caninemastcelltumors

Canine Mast Cell Tumors –

Current thoughts on an unpredictable disease
By David Hunley, DVM
RIVMA NEWS | SPRING 2007

At one point or another we’ve all said it: “Oh that? No need to worry about that. That shouldn’t be a problem.” And then, of course “that” barely perceptible, almost nonexistent skin aberration blows up to ten times its initial size, and the owner returns with a look for consternation wondering how in the world you did not diagnose this mast cell tumor sooner. Of course, dog owners don’t realize the lengths at which mast cell tumors will go in their efforts to fool us.

They can look and feel like anything: lipomas, skin tags, blisters, scabs, nodules, papules. They can be as big as your head or so small that you can’t even aspirate them effectively. They pop up on the nose, between the toes, in the mouth, on the eyelids, at the tip of the tail and everywhere in between. We seem to diagnose them and write about them all the time, and yet the first thing any oncologist will tell you about this disease is: “Mast cell tumors have a very unpredictable biologic behavior.” While this will probably always be a true statement, I believe there are some generalizations that we can make and some relatively new information that could be helpful in determining how aggressive an individual mast cell tumor may be. The goal of this article is to address these issues in the context of a discussion about the diagnosis, staging, and treatment of mast cell tumors.

Diagnosis
If there is one good thing about mast cell tumors, it is that they typically exfoliate well and have a unique appearance (due to their purplish granules) and therefore are easily diagnosed on most cytology samples. It is important to remember, however, that the granules may not stain well with Diff-Quik, although this problem can be overcome in many cases by leaving the slide in the alcohol fixative for at least two minutes prior to staining. Sometimes, however, it is not the stain’s fault. With a poorly -differentiated mast cell tumor, the neoplastic cells may not contain many granules, and all we can tell on cytology is that we are dealing with a round cell category tumor. Of course, we may have some clues guiding us toward the diagnosis of mast cell tumor, either clinically (a history of waxing and waning in size due to episodic histamine release) or cytologically (the presence of many eosinophils in the sample due to release of eosinophilic chemotactic factor by the mast cells), but at this point a biopsy is warranted.

Although the histopathology report may also yield an enigmatic diagnosis of “round cell tumor,” special staining procedures can then be performed on the sample to differentiate between the various tumors in this category. The first secondary test typically performed (usually for free) is a Giemsa stain, which helps since the mast cell granules sometimes show up better with Giemsa than with other staining methods. This test can help if you pick up some granules with the Giemsa stain (thus diagnosing mast cell tumor), but some really poorly-differentiated mast cell tumors will truly have too few granules to see even on Giemsa stains, so a negative Giemsa does not necessarily equate to “not a mast cell tumor.” At this point, if you still have a high clinical suspicion of mast cell tumor, then you can request immunohistochemistry to detect unique surface proteins present on mast cells. I recommend a CD117 stain in conjunction with concurrent stains to rule out lymphoma (CD3, CD79a), but really this could be a whole article in itself, so often it is best to simply ask the pathologist in charge of the case for his/ her recommendations. For clients who are up for aggressive therapy, obtaining this definitive diagnosis is vital for appropriate prognostic communication with the owner and in making proper treatment decisions for the patient.

Grading & Staging
Once a mast cell tumor is diagnosed, there are a few vital pieces of information that must be gathered. If the diagnosis was made cytologically, then a biopsy is still essential since it gives us the tumor grade. While the grade (1, 2, or 3) of the mast cell tumor is often touted (correctly) as the most important prognostic indicator for this disease, there are some hidden problems with this system that contribute strongly to our inability to accurately predict how these tumors will act. First, the grading system itself is inherently flawed because there is no way to classify the wide variety of mast cell tumors that we see into only three categories. True grade 1 tumors are inevitably benign, and true grade 3 tumors will all eventually metastasize, but that leaves a wide range of biologic behaviors to be lumped into the category of grade 2. For example, one mast cell tumor may be fairly well-differentiated but also very invasive, with a few too many miototic figures to be a grade 1, while another mast cell tumor may be poorly-differentiated but fairly small, with a lower mitotic rate than a typical grade 3 tumor. Both of these are labeled as “grade 2,” but the first has a low metastatic potential and the second has a high metastatic potential. This obviously creates a prognostic dilemma when dealing with grade 2 tumors, and since grade 2 tumors comprise 65% - 80% of all mast cell tumors, this is a relatively common problem. Historically, pathologies have tried to circumvent this issue by calling such masses grand 1-2 or grade 2-3 mast cell tumors, respectively, but more recently the terms “low-grade 2” and “high-grade 2” mast cell tumors have become more widely accepted, along with the notorious (and still problematic) “intermediategrade 2” tumors.

While having five grading categories is more helpful than the classic three, there is still the problem of the subjective nature of the pathologist’s interpretation of the sample. A recent study took ten pathologists and asked them to grade 60 cutaneous mast cell tumors (grades 1-3). There was complete agreement among all ten pathologists for only four of these tumors (6.7%). By way of comparison six of the 60 tumors (10%) were assigned all 3 grades by different pathologists. I think this bears repeating: If you submit a mast cell tumor to ten different pathologists, there is a 10% chance that some will call it a grade 1 and some will call it a grade 3. Talk about a prognostic dilemma! In order to bring some objectivity to this process, a panel has been designed to evaluate mast cell tumor histopathology samples for a variety of markers of cell proliferation (Ki67, PCNA, and AgNOR). This is typically used to differentiate between low, intermediate, and high-grade 2 tumors, and appears to be effective in predicting patient survival (better for low-grade 2, worse for high-grade 2). This test is available from the Animal Medical Center in NYC (Flaherty Comparative Oncology Lab, 212-329-8675) at a cost of about $200. Alternatively, however, an abstract presented at the latest Veterinary Cancer Society meeting suggests that mitotic rate alone may be helpful in predicting survival times in dogs with mast cell tumors (< 5 mitotic figures per 10 hpf is associated with a better prognosis). The mitotic rate of the tumor should be given as part of the initial histopathology report.

For all (correctly categorized) grade 2 and 3 mast cell tumors, complete staging is recommended since the presence of distant metastasis is consistently associated with a short survival time. Complete staging consists of a CBS, biochemical profile, urinalysis, thoracic radiographs, abdominal radiographis and/or ultrasound (with specific attention paid to the liver and spleen), a buffy coat smear, and a bone marrow aspirate. These tests are designed to evaluate for concurrent diseases, as well as to determine the extent of disease spread. Since mast cell tumors do not metastasize to the pulmonary parenchyma, only two views of the chest are typically needed (to look for thoracic lymphadenopathy). It has been recently shown that if the liver and spleen appear normal on ultrasound, then aspirating them to look for metastatic disease is not helpful.

The buffy coat smear is controversial since many inflammatory diseases may cause an increase in circulating mast cells (mastocythemia). However if the dog has no other evidence of illness, and if the circulating mast cells show malignant changes, then a positive buffy coat is diagnostic for tumor metastasis. The bone marrow aspirate is another test that is often left off, and the reason that I have heard given is that if the marrow is involved, we should see neoplastic cells on at least one of our other staging tests. While I believe this statement is probably true in the vast majority of cases, I have seen several cases over the last few years where the bone marrow was the only place I found metastatic disease (all patients also had a normal CBC). True grade 1 tumors should not need staging tests performed since they do not metastasize.

Treatment
I use the following general treatment recommendations for cutaneous mast cell tumors: For grade 1 tumors and low to intermediate-grade 2 tumors that show no evidence of metastasis on staging tests, a complete surgical resection should be curative. If complete surgical resection cannot be achieved (often due to unfortunate anatomic positioning), then surgery plus definitive radiation therapy will also be curative in the vast majority of cases. For high-grade 2 and grade 3 tumors that show no evidence of metastasis on staging tests, ideal treatment consists of definitive local therapy (survey +/- radiation therapy) plus chemotherapy.

For a mast cell tumor of any grade that has detectable metastasis only in the regional lymph node (Stage 2 disease), consider definitive local therapy, including surgical removal and/or radiation therapy to the tumor and lymph node, as well as chemotherapy. This appears to be a more effective option for grade 2 tumors than for grade 3 tumors.

For any tumor with distant metastasis, the dog’s survival time is likely very short, and because of this only palliative therapy is needed for control of the original mass (systemic prednisone and antihistamines, palliative radiation therapy, direct injection of triamcinolone into the tumor). Chemotherapy is the mainstay of therapy in this situation. Unfortunately, when we have to resort to treating mast cell tumors with chemotheraphy, especially when we are dealing with detectable metastatic disease, we are fighting a losing battle since all of the chemotherapy agents we use commonly for treatment of mast cell tumors are effective in less than 50% of cases. The drug that I prefer is CCNU (lomustine) since I have seen the most consistent and dramatic results with this agent. I typically us it at a dose of 70 mg/m2 given once very three weeks for a total of six doses (or more if continuous therapy is needed). It is important to check both CBC and liver enzyme levels prior to each treatment due to potential hepatotoxicity. Vinblastine is also frequently used in the treatment of metastatic mast cell tumors, typically at a dose of 2 mg/m2 given weekly for four weeks, and then biweekly for four more doses. I have seen less efficacy with this drug and an abstract presented at this year’s Veterinary Cancer Society meeting also showed minimal efficacy in a group of dogs with this disease. Many oncologists have a different opinion, however, and use this as their first choice chemotherapy agent. Others have used these drugs in a combination protocol. Regardless of the protocol chosen, however, it is likely that a dog with distant metastatic disease will live only three to six months. Although there is always more to say about this disease, I hope that some of this information helps to illustrate the reasons for the difficulties we face in predicting prognosis given the current diagnostic tests we have at our disposal. Overall, we surely treat many of these tumors very successfully, and I tend to think of canine cutaneous mast cell tumors as an extremely treatable disease. However, these tumors also have a potential to cause extreme frustration, and even though I deal with them on a daily basis, I still find the old rhyme often associated with mast cell tumors to be true:

“Not one of them is like another. Don’t ask us why. Go ask your mother.”

Dr. Hunley is available for consultation in oncology at Ocean State Veterinary Specialists, Tuesday through Friday. He can be reached at 401-886-6787.

reprinted with kind permission from Dr David Hunley DVM
Susan Frisolone
Rhode Island Veterinary Medical Association
302 Pearl Street, #108 Providence, RI 02907
www.rivma.org | 401 751 0944 | rivma@rivma.org

The above information is simply informational. It's intent is not to replace the advice of a veterinarian nor to assist you in making a diagnosis of your pet. Please consult with your own veterinarian for confirmation of any diagnosis. Your pets life may depend on it.