Practical Oncology Mast Cell Tumor

1. Practical OncologyMast Cell Tumor Wendy Blount, DVM

2. Mast Cell Tumor • Mast cell granules contain histamine and heparin, among other things • Degranulation is largely responsible for symptoms • Release of histamine • Increased gastrin secretion (anorexia, ulcers, hematemesis) • Anaphylactoid reaction • Release of heparin – less clinically significant

3. Mast Cell Tumor • Most often found on the skin • Most common skin tumor in the dog • Brachycephalics & retrievers predisposed • 2nd most common cancer in dogs • Also visceral & elsewhere • Gastrointestinal, Spleen, bone marrow • Less common sites • Oropharyngeal • Mediastinum • CNS • Nail bed, ocular & periocular

4. Mast Cell Tumor • Can have many different appearances • Can be infiltrated with fat • Symptoms can be waxing and waning • Tumor gets bigger and smaller over time • 5-15% have multiple masses at presentation • 20-50% will have more MCT in the future, even if the first are cured

5. Etiology • Allergic skin disease? • C-KIT mutation (aka SCFR, CD117) • In “high risk MCT” (high grade II & all grade III) • These have decreased survival time • can be treated with tyrosine kinase inhibitors (Palladia & Kinavet-CA1 ) • SCFR – stem cell factor receptor • C-KIT normally regulates proliferation, migration and differentiation • When C-KIT is mutated, it is constantly turned on, dysregulating cell growth an promoting malignancy

6. Clinical Signs • GI Signs • Anorexia, vomiting, melena • Pruritus and skin flushing • Facial swelling • Weakness, lethargy • Delayed wound healing • Darier’s Sign • swollen, itchy, red skin after scratching or stroking the skin

7. Clinical Signs • GI Signs • Anorexia, vomiting, melena • Pruritus and skin flushing • Facial swelling • Weakness, lethargy • Delayed wound healing • Darier’s Sign • swollen, itchy, red skin after scratching or stroking the skin

8. Staging for Metastasis Eva Gerome Bonham TX Chris Longo – Diamondhead, MS Melanie Enger, - Lufkin TX

9. Diagnosis • FNA Cytology often diagnostic • Round cells with or without granules • Granules intracellular or in background • Granules form a halo around the relatively pale nucleus • eosinophils • Give diphenhydramine before or right after aspiration • FNA can cause degranulation • Dexamethasone as well if mass is visibly inflamed

10. Diagnosis • FNA Cytology often diagnostic • Round cells with or without granules • Granules intracellular or in background • eosinophils • Give diphenhydramine before or right after aspiration • FNA can cause degranulation • Dexamethasone as well if mass is visibly inflamed

11. Diagnosis • FNA Cytology often diagnostic • Round cells with or without granules • Granules intracellular or in background • eosinophils • Give diphenhydramine before or right after aspiration • FNA can cause degranulation • Dexamethasone as well if mass is visibly inflamed

12. Diagnosis • FNA Cytology often diagnostic • Round cells with or without granules • Granules intracellular or in background • eosinophils • Give diphenhydramine before or right after aspiration • FNA can cause degranulation • Dexamethasone as well if mass is visibly inflamed

13. Diagnosis • FNA Cytology often diagnostic • Round cells with or without granules • Granules intracellular or in background • eosinophils • Give diphenhydramine before or right after aspiration • FNA can cause degranulation • Dexamethasone as well if mass is visibly inflamed

14. Staging for Metastasis • Histopathology for grading • Excisional if resectable • Incisional if not • FNA draining lymph node • Clusters of mast cells likely metastasis • Single mast cells likely not • Abdominal US with FNA liver and spleen • CBC, panel, buffy coat

15. Staging for Metastasis • Non-resectable MCT

16. Staging for Metastasis • Non-resectable MCT

17. Staging for Metastasis • Non-resectable MCT

18. Staging for Metastasis • Lymph node cytologies

19. Staging for Metastasis • Lymph node cytologies

20. Staging for Metastasis • Lymph node cytologies

21. Tumor Stage (WHO) • Stage 0 – microscopic disease only • Stage I – tumor confined to the dermis • Stage II – tumor does not infiltrate subcutaneous tissues, lymph node metastasis • Stage III – large, infiltrating tumor or multiple tumors • Stage IV – distant metastasis Consideration is being given to reducing stage of multiple dermal tumors

22. Histopathology • grade • Mitotic Index (MI) • Surgical margins – clean, narrow or dirty • Invasiveness – dermal or invasive (subcutaneous/muscle) Histopathology tells a great deal about prognosis and treatment indicated

23. Histopathologic Grading • Grade I – well differentiated, behaves benignly • Grade II – intermediate differentiation, behavior is widely variable • Low grade II – often behaves benignly • High grade II – C-kit mutation, often behaves malignantly • Determined by MSU prognostic panel (form) • Grade III – anaplastic, aggressive behavior This is the Patnaik System Obsolete system has grade I the worst and grade III the best prognosis

24. Surgery • Mainstay of low grade MCT treatment • Mast Cell Tumors often extend well beyond the visible mass • Diagnose by FNA before you excise • Lateral margins 2-3 cm beyond visible mass • Small tumors <1 cm, 1.5-2cm margins may be adequate • One fascia layer deep to visible mass • Avoid manipulating the tumor • Intraoperative cytologies on 4 lateral and deep margins can be helpful

25. Surgery Prednisone for pre-surgical cytoreduction • Out of favor by oncologists at this time • I still like use it • Stabilizes lysosomal membranes – may prevent degranulation caused by surgery • Controls inflammation around the tumor so tumor borders are easier to see • Usually makes the dog feel better, so client perceives better toleration of surgery • Prednisone 40 mg/m2 PO SID x 7days, then QOD

26. Surgery Re-excision where borders are dirty on grade I or II • Grade III tumors considered systemic • More surgery only for local palliation • 3 cm beyond original surgery • One fascia layer deeper than original surgery • Complete resection results in long survival • If clean borders, 95% cured with second excision, using these rules

27. Surgery NeoAdjuvant Therapy • Given to a patient with non-resectable tumor in hopes of making it resectable • Chemotherapy and/or radiation • Best managed by medical and/or radiation oncologists • Need to understand effects of neoadjuvant therapy on healing and when and how to do surgery

28. Sandra Goodwin – Forney TX Sandra Goodwin’s Compadre Betsy Hoffman Robinson – League City TX

29. Chemotherapy • Not indicated for multiple dermal MCT that are cured by excision • To deal with MCT at the tumor borders when radiation not possible • To improve post-surgical prognosis for high risk grade II and all grade III MCT • To palliate metastatic or systemic disease • Surprisingly, there are few studies to evaluate efficacy of various protocols

30. Chemotherapy Vinblastine and prednisone (VP) • Median survival 134 days (5 months) – gross disease after surgery • Median survival 1013 days (3 years) – microscopic disease after surgery • 45% survival at 2 years • Half of these had surgery prior to chemo • This has not been my experience with grade III • Most dead in 2-4 months • All gone within the year • Vinblastine 2-2.2 mg/m2 IV over 10 min once weekly for 4 weeks, then every other week for 4 doses • Prednisone 40 mg/m2 PO SID x 2 weeks then QOD

31. Chemotherapy CCNU • 60-70 mg/m2 PO q3-4 weeks • 4 week interval the first time, then shorten if symptoms return during the 4th week • Baseline liver tests (ALT, SAP, albumin) • Pretreat with diphenhydramine • Check before 3rd dose and then prior to each • Stop if signs of liver disease to prevent liver failure • 6-8 doses common maximum • I have reached 12 at most • Grade III median survival 2 months

32. Chemotherapy Alternating VP and CCNU • Alternate vinblastine and CCNU every 2 weeks for a total of 8 treatments • Doses on previous slides • Prednisone 2 mg/kg PO SID tapered gradually to maintenance dose of 0.5 mg/kg PO SID x 6 months • Macroscopic disease grades II and III • 3 remission, 4 PR • median duration of response 58 days • 2 patients did not reach 4th CCNU treatment due to ALT >1000

33. Chemotherapy Vinblastine, prednisone, cyclophosphamide • Study on high risk MCT • Median progression free interval of more than 2 years • Median survival 6 years • Grade III and those who needed reduction of vinblastine dose did not do as well • New protocol, but this may become a popular protocol in the future

34. Chemotherapy • Vincristine alone not effective for MCT • COP can work well for grade II MCT • Many dirty border grade II do very well with most protocols • many months, years or cured • Some grade II with dirty borders spontaneously resolve • Are malignant MCT indistinguishable from inflammatory reaction?

35. Chemotherapy • Because of the VP study, most oncologists prefer VP to CCNU or both for grade III • My experience is that outcome is similar with all 3 protocols for grade III MCT • Palliative therapy often does just as well • A significant proportion do not respond at all

36. Chemotherapy

37. Chemotherapy Palladia and Kinavet-CA1/Masivet • Tyrosine kinase (TKI) inhibitors • Prednisone and TKI are the chemo drugs with direct cytotoxicity for MCT • Probably the most effective chemo for high grade MCT • Not appropriate for low grade MCT due to toxicity A game changer for high grade very large MCT

38. Chemotherapy Palladia and Kinavet-CA1/Masivet • 25% of grade II & III MCT have C-KIT mutation • Blocking wild type or mutated KIT causes apoptosis in MCT • antiproliferative through KIT blockade • antiangiogenic through other MOA

39. Chemotherapy Palladia and Kinavet-CA1/Masivet • Indications for use: • Dogs >11-15 lbs only (not cats) • Non-resectable MCT • Dirty borders after re-excision • Multiple diffuse or coalescing high grade MCT • Concurrent conditions precluding surgery or multiple sedations for radiation therapy • High grade MCT or C-KIT mutation • Indicated with or without metastasis • Post Chemo – VP x 4 weeks, then Palladia

40. Chemotherapy Palladia and Kinavet-CA1/Masivet • Though both are TKIs, there can be resistance to one but not the other • If one fails, try the other • Stable disease is a victory with either • Palladia has more broad spectrum activity, and is thought to be more likely to cause clinical response than Kinavet • Kinavet response can take up to 2-3 weeks • Gleevec is a TKI used in people, but it is very expensive ($100-150 per pill) • Palladia $6-800, Kinavet $500 /month - 70lb dog

41. Chemotherapy Kinavet Administration • 12.5 mg/kg PO SID • Dose chart on package insert (Client Info) • Cannot be used in dogs weighing less than 15 pounds • Dose reduction in response to adverse events • stop Kinavet for 1-2 weeks • Reduce dose to 9 mg/kg/day when resumed • Weekly CBC/panel for the first 6 weeks • Then every 3 weeks x 2 • Then every 6 weeks thereafter

42. Chemotherapy Palladia Administration • 3.25 mg/kg PO QOD (or MWF) • Dose chart on package insert • With or without food • Dose reduction in response to adverse events • Stop Palladia for 1-2 weeks • 0.5 mg/kg reduction when reduced • Minimum dose 2.2 mg/kg PO QOD • Weekly CBC/panel for the first 6 weeks • Then every 3 weeks x 2 • Then every 6 weeks thereafter

43. Chemotherapy Palladia Administration • GI side effects common • Make sure owner knows to STOP drug if anorexia, vomiting, diarrhea • Dispense Cerenia and metronidazole at the first visit to have on hand • Administer H1 and H2 blockers concurrently

44. Chemotherapy Palladia Study – Bergman & Clifford, 2009 • Dogs with progressive disease on the blinded phase could enter open-label phase at any time

45. Chemotherapy Palladia Study – Bergman & Clifford, 2009 • Statistically significant improvement in objective response rate

46. Chemotherapy Palladia Study – Bergman & Clifford, 2009 • 57.2% did not respond • Among responders, median duration of response was 12 weeks • Median time to non-response or death was 18 weeks • 82% of dogs with C-KIT mutation responded • 54% of dogs without mutation responded • There was a placebo response • Likely due to spontaneously resolving degranulation • Clin Cancer Res 2009; 15:3856-3865.

47. Chemotherapy Palladia Side effects

48. Chemotherapy Palladia Side effects • Dec. albumin – 13% Palladia, 8% Placebo • Palladia given long term leads to glomerular disease and renal failure

49. Chemotherapy Kenneth Kimbrough – Longview TX Stephen Garner – Nacogdoches TX

50. Chemotherapy Kinavet-CA1