Mast Cell Tumors: Making Sense of the Pathology Report and Associated Treatment Decisions
Craig A Clifford DVM, MS, DACVIM (Oncology)
Hope Veterinary Specialists
40 Three Tun Road
Malvern, PA 19355 USA
Cliffdoc2000@yahoo.com
Introduction
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 ckit, 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
Diagnosis and Staging: Currently, no “standard of care” exists, even amongst oncologists. Routine
staging includes physical examination, bloodwork/urinalysis, thoracic radiographs, and fine needle
aspirates of draining local lymph nodes. Other ancillary diagnostics such as abdominal ultrasound and
bone marrow aspiration are patient-dependent. Buffy coat analysis has been shown to be an insensitive
indicator of MCT. The literature varies in regard to the usefulness of abdominal ultrasound and more
recent literature suggest that the liver and spleen should be aspirated regardless.
In this authors practice, abdominal ultrasound is not a routine staging modality unless clinically dictated
(patient present ill) or prior to advent of radiation therapy.
Grading: 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.
Mitotic index: The mitotic index (MI) is defined as the number of mitoses per 10 high power fields has
proven to be a useful prognostic factor. An MI >5 is associated with a poor prognosis (median survival
time of 2 months), whereas an MI ≤ 5 suggests a more favorable prognosis, with a reported median
survival time (MST) of 70 months. In the new two-tier system (Kiupel) a MI of 7 or > is associated with a
high grade tumor.
Many oncologist will use the MI, at least in part, to help dictate the need for additional therapy, ie. A low
grade tumor with a MI of 0-1 that was completely excised warrants only local control.
MCT Panels: 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.
This author generally does not run MCT panels on a routine basis unless clinically there is a discrepancy
between the biologic behavior and histopathologic description or in cases of an incompletely excised
tumor whereby the panel may help guide treatment decisions. More commonly, kit mutation status is
performed on high grade tumors in an efforts to determine the inclusion of a tyrosine kinase inhibitor to a
treatment protocol.
Margins: The standard of care regarding therapy is surgery and the use of 3 centimeters lateral and 1
fascial plane deep to the MCT margins are most likely to ensure a complete excision. This has come into
question and data has shown that 2 cm lateral and one fascial plane deep margins are sufficient for the
“average” grade II MCT. Most studies have shown that MCTs removed with clean margins have a low
recurrence rate (5-10%), a 10-20% new tumor development rate, and a 5% metastatic rate. A more
recent study evaluated tumor size to dictate surgical margins.
It is well accepted that patients with incomplete surgical removal of MCTs should undergo re-resection or
external beam radiation therapy. Local control rates of >90% (second surgery) and >95% (radiation
therapy) are published. If left untreated, studies have shown 10-40% of incompletely excised MCTs will
recur and certainly grade has some bearing upon this. Most “garden variety” grade I or II tumors can be
treated sufficiently with only local control.
The question becomes what to do with narrowly excised low grade tumors?
A recent study which evaluated 59 low grade tumors noted 29% had “narrow margins” (less than 3 mm)
and none recurred. The results of this paper suggest that narrow (≤3 mm) histologic margins are likely
adequate to prevent local recurrence of low-grade tumors. Narrowly excised high grade tumors should
undergo revision surgery to obtain more complete margins and prevent local recurrence.
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