1. Practical Oncology Mast 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 Metastasisx 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 Pruritus and skin flushing Facial swelling
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 Pruritus and skin flushing Facial swelling
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. Mast cell granules - fine
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. Agranular mast cell tumor Resembles histiocytoma
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

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 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 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

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 ($ 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

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

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

53. Chemotherapy Palladia Study – Bergman & Clifford, 2009
57.2% did not respond
Among responders, median duration of response was 12 weeks (3 months)
Median time to non-response or death was 18 weeks (4-5 months)
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:

54. Chemotherapy
Palladia Side effects

55. Chemotherapy Palladia Side effects
Dec. albumin – 13% Palladia, 8% Placebo
Palladia given long term leads to glomerular disease and renal failure
While this side effect is severe, it is balanced against the grave prognosis of high grade MCT

56. Chemotherapy
Kinavet-CA1

57. Chemotherapy
Kinavet-CA1

58. Chemotherapy Palliative Drug Therapy
Alone, or accompanying chemo and/or radiation
Prednisone 40 mg/m2/day
Wean gradually to 0.5 mg/m2/day
Antihistamines daily
H2 blocker or proton pump blocker
Cimetidine, ranitidine, famotidine
Omeprazole, esomeprazole
sucralfate if ulcerated
Hematemesis, melena

59. Radiation Therapy Curative Palliative
Low grade II non-resectable MCT without distant metastasis
Grade II Stage 0 MCT with dirty margins
Disease free interval is increased compared to no treatment
Similar outcome to re-excision (95% cure)
Palliative
Non-resectable high grade MCT
Regional lymph node metastasis
No indication to irradiate grade II MCT with clean borders

60. Treatments Not Recommended
Deionized water injections
At one time recommended for cytoreduction prior to surgery
Subsequent studies have proven ineffective
Risk causing degranulation
Pain on injection
intralesional Vetalog or DepoMedrol
Historically for those dogs who have too many dermal MCT to remove and no evidence of systemic disease
replaced by TKI or palliative drugs

61. Prognosis Stage and grade much more important for MCT and than for LSA
Grade I with clean borders are cured by surgery
Low grade II clean borders usually cured by surgery and/or radiation
High grade II clean borders should probably have adjunctive chemo and/or radiation
High grade II with dirty borders should definitely have adjunctive chemo and/or radiation and may have poor prognosis
Virtually all of grade III die of their disease, often within a few months, unless very small with clean borders

62. Prognosis Indicators of poor prognosis Dirty borders after re-excision
High grade, advanced stage, MI >5
Breed- Shar pei
Systemic signs due to degranulation
Size and growth rate
Location – perineum, scrotum, nail bed, mucocutaneous, muzzle
C-kit mutation and other histopath prognostic indicators (MSU/AMC panels)

63. Prognosis Indicators of better prognosis Clean borders on excision
Low grade, low stage, MI <5
Breed – Boxers and Pugs

64. Prognosis Indicators of better prognosis Clean borders on excision
Low grade, low stage, MI <5
Breed – Boxers and Pugs

65. Prognosis Indicators of better prognosis Clean borders on excision
Low grade, low stage, MI <5
Breed – Boxers and Pugs
Multiple primary mast cell tumors do not necessarily worsen prognosis
Dogs who tend to get one dermal MCT tend to get more, simultaneously or sequentially
Warn owners to look for more when you remove the first

66. Prognosis x

67. Prognosis MCT prognostic panel Not indicated for grade I or III
gives more information for grade II
Do chemo/radiation if high grade II
Amputate or radiate non-resectable low grade II
Cost is about $210 plus shipping
Send MCT histopath to MSU or AMC, so you can add the prognostic panel if grade II
Save center of tumor in formalin to send to MSU /AMC for panel later if grade II
Can be difficult to get unstained paraffin sections from the first lab (except TVMDL)

68. Client Handouts Mast Cell Tumors Kinavet Palladia
Chemo agents discussed Sunday

69. Acknowledgements
Philip J. Bergman, DVM, MS, PhD, DACVIM (Oncology) VIN Consultant, CMO BrightHeart Vet Centers
Louis-Philippe de Lorimier, DVM, ACVIM (Oncology) VIN Consultant, U of Ill Urbana-Champaign Visiting assistant professor, medical oncology
Karri A. Meleo, DVM, ACVIM (Oncology), ACVR VIN Consultant, Vet Onc Serv, Edmonds, WA

70. Acknowledgements Robert C. Rosenthal, DVM, BS, MS, PhD VIN Consultant
Kurt R. Verkest, BVSc, BVBiol, MACVSc (Small Animal) VIN Associate Editor, Univ Queensland, Australia
Claudia Barton, DVM, ACVIM (Internal Medicine, Oncology)
TAMU CVM

71. Acknowledgements
Craig Clifford, DVM, MS, ACVIM (Oncology) VIN Consultant
Zachary Wright, DVM, ACVIM (Oncology) Animal Diagnostic Clinic, Dallas TX