Metastasis and Paraneoplastic Flashcards
_______% of cancers have overt metastasis at diagnosis
30%
local tumors an often be dealth with successfully with
surgery and/or radiation therapy
few tumors are curable when they have spread beyond the lymph node
What cancers are highly metastatic
1) Hemangiosarcoma
2) Osteosarcoma
3) Malignant melanoma
4) Anal Sac ACA
_______ of tumors are cured with local therapy alone: clinicall signiciant metastasis never occurs
30-40%
90% of dogs diagnosed with osteosarcoma will have
a microscopic metastasis at the time of diagnosis
What are the 3 determinants of metastasis
1) Type of cancer
2) Histologic grade
3) Tumor size
Mast cell tumor histologic grade
Low-intermediate grade: 5% chance of metastasis
High-grade: 60% chance of metastasis
Soft tissue sarcoma histologic grade
Low-int grade: 10% chance of metastasis
High grade: 45% chance of met
Tumor Size grading
1: <2cm
2: 2-4cm
3: >4cm or already spread to node
How does cancer spread to different parts of the body
1) Direct extension
2) Lymphatics
3) Hematogenous
What is a classic cancer that spreads to different parts of the body using direct extension
Hemangiosarcoma
-ovary, lung, CNS (human)
What are classic cancers that spreads to different parts of the body through lymphatics
carcinomas
round cell tumors
What are classic tumors that spread via hematogenous
sarcomas
carcinomas
why is the lung/ liver often the first site that a cancer metastasizes to
theory: the closet one in which there are small blood vessel (lung is the first pass organ for many tumors, liver is first pass organ for colorectal and pancreas)
What is the first pass organ of the colon and pancreas, making it a good site for cancers of these organs to metastasize to
liver
seed and soil hypothesis
cells are dispered randomly but only grow in organs which provide the most correct factors necessary for growth of that particular tumor (fertile soil)
bone metastasis of prostate, breast, lung
In order for metastasis to occur, tumor cells need to detach from one another. How is this achieved
Cadherin downregulation
How do metastatic tumor cells move to new locations
1) Cytoskeletal proteins
2) C-met Receptor/ hepatocyte growth factor
How do metastatic tumor cells degrade extracellular matrix and basement membrane
1) Serine proteases (uPA)
2) Matrix metalloproteases
3) Cysteine proteases (cathepsins)
Once in the blood circulation, how do metastatic tumor cells survive in the blood
1) Survival in circulation
-Anchorage-independence to avoid anoikis
-Anti-apoptotic mechanisms
2) Avoid immune system- platelet cloak
cell death associated to loss of adhesion, occurs when metastatic cells enter the blood circulation
Anoikis
T/F: just because cells are in circulation does not mean they can successfully metastasize
True- if removing a tumor and you get some cells in the blood, they might not have the programming to survive in the blood and establish metastasize
-Tumor, surgery, biopsy, needle aspirates do not hasten metastasis
-Pleurovenous shunts- no difference in metastasis seen in individuals with and without
DO NOT worry about biopsies because you are worried about hasten metastasis
Once metastatic tumor cells are in capillary, what do they need to do
1) Survive after capillary arrest (shear stress, acute hypoxia, etc) - anti-apoptosis needed to survive during this capillary arrest
2) Bind to specific receptors on the target organ endothelium (sometimes) like ligands (very complicated to overcome)
What is needed for metastatic cells to undergo extravasation
induce endothelial apoptosis - similar mechanism to intravasation
What is the rate-limiting step in several models of metastasis
survival and proliferation in the new microenvironment
-need to be the right fertilizer of growth factors, matrix, support cells (fibroblasts, macrophages)
-again need to be able to avoid the immune system
the development of new blood vessels
important in tumorigenesis, wound healing, estrus cycle, inflammation
angiogenesis
When is angiogenesis seen
1) Tumorigenesis
2) Wound healing
3) Estrus cycle
4) Inflammation
What is the limit of diffusion for oxygen in tissues
200um - beyond this, cells become hypoxic
thus tumors should not be able to grow beyond 1mm (clinically meaningless) unless they have their own blood supply
Due to hypoxia, tumors cannot grow beyond _______ unless they have their own blood supply
1mm
What are the 3 mechanisms of angiogenesis
1) Classical/Sprouting angiogenesis: ingrowth of endothelial cells from existing vessels due to signals from the tumor
2) Vasculogenesis: outgrowth and recruitment of circulating endothelial precursors from blood
3) Vasculogenic Mimicry, mosaicism - tumors make other tubes lined with extracellular matrix that mimic vessels to deliver blood to them
ingrowth of endothelial cells from existing vessels due to signals from the tumor or other tissues
Classical/Sprouting Angiogenesis
outgrowth and recruitment of circulating endothelial precursors from blood
vasculogenesis
tumors make other tubes lined with extracellular matrix that mimic vessels to deliver blood to them
Vasculogenic mimicry, mosaicism
Angiogenic balance
+ factors: VEGF, bFGF, IL-8, Ang-1,2
vs
- factors: Tsp-1,2. Endostatin, Angiostatin
What factors increase + factors for pro-angiongenesis
Hypoxia
Oncogenes
Loss of TS Genes
Aberrant Signal Transduction
What do angiogenic growth factors do
1) Attract endothelial cells via chemotaxis
2) Stimulate endothelial proliferation
3) Stimulate endothelial cell invasion and migration
4) Promote endothelial cell survival
Why do we care about angiogenesis
Potentiall great target for therapy
1) Getting rid of single capillary might destroy hundreds/thousands of tumo cells
2) Endothelial cells are genetically stable and should be much less able to mutate and acquire resistance
What 4 ways can we inhibit angiogenesis by tumor cells *
1) Block angiogenic growth factors: Antibodies and small molecules (ex: Palladia)
2) Give angiogenesis inhibitors (Angiostatin and endostatin)
3) Target cytotoxic drugs to growing endothelial cells
4) Metronomic chemotherapy- small amounts of drugs given over time- rapdily dividing cells is sensitive for these (doesnt impact normal cells as much
antiangiogenic and antiproliferative therapy specifically developed for Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs
Palladia®
(toceranib phosphate)
Angiostatin and endostatin are examples of
angiogenesis inhibitors
-but need to be on continuous infusion pumps
What should you consider when giving drugs that inhibit tumor angiogenesis
1) Dont give to animals that are trying to get pregnant?
2) dont give to animals that will be getting surgery
inhibit endothelial cells from dividing which are one of the slowest dividing cells in the body
normal vasculature that doesnt need to heal is probably good
Examples of transmissible tumors
1) Transmissible V enerea Tumor (dogs)
2) Transmissible Facial Tumor Disease (Tazmanian Devil)
3) Syrian Hamster Cheek Pouch Tumor
4) Leukemia in Clams
cancer-associated alterations in bodily structure and/or function that are not directly related to the physical effects of the primary or metastatic tumor
Paraneoplastic syndromes (PNSs)
What causes paraneoplastic syndromes
tumor production of molecules (hormones, cytokines, peptides) that are released into the circulation, tumor depletion of normal small molecules or host responses to the tumor (immune mediated)
What are the GI manifestations of cancer
1) Anorexia and Cachexia
2) GI ulceration- commonly MCTs via hyperhistaminemia
What are the endocrinologic manifestations of cancer
1) Hypercalcemia - via PTHrP from lymphoma,anal sac apocrine gland adenocarcinoma, MM, thymoma, etc.
2) Hypoglycemia- insulinoma
3) Hyperestrogenism- Sertoli cell tumor
4) Hypersomatropism- Acromegaly via functional pituitaty adenoma of somatotroph cells
5) Ectopic Adrenocorticotropic Hormone Syndrome - ACTH
What are the hematologic manifestations of cancer
1) Hyperglobulinemia and Bence Jones Proteinura - MM
2) Hyperviscosity Syndrome - MM, polycythemia vera, paraneoplastic erythrocytosis
3) Anemia- leukemias and HSA
4) Erythrocytosis - increased erythropoietin (renal tumors)
5) Leukocytosis
6)
Thrombocytopenia- hematopoetic and vascular cancers
7) Coagulopathies / DIC
Paraneoplastic myasthenia gravis is reported in dogs and cats with
thymoma - can also be seen in some other cancers too
Hypertrophic osteopathy is an osteoproductive disroder of periosteum that affects the long bones and extremities and are commonly associated with
primary lung tumors or tumors that have metastasized to the lungs
What causes paraneoplastic fever
innate immune response against tumor antigens or areas of tumor necrosis
Fever mediated primarily by TNF-a, IL-1, IL-6 on the hypothalmus
Nodular dermatofibrosis is a PNS that is associated with
bilateral renal cystadenocarcinomas or cystadenomas
Superficial necrolytic dermatitis is seen in animals that have
1) Hepatic disease (hepatocutaneous syndrome)
2) Glucagon secreting tumors (PNS)
Paraneoplastic exfoliative dermatitis is reported in cats with
thymoma
What may be the first sign of malignancy
paraneoplastic syndrome
With Apocrine gland anal sac adenocarcinma that spread the the medial iliac LNs
-Difficult defecating
-Lethargy PU/PD
-Ionized calcium of 1.8
What parenoplastic syndrome is present
Hypercalcemia
Sevo has hypercalcemia os 2.1 mmol/L (1.25-1.45)
Is this mild, moderate, or severe/marked
Severe- calcium is very tightly regulated and shouldnt be much over the reference
How do you treat hypercalcemia of malignancy
1) Remove the underlying cause via surgery, chemo, or radiation
2) IV fluids to correct existing dehydration
3) Once rehydrated, furosemide to enhance calcium elimination
4) zonedronate potentially later
Zoledronate
a drug that can be used to eliminate hypercalcemia
What are the differentials for hypercalcemia
HARD IOS
1) Hyperparathyroudism
2) addisons
3) Renal
4) D (vit) toxicity
5) Idiopathic (cats)
6) Osteolytic
7) Neoplastic
8) Spurious
Also HOGS IN YARD
G= granulomatous
Y= young
What are the most common tumors associated with hypercalcemia of malignancy in dogs
Most
1) Apocrine gland anal sac adenocarcinoma *
2) Lymphoma *
3) Multiple Myeloma *
4) Thymoma
T/F: cancer is the most common cause of hypercalcemia in cats
False- cats dont get it as much as dogs
most common cause in cats is idiopathic, then renal, then cancer
What cancers typically cause hypercalcemia in cats
1) Lymphoma
2) Squamous Cell Carcinoma
What should you do when you see a patient has hypercalcemia for further diagnostics
1) Recheck rectal examination for small nodules in anal sacs
2) Thoracic radiographs - mediastinal mass,
3) Abdominal ultrasound
4) Malignancy panel - PTH/ PTHrp/ iCa++
What are possible differentials for mediastinal masses
1) Lymphoma (t-cell)
2) Thymoma- ectopic thyroid carcinoma, branchial cyst, metastatic neoplasia
What should you do to work up a mediastinal mass
ultrasound guided FNA of mass to see if lymphoma or thymoma- very different treatment procedures
Why is it important to monitor iCa++ throughout treatment of cancer (ie lymphoma)
increased calcium was a marker for disease reucurrence
Hyperglobulinemia is a paraneoplastic syndrome associated with which two cancers
1) Multiple Myeloma - plasma cells
2) Lymphoma- some B cell types can produce immunoglobulins
What should you do for a dog with significant periosteal reactions on the distal forelimbs (radius, ulna, metacarpals, phalanges). What should you do?
Thoracic Radiographs- likely caused by chest lesions
Cancerous causes of hypertrophic osteopathy
-Primary lung tumur
-Metastatic cancer to tumor
-Rhabdomyosarcoma of bladder (rare)
-esophageal sarcoma (rare)
What are the non-neoplastic causes of Hypertrophic osteopathy
1) Difilaria immitis infection
2) Patent ductus arteriosus w R to L shunting
3) Spirocerca lupia esophageal granulomas
4) Esophageal foreign body
5) Bacterial endocarditis
How do patients with hypertropic osteopathy typically present
swelling and/or edema of the distal limbs and lameness or difficulty ambulating
limbs are often painful on palpation and/or warm to touch