practical oncology mast cell tumor wendy blount, dvm
TRANSCRIPT
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
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
Staging for Metastasis
Eva GeromeBonham TX
Chris Longo – Diamondhead, MS
Melanie Enger, - Lufkin TX
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
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
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
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
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
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
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 about prognosis and treatment indicated
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 behaviorThis is the Patnaik SystemObsolete 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
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
Sandra Goodwin – Forney TXSandra Goodwin’s Compadre
Betsy Hoffman Robinson – League City TX
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
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• 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
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)– 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• 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
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?
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
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
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• 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
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• 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.
ChemotherapyPalladia Side effects
ChemotherapyPalladia Side effects• Dec. albumin – 13% Palladia, 8% Placebo• Palladia given long term leads to
glomerular disease and renal failure
ChemotherapyKenneth Kimbrough – Longview TXStephen Garner – Nacogdoches TX
ChemotherapyKinavet-CA1
ChemotherapyKinavet-CA1
ChemotherapyPalliative therapy• 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
• Non-resectable high grade MCT• Regional lymph node metastasis• Grade II Stage 0 MCT with dirty margins– Disease free interval is increased compared to
no treatment– Similar outcome to re-excision if it is possible
• 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– Reserved for those dogs who have too many
dermal MCT to remove and no evidence of systemic disease
Prognosis• Stage and grade much more important than
with LSA– Grade I with clean borders are cured by surgery– Low grade II clean borders usually cured by
surgery– High grade II clean borders should probably
have adjunctive chemo 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
PrognosisIndicators of poor prognosis• Dirty borders on 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 deletion 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
PrognosisAgNOR staining (MCT prognostic panel) • gives more information for grade II• Do chemo if high grade II• Amputate non-resectable low grade II• Cost is about $200 including 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 Handout• Mast Cell Tumors• 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