by Edwin Brodsky, DVM, Diplomate ACVIM (Oncology)
Mast Cell Tumor Proliferation
Mast cell tumors are the most common cutaneous malignancy in dogs. One of the most important prognostic factors when treating mast cell tumors is the histologic grade. The histologic grade is a measure of how aggressive a tumor appears on a biopsy. Mast cell tumors are commonly graded using a three tier grading system. Grade I mast cell tumors are well-differentiated, grade II mast cell tumors are moderately differentiated and grade III tumors are poorly differentiated. Post operative survival is associated with grade for dogs with mast cell tumors. The majority of dogs with grade I mast cell tumors are cured with surgery alone, whereas the majority of dogs with grade III mast cell tumors succumb to progressive disease. Ninety five percent of grade II mast cell tumors that are less than 4cm and non-metastatic, as well as completely excised, do not have metastasis and 95% do not recur at the primary surgical site. Thus, most small, localized grade II mast cell tumors are cured with complete surgical excision. When surgery is unable to get clean wide margins, radiation therapy can be considered to prevent local recurrence. Due to their high metastatic rate, chemotherapy is recommended for all grade III mast cell tumors. In addition, chemotherapy is recommended for any grade mast cell tumor that has exhibited metastatic behavior.
Unfortunately, there are issues when grading mast cell tumors. A big issue is the lack of agreement between pathologists when grading mast cell tumors. Histopathology is a subjective way of evaluating a tumor. There are certain objective criteria that pathologists use to grade mast cell tumors such as mitotic index and percentage necrosis. However, in the end, it is a person’s (the pathologist) opinion as to the aggressiveness of the tumor. In one study, which had multiple pathologists grade the same group of mast cell tumors, there was only 50% agreement when evaluating grade II mast cell tumors.
The mast cell tumor panel provides an objective way of evaluating grade II mast cell tumors to determine if additional systemic therapy is required after adequate local control. The panel consists of three markers of proliferation – Ki67, AgNOR and PCNA. Ki67 is a measure of the cells currently proliferating. The number of AgNORs in neoplastic mast cells gives us an idea of how rapidly the cells are proliferating. PCNA gives information as to the cell-cycle phase of the proliferating cells. Dogs that have higher numbers of proliferation markers are more likely to have an aggressive mast cell tumor and may benefit from adjuvant chemotherapy.
In addition to the proliferation markers, the mast cell tumor panel also consists of immunohistochemical (IHC) staining for the growth factor receptor KIT and PCR for the c-kit gene. Abnormal localization of the KIT receptor within the neoplastic mast cell has been associated with decreased survival rates. Furthermore, PCR of the c-kit gene can identify activating mutations in 20-30% of dogs with mast cell tumors. The presence of a mutated c-kit is associated with a more aggressive mast cell tumor. The information obtained from the panel regarding the presence of a mutated c-kit or an abnormally located KIT receptor also helps plan therapy for dogs with mast cell tumors. There are new drugs available in veterinary medicine (toceranib phosphate and masitinib mesylate) which target this abnormal growth factor receptor and may be included in patient’s treatment protocols for mast cell tumors.
Edwin Brodsky, DVM, Diplomate ACVIM (Oncology)
Veterinary Medical Center of Long Island
75 Sunrise Highway
West Islip, New York 11795
(631) 587-0800; fax (631) 587-2006