Practical OncologyMast Cell Tumor

Wendy Blount, DVM

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

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

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

Staging for Metastasis

x

x

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

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

• 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

Clinical Signs

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

DiagnosisMast cell granules - fine

DiagnosisLSA azurophilic granules – coarse

Lymphoid cells have less cytoplasm than mast cells

DiagnosisPoorly granulated MCT

DiagnosisAgranular mast cell tumorResembles histiocytoma

Diagnosis

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

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)

Staging for Metastasis• Non-resectable MCT

Staging for Metastasis• Non-resectable MCT

Staging for Metastasis• Non-resectable MCT

Staging for Metastasis• Lymph node cytologies

Staging for Metastasis• Lymph node cytologies

Staging for Metastasis• Lymph node cytologies

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 metastasisConsideration is being given to reducing

stage of multiple dermal tumors

Histopathology• grade• Mitotic Index (MI)• Surgical margins – clean, narrow or dirty• Invasiveness – dermal or invasive

(subcutaneous/muscle)

Histopathology tells a great deal aboutprognosis and treatment indicated

for mast cell tumorsStaging tells less, unless single

unresectable low grade II

x

x

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 behaviorThis is the Patnaik System

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

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

SurgeryPrednisone 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

SurgeryRe-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

SurgeryNeoAdjuvant 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

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

ChemotherapyTwo categories:1. Traditional chemo– VP – vinblastine prednisone– CCNU – popular 20 years ago– Alternating VP and CCNU– CVP – cyclophosphamide vinblastine pred

2. TKI – tyrosine kinase inhibitors– Palladia– Kinavet

ChemotherapyVinblastine 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)

ChemotherapyCCNU• 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

ChemotherapyAlternating 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

ChemotherapyVinblastine, 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

ChemotherapyVinblastine, 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)

ChemotherapyVinblastine, 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

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

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

Chemotherapy

ChemotherapyPalladia 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

toxicityA game changer for high grade very large

MCT

ChemotherapyPalladia 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

ChemotherapyPalladia 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

Chemotherapyxx

ChemotherapyPalladia 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

ChemotherapyKinavet 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

ChemotherapyPalladia 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

ChemotherapyPalladia 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

ChemotherapyPalladia Study – Bergman & Clifford, 2009

• Dogs with progressive disease on the blinded phase could enter open-label phase at any time

ChemotherapyPalladia Study – Bergman & Clifford, 2009• Statistically significant improvement in

objective response rate

ChemotherapyPalladia 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; 15:3856-3865.

ChemotherapyPalladia Side effects

ChemotherapyPalladia 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

ChemotherapyKinavet-CA1

ChemotherapyKinavet-CA1

ChemotherapyPalliative 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

Radiation Therapy• Curative– 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

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

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

PrognosisIndicators 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)

PrognosisIndicators of better prognosis• Clean borders on excision• Low grade, low stage, MI <5• Breed – Boxers and Pugs

PrognosisIndicators of better prognosis• Clean borders on excision• Low grade, low stage, MI <5• Breed – Boxers and Pugs

PrognosisIndicators of better prognosis• Clean borders on excision• Low grade, low stage, MI <5• Breed – Boxers and PugsMultiple 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

Prognosisxx

PrognosisMCT 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)

Client Handouts• Mast Cell Tumors• Kinavet• Palladia• Chemo agents discussed Sunday

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-ChampaignVisiting assistant professor, medical oncology

• Karri A. Meleo, DVM, ACVIM (Oncology), ACVRVIN Consultant, Vet Onc Serv, Edmonds, WA

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

Acknowledgements• Craig Clifford, DVM, MS, ACVIM (Oncology)

VIN Consultant

• Zachary Wright, DVM, ACVIM (Oncology)Animal Diagnostic Clinic, Dallas TX