Mast Cell Tumors CANINE

A normal mast cell is part of our immunologic defense systems against invading organisms. Mast cells are meant to participate in the war against parasites (as opposed to the war against bacterial or viral invaders). They are bound within tissues that interface with the external world such as the skin, respiratory or intestinal tract. They do not circulate through the body.

The mast cell possesses granules of especially inflammatory biochemicals meant for use against invading parasites. Think of these as small bombs that can be released. The mast cell has binding sites on its surface for a type of antibody called IgE. IgE is produced in response to exposure to antigens typical of parasites (i.e., worm skin proteins, or similarly shaped proteins). IgE antibodies, which are shaped like tiny Ys, find their way to a tissue mast cell and perch there. With enough exposure to the antigen in question, the mast cell may be covered with Y- shaped IgE antibodies like the fluff of a dandelion. The mast cell is said, at this point, to be sensitized.

As said, the IgE antibodies are Y-shaped. Their foot is planted in the mast cell while their arms lift up hoping to capture the antigen for which they were individually designed. When the antigen comes by and is grasped by the IgE antibodies, this should indicate that a parasite is near and the mast cell, like a land mine, degranulates releasing its toxic biochemical weapons. These chemicals are harmful to the parasite plus they serve as signals to other immune cells that a battle is in progress, and for them to come and join in.

At least this is what is supposed to happen.

The problem is that we live in a clean world without a lot of parasites. What unfortunately tends to happen is that the IgE/mast cell system is stimulated with other antigens that are of similar shape or size as parasitic antigens. These next best antigens are usually pollen proteins and the result is an allergy. Instead of killing an invading parasite, the mast cell biochemicals produce local redness, itch, swelling, and other symptoms we associate with allergic reactions.

And the Mast Cell Tumor?

As if the mast cell isn't enough of a troublemaker in this regard, the mast cell can form a tumor made of many mast cells. When this happens, the cells of the tumor are unstable. This means they release their toxic granules with simple contact, or even at random, creating allergic symptoms that do not correlate with exposure to any particular antigen.

Mast cell tumors are notoriously invasive and difficult to treat.

CANINE

Mast cell tumors are common in dogs and account for approximately one skin tumor in every five. The Boxer is at an especially high risk, as are the related breeds English Bulldog and Boston Terrier. Also at higher than average risk are the Shar pei, Labrador Retriever, Golden Retriever, Schnauzer, and Cocker Spaniel.

Most mast cell tumors arise in the skin but technically they can arise anywhere that mast cells are found. The mast cell tumor does not have a characteristic appearance though because of the tumor's ability to cause swelling through the release of granules, it is not unusual for the owner to notice a sudden change in the size of the growth or, for that matter, that the growth is itchy or bothersome to the patient.

Diagnosis can often be made with a needle aspirate, which collects some cells of the tumor with a needle, and the cells are examined under the microscope. The granules have distinct staining characteristics leading to their recognition. An actual tissue biopsy, however, is needed to grade the tumor and grading of the tumor is crucial to determining prognosis.

Grading the Mast Cell Tumor
The pathologist will most likely use the Patnaik system for grading the mast cell tumor when the biopsy sample is read. The grade is a reflection of the malignant characteristics of the cells under the microscope (which generally correlates to the behavior of the tumor) with Grade I being benign, Grade III being malignant, and Grade II having some ability to go either way.

GRADE I TUMORS
This is the best type of mast cell tumor to have. While it may tend to be larger and more locally invasive than may be visually apparent, it tends not to spread beyond its place in the skin. Surgery should be curative. If the original biopsy shows that the tumor has only narrowly been removed or that the tumor extends to the margins of the sample, a second surgery should promptly be done to get the rest of the tumor, if at all possible. If the grade I mast cell tumor is incompletely excised it will grow back in time; it is best to get it all and be done with it as quickly as possible. About half of all mast cell tumors are Grade 1 tumors and can be cured with surgery alone.

Between 7 and 21% of all canine skin tumors are mast cell tumors.

GRADE II TUMORS
This type of tumor is somewhat unpredictable in its behavior. Recent studies have shown that radiation therapy administered to the site of the tumor can cure greater than 80% of patients as long as the tumor has not already shown distant spread.

GRADE III TUMORS
This is the worst type of mast cell tumor to have. Grade III tumors account for approximately 25% of all mast cell tumors and they behave very invasively and aggressively. If only surgical excision is attempted without supplementary chemotherapy, a mean survival time of 18 weeks (4-5 months) can be expected.

Staging the Mast Cell Tumor

In order for a rational therapeutic plan to be devised, the extent of tumor spread (or stage of the tumor) must be determined. The World Health Organization has determined a clinical staging system based on the body areas affected by the tumor. Between the stage and the grade, a plan can be devised. The tumor is staged 0 through IV as described below:

  • Stage 0: one tumor but incompletely excised from the skin.
  • Stage I: one tumor confined to the skin with no regional lymph node involvement.
  • Stage II: one tumor confined to the skin but with regional lymph node involvement present.
  • Stage III: many tumors or large deeply infiltrating tumors, with or without lymph node involvement.
  • Stage IV: any tumor with distant spread evident. This stage is further divided into substage A (no clinical signs of illness) and substage B (with clinical signs of illness). In order to determine the tumor stage some probing of other lymphoid organs must be performed.

Your veterinarian may recommend the following tests.

Basic Blood Work
A basic blood panel is part of this evaluation and should be obtained if it has not already been done. This testing will help show any factors that limit kidney or liver function and thus determine what drugs of chemotherapy can or cannot be used. It also will show if there are circulating mast cells in the blood (a very bad sign) or if the pet has anemia (low red blood cell count) that might be related to the tumor.

Buffy Coat Smear/Bone Marrow Tap

After a patient's tube of capillary blood has been centrifuged, the buffy coat is the small layer of white blood cells that floats atop the layer of red blood cells. This layer of cells can be smeared onto a microscope slide and checked for circulating mast cells. This process was once considered an important method of evaluating mast cell spread in dogs but has more recently been found not very helpful. This test is still of use for cats but has been largely supplanted by a bone marrow tap for dogs. The idea behind both of these tests is to determine if malignant mast cells are in the bone marrow (malignant cells circulating in the blood/found in the buffy coat would indicate malignant cells in the marrow).

Local Lymph Node Aspiration
The lymph nodes local to the site of the tumor should be aspirated (if they can be found) to see if the tumor has spread there.

Aspiration of the Spleen/Radiographs
The size of the spleen can be evaluated with radiographs but ultrasound guidance is generally needed to withdraw some cells for testing. The spleen is an organ of the lymph system and tumor located in the deeper lymph organs such as the spleen and abdominal lymph nodes should be assessed. While the mast cell tumor does not spread to lungs the way other tumors do, there are many lymph nodes in the chest and it is helpful to radiograph the chest to assess the size of these lymph nodes and help determine the extent of the tumor spread.

Other Factors in Prognosis

As if grade and stage do not pose enough food for thought, other factors add in to the prognosis.

Anatomic Location
Mast cell tumors arising in the following areas tend to be the most malignant: nail bed, genital areas, muzzle, and oral cavity. Mast cell tumors that originate in deeper tissues such as the liver or spleen carry a particularly grave prognosis.

Growth Rate of Tumor
Tumors that have been present for months or years tend to be more benign.

Argyrophilic Nuclear Staining Organizing Regions (AgNORs): The pathologist can use a silver stain on the tumor sample. The uptake of this stain correlates to the rapidity with which the tumor cells grow. The higher the AgNOR count, the more malignant the tumor. There are numerous stains for certain tumor proteins (Ki-67, p53 tumor suppressor protein, c-kit gene products, and the list goes on). The idea is that further information about the behavior of a Grade II tumor could be obtained by staining for these factors. This idea is currently fraught with controversy.

Other testing features can be applied to the sample but, in general, the grade, stage, location and symptoms of the patient help point to therapy.

Therapy

Therapy for mast cell tumors consists of surgery, radiation therapy, and chemotherapy (as is the case for almost all types of cancer). What combination of the above is chosen depends on the extent of spread and malignant characteristics of the tumor.

Surgery
If the tumor can be cured with one or even two surgeries, this is ideal. Mast cell tumors are highly invasive, and very deep and extensive margins - at least 3 cm in all directions - are needed. This can be a problem for tumors located on the neck or in the mouth. Further, the inflammation associated manipulating the tumor can lead to extra swelling, bleeding, and even a drop in blood pressure. In one study, a 10% incidence of wound healing failure (dehiscence) was observed with mast cell tumors.

The biopsy sample will not only yield the grade of the tumor but will include a measurement of the tissue margin (the width of normal tissue that has been excised around the tumor). The width of the margins will go far in determining if further treatment is needed. If the margins are narrow or margins indicate there is still tumor left behind then a second surgery or even a course of radiation therapy may be desirable. Clean margins are generally defined as a 10 mm margin around the tumor in all directions. If the margin is clean, theoretically the tumor should be completely removed but it is still a good idea to keep an eye on the area over the years.

Radiation Therapy
While radiation therapy tends to be expensive and requires a facility that may not be conveniently located, radiation has the potential to permanently cure a grade I or II mast cell tumor. Radiation is most appropriate for localized disease. If the tumor shows more distant spread, radiation becomes less helpful and medications (chemotherapy) that can be delivered to the tumor through the patient's blood vessels are needed.

In January 2004, Hahn, King and Carreras published a study where radiation therapy was used to treat incompletely removed Grade III mast cell tumors. They studied 31 dogs with Grade III mast cell tumors that did not show evidence of distant spread beyond the external area where the tumor was first detected. They treated these dogs with radiation sessions given three days a week for a total of 18 sessions. Approximately 65% of dogs achieved remission and 71% were alive one year after treatment. The median remission time was approximately 28 months with dogs having ear or genital tumors doing better than dogs with tumors in other locations. Dogs with tumors less than or equal to 3 cm in diameter prior to surgery had a median survival time of 31 months. These are optimistic findings for the Grade III mast cell tumor, even though radiotherapy is an expensive treatment method.

Chemotherapy
Currently three drugs used to treat cancer have been particularly helpful in combating mast cell disease: corticosteroids (such as prednisone,) lomustine, and vinblastine.

Corticosteroids seem to be directly toxic to mast cells and can lead to a brief remission even when used alone. Corticosteroids are inexpensive treatments and definitely worth trying should more powerful chemotherapy drugs be considered too expensive or troublesome.

At this time, statistics for survival and disease-free interval with this type of combination therapy are not available.

The mast cell tumor releases histamine-containing granules that lead to inflammation and increased stomach acid secretion.

These unpleasant symptoms may be alleviated with the use of H1 blockers (antihistamines such as Benadryl® and others) as well as H2 blockers (antihistamines such as Pepcid AC® and others).  These medications help palliate the inflammatory effects of the spreading malignant mast cell tumor.

FELINE

The mast cell tumor situation is slightly different for cats although most of the same concepts hold true (so if you skipped the canine section to read the feline information it would be best to go back and read it at this point). Mast cell tumors classically affect older cats; in one study the average age was 10 years. Pathologists divide mast cell tumors into two forms: well differentiated and poorly differentiated. The well-differentiated tumor is generally more benign in its behavior while the poorly-differentiated tumor behaves more malignantly. Mast cell tumors in cats are also classified by their location into two forms: cutaneous (located in the skin) and visceral (located internally). An unlucky cat may have both.

Cutaneous Forms
The skin form of the feline mast cell tumor classically arises around the head and neck. Lesions may be solitary or multiple; multiple lesions do not necessarily bode poorly, although if there are many mast cell tumors, that would constitute rather a lot of inflammatory biochemicals and more symptoms for the cat).

Treatment of choice would be surgical excision. If surgical excision is incomplete, radiation therapy as a follow-up is generally successful at cleaning up any leftover cells.

Visceral Form
As you might surmise, mast cell tumors located internally are more serious than those in the skin. The most common organs involved are spleen, liver, and intestine. Vomiting, appetite loss, and weight loss are the most common symptoms. As with the cutaneous form surgery is the treatment of choice but not as easily accomplished; no single chemotherapy protocol has emerged as being particularly successful above the others. Unlike the canine situation, it is not all that helpful to stage the disease with buffy coat smears and bone marrow taps (though localizing the disease to the spleen with a splenic aspirate might be particularly useful - see below) as tumor cells in these locations has not altered prognosis for this disease.

The most telling piece of information for prognosis actually comes from the cat’s history of appetite. Cats that are eating decently they are first brought to the veterinarian have a median survival of 19 months, while cats that are not eating have a median survival of 8 weeks.

Splenic Mast Cell Tumor
Luckily, the spleen can be removed leading to a rapid recovery. The median survival after splenectomy is 14 months (vs. 4-6 months if the spleen is left). This is not to say that the cat is cured with splenectomy, but removing the spleen frees the cat from the bulk of the mast cells quickly and it takes time for the tumor to regrow.

Not all veterinarians are comfortable treating mast cell malignancy. Discuss with your veterinarian whether referral to a specialist would be best for you and your pet.

 

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