Neoplasia Flashcards
Neoplasm
=”new growth”
cells unresponsive to normal growth controls- able to expand outwith normal anatomical limits
Non-neoplastic lumps
hamartoma: normal components, but all mixed up. tissue is chaotically arranged, but in an appropriate site.
ex: fibroadnexal hamartoma- massive increase in fibrous connective tissue with dilated apocrine sweat glands. dilated d/t blockage by expanding fibrous tissue.
choristoma: tissue chaotically arranged but in an abnormal site (e.g. dermoid)
Normal mature skin on cornea: haired skin on cornea–>hasn’t properly differentiated to corneal epithelium
presentation of choristoma on cornea: scratching, rubbing, tear production, conjunctivitis
Changes which may precede neoplasia
Hypertrophy: increase in cell size
Hyperplasia: increase in cell number
NB: hypertrophy and hyperplasia don’t necessarily lead to neoplasia
Metaplasia: i.e. cuboidal–>squamous
Dysplasia: everything becomes a little jumbled; lose polarity
Preneoplastic changes are reversible, arise in response to physiologic demands, injury or irriation and if the inciting factor is removed, will regress.
Hyperplasia
e.g. gingival hyperplasia- v. little attachment to normal gum, pretty easy to remove, but they will regrow
overgrowth of gums; affects 30% of boxers over 5 years old (also great danes and dobermans)
cause gum recession as well as mal-alignment
symptoms: pain on eating, bleeding
e. g sebaceous hyperplasia: dome-shaped/papillated mass(es) usually on head
hyperplastic sebaceous gland duct–once you lose ducts –>neoplasm.
Functional consequences of hyperplasia
i.e. passage of feces restricted with a massively enlarged prostate
Prostatic disease in dogs: enlarged prostate can impact colon, can crush surrounding structures–>difficult defecating, urinating, blood in urine.
Veterinary tumor groupings
most tumors are a monoclonal population (i.e. one cell type)
Mesenchymal (mesoderm): CT, fat, cartilage, endothelium and related tissues, muscle, hematopoeitic and lymphoid tissue
Epithelial (endoderm, mesoderm, ectoderm): ectoderm- covering epithelium (skin); mesoderm- solid organs (renal tubules, hepatocytes); ectoderm- lining epithelium (gut).
Nervous tissue: CNS and PNS- glial and neural cells
Mixed: divergent differentiation of monoclonal cell- mammary gland (mixed mammary tumor- bits of cartilage, bone, epithelial tissue) , testicle, ovary
Undifferentiated: tend to have v. bad prognosis
Naming tumours
Mesenchymal benign: “oma” i.e. fibroma, lipoma
Mesenchymal malignant: “sarcoma” i.e. fibrosarcoma, lymphosarcoma (or lymphoma- no benign lymphoid tumours)
Epithelial benigin: “oma” i.e. papilloma, adenoma
Epithelial malignant: “carcinoma” i.e. squamous cell carcinoma, adenocarcinoma
Tumour components
parenchyma: neoplastic or transformed cells- determine biological behavior of tumor
stroma: absolutely essential for physical support and growth- non-neoplastic, host-derived support tissues— connective tissue (collagen), blood vessels, host-derived inflammatory cells
Benign vs. malignant
4 distinguishing features:
- differentation and anaplasia (total lack of differentation)
- rate of growth
- local invasion
- metastasis- spread to distant sites in body.
Characteristics of benign tumours
Differentiation: well-differentiated (can work out where they came from i.e. look how they’re supposed to), recognizable structure
Growth rate: slow, progressive expansion; v. rare mitotic figures
Local invasion: no true invasion; expansile growth; often encapsulated
Metastasis: none
see clear margins between normal and neoplastic tissue
Characteristics of Malignant tumours
Differentiation: lack of differentiation, structure often atypical
growth rate: slow to rapid (erratic); increased number of mitotic figures, as well as abnormal (asymmetrical) mitotic figures
Local invasion: infiltrative growth- not freely moveable on palpation
Metastasis: frequent
cause death if untreated.
Markers of differentiation
Cell morphology: neoplastic cells often lose any recognizable gross and histological appearance
Cell function: usually lost in malignant tumours; regulatory mechanisms lost
Cell behavior: increasingly aggressive with loss of differentiation and function
Morphology
nb: normal connective tissue all goes in same direction; abnormal has bundles going in different directions
in altered morphology: see nucleoli, wide variation in cells (anisocytosis) and wide variation in nuclear size (anisokaryosis)
Function
Maintained: bovine squamous cell carcinoma- multilayered epithelial layer, not straight surface. keratin in the middle (rather than on surface) because it’s growing DOWN into the tissue. infiltrative picture. Malignant, but function maintained.
Altered: cat sqaumous cell carcinoma- no obvious keratin production, invasive.
Species differences in tumour function
e.g. granulosa cell tumour
balance of hormones important; many produce steroids (oestrogen, progesterone, testosterone)
Bovine: common in large animals- non-malignant, rarely metastasize- polycystic ovary, solid can also occur
Mare: gc tumour- high testosterone–>anestrus, nymphomania, stallion-like behavior
Bitch: can be malignant, produces oestrogens (prolonged oestrus), if progesterone produced–>cystic endometrial hyperplasia, pyometra
Cell morphology: histo features of malignancy
Neoplastic cells have large nucleus with a prominent nucleolus–ex: neoplastic sheet of lymphoid cells; nucleus is much paler,open-faced (vesicular). variation in size of nuclei and can see nucelolus
Increased mitosis and abnormal mitotic figures
In summary: enlarged nucleus with prominent nucleolus; increased mitosis (abnormal mitotic figures); multiple nucleoli; “bizarre” cells
Mechanisms regulating numbers in normal cell populations
Baseline cell population has a lot of factors affecting it:
proliferation, differentiation, stem cells, cell death
Proliferation: normal vs. tumour
Proliferation in normal tissues: checkpoints at G1 and G2– balance of permanent+stable+labile cells
Tumor cells: spend v. little time in G0–> don’t undergo cell-cycle arrest–>pushes quiescent stable cells back into cell cycle. No checkpoints happening therefore DNA damage can become even more severe.
Mechanisms of tumour growth
altered proliferation potential: can shorten cell cycle; convert quiescent cells into dividing cells
neoplastic cells: escape normal limits on cell division; independent of external growth factors; not susceptible to apoptotic factors
Re-expression of telomerase: enzyme allowing replication and expansion of telomeres; important in immortality.
Telomerase
embryonic cells express telomerase
extreme ends of DNA templates (telomeres) not duplicated at cell divsion- very short telomeres mean cell division can’t happen
neoplastic cells often regain ability to produce telomerase–> allows immortality.
Growth modulation in normal tissue vs. neoplastic
Normal: constant transfer of information between cells; stimulatory/inhibitory/hormones
Neoplastic: cells lose dependence; not responsive to needs of whole organism–> drive their own replication
Apoptosis
Many neoplastic cells are resistant due to a functional inactivation of p53 gene–> overall growth rate increased
Activate survival singalling pathways–> cells independent of exogenous survival factors
Inactivate death factor signalling pathways–>evade apoptosis
Normally, apoptosis allows tissue homeostasis
Can be pathologically induced: withdrawal of survival factors, binding of death factors (Fas ligand, TNF-alpha), hypoxia, DNA damage (p53), cytotoxic immune cells (T-cells and NK-cells); caspases (intracellular proteases) are final effectors.
Morphological markers of apoptosis
no marked inflammatory response because remnants are membrane bound
margination of chromatin
condensation and fragmentation of nucleus
condensation of cells with preservation of organelles.
Tumor growth
as the tumor cell population expands, a higher percentage of cells leave the replicative pool by reverting to G0, differentiation and death. Despite this, there’s still SOME control.
Carcinogenesis
tumours arise from clonal growth of cells which have mutations in 4 classses of genes
- cell growth regulators (proto-oncogenes and tumour suppressor genes)
- apoptosis regulators
- DNA repair regulators
Malignant tumours usually result of the accumulation of multiple mutations involving multiple genes.
Determination of tumour growth
Stimulatory signals and inhibitory signals of proliferation
activation of survival factors, inactivation of death factors
DNA damage (p53), cytotoxic immune cells
Transformation, progression, proliferation, tumor
Normal cell–> transformation events–> single tumour cell–> 30 doublings=proliferation of genetically unstable cells–> 1g=smallest clinically detectable mass (10^9 cells)–> 10 doublings (10^12 cells) or 1 kg= maximum mass compatible with life in most species.
Tumor cell variants throughout doublings i.e. some act to be non-antigenic, some act to be invasive, some metastatic, some requiring fewer growth factors.
Clonal expansion of surviving cell variants–> solid malignancy.
Other important factors in tumour growth
blood supply: need nutrients
extrinsic growth-regulating factors- i.e. hormones
efficacy of host IR
emergence of subpopulations of aggressive tumour cells.
Tumour progression
original transformed cell–> multiple mutations lead to new subclones
with progression tumour mass is enriched with “nastier” variants i.e. can evade host immune system, and are more aggressive.
Six hallmarks of cancer
changes in cell physiology lead to malignant phenotype
- self-sufficiency in growth signals
- insensitivity to anti-growth signals
- tissue invasion and metastasis
- limitless replicative potential
- sustained angiogenesis
- evading apoptosis
Tumour evolution
stepwise tumour development: not all tumours do this, but epithelial tumours are a good example
Initiation: irrevesible genetic change produced
Promotion: specific stimuli cause outgrowth in initiated cells
Progression: benign tumour becomes increasingly malignant and eventually metastatic
initiation
irreversible genetic change introduced into basal cells of skin (for example) by an initiator
initiator=chemical or physical carcinogen
DNA lesion introduced; DNA lesion mispairing during subsequent replication=mutation fixation
Initiated cells: morphologically normal, and possible quiescent for years.
Promotion
outgrowth of initiated cells in response to selected stimuli
- promoters alter gene expression
- initiated cells have growth advantage
- not mutation so reversible (promotion is reversible, but initiation isn’t).
Progression
benign–>malignant–>metastatic
involves genetic and epigenetic (reversible, heritable changes in gene expresson that occur without mutation e.g. hypermethylation of promoter sequence–>stop tumour supressor) changes
increasingly malignant subclones selected.
Stepwise development of squamous cell carcinoma
1: epidermal hyperplasia (i.e. keratinized papilloma with no evidence of invasion (no penetration of basement membrane)
2: carcinoma in-situ (i.e. still in epidermis): invading dermis: tumour less well-differentiated
3: invasive carcinoma: extends deep into dermis
Mechanisms of invasion
one of the first things that has to open is loosening of intracellular junctions. Cells have to get more mobile.
Cells detach from mass: desmosomes dismantled; cadherin (joining) function lost
Cells attach to basement membrane via laminin receptors and secrete proteolytic enzymes: type IV collagenase and plasminogen activator
Basement membrane gets degraded
Cell has to alter structure to wiggle through gaps (alter cytoskeleton)–>penetrate basement membrane, enter ECM. contact established with ECM components- fibronectin, laminin, collagen etc.
Summary of mechanisms of invasion
enhanced tumour motility
increased protease production
altered tumour cell adhesion factors.
Neoplasia of nasal cavity
Most often in dogs: dolicocephalic>brachycephalic
deep nasal passages
carcinoma/adenocarcinoma–> local invasion (destruction of turbinates)–> many metastasize to regional lymph nodes.
Mechanisms of invasion and metastasis
1st: invasion- local invasion is essentially start of metastasis- increased net protease acitivty–> active degradation of basement membrane and ECM (matrix metalloproteases e.g. type IV collagenase, urokinase)
2nd: migration: mediated by coordinate changes in cytoskeleton and adhesion structures– stimulated by autocrine growth factors and ECM cleavage products (e.g. collagen fragments)
Pathways of tumour metastasis
1) transcoelomic/”kissing” metastases: thoracic/abdominal surface tumours- few barriers to spread e.g. mesothelioma, ovarian adenocarcinoma—-tumor cells can reimplant locally, but don’t metastasize to different sites.
2) hematogenous- via blood vessels (esp. thin walled veins): sarcomas tend to spread this way
3) lymphatic: carcinomas- NB: regional LN involvement is suggestive of widespread disease
the more malignant tumours are, the more various ways they spread.
Hematogenous spread
Metastatic cascade: steps involved in hematogenous spread of a tumor
clonal expansion–>metastatic sub clone–>intravasation (via chemotaxis into blood vessels)–>tumour cell embolus (coated with platelets–IR doesn’t kill cell)–>extravasation (at suitable cell, i.e. where microenvironment suits)–>metastatic deposit (secondary tumor)–> angiogenesis (induce own BV production)–>growth.
Hematogenous spread mechanisms and routes
tumour emboli: tumour cells from small emboli in vessels
can be recognized and attacked by host lymphocytes, but surround themselves with platelets if they’re successful tumours.
Exit site depends on: pattern of drainage of primary tumour; tumour cell/endothelial cell adhesion molecule interaction; microenvironment suitability.
veins more often than arteries: easier to digest wall because it’s thinner.
possible routes: VC–>lungs–>+/- arteries
portal system–> liver
Adrenal tumours: adrenal veins–>vena cava
primary metastasis sites: draining LNs, lungs, liver
Hemangiosarcoma
most common primary tumors are in spleen or right atrium.
Suppression of metastasis
metastatic potential cumulative effect of many genetic alterations
small number of genes identified: gene encoding E-cadherin (suppress metastasis)
Necessities for successful tumour growth
Solid tumors >1-2mm in diameter: needs blood–> angiogenesis swtich turned on. allows tumour to induce and sustain new tumor vasculature.
Complex: recruitment of endothelial cells from pre-existing vessels; endothelial cell proliferation; directed migration of endothelial cells through ECM; maturation and differentiation of the capillary sprout–> angiogenesis.
Angiogenesis
stimulation of host blood vessel growth
solid tumours >1-2mm in size
O2 and nutrients- vascular endothelial growth factor, acidic and basic fibroblast growth factor
Control: balance of angiogenesis-stimulating (e.g. VEGF) and angiogenesis inhibiting (e.g. thrombospondin) factors.
remember thrombospondin and VEGF.
lots of little BVs seen, slightly plumper than normal endothelial cells–>sign of neovascularization
Stages in tumour angiogenesis
endothelial cell recruitment–>endothelial cell proliferation–>directed migration through ECM–> maturation and differentation of capillary sprout–> tumour vessels.
some fluid out of leaky vessels–> stroma formation
Tumor vessels are unstable, with abnormal structure and function, inappropriate to location. recruit myofibroblasts
NOT neat and tidy vessels.
