Small animal Oncology

what is cancer in basic terms?

abnormal proliferation and genetic mutation

what is hyperplasia?

cells grow faster than other cells

what is dysplasia?

more mutations, more nuclei or disorders

what does in situ cancer become?

begins to become invasive cancer and grows in one place

what is invasive cancer?

gains access to blood vessels and breaks through the membranes and can move around the body

what is the development of normal cells to cancer?

1. cell with genetic mutation

2. hyperplasia

3. dysplasia

4. in situ cancer

5. invasive cancer

6. metastasis

what is metastasis?

cells break through basement membrane and get access to lymphatic vessels or blood vessels

how come metastasis cells are able to enter blood vessels?

due to having more pointy shape

how does cancer spread?

what are mast cell tumour cells?

• neoplastic transformation of mast cells - genetic mutations and grow abnormally

what are mast cells part of?

leukocyte family of cells

how are leukocytes (WBC) created?

continuously in haematopoiesis

where does haematopoiesis occur?

in the bone marrow following birth

what do pluripotent stem cells divide and differentiate into?

more specialised progenitor cells that give rise to lymphoid, myeloid and erythroid lineages

what are the lymphoid progenitor cells?

B cells, T cells and NK cells

what happens when B cells and T cells are activated?

activated by infection B cells go to plasma cells and T cells go to effector T cells

what does myeloid mean?

cells originating from bone marrow

what are the myeloid progenitor cells?

• granulocytes (neutrophil, eosinophil and basophil)

• mast cells (reside in connective and mucosal tissue)

• monocytes 9give rise to macrophages and dendritic cells in resident tissues)

what are monocytes function?

• circulate in the blood

• bigger than granulocytes and differentiated types look similar

• mature into three types which are resident in tissues

what are dendritic cells?

trigger adaptive immune response by transportation of intact and degraded pathogens

what do macrophages do?

phagocytose dead cells, debris and microorganisms

why is it dangerous if cancer cells come from macrophages

due to their ability to phagocytose

what are canine mast cells and where are they found?

• oval/irregular nucleus and granules

• mainly located under epithelial surfaces

• widely distributed throughout tissues of the body

what do granules in canine mast cells contain?

• histamine

• proteoglycans

• neutral proteases

• acid hydrolases

• chemotactic factors

what triggers extracellilar release of granules from canine mast cells?

triggered by physical, chemical, heat, trauma, toxins or immune mechanisms via antigen specific IgE binding

where do mast cells reside?

in tissues waiting for stimuli

what does the release of chemotactic factors do?

call more cells to help with protection

what are the functions of mast cells?

• immune sentinel cells to respond directly to pathogens

• send signals to other tissues to modulate both innate and adaptive immune responses

• direct response = release of granules

what percentage of canine skin tumours are mast cell tumours and whats the mean age?

16-21%

7.5-9 years old

what triggers mast cell tumour?

multifactorial but breed predisposition indicates possible genetic underpinning

what can canine mast cell tumour have?

c-kit mutations

what is KIT?

cell surface receptor expressed by normal and neoplastic mast cells

what is KIT encoded by?

proto-oncogene c-kit

what happens when KIT is stimulated by stem cell factor?

tyrosine-kinase activity

what is KIT involved in?

many activities including proliferation and survival

how is KIT situated on a cell?

two halves - one inside the cell and the other half outside the cell

what do the two arms of KIT do?

look for the lignin stem cell factor which triggers the protein to grow and survive

what happens when there is a mutation in the KIT receptor?

cells continue to proliferate and don’t die

the system of the KIT receptor function?

where does the c-kit mutation in MCTs focus?

mutations predominantly focus on econ 11 - corresponds to the juxta membrane region of the protein

what type of mutation is c-kit mutation?

mainly internal tandem duplications and deletions

what are internal tandem duplication and deletions?

when a segment of DNA inside a gene is copied and inserted right next to the original segment

what does c-kit mutation cause?

causes the receptor to be active all the time whether the receptor mutation is inside the cell/outside the cell or struggling to find the lignin

what happens if mutations are in the juxta membrane regions?

may affect the localisation of KIT at the mast cell surface

other than genetics what else could cause MCT?

• rare cases of MCTs are associated with chronic cutaneous inflammation

• limited evidence of a possible viral trigger

• environmental triggers may be possible

where are cutaneous MCTs most present?

common the trunk and extremities and less common on the back and tail

what is the trunk?

abdomen/mid section

what is a well differentiated MCT?

• tend to be solitary

• rubbery 1-4 cm

• slow growing

• better prognosis

what is an intermediate MCT?

• subcutaneous

• soft/fleshy on palpation

what is a poorly differentiated MCT?

• rapdi growth

• ulceration

• may give rise to small satellite nodules

do satellite nodules have good prognosis?

no weak prognosis

what are the histological findings of grade 1/well differentiated MCT?

• normal tissue cells still present

• lots of undyed areas due to tissue organisation still intact

• shape of mast cells are uniform and round

what are the histological findings of grade 2/intermediate MCT?

• mast cells are disordered with different shapes

• pleomorphic

• tissue structures are being lost

what are the histological findings of grade 3/ poorly differentiated MCT?

• lots of oval shaped mast cells

• limit normal cells left

• mast cells are multi nucleated

what are the factors that can influence the prognostic outcome?

• histological grade

• clinical stage

• location

• clinical appearance

• growth rate

• presence of systemic paraneoplastic signs

• breed

what areas are harder for prognosis and delay treatment?

tumour in nail bed, oral cavity, inguinal, perineal and mucocutaneous areas = worse prognosis and harder for owners to spot so delay treatment

what symptoms are associated with poorer prognosis?

ulcerations, erythema (reddening) or pruritus

what does growth rate relate to in terms of tumour?

tumour volume/duration

what tends to happen to spreading of cancer cells when the cancer gets bigger?

larger the tumour gets the more tumour cells being spread into the blood but also small tumour can be very aggressive

what are the treatment options for MCT?

• surgery

• radiotherapy

• chemotherapy

• other treatment modalities

• same for most tumour types

when would surgery be performed?

treatment for well-differentiated and intermediate tumours

when surgery is performed on poorly differentiated tumours what are the outcomes?

• used to alleviate symptoms (palliative) due to spreading but surgery can’t target all

• potentially curative if tumour is small and there is no metastatic disease

what is de-bulking surgery?

reducing size of tumour

what needs to happen to get a curative response in surgery?

larger margin and some of healthy cells removed as well

what is a clean margin?

all tumour cells removed

what places are hard to perform surgery?

nasal as can cause more problems

when is radiotherapy used?

used when complete surgical resection is not feasible

what are the three types of radiotherapy?

X rays, gamma rays and electrons

how does radiation work?

• works from outside of the tumour in

• radiation causes DNA damage which leads to cell death during cell division

why does radiation work on cancer cells?

healthy cells can repair DNA but tumour cells are growing too quickly to have time to repair DNA and prevent death

what used during radiotherapy to prevent damage to healthy cells?

lazers are used to map radiation to limiting hitting healthy cells an causing normal cell death

when is chemotherapy used?

• disseminated

• nonresectable

• high grade tumours

how is chemotherapy administrated?

• oral

• intravenous

• intra-cavity

• intra-lesion

• subcutaneous

when can chemotherapy be given?

• neo-adjuvant - pre-surgery

• adjuvant - on its own or post surgery

what are the two chemotherapy types?

• cell cycle non-specific

• cell cycle specific

what is cell cycle non specific?

disrupts the DNA double helix until tumour cells can’t repiary themselves and die

what is an example of cell cycle non-specific?

alkylating agents

what is cell cycle specific chemotherapy?

• interferes with spindle formation to prevent DNA from being separated equally = cell death

• during mitosis

what is the common outcome of chemotherapy?

cell can no longer divide = cell death

are healthy cells affected during chemotherapy?

yes and that is why there are side effects but healthy cells can repair themselves more easily due to growing more slowly

what do tyrosine kinase inhibitors do?

target c-kit receptors and can kill the tumour but not fully curative

cancer must be in place to work and can cause gastrointestinal issues when killing mast cells which degranulate and empty contents into body

what happens when mast cell tumour cells release granules?

• delayed wound healing (histamine suppression on fibroblasts and kertainocytes)

• gastrointestinal ulceration (due to vascular damage, excessive acid production and hyper motility)

• anaphylactic shock (caused by sudden release of histamine)

what are the other treatment modalities for MCT?

• corticosteroids - control inflammation and palliative

• H- 2 blockers - H 2 receptors antagonists used to mitigate the effects of histamine release

what is a feline lymphoma?

lymphoid malignancy and originates from solid organs such as lymph nodes, liver and spleen

what do lymphoid progenitors go to?

B cells, T cells and NK cells

for feline lymphoma which cells are common?

B cells and T cells

what are the primary tissues where T and B cells mature?

bone marrow and thymus

what are the secondary tissues where mature lymphocytes can be stimulated to respond to pathogens?

lymph nodes, spleen and mucosal surface or respiratory, gastrointestinal and urogenital tract

what are the functions of NK cells

• natural killer cells

• kill virus infected cells and secrete cytokines to inhibit vital replication

• part of innate immune response

what are the function of B cells?

• express cell surface immunoglobulins

• can be activated to become plasma cells and secrete immunoglobulins

• part of the adaptive immune response

what are the functions of T cells?

• express cell surface T cell receptors

• part of the adaptive immune response

• subdivided into two types

what are the two types of T cells?

• cytotoxic T cells that kill infected cells

• helper T cells which secrete cytokines to draw in more immune cells

what is feline lymphoma linked to?

feline leukaemia virus (FeLV)

when does FeLV trigger cancer/tumour?

at a young age not older

what are the two peals of feline lymphoma?

• the first at 2 years old and often FeLV positive

• the second at 10-12 years old and FLV negative

how much does FeLV infection increase the risk of lymphoma?

60 fold

what type of virus is FeLV?

gamma retrovirus that infects felidae

• FeLV is a type of virus that "hides" inside a cat's cells by inserting its own DNA, and it belongs to a group (gammaretrovirus) that often causes cancer and immune problems.

how is FeLV transmitted?

transmission via prolonged intimate contact such as biting, licking and sharing bowls

what is the progressive infection stage of FeLV?

• 1/3 develop progressive infection

• high viral loads

• excrete virus in saliva

• succumb to FeLV related disorders - anaemia and immunosuppression

what is the latent infection stage of FeLV virus?

• immune system prevents the cat from getting too ill

• viral antigens detectable

• can become progressive or regressive