Mast cell tumours made easy

Transcription

1 Mast cell tumours made easy Canine mast cell tumours Mast cell tumours (MCTs) make up 16-21% of all skin tumours, with predisposition reported in the bulldog, Boston terrier, boxer, pug, Australian cattle dog, Labrador retriever, golden retriever, Rhodesian ridgeback, schnauzer, cocker spaniel, fox terrier, Staffordshire bull terrier, beagle, Weimaraner, and Shar Pei. Those of bull dog ancestry, and pugs, seem to bear less aggressive forms, whereas Shar Pei seem to develop very aggressive MCTs. Specific genetic risk factors are the subject of intense research, but none are proved at present, with some MCTs associated with chronic inflammation/irritation. Non-germline, somatic mutations in KIT, the receptor for a growth factor called stem cell factor, are reported in up to 50% of aggressive MCTs. Diagnosis Although a protruding, rubbery, hairless mass is classical, there is no pathognomonic appearance, and MCTs can be mistaken for other tumours, especially subcutaneous MCTs feeling like lipomas on physical examination, underlining the utility of cytology. Signs of aggressiveness which might guide how comprehensive investigation and/or treatment should be include a large size, rapid growth, localised irritation, oedema, ulceration, lack of demarcation from surrounding tissues, satellite lesions, and a Darier s sign of increasing and decreasing size, due to the effects of degranulation. Other negative signs include lymph node enlargement, some locations (nail bed, oral, mucocutaneous junction, scrotal, mucosal (except conjunctiva); less so inguinal, muzzle, perineal), and if the MCT is a recurrence. Paraneoplastic signs are negative indicators and include inappetence, vomition, ulceration, diarrhoea, melaena, coagulopathy, cutaneous flushing, and anaphylactoid reactions. Up to 25% of patients have multiple MCTs. Clinical approach In addition to physical examination, cytology is the minimum for diagnosis of MCT. Fine needle aspiration cytology is accurate in up to 96% of cases, but Diff Quik-stained samples might not yield the diagnosis, even with an altered staining protocol. Giemsa staining is superior, and for anaplastic or degranulated MCTs, (immuno)histo/cytochemistry can be useful (e.g. toluidine blue metachromatic staining, tryptase staining, KIT staining). Ideally, additional testing would include haematology, biochemistry, urinalysis and an assessment of likely draining lymph nodes. Even if coagulation assays are normal, localised coagulopathy can be problematic. Histopathological grading (see below) is the most consistently accurate prognostic indicator, and although morphological criteria are part of grading, cytological grading is not possible, even though some cellular features of poor differentiation can be recognised cytologically. Staging Stage 0 One tumour incompletely excised from the dermis, identified histologically, without regional lymph node involvement

2 Stage I Stage II Stage III Stage IV Substage A Substage B One tumour confined to the dermis, without regional lymph node involvement One tumour, confined to the dermis, with regional lymph node involvement Multiple dermal tumours; large infiltrating tumours, with or without lymph node involvement Any tumour with distant metastases or recurrence with metastases (including blood or bone marrow involvement) Systemic signs absent Systemic signs present Staging is prognostically significant with both stage 0 and I having a better prognosis than more advanced stages. However, with many surveys demonstrating the lack of significance of multiple MCTs, some elements of the staging scheme are highly questionable. Thorough staging includes aspiration of any enlarged lymph nodes, and the likely sentinel lymph nodes even if not enlarged, abdominal imaging, fine needle aspiration of any abnormal organs and of ultrasonographically unremarkable liver and spleen, imaging of the primary mass to better assess invasiveness, thoracic imaging, and bone marrow aspiration. However, such thorough staging is rarely warranted. Less than 3% of cases have bone marrow involvement, and thoracic imaging more commonly reveals comorbidities, although these can be important in their own right and impact therapeutic decision making. There is little consensus on the criteria by which metastatic lymph nodes can be identified cytologically, although bizarre, clustered and proliferative mast cells are more consistent with metastasis. If there are no negative historical or physical signs and the MCT is in a location in which surgical closure is easily achieved, operating first is perfectly acceptable with retrospective staging as necessary, such as if a poorly differentiated, invasive, or highly proliferative primary mass is revealed, or if the first attempt at excision is incomplete. Standard pre-operative staging would be appropriate if some of the previously mentioned negative prognostic indicators were identified initially. In addition to standard staging tests, in demanding surgical cases in which the local anatomy is limiting, such as those involving the distal limb, an initial incisional biopsy can guide later excisional surgical planning, as a well-differentiated MCT might be expected to be likely to be completely excised with a more conservative lateral margin of surrounding grossly normal tissue compared to a poorly-differentiated MCT. Such initial grading can also influence non-surgical therapy including chemotherapy and receptor tyrosine kinase inhibitor (RTKi) therapy. Treatment Surgery is the most effective treatment modality, and also yields material for histopathological grading, the most reliable prognostic indicator. Less than 10% of well-differentiated MCTs will metastasise, compared to at least up 96% of poorly-differentiated MCTs and approximately 20% of

3 intermediately-differentiated MCTs. Up to 11% of tumours develop recurrence after complete excision is reported. At least a substantial minority of incompletely excised MCTs develop recurrence, with the lowest recurrence rate for intermediately-differentiated MCTS being 23%. Presumably pathologists comments of neoplastic mast cells being present at the margin increases the risk of recurrence. Artefactual changes occur during formalin fixation, but a lateral margin beyond 2cm seems unnecessary for intermediately-differentiated MCTs, with a deep margin or at least 4mm, and preferably at least one uninvolved fascial plane. Where reconstructive surgery is not thought likely to be successful, options include radical surgery (e.g. amputation), sole radiation therapy (perhaps followed by surgery), sole systemic therapy (perhaps followed by surgery), surgery to attain stage 0 followed by systemic therapy, however, the option most robustly supported by the literature is surgery to attain stage 0 followed by radiation therapy. Following unexpectedly incomplete initial surgery, if the incompletely excised mass in question is well- to intermediately- differentiated and has no other risk factors, the preferred option is re-excise if possible, or post-operative radiation therapy. A less well-supported option is systemic therapy. Following unexpectedly incomplete initial surgery, if the incompletely excised mass in question is poorly-differentiated or has negative risk factors, the preferred option is re-excise if possible, or post-operative radiation therapy, however high risk MCTs warrant systemic therapy regardless of the local treatments used. If radiation therapy is chosen, irradiation of local lymph nodes has been shown to be beneficial in selected surveys. Radiation therapy can be used as sole therapy (half of patients maintain their response at 12 month following irradiation), or in combination with several systemic therapies, however, the best results tend to occur when surgery results (intentionally or otherwise) in stage 0 microscopic disease which is then treated with radiation therapy. Where possible, it is best to keep radiation therapy in mind, even if surgery seems to offer a likely complete excision. Metal clips can be placed during surgery to better define the necessary radiation field if surgery is not curative. The use of grafts for wound reconstruction minimises the size of the radiation field compared to advancement flaps, however, a conservative surgery which will predictably result in stage 0 disease might progress to radiation therapy more promptly than an ambitious surgery which fails to achieve complete excision and is prone to wound healing complications. The 2 year progression-free interval with radiation therapy after incomplete surgery of intermediately-differentiated MCTs us 95%, and with lymph node involvement, incompletely resected well- and intermediately-differentiated MCT-bearing patients have a median progression-free interval of 40 months following surgery and subsequent radiation therapy. Chemotherapy is beneficial for disseminated, poorly-differentiated, or non-resectable MCTs or following incomplete excision where radiation therapy is not entertained. Presurgical/neoadjuvant steroids/chemotherapy reduces the risk of degranulation. Neoadjuvant prednisolone (1-2.2 mg/kg p/o q24h x 10d) had been reported to reduce the size of MCTs in 71% of cases and make surgery possible where the local anatomy was previously limiting based on the pre-treatment size of the MCT. However, this study reported a relatively high recurrence rate and the impact of steroids on the reliability of grading and other histopathological findings is unknown.

4 High risk MCT-bearing dogs following surgery and a 12 week protocol of vinblastine and prednisolone had a 2 year survival rate of 70% and a median survival time of 3¾ years. Vinblastine & prednisolone-based protocols result in 47% measurable responses with toxicity in 6-20% of cases. Lomustine produces measurable responses in 44% of cases. Combinations of vinblastine, prednisolone and lomustine shrink 57-65% of tumours, although with toxicity in 54% of cases. Other combinations include vinblastine, cyclophosphamide, prednisolone with a 64% response rate. Other oral protocols include chlorambucil (5 mg/m 2 p/o q48h) and prednisolone (40 mg/m 2 p/o q48h x 14 days, then 20 mg/m 2 ) which resulted in a 38% response rate with reportedly no toxicity; and hydroxyurea shrank 28% of heavily pre-treated MCTs. The evidence base for chemotherapy for stage 0 disease instead of radiation therapy is weaker than the multitude of studies on the use of radiation therapy in this setting, however, the recurrence rates are comparable and chemotherapy can combat disseminating disease, whereas radiation therapy is a purely local treatment. Receptor tyrosine kinase inhibitors currently licensed for therapy of gross intermediately- or poorlydifferentiated MCTs include masitinib and toceranib, in both cases with tumours bearing KIT mutations tending to respond better, although the absence of such mutations does not preclude a response. Toceranib induced responses in 43% of dogs for a median of 18 weeks, with an additional 18% of dogs enjoying stable disease for a median of 12 weeks. Toceranib side effects include leukopenia and muscle pain, but most commonly are gastrointestinal in nature and warrant early intervention, however, overall, quality of life was improved in responding dogs and not impaired in non-responders. There is some evidence that doses lower than that licensed (3.25 mg/kg p/o q48h) can be effective or when given 3 times a week. Masitinib studies have focussed more on time to progression with 40% reaching 2 years without progression, compared to 15% of patients receiving placebo. Gastrointetsinal side effects are quite common on masitinib, but are usually mild, and there is a small risk of proteinuria or haemolysis. There are emerging reports of combination of chemotherapeutics and RTKi (vinblastine and toceranib produces responses in 71% of cases), sometimes with additional radiation therapy (response rate of 76%). As yet there are no data on the response of microscopic disease to RTKis. Supportive care in patients with paraneoplastic signs or those at risk of such signs on treatment include blockade of histamine H1 receptors (chlorpheniramine, diphenhydramine), H2 receptor blockers (ranitidine, famotidine) or stronger acid inhibitors (omeprazole), and gastroprotectants (sucralfate). Prognosis Although inter-pathologist variation can be great, histopathological grading is the most reliable prognostic indicator reported, with most surveys adopting the Patnaik grading scheme. A newer grading scheme has recently been published with more prescriptive criteria (enlarged nuclei or in ten 400x fields thresholds of 7 mitotic figures, 3 multinucleated cells, or 3 bizarre nuclei) which based on initial data seem better at predicting survival but has not been widely compared to standard grading. As mentioned above, certain elements of staging such as lymph node involvement are important even in poorly-differentiated tumours. Visceral/marrow involvement is often dire, but subcutaneous MCTs might be better than dermal MCTs and certainly no worse (separate prognostic

5 factors for subcutaneous masses include a mitotic index >4, an invasive growth pattern, and multinucleation). Mast cells are generally regarded as terminally differentiated cells, so proliferating cells are very likely to be abnormal and various proliferative indices have been reported to be prognostically significant including Mitotic index, Ki-67, MCM7, AgNOR and PCNA, however, the impact of these findings on therapeutic decision making has not been as robustly proven. MCTs which had a KIT mutation or cytoplasmic immunohistochemical pattern were more likely to recur, disseminate or lead to death of the patient, and those with mutated KIT showed a trend towards longer survival when treated with chemotherapy. For any MCTs, after completion of planned therapy, routine monitoring with at least physical examination (and with high risk MCTs possible abdominal ultrasonography with/out cytological sampling) is recommended q3 months for at least a year and q6 months thereafter.