Genetic Welfare Problems of Companion Animals

Boxer

Mast Cell Tumour

Related terms: mastocytoma, mast cell sarcoma, mastocytosis

Outline: Boxers are predisposed to mast cell tumours, a cancer of the immune system. These can occur in various forms and can be benign or malignant. Their welfare effects range from local itching, discomfort and pain associated with localised tumours in the skin, to more severe pain, discomfort and malaise where internal organs are affected or as a result of gastrointestinal ulceration caused by the release of the chemical histamine

Summary of Information

(for more information click on the links below)

1. Brief description

Mast cell tumour (MCT) is one of the commonest neoplasms of dogs and is a cancerous growth of mast cells that are present in tissues throughout the body and are part of the immune system. These cancers are most commonly found in the skin but can occur at other sites throughout the body especially in the gastrointestinal tract (Misdorp 2004, Dobson & Scase 2007, Valent 2010). They can be solitary or can occur as multiple MCT masses. The appearance of a mast cell tumour in the skin is very variable and can be hard to distinguish from other growths.

As well as causing disease in the same way as other cancers – by causing organ damage and dysfunction, pain, debilitation and reduced appetite - mast cell tumours can also cause disease through the uncontrolled release of the biologically active chemicals that are produced in these specialised cells (Dobson & Scase 2007).

Solitary MCTs vary in behaviour from benign, where they do not spread to other parts of the body, to aggressively malignant, where they do. Although Boxers are more likely than other breeds to develop MCTs, it has been suggested that these are more likely to be of the benign type than those developed in other breeds (Dobson & Scase 2007).

The mean age at which Boxers are diagnosed with MCTs is around 8 years but these tumours can occur at any age, even in puppies (Nuttall et al 2009).

2. Intensity of welfare impact

The effects on welfare of MCTs depend on the malignancy of the tumour and the site at which it grows. They are a result of the mechanical effects of the tumour (eg due to it compressing or compromising the movement of surrounding tissues) and also of the release of histamine and other biologically active substances produced by the tumour cells that make the skin inflamed and itchy or painful, and which cause gastrointestinal ulceration and pain. Spread of the tumour to internal organs will also cause pain.

Diagnostic tests and treatments may also have adverse welfare effects (Ladue et al 1998, Chaffin & Thrall 2002, Weisse et al 2002, London et al 2009, Blackwood 2010, Robat et al 2010). Benign MCTs can often be cured. The more malignant tumours often lead to death, although recently developed drug therapies may prove successful in some cases (London et al 2009, Blackwood 2010, Robat et al 2010).

3. Duration of welfare impact

Mast cell tumours causing solitary masses on the skin may affect welfare for only a relatively short period of a few weeks, if the MCT is successfully treated. If not successfully treated, the MCT is likely to cause increasing discomfort, pain, distress and ultimately, death.

4. Number of animals affected

Boxers have a greater predisposition to neoplasia than many other breeds of dogs (Cohen et al 1974). Mast cell tumours are the second commonest malignant tumour of dogs, affecting 129 per 100,000 insured dogs each year (Dobson et al 2002, Brønden et al 2010), and represent around 20 per cent of all the skin tumours reported (Dorn et al 1968). According to UK VetCompass data, mast cell tumours affect 3.9 dogs of 1000 dogs and Boxers had the highest breed specific prevalence at 1.95% (Shoop et al 2015).

5. Diagnosis

Diagnosis is usually made by collecting cells for examination by inserting a needle into the tumour and removing cells and fluid with a syringe for microscopic examination (Baker-Gabb et al 2003). Trying to predict the tumour’s potential for growth and spread requires further tests which may include collection of samples from nearby lymph nodes, imaging with x-rays, and ultrasound examinations (Dobson & Scase 2007, Blackwood 2010).

6. Genetics

Boxers have a genetic predisposition to developing mast cell tumours but the genes involved in causing the disease are unknown (Peters 1969, Cohen et al 1974, Scott et al 1995, Baker-Gabb et al 2003, Dobson & Scase 2007)..

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

There is no way to predict which individuals will be affected and it is not known if carriers can exist, that can pass the risk of the disease on to offspring without ever developing the disease themselves.

8. Methods and prospects for elimination of the problem

It is likely, since there is clearly has a genetic basis to the Boxer’s predisposition to develop the disease that breeding only from dogs that have not had MCT would result in reduction in its prevalence. Tackling this disease by selective breeding is, at present, complicated by the fact that these tumours often develop after breeding age (Nuttall et al 2009). More rapid progress would be possible if it there was a way to detect the genes responsible for the condition.

For further details about this condition, please click on the following:
(these link to items down this page)

• Clinical and pathological effects
• Intensity of welfare impact
• Duration of welfare impact
• Number of animals affected
• Diagnosis
• Genetics
• How do you know if an animal is a carrier or likely to become affected?
• Methods and prospects for elimination of the problem
• Acknowledgements
• References

1. Clinical and pathological effects

Mast cells are part of the immune system. They are produced in bone marrow. When mature, they are found in blood vessels where they become activated by antibodies or local tissue damage, chemicals or heat. Once activated, they release a variety of biologically active chemicals that cause local inflammation (the best known being histamine), and that attract other types of immune system cells to the site. They also play a central role in allergic reactions (Gorman & Halliwell 1989, Misdorp 2004, Dobson & Scase 2007).

Mast cell tumours (MCT) are among the commonest neoplasms (clusters of cells caused by abnormal growth) of dogs. They usually occur in the skin but can occur elsewhere, especially in the gastrointestinal tract (Misdorp 2004, Dobson & Scase 2007,Valent 2010). These cancerous growths can be solitary masses of cells that are benign (ie unlikely to spread) or they can be malignant and likely to spread to other parts of the body via the lymphatic or blood systems. There are also several types of the systemic form of the disease – in which the disease is found throughout the body- and these have been defined by the type of mast cells involved and the sites at which they occur (Marconato et al 2008, Valent 2010). In mastocytosis, for example, MCTs appear throughout the body and large numbers of mast cells are found in the bone marrow. When neoplastic mast cells begin to circulate in the blood this form then becomes a type of leukaemia. Here though we focus on the common form of the disease characterised by solitary or multiple MCT masses.

The appearance of cutaneous (skin) MCTs is very variable. It can be similar to various other types of skin neoplasia. Conversely, some growths initially thought to be benign cysts or lipomas (benign tumours of fat), sometimes turn out to be MCTs which may be malignant (Nuttall et al 2009).

Tumours occur as a result of genetic mutations that result in abnormal growth of the affected cells. A gene, c-KIT, is known to be involved in some, but not all, canine mast cell tumours (London et al 1990). It influences receptors in the cell that bind with growth promoting substances and when present in its mutated form has the effect of causing affected cells to continuously divide resulting in the growth of the neoplasm. The c-KIT gene therefore predisposes animals to develop malignant mast cell tumours, and dogs with this gene are more likely to die due to MCT (Zemke et al 2002, Webster et al 2006).

Another mutation can affect the platelet derived growth factor receptor (PDGFR), which is involved in the blood supply to growing tumours. Both this and the receptor affected by the c-KIT gene contain the protein, tyrosine kinase (TK), and are affected by some modern drug treatments (tyrosine kinase inhibitors - TKIs) that can be somewhat effective against cancers caused by these mutations in humans and dogs (Blackwood 2010).

As well as causing disease in the same way as any other cancer – by causing organ damage and dysfunction, pain, debilitation and appetite reduction; the adverse effects of MCTs are also caused by the uncontrolled release of the biologically active chemicals that these cells produce. These chemicals can have adverse effects both locally and elsewhere (Misdorp 2004, Dobson & Scase 2007). Locally, there is often inflammation around the tumour mass with redness, oedema (fluid in the tissue), and pain. Wound healing in these areas may be delayed: for example, after a surgical biopsy.

Occasionally anaphylaxis, a systemic allergic response – in which the whole body is affected, may occur in dogs with mast cell tumours. Affected dogs may collapse with a failing circulation, breathing difficulties caused by swelling of tissues and fluid release into the lungs, vomiting and diarrhoea. The blood clotting mechanism can also sometimes be affected in dogs with MCTs. More commonly, affected animals develop gastrointestinal disease, especially ulceration, as a result of histamine release by the tumour. It is thought that the more severe, widespread, and malignant the mast cell tumour, the more likely it is for these more serious effects to occur (Dobson & Scase 2007).

Solitary MCTs vary from the benign to the aggressively malignant. This appears to be influenced partly by the site of the tumour. For example, those around muco-cutaneous junctions (where skin meets moist, mucous membranes eg the lips) and in the groin of male dogs tend to be more malignant. Although Boxers are more likely to have MCTs than other breeds, Dobson & Scase (2007) have suggested that these tumours are more likely to be benign in Boxers than would be expected in other breeds (2007). Boxers are said to be predisposed to a form of the disease in which multiple solitary mast cell tumours develop concurrently in different parts of the body (Goldschmidt & Shofer 1992).

MCTs are graded clinically according to the following scheme (Owen 1980), which may be helpful in prognosis (predicting how the disease may develop) and when making decisions making regarding treatments: surgery, radiation and/or drugs.

1. One small tumour confined to the skin, no lymph node involvement
2. One small tumour confined to the skin with local or regional lymph node involvement
3. Multiple skin tumours or a large infiltrating tumour with or without regional lymph node involvement
4. IV Any tumour with distant metastases (spread of the tumour to other parts of the body)

Tumours are also graded either I, II or III according to their cellular characteristics. This grading, based on the microscopic appearance of biopsy specimens, is also useful to aid decision making for treatment and to guide prognosis (Patnaik et al 1984).

The validity of the details of these schemes has been questioned (Dobson & Scase 2007) but they are generally considered to be useful. Grade I masses and the low malignancy grade II tumours are likely to be cured just by surgery. Some grade II masses seem to benefit from wider surgery and sometimes adjuvant radiation of the surrounding area (Dobson & Scase 2007). Chemotherapeutic agents (TKIs) can be useful in the treatment of the higher-grade tumours (perhaps especially in c-KIT positive animals). Such agents may prolong life rather than achieving a complete cure (Hahn et al 2008, Blackwood 2010).

The mean age at which Boxers are diagnosed with MCTs is around 8 years but these tumours can occur at any age, even in puppies (Nuttall et al 2009)..

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2. Intensity of welfare impact

The effects of mast cell tumours on welfare depend on the malignancy and the site of the tumour. They can be a result of both the mechanical effects of the tumour(s) (eg due to it compressing or compromising the movement of surrounding tissues) and of the effects of histamine and the other biologically active substances produced by the tumour cells. These chemicals make the skin in the area inflamed and itchy or painful, and can cause gastrointestinal ulceration with associated pain. Spread of the tumour to internal organs can stop them functioning properly and cause pain. There may also be adverse welfare consequences associated with diagnosis and treatment of the tumour (which may include surgery and radiotherapy) (Ladue et al 1998, Chaffin & Thrall 2002, Weiss et al 2002, London et al 2009, Blackwood 2010, Robat et al 2010). Although the lower grade forms of the disease may be completely cured, death is a common outcome for the more malignant forms and it has been reported that, despite treatment, around half of dogs with high grade tumours die within a year (Murphy et al 2004). Recently developed drugs may prove more effective (London et al 2009, Blackwood 2010, Robat et al 2010)..

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3. Duration of welfare impact

The average (median) age of diagnosis of mast cell tumour is 8.2 years, and older dogs (8 or over) are more at risk of a diagnosis compared to those below 2 years of age (Shoop et al 2015). The duration of the period when welfare is compromised depends on the malignancy, form and site of the tumour. Mast cell tumours causing solitary masses on the skin may affect welfare for only a relatively short period of a few weeks if the MCT is successfully treated. If not treated successfully, the MCT is likely to cause increasing discomfort, pain, distress and ultimately, death..

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4. Number of animals affected

Boxers have a greater predisposition to neoplasia than many other breeds of dogs (Cohen et al 1974). Mast cell tumours are the second commonest malignant tumour of dogs, affecting 129 per 100,000 insured dogs each year (Dobson et al 2002, Brønden et al 2010), and represent around 20 per cent of all the skin tumours reported (Dorn et al 1968).  UK VetCompass data for dogs overall, showed that 3.990 dogs per 1000 dogs from a random sample of 3884 were diagnosed with mast cell tumour between 2009 and 2013 (O Neill et al 2014; see also: http://www.rvc.ac.uk/vetcompass/learn-zone/infographics/canine), and Boxers had the greatest breed-specific prevalence of 1.95% (95% confidence interval: 1.40%-2.51%; Shoop et al 2015).

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5. Diagnosis

MCTs cannot be diagnosed by visual examination: their appearance is very variable (Nuttall et al 2009). Diagnosis is usually made by collecting cells for examination by inserting a needle into the tumour and removing cells and fluid with a syringe for microscopic examination (Baker-Gabb et al 2003). In addition to making the diagnosis, it is important to try to predict the tumour’s behaviour: whether benign or highly malignant. This is difficult but various special examinations involving collection of samples from nearby lymph node, cytology, histology, and imaging with X-rays and/or ultrasound examinations may be helpful (Dobson & Scase 2007). It is possible and desirable to check the likely suitability of treatment of the tumour by TKI chemotherapy (Blackwood 2010).

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6. Genetics

There is no doubt that the high prevalence of mast cell tumours in Boxers has a genetic basis as the predisposition of these dogs to developing the disease is well-recognised (Peters 1969, Cohen et al 1974, Scott et al 1995, Baker-Gabb et al 2003, Dobson & Scase 2007).

There has been some research into the genetic causes of MCTs but the genes involved have not been determined (Munday et al 2009) and there are no published studies regarding the degree of heritability or the pattern of inheritance.

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

There is no way to predict which individuals will be affected and it is not known if carriers can exist, that can pass the risk of the disease on to offspring without ever developing the disease themselves.

Return to top

8. Methods and prospects for elimination of the problem

It is likely, since there is clearly has a genetic basis to the Boxer’s predisposition to develop the disease, that breeding only from dogs that have not had MCT would result in reduction in its prevalence. Tackling this disease by selective breeding is, at present, complicated by the fact that these tumours often develop after breeding age (Nuttall et al 2009). More rapid progress would be possible if it there was a way to detect the genes responsible for the condition.

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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

Baker-Gabb BM, Hunt G and France M (2003) Soft tissue sarcomas and mast cell tumours in dogs; clinical behaviour and response to surgery. Australian Veterinary Journal 81: 732–738

Blackwood L 2010 Mast Cell Tumours: Where Do TKIs Fit In? British Small Animal Veterinary Congress 8-11th April 2010 http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=bsava2010&PID=pr54247&O=VIN accessed 19.9.2011

Brønden LB, Nielsen SS, Toft N and KristensenAT (2010) Data from the Danish Veterinary Cancer Registry on the occurrence and distribution of neoplasms in dogs in Denmark. Veterinary Record 166: 586-590

Chaffin K and Thrall DE (2002) Results of radiation therapy in 19 dogs with cutaneous mast cell tumor and regional lymph node metastasis. Veterinary Radiology and Ultrasound 43: 392–395

Cohen D, Reif JS, Brodey RS and Keiser H (1974) Epidemiological analysis of the most prevalent sites and types of canine neoplasia observed in a veterinary hospital. Cancer Research 34: 2859–2868

Dobson JM, Samuel S, Milstein H, Rogers K and Wood JL (2002) Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. Journal of Small Animal Practice 43: 240-6

Dobson JM and Scase TJ (2007) Advances in the diagnosis and management of cutaneous mast cell tumours in dogs. Journal of Small Animal Practice 48: 424–431

Dorn CR, Taylor DO, Schneider R, Hibbard HH and Klauber MR (1968) Survey of animal neoplasms in Alameda and Contra Costa counties, California II. Cancer morbidity in dogs and cats from Alameda County. Journal of the National Cancer Institute 40: 307-318

Goldschmidt MH and Shofer FS (1992) Skin Tumours of the Cat and Dog. Pergamon Press, New York

Gorman NT and Halliwell REW (1989) In: Veterinary Clinical Immunology pp 35 W.B. Saunders, Philadelphia

Hahn K, Oglivie G, Rusk T, Devauchelle P, Leblanc A, Legendre A, Powers B, Leventhal P, Kinet J-P, Palmerini F, Dubreuil P, Moussy A and Hermine O (2008) Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors. Journal of Veterinary Internal Medicine 22: 1301–1309

Ladue T, Price GS, Dodge R, Page RL and Thrall DE (1998) Radiation therapy for incompletely resected canine mast cell tumors. Veterinary Radiology and Ultrasound 39: 57–62

London CA, Galli SJ, Yuuki T, Zhi-Qing Hu bZ-Q,  Helfand SC and Geissler EN (1999)  Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. Experimental Haematology 27: 689-697

London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP, Henry CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ, Couto GC, Mauldin GN and Michels GM (2009) Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clinical Cancer Research 15: 3856-65

Marconato L, Bettini G, Giacoboni C, Romanelli G, Cesari A, Zatelli A and Zini E (2008) Clinicopathological Features and Outcome for Dogs with Mast Cell Tumors and Bone Marrow Involvement. Journal of Veterinary Internal Medicine 22: 1001–1007

Misdorp W (2004) Mast cells and canine mast cell tumours. A review. The Veterinary Quarterly 26: 156-69

Munday JS, French AF, Gibson IR and Gwynne K (2009) Widespread mismatch repair protein expression in canine cutaneous mast cell tumors. Veterinary Pathology 46: 227-32

Murphy S, Sparkes AH, Brearley MJ, Smith KC and Blunden AS (2004) Relationships between the histological grade of cutaneous mast cell tumours in dogs, their survival and the efficacy of surgical resection. Veterinary Record 154: 743-746

Nuttall T, Harvey RG and McKeever PJ (2009) Mast cell neoplasia. In: Skin Disease of the Dog and Cat 2nd edition. pp 74 – 7. Manson Publishing Ltd, London

O Neill DG, Church DB, McGreevy PD, Thomson PC and Brodbelt DC 2014 Prevalence of disorders recorded in dogs attending primary-care veterinary practices in England. PloS one 9, e90501. doi:10.1371/journal.pone.0090501

Owen L (1980) TNM Classification of Tumours in Domestic Animals. World Health Organization: Geneva, Switzerland

Patnaik AK, Ehler WJ and MacEwen EG (1984) Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Veterinary Pathology 21: 469–474

Peters JA (1969) Canine mastocytoma: excess risk as related to ancestry. Journal of the National Cancer Institute 42: 435-443

Robat C, London C, Bunting L, McCartan L, Stingle N, Selting K, Kurzman I and Vail DM  (2010) Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose-finding study. Veterinary and Comparative Oncology no. doi: 10.1111/j.1476-5829.2011.00261.x

Scott DW, Miller WH and Griffin CE (1995) Mast cell tumour. In: Muller & Kirk’s Small Animal Dermatology 5th edition pp 1056 WB Saunders, Philadelphia

Shoop SJ, Marlow S, Church DB, English K, McGreevy PD, Stell AJ, Thomson PC, O’Neill DG and Brodbelt DC 2015 Prevalence and risk factors for mast cell tumours in dogs in England. Canine Genetics and Epidemiology 2, 1. doi:10.1186/2052-6687-2-1

Valent P (2010) Diagnosis, Classification, and Therapy of Mastocytosis. 20th European College of Veterinary Internal Medicine-Companion Animal Congress, 2010

Webster JD, Yuzbasiyan-Gurkan V, Kaneene JB, Miller R, Resau JH and Kiupel M (2006) The role of c-KIT in tumorigenesis: evaluation in canine cutaneous mast cell tumors. Neoplasia 8: 104-11

Weisse C, Shofer FS and Sorenmo K (2002) Recurrence Rates and Sites for Grade II Canine Cutaneous Mast Cell Tumors Following Complete Surgical Excision. Journal of the American Animal Hospital Association 38: 71-73

Zemke D, Yamini B and Yuzbasiyan-Gurkan V (2002) Mutations in the Juxtamembrane Domain of c-KIT Are Associated with Higher Grade Mast Cell Tumors in Dogs.Veterinary Pathology 39: 529–535

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By Corporalen (Own work) [Public domain], via Wikimedia Commons