PowerPoint - Mast Cell Tumor

Report
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
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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
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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
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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
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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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