Tumors of the skeletal system

Question 1

Osteosarcoma in dogs accounts for what % of tumors originating from the skeleton?

Answer 1

85%, most common

Question 2

What is the median age for OSA in dogs? What is the distribution?

How about rib OSA?

Answer 2

Median age is 7 years with bimodal distribution, increased incidence at 18 to 24 months

Primary Rib OSA occurs in younger dogs at mean age of 4.5 – 5.4 years.

Question 4

7 common breeds affected by OSA?

Answer 4

Saint Bernard, Great Dane, Irish Setter, Doberman Pincher, Rottweiler, GSD, Golden Retriever

Question 5

Is there sex predilection for canine OSA?

Answer 5

Males are slightly more frequently affected than females (1.1-1.5:1). Intact males and females have an increased risk for OSA.

Question 6

What is the distribution for canine appendicular and axial OSA?

Answer 6

75% of OSA occurs in appendicular skeleton and 25% axial skeleton

Question 7

What is the distribution of canine appendicular OSA with regards to limb distribution?

Answer 7

Thoracic limbs affected 2x more than pelvic limbs

Thoracic limbs: distal radius and proximal humerus most common

Pelvic limbs: distal femur, distal tibia, proximal tibia are equally affected, proximal femur less common

Question 8

What is the distribution of canine axial OSA?

Answer 8

27% mandible, 22% maxilla, 15% spine, 14% cranium, 10% ribs, 9% nasal cavity, 6% pelvis

Question 9

List 3 physical factors associated with etiology for OSA?

Answer 9

Trauma to cells in physeal region

Metallic impants

Ionizing radiation

Question 10

What 4 genetic factors have been associated with etiology for canine OSA?

Answer 10

p53: missense mutations involving exons 4 to 8 have been identified in 24% to 47% of canine OSAs. In addition, comparative genomic hybridization analysis of 38 canine OSAs has found cytogenetic aberrations similar to humans OSA including loss of heterozygosity (LOH) of p53 gene in 18% of tumors.

RB: In 5 immortalized OSA cell lines the RB gene was dysregulated with hyperphosphorylated RB protein. In addition, analysis of 38 OSA samples identified copy number loss in 29% of cases, resulting in reduction or absence of RB protein expression in 62% of samples.

PTEN tumor suppressor gene: In vitro studies found that most OSA cell lines (60%) had mutations in PTEN. comparative genomic hybridization analysis found region deletions and high recurrent copy number loss involving the PTEN gene locus.

Breed inherited inheritance: especially in Scottish Deerhounds, Rottweilers, Greyhounds, Great Danes, Saint Bernard’s, and Irish Wolfhound. 33 genetic loci were identified to contribute to heritable OSA in Greyhounds, Rottweilers, and Irish wolfhound.

Question 11

How does tyrosine protein kinase MET play a role in canine OSA?

Answer 11

MET protooncogene encodes a tyrosine kinase receptor which binds to hepatocyte growth factor (HGF) leading to cell scattering, motility, and proliferation

Excessive or dysregulated MET signaling in canine OSA promotes tumorigenic phenotypes in cell lines. Also, a pilot study showed MET protooncogene was identified in majority (71%) of tumor specimens. Larger study of 59 dogs with OSA, mRNA expression of MET and HGF was detected by real time PCR in all specimens.

Question 12

How does insulin-like GF play a role in canine OSA?

Answer 12

Effects of GH are mediated through IGF-1 (produced by hepatocytes). IGF-1 induces cell mitogenesis, protects from apoptosis, and promotes angiogenesis.

Aberrant or excessive IGF-1 signaling likely participates in OSA pathogenesis.

Question 13

How does EGF play a role in OSA?

Answer 13

Protooncogene erb-2 encodes HER2, a tyrosine kinase receptor. Overexpression of HER2 protein caused by gene amplification is a negative prognostic factor in mammary carcinoma in dogs and humans.

Role of HER2 overexpression in OSA is unclear.

Question 14

How does mTOR play a role in OSA?

Answer 14

mTOR is protein kinase downstream of AKT important in regulating cell cycle progression and growth. Therefore, aberrant signaling through mTOR pathway contributes to growth, survival, and chemotherapy resistance

Study using 3 OSA cell lines looked at expression of mTOR and p70S6K (downstream effector protein of mTOR) and found pathway activity and capacity to inhibit signaling with rapamycin. Another study investigating the PK and PD of rapamycin in dogs with OSA demonstrated that modulation of mTOR was achievable in the bone tumor microenvironment.

Question 15

How does Hedgehog and Notch play a role in OSA?

Answer 15

Hedgehog-GL1 and Notch-HES1 signaling pathways are important for growth, survival, and metastases of various human tumors.

Overexpression of HHG pathway was confirmed in canine OSA cell lines.

Similarly, Notch pathway has been evaluated in canine OSA. Gene array analysis of Notch/HES1 associated genes suggested upregulation of Notch signaling which may contribute to OSA pathogenesis, however inverse relationship with survival was identified.

Question 16

What are the 5 histologic classifications for OSA?

Answer 16

osteoblastic, chrondroblastic, fibroblastic, poorly differentiated, and telengiectic

Question 17

When does metastasis occur? What % have radiographic evidence?

___% will die within 1 year, MST with amputation alone?

Sites of metastasis

Answer 17

Early in disease, 15%

90%, 19 weeks

lungs, lymph nodes, other soft tissue sites. Occurs through hematogenous routes.

Question 18

6 common features noted on radiographs with OSA?

Answer 18

cortical lysis

soft tissue sweeling

elevation of periosteum with new bone laid down (Codmans triangle)

doesnt cross articular joint

monoostotic

long transition zone

Question 19

What are 6 other differentials for lytic, proliferative, aggressive bone lesions?

Answer 19

Other primary bone tumors (CSA, FSA, HSA), metastatic lesion (especially genitourinary carcinomas), MM, LSA, fungal or bacterial osteomyelitis, or bone cysts.

Question 20

What are the 3 ways to perform a bone biopsy?

Answer 20

Open incisional: large sample of tissue can be obtained allowing for an accurate diagnosis but risks can include hematoma formation, wound breakdown, infection, local seeding, pathologic fractures.

Trephine biopsy: accuracy rate of 93.8% but has an increased risk for pathologic fracture

Jamshidi needle biopsy: accuracy rate 91.9% for tumor detection and 82.3% accuracy rate for diagnosing specific tumor subtype.

Question 21

What are the 3 stages of OSA?

Most dogs present as what stage?

Answer 21

Stage I - low grade (G1)

Stage II – high grade (G2) without metastasis

Stage III – regional or distant metastasis regardless of grade

Substage A – intracompartmental (T1)

Substage B – extracompartmental (T2)

Stage IIB

Question 22

List 3 negative prognostic indicators in dogs with OSA?

Answer 22

Dogs younger than 5 years of age treated with amputation alone had shorter survival than older dogs (contraindicated by a newer metanalysis study).

Large tumor size and humeral location are associated with poor outcome.

Higher histologic grade and MI may be predictive of poorer prognosis

Question 23

List 3 positive prognostic indicators?

Answer 23

OSA originating from flat bones, small dog size and completeness of excision are positive factors.

Small breed dogs with appendicular OSA may have improved STs compared to large breed dogs.

Question 24

OSA of the head has a _____ metastatic rate than appendicular OSA.

Answer 24

lower

Study of 183 dogs, the overall MST was 239 days. Dogs treated with mandibulectomy had 1-year survival rate of 71%.

Another study with mandibular OSA confirmed improved STs relative to appendicular OSA, however 58% of dogs developed metastatic disease.

Question 25

MST for rib OSA?

Answer 25

3 months after chest wall resection alone and 8 months when combined with adjuvant chemotherapy

Question 26

What is the DFI and MST for scapular OSA?

Answer 26

DFI is 210 days (7 mo) and MST if 246 days (8 mo) when treated with scapulectomy and chemotherapy.

Question 27

What is MST for vertebral OSA?

Answer 27

MST was 4 months in 15 dogs treated with combination of surgery, RT, and chemotherapy

Question 28

What is the local recurrence, metastatic rate, and mean ST for pelvic OSA treated with hemipelvectomy?

Answer 28

local recurrence of 21% and metastatic rate of 46% with mean ST of 533 days (1.5 yr).

Question 29

Extraskeletal OSA

Answer 29

Extra skeletal OSA affecting visceral sites (GI tract, spleen, liver, kidney, urinary bladder), skin or SQ, or mammary glands - aggressive systemic behavior with high metastatic rate. Study with soft tissue and mammary OSAs, MST for dogs with nonmammary gland soft tissue OSA was 1 month and 3 months for mammary gland OSA after surgery alone. Cause of death was local recurrence (92%) in dogs with soft tissue OSA and pulmonary metastasis (62.5%) with mammary gland OSA.

Question 30

Elevated ALP is associated with ___ prognosis with appendicular and rib OSA? Associated with shoert ___ and ST

Answer 30

Poor DFI and ST Study with 96 dogs, positive correlation between serum ALP and tumor size was identified. May be association between increased pretreatment bone ALP and negative prognosis may be due to greater tumor burden and advanced stage of disease. Elevation in bone ALP may be an epiphenomenon of either tumor burden or osteoblastic signaling pathways.

Question 31

Ezrin, RON, survivin, VEGF, COX-2, and HSP have been reported to influence DFI and ST in dogs Ezrin: cellular protein that is an anchor site for cytoskeletal fibers. High ezrin staining in primary tumor was associated with shorter DFI (116 days) compared to low ezrin staining (188 days). Hepatocyte growth factor receptor (MET) and RON: signaling promotes tumorigenesis and metastases. On a canine OSA tissue array, RON expression (not MET) was prognostic for survival with high expression associated with decreased STs. Survivin: involved in cell division and apoptosis inhibition. Dogs with low survivin expression in primary OSA tumors had longer DFI (331 days) compared to dogs with high expression (173 days). VEGF and COX2: regulators of angiogenesis. In 25 dogs with OSA treated with surgery and chemotherapy, serum VEGF concentration in lower 50th percentile was associated with longer DFI (356 days) compared to dogs with VEGF above the 50th percentile (145 days). Dogs with primary OSA tumors with strong intensity for COX2 had significantly shorter MST (86 days) than dogs with negative staining tumors (MST 423 days). HSPs: important in protein folding and protection cells after endoplasmic reticulum stressors In dogs with OSA, increased expression of HSP60 was associated with reduced DFIs and STs.

Question 32

How does CD8/Treg ratio affter ST in dogs with OSA?

Answer 32

In 12 dogs treated with amputation and chemotherapy, dogs with low CD8/Treg ratios had significantly shorter ST than dogs with high CD8/Treg ratio.

Question 33

How does lymphocytosis and monocytosis affect DFI?

Answer 33

In 69 dogs treated with amputation and chemotherapy, shorter DFI was observed in dogs presenting with relative lymphocytosis and relative monocytosis. Hypothesized that reduced DFI could be due to myeloid-derived suppressor cells which may suppress antitumor immune responses.

Answer 34

In 30 dogs with OSA treated with amputation and carboplatin, macrophage (CD204+) and lymphocyte infiltrate (CD3+ and FOXP3+) were investigated and found that dogs with more than 4.7% surface area infiltrate with CD204+ macrophages had longer DFI suggesting tumor infiltrating macrophages may contribute to inhibiting localize OSA metastatic progression.

Question 35

Who are suitable candidates for limn salvage surgery?

Answer 35

Dogs with nonmetastatic OSA and \<50% involvement of the primary bone tumor. No pathologic fracture, less than 360-degree involvement of soft tissues, firm/definable soft tissue mass rather than edematous lesion. Dogs with tumors in distal radius or ulna because they have good function after carpal arthrodesis.

Question 36

What are the advantages and disadvantages with Allograft limb salvage surgery?

Answer 36

Advantages include no external fixation device, minimal owner involvement. Disadvantages include high infection rate (40 - 50%) and permanent internal hardware.

Question 37

Metal endoprosthesis

Answer 37

Uses a metal endoprosthesis with modified bone plate, 3D printed, or custom designed endoprosthesis. No significant difference in complication rate between endoprosthesis and allografts.

Question 38

Longitudinal bone transport osteogenesis

Answer 38

Uses Ilizarov (circular) fixators and principles of distraction osteogenesis to create bone in the defect remaining after tumor resection. Advantages – low risk infection fur to the autologous, vascularized nature of replacement bone and bone remodels over time. Disadvantages – requires extensive client involvement with the fixators which stays on for an extended amount of time.

Question 39

Ulnar transposition

Answer 39

Uses ipsilateral distal ulna as an autograft to reconstruct distal radial defect. Advantages – no distant donor site morbidity, replacement bone is autologous and graft is vascularized (less chance for infection). Disadvantages – more prone to biomechanical complications (postoperatively) due its smaller size compared to the radius and permanent internal hardware.

Question 40

Intracorporeal and Extracorporeal Intraoperative Radiation Therapy

Answer 40

Osteotomy performed proximal or distal to the affected site, normal tissues are reflected off the bone, the tumor is given a single dose of 70Gy. The irradiated bone is replaced and surgical fixation of the osteotomy site is performed. Advantage – preserves limb and joint function that are not amenable to LSS with arthrodesis (proximal humerus). Complications related to surgery or RT led to implant revisions in 69% of cases within 5 to 9 months. Pathologic fracture was most common complication. Extracorporeal IORT

Question 41

What are the advanatges and disadvantages of SRT?

Answer 41

Allows delivery of high dose RT to the tumor while sparing normal tissues. UF – nonsurgical technique using a single fraction SRS evaluated in 11 dogs. Adjuvant carboplatin was used in 6 dogs before RT and 5 dogs treated with SRT alone. 4 dogs developed pathologic fractures, 1 dogs developed infection, acute effects were mild to moderate, 1 dog developed open skin wound 3 months post treatment, 1 dog developed full thickness skin wound following pathologic fracture. Overall MST was 363 days. SRT protocols for the treatment of OSA uses 2 to 3 fractions of 8 to 13 Gy per fraction ( 3 x 10Gy most common) delivered daily or EOD. Advantage – limb preservation, normal tissue sparing effect, with good to excellent limb function. Disadvantage – limited access to technique and high rate of pathologic fracture.

Question 42

Isolation of Limb Circulation and Perfusion

Answer 42

Isolated limb perfusion (ILP) – deliver high concentration of chemotherapy and compounds that are poorly tolerated systemically. Method to facilitate delivery of therapeutic drug concentrations to primary tumors to downstage before LSS. Delivery of Samarium via ILP in 9 dogs with appendicular OSA 3 weeks before amputation to induce tumor necrosis before tumor removal. No systemic toxicity was observed, the TN was 27.6% which was similar to TN of 26.8% in untreated OSA cases.

Question 43

Surgery for Nonappendicular and Less Common Appendicular Sites of OSA Pelvis? Vertebral OSA? Scapula?

Answer 43

Pelvis – hemipelvectomy can be performed, difficult surgery with excellent function and cosmetic outcome. Vertebral OSA – total en bloc vertebrectomy not well established in vet med. Pursue surgery in cases that require decompression and start RT and chemotherapy. Scapula – partial or total scapulectomy. Significant gait abnormalities may occur.

Question 44

MST associated with RT?

Answer 44

Used for palliation of bone pain. Associated with MST of 209 days (7 mo) reported in 14 dogs with appendicular OSA treated with fractionated RT ( median dose of 57Gy) to the primary tumor and chemotherapy.

Question 45

Radioisotopes for OSA

Answer 45

Sm153 (B emitter radioisotope) has been used to treat OSA and metastatic bone neoplasia. Y90 (Yttrium-hydroxide) has been reported as intralesional liquid brachytherapy with tibial OSA.

Question 46

Single-Agent Carboplatin

Answer 46

First study, 48 dogs with OSA treated with amputation and 4 doses of carboplatin (300 mg/m2 Q 21d), neutropenia was dose limiting toxicity. Median DFI and MST were 257 days and 321 days for entire study population and for dogs receiving 4 doses of carboplatin median DFI and MST was 327 and 383 days. To determine if carboplatin was comparable to cisplatin, 2 studies were done: Dogs treated with single dose of carboplatin and amputation 7 days later, then received 2 carboplatin treatments Q21d. Then dogs were randomized to receive somatostatin analog. Dogs treated with carboplatin and placebo, the median DFI and MST were 196 and 230 days. Second study used liposomal encapsulated cisplatin (SPI-77) versus single agent carboplatin administered to patients 1 week before amputation followed by 3 additional doses of SPI-77 or carboplatin Q 21d. No difference in treatment groups and dogs treated with single agent carboplatin had median DFI and ST of 123 and 207 days. Two studies conducted to substantiate the activity of carboplatin for pulmonary metastasis: 155 dogs treated with amputation and carboplatin had median DFI and ST of 256 and 307 days. 65 dogs treated with amputation and carboplatin (300 mg/m2 Q 21d for 4-6 tx) had median DFI and ST of 137 and 277 days.

Question 47

Single agent Doxorubicin

Answer 47

Better at preventing metastasis when administered every 2 weeks as compared to every 3 weeks. Study administered DOX 30 mg/m2 Q 2weeks x 5 tx to 35 dogs. The 1- and 2- year survival were 50.5% and 9.7%. Second study, to evaluated activity of MMP inhibitor (BAY-12-9566), 303 dogs were treated with amputation and DOX 30 mg.m2 Q 2 weeks x 5 tx, then randomized to receive oral placebo or BAY-12-9566. No difference in ST noted between 2 groups and overall MST was 8 months.

Question 48

Doxorubicin-Carboplatin Combined Chemotherapy

Answer 48

24 dogs treated with surgery followed by carboplatin (175 mg/m2) on day 1 and then DOX (15 mg/m2) on day 2, administered Q 21d. Associated with mild GI toxicity in 50% of dogs. Median DFI and MST were 195 and 235 days.

Question 49

Doxorubicin-Carboplatin Alternating Chemotherapy

Answer 49

Study with 32 dogs treated with amputation or LSS and then with carboplatin (300 mg/m2 or 10 mg/kg) up 3 cycles. Protocol was well tolerated. The median DFI and MST were 227 days and 320 days with 1- and 2- year survival rates 48% and 18%. Second study, 50 dogs treated with amputation and alternating carboplatin and DOX Q21d for 3 cycles. The median DFI and MST of 202 and 258 days.

Question 50

Doxorubicin-Carboplatin Modified Combination Sequencing or Dose Interval

Answer 50

Retrospective study with 33 dogs treated with amputation were given DOX every 2 weeks followed by 4 doses of carboplatin every 3 weeks. 10% dogs had grade 3 or 4 neutropenia and 16% dogs had grade 3- 4 GI toxicity. The median DFI and overall MST was 232 and 247 days. Study with 38 dogs treated with amputation and combination of 3 doses of DOX Q14 days and then 3 consecutive doses of carboplatin Q 21 days. 5.2% of dogs required hospitalization and MST was 317 with 1- and 2- year survival rates of 43.2% and 13.9%

Question 51

Head to Head Comparison Studies

Answer 51

Retrospective study with 470 dogs compared carboplatin and DOX-based protocol following amputation. 5 different chemo protocols were evaluated: carboplatin Q21 days x 4 to 6 cycles, DOX Q14 to 21 days x 5 cycles, alternating carboplatin and DOX Q 21d for 3 cycles. Median DFI and MST were 291 and 284 days. Dogs treated with 6 cycles of carboplatin had lower proportion of AEs. A second randomized study evaluated carboplatin and alternating carboplatin and DOX. Dogs treated with 6 doses of carboplatin Q 3 weeks or 3 cycles of alternating carboplatin and DOX Q3 weeks. Dogs treated with carboplatin had longer DFI of 425 days versus 135 days for alternating protocol.

Question 52

Conventional Chemotherapy Combined with Metronomic Therapies

Answer 52

Retrospective study of 30 dogs treated with amputation, received either carboplatin alone x 6 cycles or alternating carboplatin and DOX every 21 days x 5 tx and daily piroxicam and cyclophosphamide. AEs were tolerable with no significant difference in DFI between the protocols. Retrospective study evaluated the benefit of metronomic cyclophosphamide and meloxicam as maintenance therapy following amputation and carboplatin in 39 dogs. Sterile hemorrhagic cystitis was seen in 58% of dogs. The median PFS and MST were 402 and 464 days. Dogs receiving metronomic chemotherapy had longer median PFI (480 days) and MST (480 days) than dogs treated with carboplatin alone (244 and 458 days) which were not statistically significant.

Question 53

Chemoimmunotherapy

Answer 53

L-MTP-PE is a lipophilic derivative of muramyl dipeptide, synthetic analog of mycobacterium cell wall component, which can augment canine alveolar macrophage tumoricidal properties against OSA cells in vitro. Study of 27 dogs, were treated twice weekly with either L-MPT-PE or empty liposomes for 8 weeks. Dogs treated with L-MTP-PE had longer DFI (168 days) than dogs treated with empty liposomes (58 days). Another study combined L-MPT-PE with cisplatin. Dogs treated with amputation and cisplatin Q4 weeks x 4 tx followed by either L-MPT-PE or empty liposomes. Dogs treated with L-MPT-PE had longer MST (14.4 months) than dogs treated with empty liposomes (9.8 months). Second study evaluated using cisplatin and L-MPT-PE given concurrently to 64 dogs. No improvement was seen in DFI or MST in either groups. The OSA vaccine induces tumor specific T cell response against the immune epitope of HER2.neu expressed by OSA cells. Vaccines contains recombinant Listeria monocytogenes expressing chimeric human HER2/neu protein (ADXS31-164). Evaluated in 18 dogs with OSA that were treated with 3 consecutive doses of ADXS31-1 every 3 weeks after completing standard treatment (amputation or LSS and 4 doses of carboplatin). Overall, well tolerated with median DFI and MST of 615 and 956 days.

Question 54

Molecular Targeted Therapies for Dogs with OSA

Answer 54

GH and IGF-1 are important for skeletal growth, homeostasis, and cell survival therefore these factors may be involved in OSA pathogenesis due to aberrant or excessive GH and IGF-1. Study included 44 dogs with OSA (tx with amputation and carboplatin) received somatostatin analog (OncoLAR) which suppresses IGF-1. OncoLAR resulted in 43% reduction in IGF-1 and did not result in improved DFI or MST when compared to dogs that received carboplatin and the vehicle . MMPs are involved in local tissue invasion and metastasis. Therefore, MMP inhibitor has the potential to increase metastasis free period. Prospective study evaluated BAY 12-9566 (MMP-2 and 9 inhibitor) in 223 dogs with nonmetastatic OSA. Following amputation and DOX they received either BAY 12-9566 or placebo and BAY 12-9566 did not improve DFI or MST. Toceranib phosphate (TOC) has been evaluated as adjuvant treatment for dogs with appendicular OSA. Prospective trial of 126 dogs treated with amputation and carboplatin received with metronomic chemotherapy (cytoxan and piroxicam) or oral metronomic and TOC. No difference in DFI was noted with control protocol (215 days) or TOC (233 days). Suramin, polysulfonated napthylurea, increased tumor sensitivity to chemotherapy. Administered to dogs with DOX and combination was well tolerated. The median DFI and overall MST were 203 and 369 days.

Question 55

Surgery for Gross Metastatic Disease ## Footnote Study with 36 dogs that had pulmonary metastasis, metastasectomy was performed without chemotherapy and overall MST was 487 days. The MST after surgery was 176 days. Criteria for Candidates eligible for such surgery: Primary tumor in complete remission (\>300 days), 1 or 2 nodules on CRXs, pulmonary metastasis only, long doubling time (\>30 days).

Question 56

Chemotherapy and Receptor TKI for Gross OSA ## Footnote Study with 45 dogs with metastatic OSA following amputation and chemo received either cisplatin, DOX, or mitoxantrone. 1 dog achieved PR (21 days). Therefore, chemo was not effective for managing metastatic disease. Retrospective study of 23 dogs with metastatic pulmonary OSA received TOC. PR was noted in 1 dog (4.3%) and SD in 10 dogs (43.5%). Prospective study of 22 dogs with metastatic pulmonary OSA received TOC and they also measured changes in circulating VEGF and Tregs. SD and PD was noted in 17.6% and 83.4%. Median PFS and overall MST were 57 and 89 days. Also, circulating VEGF increased with TOC tx with no effect noted on Tregs.

Question 57

How does RT palliate bone pain? Pain control is noted in what % of dogs? Median time interval for pain alleviation?

Answer 57

Analgesic effects of ionizing radiation is doe to cell death of osteoblasts and resorbing osteoclasts. In addition, depletion of local inflammatory cells and inhibition of osteoclast precursor recruitment. Several palliative protocols have been published but most common is 2 to 4 fractions of 6 to 10 Gy. Associated with pain control in 74% and 93% of dogs with median time interval for pain alleviation from 53 to 130 days (2-4 mo)

Question 58

How do radiopharmaceuticals work for OSA?

Answer 58

153Sm (radioisotope that undergoes gamma and beta decay) when combined with EDTMP (bisphosphonate) concentrates in areas of increased osteoblastic activity and binds to hydroxyapatite. Dogs treated with 153Sm- EDTMP the estimated radiation dose within tumor microenvironment is 20 Gy, and after IV administration, 63-83% of dogs with OSA have improved lameness.

Question 59

Aminobisphophanates

Answer 59

NBPs inhibit bone mineralization by inducing osteoclast apoptosis by interfering with posttranslational prenylation of small GTP binding proteins (Ras, Pho, Rac). This results in failure of normal intracellular signaling and interaction with ECM which triggers apoptosis. Zoledronate is 100x more potent than pamidronate and can be safely administered over a short period of time. Complications can include osteonecrosis of the jaw. Study with 43 dogs with appendicular OSA treated with pamidronate (PAM) IV resulted in pain alleviation in 28% of the 43 dogs for more than 4 months. In a prospective study, 17 dogs with appendicular OSA were treated with Palliative RT ( 8Gy on day 1 and 2) and either saline infusion or PAM every 4 weeks x 3 tx. Dogs receiving PAM had improved limb functions compared to RT alone. Another study, 50 dogs with OSA were treated with palliative RT, DOX, and either saline or PAM. Median pain free interval treated with PAM or saline was 76 and 75 days. However dogs treated with PAM had decreased bone resorption in the primary tumor.

Question 60

Comparative aspects ## Footnote OSA is uncommon in humans and affects adolescents in their second decade of life and tends to be an aggressive tumor. Treatment includes multidrug adjuvant protocols such as high dose methotrexate, DOX, and cisplatin. Survival rate is 60 to 70% at 5 years. Poor prognostic factors include older age, advanced local or systemic stage, axial location, larger size, and percentage TN.

Question 61

What is periosteal OSA?

Answer 61

Arises from periosteal surface. Histologically similar to intraosseous OSA and have aggressive biologic behavior. Causes cortical lysis and extends into the bone and soft tissue.

Question 62

What is paraosteal OSA?

Answer 62

Arises from periosteal surface but is less aggressive than periosteal OSA. Cortical lysis is mild on radiographs. Histologically they are more benign and do not invade medullary canal and grow out from the bone.

Question 63

Chondrosarcoma is the __ most common primary bone tumor, accounts for \_\_% bone tumors.

Answer 63

2nd most common primary bone tumor, accounts for 5% to 10% bone tumors.

Question 64

Etiology for CSA? Sex predilection? Where do they commonly occur? What is the most common site? Metastasis?

Answer 64

Etiology is unknown, no sex predilection, 61% of tumors occur on flat bones. Nasal cavity is the most common site. Lower metastatic potential.

Question 65

MST for dogs with nasal CSA? rib CSA? appendicular CSA? Metastatic risk? Chemotherapy?

Answer 65

MST for dogs with nasal CSA is 210 to 580 days (7-19mo) MST for dogs with rib CSA varies ranging from 1080 days to 3820 days (3-10 yrs) MST for dogs with appendicular CSA treated with amputation alone was 979 days (2.7 yr) Metastatic rate and MSTs for grade I (0% and 6 years), grade II (31% and 2.7 years), and grade III (50% and 0.9 years). Adjuvant chemotherapy drug is unknown.

Question 66

Hemangiosarcoma accounts for what % of bone tumors? Age distribution? Metastasis? Can be confused with?

Answer 66

\<5% Seen in middle age to older dogs and dogs of any size. Highly metastatic and metastasis seen within 6 months of diagnosis. Mets to lungs, liver, spleen, heart, skeleton, muscle, kidney, brain, and bones. Appendicular HSA may be confused with telangiectatic OSA. Study of 41 dogs with appendicular HSA, favored pelvic limb especially tibia. MST was 299 days with amputation and chemotherapy.

Question 67

Fibrosarcoma accounts for what % of bone tumors? Can be confused with? Treatment? Chemotherapy? Mets to what 4 locations?

Answer 67

Rare and accounts for \<5% of bone tumors. Difficult to distinguish FSA from fibroblastic OSA histologically. Limb amputation or LSS may be curative but metastatic potential mat be considerable. No evidence that chemotherapy is beneficial. Mets to heart, pericardium, skin, and bones instead of lungs.

Question 68

Where does MLO arise from? Median age Local recurrence? Median time Mets? Median time? MST

Answer 68

Skull of dogs ## Footnote Based on study of 39 dogs, median age is 8 years, median weight is 29 kg, no breed or sex predilection. Local tumor recurrence reported in 47% of dogs with median time of 797 days. Metastasis noted in 56% with time to metastasis of 542 days. MST was 800 days. Local tumor excision with complete surgical margins allows for long term tumor control for low grade lesions. Role of chemotherapy or RT is not well defined.

Question 69

What are the common locations for metastasis to bone? Occur where on bone?

Answer 69

Lumbar vertebrae, femur, humerus, rib, pelvis are common sites possibly because it is spreading from urogenital tumors such as prostate, bladder, urethral, and mammary cancer. Metastatic lesions typically seen in diaphysis, likely due to nutrient foramen

Question 70

What do osteomas look like radiographically? Painful? Important diffferential if occuring on skull? Treatment?

Answer 70

well circumscribed and non-painful on palpation. Most important differential is MLO if occurring on the skull. Treatment is surgical excision which is curative.

Question 71

Who gets Multiple Cartilaginous Exostosis? Etiology Lesions are located where? Treatment?

Answer 71

Seen in growing dogs and etiology may have heritable component (these dogs should be neutered). bones that form endochondral ossification and lesions stop growing at skeletal maturity. Present with nonpainful or moderately painful palpable mass on surface of bone. Biopsy is necessary to confirm diagnosis. Tx involves surgical excision if clinical signs do not resolve at skeletal maturity. Advice owners of possibility of malignant transformation (such as to CSA).

Question 72

Bone cysts?

Answer 72

Affects young animals and causes mild to moderate lameness. Can cause pathologic fractures. Familial tendency in Doberman Pinchers and Old English Sheepdog. Lesions seen in metaphyseal areas of long bone and can cross growth plates. Etiology and pathogenesis is unknown but speculate that it could be secondary to trauma to the growth plate. Biopsy needed for diagnosis. Treatment involves curettage and packing the space with autogenous bone graft. Aneurysmal bone cysts (ABCs) – multiloculated masses filled with blood. Could be due to trauma or benign bone tumor which disrupts the vasculature. Age ranges from 2 to 14 years. Treatment includes en bloc resection and reconstruction of bone.

Question 73

What are the 4 periarticular tumors? Clinical signs associated with these tumors? Age and breed?

Answer 73

Periarticular Tumors – HS, SCS, synovial myxoma/myxoma sarcoma, malignant fibrous histiocytoma Clinical signs: lameness and firm mass or swelling near joint (especially large joints such as stifle) Age and Breed: Middle-aged and larger breed dogs

Question 74

How do you diagnose periarticular tumors? Staining pattern for HS, SCS, myxoma sarcoma? Metastatic rate?

Answer 74

Diagnosis: biopsy with IHC staining HS: vimentin +, CD18 +, cytokeratin – SCS: vimentin +, CD18 -, cytokeratin + Myxoma sarcoma: vimentin +, HSP +, CD18 + (20-40%), cytokeratin - Metastatic rate HS: 91% SCS: 8 to 32%

Question 75

What is the treatment for HS? SCS? Myxoma sarcoma?

Answer 75

Treatment: HS: amputation and adjuvant CCNU which has MST of 568 days (1.5 yr) than amputation alone (161 days or 5 mo). SCS: amputation with a MST of 455 to 967 days which is dependent on histologic grade. Grade I: 365 to 1460 days (1-4 yr) Grade II: 156 to 1095 days (5 mo - 3 yr) Grade III: 183 days (6 mo) Myxoma sarcoma: either amputation or local resection (synovectomy) and has ST of \> 2 years even with incomplete excision.

Question 76

What is the most common primary bone tumor in cats? Most common location? For appendicular OSA which limbs are the common location? Common location for axial OSA? Metastatic risk? Age?

Answer 76

Rare tumors with OSA being most common (70 to 80% of primary bone tumors) Location: appendicular is twice more common than axial sites. Appendicular: pelvic limbs more common (distal femur and proximal tibia) Axial: skull and pelvis most common Metastatic rate: 5 to 10%, less than dog Age: 8.5 to 10.7 years

Question 77

What is osteochondroma? Osteochondromatosis?

Answer 77

Osteochondroma: solitary lesions that continue to grow after skeletal maturity in sites not associated with endochondral ossification (skull). Have potential for transformation and metastasis. Osteochondromatosis (MCE): occurs after skeletal maturity, lesions seldom affects long bones, probably viral rather than familial origin. Virtually all cats are FeLV positive.

Question 78

Clinical signs associated with feline appendicular OSA? MCE? Common location?

Answer 78

Clinical signs associated with appendicular OSA: lameness, swelling, and deformity. MCE: rapidly progressing, conspicuous hard swelling over affected site. Location: scapula, vertebrae, and mandible

Question 79

MST for feline appendicular OSA? Axial OSA?

Answer 79

Treatment is amputation for appendicular OSA which has MST if 24 to 44 months. The MST for axial OSA is 6.7 months due to inability of achieving complete resection.

Question 80

Frequency of FSA, CSA, HSA in cats and order?

Answer 80

Rare tumors with the following order: FSA\>CSA\>HSA.