Genetic welfare problems of companion animals

 

Osteosarcoma

 

Breed: Rottweiler

 

Condition:  Osteosarcoma

Related terms: bone tumour, bone cancer, bone neoplasia

Outline: Rottweillers are predisposed to developing osteosarcoma (bone tumours). It has been estimated that between 5 and 12% become affected. The disease can occur at any age but the average age at diagnosis is about 8 years. It is an aggressively malignant form of cancer which causes almost 100% mortality unless successfully treated, and treatment is successful in only about 10% of cases. It causes severe and progressive pain which can be difficult or impossible to alleviate. The genetic basis of the disease is yet to be elucidated. It has a familial pattern of incidence and it seems likely that the prevalence may be reduced by breeding only from lines that have not (or very rarely) been affected.

 


 

Summary of Information

(for more information click on the links below)

 

 

1.           Brief description

Osteosarcoma is the most common bone tumour in dogs, accounting for 80% to 85% of primary bone tumours in the species (Shell & Rosenthal 2007, Modiano 2010), and 90% in large breeds (Blackwood 1999). It accounts for 5% of all tumours in dogs (Blackwood 1999).

It is a tumour mainly of middle-aged to older, dogs of large breeds. Dogs weighing over 40kg account for 29% of cases whilst dogs weighing less than 15kg account for fewer than 5% (Milner 2004).

Osteosarcoma is a primary bone tumour which develops from bone-forming cells called osteoblasts (Milner 2004). Osteosarcomas can occur anywhere in the dog’s skeleton, and sometimes elsewhere in the body (Shell & Rosenthal 2007). They usually arise in the medullary cavity (the cavity which contains the bone marrow) of long bones of the body in the areas at which the shaft meets the end of the bone - the metaphyses (Ehrhart & Fan 2009). The most common sites for these tumours are the humerus (upper arm) bone just below the shoulder, the forelimb above the carpal (wrist) area and close to, and above or below, the stifle (knee) (Shell & Rosenthal 2007, Ehrhart & Fan 2009). In Rottweilers the forelimb sites are most often affected (Rosenberger et al 2007).

Osteosarcoma is highly invasive tumour which spreads rapidly. The commonest site to which it spreads (or metastasises) is the lungs, though the tumour may spread elsewhere (Blackwood 1999, Ehrhart & Fan 2009).

Pain from tumour invasion of the bone is the most significant clinical sign, and as the limb bones are usually affected, the dogs become lame. The pain is major and often rapidly becomes resistant to control through the use of the usual painkillers (so called refractory pain, Ehrhart & Fan 2009). Following the development of chronic pain and lameness, affected dogs may show significant pain on gentle touching or manipulation of the limb as the conditions of hyperalgesia (extreme sensitivity to pain) and allodynia (skin pain due to something which would not normally cause pain eg being touched) may develop (Ehrhart & Fan 2009). There will often be swelling of the limb at the site of the tumour and it may feel hot to the touch (Milner 2004, Ehrhart & Fan 2009). As metastases (sites of spread) occur, other signs of disease occur eg weight loss, inappetance and breathing problems, due to damage to other organs.

The outlook for dogs with osteosarcoma is poor despite the availability of various treatment options, as in 90% of cases the tumour has spread to other sites by the time of diagnosis (Blackwood 1999, Shell & Rosenthal 2007). Without treatment the mortality rate is 100% (Milner 2004).

 

2.           Intensity of welfare impact             

Osteosarcoma has a huge impact on the welfare of affected dogs as it rapidly causes major bone pain which is constant unless it can be successfully alleviated. The pain is often resistant to control through the use of the usual painkilling drugs so its relief is not simple (Ehrhart & Fan 2009). Euthanasia is frequently necessary due to disease progression or refractory pain.

 

3.           Duration of welfare impact

 

Usually this is a condition of middle-aged to older dogs, though it can occur at any age. All affected animals will die without treatment, usually within a few months (Modiano 2010). Only 10% of affected dogs are cured but treatment can prolong survival times (Ehrhart & Fan 2009).

 

4.           Number of animals affected

 

Rottweilers are considered to be at high risk of osteosarcome and are five times more likely to develop the tumour than the average dog (Comstock et al 2006). It has been suggested that between 5 and 12% of all Rottweilers develop osteosarcoma (Rosenberger & Crawford 2004, Comstock et al 2006).

 

5.           Diagnosis

The diagnosis of osteosarcoma is confirmed by radiographs (x-rays) and biopsy. Further diagnostic tests may be necessary to help determine the stage of the disease, the most appropriate treatment protocol and for monitoring of response to treatment.

 

6.           Genetics

The diagnosis of osteosarcoma is confirmed by radiographs (x-rays) and biopsy. Further diagnostic tests may be necessary to help determine the stage of the disease, the most appropriate treatment protocol and for monitoring of response to treatment.


7.           How do you know if an animal is a carrier or likely to become affected?

There are no tests to determine which animals are likely to develop osteosarcoma and currently, as the causal genes have not been identified, it is not known whether ‘carrier’ animals, otherwise unaffected by the disease, may pass on a genetic predisposition to develop the disease to their offspring.

 

8.          Methods and prospects for elimination of the problem

 

Knowledge of the genes involved in osteosarcoma and the patterns of inheritance of the disease are likely to be helpful in trying to reduce its prevalence. As far as we are aware there are no breeding schemes, at present, aimed at trying to reduce its prevalence.

 

 


 

For further details about this condition, please click on the following:

 

 

 

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1.           Clinical and pathological effects

 

Osteosarcoma is the most common bone tumour of dogs, accounting for 80% to 85% of primary bone tumour cases in the species (Shell & Rosenthal 2007, Modiano 2010), and 90% of bone tumours in large breeds (Blackwood 1999). It accounts for 5% of all tumours in dogs (Blackwood 1999).

It is a tumour mainly of middle-aged to older dogs of large breeds. Those weighing over 40kg account for 29% of cases whilst dogs weighing less than 15kg account for fewer than 5% (Milner 2004).

Bone cancers can either be primary - starting from cells within the bone tissue - or secondary (or metastatic), having started elsewhere in the body and spread to bone. Osteosarcoma is a primary bone tumour which develops from bone-forming cells called osteoblasts (Milner 2004). Normal bones contain various cells and the osteoblasts are responsible for forming the new bone matrix called osteoid - the non-cellular substance in which the cells sit.

In tumour cells, their genetic material - the DNA (deoxyribonucleic acid) - has become damaged and the cells become abnormal in both structure and function. The causes of the genetic damage are varied. There may be an inherited trait that makes the cells more vulnerable to cancerous growth, or it may follow damage to the DNA by trauma, viruses or radiation exposure.

In animals with osteosarcoma, osteoblasts produce abnormal osteoid and may also sometimes produce cartilage and collagen (Modiano 2010). The cells also become invasive and canine osteosarcomas are usually described as aggressively malignant tumours (Blackwood 1999, Milner 2004, Modiano 2010). They grow into, invade, and damage surrounding tissues and spread, through the blood stream, to distant parts of the body where they continue to grow as metastases causing further damage to these tissues.

The aetiology (cause) of osteosarcoma in dogs is not fully understood (Blackwood 1999) but the various risk factors listed below are thought to play a role.

  1. The size and weight of the dog.  Dogs of large or giant breeds are at significantly increased risk of developing the disease (Kirkwood 1985, Milner 2004, Shell & Rosenthal 2007). Shell and Rosenthal (2007) suggest it is related to bone length, however Milner (2004) suggested that prevalence correlates most closely with body mass. The reason for this is not clear but it is hypothesised that it may be linked with rapid, early bone growth and/or increased stress in weight-bearing bones leading to micro-fractures within the bone tissue (Blackwood 1999, Dickerson et al 2001, Chun & de Lorimier 2003, Liptak et al 2004a).  Both lead to increased cell turnover and possibly the increased chance of cell gene mutations.
  2. Breed. Dogs of some large and giant breeds including Scottish deerhounds, Great Danes, Rottweilers, St Bernard’s, Irish wolfhounds, Borzoi and greyhounds are considered to be predisposed to osteosarcoma. In several breeds, including the Rottweiler, there has been shown to be a genetic influence specific for the breed, in addition to that related to body size (Modiano 2010, Comstock et al 2006).
  3. Gender. Some studies have shown males to be at slightly increased risk of the condition (Shell & Rosenthal 2007). Modiano (2010) suggested that males have a 20 to 50% greater risk than females, but Rosenberger et al (2007) did not find any gender bias in the breeds investigated, including Rottweilers.
  4. Previous fractures or orthopaedic interventions. These seem to increase the risk, particularly in cases in which there were complications with bone repair and healing (Blackwood 1999), or which involved surgical implants or bone infections (Milner 2004).
  5. Neuter status. Some studies have suggested that neutered animals are more at risk than entire ones (Cooley et al 2002, Ru et al 1998).

Canine osteosarcomas usually arise in the medullary cavity (the bone marrow cavity) of the long bones of the body in the areas of the junction between the shafts and the ends of the bones – the metaphyses (Ehrhart & Fan 2009). The metaphyses are the parts of the bone in which growth of bone length occurs.

C:\Users\Steph\Pictures\Images\Long bone.png

Figure 1. The metaphyses regions of the medullary cavity (located roughly between the epiphyses and diaphysis areas in the diagram), are the areas of bone most commonly affected by osteosarcomas in the dog.

(Image from Wikipedia: http://en.wikipedia.org/wiki/Bone) 

 

The most common sites for the tumour are the end of the radius (the main bone of the forelimb below the elbow)) farthest from the body (called the distal end), the end of the humerus (the upper forelimb bone) nearest to the body (called the proximal end), the distal end of the femur (the upper hind leg bone) and the proximal end of the tibia (the bone below the stifle/knee) (Shell & Rosenthal 2007, Ehrhart & Fan 2009). In Rottweilers, the forelimbs (distal radius and proximal humerus) are more often affected than the hindlimbs (Rosenberger et al 2007). Although the bones of the limbs are most often affected, osteosarcomas can occur anywhere in the skeleton and sometimes elsewhere in the body (Shell & Rosenthal 2007).

C:\Users\Steph\Pictures\Images\Osteosarcoma_dog.gif

Figure 2. The sites most commonly affected by osteosarcoma.

(Image property of http://www.marvistavet.com, to whom we are grateful for permission to reproduce it here).

 

The signs caused by the tumour depend both on its primary location and the location of any secondary metastases. The most common site for metastases is the lungs, but the tumour may spread elsewhere (Blackwood 1999, Ehrhart & Fan 2009). Although the tumours tend to start in the medullary cavities of bones, they rapidly invade the hard cortical bone surrounding them and cause significant destruction of it. This can lead to the bone fracturing as a consequence (a pathological fracture) but even in the absence of fractures the tumour causes pain.

C:\Users\Steph\Pictures\Images\Osteosarcoma_ankle.gif

Figure 3. An x-ray of canine osteosarcoma in the distal radius. The difference in bone consistency around the joint (red arrow) compared to higher up the radius is due to the presence of the tumour within the outer cortical bone as well as the inner medullary cavity, resulting in pain.

(Image property of www.marvistavet.com, to whom we are grateful for permission to reproduce it here).

 

C:\Users\Steph\Pictures\Images\Images available for use\Distal Femur osteosarcoma wiki.JPG

Figure 4. An x-ray of the distal femur of a dog with osteosarcoma. The dark area of the femur (red arrow) indicates the damage caused by the tumour within the bone. These tumours cause pain. (Image from Wikipedia: www.wikipedia.org/ osteosarcoma)

 

When limb bones are affected, there is lameness. Sometimes the pain seems to coincide with minor trauma such as can occur in jumping or rough play and it often responds temporarily to painkillers and rest. However, in these cases, the bone pain returns rapidly and is often then refractory (does not respond) to the frequently used painkillers (Ehrhart & Fan 2009). Often, following the development of this chronic (long-term) pain and lameness, dogs may show significant pain on gentle touching or manipulation of the affected limb as the conditions of hyperalgesia (extreme sensitivity to pain) and allodynia (skin pain due to a gentle stimulus which would not normally cause pain) develop (Ehrhart & Fan 2009).

As well as the significant pain they cause, there will often be swelling of the limb at the site of the tumour and it may feel hot to the touch (Milner 2004, Ehrhart & Fan 2009). As metastatic spread occurs to other parts of the body, signs of disease due to damage to other organs develop. The dogs will generally deteriorate in their demeanour and attitude to life and suffer weight loss and inappetance. Breathing problems may occur when the lungs are affected.

The outlook for dogs with osteosarcoma is poor. Due to the highly malignant nature of the tumour, the mortality rate is 100% without treatment (Milner 2004). A true cure occurs in less than 10% of cases (Ehrhart & Fan 2009) as in 90% of cases the tumour has spread to other parts of the body by the time of diagnosis (Blackwood 1999, Shell & Rosenthal 2007).

A variety of treatments have been tried, including limb amputation, limb-sparing surgeries, various chemotherapy protocols, and radiotherapy. Some of these treatments are aimed at a cure or extension of symptom-free survival. Others are aimed at relieving symptoms, particularly the pain. Despite all the various treatment options, the prognosis (outlook) for individuals with osteosarcoma is poor. A recent study suggested median survival times ranged from three months to one year and that fewer than 20% of dogs survived for more than two years after initial diagnosis, whatever their treatment protocol (Selvarajah & Kirpensteijn 2010). Most of these treatment modalities and other newer research treatments, which may show promise, such as immunotherapy and therapeutic radiopharmaceutical agents are available only from specialist veterinary oncologists (cancer specialists) at referral centres (Ehrhart & Fan 2009). The standard treatment protocol, certainly within the USA, tends to be surgery with chemotherapy (Modiano 2010).  Apparent spontaneous regression (disappearance) of the osteosarcoma has been reported in four cases (Mehl et al 2001).

Deciding the appropriate treatment course for an individual dog is complex and owners are recommended to seek specialist veterinary guidance – the ability to control the animal’s pain and suffering must be central to any decision making process.

 

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2.               Intensity of welfare impact

Osteosarcoma has a huge impact on the welfare of affected dogs. It rapidly causes major bone pain which is constant unless it can be alleviated. The pain is often difficult or impossible to relieve using the usual painkilling drugs, so control is not simple but it often responds, at least for a time, to radiation therapy (Ehrhart & Fan 2009). Unfortunately, dogs also often develop excessive sensitivity (hyperalgesia and allodynia) to touch or manipulation of the affected limb or area (Ehrhart & Fan 2009). Euthanasia, on humane grounds, will be necessary for most affected dogs at some stage.

Treatments can have adverse welfare impacts. Some dogs may be stressed by repeated visits to the vet and treatments may involve major surgery, regular radiation treatment or injections of chemotherapeutic agents. Some of these procedures may cause pain as the affected area is manipulated and treated. Some chemotherapeutic drugs cause significant side effects which affect welfare: eg cisplatin can cause kidney damage and doxorubicin can exasperate heart conditions.


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3.           Duration of welfare impact

 

Osteosarcoma is usually a disease of middle-aged to older dogs, with the average age of onset at seven years, but it can occur at any age and there may be a small peak of cases at around the age of eighteen months old (Shell & Rosenthal 2007). The average age of Rottweilers at diagnosis in the study by Rosenberger et al (2007) was 8.3 years. Osteosarcoma causes 100% mortality, usually within a few months, if not treated, and only 10% of dogs treated aggressively are cured (Ehrhart & Fan 2009). The disease causes constant and progressive pain until death unless treatment is successful.

In 90% of dogs the cancer has spread by the time of diagnosis. Survival times for these animals range from a few days to a few years with the median survival time being 76 days from diagnosis, but dogs having both chemotherapy and radiation therapy may live longer (Boston et al 2006). Selcarajah & Kirpensteijn (2010) suggested longer median survival times ranging from 3 months to 1 year and but that less than 20% of dogs survive for more than 2 years after the diagnosis, whatever the treatment protocol.



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4.           Number of animals affected

 

It has been suggested that about 5 to 12% of Rottweillers develop osteosarcoma (Rosenberger & Crawford 2004, Comstock et al 2006). Rottweilers are five times more likely to develop osteosarcoma than the average dog (Comstock et al 2006).


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5.           Diagnosis

 

Osteosarcoma may be suspected in a Rottweiler showing chronic pain with a painful swelling in one of the characteristic locations, in a long bone, and is usually confirmed by radiography (x-rays) of the area and a biopsy of the lesion for microscopic examination (Shell & Rosenthal 2007, Ehrhart & Fan 2009).

As rapid metastatic spread usually occurs, other diagnostic tests will be done to evaluate the stage of the disease and help decide the most appropriate treatment options. These tests may include radiographs of the chest, ultrasound examinations of abdominal organs and nuclear scintigraphy (x-rays taken after a radioactive dye which concentrates in tumour cells has been injected into the body) to check for lung or bone metastases (Ehrhart & Fan 2009). Blood tests to measure total and bone alkaline phosphatase may help determine the prognosis. Alkaline phosphatise is an enzyme released from bone cells when they are being damaged – high levels indicate reduced survival times (Shell & Rosenthal 2007).

 

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6.           Genetics

Rottweilers have a predisposition for osteosarcoma (Ru et al 1998, Chun & de Lorimier 2003, Liptak et al 2004b, Hillers et al 2005, Boston et al 2006, Rosenberger et al 2007).

A familial pattern of incidence was recognised in Rottweilers some time ago (Blackwood 1999) and more recently the genetics of the condition in the breed has been investigated. Three areas of the genome have been linked to an increased risk of osteosarcoma in the breed (Comstock et al 2006) but the specific genes involved and their pattern of inheritance are yet to be determined.

The pattern of inheritance of osteosarcoma in Scottish deerhounds has been clarified. In this breed, the condition appears to be inherited as a dominant major gene (Phillips et al 2007) but the pattern of inheritance in Rottweilers appears to be different.

 

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7.           How do you know if an animal is a carrier or likely to become affected?

There are no tests to determine whether or not a Rottweiler is likely to develop osteosarcoma, and it is not known whether ‘carrier’ animals, otherwise unaffected by the disease, may pass on a genetic predisposition to develop the disease to their offspring. Several genes may be involved (Comstock et al 2006).


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8.          Methods and prospects for elimination of the problem

There is evidence that both genetic and environment influences may play a role in the development of osteosarcoma in dogs. Good general advice for prospective breeders concerning conditions in which the mode of inheritance is unknown, is to avoid breeding from animals with affected relatives (Bell 2010). The problem is that most dogs have passed breeding age before developing the condition, and in some cases the parents may develop disease after their offspring’s breeding age has also passed. It is likely that more rapid progress would become possible if the genes involved were determined and could be tested for.

 

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9.          Acknowledgements

UFAW is grateful to Rosie Godfrey BVetMed MRCVS and David Godfrey BVetMed FRCVS for their work in compiling this section.

 

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10.          References

Bell JS (2010) Genetic Testing and Genetic Counseling in Pet and Breeding Dogs. 35th World Small Animal Veterinary Association World Congress Proceedings. 2-5th June 2010, Geneva, Switzerland. http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2010&Category=&PID=56159&O=Generic. Accessed 1.10.11.

 

Blackwood L (1999) Bone tumours in small animals. In Practice: 31-37

Boston SE, Ehrhart NP, Dernell WS, Lafferty M and Withrow SJ (2006) Evaluation of survival time in dogs with stage III osteosarcoma that undergo treatment: 90 cases (1985–2004). Journal of American Veterinary Medical Association 228: 1905–1908

Chun R and de Lorimier L-P (2003) Update on the biology and management of canine osteosarcoma. Veterinary Clinics of North American Small Animal Practice 33(3): 491-516

Cooley DM, Beranek BC, Schlittler DL, Glickman NW, Glickman LT and Waters DJ (2002) Endogenous gonadal hormone exposure and bone sarcoma risk. Cancer Epidemiology Biomarkers & Prevention 11: 1434-1440

Comstock, Karlsson E, Wade C, Keller ET, Lander E, Baker L and Lindblad-Toh K (2006) Regions of the Canine Genome Associated with Osteosarcoma Identified by a Whole Genome Case-Control Association Study. Paper presented at: Genes Dogs & Cancer: Fourth International Canine Cancer Conference. Chicago, USA: International Veterinary Information Services

Dickerson ME, Page RL, LaDue TA, Hauck ML, Thrall DE, Stebbins ME and Price GS (2001) Retrospective analysis of axial skeleton osteosarcoma in 22 large-breed dogs. Journal of Veterinary Internal Medicine 15(2): 120-4

Ehrhart NP and Fan TM (2009) Osteosarcoma in Bonagura JD & Twedt DC eds. Kirk’s Current Veterinary Therapy XIV Saunders Elsevier: St Louis, USA

Hillers KR, Dernell WS, Lafferty MH, Withrow SJ and Lana SE (2005) Incidence and prognostic importance of lymph node metastases in dogs with appendicular osteosarcoma: 228 cases (1986–2003). Journal of the American Veterinary Medical Association 226: 1364–1367

Kirkwood JK (1985) The influence of size on the biology of the dog. Journal of Small Animal Practice 26: 97-110

Liptak JM, Dernell WS, Ehrhart N and Withrow SJ (2004a) Canine appendicular osteosarcoma: Diagnosis and palliative treatment. Compendium of Continuing Education Practising Vet 26(3): 172-182

Liptak JM, Dernell WS and Straw RC (2004b) Proximal radial and distal humeral osteosarcoma in 12 dogs. Journal of American Animal Hospital Association 40: 461–467

Mehl ML, Withrow SJ, Seguin B, Powers BE, Rosenthal RC, Dolginow SZ and Park RD (2001) Spontaneous regression of osteosarcoma in four dogs. Journal of American Veterinary Medical Association 219(5): 614-617

 

Milner R (2004) Osteosarcoma: The Nemesis of Large Breed Dogs. Presented at the University of Florida College of Veterinary Medicine 8th Annual Dog Owners & Breeders Symposium on July 31, 2004. Courtesy of the American Kennel Club’s Canine Health Foundation

 

Modiano J (2010) Bone Cancer in Dogs – What is the State of Practice and New Research? Discoveries 32. Available at http://www.modianolab.org/cancer/cancer_osteosarcoma.shtml accessed 12.5.11

Phillips JC, Stephenson B, Hauck M and Dillberger (2007) Heritability and segregation analysis of osteosarcoma in the Scottish deerhound. Genomics 90(3): 354-63

Rosenberger J and Crawford C (2004) Unpublished data compiled from 1996-2004 case records seen at the University of Florida, Veterinary Medical Teaching Hospital. In Milner R’s Osteosarcoma: The Nemesis of Large Breed Dogs. Presented at the University of Florida College of Veterinary Medicine 8th Annual Dog Owners & Breeders Symposium on July 31, 2004

Rosenberger JA, Pablo NV and Crawford C (2007) Prevalence of and intrinsic risk factors for appendicular osteosarcoma in dogs: 179 cases (1996–2005). Journal of American Veterinary Medical Association 231: 1076-1080

Ru G, Terracini B and Glickman LT (1998) Host related risk factors for canine osteosarcoma. Veterinary Journal 156: 31–39

Selvarajah GT and Kirpensteijn J (2010) Prognostic and predictive biomarkers of canine osteosarcoma. Veterinary Journal 185(1): 28-35

 

Shell L and Rosenthal R (2007) Osteosarcoma. On-line. VIN Associate. http://www.vin.com/Members/Associate/Associate.plx?DiseaseId=1975. Accessed 12.5.11.

 

 

 

 

 

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