Unit 7: Neoplasia Flashcards
what is neoplasia
excessive and disorganized cell or tissue growth that is unresponsive to normal growth control mechanisms
what is required for the normal structure of a tissue to be maintained after damage
the rate of cell proliferation must balance with the rate of differentiation (leading to cell death)
what happens if there is discrepancy between rate of cell proliferation and rate of differentiation in attempt of tissue repair
the tissue will become abnormal at both the gross and histologic levels which can lead to increase of decreased mass of the affected tissue
what is hyperplasia
- increased numbers of cells
- the main mechanism that causes increased size in organs and tissues consisting of labile and stable cell types
when does hyperplasia result
- when the cells of a tissue are stimulated to undergo mitosis
what is hypertrophy
- increased size of cells
- the only method of adaptation that can occur in tissues made up of permanent cells (cells can’t multiply)
- there is an increase in the amount of cytoplasm and the number of cytoplasmic organelles
hyperplasia vs hypertrophy
- both can be physiologic, occurring in response to an increased demand
- both are reversible if the demand is removed
- can occur together and lead to organ enlargement
- can be pathologic, without an increased demand
what is atrophy
- “waste away” as a result of degeneration of cells
why do you experience atrophy when you have a cast on
- lack of use of the muscles results in reduction in the structural components of the cell (decreased synthesis, increased catabolism or both)
atrophy is the opposite of…
hypertrophy and hyperplasia
what is the significance of decreased cell size in atrophy
- to re-establish equilibrium between cell size and reduced blood supply, nutrition or trophic stimulation
when can the term atrophy not be used to describe an organ
when it is hypoplastic (underdeveloped) or aplastic (completely undeveloped)
osteoporosis: example of disuse atrophy
- the result of bone resorption occurring more rapidly than formation
- weight-bearing exercise is important to prevent osteoporosis
what is disuse atrophy
- atrophy caused by lack of the use of muscles
- causes a rapid decrease in the size of muscle cells (fibres)
- can be reversed quick when activity is resumed
what happens if skeletal muscle fibres are lost
- only capable of limited regeneration so if fibres are lost muscle mass can only be restored by hypertrophy (increasing size) of muscle fibres - slow process
what is denervation atrophy
the result of lack of stimulation of muscle fibres by lower motor neurons
- seen in the limbs of people with spinal chord injuries
what is senile atrophy
cell loss associated with normal aging
what is pressure atrophy
atrophy as the result of ischemia due to compression of blood vessels
how can atrophy result from the lack of trophic hormones
the lack of estrogen following menopause leads to atrophy of the vaginal epithelium and endometrium
what is metaplasia
- abnormal growth resulting from abnormalities in differentiation and maturation
- the normal phenotype of mature cells is replaced by another type of mature cell which is not normal for that site
- a reversible change
what is squamous metaplasia characterized by
- non-cancerous (benign) changes in squamous cells in the epithelium
why does epithelial metaplasia occur
- ## stem cells have the potential to differentiate in different ways in response to chronic irritation
what is osseous metaplasia
- areas of bone formation seen amongst the dense, fibrous scars
does metaplasia have any clinical significance?
- generally no
- may have survival advantages
functional deficit from metaplasia of ciliated columnar epithelium of the bronchi
- infection can happen due to loss of the mucus/ciliary clearance mechanism
what happens if the influences that caused metaplasia persist?
- neoplastic transformation may occur if other factors are favourable to abnormal cell growth - squamous cell metaplasia leads to squamous cell neoplasia
what is dysplasia
- abnormality of both differentiation and maturation, primarily seen in epithelial tissue
- characterized by increased nuclear size, increased chromatin content, cytoplasmic abnormalities, increased rate of multiplication and disorderly maturation
- loss of the uniformity of individual cells
dysplasia as a premalignant lesion
- the risk of developing cancer increases with the “severity” of the dysplasia, its duration and its site
how does dysplasia differ from neoplasia
- dysplastic lesions are NON-invasive (neoplasia is) and may spontaneously revert to normal
- dysplasia may look like cancer but so not yet show evidence of invasive behaviour
what is a tumour/neoplasm
the resulting mass of abnormal tissue due to excessive and disorganized growth of cells or tissues that is unresponsive to normal growth control
what is oncology
the study of tumours
how do cancer cells differ from normal cells
- cancer cells contain genetic damage to growth-promoting proto-oncogenes and growth-suppressing cancer suppressor genes which cause them to behave abnormally
what are the 10 hallmarks of cancer
- self sufficient growth signals
- insensitivity to growth inhibitory signals
- altered cell metabolism
- evasion of cell death
- limitless potential for replication
- angiogenesis
- invasion of metastasis
- evasion of immune surveillance
- genomic instability
- tumour-promoting inflammation
which of the hallmarks of cancer are considered the 2 enabling factors
- self sufficient growth signals - proton-oncogenes are mutated to oncogenes which promote cell growth
- insensitivity to growth inhibitory signals - cancer suppressor genes are mutated and lose control of the cell cycle, allows growth of tumours and prevents their apoptosis
self sufficient growth signals - hallmark of cancer
- proto-oncogenes are mutated to oncogenes, and oncoproteins are produced which promote cell growth without external signals
insensitivity to growth inhibitory signals - hallmark of cancer
- the protein products of tumour suppressor genes are disrupted, allowing cells to become refractory to growth inhibition
- the RB cancer suppressor gene is inactivated by growth factors which allow cells to enter the S phase
- loss of normal cell cycle control
- mutations in molecules that act to inhibit cell proliferation impairs their effects
almost all cancers have disabled G1 checkpoints due to defects in…
RB, p16, cyclin D or CDK4
TP53 tumour suppression gene
- a commonly mutated gene is cancer
- has anti-proliferative effects and regulated apoptosis
- known as the “guardian of the genome”
- in cells with mutations of TP53, DNA damage does not induce cell cycle arrest or DNA repair - damaged cells proliferate and neoplasms arise
altered cell metabolism - hallmark of cancer
- Warburg effect = distinct form of metabolism displayed by cancer cells
- in cancers, oncogenic mutations involving growth factor signalling pathways and MYC deregulate normal metabolic pathways
evasion of cell death - hallmark of cancer
- mutation in any gene that regulates apoptosis prevents apoptosis of tumour cells and allows them to persist
limitless potential for replication - hallmark of cancer
- when telomeres are shortened to a certain point, cells can no longer divide effectively
- tumour cells show activation of telomerase which acts to maintain normal telomere length
- thus capable of replicating indefinitely
angiogenesis - hallmark of cancer
- tumours need blood to grow and metastasize
- tumour-associated neoangiogenic factors may be produced by tumour cells which aid in the formation of new blood vessels
- the balance between angiogenic and anti-angiogenic factors control tumour growth
invasion and metastasis - hallmark of cancer
- the appearance of new “tumour associated antigens” on surfaces of cancer cells represents expression of the altered genome
- tumour associated antigens may invoke an immune response
evasion of immune surveillance - hallmark of cancer
- cancer evades the immune system, preventing it from recognizing and destroying cancer cells
genomic instability - hallmark of cancer
- constant but rare genome instability can contribute to the development of cancer
- fosters activation of genetic mutations
tumour-promoting inflammation - hallmark of cancer
- chronic inflammation modifies the tumour environment, aiding in tumour progression
integration of cancer hallmarks
- cancer results from the accumulation of multiple mutations
- main factors in cancer development are transformation of proton-oncogenes into oncogenes and loss of function of tumour suppressor genes
tumours are heterogenous…
- mutations do not occur in all tumour cells at once, but rather in individual cells
- the rate at which these mutant subclones are generated is variable between tumour types
what are known agents that cause specific types of cancer
cigarette smoke = lung cancer
Human pappiloma virus (HPV) = cervical cancer
what are the main carcinogenic agents and why
- chemicals, radiation and viruses
- all have the ability to directly cause genetic damage
latent period of carcinogens
- “first hit” = exposure to the carcinogen
- after exposure several changes and mutations occur in the latent period
- then a tumour starts to develop
what do all chemical carcinogens have in common
- highly reactive electrophiles which will react with electron-rich atoms in nucleic acids and cellular proteins
what are mutagens
- agents that produce mutations - permanent transmissible changes in genetic material
what are tumour promoters
- agents that enhance the carcinogenicity of some chemicals which by themselves would not be tumorigenic
- all promoters are inducers of cell proliferation
true or false most chemical carcinogens are tumourgenic
true
carcinogens present in cigarette smoke are associated with…
cancer of the lung, oropharynx, esophagus and bladder
polycyclic hydrocarbons (tars) - the most important chemical carcinogens:
- inhaled and absorbed, then converted to an epoxide in the liver
- epoxides combine with the nucleic acid guanine in DNA leading to neoplastic transformation
- accounts for more cancers than all other carcinogens combined
what is lung cancer and its subtypes
- refers to bronchogenic carcinoma, can be broken down into 4 histologic types…
1. adenocarcinoma (most common)
2. squamous cell carcinoma:
3. small-cell lung carcinoma
4. large-cell carcinoma
how is small-cell lung carcinoma different than other types of lung cancer
it has metastasized by the time of diagnosis
where do carcinomas of the lung metastasize to
regional lymph nodes, the liver, brain, bone marrow and adrenal gland - also spreads through the lung and pleura
role of asbestos is carcinogenesis
- associated with an increased risk of developing bronchogenic carcinoma and malignant mesothelioma
- malignant mesothelioma originates from the lining of the pleura, peritoneum and pericardial sac.
- causes an extremely aggressive cancer - mortality 100%
why is it difficult to identify chemical carcinogens
- there is a long lag period between the exposure and the development of cancer
- isolating the edict of a single chemical is almost impossible
discovery of radiation carcinogens
- exposure to nuclear fallout was associated with increased incidence of cancer (leukemia) in survivers of atomic bomb explosion
- occupation exposure to radium was also seen to lead to development of osteosarcoma (radium was deposited in bones)
what are the mutagenic effects of radiation carcinogens
- chromosome breakage
- translocations
- point mutations
- genomic instability
Ultraviolet radiation - major cause of skin cancer
- particularly seen in malignant melanoma, squamous cell carcinoma and basal cell carcinoma
- caused by excessive exposure to the sun
- fair-skinned individuals are particularly at risk
how does UV light work as a carcinogen
- causes the formation of linkages between pyrimidine bases in DNA
- if DNA repair mechanisms are not working skin cancer results
radiation from X rays
- no increased risk of cancer
- x-rays of abdomen during pregnancy may increase incidence of leukemia in the fetus
what does oncogenic mean
tumour causing
oncogenic (tumour causing) DNA viruses
- insert their nucleic acid directly into the host cell genome
- replication of the virus is minimal but activate oncogenes
- include papillomaviruses, Epstein-Barr virus and HepB virus
papillomaviruses - oncogenic DNA virus
- known to cause warts and are associated with cervical cancer
- high-risk HPV genome codes for viral proteins that interact with growth-regulating proteins
- inactivated RB and P53 (tumour suppressors), activates cyclins and inhibits apoptosis
EBV - oncogenic DNA virus
- the cause of nasopharyngeal carcinoma and Burkitt’s lymphoma, also seen in the development of central nervous lymphoma
- EBV has strong tropism for B cells - cause them to proliferate and develop lymphoblastoid cell lines
- in immunosuppressed patients, sustained population of B cells is at increased risk of acquiring mutations leading to oncogene activation
HBV and HCV - oncogenic DNA viruses
- associated with hepatocellular carcinoma
- ongoing hepatocyte injury and regeneration predisposes cells to mutations
- chromosomal deletions may inactivate tumour suppressor genes and activate growth-controlling genes
oncogenic RNA viruses:
- majority of them are retroviruses
- cause neoplastic transformation by 2 mechanisms
1. acute-transforming viruses: contain viral oncogene which induces uncontrolled cell proliferation
2. slow-transforming viruses: insert their reverse-transcribed DNA near a cellular oncogene and retroviral “promoters” cause over expression (termed insertional mutagenesis)
examples of oncogenic RNA viruses
- adult T-cell leukemia/lymphoma - caused by HTLV-1 which has tropism for CD4+ T cells, Tax activates T cell genes causing polyclonal proliferation
- Avian leukemia-sarcoma complex
- feline leukemia virus
- bovine leukemia virus
- enzootic nasal tumour virus
- jaagsiekte sheep retrovirus
the wheelbarrow test for Jaagsiekte sheep retrovirus
- the adenocarcinomas that develop with this virus result in accumulation of mucous fluid within the lungs and airways
- the hindlimb are raised above the animals head and if fluid pours from its nose and mouth is likely to have said tumour
oncogenic bacteria viruses: helicobacter pylori example
- helicobacter pylori is linked to the pathogenesis of gastric epithelial cancers and gastric B-cell lymphomas
tumours are typically classified based on their…
- detected or predicted biological behaviour
- tissue of origin
- histologic appearance
- site at which they may arise
cell types that tumours can arise from
- epithelial
- mesenchymal
- undifferentiated
tumours of epithelial origin
benign tumours: termed adenomas if they originate from glandular tissue or papillomas if they originate from epithelial surfaces
malignant tumours: termed carcinomas
types of malignant epithelial tumours
- adenocarcinomas: derived from glandular epithelium
- squamous cell carcinoma: derived from squamous epithelium (such as skin)
- urothelial carcinomas: derived from urothelial epithelium (such as the bladder)
tumours of mesenchymal origin
benign tumours: named after their cell type of origin, followed by the sufficient -oma
- e.g. fibroma
malignant tumours: named after their cell type of origin, followed by the suffix -sarcoma
- e.g. fibrosarcoma
what does the term cancer refer to
a MALIGNANT neoplasm, whether it is a carcinoma or a sarcoma
tumours of undifferentiated cells: those of germ cell lines and from embryonic pluripotent cells (only present in fetus and young children)
- tumours from embryonic cells are termed blastomas
- tumours from germ cell lines are termed teratomas
tumours derived from germ cells (teratomas)
- teratomas contain elements of all 3 germ layers (endoderm, ectoderm, mesoderm)
- seminomas and dysgerminomas (male and female respectively) are tumours arising from germline cells that fail to differentiate, instead forming a tumour of uniform round cells
exceptions when naming tumours
- melanomas, lymphomas and plasmacytomas are MALIGNANT tumours with the suffix -oma instead of sarcoma
- leukemias (tumours of blood-forming organs) are also termed malignant
- some tumours are termed mixed if they contain epithelial and mesenchymal components
the terms undifferentiated or anaplastic may be applied to a tumour if…
it can only be recognized as of epithelial or mesenchymal origin but the actual tissue of origin cannot be determined as the cells ate undifferentiated
biological behaviour of benign tumours
- grow slowly, noninvasive and don’t metastasize
- complete excision is often curative
- well differentiated cells that resemble normal cell type of the tissue
- cause compression of surrounding tissue altering function
- blood vessels are well formed, therefore necrosis is unusual
biological behaviour of malignant tumours
- grow rapidly, invasive and metastasize
- often life threatening, require aggressive therapy
- poor differentiation, origin of cells may not be recognizable (anaplasia), boundary is not clear
- cells are irregularly sized and shaped
- show necrosis and hemorrhage,
why is it important to determine if a tumour is benign or malignant
- determines how to treat the tumour
- benign tumours may be cured by surgical excision
- malignant tumours may need more aggressive therapy
main criteria to determine if a tumour is benign or malignant
Grade: how malignant the tumour appears to be
Stage: how malignant the tumour appears to be systemically
grade of disease: differentiation and anaplasia
- each cancer is graded based on the degree of cell differentiation
- graded on both histological grade and biological behaviour
- differentiation refers to the extent to which the tumour cells resemble normal parenchymal cells of their tissue of origin
grade of benign tumours
low grade
- composed of well differentiated cells that closely resemble normal cells of that tissue type
grade of malignant tumours
high grade
- show a wide range of parenchymal cell differentiation, at the extreme Are those completely undifferentiated where their tissue of origin cannot be determined
- anaplasia (lack of differentiation) is a hallmark of malignancy
criteria of histological changes used to determine the grade of MALIGNANT tumours:
- variation in pleomorphism
- variation in NUCLEAR size and shape = anisokaryosis
- variation in CELL size and shape = anisocytosis - increased nuclei size relative to cell size (N:C)
- hyperchromatic (dark staining nuclei)
- nuclear chromatin that is coarse or clumped and nucleoli may be multiple and large in size
- multinucleate giant cells
- mitotic figures are numerous and may be atypical
anaplastic cells
- fail to develop normal “architecture” (lack cell polarity)
well differentiated tumour cells vs anaplastic tumour cells
- well-differentiated cells retain functional abilities similar to normal counterparts
- with increasing anaplasia, there is less likelihood of specialized function activity
tumours that don’t follow general guidelines: canine seminoma example
- a tumour seen in semen-producing germ cells of the testis - appear anaplastic and contain numerous mitotic figures
- usually behave in a benign fashion
tumours that don’t follow general guidelines: canine intestinal adenocarcinoma
- appear very well-differentiated
- invade through the wall of the intestine and spread broadly through the abdominal cavity
stage of cancer is based on 3 components…
- rate of growth
- local invasion
- metastasis
Determining stage of disease: rate of growth
- benign tumours grow slowly
- malignant tumours grow more quickly
- rate of growth of malignant tumours correlates with their level of differentiation
- the most poorly differentiated (anaplastic) tumours grow the fastest
Determining stage of disease: local invasion
- benign tumours remain localized and defined relative to surrounding tissue - may have a fibrous capsule
- malignant lesions show invasion and destruction of surrounding tissue, not clearly separated
- may be able to predict by feeling the tumour - benign will be freely movable while malignant will be fixed in place and might blend with adjacent tissue
determining stage of disease: metastasis
- invasive and metastatic behaviour are characteristics of malignancy
- metastasis via lymphatics = carcinoma and melanoma, occurs early on
- metastasis via the bloodstream = neoplastic cells not killed by the immune system are coated with fibrin and trapped in capillaries, occurs early on
- metastasis via seeding = rafts of tumour cells break off and disseminate within the body cavity
what is metastasis
the development of secondary implants away from the primary tumour site
the TNM system
a formal scheme for staging malignancies
T(0-4) - describes the increasing size of the primary tumour
N(0-4) - indicates progressively advancing lymph node involvement
M(0-4) - indicates presence/absence of distant tumour metastases
why is it difficult to determine if someone has been cured from cancer
- cancer cells which metastasize remain dormant before developing
- survival for five years after treatment is considered a sign or cure of most cancers - patients still may develop metastatic disease after this
how do benign neoplasms effect hosts
- appearance of a mass (lump)
- can cause problems if they put pressure on blood or lymphatic vessels
- mass in the skull could cause injury to the brain
effects of a primary tumour
- depend on its site and rate of growth
- my compress or destroy adjacent structures, causing functional changes, pain and inflammation
a malignant tumour in the bladder will lead to problems with urination such as…
- increased frequency
- hemorrhagic urine
- dribbling of urine and incontince
carcinoma of the breasts
- most common cancer in women
- sensitive to estrogen - causes the cancer to grow rapidly
- usually present as a mass in the chest wall
- ulceration and nipple retraction are late features
- cancer spreads directly along the ductal system of the breast
- spread can also occur via the bloodstream with metastases occurring to bone, lungs and liver
what are paraneoplastic syndromes
- clinical effects produced by cancer which are unrelated to the direct involvement of the tissue by the tumour
- include those such as anemia, hemorrhage, immunodeficiency, DIC, etc.
how are paraneoplastic syndromes mediated
- by a variety of tumour cell products such as hormones
tumour cell product mediating paraneoplastic syndromes - insulinoma
- tumour of pancreatic beta cells
- one of the substances it secretes is insulin - as a result insulin levels are not regulated
- too much insulin makes the person hypoglycaemic
example of a paraneoplastic syndrome being very characteristic of a certain cancer
hypercalcemia is often associated with lymphosarcoma
paraneoplastic syndromes associated with lung cancer
- hypertrophic pulmonary osteoarthropathy: clubbing of the fingers
- associated with lung cancer and other neoplasms inside the thorax
what is cancer cachexia
- weight loss, wasting and emaciation that occur with advanced cancer
- can be considered a paraneoplastic syndrome
- several mechanisms in action
- secretion of TNF and interleukins by macrophages have a role
what are tumour markers
- the presence of tumour cell products that can indicate a neoplasm may be present
- their levels can be used to monitor the response to therapy
tumour marker example - carcinoembryonic antigen
- found in most malignant neoplasms of the colon and pancreas
tools and signs used to diagnose cancer
- external masses identified by visual appearence
- internal masses require evaluation of serum and blood, evaluation of a CBC and imaging techniques such as radiography and CAT scans
- can also use tumour markers
how can we confirm that a mass is a neoplasm
- lab examinations including exfoliative cytology, fine-needle aspiration cytology, biopsy and an expanding variety of chemical tests
early screening tests to diagnose cancer early
- performed on clinically normal people
- by the time a mass is identified disease is already in the advanced stage
- women have annual cytological examinations of the cervix
- sigmoidoscopy and colonoscopy allow early identification of colonic cancer
cancer staging is an effort to…
identify the extent of its involvement in a given patient prior to starting therapy
- the TNM system is used to classify the tumour based on size and appearance of the primary tumour, involvement of lymph nodes and the extent of metastasis
the outcome of cancer treatment depends on…
the stage of the cancer at the time of diagnosis and the type of cancer
4 categories of treatment approaches for cancer
- surgical removal
- radiation therapy
- chemotherapy
- immunotherapy
cancer therapy - surgery
- excision of malignant neoplasms if difficult because of their invasive growth habit
- local recurrence is likely if neoplastic cells remain
- local lymph nodes may be removed if there is high risk of metastasis
- if the tumour has metastasized surgery of the primary tumour is only useful relieve symptoms of the mass or to debunk the area to enhance chemo
what is palliation
affording relief but not curing a condition - often to reduce pain associated with the disease process
cancer therapy - radiation
- has a more destructive effect against rapidly dividing cells than normal cells
- associated risk of injuring normal cells
- can be delivered from an external source or internally by radioactive sources
- tumours which divide rapidly such as lymphosarcoma are more radiosensitive
cancer therapy - chemotherapy
- a variety of anticancer drugs act in several ways
1. interfere with cell metabolism and RNA protein synthesis (antimetabolites)
2. block DNA replication or mitotic division (antimitotics)
3. exert hormonal effects which influence tumour growth
cancer therapy - immunotherapy
- how the immune system can help control cancer by stimulating it
- developing are: tagging tumour-associated antigens with cytotoxic drugs that are carried directly to the site of cancer
