Mast cell tumors in dogs (Proceedings)

Incidence and Risk Factors

Mast cell tumors (MCT) are the most common skin tumors in the dog. They represent 16-21% of all skin tumors. There are two forms in the dog, the dermal form and visceral form in the dog.

Average age at diagnosis is 9 years old (range 3weeks to 19 years). Brachycephalic breeds, Labradors, Beagles and schnauzers have been reported to be at an increased risk. Boxer's tend to develop lower grade tumors even though they appear to be the breed most commonly affected.

On rare occasions MCTs have been associated with chronic inflammation or the application of skin irritants.

Some MCTs have shown p53 mutations, others have shown mutations in the expression of proteins p21 and p27 (regulators of the cell cycle), but the most common mutation is associated with c-kit (the tyrosine kinase receptor for stem cell factor).  C-kit mutations in the juxtamembrane region lead to unchecked progression through the cell cycle and may lead to secretion of mast cell granule constituents in vivo and in vitro. Positive c-kit over-expression in a mast cell tumor may be associated with a poorer prognosis. European studies indicate that estrogens and progesterones in intact female dogs may create a more favorable response to chemotherapy; however, there are too few intact female dogs in the United States to apply this theory to our patients.

Clinical Signs

MCTs have a widely varied range of appearances and presentations. Complications related to the release of bioactive constituents within the granules are responsible for the majority of systemic and local signs associated with MCTs.

These signs include:

• Gastrointestinal Ulceration due to high histamine levels

• Hypotension with large histamine release

• Coagulation abnormalities (especially around the tumor) due to heparin

• Delayed wound healing due to vasoactive amines and proteolytic enzymes

Most tumors are solitary, but 11-14% of dogs will have multiple cutaneous tumors. Low grade masses can be present for months to even years with very little growth. Appearance can vary from solitary, nonulcerated, small, rubbery lesions to large diffuse soft and ulcerated masses. Surrounding tissues may become edematous and inflamed. Subcutaneous MCTs can feel just like lipomas and may be surrounded by fat making a diagnosis difficult. Darier's sign may be present after manipulation or release of granules.

Pathology and Diagnostics

Histologic grade has been established as a strong prognostic factor for mast cell tumors. There are 3 grades of mast cell tumors according to the Patnaik grading scale. Grade cannot be determined by cytology- only histology can determine the grade! Most tumors are low to intermediate grade.

Table 1 Histologic Grade Patnaik Grade Microscopic Description Anaplastic, undifferentiated (high grade) 3 Highly cellular, undifferentiated cytoplasmic boundaries; nuclei irregular in size and shape; frequent mitoses, sparse granules Intermediate grade 2 Cells closely packed with indistinct cytoplasmic boundaries; nucleus:cytoplasmic lower than in anaplastic type; infrequent mitoses, more granules than anaplastic type Well differentiated (low grade) 1 Clearly defined cytoplasmic boundaries with regular, spherical, or ovoid nuclei; rare or absent mitoses; abundant, large, deep-staining cytoplasmic granules

(Withrow & MacEwen, 2006, p403)

Special stains can be used to differentiate anaplastic MCT from other round cell tumors if cytology alone cannot.  Toludine blue or Geimsa stains may stain granules better than other stains. MCTs are vimentin positive, most are α-1-antitrypsin positive and they may stain positive for CD117 (kit).

The metastatic potential can be estimated based on grade:

• Grade 1 (well differentiated) - <10% metastatic rate

• Grade 2 (intermediate) – anywhere in between

• Grade 3 (undifferentiated tumors) - 55-96% metastatic rate

Diagnostic workup (what to do and when?)

A FNA is often all that is needed for an initial diagnosis of a mast cell tumor.  However, a biopsy is needed for grading purposes. Baseline blood work, regional lymph node aspirates, chest radiographs and abdominal ultrasound are all part of complete staging.  A high grade tumor requires all of these tests, a grade 1 MCT likely does not.

World Table 2: Health Organization Clinical Staging for Mast Cell Tumors Stage Description O

One tumor incompletely excised from the dermis, identified histologically, w/o regional lymph node involvement

0a. Without systemic signs

0b. With systemic signs I

One tumor confined to the dermis, w/o regional lymph node involvement

Ia. Without systemic signs

Ib. With systemic signs II

One tumor confined to the dermis, with regional lymph node involvement

IIa. Without systemic signs

IIb. With systemic signs III

Multiple dermal tumors; large, infiltrating tumors with or without regional lymph node involvement

IIIa. Without systemic signs

IIIb. With systemic signs IV Any tumor with distant metastasis, including blood or bone marrow involvement

Mast cells are found in normal organs.  You may see them while staging.  It can be very hard to determine when they are behaving themselves or when they are doing bad things. In a study of normal beagle dogs, 24% of normal lymph node aspirates had mast cells in them. Mast cells that cluster together in a lymph node tend to be behaving badly. Effacement of any organ with mast cells typically represents a metastatic process. Individual anaplastic looking mast cells can be an indication of metastasis. Buffy coats have fallen out of favor in the dog. They are rarely positive for mast cells. Other diseases cause mastocytosis more commonly, such as:

• Acute inflammatory disease (parvovirus)

• Inflammatory skin disease

• Regenerative anemias

• Neoplasia other than MCTs

• Trauma

Prognostic Factors

Histologic grade is strongly predictive of outcome. Dogs with high grade tumors often die of their disease with local therapy alone. Dogs with low grade tumors are often cured of their disease with the appropriate local therapy.

Clinical stage is prognostic. Lower stage tumors (0&1) have a better prognosis than higher grade tumors.

Location of the primary tumor plays a role in overall survival. Preputial, scrotal, subungual, oral, and other muco-cutaneous junction or mucous membrane locations are associated with higher grade tumors and a worse prognosis.  Visceral or bone marrow disease usually indicates a very grave prognosis.

Cell proliferation rates are prognostic. The mitotic index or markers of proliferation (AgNORs, PCNA or Ki67) are predictive of the post-surgical outcome. Similarly, the growth rate of MCTs is also prognostic.  Those that are slow growing, localized or present for a long time typically are lower grade.

Local recurrence after surgical resection may indicate a worse prognosis.

Systemic signs carry a worse prognosis. Systemic illness associated with metastasis or systemic effects of degranulation may be associated with a higher grade tumor.

The breed of dog may play a role in prognosis. Boxers tend to have lower to intermediate grade MCTs and typically have a better prognosis

C-kit mutations have been shown to be associated with prognosis. A mutation in c-kit may be associated with a worse prognosis and a higher grade tumor.

The size of the tumor is important. Large tumors may be harder to treat with local therapies such as surgery or radiation and may carry a worse prognosis.

Treatment

Surgery is the mainstay of therapy for a mast cell tumor. If the mass can be removed completely with adequate margins- it should be! If inadequate margins are achieved with a first surgery and a second is possible to get better margins- it should be done! Surgery can be done to determine the grade of the tumor before complete staging is done. Adequate margins include 2-3 cm margins around the tumor and one fascial plane deep. Lymph nodes that are involved should also be removed at the time of surgery. Cytoreduction before other therapies is also good for overall survival. Amputation may be an option for owners whose dogs have a distal extremity MCT and who cannot afford radiation therapy.

Radiation therapy is another very effective local therapy for MCTs. It can be a curative option for local microscopic disease in many cases with 2 year control rates of 85-95% for low grade tumors. Radiation therapy alone in the face of measurable disease has resulted in a 1 year control rate of about 50%. Radiation therapy can be palliative for large high grade MCTs, but the risk of degranulation can be high and the result could be fatal.

Chemotherapy is indicated in addition to local therapy for high grade MCTs. If possible, treat the primary tumor with surgery and/or radiation and treat systemically with chemotherapy to help prevent metastasis. Effective chemotherapy agents include Vinblastine, Vincristine, CCNU, Cytoxan, Chlorambucil and prednisone.  Chemotherapy can be used after surgery in those patients with microscopic disease who cannot afford radiation therapy.

Receptor tyrosine kinase inhibitors (RTKIs) are a relatively new class of anti-cancer drugs that target specific growth factor receptors that are often constitutively turned on in neoplastic cells.  Torcerenib (Palladia®) is the new drug created by Pfizer and the first anticancer drug approved by the FDA for treating cancer in dogs.  This RTKI inhibits c-kit, PDFGR, FGFR, VEGFR and a few others.  Because of its multi-targeted nature, this drug has been used off-label as an anticancer agent against many other tumor types as well.  However, this also leads to more side effects. 

This drug has been shown to induce responses in up to 40% of mast cell tumors.  It is most effective in those tumors with mutated c-kit and those that over express wild type c-kit (i.e. high grade mast cell tumors).  Response rates are similar to those reported for other chemotherapy drugs such as vinblastine and CCNU.  C-kit staining may be necessary to determine which cases have a better chance of responding to this drug.  Michigan State offers a test to look for c-kit mutations, and we are planning to do the same at TAMU soon.

Palladia is given orally at 3.25 mg/kg PO every day initially.  We are seeing a lot of side effects and dose reductions are often necessary.  New unpublished data suggests that every other day dosing or a MWF schedule may be more appropriate.  Side effects include neutropenia, thrombocytopenia, diarrhea, vomiting, lethargy, bone or muscle pain and possibly hyperpigmentation of the skin.

Ancillary therapies are important for animals with gross disease. There are several drugs that can help control the symptoms caused by mast cell degranulation:

• Prednisone – to stabilize the membrane and decrease degranulation

• Benadryl- H1 blocker

• H-2 blockers- famotidine, ranitidine

• Proton pump inhibitors- omeprazole

• Sucralfate- heals ulcers

• Pain medications

• Heparin antagonists (Protamine)