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.
Characteristics and functions of tumour vasculature
dilated, tortuous, permeable
vessel leakiness–>perivascular fibrin–>tumour stroma formation
Endothelial cells produce growth factors–> platelet derived growth actor (PDGF), IL-1–>stimulate tumour cell growth.
nb: tumour lymphangiogenesis has many similarities.
Tumour parenchyma
majority tissue
neoplastic cell population
primarily decides biological behavior
tumour stroma
non-neoplastic support structures
extracellular connective tissue proteins (mainly collagen) and glycoproteins embedded in a proteoglycans MATRIX
blood vessels- nutrition
fibroblasts- collagen-making
inflammatory and immune cells
Stroma is supportive tissue and provides nutrtion
Mesenchymal tumour organisation
mesenchymal tumours- often spindle shaped cell
produce ECM in their stroma
i.e. osteosarcoma produces bone–> ECM is bone, but not normal, good bone
fibrosarcoma–> ECM is collagen
Epithelial tumour organisation
surrounding mesenchymal non-neoplastic cells produce ECM
may also produce a capsule– localizes initirally and may prevent metastasis
NB: plasmocytoma can (not necessarily) produce amyloids (Beta plated sheet)
Histopathological features of mesenchymal tumour (fibrosarcoma)
malignant: abnormal mitotic figure
spindle-shaped cells
often with more than 1 nuclei
collagen surrounding–> fibroblasts producing collagen
Histopathological features of epithelial tumour
epithelial cells like to form sheets, glands, ducts, tubules
epithelial cells have polygonal shape nucleus with quite a bit of cytoplasm
stroma produced by non-neoplastic mesenchymal cells (i.e. fibroblasts)
lots of collagen–> scar, distorted tissue (white on gross anatomy)
Tumour-stromal interactions
Complex, 2-way communication
-wide variety of signalling molecules i.e. growth factors, CKs, hormones, inflammatory mediators
Modulate growth rate, differentiation state, behaviour of both cells groups (become very dependent on each other).
e.g. tumour cells release platelet derived growth factor (PDGF)
tumour-derived TGF alpha (transforming growth factor)–> fibroblasts differentiate to myofibroblasts; pericytes at edge of vessels. pericytes allow for angiogenesis.
nb: tumour can grow to 2mm maximum before needing angiogenesis
tumor-stromal interaction example: adenocarcinoma in the eye
neoplastic epithelial cells upregulate fibroblasts–> fibroblasts become very reactive, producing lots of collagen–> scarring, desmoplastic response.
PGDF from tumour cells–> tumour-associated fibroblasts activated–> increased collagen production
parenchyma: neoplastic epithelial cells
scirrhous/desmoplastic response: dense collagenous stroma
Cylical and dependent tumour-stromal interactions
tumor and stroma feed off each other
tumour production results in production of: growth factors, inflammatory mediators, proteases, tumour antigen
tumour production stimulates a stromal response
stromal response: inflammatory cells, stromal fibroblasts, ECM, vascular endothelium
tumour response to stromal response: proliferation rate, differentiation rate, local invasiveness, metastatic capacity.
Inflammation and tumours
often heavy infiltrations of neutrophils, eosinophils, mast cells, lymphocytes, histiocytes
chemokines and cytokines attract these cells
e.g. feline injection site sarcoma–> often see an increased number of lymphocytes
inflammation is not necessarily protective–some human studies suggest that NSAIDS reduce the incidence of some tumours.
Tumour immunity
components: tumour antigens, immunosurveillance, antitumour effector mechanisms (NK cells, macrophages, T cells, B cells); evasion of immune response (emboli can wrap themselves in platelets); tumour immunotherapy (chemo attacks rapidly dividing cells)
Tumour antigens
surface expressed proteins/glycoproteins/glycolipids or carbohydrates
tumour specific +/- tumour associated
clinical applications: diagnostic tool; therapeutic tool
therapeutic tool: monitoring response to therapy; complex imaging uses antibodies against tumour restricted antigens–> localize tumours, find metastases.
Tumour-specific antigens
often newly expressed
-oncongenic viruses (papillomaviruses); altered cellular products (mutate genes); re-expressed embryonic or oncofetal antigens (e.g. carcinoembryonic antigen, alpha fetoprotein)
Tumour-specific shared antigens: expressed by many tumours and only limited normal adult tissues; e.g. MAGE family of proteins
Tumour-associated antigens
Shared by tumours and normal tissues e.g. differentation antigens–> expressed at a specific differentation stage in normal tissue but upregulated in neoplastic cells
If expressed at higher levels on tumor cells than normal cells, basically function like tumour-specific antigens.
Immuno-surveillance
Suppreses tumour development: recognizes self antigens on tumour cells as “foreign”–> immune system attacks as if it’s infected with microbes.
Failure to suppress–> tumour emergence—- nb: tumour susceptibility of immune-suppressed transplant recipients
Canine cutaneous histiocytoma: an example of good immunosurveillance
seen in young dogs: tumours regress–> T-cells triggered and tumour regresses–> areas of coagulative necrosis.
histiocytes=resident skin macrophages=langerhans
on histopathology, can see neoplastic population of “bean shaped” histiocytes, and an infiltration of mature lymphocytes (dark round cells)
Immunohistochemistry: direct method
enzyme-labelled primary antibody reacts with tissue antigen
positive= brown (if antigen is expressed)
background=blue
Immunohistochemistry: indirect method
enzyme labelled with secondary antibody reacts with primary antibody that’s bound to tissue antigen.
Antitumour effector mechanims
dependent on: immune responsiveness of host and characteristics of tumour antigen (how aggressive is the tumour)
innate immune system: first line of non-specific attack (NK cells and macrophages)–> no APC (dendritic cell) priming required
adaptive/acquired immune system: slower, but more effective
- cell-mediated (T-cell) and humoral (B-cell)
- antigens must be presented in a recognizeable form–> central role of dendritic cells- priming.
Natural killer cells
lymphocytes
bone marrow derived
lack usual B and T cell markers
kill neoplastic and virally-infected cells
specifically target MHC-free cells
NK cell+ tumour–> lytic granules release–> apoptosis of target cells.
Macrophage
T-cells and NK cells produce IFN-gamma
IFN-gamma timulates circulating macrophages to release: reactive O intermediates, lysosomal enzymes, NO, TNF-alpha–> work to rupture cells–> tumour cells killed
direct contact between macrophages and tumour cell is essential
macrophage response is quick but all consuming (i.e. does a lot of damage).
Cytotoxic T lymphocytes (CD8)
primary effectors of adaptive anti-tumour immune response
-primed by dendritic cells to recognized tumour antigens on cell surface–> stimulate apoptosis
T-cell recognition of tumour antigen leading to T-cell activation
CD8+ T lymphocytes and tumour antigens
tumour cells express 4 different types of tumour antigens
1) product of oncogene or mutated suppressor gene
2) mutated self-protein
3) overexpressed or abberantly expressed self-protein
4) oncogenic virus
Action of cytotoxic T cells
attach to target cells–> immunologic synapse forms–> lytic granules release (perforins/granzymes)
Perforins: pore forming proteins–> mediate entry into cell–> granzymes: serine proteases
Granzymes initation apoptosis
Centrol role of dendritic cells in adaptive immune response
Ag release from dying tumour cells or Ag secretion from live tumour cells–> antigens ingested by dendritic cells and get fragmented
fragmented antigens are linked to apropriate MHC and presented on the surface of the dendritic cell
APC can activate T-cells and B-cells
Antigen activated T-cells–> CD8–>CD8+ cytotoxic T-cells- MHC I
Antigens-activated T-cells–>CD4–>CD4+ helper t-cells–> MHC II
Antigen-activated B cells–> immunoglobulin secreting plasma cells
B-lymphocytes
antibody producing B lymphocytes mediate humoral immune response to tumours
Antibodies recognize tumour antigens–> activate local complement cascade–> generate membrane attack complex–> tumour cell membrane damaged–> rapid cell death by necrosis.
Helper-T lymphocytes (CD4)
enhance CTL and B-cell function
-action mediated through cytokine secretion
IL-2–> derives CD8+ proliferation
IFN-gamma–> stimulates CD8+ T cell differentiation
nb: CD4 is not essential for generation or maintenance of a CTL response
Immune evasion by tumours
1) failure to produce tumour antigen: favored in clonal expasion or antigen hidden by fibrin or antibodies
2) mutations in MHC genes or genes needed for antigen processing (Class I MHC deficient tumor cell)
3) production of immuno-suppressive proteins (i.e. TGF-beta)
also, tumour cells can hide in platelets
4) tolerance to self-antigens (e.g. those shared with normal tissue): presentation of non-self antigens without co-stimulatory molecules
Tumor evasion of IR: altered MHC expression
CTLs only recognize tumour antigens on tumour cells with MHC I molecules. Tumor cells that lose of down-regulated expression of class I MHC have distinct selective advantage.
Tumor evasion of IR: antigen masking
tumors may become invisible to immune system by losing or masking tumour antigens.
outgrowth of clonal tumour variants that don’t express tumour antigens will be favored during tumour evolution.
antigens may be hidden if they’re complexed with glycocalyx molecules, fibrin or even antibodies.
Tumor evasion of IR: tolerance
immune system is tolerant to self-antigens.
tumour antigens shared with normal tissue are usually not able to evoke an IR because body has been “tolerized” to the antigen.
tolerance can also result from presentation of non-self-antigensin a “tolerogenic” context, i.e. in the absence of co-stimulatory molecules required for effective T-cell activation.
Tumor evasion of IR: immunosuppression
Tumour cells or products may be immunosuppressive.
many tumours produce TGF alpha (transforming growth factor) which inhibits proliferation and function of lymphocytes and macrophages
tumours produce Fas ligand. Fas ligand expressed by tumor cells binds to Fas receptors on nearby T-cells and trigger apoptosis. By this mechanism, T-cell clones that recognize a tumour may be specifically deleted.
Tumor cells release tumour antigens into circulation that form immune complexes with antibodies–> these complexes may be immunosuppressive.
Tumour immunotherapy
Effective immunotherapy is preferable to cytotoxic chemo (which is indiscriminately targeting dividing cells)
Strategies of tumor immunotherapy:
1) provide mature effector cells: recognize and destroy tumours–> passive immunotherapy
2) stimulate host IR against tumour: active immunotherapy–> coupling toxins to monoclonal antibodies that may allow targeted delivery of therapeutic agents to tumor cells.
Direct systemic effects of tumours on host
Tumors replace normal tissue so they will affect normal function
- space occupying effect: only so much space to be had
- erosion of vessels: acute hemorrhage
- emboli into vessels: may cause infarcts at distant sites (kidneys, spleen)
Paraneoplastic syndroms
indirect/remote effects
caused by tumour cell products
75% occurrence in human patients, but a lot lower incidence in vet med
may occur early allowing early tumour diagnosis- i.e. if tumour specific: anal sac carcinoma affects apocrine glands–> may present with hypercalcemia
must treat associated metabolic abnormalities
severity reflects tumour burden: can reflex response to therapy, or recurrence/spread
Cachexia
complex etiology
anorexia, poor digestion (if GI/liver tumour), nutritional demands of tumour tissue, nutrient-loss in effusions or exudates, metabolic and endocrine derangements
muscle (lots of muscle loss) and fat loss
extra calories do not reverse the catabolic state
cytokines and hormones implicated: TNF alpha, IL-1, IL-6 and prostaglandins
Cancer-related hypercalcaemia
clinical signs: muscle weakness, cardiac arrhythmia (affects cardiac myocytes), anorexia, vomiting, renal failure
excess PTH is a major calcium regulator
(apocrine gland carcinoma of anal sac in dog (90%), lymphoma (20%), multiple myeloma (15%)
increased PTH–> increased mobilization of caclium from bones (lose strength) + increased absorption from kidney + increased reabsorption from intestine
in hypercalcemia, will see collagen ntrying to replace bone that’s been weakened d/t calcium mobilization.
Cancer-related hypoglycemia
Direct: insulinomas: functioning tumour of pancreatic islet beta cells
Paraneoplastic: other tumour cell types
Clincal signs: nervous system (high glucose requirement); lethargy, incoordination, muscle weakness, seizures
Gastric/duodenal ulceration and hemorrhage related to tumours
pancreatic carcinoma stimulates increased gastrin production
visceral mast cell tumours (spleen/liver): produce histamine, heparin, prostaglandins, proteases
Tumours release histamine into bloodstream–> binds to receptors on parietal cells of stomach–> leads to increased HCl secretion–> ulceration
Sertoli cell tumours in dogs
sertoli cell tumours secrete estrogen–> feminisation syndrom–> skin thinning, pendulous abdomen, gynecomastic
Cancer-related anaemia
possible causes: anaemia of chronic disease, bone marrow invasion (myelophthiasis), hemolysis, bloods loss
i.e. hemangiosarcoma
Genetics and cancer
heritable DNA changes: i.e. in germline sequences (affect all cells)
- enhanced, decreased or absent expression of normal proteins
- expression of abnormal proteins e.g. p53 not expressed/inactive
- oncogene-encoded proteins overexpressed
Altered profile of tumour cell determines tumour phenotype
Genetics and cancer etiology
heritable changes in germline sequences of all cells
somatic changes that accmulate in individual cells and tissues over time
cancer syndromes: mendalian inheritance of specific types of cancer in genetically related animals (more in humans than vet med)
sporadic tumours: occur randomly in the population, no specific germ-line characteristics
Germline mutations and cancer syndroms
human: BRCA1 and 2: breast and ovarian cancers
canine (german shepherds): hereditary multifocal renal cystadenocarcinoma (large cystically dilated structures, glandular epithelium, malignant) and nodular dermatofibrosis (skin, lots of collagen)
- bilateral multifocal renal tumours
- uterine leiomyomas (benign smooth muscle tumours)
- skin nodules (dermatofibrosis)
Acquired somatic mutations
intrinsic factors: by-products of metabolism (ROS)
extrinsic factors: 1) chemical- initiation and promoters 2) radiation- complete carcinogens, initiators and promoters 3) viruses
Etiology of neoplasia
chemical carcinogens, radiaton, oncogenic viruses, oxidative damage–> all result in DNA damage
if DNA repair is unsuccessful–> survival of cells with mutations–> cancer
Events in checmical carcinogenesis
Initiation: Carcinogen–> binds to DNA: adduct formation. DNA repair results in a normal cell or cell death
if unable to repair–> permanent DNA lesion: initiated cell
Initiated cell no morpholoically visible and can be initiated for months or years before promotion
Promotion: cell proliferation of initated cell and altered differentiation–> preneoplastic clone–> benign neoplasm
Progression: benign neoplasm–> malignant neoplasm
Bracken fern in cattle: example of chemical carcinogenesis
Bracken fern causes enzootic bovine hematuria
Urinary bladder: vascular hyperplasia/ectasia (dilation of ducts/vessels)–> hematuria
wide range of mesenchymal and epithelial tumours seen
Bright blindness
Pathogenesis of enzootic bovine hematuria (d/t bracken fern)
Bracken fern–> immunosuppressants and carcinogens (querectin)
Carcinogens cause hemangioma
Immunosuppresants- affect urinary bladder mucosa
if vascular endothelium of bladder mucosa is affected–> hemangioma–> + ras*–> hemangiosarcoma
if epithelium of bladder mucosa is affected–> polyps–> +ras*–>transitional cell carcinoma
Bovine papillomavirus types 1 and 2 also affect urinary bladder mucosa epithelium–>polyps–>+ras*–>papillary carcinoma.
Virueses and cancer
Retroviruses: FeLV, FIV, Jaagsiekte sheep retrovirus (lots of mucus and foam- affects type II pneumocytes), bovine leukosis virus
Herpesviruses: Marek’s disease virus, kaposi’s sarcoma virus, Lucke frog viurs, Epstein-barr virus
Papillomaviruses: rabbit PV, BPV, canine PV, goat PV
Viral oncogenesis
Dominant oncogenes: host cell origin or non-host cell origin
Insertional mutagenesis: virus might activate expression of cellular oncogenes
Hit and run mechanism: transient residence in target cell and damages cell just enough to cause tumour e.g. BPV 1 and 2
Indirect mechanisms: suppression of host immune system, stimualtion of target cell proliferation
Viral-induced tumours
FeLV: causes panimmunosuppresion–> feline leukemias and lymphomas
bovine leukosis virus: cow leukemias and lymphomas
FIV: cat lymphoma
Jaagsiekte sheep retrovirus: pulmonary carcinomas in sheep
avian leukosis virus: leukemias and lymphomas in poultry
marek’s disease (herpesviruse): lymphoproliferative disease in poultry
Leukemia vs. lymphoma
leukemia: tumour of malignant hematopoietic cells that originates in bone marrow. significant number of neoplastic cells in circulation
lymphoma: solid tumours arising in lymphoid tissues outside bone marrow
Classification of leukemias
Chronic lymphoid leukemia and chronis myeloid leukemia
acute lymphoid leuekmia (lymphoblastic) and acute myeloid leukemia
Lymphoma/lymphosarcoma
Solid tumour composed of lymphocytes
most common tumour in domestic animals
Multicentric: bilateral node enlargment, node replaced by soft white tissue; infiltration of liver and splenic white pulp
Thymic: firm white mass replacing thymus (T-cells in thymic lymphoma); compression of heart and lungs
Alimentary: nodule, plaque, or ulcers in alimentary tract (can just replace normal well and look like a diffuse thickening– ddx: IBD); enlarged mesenteric LNs
Bovine lymphoma/lymphosarcoma
Enzootic bovine lymphoma (cleared from UK): adult cattle, caused by BLV– horizontal spread: infected lymphocytes from arthropods or needles
Sporadic bovine lymphosarcoma: in young catle (less than 2 years)–multicentric, thymic–> dissemminated disease, see in kidneys and liver.
Feline lymphosarcoma
older cats (>10 years od)
currently 80-90% found are FeLV -ve due to vaccination
Mostly alimentary: predominantly B-cell
can also be thymic, multicentric, renal
Feline lymphosarcoma in young-middle aged cats
a manifestation of FeLV
thymic and multicentric most common
(renal and alimentary also seen)
T-cell forms
Canine lymphosarcoma
middle aged dogs
multicentric: 80-85%
can alst be alimentary, thymic, cutaneous
70-80% B-cell
hypercalcemia=paraneoplastic syndrome in 20% of cases
NO retroviral or other cause known
Jaagsiekte “driving sickness” sheep retrovirus
ovine pulmonary carcinoma/pulmonary adenomatosis
transmissible retrovirus induced pulmonary neoplasia
high incidence in scotland, s. africa, peru (not australia or NZ)
Mostly in mature sheep
copious nasal discharge+intensive husbandry encourages horizontal transmission
death after several months- no detectable specific humoral immune response to this retrovirus
Jaagsiekte gross findings
early stages: enlarged lungs, heavy and wet with firm, grey, variably sized nodules
Later stages: confluent nodules; large volumes of both lungs infiltrated
cut section: airways full of oedematous fluid and mucoid secretion
slow growing tumour affects immune balance–> compromised lung function–> secondary pneumonia
froth in airways d/t increased surfactant production
Jaagsiekte microscopic findings
bronchioalveolar carcinoma: cuboidal or culmnar epithelial cells line airaways or alveoli–> type II alveolar epithelial cells and clara cells
form papillary or acinar structures
possible sequelae: bronchopneumonia, abscesses, fibrous pleural adhesions
metastases (seen in later disease): tracheobronchial and mediastinal LNs–> pleura, muscle, liver, kidneys
Lymphoid leukosis in chicken
retrovirus
genetic selection eradicated retroviruses from commercial strains of poultry
no economic probem today in poultry industry–> tends to be backyard chicken problem
Marek’s disease in chickens
very important disease: most common and important lymphoproliferative disease in chickens
heavy economic losses
herpesvirus
Marek’s disease transmission and clinical signs
Natural transmission: young chickens; horizontal direct and indrect contact; airborne route- infectious viral particles spread from feather follicles.
High resistance of viral particles in natural environment
Clinical signs: classic, chronic paralytic form (young adults: reproductive and laying hens)
-incoordination, ataxia, gait abnormalities, asymmetric progressive paresis, then paralysis
gross lesions: asymmetric hypertrophy and discoloration of brachial and celiac plexuses and large peripheral nerves.
visceral lymphoid tumours
hepatomegaly+diffuse or multinodular neoplastic infiltration
grey eye: difuse infitration of iris
Equine sarcoids
non-productive infection by BPV (1 and 2)
transforming proteins of BPV 1 and 2 isolated from lesions; no infectious virions produced
mode of transmission not establish.
locally aggressive (proliferative but not productive), non-metastatic fibroblastic skin tumours
30% of all equine skin tumours: affect any breed, age, sex by 3-6 year olds most common
any position: head, legs, ventral trunk
lots of spindle cells: biphasic tumour
hyperplastic epithelium, lots of fibroblasts
ddx: proudflesh
Tumour susceptibility in dogs
Lymphoma/sarcoma: boxer
malignant histiocytosis: bernese mountain dogs
(disseminated histiocytic sarcoma): several breeds
hemangiosarcoma: GSD
osteosarcoma: giant breeds, boxer, GSD, rottweiller
mast cell tumour (skin): boxer, bulldog, retriever
Diagnosis of neoplasia: cytolosy
cells shed naturally into body fluids: urine, CSF, fluid in pleural or peritoneal cavities
cells obtained by exfoliation: tracheal wash, prostatic wash
cells aspirated by needle: blood or bone marrow; or needle aspiration of solid tumours
Diagnosis: biopsy
needle: core of tissue 1-2mm wide x 2cm long
endoscopic: small forceps to collect small (2-3mm) fragments from GIT, respiratory or genitourinary tracts
incision: sample of lesion removed with scalpel
excision: entire tumor removed
Features of malignancy
abnormal morphology
invasion/metastasis
high mitotic index/abnormal mitoses
high nucleus: cytoplasm ratio
absence of encapsulation
lack of differentiation
enlarged nucleus with prominent nucleolus
multiple nucleoli
bizarre cells
Differentials for canine round cell tumours
lymphoma/sarcoma
canine cutaneous histiocytoma
mast cell tumour
plasmacytoma
transmissible veneral tumour
