Mast cell tumors (MCT) are commonly identified tumors in dogs, comprising close to 25% of all diagnosed skin tumors. These tumors may be seen in any age dog, but are more typically found in middle aged to older patients. Breeds at an increased risk for developing these tumors include boxers, Boston terriers, Labrador retrievers, beagles and schnauzers. The etiology of MCTs is largely unknown, although genetic factors and molecular alterations may play prominent roles. Recently, there has been an increased focus on understanding these genetic and molecular alterations, including the identification of activating mutations in the growth pathway involving c-kit, the receptor for stem cell factor, which promotes the malignant process within mast cell tumors when mutated. Since this mutation is not present in all dogs, it is likely only a contributing mechanism to a more complex process of neoplastic transformation.
Controversies with MCTs
The pathology and behavior of a MCT depends substantially on the histologic pattern of the tumor, which is associated with the tumor grade. However, there is variation within the grading scheme used among pathologists that lends itself to subjectivity in assigning a tumor to a particular category. Traditionally, these categories are grade I (well-differentiated or low grade), grade II (intermediate grade), and grade III (poorly-differentiated or high grade). Subsequently, guiding the appropriate therapy and providing prognostic information based on the traditional grading scheme has become complicated and unpredictable. The introduction of a two tier system (Kiupel) of low and high grade designed to minimize the subjectivity was introduced several years ago and has since been further validated. In a study of 137 surgically resected cutaneous MCTs, the relationship between grade and survival was evaluated. All grade I MCTs were low grade in the Kiupel system, and all grade III were deemed high grade. Among grade II, 71 (85.6%) were low grade, and 12 (14.4%) were high grade, with a 1-year survival probability of 94% and 46%. Per this study, the 2-tier system had a high prognostic value and was able to correctly predict the negative outcomes of some grade II MCTs. Currently pathologists are reporting both grading schemes.
To assist in more objectively categorizing a grade II MCT, which account for 70% of all MCTs, various immunohistochemical and molecular tests of tumor cell proliferation are now recommended in addition to routine histopathology. These markers of proliferation are now clinically available and are readily performed on tissue biopsy samples in the form of MCT panels (www.dcpah.msu.edu/Sections/Immunohistochemistry/FAQ.php#08). These assays provide clinicians with the ability to make more sound recommendations regarding the appropriate adjuvant therapy. This particular panel evaluates argyrophilic staining nucleolar organizing regions (AgNOR), proliferation cell nuclear antigen (PCNA), Ki-67, c-kit pattern assessment, and PCR for c-kit gene mutation. AgNOR frequency is an indirect measure of tumor cell proliferation and may be equally or even more important as the tumor grade in terms of predicting the biologic behavior of the MCT. PCNA and Ki-67 are also indirect measures of tumor cell proliferation and are most useful when interpreted in conjunction with one another. c-kit is the protein receptor for stem cell factor found in many cells including mast cells. A genetic mutation of the c-kit gene, which encodes for the c-kit receptor itself, has been identified in some MCTs. When mutated, the receptor is constitutively active and promotes the malignant process within the cells. Mutations within the c-kit gene are associated with a more aggressive phenotype. With the new two tier system, ideally this should decrease the need for further panels, as low grade tumors for the most part are associated with longterm survival.
When should one use a MCT panel?
If one goes on the assumption that the new grading scheme will soon become standard of care, then the data suggest 5% of “low grade” tumors will behave more aggressively. Ideally, a MCT panel, may help differentiate these patients and thereby guide the clinician to either a more aggressive surgery or adjuvant therapy that could benefit that patient. Although more recent data suggest 15% may metastasize, to run MCTs panels on all “low grade” tumors seems overkill. It also takes away the validity of grading scheme if it is being suggested to be run in conjunction with grading.
Ideally, the MCT panel should be reserved for cases in which the biopsy results do not fit the clinical picture; ie a more aggressive site (muzzle), fast growing tumor, severely ulcerated, large tumor, lymph node involvement, etc. Another application may be in patients with incompletely excised Grade II tumors. A recent study, evaluated whether the extent of surgical excision affects recurrence rate in dogs with grade II MCTs that had a low proliferation activity, determined by Ki67 and AgNOR. Eighty-six dogs with cutaneous MCT were evaluated. All dogs had surgical excision of their MCT with a low Ki67 index and combined AgNORxKi67 (Ag67) values. Twenty-three (27%) dogs developed local or distant recurrence during the median follow-up time. Of these dogs, six had local recurrence,,of which one had complete excision and five had incomplete excisions. This difference in recurrence rates between dogs with complete and incomplete histologic margins was not significant. The authors hypothesized that ancillary therapy may not be necessary for patients with incompletely excised grade II MCT with low proliferation activity, thus, in these select cases, a MCT panel may provide additional information regarding treatment.
For high grade tumors, performing portions of the panel may be useful for treatment decision. Knowing a kit mutation status in a high grade tumor may change the treatment choice from purely chemotherapy to a combination of chemotherapy and a TKI, whereby a higher response rate is noted in kit mutation positive patients. Currently studies are underway utilizing mutation status to help logically guide treatment decision for a more personalized medicine approach, albeit on a very basic level.
Submitted by Craig A. Clifford DVM, MS, DACVIM (Oncology)
Hope Veterinary Specialists, Malvern, PA
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