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Biology, diagnosis and treatment of canine appendicular osteosarcoma: similarities and differences with human osteosarcoma
Contents lists available at The Veterinary Journal Biology, diagnosis and treatment of canine appendicular osteosarcoma:Similarities and differences with human osteosarcoma Emanuela Morello , Marina Martano, Paolo Buracco School of Veterinary Medicine, Department of Animal Pathology, via Leonardo da Vinci 44, 10095 Grugliasco, Italy Osteosarcoma (OSA) is the most common primary bone tumour in dogs. The appendicular locations are Accepted 28 August 2010 most frequently involved and large to giant breed dogs are commonly affected, with a median age of Available online xxxx 7–8 years. OSA is a locally invasive neoplasm with a high rate of metastasis, mostly to the lungs. Dueto similarities in biology and treatment of OSA in dogs and humans, canine OSA represents a valid and important tumour model. Differences between canine and human OSAs include the age of occurrence (OSA is most commonly an adolescent disease in humans), localisation (the stiﬂe is the most common site of localisation in humans) and limited use of neoadjuvant chemotherapy in canine OSA.
Ó 2010 Elsevier Ltd. All rights reserved.
extends into surrounding soft tissues and has a high rate of metas-tasis. Metastasis occurs mainly to the lungs via the haematogenous Spontaneous tumours in dogs may serve as models for human route, as well as to other bones, visceral organs, the brain, subcuta- cancer biology and translational cancer therapeutics, having great- neous tissue and skin ().
er similarity than many current experimental tumour models. Ca- Lymph nodes are involved less commonly, with reported frequen- nine osteosarcoma (OSA) is a suitable model for OSA in humans cies of 4.4–9.0% due to the relatively high incidence of the tumour in dogs, similar- The use of chemotherapy as part of standard ities in biological behaviour, common molecular features, large curative-intent treatment is associated with an increase in the rate body size of breeds more frequently affected and sharing of the of bone and soft tissue metastases same environment. The lack of speciﬁc chemotherapeutic drugs In dogs, appendicular OSAs most often affect the metaphyses of in veterinary medicine and the sometimes prohibitive costs of long bones. The fore limbs are affected twice as often as the hind treatment for the management of cancer in dogs allow early access limbs, with the distal radius and proximal humerus being the most to novel therapeutics. Dogs have a naturally shorter life span, with frequent sites, followed by the distal femur and proximal and distal more rapid progression and early metastatic failure of cancer, tibia (). Large and giant permitting more rapid completion of clinical trials in this species breeds are more commonly affected; only 5% of OSAs occur in dogs compared to human patients. This paper gives an overview of the <15 kg ). Greyhounds, Rottweilers, Great Danes, biology and treatment options of OSA in dogs and humans.
Saint Bernards, Doberman Pinschers, Irish Setters, Golden Retriev-ers and German Shepherds have an increased risk of developingOSA, even though the predisposition seems to be related to size Clinical presentation of appendicular osteosarcoma rather than breed (Afamilial pattern of occurrence has been observed in the Saint Ber- Canine OSA accounts for 85–98% of all canine bone tumours nard, Rottweiler and Scottish Deerhound ( ). Appendicular locations are more common (75%), but OSA can also affect the axial skeleton Males are more often affected than females (ratio 1.5:1), but (24%) and, occasionally, soft tissues (1%). Appendicular OSA is a lo- this ﬁnding is not consistent among publications cally aggressive malignant neoplasm which destroys bone locally, Affected females mainly belong to the Great Dane, Saint Bernard and Rottweiler breeds. The age at Corresponding author. Tel.: +39 011 6709062; fax: +39 011 6709165.
E-mail address: (E. Morello).
presentation has a bimodal distribution; a ﬁrst peak is reported at 1090-0233/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi: Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx 18–24 months, but most dogs are 7–9 years old plates) after orthopaedic procedures have been associated with ). Neutered dogs have twice the risk of developing OSA com- the development of OSA pared with sexually intact dogs A study on 683 Rottweilers undergoing gonadectomy before 1 year of age found Hypotheses to explain this phenomenon include a direct effect of a strong inverse association between lifetime exposure to gonadal metal implants, infection, instability of the implant and corrosion hormones and incidence of OSA, suggesting that sex hormones ). However, given the large number of orthopae- may play a role in tumour development dic surgical implants routinely applied and the fact that no conclu- Human OSA is the most common primary solid bone tumour in sions have been drawn on the role of metallic implants in sarcoma childhood and adolescence ( development, the occurrence of malignant lesions at the same site ). The incidence is higher in the second decade of life, during may be no more than a coincidence (). Under- periods of rapid bone turnover, with a median age of 16 years lying diseases, such as spontaneous or post-orthopaedic surgery ). After 10 years of age, males are more frequently af- bone infarcts and osteochondritis dissecans, have also been re- fected than females. A second peak in incidence occurs in older pa- ported as possible causative factors in dogs tients, usually associated with underlying bone pathology, such as Paget's disease, medullary infarcts or prior irradiation ( ). A study by on two groups of dogs ). The metaphysis of long bones is the primary site in more of different sizes (<15 kg; >25 kg) failed to demonstrate increased than 80% of cases. OSAs develop most commonly at sites of rapid microdamage in the distal metaphyseal radius in the large size bone turnover, such as the distal femur, proximal tibia and proxi- group, suggesting that microdamage is unlikely to be an important risk factor for OSA.
Metastases are clinically detectable in approximately 20% of hu- man patients on initial presentation and Genetic alterations metastatic spread is usually by the haematogenous route. The In one study, 27 p53 tumour suppressor gene mutations (20 lungs are the most common metastatic site (80–85%), followed point mutations and 7 deletions) were observed in 24/59 (40.7%) by bone (10%), which is usually involved only after pulmonary canine OSAs Cases of OSA with mutated metastasis ). Less frequent sites of metasta- p53 had a decreased survival time compared to dogs without p53 ses include lymph nodes (<10%), liver, adrenal glands, central ner- alterations (In two other studies, p53 was vous system, muscle and skin ). Patients without over-expressed in the majority of canine OSAs and alterations in its clinically detectable metastases are presumed to have micrometa- expression correlated with highly aggressive tumour behaviour and higher tumour grade Mutations in p53 have also been observed in other studies Aetiology and risk factors for osteosarcoma of canine OSA by and .
The aetiology of most OSAs remains unknown both in humans Over-expression of erb-B2, which encodes human epidermal and dogs. Some factors have been identiﬁed as possibly being in- growth factor receptor 2 (HER-2), was observed in 86% and 40% volved in development of canine OSA.
of canine OSA cell lines and tissue samples, respectively ). Deletions, mutations and down-regulation of the PTEN tumour suppressor gene have also been detected in OSA celllines and tumour samples Hepatocyte growth Ionising radiation factor (HGF) and its receptor c-Met were expressed in most OSA In both therapeutic and experimental settings, exposure to ion- ising radiation can induce OSA. Beagles administered aerosols con- A role for insulin-like growth factor-1 (IGF-1) and its recep- taining plutonium dioxide developed OSAs in the lungs, skeleton tor (IGF-1R) in cell growth and invasion in OSA canine cell lines has and liver, beginning about 3 years after exposure ( been demonstrated (Matrix metalloprotein- ). Skeletal malignancies, most of which were OSAs, ases 2 and 9, which may contribute to local disease progression were documented among 234 young adult beagles given single and metastatic spread, are expressed in OSA cell lines and tissues intravenous injections of monomeric 239Plutonium citrate ( ). Similarly, ezrin, a ). In another experimental study, 36/117 young adult membrane cytoskeleton linker also potentially involved in metas- beagles injected with 241Americium developed OSA ( tasis, was detected in 83% of primary canine OSAs and its presence was associated with a shorter median disease-free interval com- Several reports of OSA as a late complication of radiation ther- pared to OSAs with low ezrin expression (). Con- apy in dogs have been described. A vertebral OSA occurred in a dog 5 years after 60Cobalt teletherapy for a spinal cord tumour transcription 3 (STAT3) was present in a subset of canine OSA tu- (Secondary OSAs developed within the ﬁeld mours and cell lines, but not in normal canine osteoblasts ( of megavoltage irradiation 1.7–5 years after treatment in 3/87 (3.4%) of spontaneous tumour-bearing dogs irradiated for soft tis-sue sarcomas (). OSA has also been reported after orthovoltage irradiation of oral acanthomatous epulis (). In an experimental study, 21% of dogs Factors associated with the development of OSA in humans in- undergoing intra-operative radiation therapy (>25 Gy) to the ver- clude the faster growth rate of bone at puberty, exposure to tebral column, followed in some cases by external beam radiation, developed OSA 4–5 years post-treatment hereditary retinoblastoma (mutations in the RB gene), Li-Fraumenisyndrome (mutations in the p53 gene), Bloom syndrome, Minor chronic trauma Rothmund–Thomson syndrome and Werner's syndrome Long-standing metallic implants (e.g. Jonas intramedullary Radiation-induced OSAs are rare and splints and older generation tibial plateau levelling osteotomy typically occur in adults because of the long interval (5–20 years) Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), doi: E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx between radiation exposure and neoplastic transformation scintigraphy overestimated the local extent of OSA more than radi- ography, providing a larger margin of safety when determining the In human OSAs, tumorigenesis has been associated with altera- site of the proximal osteotomy, but also decreasing candidates for tions in tumour suppressor proteins (p53, Rb, PTEN), alterations in limb-sparing surgery oncogene expression (erbB-2, MET) and dysregulated cell signal- Thoracic radiographs are performed to evaluate metastatic ling and kinase pathways, such as vascular endothelial growth fac- spread to the lungs. Only a few patients (<5–10%) are positive for tor (VEGF), platelet-derived growth factor (PDGF), mTOR, c-Kit, radiographic lung metastasis at presentation, but OSA is consid- metalloproteinases and ezrin ered to be a tumour with a high metastatic potential, since approx- imately 90% of dogs with OSA treated by amputation only die ofmetastatic disease, usually to the lung, within 1 year of diagnosis(). CT of the thorax is superior to radiography History and physical examination in detecting smaller lung lesions (). Using nu-clear scintigraphy, the incidence of occult bone metastasis at the time of diagnosis of the primary tumour is 7.9%; lesions appearas non-speciﬁc areas of increased uptake of radiopharmaceutical Dogs with appendicular OSA are referred for the onset of pro- that should be veriﬁed by radiographs or biopsy gressive lameness and leg swelling Lameness is usually intermittent and initially mild, but progresses to becomepersistent and severe. The mass at the primary site is usually ﬁrmand often painful on palpation. Acute non-weight bearing lame- ness is typically associated with a pathological fracture.
In humans, at least two orthogonal radiographic views are re- quired when a bone lesion is suspected. The classical radiographic appearance is of ill-deﬁned borders, an osteoblastic and/or osteo-lytic lesion and an associated soft tissue mass. MRI represents Human patients with OSA present with pain of several months' the primary mode of evaluation of OSA in humans and can clearly duration (2–4 months before diagnosis), usually related to strenu- demonstrate the extent of tumour invasion of the surrounding soft ous exercise or trauma, and the pain interferes with sleep. On clin- tissue, neurovascular involvement, extent of bone marrow replace- ical examination, a visible swelling with a hard painful mass, ment and presence of discontinuous metastases ( decreased joint mobility or localised warmth or erythema may MRI is also useful to assess the possibility of limb salvage.
be present. Approximately 5–10% of patients with OSA present CT-guided core biopsy is frequently used for tissue biopsy for his- with a pathological fracture topathological diagnosis ). A CT scan of the chest and a nuclear scintigraphy bone scan are recommended torule out metastasis to the lungs and bone. Interest in the use of Diagnosis and staging positron-emission tomography (PET) for staging OSAs and moni-toring treatment is increasing ().
A diagnosis of primary malignant bone tumour is often sug- gested by clinical presentation and radiographic ﬁndings. Initial diagnosis can be attempted by ﬁne needle aspiration and cytology Dogs with appendicular OSA can be managed with either palli- Alkaline phosphatase (ALP) staining of cytology samples is useful ative- or curative-intent therapy. Curative-intent treatment is for differentiating between OSA and other primary bone tumours aimed at local tumour control and prevention or delay of meta- Bone biopsy can be performed via closed static disease.
(Jamshidi needle or Michelle's trephine) or open techniquesThe diagnostic quality of cytological or histo-logical bone samples can be improved by image-guided techniques Limb amputation remains the current standard of care for local Diagnostic imaging plays an important role in diagnosis and management (). It staging of dogs with OSA. Cranio-caudal and latero-medial radio- avoids the risk of pathological fracture, eliminates pain and is a graphic views of the primary lesion, including the joint above well tolerated procedure, with minimal complications; even large and below the affected bone, are required. The radiographic breed dogs show good functional results and the majority of own- appearance of OSA in long bones includes cortical bone lysis and/ ers are satisﬁed with the pet's quality of life ( or a proliferative sunburst pattern, periosteal proliferation, sub- ). Contraindications to amputation periosteal new bone formation and soft tissue swelling, with calci- may be severe obesity or concurrent debilitating orthopaedic or ﬁcation extending into surrounding soft tissue.
neurological diseases; however, each case needs to be evaluated Several studies have been performed to evaluate the accuracy of on an individual basis.
radiography, bone scintigraphy, computed tomography (CT) andmagnetic resonance imaging (MRI) in assessing the local extent Limb-sparing surgery of appendicular OSA ( Limb-sparing in dogs can be achieved with surgical and/or radi- ). In one study, MRI was recognised as the best modality ation techniques. Good results have been reported with recon- for preoperative assessment of intramedullary extent of appendic- structive limb-sparing procedures for OSA of the distal radius, ular OSA when limb-sparing was an option ( whereas limb-sparing surgery at other sites is associated with a Another study comparing radiographs, MRI and CT in 10 post- higher complication rate and poor limb function ( amputation OSA cases failed to identify a superior modality in pre- ). Conversely, a lower complication rate dicting extent of tumour inﬁltration ). Nuclear and good restoration of limb function have been reported after Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010),
E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx ablative limb-sparing techniques for OSA in the ulna, scapula, met-acarpus, metatarsus and ischium.
Several surgical techniques have been used to preserve the limb and they represent a valid alternative to amputation. After surgicalresection of the OSA, the defect may be ﬁlled with a frozen corticalallograft (an endoprosthesis ) or with theresected (), autoclaved(or irradiated().
Bone or metallic implants are ﬁxed in position with a bone plateand screws, and arthrodesis of the adjacent joint is performed. Acombination of allograft and prosthesis has been used to preservethe limb for OSA of the proximal femur (Themore common complications associated with cortical allograft,pasteurised autograft and endoprosthesis include local tumourrecurrence (15–28%), infection (31–60%) and implant failure orloosening (11–40%) ().
Fig. 2. Post-operative lateral radiograph of a dog with osteosarcoma treated by After excision of OSAs from the distal radius or tibia, large sur- limb-sparing surgery after pasteurised autograft replacement and plate ﬁxation.
gical defects have been replaced by vascularised, viable, regener-ated bone by single (or double transport osteogenesis( Transverse ulnar bone transport osteogenesis has also beeninvestigated experimentally (These procedurescan achieve good limb function and absence of infection, but prob-lems include local tumour recurrence, owner compliance in dis-tracting the apparatus several times per day and apparatusfailure. Limb-sparing surgery has also been performed by rollingthe distal ulna into the distal radial defect after tumour excision,thus using the ulna as a vascularised transposition autograft). However, the procedure is more likely to havebiomechanical complications compared to the standard corticalallograft technique ( Surgery alone is considered to be palliative. The reported mean survival time after surgery alone is 103–175 days ). The 1- and 2-year survival is 11–20% and 2–4%, respectivelyThere are no statistical differences in sur-vival between amputation and limb-sparing surgery if adequatesystemic chemotherapy is given ). Animprovement in survival with limb-sparing is only evident if thesurgical ﬁeld becomes infected; the median survival time for dogswith infected surgical sites after limb-sparing is 685 days com-pared to 289 days in the absence of infection (). Similar ﬁndings have also been reportedin humans with limb-sparing surgery Adjuvant chemotherapy can improve survival of dogs with OSA when associated with surgery and/or radiotherapy. Chemotherapyprotocols include doxorubicin, cisplatin, carboplatin and lobaplatinused alone or in combination ). A local cisplatin deliverysystem has been described (). Administration of chemotherapy in addi-tion to surgery and/or radiotherapy increases the median survivaltime from 103–175 days to 262–450 days. The 1- and 2-year sur-vival rates with chemotherapy range from 31–48% to 10–26%,respectively. Survival times for dogs treated with single agentplatinum compounds are similar to those reported with combined Fig. 1. Distal aspect of the radius of a dog with osteosarcoma treated by limb- protocols ().
sparing surgery with an endoprosthesis. (a) Intra-operative view showing the The most efﬁcacious chemotherapeutic agent and the ideal tim- biodegradable cisplatin-impregnated open-cell polylactic acid implant and closed ing to start adjuvant chemotherapy have not been identiﬁed. How- continuous suction drain. (b) Post-operative lateral radiograph. Images courtesy ofDr. Julius M. Liptak.
ever, there is no substantial advantage in early post-operative Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), doi:
E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx Fig. 3. Single bone transport osteogenesis limb-sparing surgery in the distal radius of a dog with osteosarcoma. Post-operative image of the circular ﬁxator (a). Post-operativelateral (b) and cranio-caudal (c) radiographs of distal radius.
metastatectomy resulted in signiﬁcantly prolonged survival in se- Table 1Chemotherapeutic agents used for dogs with appendicular osteosarcoma.
lected patients ( Immunotherapy has been combined with chemotherapy to Anti-tumour activity was observed when the immunomodulatory agent L-muramyl tripeptide-phosphatidylethanolamine (L-MTP- PE) was administered to dogs with OSA after limb amputation or limb-sparing surgery and completion of cisplatin treatment(L-MTP-PE adminis- Cisplatin + doxorubicin tered with doxorubicin enhanced canine monocyte activation in- duced by doxorubicin or L-MTP-PE alone () and induced cytotoxic activity of pulmonary alveolar macrophages against OSA cells when compared to dogs treated with doxorubicin or L-MTP-PE alone (Kurzman et al., 1999).
Radiation therapy has a role in curative-intent local treatment of canine appendicular OSA. proposed a full- Carboplatin + doxorubicin course fractionated external beam protocol in conjunction with cisplatin, but there was no substantial improvement over a pallia- tive protocol. A single fraction of 70 Gy given intra-operatively Carboplatin + doxorubicin + piroxicam after exteriorisation of the tumoral bone segment has been used in combination with chemotherapy ( Post-operative complications may be high (69%) and include deep infection, fracture of irradiated bone, implant failure and local recurrence. This procedure should only be performed in a NR, not reported.
dogs bearing appendicular OSAs at sites in which limb-sparingtechniques are not an option.
A stereotactic radiosurgery protocol has also been used, in which dogs are irradiated with a single large targeted dose (30– chemotherapy so it is better 50 Gy), with or without chemotherapy (This al- to wait an adequate time to allow the patient to recover from sur- lows normal tissue to be spared and avoids the need for surgery in gery and early healing of the surgical wound some cases, although pathological fractures may occur.
Chemotherapy is usually less effective in the presence of macro-scopic metastatic disease (The efﬁcacy of aer- osol-delivered gemcitabine has been investigated by The aim of palliative-intent treatment is to alleviate pain. Radi- in dogs with pulmonary metastatic OSA. Pulmonary ation therapy is a valid method of palliation for appendicular OSA, Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx inducing relief of pain, reduced lameness and improving quality of In humans, 5-year survival of 10–20% has been reported after life, whereas radiation-induced acute side effects are rare. Radia- amputation without chemotherapy, whereas a 5-year survival tion therapy protocols include a two-fraction protocol rate of 60–78% has been reported for non-metastatic patients three-fraction protocols when surgery is combined with systemic multi-agent chemo- ), four-fraction protocol therapy (). Despite multimodality treatment, () and expedited protocol ( 30–40% of OSA patients still experience relapses within 3 years ). The effectiveness and duration of analgesia among these of treatment.
protocols range from 50–93% and 53–180 days, respectively. Most An increase in 5-year survival has been obtained by combining dogs died or were euthanased because of local disease progression, L-MTP-PE immunotherapy with chemotherapy in non-metastatic metastatic disease or pathological fractures.
patients. Radiation therapy is mainly used as palliation for unre- It is not clear if dogs with OSA beneﬁt from more durable pain sectable tumours, as well as for incompletely resected tumour relief when chemotherapy is combined with radiotherapy excision margins Pain palliation has also been achieved by use of radiopharmaceuticals such as 153Samar- ported that longer survival (median survival time 130 days) can be ium (Extracorporeal irradiation, includ- achieved in dogs with metastatic (stage III) appendicular OSA using ing stereotactic radiosurgery or surgically exposed, irradiated and palliative radiation compared with surgery alone. Palliative-intent reimplanted bone, are among the more innovative and promising treatment for canine OSA has also been attempted by intravenous curative-intent uses of radiation therapy administration of 153Samarium Bisphosphonates have been proposed for palliative-intent treat- ment in dogs with OSA. Clinical applications include therapy for tu- Prognostic factors mour-related hypercalcaemia, inhibition of bone metastasis andpain relief. Zoledronic acid pamidronate () and alendronate () pro-vided pain palliation in some treated dogs. However, when com- Negative prognostic indicators associated with a shorter sur- bined with chemotherapy, pamidronate did not improve pain vival time in dogs with appendicular OSA include young age alleviation (). Some success in providing pain palli- ation in dogs with metastatic appendicular OSA has been achieved pre-treatment total and bone-speciﬁc serum ALP activities using metronomic chemotherapy with doxycycline, piroxicam and cyclophosphamide ( ), metastatic spread to regional lymph nodes high histological grade (grade III) ( stage III OSA (distantmetastases to bone and/or other sites) In humans, multimodality treatment is recommended for OSA.
proximal humeral, rib or scapular involvement For high grade OSAs, preoperative (neoadjuvant) chemotherapy, ), higher body weight wide surgical resection and post-operative chemotherapy are used.
incompleteness of excision () and tumour vol- The most effective chemotherapeutic agents are doxorubicin, cis- ume ). Percent tumour necrosis induced platin, methotrexate and ifosfamide. Combined treatment serves by chemotherapy or radiation therapy is predictive of local tumour to avoid chemoresistance and to increase the degree of tumour necrosis. There is usually a delay of 3–4 weeks after the last admin-istration of neoadjuvant chemotherapy before the tumour is excised.
Adjuvant chemotherapy is usually started 2 weeks after surgery.
Tumour necrosis after administration of preoperative chemo- In humans, negative prognostic factors include metastases at therapy is an important factor in determining the post-operative presentation, metastatic spread to lymph nodes, poor response to chemotherapy regimen Patients with preoperative chemotherapy, large tumour volume, increased activ- P90% tumour necrosis at the time of surgery (good responders) ities of ALP and lactate dehydrogenase (LDH) in serum, primary will usually receive the same treatment regimen post-operatively localisation in the axial skeleton and inadequate surgical margins as pre-operatively. In patients with <90% tumour necrosis (poor responders), post-surgery treatment usually includes a salvage ). In one study, time to relapse was longer in regimen, either an increased dose or duration of the same chemo- patients treated by neoadjuvant chemotherapy than in those given therapeutic agents or a different protocol, but neither have been adjuvant chemotherapy ( shown to improve survival ().
Amputation and limb-sparing procedures are the two principal surgical options in humans. No signiﬁcant differences in survival rates and local recurrence (2.8–6%) are reported when amputationor limb-sparing surgery are used. Limb salvage is possible in more Dogs with OSA represent a unique model for OSA in humans than 85% of human appendicular OSAs ( due to their similar clinical presentation and molecular features, but is contraindicated when resection along with the relatively high number of dogs diagnosed with with wide surgical margins is not feasible, in cases of neurovascu- OSA each year. Differences and similarities between human and ca- lar involvement or with pathological fractures. The options nine OSA are summarised in . Improvements in diagnostic available for limb salvage include tumour removal and endopros- and imaging techniques, chemotherapy and surgical procedures thetic replacement, rotationplasty, allografts and autografts.
have improved outcomes in both human and canine patients.
Limb-sparing complications include infection (11%) and implant However, there is still a need for effective treatment of OSA, mainly failure. Tumour excision usually includes resection of both primary to control metastatic disease. Important comparative advances and metastatic sites; excision of all clinically detectable tumours is have been made in the study of tumour biology and progression, associated with a 5-fold increase in survival compared with risk factors and the evaluation of novel cancer strategies. There is excision of the primary tumour alone.
likely to be increasing interest from the human cancer drug Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), doi: E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx Table 2Similarities and differences between human and canine appendicular osteosarcomas.
>8000 cases/year Middle-aged to older dogs Adolescent disease Peak of incidence 7–9 years Peak of incidence at 10–20 years Second small peak at 18–24 months Median peak age at 16 years Median peak age at 7 years Large/giant breeds Familiar pattern in Saint Bernard, Rottweiler and Scottish Deerhound Males slightly more than females: Ratio 1.1–1:5:1 Males more than females: Ratio 1.6:1 75% appendicular skeleton, metaphysis of long bones, mainly distal radius, proximal Metaphysis or diaphysis of long bones (80–90%) humerus, distal femur and proximal and distal tibia Bones of the knee joint (50%)Proximal humerus (25%) Not completely known Not completely known IGF-1/IGF-1R: Over-expressed; Poor clinical outcome IGF-1/IGF-1R: Over-expressed; Poor clinical outcome HGF/c-Met: Over-expressed; Contributes to malignant phenotype HGF/C-Met: Over-expressed; Contributes to malignantphenotype ErbB-2/HER-2: Over-expressed; Poor clinical outcome ErbB-2/HER-2: Over-expressed; Poor clinical outcome PTEN: Mutated or down-regulated PTEN: Mutated or down-regulated Ezrin: Detected; Contributes to malignant phenotype Ezrin: Detected; Contributes to malignant phenotype Matrix metalloproteinases: Expressed Matrix metalloproteinases: Expressed PDGF-b: Expressed PDGF-b: Expressed Hard painful mass Hard painful mass Uncommon pathological fracture (3%) Uncommon pathological fracture 10% of cases with metastasis at diagnosis: Lung, bone (7.4%) 20% of cases with metastasis at diagnosis: Lung, bone Regional lymph node metastasis (4.4–9.0%) Regional lymph node metastasis < 10% Limb-sparing techniques (90% cases) Limb-sparing techniques Amputation (rare) Adjuvant chemotherapy: Doxorubicin, platinum Neoadjuvant chemotherapy: Doxorubicin,methotrexate, isofosfamide, platinum and adjuvantpost-surgery 60% survival at 1 year with chemotherapy 70% survival at 5 years with chemotherapy Negative prognostic Metastasis at diagnosis: Lungs, bones, lymph nodes Metastasis at diagnosis: Lungs, bones, lymph nodes High serum ALP, LDH activities High serum ALP, LDH activities Age: Youngest affectedPoor response to neoadjuvant chemotherapy: % tumournecrosis Positive prognostic Post-operative limb-sparing infection Post-operative limb-sparing infection High percentage of tumor necrosis induced by chemotherapy or radiotherapy High percentage of tumor necrosis induced bychemotherapy or radiotherapy IGF-1, insulin-like growth factor-1; IGF-1R, IGF-1 receptor; HGF, hepatocyte growth factor, HER-2, human epidermal growth factor receptor 2; PTEN, phosphatase and tensinhomolog, PDGF-b, platelet-derived growth factor-b; VEGF, vascular endothelial growth factor; P-gp, P-glycoprotein; ALP, alkaline phosphatase; LDH, lactate dehydrogenase.
industry in conducting clinical trials in dogs with OSA before or Bacon, N.J., Ehrhart, N.P., Dernell, W.S., Lafferty, M., Withrow, S.J., 2008. Use of concomitantly with trials in human patients.
alternating administration of carboplatin and doxorubicin in dogs withmicroscopic metastases after amputation for appendicular osteosarcoma: 50cases (1999–2006). Journal of the American Veterinary Medical Association232, 1504–1510.
Conﬂict of interest statement Bailey, D., Erb, H., Williams, L., Ruslander, D., Hauck, M., 2003. Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicularosteosarcoma in the dog. Journal of Veterinary Internal Medicine 17, 199–205.
None of the authors of this paper has a ﬁnancial or personal Barnard, S.M., Zuber, R.M., Moore, A.S., 2007. Samarium Sm 153 lexidronam for the relationship with other people or organisations that could inappro- palliative treatment of dogs with primary bone tumors: 35 cases (1999–2005).
priately inﬂuence or bias the content of the paper.
Journal of the American Veterinary Medical Association 230, 1877–1881.
Bateman, K.E., Catton, P.A., Pennock, P.W., Kruth, S.A., 1994. 0–7–21 radiation therapy for the palliation of advanced cancer in dogs. Journal of VeterinaryInternal Medicine 8, 394–399.
Berg, J., Lamb, C.R., O'Callaghan, W., 1990. Bone scintigraphy in the initial evaluation of dogs with primary bone lesions. Journal of the American Veterinary Medical Bacci, G., Longhi, A., Versari, M., Mercuri, M., Briccoli, A., Picci, P., 2006. Prognostic Association 196, 917–920.
factors for osteosarcoma of the extremity treated with neoadjuvant Berg, J., Gebhardt, M.C., Rand, W.M., 1997. Effect of timing of postoperative chemotherapy. Cancer 106, 1154–1161.
chemotherapy on survival of dogs with osteosarcoma. Cancer 79, 1343–1350.
Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx Berg, J., Weinstein, M.J., Shelling, S.H., Rand, W.M., 1992. Treatment of dogs with Ferracini, R., Angelini, P., Cagliero, E., Linari, A., Martano, M., Wunder, J., Buracco, P., osteosarcoma by administration of cisplatin after amputation and limb sparing: 2000. MET oncogene aberrant expression in canine osteosarcoma. Journal of 22 cases (1987–1990). Journal of the American Veterinary Medical Association Orthopedic Research 18, 253–256.
Fieten, H., Spee, B., Ijzer, J., Kik, M.J., Penning, L.C., Kirpensteijn, J., 2009. Expression Berg, J., Weinstein, M.J., Springﬁeld, D.S., Rand, W.M., 1995. Results of surgery and of hepatocyte growth factor and the proto-oncogenic receptor c-Met in canine doxorubicin chemotherapy in dogs with osteosarcoma. Journal of the American osteosarcoma. Veterinary Pathology 46, 869–877.
Veterinary Medical Association 206, 1555–1560.
Flint, A.F., U'Ren, L., Legare, M.E., Withrow, S.J., Dernell, W.S., Hanneman, W.H., Bergman, P.J., MacEwen, E.G., Kurzman, I.D., Henry, C.J., Hammer, A.S., Knapp, D.W., 2004. Overexpression of the erB-2 proto-oncogene in canine osteosarcoma cell Hale, A., Kruth, S.A., Klein, M.K., Klausner, J., Norris, A.M., McCaw, D., Straw, R.C., lines and tumors. Veterinary Pathology 41, 291–296.
Withrow, S.J., 1996. Amputation and carboplatin for treatment of dogs with Fossey, S.L., Liao, A.T., McCleese, J.K., Bear, M.D., Lin, J., Li, P.K., Kisseberth, W.C., osteosarcoma: 48 cases (1991–1993). Journal of Veterinary Internal Medicine Cheryl, A., London, C.A., 2009. Characterization of STAT3 activation and 10, 76–81.
expression in canine and human osteosarcoma. BMC Cancer 9, 1–15.
Boston, S.E., Ehrhart, N.P., Dernell, W.S., Lafferty, M., Withrow, S.J., 2006. Evaluation Garzotto, C.K., Berg, J., Hoffmann, W.E., Rand, W.M., 2000. Prognostic signiﬁcance of of survival time in dogs with stage III osteosarcoma that undergo treatment: 90 serum alkaline phosphatase activity in canine appendicular osteosarcoma.
cases (1985–2004). Journal of the American Veterinary Medical Association Journal of Veterinary Internal Medicine 14, 587–592.
Gellasch, K.L., Kalscheur, V.L., Clayton, M.K., Muir, P., 2002. Fatigue microdamage in Boston, S.E., Duerr, F., Bacon, N., LaRue, S., Ehrhart, E.J., Withrow, S., 2007.
the radial predilection site for osteosarcoma in dogs. American Journal of Intraoperative radiation for limb sparing of the distal aspect of the radius Veterinary Research 63, 896–899.
without transcarpal plating in ﬁve dogs. Veterinary Surgery 36, 314–323.
Gillette, S.M., Gillette, E.L., Powers, B.E., Withrow, S.J., 1990. Radiation-induced Boudrieau, R.J., McCarthy, R.J., Sisson, R.D., 2005. Sarcoma of the proximal portion of osteosarcoma in dogs after external beam or intraoperative radiation therapy.
the tibia in a dog 5.5 years after tibial plateau leveling osteotomy. Journal of the Cancer Research 50, 54–57.
American Veterinary Medical Association 227, 1613–1617.
Gorman, E., Barger, A.M., Wypij, J.M., Pinkerton, M.E., 2006. Cutaneous metastasis of Britt, T., Clifford, C., Barger, A., Moroff, S., Drobatz, K., Thacher, C., Davis, G., 2007.
primary appendicular osteosarcoma in a dog. Veterinary Clinical Pathology 35, Diagnosing appendicular osteosarcoma with ultrasound-guided ﬁne-needle aspiration: 36 cases. Journal of Small Animal Practice 48, 145–150.
Green, E.M., Adams, W.M., Forrest, L.J., 2002. Four fraction palliative radiotherapy Brodey, R.S., Abt, D.A., 1976. Results of surgical treatment in 65 dogs with for osteosarcoma in 24 dogs. Journal of the American Animal Hospital osteosarcoma. Journal American Veterinary Medical Association 168, 1032– Association 38, 445–451.
Hahn, K.A., Hurd, C., Cantwell, H.D., 1990. Single-phase methylene diphosphate Buracco, P., Martano, M., Morello, E., Vasconi, M.E., 2002. Pasteurized tumoral bone scintigraphy in the diagnostic evaluation of dogs with osteosarcoma.
autograft as a novel procedure of limb sparing in dogs: a clinical report in a Journal of the American Veterinary Medical Association 196, 1483–1486.
canine distal radial osteosarcoma. Veterinary Surgery 31, 525–532.
Hammer, A.S., Weeren, F.R., Weisbrode, S.E., Padgett, S.L., 1995. Prognostic factors in Carberry, C.A., Harvey, H.J., 1986. Owner satisfaction with limb amputation in dogs dogs with osteosarcomas of the ﬂat or irregular bones. Journal of the American and cats. Journal of the American Animal Hospital Association 23, 227–232.
Animal Hospital Association 31, 321–326.
Carrle, D., Bielack, S.S., 2006. Current strategies of chemotherapy in osteosarcoma.
Harasen, G.L.G., Simko, E., 2008. Histiocytic sarcoma of the stiﬂe in a dog with International Orthopaedics 30, 445–451.
cranial cruciate ligament failure and TPLO treatment. Veterinary and Chun, R., Garret, L.D., Henry, C., Wall, M., Smith, A., 2005. Toxicity and efﬁcacy of Comparative Orthopaedics and Traumatology 21, 375–377.
cisplatin and doxorubicin combination chemotherapy for the treatment of Hillers, K.R., Dernell, W.S., Lafferty, M., Withrow, S.J., Lana, S.E., 2005. Incidence and canine osteosarcoma. Journal of the American Animal Hospital Association 41, prognostic importance of lymph node metastases in dogs with appendicular osteosarcoma: 228 cases (1986–2003). Journal of the American Veterinary Cooley, D.M., Beranek, B.C., Schlittler, D.L., Glickman, N.W., Glickman, L.T., Waters, Medical Association 226, 1364–1367.
D.J., 2002. Endogenous gonadal hormone exposure and bone sarcoma risk.
Holmberg, B.J., Farese, J.P., Taylor, D., Uhl, E.W., 2004. Osteosarcoma of the humeral Cancer Epidemiology Biomarkers and Prevention 1, 1434–1440.
head associated with osteochondritis dissecans in a dog. Journal of the Davis, G.J., Kapatkin, A.S., Craig, L.E., Heins, G.S., Wortman, J.A., 2002. Comparison of American Animal Hospital Association 40, 246–249.
radiography, computed tomography, and magnetic resonance imaging for Jankowski, M.K., Steyn, P.F., Lana, S.E., Dernell, W.S., Blom, C.M., Uhrig, J.L., Lafferty, evaluation of appendicular osteosarcoma in dogs. Journal of the American M., Withrow, S.J., 2003. Nuclear scanning with 99mTc-HDP for the initial Veterinary Medical Association 220, 1171–1176.
evaluation of osseous metastasis in canine osteosarcoma. Veterinary and De Maria, R., Miretti, S., Iussich, S., Olivero, M., Morello, E., Bertotti, A., Christensen, Comparative Oncology 1, 152–158.
J.G., Biolatti, B., Levine, R.A., Buracco, P., Di Renzo, M.F., 2009. Met oncogene Jehn, C.T., Lewis, D.D., Farese, J.P., Ferrell, E.A., Conley, W.G., Ehrhart, N., 2007.
activation qualiﬁes spontaneous canine osteosarcoma as a suitable pre-clinical Transverse ulnar bone transport osteogenesis: a new technique for limb salvage model of human osteosarcoma. Journal of Pathology 218, 399–408.
for the treatment of distal radial osteosarcoma in dogs. Veterinary Surgery 36, Dernell, W.S., Ehrhart, N.P., Straw, R.C., Vail, D.M., 2007. Tumors of the skeletal system. In: Withrow, S.J., Vail, D.M. (Eds.), Withrow and MacEwen's Small Jeys, L.M., Grimer, R.J., Carter, S.R., Tillman, R.M., Abudu, A., 2007. Post operative Animal Clinical Oncology. Saunders, Elsevier, St. Louis, MI, USA, pp. 540–582.
infection and increased survival in osteosarcoma patients: are they associated? Dickinson, P.J., McEntee, M.C., Lipsitz, D., Keel, K., LeCouteur, R.A., 2001. Radiation Annals of Surgical Oncology 14, 2887–2895.
induced vertebral osteosarcoma following treatment of an intradural Kent, M.S., Strom, A., London, C.A., Seguin, B., 2004. Alternating carboplatin and extramedullary spinal cord tumor in a dog. Veterinary Radiology and doxorubicin as adjunctive chemotherapy to amputation or limb-sparing Ultrasound 42, 463–470.
surgery in the treatment of appendicular osteosarcoma in dogs. Journal of Dubielzig, R.R., Biery, D.N., Brodey, R.S., 1981. Bone sarcomas associated with Veterinary Internal Medicine 18, 540–544.
multifocal medullary bone infarction in dogs. Journal of the American Khanna, C., Wan, X., Bos, S., Cassaday, R., Olomu, O., Mendoza, A., Yeung, C., Gorlick, Veterinary Medical Association 79, 64–68.
R., Hewitt, S.M., Helman, L.J., 2004. The membrane cytoskeleton linker ezrin is Ehrhart, N., Dernell, W.S., Hoffmann, W.E., Weigel, R.M., Powers, B.E., Withrow, S.J., necessary for osteosarcoma metastasis. Nature Medicine 10, 182–186.
1998. Prognostic importance of alkaline phosphatase activity in serum from Kirpensteijn, J., van den Bos, R., Endenburg, N., 1999. Adaptation of dogs to the dogs with appendicular osteosarcoma: 75 cases (1990–1996). Journal of the amputation of a limb and their owners' satisfaction with the procedure.
American Veterinary Medical Association 213, 1002–1006.
Veterinary Record 144, 115–118.
Ehrhart, N., 2005. Longitudinal bone transport for treatment of primary bone Kirpensteijn, J., Kik, M., Rutteman, G.R., Teske, F., 2002a. Prognostic signiﬁcance of a tumors in dogs: technique description and outcome in 9 dogs. Veterinary new histologic grading system for canine osteosarcoma. Veterinary Pathology Surgery 34, 24–34.
Fan, T.M., de Lorimer, L.P., Charney, S.C., Hintermesister, J.G., 2005. Evaluation of Kirpensteijn, J., Teske, E., Kik, M., Klenner, T., Rutteman, G.R., 2002b. Lobaplatin as an intravenous pamidronate administration in 33 cancer-bearing dogs with adjuvant chemotherapy to surgery in canine appendicular osteosarcoma: a primary or secondary bone involvement. Journal of Veterinary Internal phase II evaluation. Anticancer Research 22, 2765–2770.
Medicine 19, 74–80.
Kirpensteijn, J., Kik, M., Teske, E., Rutteman, G.R., 2008. TP53 gene mutations in Fan, T.M., de Lorimier, L.P., O'Dell-Anderson, K., Lacoste, H.I., Charney, S.C., 2007.
canine osteosarcoma. Veterinary Surgery 37, 454–460.
Single-agent pamidronate for palliative therapy of canine appendicular Knapp-Hoch, H.M., Fidel, J.L., Sellon, R.K., Gavin, P.R., 2009. An expedited palliative osteosarcoma bone pain. Journal of Veterinary Internal Medicine 21, 431–439.
radiation protocol for lytic or proliferative lesions of appendicular bone in dogs.
Fan, T.M., Charney, S.C., de Lorimier, L.P., Garrett, L.D., Griffon, D.J., Gordon-Evans, Journal of the American Animal Hospital Association 45, 24–32.
W.J., Wypij, J.M., 2009. Double-blind placebo-controlled trial of adjuvant Kraegel, S.A., Madewell, B.R., Simonson, E., Gregory, C.L., 1991. Osteogenic sarcoma pamidronate with palliative radiotherapy and intravenous doxorubicin for and cisplatin chemotherapy in dogs: 16 cases (1986–1989). Journal of the canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal American Veterinary Medical Association 199, 1057–1059.
Medicine 23, 152–160.
Kuntz, C.A., Asselin, T.L., Dernell, W.S., Powers, B.E., Straw, R.C., Withrow, S.J., 1998.
Farese, J.P., Milner, R., Thompson, M.S., Lester, N., Cooke, K., Fox, L., Hester, J., Bova, Limb salvage surgery for osteosarcoma of the proximal humerus: outcome in 17 F.J., 2004. Stereotactic radiosurgery for treatment of osteosarcomas involving dogs. Veterinary Surgery 27, 417–422.
the distal portions of the limbs in dogs. Journal of the American Veterinary Kurzman, I.D., MacEwen, E.G., Rosenthal, R.C., Fox, L.E., Keller, E.T., Helfand, S.C., Medical Association 225, 1567–1572.
Vail, D.M., Dubielzig, R.R., Madewell, B.R., Rodriguez, C.O., Obradovich, J., Fidel, Federman, N., Bernthal, N., Eilber, F.C., Tap, W.D., 2009. The multidisciplinary J., Rosemberg, M., 1995. Adjuvant therapy for osteosarcoma in dogs: results of management of osteosarcoma. Current Treatment Options in Oncology 10, 82– randomized clinical trials using combined liposome-encapsulated muramyl tripeptide and cisplatin. Clinical Cancer Research 1, 1595–1601.
Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), doi: E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx Kurzman, I.D., Shi, F., Vail, D.M., MacEwen, E.G., 1999. In vitro and in vivo Messerschmitt, P.J., Garcia, R.M., Abul-Karim, F.W., Greenﬁeld, E.M., Getty, P.J., 2009.
enhancement of canine pulmonary alveolar macrophage cytotoxic activity Osteosarcoma. Journal of the American Academy of Orthopaedic surgeons 17, against canine osteosarcoma cells. Cancer Biotherapy and Radiopharma- ceuticals 14, 121–128.
Misdorp, W., 1980. Skeletal osteosarcoma. Animal model: Canine osteosarcoma.
Lana, S.E., Ogilvie, G.K., Hansen, R.A., Powers, B.E., Dernell, W.S., Withrow, S.J., 2000.
American Journal of Pathology 98, 285–288.
Identiﬁcation of matrix metalloproteinases in canine neoplastic tissue.
Misdorp, W., Hart, A.A., 1979. Some prognostic and epidemiologic factors in canine American Journal Veterinary Research 61, 111–114.
osteosarcoma. Journal of the National Cancer Institute 62, 537–545.
Langova, V., Straw, R., Mutsaers, A.J., Thamm, D., 2004. Treatment of eight dogs with Moore, A.S., Dernell, W.S., Ogilvie, G.K., Kristal, O., Elmslie, R., Kitchell, B., Susaneck, nasal tumours with alternating doses of doxorubicin and carboplatin in S., Rosenthal, R., Klein, M.K., Obradovich, J., Legendre, A., Haddad, T., Hahn, K., conjunction with oral piroxicam. Australian Veterinary Journal 82, 676–680.
Powers, B.E., Warren, D., 2007. Doxorubicin and BAY 12-9566 for the treatment LaRue, S.M., Withrow, S.J., Wrigley, R.H., 1986. Radiographic bone surveys in the of osteosarcoma in dogs: a randomized, double-blind, placebo-controlled study.
evaluation of primary bone tumors in dogs. Journal of the American Veterinary Journal of Veterinary Internal Medicine 21, 783–790.
Medical Association 188, 514–516.
Morello, E., Buracco, P., Martano, M., Peirone, B., Capurro, C., Valazza, A., Cotto, D., LaRue, S.M., Withrow, S.J., Powers, B.E., Wrigley, R.H., Gillette, E.L., Schwarz, P.D., Ferracini, R., Sora, M., 2001. Bone allografts and adjuvant cisplatin as treatment Straw, R.C., Ritcher, S.L., 1989. Limb-sparing treatment for osteosarcoma in of canine appendicular osteosarcoma: 18 dogs (1991–1996). Journal of Small dogs. Journal of the American Veterinary Medical Association 195, 1734–1744.
Animal Practice 42, 61–66.
Lascelles, B.D., Dernell, W.S., Correa, M.T., Lafferty, M., Devitt, C.M., Kunz, C.A., Straw, Morello, E., Vasconi, E., Martano, M., Peirone, B., Buracco, P., 2003. Pasteurized R.C., Withrow, S.J., 2005. Improved survival associated with postoperative tumoral autograft and adjuvant chemotherapy for the treatment of canine wound infection in dogs treated with limb-salvage surgery for osteosarcoma.
distal radial osteosarcoma: 13 cases. Veterinary Surgery 32, 539–544.
Annals of Surgical Oncology 12, 1073–1083.
Mueller, F., Poirier, V., Melzer, K., Nitzl, D., Roos, M., Kaser-Hotz, B., 2005. Palliative Leibman, N.F., Kunz, C.A., Steyn, P.F., Fettman, M.J., Powers, B.E., Withrow, S.J., radiotherapy with electrons of appendicular osteosarcoma in 54 dogs. In Vivo Dernell, W.S., 2001. Accuracy of radiography, nuclear scintigraphy, and 19, 713–716.
histopathology for determining the proximal extent of distal radius Mueller, F., Fuchs, B., Kaser-Hotz, B., 2007. Comparative biology of human and osteosarcoma in dogs. Veterinary Surgery 30, 240–245.
canine osteosarcoma. Anticancer Research 27, 155–164.
Levine, R.A., Forest, T., Smith, C., 2002. Tumor suppressor PTEN is mutated in canine Muggenburg, B.A., Guilmette, R.A., Mewhinney, J.A., Gillett, N.A., Mauderly, J.L., osteosarcoma cell lines and tumors. Veterinary Pathology 39, 372–378.
Grifﬁth, W.C., Diel, J.H., Scott, B.R., Hahn, F.F., Boecker, B.B., 1996. Toxicity of Liptak, J.M., Dernell, W.S., Straw, R.C., Jameson, V.J., Lafferty, M.H., Rizzo, S.A., inhaled plutonium dioxide in beagle dogs. Radiation Research 145, 361–381.
Withrow, S.J., 2004a. Intercalary bone grafts for joint and limb preservation in Murphy, S.T., Parker, R.B., Woodard, J.C., 1997. Osteosarcoma following total hip 17 dogs with high-grade malignant tumors of the diaphysis. Veterinary Surgery arthroplasty in a dog. Journal of Small Animal Practice 38, 263–267.
Nemanic, S., London, C.A., Wisner, E.R., 2006. Comparison of thoracic radiographs Liptak, J.M., Dernell, W.S., Ehrhart, N.P., Withrow, S.J., 2004b. Canine appendicular and single breath-hold helical CT for detection of pulmonary nodules in dogs osteosarcoma: diagnosis and palliative treatment. Compendium of Continuing Education for the Practising Veterinarian 26, 172–182.
Liptak, J.M., Dernell, W.S., Lascelles, B.D., LaRue, S.M., Jameson, V.J., Powers, B.E., O'Brien, M.G., Straw, R.C., Withrow, S.J., Powers, B.E., Jameson, V.J., Lafferty, M., Huber, D.J., Withrow, S.J., 2004c. Intraoperative extracorporeal irradiation for Ogilvie, G.K., LaRue, S.M., 1993. Resection of pulmonary metastases in canine limb sparing in 13 dogs. Veterinary Surgery 33, 446–456.
osteosarcoma: 36 cases (1983–1992). Veterinary Surgery 22, 105–109.
Liptak, J.M., Pluhar, G.E., Dernell, W.S., Withrow, S.J., 2005. Limb-sparing surgery in a O'Day, K., Gorlick, R., 2009. Novel therapeutic agents for osteosarcoma. Expert dog with osteosarcoma of the proximal femur. Veterinary Surgery 34, 71–77.
Reviews in Anticancer Therapy 9, 511–523.
Liptak, J.M., Dernell, W.S., Ehrhart, N., Lafferty, M.H., Monteith, G.J., Withrow, S.J., Ogilvie, G.K., Straw, R.C., Jameson, V.J., Walters, L.M., Lafferty, M., Powers, B.E., 2006. Cortical allograft and endoprosthesis for limb-sparing surgery in dogs Withrow, S.J., 1993. Evaluation of single agent chemotherapy for treatment of with distal radial osteosarcoma: a prospective clinical comparison of two clinically evident osteosarcoma metastases in dogs: 45 cases (1987–1991).
different limb-sparing techniques. Veterinary Surgery 35, 518–533.
Journal of the American Veterinary Medical Association 202, 304–306.
Lloyd, R.D., Taylor, G.N., Angus, W., Bruenger, F.W., Miller, S.C., 1993. Bone cancer Phillips, J.C., Stephenson, B., Hauck, M., Dillberger, J., 2007. Heritability and occurrence among beagles given 239Pu as young adults. Health Physics 64, 45– segregation analysis of osteosarcoma in the Scottish deerhound. Genomics 90, Lloyd, R.D., Taylor, G.N., Angus, W., Miller, S.C., Boecker, B.B., 1994. Skeletal Phillips, B., Powers, B.E., Dernell, W.S., Straw, R.C., Khanna, C., Hogge, G.S., Vail, D.M., malignancies among beagles injected with 241Am. Health Physics 66, 172–177.
2009. Use of single agent carboplatin as adjuvant or neoadjuvant therapy in Loukopoulos, P., Robinson, W.F., 2007. Clinicopathological relevance of tumour conjunction with amputation for appendicular osteosarcoma in dogs. Journal of grading in canine osteosarcoma. Journal of Comparative Pathology 136, 65–73.
the American Animal Hospital Association 45, 33–38.
Loukopoulos, P., Thornton, J.R., Robinson, W.F., 2003. Clinical and pathologic Pooya, H.A., Séguin, B., Mason, D.R., Walsh, P.J., Taylor, K.T., Kass, P.H., Stover, S.M., relevance of p53 index in canine osseous tumors. Veterinary Pathology 40, 237– 2004. Biomechanical comparison of cortical radial graft versus ulnar transposition graft limb-sparing techniques for the distal radial site in dogs.
Loukopoulos, P., O'Brien, T., Ghoddusi, M., Mungall, B.A., Robinson, W.F., 2004.
Veterinary Surgery 33, 301–308.
Characterization of three novel canine osteosarcoma cell lines producing high Powers, B.E., LaRue, S.M., Withrow, S.J., Straw, R.C., Richter, S.L., 1988. Jamshidi level of matrix metalloproteinases. Research in Veterinary Science 77, 131–141.
needle biopsy for diagnosis of bone lesions in small animals. Journal of the American Veterinary Medical Association 193, 205–210.
histopathological diagnosis in canine osteosarcoma. Veterinary Record 157, 784.
Powers, B.E., Gillette, E.L., McChesney, S.L., LeCouteur, R.A., Withrow, S.J., 1989. Bone MacEwen, E.G., Kurzman, I.D., Helfand, S., Vail, D., London, C., Kisseberth, W., Rosenthal, R.C., Fox, L.E., Keller, E.T., Obradovich, J., Madewell, Rodriguez, C., irradiation. International Journal Radiation Oncology, Biology and Physics 17, Kitchell, B., Fidel, J., Susaneck, S., Rosenberg, M., 1994. Current studies of liposome muramyl tripeptide (CGP 19835A lipid) therapy for metastasis in Powers, B.E., Withrow, S.J., Thrall, D.E., 1991. Percent tumor necrosis as a predictor spontaneous tumors: a progress review. Journal of Drug Targeting 2, 391–396.
of treatment response in canine osteosarcoma. Cancer 67, 126–134.
MacEwen, E.G., Pastor, J., Kutzeke, J., Tsan, R., Kurzman, I.D., Thamm, D.H., Wilson, Ramirez III, O., Dodge, R.K., Page, R.L., Price, G.S., Hauck, M.L., LaDue, T.A., Nutter, F., M., Radinsky, R., 2004. IGF-1 receptor contributes to the malignant phenotype Thrall, D.E., 1999. Palliative radiotherapy of appendicular osteosarcoma in 95 in human and canine osteosarcoma. Journal of Cellular Biochemistry 92, 77–91.
dogs. Veterinary Radiology and Ultrasound 40, 517–522.
Malawer, M.M., Helman, L.J., O'Sullivan, B., 2008. Sarcomas of bone. In: DeVita, V.T., Reinhardt, S., Stockhaus, C., Teske, E., Rudolph, R., Brunnberg, L., 2005. Assessment Lawrence, T.S., Rosenberg, S.A. (Eds.), DeVita. Hellman and Rosenberg's Cancer of cytological criteria for diagnosing osteosarcoma in dogs. Journal of Small Principles and Practice of Oncology. Lippincott Williams and Wilkins, Animal Practice 46, 65–70.
Philadelphia, PA, USA, pp. 1794–1833.
Riser, W.H., Brodey, R.S., Biery, D.N., 1972. Bone infarctions associated with Marcellin-Little, D.J., DeYoung, D.J., Thrall, D.E., Merrill, C.L., 1999. Osteosarcoma at malignant bone tumors in dogs. Journal of the American Veterinary Medical the site of bone infarction associated with total hip arthroplasty in a dog.
Association 160, 414–421.
Veterinary Surgery 28, 54–60.
Rodriguez, C.O., Crabbs, T.A., Wilson, D.W., Cannan, V.A., Skorupski, K.A., Gordon, N., Massin, P., Bocquet, L., Huten, D., Badelon, O., Duparc, J., 1995. Radiographic and Koshkina, N., Kleinerman, E., Anderson, P.M., 2010. Aerosol gemcitabine: histologic observations of autoclaved and non autoclaved allografts in the distal preclinical safety and in vivo antitumor activity in osteosarcoma bearing femoral metaphysis in dogs. Revue de chirurgie orthopedique et reparatrice del dogs. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23, 197–206.
l'appareil moteur 81, 189–197.
Rosenberger, J.A., Pablo, N.V., Crawford, P.C., 2007. Prevalence of and intrinsic risk Mauldin, G.N., Matus, R.E., Withrow, S.J., Patnaik, A.K., 1988. Canine osteosarcoma factors for appendicular osteosarcoma in dogs: 179 cases (1996–2005). Journal treatment by amputation versus amputation and adjuvant chemotherapy using of the American Veterinary Medical Association 23, 1076–1080.
doxorubicin and cisplatin. Journal of Veterinary Internal Medicine 2, 177–180.
Rovesti, G.L., Bascucci, M., Schmidt, K., Marcellin-Little, D.J., 2002. Limb sparing Mehl, M.L., Seguin, B., Dernell, W.S., Lafferty, M., Kass, P.H., Withrow, S.J., 2005.
using a double bone-transport technique for treatment of a distal tibial Survival analysis of one versus two treatments of local delivery cisplatin in a osteosarcoma in a dog. Veterinary Surgery 31, 70–77.
biodegradable polymer for canine osteosarcoma. Veterinary and Comparative Ru, G., Terracini, B., Glickman, L.T., 1998. Host related risk factors for canine Oncology 3, 81–86.
osteosarcoma. The Veterinary Journal 156, 31–39.
Mendoza, S., Konishi, T., Dernell, W.S., Withrow, S.J., Miller, C.W., 1998. Status of the Sagartz, J.E., Bodley, W.L., Gamblin, R.M., Couto, C.G., Tierney, L.A., Capen, C.C., 1996.
p53, Rb and MDM2 genes in canine osteosarcoma. Anticancer Research 18, P53 tumor suppressor protein overexpression in osteogenic tumors of dogs.
Veterinary Pathology 33, 213–221.
Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), E. Morello et al. / The Veterinary Journal xxx (2010) xxx–xxx Seguin, B., Walsh, P.J., Mason, D.R., Wisner, E.R., Parmenter, J.L., Dernell, W.S., 2003.
Ta, H.T., Dass, C.R., Choong, P.F.M., Dunstan, D.E., 2009. Osteosarcoma treatment: Use of an ipsilateral vascularized ulnar transposition autograft for limb-sparing state of the art. Cancer Metastasis Reviews 28, 247–263.
surgery of the distal radius in dogs: an anatomic and clinical study. Veterinary Thompson, J.P., Fugent, M.J., 1991. Evaluation of survival times after limb Surgery 32, 69–79.
amputation, with and without subsequent administration of cisplatin, for Shapiro, W., Fossum, T.W., Kitchell, B.E., Couto, C.G., Theilen, G.H., 1988. Use of treatment of appendicular osteosarcoma in dogs: 30 cases (1979–1990). Journal cisplatin for treatment of appendicular osteosarcoma in dogs. Journal of the of the American Veterinary Medical Association 200, 531–533.
American Veterinary Medical Association 192, 507–511.
Thrall, D.E., 1984. Orthovoltage radiotherapy of acanthomatous epulides in 39 dogs.
Shi, F., MacEwen, E.G., Kurzman, I.D., 1993. In vitro and in vivo effect of doxorubicin Journal of the American Veterinary Medical Association 184, 826–829.
Tomlin, J.L., Sturgeon, C., Pead, M.J., Muir, P., 2000. Use of the bisphosphonate drug monocyte activation. Cancer Research 53, 3986–3991.
alendronate for palliative management of osteosarcoma in two dogs. Veterinary Sinibaldi, K.R., Rosen, H., Liu, S.K., DeAngelis, M., 1976. Tumors associated with Record 29, 129–132.
metallic implants in animals. Clinical Orthopaedics and Related Research 118, Tommasini-Degna, M., Ehrhart, N., Ferretti, A., Buracco, P., 2000. Bone transport osteogenesis for limb salvage following resection of primary bone tumors: Sinibaldi, K.R., Pugh, J., Rosen, H., Liu, S.K., 1982. Osteomyelitis and neoplasia experience with six cases (1991–1996). Veterinary Comparative Orthopaedic associated with use of the Jonas intramedullary splint in small animals. Journal and Traumatology 13, 18–22.
of American Veterinary Medical Association 181, 885–890.
van Leeuwen, I.S., Cornelisse, C.J., Misdorp, W., Goedegebuure, S.A., Kirpensteijn, J., Spodnick, G.J., Berg, J., Rand, W.M., Schelling, S.H., Couto, C.G., Harvey, H.J., Rutteman, G.R., 1997. P53 gene mutations in osteosarcomas in the dog. Cancer Henderson, R.A., MacEwen, G., Mauldin, N., MacCaw, D.L., Moore, A.S., Letters 111, 173–178.
Morrison, W., Norris, A.M., O'Bradovich, J., O'Keefe, D.A., Page, R., Ruslander, Vignoli, M., Ohlerth, S., Rossi, F., Pozzi, L., Terragni, R., Corlazzoli, D., Kaser-Hotz, B., D., Klausner, J., Straw, R.C., Thompson, J.P., 1992. Prognosis for dogs with 2004. Computed tomography-guided ﬁne-needle aspiration and tissue-core appendicular osteosarcoma treated by amputation alone: 162 cases (1978– biopsy of bone lesions in small animals. Veterinary Radiology and Ultrasound 1988). Journal of the American Veterinary Medical Association 200, 995–999.
Spugnini, E.P., Vincenzi, B., Caruso, G., Baldi, A., Citro, G., Santini, D., Tonini, G., 2009.
Yamamoto, T., Hitora, T., Marui, T., Akisue, T., Nagira, K., Kawamoto, T., Yoshiya, S., Zoledronic acid for the treatment of appendicular osteosarcoma in a dog.
Kurosaka, M., 2002. Reimplantation of autoclaved or irradiated cortical bones Journal of Small Animal Practice 50, 44–46.
invaded by soft tissue sarcomas. Anticancer Research 22, 3685–3690.
Stevenson, S., 1991. Fracture-associated sarcomas. Veterinary Clinics of North Wallach, S.T., Wisner, E.R., Werner, J.A., Walsh, P.J., Kent, M.S., Fairley, R.A., Hornof, America Small Animal Practice 21, 859–872.
Straw, R.C., Withrow, S.J., 1996. Limb-sparing surgery versus amputation for dogs intramedullary osteosarcoma extent in pre-operative planning of canine limb- with bone tumors. Veterinary Clinics of North America Small Animal Practice salvage procedures. Veterinary Radiology and Ultrasound 43, 432–441.
Walter, C.U., Dernell, W.S., Larue, S.M., Lana, S.E., Lafferty, M.H., Ladue, T.A., Straw, R.C., Withrow, S.J., Powers, B.E., 1990. Management of canine appendicular Withrow, S.J., 2005. Curative-intent radiation therapy as a treatment modality osteosarcoma. Veterinary Clinics of North America Small Animal Practice 20, for appendicular and axial osteosarcoma: a preliminary retrospective evaluation of 14 dogs with the disease. Veterinary and Comparative Oncology Straw, R.C., Withrow, S.J., Richter, S.L., Powers, B.E., Klein, M.K., Postorino, N.C., LaRue, S.M., Ogilvie, G.K., Vail, D.M., Morrison, W.B., McGee, M., Dickinson, K., White, R.A., Jefferies, A.R., Gorman, N.T., 1986. Sarcoma development following 1991. Amputation and cisplatin for treatment of canine osteosarcoma. Journal irradiation of acanthomatous epulis in two dogs. Veterinary Record 118, 668.
of Veterinary Internal Medicine 5, 205–210.
Withrow, S.J., Liptak, J.M., Straw, R.C., Dernell, W.S., Jameson, V.J., Powers, B.E., Straw, R.C., Withrow, S.J., Doulple, E.B., Brekke, J.H., Cooper, M.F., Schwarz, P.D., Johnson, J.L., Brekke, J.H., Douple, E.B., 2004. Biodegradable cisplatin polymer in Greco, D.S., Powers, B.E., 1994. The effect of cis-diamminedichloroplatinum II limb-sparing surgery for canine osteosarcoma. Annals of Surgical Oncology 11, released from D,L,-polylactic acid implanted adjacent to cortical allografts in dogs. Journal of Orthopaedic Research 12, 871–877.
Please cite this article in press as: Morello, E., et al. Biology, diagnosis and treatment of canine appendicular osteosarcoma: Similarities and differenceswith human osteosarcoma. The Veterinary Journal (2010), doi:
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