Practical Oncology Mast 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 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 Staging for Metastasis Eva Gerome Bonham 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 metastasis Consideration 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 behavior This is the Patnaik System 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 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 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 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 Sandra Goodwin – Forney TX Sandra 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 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 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 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 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 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 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 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 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 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 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 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 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 Chemotherapy Palladia Study – Bergman & Clifford, 2009 • Dogs with progressive disease on the blinded phase could enter open-label phase at any time Chemotherapy Palladia Study – Bergman & Clifford, 2009 • Statistically significant improvement in objective response rate 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. Chemotherapy Palladia Side effects Chemotherapy Palladia Side effects • Dec. albumin – 13% Palladia, 8% Placebo • Palladia given long term leads to glomerular disease and renal failure Chemotherapy Kenneth Kimbrough – Longview TX Stephen Garner – Nacogdoches TX Chemotherapy Kinavet-CA1 Chemotherapy Kinavet-CA1 Chemotherapy Palliative 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 Prognosis Indicators 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) Prognosis Indicators of better prognosis • Clean borders on excision • Low grade, low stage, MI <5 • Breed – Boxers and Pugs Prognosis Indicators of better prognosis • Clean borders on excision • Low grade, low stage, MI <5 • Breed – Boxers and Pugs 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 Prognosis AgNOR 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-Champaign Visiting assistant professor, medical oncology • Karri A. Meleo, DVM, ACVIM (Oncology), ACVR VIN 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
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