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Golden Retriever Lifetime Study

Update v16-1

Golden Retriever Lifetime Study Update v16-1

Mast cells are a type of white blood cell that participate in local immune function. They contain granules that release histamine, heparin, and other enzymes involved in allergic reactions and fighting off infectious agents. Mast cell tumors are most commonly found in the skin and subcutaneous tissues and account for 7 percent to 21 percent of canine skin tumors1. They readily are diagnosed via fine needle aspirate and/or surgical biopsy.

The biologic behavior of these tumors varies greatly. Therefore, grading systems and additional tests are used to help determine the prognosis for each.

Mast cell tumor grading systems

The Patnaik system is based on a study published in 1984 and correlates well with 1,500 day (4 year) survival rates2.

Grade I
Well differentiated, clear cell boundaries, rare mitotic figures (dividing cells). 93% survival > 1,500 days

Grade II
Intermediate differentiation, closely packed cells, infrequent mitotic figures, moderate intracellular granules. 47% survival > 1,500 days

Grade III
Undifferentiated, poorly distinguished cell boundaries, frequent mitotic figures, few intracellular granules. 6% survival >1,500 days

A more recently proposed 2-tier grading system (2011), aims to better predict the biologic behavior of mast cell tumors3.

Low Grade

Few mitotic figures, normal nuclear appearance.

Median survival time > 2 years.

High Grade

High mitotic index, multinucleated cells, misshapen or enlarged nuclei (karyomegaly).

High risk of developing additional tumors or metastasis. Median survival time < 4 months

Mitotic index, reported as the number of mitotic figures or dividing cells per 10 high-power microscope fields, also has been shown to correlate with biologic behavior4. Grade II tumors with a MI < 5 had a median survival of 80 months. Grade II tumors with a MI > 5 had a median survival time of only three months.

Additional mast cell tumor testing

Once diagnosed, canine mast cell tumors should be staged in each patient to further clarify the prognosis and determine if aggressive surgery and treatments are warranted. This is most helpful for intermediate grade tumors, which show the greatest variation in their biologic behavior. Staging involves routine blood tests, aspiration or biopsy of regional lymph nodes, and thoracic and abdominal radiographs and/or ultrasound to determine the location and spread of the disease. The most common sites for metastasis of MCT are the regional lymph node(s), liver and spleen.

Additional tests can be completed on tissue samples to help determine prognosis. Cell proliferation analysis, reported as proliferation index, looks at proteins such as Ki67, PCNA and AgNORs, to determine how many mast cells are proliferating and how rapidly. Ki67 is a protein made by growing cells, so the relative number of Ki67-positive cells is expressed as a proliferation index and is a good marker of tumor growth. Proliferating cell nuclear antigen is another protein made during cell growth, similar to Ki67, and also is reported as a proliferation index. AgNOR is an acronym for argyrophilic nucleolar organizing regions, which are essentially proteins involved in rRNA transcription that take up silver stain.

 

The number of AgNORs visible in a tissue sample is directly related to the rate of cellular protein production. It is reported as the average number of AgNORs per cell. Studies suggest that evaluation of these three parameters as a group is more accurate than any single test result. They are included in many mast cell panels offered by laboratories.

The KIT protein is another area of focus for prognostic information pertaining to MCTs. In normal mast cells it is found on the cell surface. However, in neoplastic cells it is found in the cytoplasm. Immunohistochemical staining shows different patterns of KIT protein expression that can be correlated with survival rates.

Finally, PCR testing can identify mutations in the c-KIT gene which is found in 20 percent to 30 percent of canine MCTs. These mutations play a role in tumorigenesis and patients with more c-KIT mutations are more likely to experience recurrent disease and decreased survival time.

Treatment

Treatment for low-grade MCTs is surgical resection with wide margins. The current recommendation is to remove 2cm of tissue laterally plus 1cm and 1 fascial plane deep to the tumor. H1 blockers such as diphenhydramine (Benadryl) or loratidine (Claritin) should be given prior to and following surgery to help mitigate the effects of local histamine release caused by tumor handling.

Dogs with MCTs also need protection against stomach ulceration. Since histamine stimulates the secretion of stomach acid, H2 blockers such as famotidine (Pepcid), proton pump inhibitors such as omeprazole (Prilosec), and the mucosal protectant sucralfate (Carafate), can help prevent and treat ulcer formation.

For high-grade tumors or those not amenable to full resection or surgery, additional therapy is needed. Chemotherapy with drugs such as vinblastine, lomustine (CCNU), cyclophosphamide and prednisone can be used for tumors for which surgery and radiation have failed or are not feasible. Newer therapies use tyrosine kinase inhibitors such as toceranib (Palladia) and masitinib (Kinevet) targeted at the c-KIT mutation found in certain canine MCTs. These drugs inhibit the signal cascade that triggers cell division, and can have some effect even in cells without the c-KIT mutation. MCTs are very responsive to radiation therapy, which may be used in combination with surgery and chemotherapy.

Mast cell tumors are one of the four major cancers being studied in the Golden Retriever Lifetime Study. High-grade MCTs carry a poor prognosis. As of December 2015, 10 study dogs have been diagnosed with mast cell tumors (2 grade I, 8 grade II). Our goal is to collect clinical and lifestyle data that will help us better understand the incidence of and risk factors for this disease.

  1. Pergamon Press Ltd. 1992, “Skin tumors of the dogs and cat,” by M.H. Goldschmidt & F.S. Shofer
  2. Veterinary Pathology, Vol. 21, pp. 469-474, 1984, “Canine Cutaneous Mast Cell Tumor: Morphological Grading and Survival Time in 83 Dogs,” by A.K. Patnaik.
  3. Veterinary Pathology, Vol. 48, no. 1, pp. 147 – 155, 2011, “Proposal of a 2-Tier Histologic Grading System for Canine Cutaneous Mast Cell Tumors to More Accurately Predict Biological Behavior,” by M. Kiupel, et al.
  4. Veterinary Pathology, Vol 44, pp. 335-341, 2007, “Mitotic Index is Predictive for Survival for Canine Cutaneous Mast Cell Tumors,” by E.M. Romansik, et al.
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