PROGNOSTIC TESTING INTO FELINE CUTANEOUS MAST CELL TUMOURS

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1 Vet Times The website for the veterinary profession PROGNOSTIC TESTING INTO FELINE CUTANEOUS MAST CELL TUMOURS Author : Melanie Dobromylskyj Categories : Vets Date : October 21, 2013 David Rendle looks at this common skin tumour in cats and considers the differences from canine MCTs before looking at ongoing research Summary Feline cutaneous mast cell tumours are the second most common skin tumour in cats, but unlike in dogs, there is no histological grading system for them. Prognostic tests routinely used in dogs are not as well studied in cats and rarely used in practice. This is despite these tumours having variable biological behaviour and being potentially malignant, which can be difficult to accurately predict from the histological appearance alone. The arrival of tyrosine kinase receptor inhibitors on the veterinary drug market also creates another potential treatment option for cats with the more malignant forms of the tumour. This essay discusses the similarities and differences between feline and canine mast cell tumours, the different histological types seen in cats and the prognostic indicators currently used. It also covers the ongoing research into prognostic markers such as Ki67 and KIT-staining patterns in this species. Key words feline, mast cell tumour, diagnosis, histology, prognostication GENERAL practitioners are very aware of canine cutaneous mast cell tumours (MCTs) and their clinical importance. However, there is much less appreciation of their counterpart in 1 / 16

2 felines. MCTs are the second most common skin tumour seen in felines; a large retrospective study1 that looked at 340 skin tumours in cats found a MCT incidence of 21 per cent, second only to a group of tumours previously classified together as basal cell tumours. This study placed prevalence of MCTs above squamous cell carcinoma or fibrosarcoma (third and fourth most prevalent respectively). There is a wide range of prevalence in the textbooks, with MCTs accounting for eight per cent to 15 per cent and up to 21 per cent of all feline skin tumours2,3. MCTs in cats are generally divided into cutaneous or visceral forms. Although the cutaneous form is more common than the visceral, it should be remembered cutaneous tumours can be secondary lesions arising from primary visceral masses. The most common visceral locations include the spleen and intestines, although in theory they could arise anywhere (the author has diagnosed an MCT within the urinary bladder wall of a cat). MCTs are also regularly diagnosed within the oral cavity and conjunctiva of cats. Similar to dogs, the biological behaviour of feline cutaneous MCTs varies from benign to malignant; the majority of solitary cutaneous masses without lymph node involvement follow a benign course, with rare local recurrence and a long survival time. However, unlike in dogs, there is no established grading scheme for feline MCTs and the prognostic factors are not as well-defined. The introduction of tyrosine kinase receptor inhibitors into the veterinary market creates another potential treatment option for cats with these tumours and there have been several studies published with a particular interest in prognostication, KIT receptor expression/dysregulation in these cases. When considered as a group, the mean age at presentation for feline MCTs varies from eight to 10.5 years and has a range from less than one year up to 20 years1,4,5,6. Most often, these tumours arise in the cutaneous and subcutaneous tissues of the head, neck and trunk1,4. However, case signalment varies depending on the histological type of the MCT, with certain types more likely to arise in particular breeds (particularly Siamese) and at a much younger age. MCTs in cats have been associated with several paraneoplastic syndromes, similar to those seen in dogs. One case reported in the literature showed the unusual finding of anaemia secondary to phagocytosis of red blood cells by the neoplastic mast cells7; it should be remembered anaemia in a MCT case is much more likely to be associated with chronic inflammation or to be secondary to blood loss seen with gastrointestinal ulceration. In contrast to dogs, circulating mast cells are often a feature of feline MCTs, with mastocytaemia identified in up to 43 per cent of cases8. In dogs, mastocytaemia can be associated with various inflammatory, hypersensitivity or other pathological processes, but in cats, it appears to be almost exclusively associated with MCT; therefore, MCT should be an important differential diagnosis in any cat presenting with mastocytaemia. 2 / 16

3 Eosinophilia, together with eosinophilic peritoneal and pleural effusions, has also been reported as a paraneoplastic syndrome in cats with visceral MCTs, however, in contrast to mastocytaemia, the other potential causes of eosinophilia in cats are many and varied, including parasites, allergy and hypereosinophilic syndromes. Grossly, MCTs can vary widely in their appearance. Several papers and books describe two distinct clinical presentations; the first is of a solitary, firm, round and welldemarcated nodule measuring between 0.5cm and 3cm diameter and located within the epidermis/dermis or the subcutis. The second is of multiple, raised, firm, round and welldemarcated, white to yellow papules and nodules measuring between 0.2cm and 1.0cm in diameter and that are firmly fixed in place to the skin. In both cases the masses can be hairy, alopecic and/or ulcerated4. In the absence of a grading system, histopathologists broadly classify feline cutaneous MCTs into one of two types; mastocytic and atypical (previously called histiocytic). The more common mastocytic type is further subdivided into a well-differentiated form and a poorly differentiated (termed pleomorphic) form. In cases of well-differentiated MCTs, the cytological appearance of sheets of monomorphic, welldifferentiated mast cells makes for a straightforward diagnosis (Figure 1). However, fine needle aspirations (FNAs) from pleomorphic or atypical types will often contain poorly granulated, odd-looking mast cells, together with several other cell types, including eosinophils, plasma cells and lymphocytes, making a cytological diagnosis more challenging. ) is the most common histological type, accounting Figure 2a The well-differentiated mastocytic form ( for up to 60 per cent of all feline cutaneous MCTs5. This type is characterised by a variably well demarcated but non-encapsulated tumour, composed of sheets of cells closely resembling normal mast cells. The tumour cells do not vary much in their appearance and mitotic figures are rare. Unlike canine MCTs and other feline forms, only small numbers of eosinophils are normally seen infiltrating these tumours; aggregates of lymphocytes are far more common2,3,5. The pleomorphic (poorlydifferentiated) mastocytic form is less common, accounting for around 28 per cent of cases5. These tumours tend to infiltrate more deeply into the dermis and subcutis and are composed of pleomorphic cells with eccentric nuclei and prominent nucleoli; studies report highly variable mitotic rates. These tumours may also contain giant cells with multilobulated and/or multiple nuclei and often contain large numbers of eosinophils2,3,5,9. Atypical tumours, also called poorly granulated or histiocytic (although this term is now discouraged to avoid confusion with true histiocytic lesions), are relatively rare (10 per cent to 20 per cent) and ). are reported mainly, but not exclusively, in juvenile to middle-aged Siamese cats (Figure 3a This tumour is the most common form in cats less than four years old and has even been described in two litters of Siamese kittens aged less than six months10. The lesions are normally small and located within the deep dermis or subcutis; they may also present as multiple nodules and sometimes spontaneously regress four to 24 months after diagnosis10,11. Histologically, these 3 / 16

4 tumours contain large, polygonal to spindleshaped cells, which often have large nuclei. The mitotic rate is variable and the mass often contains large numbers of eosinophils and multiple lymphoid aggregates5. Further special stains for mast cell granules can help confirm a diagnosis of MCT, just as in dogs. The most commonly used stains are Toluidine blue, which stains the cytoplasmic granules blue, and Giemsa, which stains them purple (Figures 2c, 2d and 3b, 3c). Given the presence of mixed infiltrates of lymphocytes, eosinophils and plasma cells, together with the sometimes atypical appearance of the neoplastic mast cells, differential diagnoses may also include a mixed inflammatory lesion of some form, particularly those with a marked eosinophilic component. Immunohistochemical staining may occasionally be used to distinguish MCT from other cutaneous round cell tumours such as lymphoma, plasmacytoma or amelanotic melanoma. For example, negative staining for cell markers for T-lymphocytes and B-lymphocytes, plasma cells and melanocytes allows the exclusion of these tumours from the differential list. KIT is a cell marker that is fairly specific for mast cells and so can also potentially be used to aid diagnosis; studies report various percentages of positive KIT staining for cutaneous MCTs, from 69 per cent to 84 per cent and 93 per cent, although the study with the lowest percentage does not break them down into the different histological forms5,6,12. Although none of these studies found any correlation between KIT-positivity and histological type, the negative-staining MCTs reported were most often of the well-differentiated form5,6, when KIT-positivity is least likely to be needed from a diagnostic point of view. Interestingly, the percentage of KIT positive-staining MCTs from the spleen or intestines is much lower (35 per cent and 33 per cent, respectively)12. In terms of prognostication, the most useful indicators are the histological type and the mitotic index. In one study, the 20 per cent of MCTs that were malignant were all either pleomorphic or atypical forms of tumour5, although it should be remembered not all pleomorphic or atypical tumours are by definition malignant9. The presence of multiple tumours is also correlated with a bad outcome; 75 per cent of such cases in one study had an unfavourable outcome, as compared to 10 per cent of cases with a solitary mass5. In some of these cases, it is likely the cutaneous lesions represented metastatic spread from an internal, visceral mass. Mitotic index (MI) is another useful prognostic indicator in these tumours, especially since it is easy to perform at no additional cost to the client. Several studies show a correlation between higher mitotic rates and poor outcomes5,13, but the authors are not always eager to state a specific magic number as a cut-off point. In one paper, the authors divided the cats into two groups that were either alive or dead 24 months after the initial diagnosis. In the alive group, the MI varied from 0 to 29 per 10 HPFs, while in the dead group the range was from eight to 29. So, cats with an MI of less than eight survived, but those with an MI greater than eight could either be dead or alive after 24 months5. A later study from the same authors was more specific, stating cases with an MI greater than five per 10 HPFs had a decreased likelihood of survival, but this study mostly looked 4 / 16

5 at well-differentiated forms and a few atypical tumours, with no pleomorphic forms included13. A paper that specifically looked at 15 pleomorphic cases reported that 14 had a very low MI (often less than one per 10 HPFs), and the one case with a higher mitotic rate (one to two for every HPF) had a poor outcome9. Further prognostic tests routinely available for use in canine MCTs are starting to be researched in feline cases, but most studies are still rather small. One study looked at Ki67 and found a higher score correlated with an unfavourable outcome, but it was also correlated with the MI and so did not add much prognostic information for the clinician5. This same study also looked at KITstaining patterns, dividing cases into the three patterns originally described and used for canine MCT prognostication14 and looking for aberrant KIT-protein expression5. In terms of outcome (dead or alive after 24 months), the alive group had four cases with no KIT staining, seven cases with membraneous (normal) and seven cases with cytoplasmic (aberrant), while the dead group had five cases with cytoplasmic staining, but none with either absent or membraneous. A later study reported a correlation between cytoplasmic KIT staining and an unfavourable outcome, but it is unclear whether this adds any further useful prognostic information, since it was also correlated with an increased mitotic rate13. This study also reported mutations in the c-kit gene (exons 8, 9 and 11) were present in 56 per cent of tumours, but were not significantly related to either the protein expression pattern or to the survival outcome. Interestingly, cats sometimes had multiple nodules that had different mutation statuses, suggesting c-kit mutations may play a complex role in the development of these multiple neoplasms. Despite being the second most common type of skin tumour diagnosed in cats, feline MCTs remain little studied in comparison to their canine counterparts. The best prognostic indicators available are the clinical presentation, histological type and mitotic index (Table 1). Further and larger studies may reveal additional, useful prognostic markers, but at present there is little indication that Ki67, KIT-staining patterns or c-kit mutation status add much additional information over and above those factors mentioned previously. There is also a general lack of information regarding the significance, if any, of the anatomical location of these tumours. Maybe the arrival of the tyrosine kinase receptor inhibitors will stimulate interest in researching these feline tumours a little more in the near future? References 1. Miller M A, Nelson S L, Turk J R, Pace L W, Brown T P, Shaw D P, Fischer J R and Gosser H S (1991). Cutaneous neoplasia in 340 cats, Vet Pathol 28(5): Gross T L, Ihrke P J, Walder E J and Affolter V K (2005). Skin Diseases of the Dog and Cat (2nd edn), Blackwell Science. 3. Meuten D J (2002). Tumours in Domestic Animals (4th edn), Blackwell Publishing. 4. Litster A L and Sorenmo K U (2006). Characterisation of the signalment, clinical and survival characteristics of 41 cats with mast cell neoplasia, J Fel Med and Surg 8(3): 5 / 16

6 Sabattini S and Bettini G (2010). Prognostic value of histologic and immunohistochemical features in feline cutaneous mast cell tumors, Vet Pathol 47(4): Rodriguez-Cariño C, Fondevila D, Segalés J and Rabanal R M (2009). Expression of KIT receptor in feline cutaneous mast cell tumors, Vet Pathol 46(5): Madewell B R, Gunn C and Gribble D H (1983). Mast cell phagocytosis of red blood cells in a cat, Vet Pathol 20(5): Skeldon N C A, Gerber K L, Wilson R J and Cunnington S J (2010). Mastocytaemia in cats: prevalence, detection and quantification methods, haematological associations and potential implications in 30 cats with mast cell tumours, J Fel Med and Surg 12(12): Johnson T O, Schulman F Y, Lipscomb T P and Yantis L D (2002). Histopathology and biologic behaviour of pleomorphic cutaneous mast cell tumours in fifteen cats, Vet Pathol 39(4): Chastain C B, Turk M A and O Brien D (1988). Benign cutaneous mastocytomas in two litters of Siamese kittens, JAVMA 193(8): Wilcock B P, Yager J A and Zink M C (1986). The morphology and behaviour of feline cutaneous mastocytomas, Vet Pathol 23(3): Mallet C L, Northrup N C, Saba C F, Rodriguez C O, Rassnick K M, Gieger T L, Childress M O and Howerth E W (2012). Immunohistochemical characterisation of feline mast cell tumours, Vet Pathol 50(1): Sabattini S, Guadagni Frizzon M, Gentilini F, Turba M E, Capitani O and Bettini G (2013). Prognostic significance of Kit receptor tyrosine kinase dysregulations in feline cutaneous mast cell tumours, Vet Pathol, epub. 14. Webster J D, Yuzbasiyan Gurkan V, Miller R A, Kaneene J B and Kiupel M (2007). Cellular proliferation in canine cutaneous mast cell tumours: associations with c-kit and its role in prognostication, Vet Pathol 44(3): / 16

7 Figure 1. Fine needle aspirate from a feline cutaneous mast cell tumour. This 15-year-old, female domestic short-haired cat presented with a small skin mass on the right flank of two months duration. Cytological examination of the FNA smear revealed numerous round cells exhibiting mild to moderate variation in cell and nuclear size, with cytoplasm containing abundant, deeply staining purple granules (40 x ). 7 / 16

8 Figure 2. Feline cutaneous mast cell tumour, well-differentiated mastocytic type. Three-yearold female neutered domestic shorthaired cat with a small, slightly raised and hairless skin mass on the right thigh. (2a) Low power (10 ) and (2b) high power (40 ) views of the sheets of well-differentiated neoplastic mast cells, with mild to moderate anisokaryosis and anisocytosis, and well granulated cytoplasm. HE stain. Special stains for mast cell granules (2c) Giemsa (40 ) and (2d) Toluidine blue (40 ) confirm the presence of large numbers of positive-staining cytoplasmic granules. 8 / 16

9 Figure 2. Feline cutaneous mast cell tumour, well-differentiated mastocytic type. Three-yearold female neutered domestic shorthaired cat with a small, slightly raised and hairless skin mass on the right thigh. (2a) Low power (10 ) and (2b) high power (40 ) views of the sheets of well-differentiated neoplastic mast cells, with mild to moderate anisokaryosis and anisocytosis, and well granulated cytoplasm. HE stain. Special stains for mast cell granules (2c) Giemsa (40 ) and (2d) Toluidine blue (40 ) confirm the presence of large numbers of positive-staining cytoplasmic granules. 9 / 16

10 Figure 2. Feline cutaneous mast cell tumour, well-differentiated mastocytic type. Three-yearold female neutered domestic shorthaired cat with a small, slightly raised and hairless skin mass on the right thigh. (2a) Low power (10 ) and (2b) high power (40 ) views of the sheets of well-differentiated neoplastic mast cells, with mild to moderate anisokaryosis and anisocytosis, and well granulated cytoplasm. HE stain. Special stains for mast cell granules (2c) Giemsa (40 ) and (2d) Toluidine blue (40 ) confirm the presence of large numbers of positive-staining cytoplasmic granules. 10 / 16

11 Figure 2. Feline cutaneous mast cell tumour, well-differentiated mastocytic type. Three-yearold female neutered domestic shorthaired cat with a small, slightly raised and hairless skin 11 / 16

12 mass on the right thigh. (2a) Low power (10 ) and (2b) high power (40 ) views of the sheets of well-differentiated neoplastic mast cells, with mild to moderate anisokaryosis and anisocytosis, and well granulated cytoplasm. HE stain. Special stains for mast cell granules (2c) Giemsa (40 ) and (2d) Toluidine blue (40 ) confirm the presence of large numbers of positive-staining cytoplasmic granules. 12 / 16

13 Figure 3. Feline cutaneous mast cell tumour, atypical type. One-year-old, male, neutered Siamese cat with a mass near the base of the right ear. (3a) High power view (40 ) of the mass demonstrates variably sized and shaped neoplastic mast cells, with moderate to marked variation in nuclear size and shape, often large and prominent nucleoli and mitotic figures. The tumour also contains large numbers of eosinophils, lymphocytes and plasma cells. Special stains for mast cell granules (3b). Giemsa (40 ) and (3c). Toluidine blue (40 ) show only a small proportion of cells contain large numbers of positivestaining cytoplasmic granules. 13 / 16

14 Figure 3. Feline cutaneous mast cell tumour, atypical type. One-year-old, male, neutered Siamese cat with a mass near the base of the right ear. (3a) High power view (40 ) of the mass demonstrates variably sized and shaped neoplastic mast cells, with moderate to marked variation in nuclear size and shape, often large and prominent nucleoli and mitotic figures. The tumour also contains large numbers of eosinophils, lymphocytes and plasma cells. Special stains for mast cell granules (3b). Giemsa (40 ) and (3c). Toluidine blue (40 ) show only a small proportion of cells contain large numbers of positivestaining cytoplasmic granules. 14 / 16

15 Figure 3. Feline cutaneous mast cell tumour, atypical type. One-year-old, male, neutered Siamese cat with a mass near the base of the right ear. (3a) High power view (40 ) of the mass demonstrates variably sized and shaped neoplastic mast cells, with moderate to marked variation in nuclear size and shape, often large and prominent nucleoli and mitotic figures. The tumour also contains large numbers of eosinophils, lymphocytes and plasma cells. Special stains for mast cell granules (3b). Giemsa (40 ) and (3c). Toluidine blue (40 ) show only a small proportion of cells contain large numbers of positivestaining cytoplasmic granules. 15 / 16

16 TABLE 1. When to worry 16 / 16 Powered by TCPDF (