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Metastasis and Paraneoplastic Flashcards

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1
Q

_______% of cancers have overt metastasis at diagnosis

A

30%

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1
Q

local tumors an often be dealth with successfully with

A

surgery and/or radiation therapy

few tumors are curable when they have spread beyond the lymph node

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2
Q

What cancers are highly metastatic

A

1) Hemangiosarcoma
2) Osteosarcoma
3) Malignant melanoma
4) Anal Sac ACA

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3
Q

_______ of tumors are cured with local therapy alone: clinicall signiciant metastasis never occurs

A

30-40%

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4
Q

90% of dogs diagnosed with osteosarcoma will have

A

a microscopic metastasis at the time of diagnosis

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5
Q

What are the 3 determinants of metastasis

A

1) Type of cancer
2) Histologic grade
3) Tumor size

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6
Q

Mast cell tumor histologic grade

A

Low-intermediate grade: 5% chance of metastasis

High-grade: 60% chance of metastasis

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7
Q

Soft tissue sarcoma histologic grade

A

Low-int grade: 10% chance of metastasis

High grade: 45% chance of met

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8
Q

Tumor Size grading

A

1: <2cm
2: 2-4cm
3: >4cm or already spread to node

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9
Q

How does cancer spread to different parts of the body

A

1) Direct extension
2) Lymphatics
3) Hematogenous

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10
Q

What is a classic cancer that spreads to different parts of the body using direct extension

A

Hemangiosarcoma
-ovary, lung, CNS (human)

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11
Q

What are classic cancers that spreads to different parts of the body through lymphatics

A

carcinomas
round cell tumors

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12
Q

What are classic tumors that spread via hematogenous

A

sarcomas
carcinomas

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13
Q

why is the lung/ liver often the first site that a cancer metastasizes to

A

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)

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14
Q

What is the first pass organ of the colon and pancreas, making it a good site for cancers of these organs to metastasize to

A

liver

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15
Q

seed and soil hypothesis

A

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

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16
Q

In order for metastasis to occur, tumor cells need to detach from one another. How is this achieved

A

Cadherin downregulation

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17
Q

How do metastatic tumor cells move to new locations

A

1) Cytoskeletal proteins
2) C-met Receptor/ hepatocyte growth factor

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18
Q

How do metastatic tumor cells degrade extracellular matrix and basement membrane

A

1) Serine proteases (uPA)
2) Matrix metalloproteases
3) Cysteine proteases (cathepsins)

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19
Q

Once in the blood circulation, how do metastatic tumor cells survive in the blood

A

1) Survival in circulation
-Anchorage-independence to avoid anoikis
-Anti-apoptotic mechanisms
2) Avoid immune system- platelet cloak

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20
Q

cell death associated to loss of adhesion, occurs when metastatic cells enter the blood circulation

A

Anoikis

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21
Q

T/F: just because cells are in circulation does not mean they can successfully metastasize

A

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

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22
Q

Once metastatic tumor cells are in capillary, what do they need to do

A

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)

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23
Q

What is needed for metastatic cells to undergo extravasation

A

induce endothelial apoptosis - similar mechanism to intravasation

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24
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
25
the development of new blood vessels important in tumorigenesis, wound healing, estrus cycle, inflammation
angiogenesis
26
When is angiogenesis seen
1) Tumorigenesis 2) Wound healing 3) Estrus cycle 4) Inflammation
27
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
28
Due to hypoxia, tumors cannot grow beyond _______ unless they have their own blood supply
1mm
29
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
30
ingrowth of endothelial cells from existing vessels due to signals from the tumor or other tissues
Classical/Sprouting Angiogenesis
31
outgrowth and recruitment of circulating endothelial precursors from blood
vasculogenesis
32
tumors make other tubes lined with extracellular matrix that mimic vessels to deliver blood to them
Vasculogenic mimicry, mosaicism
33
Angiogenic balance
+ factors: VEGF, bFGF, IL-8, Ang-1,2 vs - factors: Tsp-1,2. Endostatin, Angiostatin
34
What factors increase + factors for pro-angiongenesis
Hypoxia Oncogenes Loss of TS Genes Aberrant Signal Transduction
35
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
36
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
37
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
38
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)
39
Angiostatin and endostatin are examples of
angiogenesis inhibitors -but need to be on continuous infusion pumps
40
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
41
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
42
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)
43
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)
44
What are the GI manifestations of cancer
1) Anorexia and Cachexia 2) GI ulceration- commonly MCTs via hyperhistaminemia
45
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
46
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
47
Paraneoplastic myasthenia gravis is reported in dogs and cats with
thymoma - can also be seen in some other cancers too
48
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
49
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
50
Nodular dermatofibrosis is a PNS that is associated with
bilateral renal cystadenocarcinomas or cystadenomas
51
Superficial necrolytic dermatitis is seen in animals that have
1) Hepatic disease (hepatocutaneous syndrome) 2) Glucagon secreting tumors (PNS)
52
Paraneoplastic exfoliative dermatitis is reported in cats with
thymoma
53
What may be the first sign of malignancy
paraneoplastic syndrome
54
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
55
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
56
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
57
Zoledronate
a drug that can be used to eliminate hypercalcemia
58
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
59
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
60
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
61
What cancers typically cause hypercalcemia in cats
1) Lymphoma 2) Squamous Cell Carcinoma
62
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++
63
What are possible differentials for mediastinal masses
1) Lymphoma (t-cell) 2) Thymoma- ectopic thyroid carcinoma, branchial cyst, metastatic neoplasia
64
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
65
Why is it important to monitor iCa++ throughout treatment of cancer (ie lymphoma)
increased calcium was a marker for disease reucurrence
66
Hyperglobulinemia is a paraneoplastic syndrome associated with which two cancers
1) Multiple Myeloma - plasma cells 2) Lymphoma- some B cell types can produce immunoglobulins
67
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
68
Cancerous causes of hypertrophic osteopathy
-Primary lung tumur -Metastatic cancer to tumor -Rhabdomyosarcoma of bladder (rare) -esophageal sarcoma (rare)
69
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
70
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
71

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