Satellite Article Mast Cell Tumours (Mastocytosis) in the Horse: a Review of the Literature and Report of 11 Cases T

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Satellite Article Mast cell tumours (mastocytosis) in the horse: A review of the literature and report of 11 cases T. S. MAIR* AND C. KRUDEWIG† Bell Equine Veterinary Clinic, Mereworth, Maidstone, Kent ME18 5GS; and †Division of Veterinary Pathology, Infection and Immunity, School of Clinical Veterinary Science, University of Bristol, Langford House, Langford BS40 5DU, UK. Keywords: horse; mast cell tumour; mastocytosis; mastocytoma; neoplasia

Summary of mast cells in the lesion is truly neoplastic (Altera and Clark 1970; Prasse et al. 1975; Johnson 1998). Mast cell tumours are uncommon tumours in horses, In man, a World Health Organisation consensus compared to some other species of domesticated classification for mastocytosis exists, which is widely accepted animals. They are most frequently located in the and includes 3 major categories (Valent et al. 2001; Horny skin, but they can also arise at other sites, including the et al. 2007): upper respiratory tract and eye. Cytology or histopathology is required for diagnosis. Treatment 1) Cutaneous mastocytosis, a benign disease in which mast options include surgical excision, laser ablation, cell infiltration is confined to the skin, is preferentially seen cryotherapy, intralesional injection of corticosteroids or in young children and exhibits a marked tendency to water, and radiotherapy. Malignant and systemic forms regress spontaneously. are very rare. 2) Systemic mastocytosis, which is commonly diagnosed in adults and includes 4 major subtypes: (i) indolent systemic Introduction mastocytosis, the most common form involving mainly skin and bone marrow; (ii) a unique subcategory termed Mast cell tumours (mastocytosis) comprise a neoplastic disease systemic mastocytosis with an associated nonmast cell involving mast cells and their progenitors. Although mast clonal haematological disease; (iii) aggressive systemic cell tumours are common in many species of domesticated mastocytosis usually presenting without skin lesions; and animals, they appear to be unusual tumours in the horse, (iv) mast cell leukaemia, probably representing the rarest accounting for only 6.9% of cases in one survey of cutaneous variant of human leukaemias. neoplasms at a large equine referral hospital (Scott and Miller 3) The extremely rare localised extracutaneous mast cell neoplasms, either presenting as malignancy (mast cell 2003). The condition has been reported sporadically in horses sarcoma) or as benign tumour termed extracutaneous in the literature since 1908 (Rooney and Robertson 1996). In mastocytoma. other domestic animals, they are most frequently located in the skin, but they have also been identified in other tissues This report reviews the details of previously documented including the gastrointestinal tract, salivary glands, eyes, testes cases of equine mast cell tumours, and summarises the and spleen (Head et al. 2002). In the horse they are considered features of a further 11 cases diagnosed at the Bell Equine to be uncommon cutaneous tumours, and have only rarely Veterinary Clinic over a 10 year period (1997–2006). been described in other locations such as the eye, the respiratory tract and the oral cavity (Lykkjen et al. 2006; Seeliger et al. 2007). The case report by Brown et al. (2008) Clinical features of previously reported cases provides details of another unusual location for this tumour in the horse (i.e. the testes). Equine mast cell tumours are also Several different forms of equine mast cell tumours have been sometimes described as mastocytosis or mastocytomas, recognised. Solitary tumours are most common, and these are because in many cases it is unclear whether the proliferation most frequently located in the skin, similar to cutaneous mastocytosis recognised in man and other species (Altera and *Author to whom correspondence should be addressed. Clark 1970; Nyrop et al. 1986; McEntee 1991; Nyrop 1992; 178 EQUINE VETERINARY EDUCATION / AE / April 2008

Johnson 1998). In rare cases of ‘systemic’ or ‘multicentric’ Reppas and Canfield 1996; Ritmeester et al. 1997). These mastocytosis, multiple organs and tissues may be affected in reports have documented intraosseous tumour, synovial the same animal. infiltration and spread to local lymph nodes. No other organ A wide range of ages of affected horses has been reported systems were involved in these cases, so widespread from 1–18 years (mean age 9.5 years) (McEntee 1991). There metastasis appears to be extremely rare. Recently however, a does not appear to be any breed predilection, but 10 of the multicentric form of mastocytoma with involvement of the 30 cases (33%) recorded by McEntee (1991) were Arabians. thoracic and abdominal cavities was reported (Tan et al. 2007). Male horses may be predisposed (Altera and Clark 1970; The affected horse, a 9-year-old Paint Horse gelding presented Stannard 1976; Doran and Collins 1986; Samii et al. 1997). with lethargy and decreased appetite, followed by the Solitary cutaneous tumours are usually slow growing, appearance of multiple, small cutaneous circular nodules nonmetastatic and superficial. Typically, they are well- (<1 cm diameter) on the face, neck, lateral thorax, lateral demarcated, and vary from 0.5–20 cm in diameter. The most abdomen and upper limbs. A few days later he developed common locations are the head (lip, nostril, jaw, periorbital dyspnoea associated with a large volume of pleural effusion. area), trunk, and limbs (Scott and Miller 2003). The tumours At post mortem examination, a large multilobulated mast cell are found in the dermis or subcutaneous tissues, may be firm mass was found in the cranial mediastinum with tumour or fluctuant on palpation, and often are partially infiltration of the mediastinal lymph nodes, and tumour encapsulated. Mast cell tumours on the limbs, however, deposits in the lungs and abdominal cavity. often are firm and immovable, and found in proximity to joints (Scott and Miller 2003). In the limbs, they are also Diagnosis often calcified and may be visible radiographically (Samii et al. 1997). The skin overlying the mast cell tumour is Diagnosis of cutaneous mast cell tumours can generally be usually intact, although alopecia, hyperpigmentation or easily achieved by either fine needle aspiration or surgical ulceration may be present. Occasionally the lesions may excisional biopsy. Histologically, these tumours show a well- sporadically discharge caseous material. They are usually differentiated cellular pattern, with single to multifocal nonpainful and nonpruritic. coalescing nodules and sheets of mast cells (Altera and Clark These tumours typically demonstrate a slowly progressive 1970; McEntee 1991; Scott and Miller 2003) (Fig 1a). Mitotic or static growth pattern, although rarely a chronic lesion may figures are usually few in number. The subcutaneous layers are show sudden onset of rapid growth (McEntee 1991). Single frequently involved, and the tumour may sometimes infiltrate lesions are most frequent, but occasionally horses may have the underlying superficial musculature. In addition, they 2 widely separated lesions or a cluster of 2–3 lesions close to commonly show foci of necrosis, collagenolysis, fibrosis and each other (Altera and Clark 1970; McEntee 1991). Mast cell dystrophic mineralisation (McEntee 1991; Ward et al. 1993). tumours have also been reported involving the eye, affecting Eosinophilic infiltration in tissues (due to the elaboration of the conjunctiva, sclera, membrana nictitans and globe chemotactic factors and cytokines) appears to be a consistent (Martin and Leipold 1972; Doran and Collins 1986; Hum and feature of mast cell tumours in large and small animals (Hill Bowers 1989; McEntee 1991; Lavach 1992; Nyrop 1992; et al. 1991; Riley et al. 1991; Ritmeester et al. 1997; Grover Ward et al. 1993; Malikides et al. 1996), the nasal cavity and 2003). Old lesions may contain considerable amounts of nasopharynx (McEntee 1991; Richardson et al. 1994; fibrosis and dystrophic mineralisation, with only small areas of Malikides et al. 1996), trachea (Wenger and Caron 1988), mast cell accumulation (Scott and Miller 2003) (Fig 1b); these and tongue (Seeliger et al. 2007). A recent report (Taylor et al. lesions may be misdiagnosed as calcinosis circumscripta. 2005) also described a mast cell tumour that originated Chronic lesions with significant eosinophilic inflammation also within the synovial membrane of the tarsocrural joint, with need to be differentiated from collagenolytic granuloma no external cutaneous masses. and parasitic eosinophilic granulomatous dermatitis (e.g. A congenital form of widespread cutaneous mastocytosis habronematosis). has been recorded rarely (Prasse et al. 1975; Scott and Miller Neoplastic mast cells in the horse are usually well- 2003). This is characterised by multifocal cutaneous nodules differentiated and contain numerous granules, but these are mainly on the trunk and lateral hindlimbs of the newborn foal. often not visible with haematoxylin and eosin stain. These There was also mast cell accumulation in the bone marrow in granules contain a variety of biologically active mediators, and one recorded case (Prasse et al. 1975). The cutaneous nodules also acidic proteoglycans. The latter can be visualised typically grow to several cm in size, and may then ulcerate and with metachromatic stains such as toluidine-blue or Giemsa regress, only to be replaced by new lesions. One foal was (Fig 1a). Recently, equine mast cells have been shown to observed until one year of age, at which time only a few express tryptase and the trans-membranous tyrosine kinase nodules remained (Prasse et al. 1975). The disease has been receptor protein KIT (Seeliger et al. 2007). considered to be similar to human cutaneous mastocytosis In the dog, where mast cell tumours and soft tissue occurring in young children. sarcomas are the most common malignant cutaneous Malignant mast cell tumours are rare, but there have been tumours, histological grading can be used to assess the a few reports of apparently malignant forms in horses (Martin prognosis (Patnaik et al. 1984). Additionally, recent studies and Leipold 1972; Riley et al. 1991; Malikides et al. 1996; indicate that the expression of the antigen K67, expressed EQUINE VETERINARY EDUCATION / AE / April 2008 179

during the cell cycle, might have prognostic value (Scase et al. Review of 11 cases of equine mast cell tumours 2006; Webster et al. 2007). Variability in the histological appearance of mast cell tumours in large animals makes such A review of cases of mast cell tumours diagnosed at the Bell a classification system less useful (McEntee 1991; Riley et al. Equine Veterinary Clinic over a 10 year period (1997–2006) 1991; Ritmeester et al. 1997). However, due to the overall revealed records of only 11 horses with confirmed mast cell benign behaviour of mast cell tumours in the horse, there is tumours. These included 5 Arabians or Arabian crosses less clinical need for a grading system for these tumours in (45%), 4 ponies, one cob and one hunter-type. The mean this species. age of the affected horses was 11.5 years (range 2–25 years), and there were 6 geldings and 5 mares. All Treatment and prognosis horses were initially presented with solitary lesions. The location of the lesion at initial presentation included the skin The natural clinical course of mastocytosis is variable. Most of the face and external nares (4 horses) (Fig 2), the neck affected human patients, in particular those with cutaneous (one horse), and the cannon (2 horses) (Fig 3a). Both lesions mastocytosis and indolent systemic mastocytosis, remain in of the cannon region had calcification of the tissue visible an indolent stage over many years or even decades, while radiographically (Fig 3b). Lesions were also recorded in the others, in particular those with aggressive systemic mucosa of the rostral nasal cavity (2 horses), the lateral mastocytosis or mast cell leukaemia, show a progressive nasopharynx (one horse) (Fig 4) and the dorsal surface of the course, usually with a fatal outcome (Horny et al. 2007). In epiglottis (one horse) (Fig 5). horses, the majority of mast cell tumours are benign, and Initial treatments included sharp surgical excision (7 cases), treatment is required for cosmetic reasons or if the lesion is intralesional injection of distilled water (2 cases), laser ablation causing local untoward effects. (one horse with a nasopharyngeal tumour) and intralesional Rarely, a cutaneous mast cell tumour may spontaneously injection of methylprednisolone acetate (one horse with a resolve (Pascoe and Knottenbelt 1999), but in most cases mast cell tumour of the epiglottis). In all cases where surgical surgical treatment is indicated. Surgical excision of excision was undertaken, the wound healed by first intention cutaneous mast cell tumours is usually curative, and it has and there was no local recurrence (follow-up period been reported that even incomplete surgical excision or 1–10 years). In both cases where intralesional injection of biopsy may be followed by spontaneous remission (Stannard distilled water was undertaken (one cutaneous tumour on the 1976; McEntee 1991; Samii et al. 1997; Johnson 1998; Scott neck and one tumour in the nares), this treatment failed to and Miller 2003). In the series of 30 cases reported by completely resolve the lesion, and further treatment by McEntee (1991), there were no recurrences after surgical surgical excision was required. In the single case treated by excision in over 90% of horses followed for 6 years or more. surgical laser ablation, repeat endoscopic examination after Other reportedly effective treatments include intra- and 6 weeks showed complete resolution of the lesion. sublesional injection of corticosteroids (e.g. 5–10 mg Intralesional injection of methylprednisolone acetate resulted triamcinolone acetonide or 10–20 mg methylprednisolone in complete resolution of the lesion on the epiglottis in one acetate), cryosurgery or radiotherapy (Scott and Miller 2003). horse within 3 weeks. Glucocorticoids have been used successfully to treat canine Although no local recurrence of mast cell tumours at the mast cell tumours (Takahashi et al. 1997), and their use has same site was recorded in any of the horses, further been described previously to treat articular mastocytosis in a presentation of mast cell tumours at other sites was horse (Taylor et al. 2005). There are also anecdotal reports encountered in 2 cases. In one horse (a 4-year-old Arabian that cimetidine (5 mg/kg bwt q. 24 h, per os) and mare), the initial lesion was a mast cell tumour on the right intralesional injections of distilled water or cisplatin may be external nares, which was surgically excised; this horse had a effective (Pascoe and Knottenbelt 1999). There are very few further mast cell tumour on the face (close to the left eye) documented reports of long-term follow-up of horses 7 years later (which was surgically excised), followed by a treated for mast cell tumours, but the prognosis is generally further occurrence of a mast cell tumour on the cannon considered to be very good. 3 months later (which was surgically excised), and then a Visceral metastasis of equine cutaneous mast cell tumours further occurrence of another mast cell tumour over the is rare, and in most cases a good prognosis can be predicted. scapula 2 months later (which was also surgically removed). Mechanical manipulation of mast cell tumours in dogs and Another horse (9-year-old Arabian gelding) presented with a humans can lead to a characteristic erythema and wheal solitary tumour in the rostral nasal cavity, which was surgically reaction (Darrier’s sign) caused by vasoactive amines excised. A further occurrence of a mast cell tumour was (histamine and others), neutral proteases and proteoglycans noted over the rump 2 months later, and this was also (e.g. heparin) being released from the tumour cells. This surgically excised. This horse was subsequently affected by occurrence has not been recorded in the horse. Likewise, numerous cutaneous mast cell tumours over the next 5 years; other complications of surgical excision that are recognised in lesions occurred predominantly over the head, neck, rump dogs, such as gastrointestinal ulceration, post operative and perineum, and around the nares. These lesions haemorrhage and delayed wound healing, have not been characteristically would ulcerate, discharge caseous material reported in horses. and spontaneously resolve, although a few lesions remained 180 EQUINE VETERINARY EDUCATION / AE / April 2008

Fig 2: Mast cell tumour in the nares of an 8-year-old Arab gelding. This lesion was successfully treated by surgical excision.

Fig 1a: Cutaneous mast cell tumour, consisting of sheets of large round cells with pale eosinophilic to amphophilic cytoplasm, separated by collagenous fibres. Bar 100 µm. Inset: toluidine-blue staining confirms numerous, metachromatic, intracytoplasmic granules in tumour cells.

Fig 3a: Mast cell tumour on the lateral cannon of a 18-year-old Arab gelding. The tumour had been slowly enlarging over 4 weeks, and had recently ulcerated. This lesion was surgically excised, and found to extend deeply between and around the flexor tendons. No recurrence at this site was noted over Fig 1b: Mast cell tumour of the ventral abdomen consisting 6 months. predominantly of large areas of eosinophilic degranulation (E) surrounded by fibrosis. There is one nodule of mast cells (M). Inset (area of M): toluidine-blue staining reveals round cells with metachromatic granules (purple), consistent with mast cells. as chronic, firm dermal nodules. The owner opted to manage these lesions conservatively without any specific treatment, and the horse has remained fit and well, and in full work as a general riding horse.

Conclusions

Mast cell tumours are uncommon tumours in horses. Although they most commonly arise in the skin, they can also occur in other sites, including the upper respiratory tract and eye. Lesions on the limbs often become calcified which may be visible radiographically. Cytology/histopathology is needed for the diagnosis, and usually reveals sheets/nodules of mast cells, Fig 3b: Oblique radiograph of the mast cell tumour shown in which are confirmed by special staining. Treatment options Figure 3a. There is dystrophic calcification of the mass. EQUINE VETERINARY EDUCATION / AE / April 2008 181

Grover, S. (2003) Principles of treatment for mast cell tumors. Clin. Tech. small anim. Pract. 18, 103-106. Head, K.W., Else, R.W. and Dubielzig, R.R. (2002) Tumors of the alimentary tract. In: Tumors in Domestic Animals, Ed: D.J. Meuten, Iowa State Press, Ames, Indiana. pp 401-482. Hill, J.E., Langheinrich, K.A. and Kelley, L.C. (1991) Prevalence and location of mast cell tumors in slaughter cattle. Vet. Pathol. 28, 449-450. Horny, H.-P., Sotlar, K. and Valent, P. (2007) Mastocytosis: state of the art. Pathobiol. 74, 121-132. Hum, S. and Bowers, J.R. (1989) Ocular mastocytosis in a horse. Aust. vet. J. 66, 32. Johnson, P.J. (1998) Dermatologic tumors (excluding sarcoids). Vet. Clin. N. Am.: Equine Pract. 14, 625-658. Lavach, J.D. (1992) Ocular neoplasia. In: Current Therapy in Equine Medicine, Ed: N.E. Robinson, W.B. Saunders, Philadelphia. pp 604-608. Lykkjen, S., Strand, E., Haga, H.A. and Lie, K.I. (2006) Radical surgical Fig 4: Endoscopic view of mast cell tumour in the wall of the resection of locally invasive oro-cutaneous tumors in the buccal nasopharynx (just distal to the pharyngeal ostium of the right region of 2 horses. Vet. Surg. 35, 319-323. Eustachian tube) in a 25-year-old cross-bred horse. This lesion was successfully treated by surgical diode laser ablation. Malikides, N., Reppas, G.P., Hodgson, J. and Hodgson, D.R. (1996) Mast cell tumors in the horse-4 case reports. Equine Pract. 18, 12-17. Martin, C.L. and Leipold, H.W. (1972) Mastocytoma of the globe in a horse. J. Am. anim. hosp. Ass. 8, 32-34. McEntee, M.F. (1991) Equine cutaneous mastocytoma: Morphology, biological behavior and evolution of the lesion. J. comp. Pathol. 104, 171-178. Nyrop, K.A. (1992) Cutaneous mastocytosis. In: Current Therapy in Equine Medicine, Ed: N.E. Robinson, W.B. Saunders, Philadelphia. pp 702-703. Nyrop, K.A., Debowes, R.M., Coffman, J.R. and Leipold, H.W. (1986) Equine cutaneous mastocytoma. Comp. cont. Educ. pract. Vet. 8, 757-761. Pascoe, R.R. and Knottenbelt, D.C. (1999) Manual of Equine Dermatology, W.B. Saunders Co, Philadelphia. Patnaik, A.K., Ehler, W.J. and Macewen, E.G. (1984) Canine cutaneous mast cell tumors: Morphologic grading and survival time in 83 dogs. Vet. Pathol. 21, 469-473. Prasse, K.W., Lundvall, R.L. and Cheville N.F. (1975) Generalized mastocytosis in a foal, resembling urticaria pigmentosa of man. J. Fig 5. Endoscopic view of a mast cell tumour on the dorsal Am. vet. med. Ass. 166, 68-70. surface of the epiglottis in a 5-year-old pony. This tumour Reppas, G. and Canfield, P.J. (1996) Malignant mast cell neoplasia resolved following intralesional injection of corticosteroid; with local metastasis in a horse. N. Z. vet. J. 44, 22-25. there was no recurrence over a 5 year period. Richardson, J.D., Lane, J.G. and Nicholls, P.K. (1994) Nasopharyngeal mast cell tumour in a horse. Vet. Rec. 134, 238-240. include surgical excision, laser ablation, cryotherapy, Riley, C.B., Yovich, J.V. and Howell, J.M. (1991) Malignant mast cell tumours in horses. Aust. vet. J. 68, 346-347. intralesional injection of corticosteroids or water, and radiotherapy. Local recurrence is rare, but further growth of Ritmeester, A.M., Denicola, D.B., Blevins, W.E. and Christian, J.A. (1997) Primary interosseous mast cell tumor of the third phalanx in mast cell tumours at other sites may occur in a small number a Quarter Horse. Equine vet. J. 29, 151-152. of cases. Malignant and systemic forms of mast cell tumours Rooney, J.R. and Robertson, J.L. (1996) Mastocytosis and are rare. mastocytoma. In: Equine Pathology, Iowa State University Press, Ames. p 307. References Samii, V.F., O’Brien, T.R. and Stannard, A.A. (1997) Radiographic features of mastocytosis in the equine limb. Equine vet. J. 29, Altera, K. and Clark, L. (1970) Equine cutaneous mastocytosis. Pathol. 63-66. Vet. 7, 43-55. Seeliger, F., Heb, O., Probsting, M., Kleinschmidt, S., Woehrrmann, T. Brown, J.A., O’Brien, M.A., Hodder, A.D.J., Peterson, T., Claes, A., Liu, and Germann, P.G. (2007) Confocal laser scanning analysis of an I.K.M. and Ball, B.A. (2008) Unilateral testicular mastocytoma in a equine oral mast cell tumor with atypical expression of tyrosine Peruvian Paso stallion. Equine vet. Educ. 20, 172-175. kinase receptor C-KIT. Vet. Pathol. 44, 225-228. Doran, R.E. and Collins, L.G. (1986) Mastocytoma in a horse. Equine Scase, T.J., Edwards, D., Miller, J., Henley, W., Smith, K., Blunden, A. vet. J. 18, 500-502. and Murphy, S. (2006) Canine mast cell tumors: correlation of 182 EQUINE VETERINARY EDUCATION / AE / April 2008

apoptosis and proliferation markers with prognosis. J. vet. intern. Valent, P., Horny, H.P., Escribano, L., Longley, B.J., Li, C.Y., Schwartz, Med. 20, 151-158. L.B., Marone, G., Nunez, R., Akin, C., Sotlar, K., Sperr, W.R., Wolff, Scott, D.W. and Miller, W.H. Jr. (2003) Mast cell tumor. In: Equine K., Brunning, R.D., Parwaresch, R.M., Austen, K.F., Lennert, K., Dermatology, Elsevier Science, St Louis. pp 746-753. Metcalfe, D.D., Vardiman, J.W. and Bennett, J.M. (2001) Stannard, A.A. (1976) Equine dermatology. Proc. Am. Ass. equine Diagnostic criteria and classification of mastocytosis: A consensus Practnrs. 22, 273. proposal. Leuk. Res. 25, 603-625. Takahashi, T., Kadosawa, T., Nagase, M., Mochizuki, M., Matsunaga, S., Nishimura, R. and Sasaki, N. (1997) Inhibitory effects of Ward, D.A., Lakritz, J. and Bauer, R.W. (1993) Scleral mastocytosis in glucocorticoids on proliferation of canine mast cell tumour. J. vet. a horse. Equine vet. J. 25, 79-80. med. Sci. 59, 995-1001. Webster, J.D., Yuzbasiyan-Gurkan, V., Miller, R.A., Kaneene, J.B. and Tan, R.H.H., Crisman, M.V., Clark, S.P., Gagea, M. and Zimmerman, K. Kiupel, M. (2007) Cellular proliferation in canine cutaneous mast (2007) Multicentric mastocytoma in a horse. J. vet. intern. Med. cell tumors: associations with c-KIT and its role in prognostication. 21, 340-343. Vet. Pathol. 44, 298-308. Taylor, S., Martinelli, M.J., Trostle, S.S. and Kemper, T. (2005) Articular mastocytosis in the tarsocrural joint of a horse. Equine vet. Educ. Wenger, I.E. and Caron, J.P. (1988) Tracheal mastocytosis in a horse. 17, 207-211. Can. vet. J. 29, 563-565.