Principles of Oncology Flashcards
Neoplastic Predisposition:
Boxers
- MCT
- Lymphoma
- others
Neoplastic Predisposition:
Flat Coat Retrievers
soft tissue sarcomas
Neoplastic Predisposition:
Irish Wolfhound
- osteosarcoma
Neoplastic Predisposition:
GSD
- Haemangiosarcoma
Give examples of hormonal factors in the aetiology of cancer
Steroid hormones oestrogen and progesterone in females
- Mammary tumours
Androgens in males
- Prostate carcinoma
- Perianal adenoma
Give examples of exposure to biological agents (oncogenic pathogens) as an environmental factor in the aetiology of cancer
- Retroviruses (e.g. FeLV causing lymphoma in cats)
- Poxviruses (e.g. BPV which also causes equine sarcoids)
- Others (Helicobacter pylori and gastric carcinoma) - Helicobacter pylori (H. pylori) is a type of bacteria. These germs can enter your body and live in your digestive tract. After many years, they can cause sores, called ulcers, in the lining of your stomach or the upper part of your small intestine
Describe proto-oncogenes
- Genes whose normal function is to promote cell growth/proliferation or inhibit apoptosis
- Activated during certain specific periods of tissue development (e.g. foetal growth) or remodelling + repair
- Tightly controlled expression
- Loss of control following mutation = oncogene
- Some viruses contain oncogenes
- These accelerate proliferatiion
Describe tumour suppressor genes
Prevent cancer
e.g. p53 and retinoblastoma protein (Rb)
- Normally act to prevent uncontrolled prolferation
- Cause cell cycle arrest and programmed cell death if the cell is damaged
- Eradicate pre=-malignant cell from body
What are the hallmarks of cancer
(6)
- Sustaining proliferative signalling
- Evading growth suppressors
- Activating invasion + metastasis
- Enabling replicative immortality
- Inducing angogenesis
- Resisting cell death
How can tumour cells become self-sufficient?
- Synthesising own growth factors
E.g. Epidermal growth factor
Autocrine + paracrine
Altering receptors
Activating mutations so receptor is always on even without ligand OR
Overexpression of receptor to respond to relatively low levels of ligand (breast example)
Mutation of signalling molecules
Activating mutations switch on proliferation in absence of receptor ligation e.g. Ras, Raf
a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
Describe mast cell tumours and mutations in KIT (stem cell factor receptor)
- SCF acts through KIT (c-kit) receptor, which has tyrosine kinase activity
- KIT gene mutations found in 30-50% of canine mast cell tumours
- Presence of mutation seems to be associated with more aggressive disease
- Normally: binding of ligand –> phopshorylation –> cell signalling pathways - survival + proliferation
- Abnormal: mutation in juxtamembrane region: receptor autophosphorylates - constantly signalling survival + proliferation
Describe treatment of canine mast cell tumour
Receptor tyrosine kinase inhibitors
- Toceranib (Palladia)
- Masitinib (Masivet)
Withdraw ability of survival and proliferation from mutant cell
-also have off-target effect on angiogenesis of the tumor (as VEGF receptor is a tyrosine kinase)
germline mutation in Bull Mastiff
- Eg germline p53 mutation in bull mastiff - breed predisposed to lymphoid neoplasia e.g. lymphoma - polymorphisms in tumour suppressor genes which increase risk of mutation
Describe the initiation of cell death in a normal cell
- Castpase cascade facilitates cell death
- Extrinsic pathway by death receptors on surface - caspase 8
- Intrinsic pathway from DNA damage - mitochondria release cytochrome C
- Either pathway enabled caspase casade which cause apoptosis
- Can take advantage by using chemotoxic agents to try and stimulate intrinsic pathways to drive cell into programmed cell death
How can tumour cells avoid apoptosis
- No expression of death receptor - block extrinsic pathway
- Over-expression of molecules which inhibit caspase cascade
How do tumour cells avoid senescence
- Most cells can only undergo limited number of divisions before they become sensecent + die
- Cancer cells must achieve immortality
- Telomeres at the end of chromosomes become eroded after each cell division
- Once they are critically shortened the cell undergoes apoptosis
- Telomerase enzyme adds new telomeres + is often upregulated in cancer cells - typically only expressed in germline cells
- Telomerase inhibitors now in clinical trials
Describe tissue invasion + metastasis
- More malignant tumours can invade local tissues + metastasise to distant sites via lymphatics or blood
- They can do this due to…
- Matric metalloproteinases to disrupt surrounding tissues: “melts” ECM and allows growth into tissue
- Alteration in cell adhesion molecules to detach + migrate (e.g. decreased E-cadherin in canine mammary tumours)
What possible mechanisms can tumours use to avoid detection by the immune system?
(4)
- Downregulate immunogenic antigens
- Kill tumour infiltrating lymphocytes
- Produce immunosuppressive mediators
- Induce tolerance
Describe possible mechanisms to counter a tumour avoiding immune destruction
- Anti-cancer vaccines: stimulate immune system to target the tumour
- Monoclonal antibodies
E.g. combination anti CTLA-4 (prevents tolerance tumour cell) with anti PD-1 (blocks death recpetor that tumour cells use to kill lymphocytes)
- Immune modulators
Describe how we can target tumour-promoting inflammation to tackle cancer
- Anti-inflammatory drugs
- E.g. Cox2 inhibitors in bladder cancer
- Remove -ve inflammatory reaction = good
Describe staging of cancer patients
(TNM)
- After making diagnosis of cancer
- Staging assesses extent of disease in body
- Performed by clinican
- Assess
Primary tumour (T) - T3 = greater than 5cm, T2 = 3-5 cm
Drainage lymph node (N)= N0 = no metastasis, N1 = evidence of
Distant metastasis (M) = M0, M1
Important for treatment planning, prognosis and communication
**Some tumors don’t fit into the TNM system -> lymphoma
Give examples of cancer staging systems
(2)
- TMN system
- WHO system (ex: lymphomas)
Describe the WHO system for cancer staging
For some types of tumour TMN does not work - WHO system used for staging lymphoma
In stages
- Stage 1: single LN involved
- Stage 2: regional area (one side of the diaphragm)
- Stage 3: generalised lymphadenomegaly (both sides of diaphragm)
- Stage 4: liver + spleen involvement
- Stage 5: involvement of BM or other organ systems (e.g. CNS or kidney)
Give examples of baseline test that can be used to asses the cancer patient
- Haematology/CBC
- Biochemistry
- Urinalysis
Decribe the use of biochemistry as a baseline test to asses a cancer patient
- Geneal health screen
- Assess organ damage/fucntion
Prior to GA
Asses drug metabolism (liver/kidneys)
Affects choice + dose of drugs
- for paraneoplastic effects e.g. hypercalcaemia due to PTH-rp secretion
Give examples of coagulopathies due to tumours
- E.g. bleeding tendencies
- Hyper or hyocoagulable
- Thrombocytopenia e.g if bone marrow involvement/DIC
e.g. dog with mast cell tumour releasing heparin
Heparin is made by the liver, lungs, and other tissues in the body and can also made in the laboratory
- Hypercalcaemia
PD/PU/ lethargy, anorexia, depression, vomiting, weakness, bradycardia
- Hypoglycaemia
Weakness, collapse, seizures
E.g. insulinoma or secretion of insulin-like substances
- Hyperviscosity with hyperglobulinaemia, polycytheamia
Neurological signs, retinal detachment, seizures
E.g. antibody production from myeloma
What approaches are available to address cancer?
- Surgery
- Radiation Treatment
- Chemotherapy
- Novel treatment options
- (+supportive care)
Describe surgery used against cancers
Treatment of choice for many primary carcinomas and sarcomas, mast cell tumours
May be sole treatment modality but often used in combination wtih radiation or chemotherapy
Describe chemotherapy for cancer
Disseminated disease/tumours with high metaststic potential
- Haematopoetic tumours e.g. lymphoma, leukemias
- Systemic/high grade mast cell tumours
- Adjunctive treatment for highly metastatic tumours e.g. OSA, HSA, high grade STS
- Situations where Sx or radiation treatment is not possible
Give an example of an adverse effect of cancer therapy and how this can be prevented
GI problems
- H2 blockers/sucralfate/omeprazole
- Anti-emetics e.g. maropitant, ondasetron
- Appetite stimulants - mirtazepine
Some alternative Tx to SCC
(2)
- Plesiotherapy
- Photodynamic therapy - Give patient photosensitizing chemical that gets localized in tumor then expose to light and causes oxidizin damage to the tumor
Give examples of supportive care for cancer therapy patients
Antibiotics if chemotherapy causes neutropenia
Analgesics
- NSAIDs
- Opiods e.g. tramadol, buprenorphine
- Gabapentin
- Paracetamol
Physiotherapy - keep petient mobile + active
How can inflammation caused by injection lead to cancer?
- Chronic inflammation can lead to cell mutation
- Tumour microenvironment is rich in fibroblast-like cells and inflammatory cells (cytokine + growth factor release)
- Tumour infiltrating lymphoytes can produce PDFG
- ISS cells have growth factor receptors
Proliferation
Angiogenesis
Metastasis
FISS
- Vaccine-associated sarcomas consist of cells that are morphologically and immunohistochemically compatible with fibroblasts and myofibroblasts.
- Stimulation of these cells by highly immunogenic and persistent adjuvants or other vaccine components resulting in inflammation that alone or in association with unidentified carcinogens or oncogenes leads to neoplastic transformation and tumor development
What cell type are ISSs typically
Vaccine associated sarcomas in cats are most often fibrosarcomas but many other types of sarcomas have also been reported.
Sarcomas in the cats are usually characterized by:
- Cellular pleomorphism
- High mitotic activity
- Large central zones of necrosis
- Features consistent with an aggressive biological behavior
- Highly locally invasive + v infiltrative
- Can be cystic
Describe the advantages and disadvantages of cytology as a diagnostic approach to injection site sarcoma
- Not as accurate as biopsy - histo is the gold standard
- Often diagnostic, though difficult if lots of inflammation or mass it cycstic (may just get fuid which is not representative)
- Cheap, quick, no anaesthesia required
- No information on grade
Describe the advantages and disadvantages of incisional biopsy (wedge) as a diagnostic approach to injection site sarcoma
More accurate, allows appropriate treatment
Gives grading information, does not change prognosis
More expensive, require anesthesia
Can make later treatment more difficult
Describe the advantages and disadvantages of excisional biopsy as a diagnostic approach to injection site sarcoma
- More accurate
- Gives grading information, impairs patients prognosis! (if you need to do a second one then it becomes much more extensive … for insistence if you send it off and then it comes back saying that all your margins are infected then you have to do it again and remove the whole scar … hard!)
- More expensive, requires anesthesia
- Can make successful later treatment impossible
OUt of cytology, incisional biopsy and excisional biopsy, which would you use to investigate injection site sarcoma in the cat
- Cytology
- Folowed by incisional biopsy
1,2,3 rule for FIIS
When should you always incisional biopsy a suspected injection site sarcoma?
FIIS: How big does a long nodule have to be to be seen on x ray?
CT?
8 mm … less than this you wont see on x ray versus
on CT 2 or 3 mm are visible on CT
Tx for ISS
- Aggressive multi-modality treatment
- Radical surgery necessary at initial excision
Amputation if poss
+/- dorsal spinous processes, dorsal scapula
Wide + deep surfical margins (3cm minimum)
- Adjuvant radiation therapy (after resection)
- Wai 10-14d post op
- RT protocols
Hyperfractionated (curative) small doses frequently
Hypofractionated (palliative) large doses weekly)
Chemotherapy
Comment on the use of pre-op radiotherapy for injection site sarcoma
- Very select cases
- Increases risk of wound dehiscence
- Makes tissue abmormal
- RT more effective against microscopic disease
ISS: Cytotoxic Chemo
high grade, aggressve behavior or metastatic
AC protocol (3 wk cycle)
- Doxorubicin (main drug used)
- Cyclophosphamide
Carboplatin
4-6 cycles
Comment on future possible therapies to target injection site sarcomas
Use of targeted therapy
- Metronomic chemotherapy
- Cox inhibitors
- Tyrosine kinase inhibitors
- Electrochemotherapy
- Immunotherapy - melanin vaccines
Give examples of injection site guidlines for rabies, FeLV and FVRCP+/-C
Rabies: distal right hindlimb (51.7%)
FeLV: distal left hindlimb (28.6%)
FVRCP: distal right forelimb
**Or at base of tail
