through mutations
  • neoplasms arise from single cells that have become transformed by cumulative mutational events
  • because of this persumed single-cell origin, neoplasms are clonal proliferations that evolve and expand by clonal evolution with cumulative acquisition of mutations that confer growth advantages
  • a carcinogen is an environmental agent that causes tumours - carcinogenic (cancer-causing) or oncogenic (tumour-causing)
  • the ultimate site of action of all carcinogens is the DNA in which genes are encoded - subsequent DNA damage (mutations) is crucial in carcinogenesis
  • usually more than one carcinogen is necessary for the complete neoplastic transformation of a cell, in several discrete steps = the multistep carcinogenesis hypothesis
41
Q

CARCINOGENS

A
  • most tumours involve both environmental factors and inherited factors, but 70% to 85% of cancer risk is due to environmental agents
  • may be identified from:
    • epidemiological studies
    • assessment of occupational risks
    • direct accidental exposure
    • carcinogenic effects in laboratory animals
    • transforming effects on cell cultures
    • mutagenicity testing in bacteria
    • genome sequencing and mutational signature analysis
42
Q

CHEMICAL CARCINOGENS

A
  • poli- and polycyclic aromatic hydrocarbons: fuel, processed or smoked meat/fish
    : 3,4 Benzopyrene in cigarette smoke = lung cancer
  • aromatic amines: rubber industry: B-naphthylamine = bladder carcinoma
  • Azo dyes - used in food industry = liver cancer
  • amide and nitrosamines: used in fertilizers; food additives
    : gastric/ other GIT carcinomas
43
Q

ONCOGENIC VIRUSES

A
  • clusters of cancer cases in space and time suggest viral aetiology
  • tumours associated with viruses tend to be more common in younger people
  • immunosuppressin favours viral oncogenesis
  • oncogenic DNA viral genome is directly integrated into host cell DNA
  • oncogenic RNA viral genome is reverse transcribed into DNA by reverse transcriptase prior to integration (oncogenic retrovirus)
44
Q

ONCOGENIC RNA VIRUSES

A
  • Human T-cell leukaemia (lymphotropic) virus (HTLV-1)
  • activation of T-cell gene for T-cell growth factors and receptors
  • lymphocyte proliferation
  • risk for further mutations
  • neoplastic T-cell transformation (latent period 20 - 30 years)
  • endemic in Southern Japan and Carribean
45
Q

ONCOGENIC DNA VIRUSES

A
  • more common in younger people
  • immunosuppressinfavours viral oncogenesis
  • direct integration in the genome of non-permissive host cells
  • transcription of early genes during virus replication
  • production of transforming proteins
  • activation and expression of oncogenes
  • neoplastic transformation
46
Q

RADIATION CARCINOGENESIS

A
  • ultraviolet radiation (UVB > UVA)
  • squamous carcinoma (solar keratosis)
  • basal cell carcinoma
  • malignant melanoma on skin
  • pyrimidine dimers in DNA which results in transcription errors if not repaired
  • abnormal DNA repair e.g. xeroderma pigmentosum = high risk
  • papillary thyroid carcinoma in children
  • carcinoma of the lung, breast, bone and leukaemia (except CCL)
47
Q

TRANSPLACENTAL CARCINOGENESIS

A
  • diethylstilbesterol to pregnant women
  • risk for vaginal clear cell adenocarcinoma in female progeny
48
Q

GENETIC ABNORMALITIES IN TUMOURS

A

Genetic mechanisms are fundamental to neoplastic cell transformation - multiple genetic alterations:
- expression of telomerase inhibits cell ageing
- loss of tumour suppressor genes
- abnormal expression of growth promoting oncogenes
- genomic instability
- chromosome instability e.g. Fanconi’s anaemia
- microsatellite instability with defective DNA repair e.g. inherited non-polyposis colon cancer

49
Q

GENETIC INSTABILITY

A

Genomic integrity depends on genes and their products (e.g. p53) that sense and repair DNA damage. A loss of these protective genes would indicate genomic instability
- Chromosomal instability (e.g. Fanconi anaemia) = chromosome breaks
- Microsatellite instability or hypermutation (e.g. Lynch syndrome or hereditary nonpolyposis colorectal cancer) = defective DNA mismatch repair genes

50
Q

EPIGENETIC CONTRIBUTION TO TUMOUR GROWTH

A
  • aberrant expression of normally repressed non-mutated genes or
  • repression/silencing of normally active genes
  • mechanisms: hypermethylation of promoter DNA sequences
    : histone modifications
    : interference with gene transcription by microRNA (short sequences of inhibitory RNA)
51
Q

HANAHAN AND WEINBERG - THE “HALLMARKS” OF CANCER = THE PROPERTIES OF TUMOURS

A
  • evading growth suppressors
  • avoid immune destruction
  • enabling replicative immortality
  • tumour-promoting inflammation
  • activating invasion and metastasis
  • inducing angiogenesis
  • genome instability and mutation
  • resisting cell death
  • deregulating cellular energetics
  • sustaining proliferative signalling
  • evading growth suppressors
52
Q

LABORATORY DIAGNOSIS OF NEOPLASIA

A
  • biopsies/ fine-needle aspiration/ resections
  • different diagnostic techniques: routine macro- and histopathology
    : immunohistochemistry
    : electron microscopy
    : molecular pathology
    : flow cytometry

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