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. Staging for Metastasis x x

6. 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

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. 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

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 Mast cell granules - fine

11. Diagnosis LSA azurophilic granules – coarse Lymphoid cells have less cytoplasm than mast cells

12. Diagnosis Poorly granulated MCT

13. Diagnosis Agranular mast cell tumor Resembles histiocytoma

14. Diagnosis

15. Staging for Metastasis • Histopathology for grading • Excisional if resectable • Incisional if not • May not heal well • Degranulation may be a problem • 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

16. Staging for Metastasis • Staging less important for high risk MCT • High grade II & Grade III • palliative treatment for best outcome • Palliative drugs, chemo, radiation • Cure is unlikely, especially for grade III (Maddie) • Staging more important for single local low grade II that is not resectable • If staging is clean for metastasis, then radiation can be curative (Sadie)

17. Staging for Metastasis • Non-resectable MCT

18. Staging for Metastasis • Non-resectable MCT

19. Staging for Metastasis • Non-resectable MCT

20. Staging for Metastasis • Lymph node cytologies

21. Staging for Metastasis • Lymph node cytologies

22. Staging for Metastasis • Lymph node cytologies

23. 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

24. 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 for mast cell tumors Staging tells less, unless single unresectable low grade II

25. x x

26. Histopathologic Grading • Grade I – well differentiated, behaves benignly (dermal in cats) • Grade II – intermediate differentiation, behavior is widely variable • Low grade II – often behaves benignly • High grade II – may have C-kit mutation, often behaves malignantly • Grade III – anaplastic, aggressive behavior This is the Patnaik System

27. Histopathologic Grading • We used to think grade II unpredictable • Now that we divide grade II into low and high, there is much more predictability • Most path labs now give you high or low grade II in the report • Be sure to request this and for border reads • More information from MSU prognostic panel (form) - $210 • Obsolete system has grade I the worst and grade III the best prognosis

28. 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

29. 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 20 mg/m2 PO SID x 7days, then QOD

30. 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

31. 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

32. Chemotherapy • Not indicated for multiple dermal MCT that are cured by excision • To deal with multiple dermal MCT when removing all becomes impossible • To deal with MCT at the tumor borders when radiation not possible • Radiation more likely to be curative • 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

33. Chemotherapy Two categories: • Traditional chemo • VP – vinblastine prednisone • CCNU – popular 20 years ago • Alternating VP and CCNU • CVP – cyclophosphamide vinblastine pred • TKI – tyrosine kinase inhibitors • Palladia • Kinavet

34. 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 • Most grade III have gross disease after surgery • Most dead in 2-6 months • All gone within the year • Vinblastine 2-2.2 mg/m2 IV slow IV push once weekly for 4 weeks, then every other week for 4 doses • Prednisone 40 mg/m2 PO SID, then 20 mg/m2 PO SID x 2 weeks, then 20 mg/m2 PO QOD (intervals)

35. 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, bile acids) • 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

36. 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

37. Chemotherapy Vinblastine, prednisone, cyclophosphamide • All dogs had either high grade II with lymph node metastasis or grade III MCT • Dogs with macroscopic disease: • 4 grade II, 7 grade III • 64% had a measurable response to treatment • 46% CR, 18% PR • 18% SD, 18% PD • Median PFST was 74 days • Median OST was 145 days • 54% also had radiation treatment

38. Chemotherapy Vinblastine, prednisone, cyclophosphamide • Dogs with microscopic disease: • 22 grade II, 3 grade III • 10 recurrent disease, 2 multiple tumors, 13 first time single tumor • Two subgroups: • A – 19 dogs with local microscopic disease. • Median PFST was 222 days (7 months) • Median OST was >2092 days (6 years) • B - 5 dogs with absolute local control (ALC) • Median PFST was 865 days (2.5 yrs) • median OST was >1261 days (3.5 years)

39. Chemotherapy Vinblastine, prednisone, cyclophosphamide • Protocol: • Prednisone 1 mg/kg PO SID, tapered and discontinued over 24 – 32 weeks • Week 1 - Vinblastine 2-2.2 mg/m2 IV • Week 2 - Cyclophosphamide 200–250 mg/m2 either PO over 4 days or IV on day 1 • Week 3 – prednisone only • Continue 3 week cycle for 6 months, or until death or chemo abandoned

40. Chemotherapy • Vincristine alone not effective for MCT • Historically, many dirty border grade II did very well with most chemo protocols • many months, years or cured • Historically, some grade II with dirty borders spontaneously resolved • Are malignant MCT indistinguishable from inflammatory reaction? • Now that we can divide grade II into low and high grade, prediction of behavior is more accurate • Even so, even high grade II with dirty borders or metastasis can do very well with chemo and/or radiation • Grade III is still way worse than high grade II

41. Chemotherapy - Summary • Traditional chemo • VP or alternating VP & CCNU preferred to CCNU alone for grade III • TKI • Studies comparing traditional to TKI not available • many oncologists prefer TKI as first line therapy for high risk MCT • Others do traditional chemo, then follow with TKI • Many oncologists feel that if there is a good response to TKI, it is more durable than traditional chemo • Side effects of TKI are not common in the first 6 weeks, but eventually occur, can be significant and potentially life threatening

42. Chemotherapy

43. 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

44. 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

45. 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

46. Chemotherapy x x

47. 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

48. 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

49. Chemotherapy Palladia Administration • 2.5 mg/kg PO QOD (or MWF) • Dose chart on package insert is higher • 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

50. 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