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Cutaneous mast cell tumours of the dog
- 2. 9y1m, MN, Labrador Mass first noticed 25th June 2014 Referred last week after diagnosis of MCT on the left proximal hindlimb (FNA and cytology) Admitted to the SAH for staging/surgical assessment of mass. Max also had other lumps that had been diagnosed as lipomas and one suspicious lump in the submandibular region. Other than multiple masses Max was normal on physical exam.
- 3. Haematology and Biochemistry Tumour mapped Chest xrays Abdominal ultrasound + Aspiration of spleen Repeat FNA for submandibular lump
- 4. Very common Account for 20% of all skin tumours in dogs Commonly affects middle aged to older dogs May demonstrate rapid growth Solitary or multiple sites Varied appearance May arise from any skin site on the body Size may alter relatively quickly Gastrointestinal effects (including possible PNS)
- 6. Granules contain: - histamine - heparin - vasoactive amines Degranulation may occur leading to their release Local effects Systemic effects (hyperhistaminaemia – PNS)
- 7. FNA Biopsy- excisional vs incisional Staging • Regional LN aspiration (if appropriate) • Chest xrays • Abdominal ultrasound • Other tests prior to treatment: - Haematology/biochemistry - Urinalysis
- 8. Stage Description: 0: One tumour incompletely excised from the dermis, without regional lymph node involvement I: One tumour confined to the dermis, without regional lymph node involvement II: One tumour confined to the dermis, with regional lymph node involvement III: Multiple dermal tumours or large infiltrating tumour, with or without regional lymph node involvement IV: Any tumour with distant metastasis or recurrence with metastasis
- 9. Patnaik (graded 1-3 below) vs Kiupel (low or high grade)
- 10. Aim: complete resection • Low grade (1,2) - wide local excision (or radiotherapy in some cases) - Cytoreductive surgery + radiotherapy - Cytoreductive surgery + chemotherapy • High grade (3) - Wide local excision + chemotherapy (+/- radiotherapy)
- 11. Max’s owners decided on surgical excision He is booked in Tuesday 29nd July o Marginal resection has been selected by the owners Max’s owners decided early on that they did not wish max to receive chemotherapy. Max was not sent home with any gastrointestinal protectants as he had not exhibited any GI signs. (Anti-histamines were suggested- H1 antagonist)
- 12. Only indicated for management of high grade malignant/metastatic tumours Varied response Options include • Vinblastine + prednisolone • Lomustine + prednisolone • Vinblastine + lomustine • Tyrosine kinase inhibitors (Masitinib, Toceranib)
- 13. A common protocol would be radiation mon/wed/fri for 4 weeks May also see daily treatment mon-fri for 3.5-4 weeks
- 14. H2 antagonists: • eg Famotidine (0.5-1 mg/kg p.o. q12-24h.) Omeprazole: • 0.5-1 mg/kg p.o, iv q24h (for maximum of 8weeks) Sucralfate (if evidence of GI ulceration/bleeding) • If <20kg: 500mg/dog p.o. q6-8h • >20kg: 1-2g/dog p.o. q6-8h H1 antagonists • eg Loratadine (5-15mg q24h)
- 15. Major prognostic factors: • Tumour grade • Mitotic index • Surgical margins • Tumour stage (eg LN involvement) Minor prognostic factors: • C-kit expression pattern • Ki-67 expression
- 16. J Vet Intern Med. 1990 Sep-Oct;4(5):242-6. Plasma histamine and gastrin concentrations in 17 dogs with mast cell tumors. Fox LE1, Rosenthal RC, Twedt DC, Dubielzig RR, MacEwen EG, Grauer GF http://www.ncbi.nlm.nih.gov/pubmed/2124627 Canine Mast Cell Tumors http://www.vetmed.wsu.edu/deptsOncology/owners/mastcell.aspx Mast Cell Tumors http://www.veterinarycancer.com/mastcelltumors2.html Canine and feline skin tumors (Part 2) James Warland MA VetMB MRCVS, Jane Dobson MA BVetMed DVetMed Dipl. ECVIM-CA and Onc MRCVS - 18/02/2012 http://vetgrad.com/show10MinuteTopUp.php?type=&Entity=10MinuteTop Ups&ID=78
- 17. Not all lumps are lipomas: Canine Mast Cell Tumours Dr Angela Frimberger VMD, MANZCVS, Diplomate ACVIM(Onc) Dr Antony Moore BVSc, MVSc, MANZCVS, Diplomate ACVIM(Onc) http://www.ava.com.au/sites/default/files/AVA_website/pdfs/NS W_Division/SMALL%20ANIMAL%20%20Frimberger%20%26%20Mo ore%20%20Mast%20Cell%20Tumors%20%20Not%20all%20lumps%20 are%20lipomas.pdf Radiation therapy for canine mast cell tumors, Monique N. Mayerhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823470/pd f/16604985.pdf Mast Cell Tumours (MCTs) http://www.caninecancer.com/Mast.html
Editor's Notes
- SM lump had FNA repeated as was very firm and suspected not just lipoma even though originally dx as lipoma – result of FNA…
- -bloods showed mild hypoalbuminaemia of 27 and elevations in cholesterol and triglycerides- otherwise unremarkable -Tumour mapped to allow monitoring of progression/ success of treatment. As an incidental finding- marked spondylosis was seen on the chest xray Abdo u/s showed no evidence of tumour spread Spleen aspirates showed a few mast cells – this is inconclusive as some mast cells are normally present in the spleen (may require further monitoring) NB: max was quite itchy: may increase No. of mast cells FNA: Repeat so that we could be sure that we weren’t missing a significant tumour and only treating part of the disease problem -- results consistent with reactive lymph node (so removal advised)
- - Approximately 50% of cutaneous MCTs are found on the trunk and perineal region, approximately 40% on the extremities, and about 10% arise from sites on the head and neck. -MCT can look like just about anything, ranging from benign-appearing lumps (such as a lipoma), to more angry or ulcerated lumps, masses with a stalk or focal thickenings in the skin -Among the most commonly affected are beagles, Boston terriers, boxers, bulldogs, bullmastiffs, bull terriers, dachshunds, English setters, fox terriers, golden retrievers, Labrador retrievers, schnauzers, American Staffordshire terriers, and weimaraners -Change in size explained on next slide -GI effects include: vomiting, anorexia, melena, gastric ulceration -Ddx for melena would include: gastric tumour, primary gastric ulceration, secondary tumour. - PNS (hyperhistaminaemia) explained later
- Changes in size can be attributed to these factors^^^ Degran. d/t trauma or may be spontaneous this can lead to local or systemic effects Local effects: erythema, wheal formation, Darier’s sign (anaphylaxis and hypotension d/t vasoactive amines and histamine) Systemic effects: in one study: plasma histamine and gastrin concentrations were measured in 17 dogs with MCT. Plasma histamine concentrations in dogs with MCT were significantly higher than those in normal dogs. Conversely, plasma gastrin concentrations in dogs with MCT were significantly lower than gastrin concentrations in normal dogs. Additionally, plasma gastrin concentrations were inversely related to plasma histamine concentrations, which provided indirect evidence for the presence of hyperacidity secondary to hyperhistaminemia. not related to clinical stage of disease, tumor histologic grade, or tumor size. (not a prognostic indicator) but relevant for treatment plan. How it works: histamine acts on H2 receptors in gastric parietal cells increased acidity/motility (increased plasma histamine/ decreased plasma gastrin) Max’s tumour changed: had been much firmer and larger (golf ball size) before being referred, this was initially why the vet referred max as they were unsure that they could get good margins and still close.
- Can often dx mct on aspiration from lesion Biopsy to get the histological grade of the tumour- relates to tumour behaviour, treatment recommendations and px. Can also perform “mast cell tumor proliferation panels” on all biopsy specimens. The panel consists of a cell proliferation analysis (PCNA, AgNOR, Ki-67), a c-kit PCR, and KIT immunohistochemistry (IHC) to analyze the expression of this tyrosine kinase receptor. Research indicates that a prognosis developed from this combination of tests is highly correlated with survival rates. Biopsy technique used depends on area and whether surgeon able to get margins (in this case 3cm gross margins laterally and one fascial plane deep) Staging may sometimes be appropriate to do bone marrow aspirate (as can metastasise here but would be haematology abnorms to indicate this) - may also be approp to do faecal occult blood tests – pick up GI bleed when melena not present, then can treat for hyperhistaminaemia (eg famotidine) Other tests to rule out concurrent disease and to have a base line before starting any treatment.
- Stage 0 refers to those that have had incomplete surgical resection.
- Kiupel was introduced to try remove prognostic uncertainty as grade 2 very variable. a Kiupel high grade MCT was characterized by: at least 7 mitotic figures in 10 hpf; or at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; or at least 3 bizarre nuclei in 10 hpf karyomegaly (nuclear diameters of at least 10% of neoplastic mast cells vary by at least 2-fold) One advantage in this system is its simplicity, eliminating some of the subjectivity inherent in the Patnaik system.
- Cytoreductive surgery + chemotherapy when other poor prognostic criteria Obviously each case is different and have to select the most appropriate treatment for that animal Photodynamic therapy is a new treatment modality that uses a dye injected into the blood stream that localizes in cancer cells. A laser of a particular wavelength is then used to excite the cells and cause cell death.
- Marginal resection as would need to do a skin flap to close and owners weren’t keen for surgery, so keep as minimal as possible Hopefully low grade and this may be curative! If histopath. reveals high grade some further treatment may be necessary at the surgical site if clear margins weren't achieved ie radiation therapy. Surgical excision to include the submandibular LN as well Chemo not overly appropriate in max’s case anyway as no real evidence of systemic spread or it being high grade and it is resectable. Anti-histamine: Loratadine 1/day (10mg SID) shown to stabilise mast cells very well
- 40% response rates for measurable disease Vinblastine: week 1-4: 2mg/m2 IV q1 week (in 1 study response rate was 47% and median response duration was 5months) week 6-12: 2mg/m2 IV q2wks Pred: wk1-2: 1mg/kg po SID wk3-12: 0.5 mg/kg po SID Bloods: Haem prior to each vinblastine dose (as it is myelosuppresive) Lomustine dogs: 60-80mg/m2 po q 3wks (give 6 doses or until dz progression) (42% overall response rate Pred: wk 1-2: 2mg/kg or 40mg/m2 SID WK 3-4: 1mg/kg or 20 mg/m2 SID wk 5+6: 1mg/kg or 20 mg/m2 EOD …………THEN STOP Bloods: ensure adequate liver function before use (could use concurrent denosyl – S-adenosylmethionine) [NB delayed toxicity in cats, 3-4 weeks] Haem: prior to each dose – monitor PLTs closely Biochem: prior to q second dose………………………………..if liver abnormalities, do bile acid stim +/- u/s liver Vinblastine + lomustine: 65% response rate in dogs with nonresectable mcts in one study TKIs- both for treatment of dogs with non resectable MCTs. Length of treatment not sure some clinicians think 6 months, drug companies say ~12months. Basically until get remission then can try stopping (but if gross dz still present keep going) Masitinib (more specific- primarily targets c-kit)- dose rate 12.5 mg/kg SID - adv.rxns: decrease dose 9mg/kg SID (inclu: GI upset, renal tox., myelosupp etc) -recheck: 2wks,1,3,6 months + q3-6 months thereafter - monitor: haem/biochem + urinalysis @ each visit Toceranib (other uses including mammary gland carc/sts/multiple myeloma/melanomas and other carcinomas) Active against several of the RTK (receptor tyrosine kinase) family – antiangiogenic and anti-tumour activity - dose rate for MCT: 3.25mg/kg po EOD (or mon/wed/fri) If adv.rxns – decrease dose to 2.5mg/kg (incl: vasc dusfuncn thromboemb/oedema, GI, neutropenia) Recheck- 2wks,1,3,6 months + q3-6months thereafter - monitor: haem/biochem + urinalysis @ each visit
- Radiation therapy is an effective treatment option for incompletely resected mast cell tumours (various protocols) Example study: Thirty-seven dogs with grade II, stage 0 mast cell tumours treated postoperatively with radiation therapy alone or with prednisone had a disease-free rate of 97% at 1 y after treatment, and 93% at 3 y after treatment therefore can see very effective!! Palliative radiation therapy may relieve symptoms of extensive or systemic disease. When the tumour is poorly differentiated or metastasis is already confirmed, high-dose intermittent radiation treatments may improve the quality of life by stopping bleeding or reducing the size of a bulky or irritating tumour – often once/wk for 3-4wks
- Animals with mastocytosis or any bulky mast cell disease should receive H2 antagonists, as rapid degranulation of neoplastic mast cells may follow surgery or chemotherapy Objective is to treat/prevent gastrointestinal ulceration. This is most likely to occur in dogs with larger, bulky disease, with recurrence of cutaneous disease, or with systemic spread of MCT. H2 antagonists such as famotidine reduce gastric acid production by competitive inhibition of the action of histamine on H2 receptors of the gastric parietal cells. H1 antagonists should be considered for use in addition, before and after surgical removal of canine MCTs to help prevent the negative effects of local histamine release on fibroplasia and wound healing. Sucralfate may decrease bioavailability of h2 antags, little evidence to suggest this is of clinical importance but may be good idea to give sucralfate at least 2 hours before these drugs. Loratadine has been shown to be very effective at inhibiting histamine release by blocking degranulation from normal canine mast cells, and therefore may be a good choice for palliation of dogs with MCT
- All MCT express c-kit but the pattern of expression within cells has been found to be prognostic, with 3 different patterns identified. Ki-67 is a proliferative index that has been shown to have some prognostic value. In Patnaik grade 2 tumours with <1.8% positivity, 77 to 95% of dogs lived 3 years; whereas dogs with tumours that had >1.8% positivity had 3-year survival of 21 – 33%. The prognosis for completely removed grade I and grade II tumors is excellent. The prognosis for incompletely removed grade I and II tumors treated with radiation therapy after surgery is also excellent with approximately 90-95% of dogs having no recurrence of tumor within 3 years of receiving radiation therapy. The prognosis for dogs with grade III tumors is considered guarded as local recurrence and/or spread is likely in most dogs. Only 15% of dogs with Grade 3 MCT will be alive 7 months after surgery, and only 6% will be alive after 2 years. Once mast cell cancer has metastasized, dogs tend to die within several months as the symptoms of systemic illness (e.g., gastric ulcers) can no longer be managed and the animal loses its quality of life.