Signalment

6-month-old entire male boxer dog.

Presenting signs

A rapidly enlarging mass on the skin of his left cheek.

Case history

The relevant history in this case was:

Clinical examination

On examination he was very bright and alert. Dermatological examination revealed a firm, raised, reddened, dome-like lesion on the left cheek measuring 1.5 cm in diameter. The mass did not appear to be painful or to be causing him to be pruritic and there was no enlargement of the sub-mandibular lymph node (Fig. 15.1).

Figure 15.1 Case 15.1 The appearance of the mass at initial presentation.

Courtesy of Professor Dick White, Dick White Referrals

Diagnostic evaluation

A fine needle aspirate of the mass was obtained and this revealed clusters of medium-sized round cells (slightly larger than neutrophils) with an obvious pale blue cytoplasm and a low nuclear : cytoplasmic ratio, round to oval nuclei with a finely stippled chromatin pattern. Some nuclei contained nucleoli but this was not a consistent feature in all cells.

Diagnosis

Treatment

In the light of the diagnosis and the potential for natural resolution, no further treatment was undertaken, but the dog was examined at 7-day intervals to ensure that there was not continual tumour growth. Although the tumour did grow a little more to approximately 2.0 cm in diameter, after 5 weeks the tumour appeared to be shrinking and within 2 further weeks the tumour had resolved completely.

Outcome

No further tumours were seen on the dog.

Theory refresher

Histiocytomas are benign tumours that are almost always seen on the skin of young dogs, especially between 1 and 2 years of age, although they can develop at any point in a dog’s life. In a recent UK survey of insured animals, canine cutaneous histiocytoma was the most common single tumour type reported, with a standardized incidence rate of 337 per 100 000 dogs per year. In other publications, histiocytomas account for approximately 12% of all skin tumours in the dog and are therefore considered to be common throughout the world but they are rarely seen in the cat. There appears to be no gender predisposition but Scottish terriers, boxers, dobermans, Labradors and cocker spaniels have been reported to have a higher incidence than other breeds. They usually present as solitary lesions, more commonly on the head and neck, but they can also very occasionally occur in multiple locations. They appear as raised, often erythematous, initially smooth, dome-like mass lesions that grow rapidly and they can become ulcerated. They are histologically fascinating, as under a microscope they often appear to a non-veterinary pathologist to be a high-grade, malignant neoplasm and yet they are benign and many, as in this case, will spontaneously regress. Fine needle aspiration therefore is always a sensible recommendation, as this is an easy cytological diagnosis and although many histiocytomas do require surgical excision, a large number can be treated conservatively without concern. If the mass is not ulcerated then recommending regular re-examination and no further treatment is usually best. However, if the mass becomes ulcerated, if the dog is troubled by the tumour, or if the cytology is uncertain then surgical excision is to be recommended. Surgical removal, when undertaken, is by simple cutaneous excision and routine closure. Cryosurgery has also been reported to give good results. The prognosis therefore for cutaneous histiocytomas is usually excellent.

Cutaneous histiocytosis is similar in some ways to histiocytoma, in that this condition is caused by collections of proliferating histiocytes resulting in the development of multiple nodules and plaques affecting the head and face, trunk and limbs and also possibly erythema, swelling and depigmentation of the nasal planum or nares. It too is seen in young dogs but a recent study suggested that the mean age of occurrence was 4 years of age (i.e. slightly older than the peak age of occurrence for cutaneous histiocytomas). Cutaneous histiocytosis is also a benign condition but it naturally regresses less commonly than cutaneous histiocytoma and so many cases require treatment in the form of immunosuppression, with prednisolone being the most commonly used first-line treatment and drugs such as azathioprine or cyclosporine being reserved for persistent cases. There is also evidence to suggest that a combination of tetracycline and niacinamide may be effective in some cases, along with vitamin E and essential fatty acid supplementation. Some dogs do require long-term treatment, and recurrence appears to be significantly more likely in dogs with nasal planum or nares lesions than dogs without lesions in these locations.

Systemic histiocytosis is a variant on cutaneous histiocytosis, in which aggregations of benign proliferating histiocytes occur resulting in dermatological lesions as previously described but in systemic histiocytosis there is systemic involvement with nodular lesions developing in internal organs. It is therefore considered that systemic histiocytosis and cutaneous histiocytosis represent two different clinical manifestations of similar reactive proliferative dermal dendritic cells with different predilection sites and as such they are often grouped together as ‘reactive histiocytosis’. The reported target sites for systemic histiocytosis include the liver, the spleen, the lungs, lymph nodes, bone marrow and ocular tissues. Clinically the patients with this form of the disease are usually middle-aged and present with nodular or plaque-like skin lesions but with accompanying non-specific signs such as lethargy and inappetance. The clinical examination findings will vary depending on the organs affected. The diagnosis is made by histopathology. The clinical lesions can wax and wane but spontaneous recovery is not common, hence treatment with immuno suppressives is usually required. Interestingly, some studies suggest that the response of systemic histiocytosis to corticosteroids alone is variable but the response is more consistent using drugs such a cyclosporine and luflenomide.

Disseminated histiocytic sarcoma (previously known as malignant histiocytosis), is a serious malignant neoplasm which, despite the similarity in the name to the three conditions described above, has a significantly different presentation and prognosis. The disease was first reported in Bernese mountain dogs but there also appears to be breed predispositions in the flat-coated retriever and the rottweiler and it has been reported to occur in other breeds. The initial clinical presentation varies depending upon whether the disease is localized to one organ (solitary histiocytic sarcoma) or whether it has disseminated widely through the body (disseminated histiocytic sarcoma, or malignant histiocytosis), but in general the signs can be quite non-specific (e.g. lethargy, inappetance, weight loss, vomiting, diarrhoea or coughing). Clinical examination can reveal lymphadenopathy and organomegaly whilst clinical pathological testing can reveal anaemia (often regenerative in nature), thrombocytopaenia, elevations in hepatobiliary markers and hypoalbuminaemia. Diagnosis is based on histopathology (including on bone marrow biopsies). In the disseminated form of the disease, the condition can progress extremely rapidly and is invariably fatal, with mean survival times of approximately 3 months being reported. The response to chemotherapy is generally not good, although one report describes the use of Lomustine with some limited success. Solitary histiocytic sarcomas require surgical excision but the time to recurrence is often short and the prognosis guarded.

Signalment

10-year-old neutered female golden retriever.

Presenting signs

A non-healing ulcer at the base of her tail.

Case history

The relevant history in this case was:

Clinical examination

The tail was clipped and cleaned to reveal a large, raised ulcerated lesion as shown in Figure 15.2. No other masses were palpable and no other abnormalities were noted.

Figure 15.2 Case 15.2 The appearance of the lesion at the base of the tail after it had been clipped

Diagnostic evaluation

Fine needle aspirates and impression smears were obtained from the mass. These revealed large numbers of medium to large round cells with an obvious granular cytoplasm, the granules staining purple-red under Giemsa staining. The cells had large nuclei with obvious nucleoli. Some of the cells had fractured in the preparation and there were many granules obvious extracellularly.

Diagnosis

Treatment

In the light of the location of the tumour, surgical excision was thought to be the most appropriate first-line treatment with a view to submitting the mass for histopathology for grading. The mass was excised with lateral margins of 2 cm and a deep margin of one fascial plane, as shown in Figures 15.3 and 15.4.

Figure 15.3 Case 15.2 The use of a surgical marker pen to draw where the incisions will be to achieve a 2-cm lateral margin

Figure 15.4 Case 15.2 The tail after the mass has been excised as described and the surgeon is now measuring the size of the flap required to repair the deficit

The deficit then required closure, which was achieved with a rotation flap, as shown in Figures 15.5–15.7. The reason a rotation flap was used is that this avoids tension at the surgical repair site which is especially important in an area of skin that is hard to immobilize. Attempting simple appositional closure at this site would have inevitably led to postoperative dehiscence and the need for more complicated reconstructive surgery.

Figure 15.5 Case 15.2 A skin flap the width of the deficit that requires closure is made utilizing skin from the lateral aspect of the right thigh

Figure 15.6 Case 15.2 The skin flap is rotated into place to repair the tail wound and stapled routinely

Figure 15.7 Case 15.2 The deficit over the right thigh is then closed, making every effort to avoid wound tension

Outcome

The histopathology returned to confirm the tumour to be a grade II mast cell tumour with complete surgical margins in all planes, so no further treatment was recommended.

Theory refresher

Mast cells are inflammatory leucocytes located within the dermis and subcutis that play an important role in allergic responses, wound healing and in acute and chronic inflammatory responses. As such, mast cells contain a number of different inflammatory mediators including histamine, heparin and the proteases tryptase and chymase which explains why some mast cell tumours cause a local inflammatory reaction around themselves and also why there is the potential for mast cell tumours to cause paraneoplastic problems such as gastric ulceration via parietal cell stimulation. Mast cell tumours (MCT) are common, being cited as the most frequently diagnosed cutaneous tumour of the dog and the second most frequently diagnosed cutaneous tumour in cats. In dogs, MCTs account for approximately 20% of all cutaneous tumours and there is a predilection for the disease in some breeds, such as boxers, bulldogs, Staffordshire bull terriers, Boston terriers, Rhodesian ridgebacks, pugs, weimaraners, Labrador retrievers, beagles and golden retrievers, thereby implying a genetic component to the aetiology of the disease. In cats, the Siamese seems over-represented in the incidence reports.

MCTs are a heterogeneous group of lesions, in that they have a variety of different presentations and that their behaviour can vary markedly from animal to animal and also from tumour to tumour. They can look like a well-circumscribed nodule that may or may not be erythematous or alopecic (Fig. 15.8). They can also arise from lesions that have been present for significantly long periods of time, initially appearing like a mass which should cause no concern for many months or even years. In addition, as well as solid cutaneous masses, MCTs can also present as soft, fluctuant subcutaneous lesions that may be initially misdiagnosed on palpation as a lipoma (Fig. 15.9). More aggressive MCTs, however, can develop rapidly into large, ulcerated, exudative lesions which may cause considerable morbidity for the patient.

Figure 15.8 Case 15.2 A small, well-demarcated skin lesion that was firm to touch. Fine needle aspiration revealed the mass to be mast cell tumour

Figure 15.9 A soft, fluctuant swelling on the carpus of a 2-year-old English bull terrier, fine needle aspiration of which revealed the mass to be a mast cell tumour. The dog was treated with 7 days of prednisolone to reduce the size of the mass and then taken to surgery for excision. However, at surgery it was not possible to remove the entire tumour despite the cytoreductive steroidal therapy. Histopathology was suggestive of an intermediate grade tumour so postoperatively he was treated with hypofractionated external beam radiotherapy

It is primarily because of this variation in appearance and the propensity of MCTs to mimic the appearance of other different cutaneous tumours that the authors have to recommend that all cutaneous masses undergo fine needle aspiration prior to any surgical excision being attempted. This argument is made stronger by the fact that mast cells are usually easily identified by cytology; MCTs often exfoliate large numbers of individual round cells that have round nuclei which often seem pale in appearance compared to the cytoplasm. The cytoplasm itself usually contains large numbers of granules that stain purple-red when using a Wright-Giemsa preparation and frequently the cells will have granules scattered in the space around them from other mast cells that were shattered in the process of obtaining the aspirate and forming the smears (see Fig. 15.10). Diff-Quick can be used and will also usually show the presence of the granules but sometimes Diff-Quick will not reveal the presence of the granules as well as a Giemsa stain, so it is recommended that Romanowski stains are used for this cytology whenever possible.

Figure 15.10 A fine needle aspirate from a high-grade mast cell tumour, illustrating the individual round cells and their highly granular cytoplasm with the magenta coloured granules characteristic of mast cells. Preparation stained with Wright-Giemsa stain and viewed at ×100 magnification.

Courtesy of Mrs Elizabeth Villiers, Dick White Referrals

The one drawback of cytology is that it cannot accurately determine the grade of the tumour, so this is a useful technique simply to identify the tumour preoperatively. Tumour grading can only be done by histopathology and generates three possible outcomes; grade I (well differentiated), grade II (intermediately differentiated) and grade III (poorly differentiated). Tumour grading is important, as it is the strongest indicator yet available as to the tumour’s behaviour; the median survival times of dogs with grades I and II tumours were reported to be in excess of 1300 days in one study in comparison with 278 days for dogs with grade III tumours.

Once a MCT has been identified, all thoughts turn to treatment but it is important to remember that all MCTs have a metastatic potential and that whilst some will be essentially benign, some will be highly malignant and most fall somewhere between these two extremes. There is also some variation in behaviour between breeds; although boxers, bulldogs and pugs are very prone to developing MCTs they frequently behave less aggressively in these breeds. Overall, however, there have been many studies assessing the behaviour of MCTs and their response to treatment to establish the optimal way to approach this disease. One clear principle emerges: the best first-line treatment for MCTs is surgical excision if at all possible. Although there are difficulties and inconsistencies, both with the histological grading systems that are generally utilized and between different pathologists, it appears that well-differentiated tumours (grade I) are best managed by local excision alone and intermediately differentiated tumours (grade II) should be managed by local excision with 2-cm lateral margins and a deep margin of one facial plane. Whilst poorly differentiated, grade III tumours still require surgery as a first-line treatment, adjunctive therapy should usually be considered postoperatively but which adjunctive treatment to use is also subject to debate. The concern with grade III MCTs is that they have a higher metastasis rate and lower survival times after surgery alone when compared to dogs with grade I or II tumours so further treatment is sensible to help remove any metastasizing cells or secondary tumours. The problem comes in that no large scale studies have been published to indicate which is the most effective chemotherapeutic approach to take in these cases. However, there are three approaches the medical author (RF) usually uses in cases that require chemotherapy:

A fourth, new approach lies in the recent development of the tyrosine kinase inhibitor, masitinib, for veterinary medicine. Tyrosine kinase is known to play a critical role in the development of canine MCT and masitinib blocks the KIT receptor on this enzyme and has now been shown to be safe and effective in delaying tumour progression in dogs with non-resectable grade II or III tumours.

In general therefore, the authors will recommend chemotherapy for all cases with grade III tumours or possibly as palliative treatment for cases with non-resectable grade II tumours and would utilize masitinib first, then either prednisolone and vinblastine, or chlorambucil and prednisolone, depending on the individual animal’s situation, and reserve Lomustine for cases that do not respond to either of the first three options.

Radiotherapy has also been cited as a useful treatment in canine MCT and has generally been reported as adjunctive therapy to incompletely excised grade II tumours, with up to 97% 1-year survival rates being reported. It can also be useful as a cytoreductive treatment to be used before surgery in very large tumours or those that may prove to be difficult to resect, using the radiation to shrink the tumour mass to facilitate easier or more complete excision. However, there is a concern that irradiating the large number of mast cells present in a gross tumour mass may precipitate substantial histamine release resulting in paraneoplastic problems such as gastro-duodenal ulceration and more concerningly, a hypotensive crisis. Therefore it is usual for up to 14 days of prednisolone +/− vinblastine to be given before the radiotherapy to help prevent these difficulties.

The use of deionized water to treat incompletely excised tumours has been reported in the literature, based on the rationale that mast cells are highly sensitive to hypotonic shock. Its usefulness is still unclear, as although after the initial reports of the technique were encouraging, one study showed it generated no benefits at all. However, a more recent study in The Netherlands suggested it may be an efficacious technique, so further work is required to clarify whether this technique has any merit. However, at this time the authors do not recommend its use.

The clinical approach to MCT cases, therefore, must be to firstly make an accurate diagnosis using cytology whenever possible and the authors highly recommend undertaking fine needle aspirates of any cutaneous mass before considering surgical excision in an attempt to establish the diagnosis. Once this has been done, the draining lymph nodes must be carefully palpated and if enlarged, they must be aspirated too. Abdominal ultrasound should be undertaken, as if there is a malignant potential for the tumour then secondary disease in the abdominal lymph nodes, liver or spleen is possible and this should be assessed before the primary tumour is excised. Pulmonary metastasis with MCTs is very unusual but thoracic radiographs should be considered as well. If there are considerable cost restrictions, as the majority of cases will be grade I and II with a lower metastatic potential than a grade III tumour, it is not unreasonable to simply undertake a good surgical excision once the aspirates have confirmed the mass to be an MCT (2-cm lateral margins and one fascial plane deep if possible) and submit the tissue for histopathology. The exceptions to this are MCTs found on the subungual area (the nail bed) and on mucocutaneous junctions, as tumours in these regions frequently behave aggressively and full staging before surgery is necessary. If after the histopathology the tumour is shown to be grade III, then postoperative staging is also essential.

Examination of the buffy coat is not considered necessary by the authors in canine cases, as systemic mastocytosis is rare in the dog and therefore this test is rarely of diagnostic use unless a complete blood count indicates bone marrow pathology. Likewise, MCT metastasis to the lungs is unusual, so thoracic radiographs should only be considered if there is evidence suggestive of pulmonary disease on the clinical examination (i.e. tachypnoea, dyspnoea, cyanosis despite normal lung sounds, coughing, dull areas on thoracic percussion, etc.).

Although currently the histological grade is the strongest predictor of MCT behaviour, there are some newer tests that are likely to become more commonplace to help assess how aggressive an MCT may be. Ki-67 is an antigen expressed during the cell cycle and appears to be strongly associated with the prognosis of MCTs in a manner that is independent of the histological grade. The immunohistochemical quantification of Ki-67 is an important tool in our assessment of MCTs and is worth requesting to be assessed in cases where either the pathologist is unable to be certain as to the grading, or if there is a clinical suspicion that the tumour may be behaving aggressively (e.g. rapid development of lesion, location on a mucocutaneous junction). Likewise, KIT is a stem cell factor receptor that activates tyrosine kinase usually located on the cell membrane but many MCTs express the receptor within the cytoplasm, indicating a mutation in the proto-oncogene c-kit which encodes for KIT. Assessment for aberrant cytoplasmic KIT may also be a helpful marker to predict MCT behaviour.

A common problem following MCT excision is to find that the tumour was a grade II but that the margins are dirty. In this situation there are three main options:

Multiple MCTs produce a unique challenge, as traditionally, dogs with multiple MCTs are classified as having advanced disease because, by the WHO assessment, they have stage III disease (as if they had gross metastases). However, this does not appear to be clinically accurate, as each tumour needs to be assessed individually and in this situation the WHO grading system is not useful. Dogs with multiple MCTs do justify careful clinical staging with lymph node palpation and aspiration if appropriate, abdominal ultrasound and thoracic radiography before surgical excision and submission of all the tumours for grading. The treatment that needs to be undertaken is surgical excision of all the lesions individually if at all possible. If all the tumours are grade I or II and the surgery was carried out well, then the authors would not routinely recommend adjunctive therapy in these cases.