Mast cell tumors: Margins, markers and prognostic factors (Proceedings)

Mast cell tumors (MCT's) are the most common tumor in the dog and the second most common tumor in the cat. MCT's are primarily a disease of older dogs and cats, however, extremely young dogs and cats have been reported to have MCT's. Canine breeds reported to be at increased risk for MCT's are boxers, Boston terriers, Labrador retrievers, terriers and beagles. The only feline breed that has been reported to be at increased risk for MCT's are Siamese. Most reports show no significant gender predilection for MCT's in dogs or cats. The etiology of MCT's is presently unknown. Many have suspected a viral etiology due to MCT transplantability to susceptible laboratory dogs (extremely young or immunocompromised) with tumor cells and cell-free extracts. Recent evidence shows that a significant percentage of dogs with higher-grade MCT's have genetic mutations in c-kit (stem cell factor receptor) which may be responsible for the genesis and/or progression of MCT's in dogs. Not all dogs with MCT's have c-kit mutations, suggesting that they are not the only mechanisms for the development and/or progression of MCT's. Eighty-five to ninety percent of dogs and cats with

MCT's have solitary lesions. It is important to note that not all dogs or cats with multiple MCT's have metastatic or systemic mastocytosis. Studies suggest that well-differentiated MCT's are slow-growing, usually < 3-4 cm in diameter, without ulceration of overlying skin, variably alopecic and commonly are present for more than 6 months. In contrast, poorly differentiated MCT's are rapidly growing, variably sized (but generally large), with ulceration of the underlying skin and inflammation/edema of surrounding tissues and lastly rarely are present for more than 2-3 months before presentation. Since most MCT's are of moderate-differentiation, signs may be somewhere between these two extremes.

History & Clinical Signs

The history and clinical signs of dogs and cats with MCT's can be extremely variable. Most do not show any clinical signs referable to their MCT, however, some may have signs referable to the release of heparin, histamine and/or other vasoactive amines. Mechanical manipulation or extreme changes in temperature can lead to degranulation of MCT's and subsequent erythema/wheal formation (Darier's sign) and gastrointestinal ulceration (anorexia, vomiting, melena, etc.).

Diagnosis & Staging

Fine needle aspiration and cytology (FNAC) is the mainstay for diagnosis of MCT prior to surgical removal. Mast cells of MCT's have a characteristic discrete cell cytological appearance with eccentrically placed nuclei and abundant red to purple (ie metachromatic) cytoplasmic granules. Occasional MCT's, predominately undifferentiated MCT's, do not have the classic metachromatic cytoplasmic granules and must be diagnosed via other means (histopathology, special stains, etc.). Once a diagnosis is obtained, staging (looking for disease elsewhere) is routinely recommended, however, the completeness of staging is presently extremely controversial. After an FNAC diagnosis of MCT has been made, this author recommends routine staging diagnostics (full physical examination, bloodwork/urinalysis, FNAC of any local lymph nodes and abdominal ultrasound). Additional diagnostics such as thoracic radiography and bone marrow aspiration/cytology may be employed.

The use of buffy coat cytology and liver/spleen FNAC is presently controversial in the routine staging of dogs with MCT and this author does not routinely employ these diagnostics for staging of MCT's in dogs. Some oncologists have begun to either not routinely utilize bone marrow aspiration & cytology (BMAC) for MCT staging, or have begun to utilize results of CBC/plt to delineate whether or not to perform a BMAC. This is incredibly controversial and results of a recent publication concerning incidence and risk factors of bone marrow infiltration for canine MCT will be presented at the lecture.

Treatment

Once the diagnosis of MCT has been made with FNAC and/or incisional biopsy and staging has been completed showing no evidence of metastasis to other sites, surgical excision is the preferred choice of therapy. The standard recommendation for complete surgical removal of MCT's has been three centimeters lateral and 1 fascial plane deep to the MCT. The derivation of this recommendation is unknown. This author still recommends continuing use of 3 cm lateral margins and one fascial plane deep margins whenever possible, but we recently published studies which show that 2 cm lateral and one fascial plane deep margins are sufficient for most grade II MCT. At present, the Seguin et al grade II MCT in dogs paper (2001) has the best information even though the followup time was relatively short (median of only 540 days). Those investigators found a 5% recurrence rate in the face of clean margins, an 11% second primary tumor development rate, and a 5% metastatic rate.

Recent studies in cats with skin/SQ MCT suggest that the vast majority are minimally invasive tumors with low recurrence rates suggesting that as wide and deep surgical margins may not be as necessary in cats as it is in dogs. It can not be over-emphasized as discussed above that cats with dermal MCT should be staged to ensure they do not have a splenic primary MCT that is metastasizing to dermal and/or other sites.Dogs and cats with incomplete surgical removal of their MCT should undergo re-resection whenever possible. When re-resection is not feasible, external beam radiation therapy has been found to be an excellent post-operative therapeutic modality affording 75-85% control at 4-5 years in dogs with incompletely resected grade II MCT. Recurrence rates for completely resected grade II MCT hover in the 5-20% range in the veterinary oncology literature. Recurrence rates for incompletely resected MCT's hover in the 25-40% range. At present, we have to recommend additional local therapy for all incompletely resected MCT's in the face of such low-moderate recurrence rates, and additional recent studies will be discussed at the lecture that may help better predict which cases truly need additional local therapy will be discussed.

The results of a study utilizing radiation therapy for incompletely resected grade III MCT in dogs has been recently published by Hahn et al from Gulf Coast Veterinary Specialists. Thirty-one dogs received 52 Gy of external beam radiation in 18 fractions on a M-W-F basis to the surgical site and draining lymph nodes with no additional therapy (ie no chemotherapy). These investigators found a median survival time of ~ 28 months (range 3-52 months). Only one dog went on to develop systemic MCT metastasis. The results of this trial are controversial within the veterinary oncology community as previous metastatic rates for grade III MCT have been reported to be 55%-96%. At this time, most oncologists are continuing to use chemotherapy in the treatment of grade III MCT; however, results of this study suggest that the more aggressive use of radiation therapy may be beneficial for grade III MCT.

As discussed above, surgery and radiation therapy should be considered the mainstays of therapy for MCT's. Chemotherapy is a very distant third modality that may be useful for dogs and cats with systemic or metastatic mast cell tumor. Recent studies suggest that CCNU (lomustine), vinblastine, possibly cyclophosphamide and finally prednisone have limited activity against MCT. The results of studies utilizing chemotherapy will be presented in detail at the lecture.

Prognosis

Histopathologic examination of MCT's has been found to be an important prognostic indicator by multiple groups. The Patnaik grading scheme (well-differentiated = grade I, moderately-differentiated = grade II and poorly-differentiated = grade III) has shown that 83%, 44% and 6% of dogs with grade I, II and III tumors were alive approximately 4 years after surgery, respectively. This grading scheme has not been found to be of use for cats with MCT. Additional negative prognostic factors include advanced stage, caudal half of body location, high growth rates, aneuploidy and presence of systemic signs. Newly discovered molecularly-based negative prognostic factors include increased AgNOR (silver nucleolar organizing regions) scores, increased PCNA/Ki67 immunohistochemistry (IHC) expression (proliferation markers), increased vascularity and/or mitotic index and increased c-kit IHC expression. The use of panels of the aforementioned prognostic factors is strongly recommended due to their significant predictive ability for both the subsequent development of metastasis as well as subsequent development of recurrence.

References

Thamm DH, Mauldin EA, Vail DM. Prednisone and vinblastine chemotherapy for canine mast cell tumor--41 cases (1992-1997). J Vet Intern Med. 1999 Sep-Oct;13(5):491-7.

LaDue T, Price GS, Dodge R, Page RL, Thrall DE. Radiation therapy for incompletely resected canine mast cell tumors. Vet Radiol Ultrasound. 1998 Jan-Feb;39(1):57-62.

Patnaik AK, Ehler WJ, MacEwen EG. Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol. 1984 Sep;21(5):469-74.

Rassnick KM, Moore AS, Williams LE, London CA, Kintzer PP, Engler SJ, Cotter SM. Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med. 1999 Nov-Dec;13(6):601-5.

Chaffin K, Thrall DE. Results of radiation therapy in 19 dogs with cutaneous mast cell tumor and regional lymph node metastasis. Vet Radiol Ultrasound. 2002 Jul-Aug;43(4):392-5.

Turrel JM, Kitchell BE, Miller LM, Theon A. Prognostic factors for radiation treatment of mast cell tumor in 85 dogs. J Am Vet Med Assoc. 1988 Oct 15;193(8):936-40.

Frimberger AE, Moore AS, LaRue SM, Gliatto JM, Bengtson AE. Radiotherapy of incompletely resected, moderately differentiated mast cell tumors in the dog: 37 cases (1989-1993). J Am Anim Hosp Assoc. 1997 Jul-Aug;33(4):320-4.

Seguin B, Leibman NF, Bregazzi VS, Ogilvie GK, Powers BE, Dernell WS, Fettman MJ, Withrow SJ. Clinical outcome of dogs with grade-II mast cell tumors treated with surgery alone: 55 cases (1996-1999). J Am Vet Med Assoc. 2001 Apr 1;218(7):1120-3.

O'Keefe DA, Couto CG, Burke-Schwartz C, Jacobs RM. Systemic mastocytosis in 16 dogs. J Vet Intern Med. 1987 Apr-Jun;1(2):75-80.

Al-Sarraf R, Mauldin GN, Patnaik AK, Meleo KA. A prospective study of radiation therapy for the treatment of grade 2 mast cell tumors in 32 dogs. J Vet Intern Med. 1996 Nov-Dec;10(6):376-8.

Simpson AM, Ludwig LL, Newman SJ, Bergman PJ, Hottinger HA, Patnaik AK. Canine cutaneous mast cell tumors: A prospective study of surgical margins. J Am Vet Med Assoc 2004;224(2):236-240.

Hahn KA, King GK, Carreras JK. Efficacy of radiation therapy for incompletely resected grade-III mast cell tumors in dogs: 31 cases (1987-1998). J Am Vet Med Assoc 2004;224(1):79-82.

Scase TJ, Edwards D, Miller J, et al. Canine mast cell tumors: correlation of apoptosis and proliferation markers with prognosis. J Vet Intern Med. 2006;20(1):151-8.

Seguin B, Besancon MF, McCallan JL, et al. Recurrence rate, clinical outcome, and cellular proliferation indices as prognostic indicators after incomplete surgical excision of cutaneous grade II mast cell tumors: 28 dogs (1994-2002). J Vet Intern Med 2006;20(4):933-40.

Endicott MM, Charney SC, McKnight JA, Loar AS, Barger AM, Bergman PJ. Clinicopathologic findings and results of bone marrow aspiration in dogs with cutaneous mast cell tumors: 157 cases (1999-2002). Vet Comp Oncol 2007, 5(1):31-37.

Camps-Palau MA, Leibman NF, Elmslie R, Lana SE, Plaza S, McKnight JA, Risbon R, Bergman PJ. Treatment of canine mast cell tumours with vinblastine, cyclophosphamide and prednisone: 35 cases (1997-2004). Vet Comp Oncol 2007, 5(3):156–167.

Webster JD, Yuzbasiyan-Gurkan V, Thamm DH, Hamilton E, Kiupel M. Evaluation of prognostic markers for canine mast cell tumors treated with vinblastine and prednisone. BMC Vet Res. 2008 Aug 13;4(1):32.

Marconato L, Bettini G, Giacoboni C, Romanelli G, Cesari A, Zatelli A, Zini E. Clinicopathological features and outcome for dogs with mast cell tumors and bone marrow involvement. J Vet Intern Med. 2008 Jul-Aug;22(4):1001-7.

Stanclift RM, Gilson SD. Evaluation of neoadjuvant prednisone administration and surgical excision in treatment of cutaneous mast cell tumors in dogs. J Am Vet Med Assoc. 2008 Jan 1;232(1):53-62.

Ozaki K, Yamagami T, Nomura K, Narama I. Prognostic significance of surgical margin, Ki-67 and cyclin D1 protein expression in grade II canine cutaneous mast cell tumor. J Vet Med Sci. 2007 Nov;69(11):1117-21.

Henry CJ, Downing S, Rosenthal RC, Klein MK, Meleo K, Villamil JA, Fineman LS, McCaw DL, Higginbotham ML, McMichael J. Evaluation of a novel immunomodulator composed of human chorionic gonadotropin and bacillus Calmette-Guerin for treatment of canine mast cell tumors in clinically affected dogs. Am J Vet Res. 2007 Nov;68(11):1246-51.

Gil da Costa RM, Matos E, Rema A, Lopes C, Pires MA, Gärtner F. CD117 immunoexpression in canine mast cell tumours: correlations with pathological variables and proliferation markers. BMC Vet Res. 2007 Aug 21;3:19.

Cooper M, Tsai X, Bennett P. Combination CCNU and vinblastine chemotherapy for canine mast cell tumours: 57 cases. Vet Comp Oncol. 2009 Sep;7(3):196-206.

Stefanello D, Valenti P, Faverzani S et al. Ultrasound-guided cytology of spleen and liver: a prognostic tool in canine cutaneous mast cell tumor. J Vet Intern Med. 2009 Sep-Oct;23(5):1051-7. Epub 2009 Jul 28.

London CA, Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP, Henry CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ, Couto GC, Mauldin GN, Michels GM. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res. 2009 Jun 1;15(11):3856-65. Epub 2009 May 26.

Krick EL, Billings AP, Shofer FS, Watanabe S, Sorenmo KU. Cytological lymph node evaluation in dogs with mast cell tumours: association with grade and survival. Vet Comp Oncol. 2009 Jun;7(2):130-8.

Hahn KA, Ogilvie G, Rusk T, Devauchelle P, Leblanc A, Legendre A, Powers B, Leventhal PS, Kinet JP, Palmerini F, Dubreuil P, Moussy A, Hermine O. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med. 2008 Nov-Dec;22(6):1301-9. Epub 2008 Sep 24.