IN THIS ARTICLE
Western Biomedicine Perspective on Mast Cell Tumors
Diagnosing Mast Cell Tumors
Standard of Care Conventional Medicine Treatment and General Prognosis
An Integrative Approach to Mast Cell Tumor Management
THE BASICS OF MAST CELL CANCER
Mast cell tumors are the most common type of skin tumor in dogs. A diagnosis can usually be made with a fine needle aspirate, however the biological behavior and metastatic potential of mast cell tumors is dependant upon tumor grade which can only be determined by a surgical biopsy.
Mast cells are normal cells in the body and are part of the immune system. They are the cells reponsible for the itch and swelling you get around a bug bite, for example.
Mast cells contain histamine, heparin and other vasoactive substances which help the immune system respond to local problems. Cancerous mast cells grow without the proper cell regulation and often release these granules inappropriately so that swelling occurs around the site of the tumor.
Potential complications associated with mast cell degranulation (and thus release of these chemicals) may include stomach ulcers, reddening or swelling of the tissue surrounding the mass, delayed healing at the site of removal, clotting abnormalities and, rarely, low blood pressure.
If your dog has a mass that comes and goes in the same area over a long period of time or one that gets bigger and smaller, I recommend making an appointment with your veterinarian to evaluate the mass and do a procedure called a "fine needle aspirate" where they take a sample of the mass with a needle and send it in to have a pathologist evaluate the cells under a microscope.
It is often helpful to mark the spot in some way so that you and your vet will be able to find the area again. Sometimes the mass is hard to find if it has decreased in size by the time you are at the clinic. I have seen masses disappear only to reappear again later. I like to use a sharpie marker on light fur or white out on dark fur.
Dogs that develop one mast cell tumor are prone to developing others in the future. All new masses should be aspirated regardless of gross physical appearance and surgically removed if suspicious cells are noted on cytology.
PREDICTING BEHAVIOR OF MAST CELL TUMORS
Tumor Grading:
Tumor grading requires a surgical biopsy. Two grading systems are currently in use for histological grading of mast cell tumors. Patnaik grade III tumors and Kiupel high grade tumors are significantly more likely to have metastasis than tumors lower in grade. However 6% of Patnaik grade 1 tumors, 17% of Patnaik grade II tumors, and 15% of Kiupel low-grade tumors were associated with metastasis at the time of diagnosis.
These results highlight the importance of the combined information of tumor grade, clinical staging and molecular markers in more accurately predicting malignant behavior and overall survival in individual patients with mast cell cancer.
Mitotic Index:
Mitotic index within the biopsy sample has also been prognostic. The reported median survival time is 70 months for dogs with tumors having a mitotic index of less than 6 mitotic figures per 10 high power field. The reported median survival time is 5 months for dogs with tumors having a mitotic index greater that 6.
TREATMENT
Surgery
Wide surgical excision is the treatment of choice. The general recommendation to ensure that all cancer cells are likely to be removed in the first surgical procedure is for the surgeon to remove an area that is equal to the diameter of the mast cell tumor all the way around the mass and one fascial plan deep. The fascia is the connective tissue between the muscles which acts as a good barrier to cancer cells.
This can require a large incision in some cases. The good news is that most dogs do very well with surgery and if the first surgery is appropriately aggressive this may save your dog from needing to undergo additional local treatments like a second surgery, radiation or electrochemotherapy.
In some locations, like the legs and head, where there is bone just beneath the skin it is not possible to remove all the individual cells in the area. In these boney locations it is typical for some cells to remain in the area. Removing the bulk of the tumor is helpful to increase our ability to control most tumors that have not spread yet to other areas. The less disease left after surgery, the more likely the area will heal well and that other treatments will be helpful.
Tumor regrowth in the same area is more common in patients with incompletely removed mast cell tumors. Radiation, electrochemotherapy or chemotherapy may be considered post surgery to help keep the tumor from growing back at the surgical scar.
Additional treatment recommendations beyond surgery are dependant upon tumor grade, margins (if the mast cell tumor was completely removed surgically) and c-kit status.
Radiation
When the tumor is in a location that surgery cannot be performed, radiation can be very helpful to shrink the tumor, sometimes making it amenable to surgery afterwards. There are many different radiation protocols depending on your dog's situation. It is best to consult with an oncologist and a radiation oncologist to determined the best protocol.
Radiation is also the historical mainstay of treatment to kill cancer cells that are remaining at the surgical site and for, low grade mast cell tumors, has a high cure rate.
Electrochemotherapy
Electrochemotherapy is a relatively newer technology and has been effective in preventing regrowth of mast cell cancer at the surgical scar when surgical margins are not clear of cancer cells. I have this technology at our clinic and this is my preferred post-surgery treatment over radiation because it can be delivered in two treatments, compared to 15-18 treatments of radiation. This makes the treatment less expensive and is also less anesthesia episodes.
Prednisone
The effectiveness of Prednisone alone for the control or treatment of mast cell tumors has been disappointing, with responses lasting only a few weeks in the majority of cases.
PROGNOSIS
Prognosis depends on the characteristics of you dog's mast cell tumor, number of tumors, treatment elected, whether there are DNA mutations, and whether the cancer has spread to other sites yet. The simplest way to generalize prognosis is with tumor grade, which is determined by a pathologist on surgically removed tumor tissue.
Low grade mast cell tumors that are treated with adequate local treatment (surgery or combination of surgery and radiation) have 1 year survival rates of 100 and 94% respectively with two-year local tumor control rates of 85%-95%.
High grade mast cell tumors have a less favorable prognosis because over 50% of high grade tumors will metastasize, or spread to distant sites in the body. With surgery alone, approximately 46% of dogs will survive one year.
Local lymph nodes, spleen and liver are the most common sites of metastasis. Lung involvement is uncommon but has been reported and, in cases of disseminated disease, mast cells may be observed in the blood or bone marrow.
Follow-up chemotherapy and/or tyrosine kinase inhibitors are recommended after adequate local treatment with surgery (+/- radiation/electrochemotherapy). Improved survival times are seen with the addition of these medical treatments. The median survival time for dogs with grade III mast cell tumors treated with surgery and chemotherapy is approximately 6-12 months.
Stage V disease is diagnosed when there is evidence the cancer is spreading to other areas in the body. Unfortunately dogs with tumor spread to internal organs (Stage V disease) have a poor overall prognosis (average 3 months). Chemotherapy can be considered in an attempt to slow tumor progression.
CHEMOTHERAPY: DETAILS AND STATISTICS
Tyrosine Kinase Inhibitors
Mast cell tumors, in the bulky disease setting, are notoriously resistant to traditional chemotherapy agents. Toceranib (Palladia) and Masitinib (Kinavet) are veterinary tyrosine kinase inhibitors which were developed to treat aggressive mast cell tumors. These drugs inhibit KIT signaling, which is involved in tumor progression. Tumors with mutations in the c-kit gene are more likely to respond to these drugs, although tumors without c-kit mutations can also respond through other mechanisms.
Toceranib was evaluated prospectively for the treatment of recurrent non-metastatic grade II and III MCTs in a multi-institutional placebo-controlled study. Of the 145 dogs receiving toceranib, 42.8% experienced an objective response and the median time to tumor progression was 18 weeks. In the bulky disease setting a response rate of 70% was seen in tumors with c-kit mutations and a response rate of 40% was seen in tumors with wild-type c-kit (no mutation). Toceranib has shown activity in inhibiting other receptors involved in cancer progression including inhibition of VEGF receptor activation.
Potential side effects include anorexia, vomiting, diarrhea, protein loss through the urine and low white blood cell count. Blood counts (CBC) need to be monitored every other week for four weeks, then a CBC/chemistry profile/UA need to be performed every four to six weeks.
Masitinib is currently not available in the US.
Chemotherapy for incompletely or narrowly excised mast cell tumors:
Chemotherapy is recommended for high grade mast cell tumors to help slow metastasis or for incompletely removed low grade tumors when radiation cannot be pursued. The most common reason radiation is declined is due to cost or concerns about daily anesthesia. In the United States, radiation typically runs between $3000-$6000 for a course of therapy depending on the protocol and where in the country you live.
While chemotherapy is generally considered less effective for local disease control than radiation and electrochemotherapy, a number of studies have been published which show benefit to follow-up chemotherapy when radiation or electrochemotherapy are not an option.
CCNU and Vinblastine:
A study evaluating CCNU and Vinblastine for mast cell cancer (Vet Comp Oncol. 2009 Sept) reported a median progression free interval of 8.7 months for dogs with microscopic disease. Survival times of over 2 years have also been noted in dogs treated with single agent vinblastine for incompletely excised mast cell tumors. We have seen many good results with this single agent protocol in a microscopic disease setting (incomplete margins, no metastasis) at our clinic.
Palladia
Palladia or a combination of vinblastine and Palladia is recommended for incompletely excised mast cell tumors that have a mutation in the c-kit gene.
Chemotherapy for treatment of non-resectable or metastatic mast cell cancer:
CCNU, Vinblastine and prednisone
A 2010 study (Vet Comp Oncol. 2010, June) evaluated response rate and survival time in 17 dogs with nonresectable mast cell tumors and 35 dogs with metastatic or high grade mast cell tumors treated with a combination of CCNU, high dose Vinblastine and prednisone. Response rate in dogs with measurable disease was 65%, with 5 dogs experiencing a complete response lasting a median of 4.5 months. Six dogs experienced a partial response lasting a median of 2 months. Dogs who received this treatment for metastatic grade II tumors had a median progression free survival of 2.6 years, compared to 6 months in dogs who had grade III tumors.
Another study evaluating CCNU and Vinblastine for mast cell cancer (Vet Comp Oncol. 2009 Sept) reported a 60% response rate in patients with macroscopic disease with a median progression free interval of 7.5 months.
Vinblastine and Cytoxan
Vinblastine has also been used in combination with Cytoxan and prednisone for microscopic disease with a reported 2.4 year median progression free survival time and median overall survival time of over 5.7 years. (Vet Comp Oncol. 2007)
Vinorelbine
Response rate to Vinorelbine is 13% (J Vet Intern Med. 2008 Mar-Apr).
Palladia
Palladia was evaluated in the gross disease setting in dogs with metastatic or recurrent mast cell cancer. The overall response rate was 40% and an additional 20% of dogs experienced stable disease for an overall biological activity of 60%. Median response duration was 3-4 months. Dogs who had tumors with mutation in the c-kit gene were more likely to respond (70%) than those without gene mutation (40%).
In a 2012 study, Palladia was evaluated with Course fraction radiation and prednisone as a treatment for dogs with mast cell tumors that could not be surgically removed. Complete remission (tumor visibly resolving) was seen in 59% of dogs and a partial remission (decrease in size but visible tumor still present) was seen in 18% of dogs. Average to maximum tumor shrinkage was 30 days and the median duration of response was 10.5 months.
Treatment for dogs with grade II, stage II (lymph node metastasis) mast cell tumors:
Two studies suggest that dogs with grade II, stage II (lymph node metastasis only) can achieve long term median survival and extended disease free intervals with adequate local tumor control followed by chemotherapy. Adequate local tumor control is defined as complete surgical resection of the primary mast cell tumor and removal of the affected lymph node or incomplete surgical removal of the primary mast cell tumor and lymph node followed by radiation.
One study showed a survival advantage to dogs that were treated with radiation post surgery (VCO Sept 2015). In this study, 21 dogs with grade II, stage II mast cell tumors treated with adequate local control followed by a combination of prednisone, vinblastine and CCNU (lomustine) had a median survival time of 3.7 years (range: 6.2 months- 6.5 years). Dogs that underwent surgery, radiation and chemotherapy had a median survival time of 5.7 years (range: 10 months- 6.5 years) compared to a median survival time of 3 years ( range: 6.2 months- 5.5 years) in dogs that received surgery and chemotherapy alone. Two patients develops local recurrence in the radiation field and four (19%) developed new mast cell tumors in other locations.
AN INTEGRATIVE APPROACH TO DISEASE CONTROL
For my patients at OVRS, I offer an Integrative Treatment program, adding Traditional Chinese Medicine treatments (acupuncture, herbal therapies, fresh food nutrition) to conventional treatment with chemotherapy, surgery and radiation. I have, personally, seen a great benefit to adding these interventions, especially fresh balanced diet and herbs, to our treatment protocol. This does, however, significantly increase the monthly cost of feeding and can add hundreds of dollars to pet care expenses so not all of my clients are able or willing to invest in these changes in a way that is effective.
For pet parents who are in a position to pursue these lifestyle adjustments, my success rate in decreasing the frequency and number of new mast cell tumors in patients with a history of multiple mast cell tumors has, anecdotally, been very high. I determine "success" in preventing new mast cell tumor development based on prior history of mast cell tumor development frequency in each individual patient before treatment compared to after dietary and herbal interventions.
These patients can still develop new mast cell tumors and should be closely monitored for any new masses, which should be evaluated cytologically.
With lifestyle changes including fresh balanced diet, herbal therapies and select nutraceuticals, in almost every case I have treated so far we are able to at least decrease the number and frequency of new mast cells and in many cases are able to control the cancer for extended periods of time when additional surgery is not in the pet's best interest. The earlier I see patients the better chance there is for prevention. This is true for all cancers. Prevention is always the best cure. But mast cell tumors seem particularly controllable with these treatments.
There is nothing in conventional medicine that has been effective in preventing new tumors in the same way I see with natural medicine and fresh balanced diet.
We do not have published statistics for response rates yet, because that will take me or some other veterinarian treating enough cases with the same clinical picture (tumor grade, type and treatment approach) that a meaningful statistical analysis can be performed and then creating time to write a paper and submit it for publication. The paper then would have to be accepted for publication. There are, right now, only a small handful of oncologists who are trained in Chinese herbal medicine and routinely using it in patient care.
THE REALISTIC GOAL OF NATURAL MEDICINE AND LIFESTYLE CHANGES
While I would love to say that there is a reliable 100% effective cure for mast cell cancer that works for every dog, that is not honest and does not help intelligent pet parents make informed treatment decisions. There is no "magic bullet" for cancer. Anyone that tells you that is not being truthful and, in many cases, may have an agenda of selling an idea or a product. When searching the internet and social media for information, it is important to consider the source, their level of experience, and their personal interest in your buy-in to their claim.
However, it is also important to develop an appreciation for the very real importance of prevention and healthy lifestyle and diet. There are definitely great gains that can be made by making the environment within the body a less hospitable place for cancer to thrive and to help the cells in the body behave optimally. Nutrition is one daily influence that should not be discounted.
REALISTIC GOALS FOR PATIENTS WITH MEASURABLE CANCER DISEASE
The goal of these natural medicine and lifestyle interventions is to increase quality of life, support energy levels and possibly improve response to chemotherapy and radiation. There have been many studies recently published suggesting that certain herbal formulas may increase sensitivity of cancer cells to chemotherapy and radiation. Many herbs have shown antitumor properties (antiangeogenic, antimetastatic), often with numerous anti-tumor pathways targeted in a single herb.
For mast cell cancer I have seen remissions with natural medicine alone. This does require lifelong continuation of diet and supplements and the remissions are not always permanent.
The strength in herbal therapy for cancer lies in its ability to target many pathways of cancer growth with very low risk of side effects while supporting and strengthening the immune system and bone marrow. Acupuncture, herbal therapy and a cancer appropriate diet also help decrease inflammation that occurs as a contributing cause and result of cancer in the body. We are, however, still awaiting studies comparing remission rates and survival times in veterinary patients treated with conventional therapies versus those who also receive Traditional Chinese Medicine as part of their treatment protocol.
Oxidative stress and derangement of oxidative damage protection mechanisms have been confirmed via clinical trial in dogs with newly diagnosed mast cell tumors. Studies like this provide proof of principle and are the first step in biomedicine validation of treatments like herbal and antioxidant therapies in patients with mast cell cancer.
One way to think about this type of intervention is that we are looking to create an "anticancer lifestyle". This includes a focus on decreasing chronic low grade inflammation in the body, which is a risk factor for carcinogenesis (cancer development), feeding a "clean" balanced diet, maximizing phytonutrients and minimizing exposure to potential carcinogens and chemicals that may compromise cellular or immune function.
Clean diet – minimizing exposure to avoidable chemicals, colorings, preservatives and carcinogens
Fresh Foods – incorporating less processed foods to provide natural phytonutrients, antioxidants and essential fatty acids which are destroyed during processing
Minimizing glycemic load – high glycemic load contributes to inflammation. Foods with a lower glycemic index (meaning foods that cause less of a spike in blood sugar after feeding) can be considered
Supporting the gut microbiome, which is known now to be very important in immune function, normalizing inflammatory responses in the body and impacting response to anticancer therapies in cancer patients, especially those receiving immunotherapies. Herbal therapies that support immune function and beneficially alter the tumor microenvironment and other epigenetic factors involved in cancer would be considered a type of immunotherapy.
Herbs which have shown some potential to be beneficial in tumor control or creating beneficial changes in the body which make it a less hospitable environment for cancer
NUTRITIONAL AND NUTRACEUTICAL CONSIDERATIONS
VITAMIN D
Vitamin D plays an important role in many physiological functions. Directly relating to cancer, vitamin D is important in normal cell maturation (cellular differentiation), replication (proliferation), appropriate cell death (apoptosis), and the formation of new blood vessels (angiogenesis) which are required for cancerous masses to receive the nutrients they need to continue growing. Vitamin D also plays a role in controlling inflammation in the body. We know that chronic low-grade inflammation is one of the main contributing factors to cancer development and progression.
A number of mechanisms have been outlined involving vitamin D, vitamin D receptor (VDR) expression and cancer progression. And the protective effect of vitamin D against development and progression of cancer has been documented in people with a variety of cancer types.
I recommend only starting vitamin D supplementation based on individual patient need after measuring blood levels. Some patients have optimal levels already and will not benefit from supplementation. Supplementation in these patients carries some risk of increasing the level too high. Although this is extremely rare in my experience and it seems vitamin D toxicity is not as easy to create with supplementation as is generally stated, I have seen patients develop high calcium levels from oversupplemletation with vitamin D3. Work with a veterinarian to determine your dog's individual need.
Canine Atopy (allergic skin disease)
Vitamin D3 was shown to be effective in decreasing clinical signs associated with canine atopy in a double blinded, placebo controlled clinical trial.
Vitamin D and Mast Cell Tumors (MCT)
Low vitamin D levels have been suggested as a risk factor for mast cell tumor development in dogs.
Mast cell tumors were shown to have more vitamin D receptors than normal mast cells and as tumor grade increased (higher grade is associated with more aggressive behavior), the number of vitamin D receptors increased. This suggests that Vitamin D therapy might play a role in treatment of mast cell cancer by using these receptors as a target for therapy.
DIET
Dietary habits and highly processed diets have been established as a well-known risk factor for cancer in humans. While we do not have many fresh diet studies relevant to cancer prevention or treatment in dogs yet, it is logical and rational to consider that the same is likely true for our companion animals.
In a study out of Helsinki's veterinary school, dogs fed processed kibble were at higher risk of developing mast cell tumors than dogs fed a fresh balanced diet. Additionally, in a crossover study, elevated inflammatory markers were documented in the blood of dogs fed processed kibble versus fresh balanced diets. When dogs were switched to opposite diets, within 3 weeks inflammatory markers increased in dogs switched from fresh food to kibble and decreased in dogs switched from kibble to fresh food diets.
For this reason, a balanced fresh food diet should be strongly considered for dogs where interventions to decrease risk factors associated with multiple mast cell tumor development are desired. Options from complete diet change to at least supplementing with some fresh organic meats and vegetables can be pursued depending on family decisions.
MEDICINAL MUSHROOMS
Maitake Mushroom has been shown to decrease mast cell degranulation.
CHINESE HERBAL MEDICINE AND WESTERNS HERBS FOR YOUR PET
While there are a few formulas I commonly recommend, generalizing treatment is not the best medicine. This blog article is already too long to go into additional details.
Milk thistle, Quercitin, Bupleurum, Albizia, Nettle Leaf and Si Wu Tang are simple examples of some of the supplements I have found that may be helpful in managing mast cell symptoms in appropriate patients.
If you are interested in natural medicine options for your dog, working with a veterinarian who is familiar with herbal medicine in animals is the best course of action. Fortunately there are many veterinarians who have pursued training in herbal medicine.
There are also many veterinarians who are members of my MettaPets Veterinary Professional Membership who are able to pursue a tele-consult with me on your pet's behalf if you establish a legal doctor-client-patient relationship with them through becoming a patient at their clinic. I am currently working on getting a list posted for your to reference if you are motivated to pursue a tele-consult for my perspective on your pet's care.
As with anything else, opinions about natural medicine should be sought out from veterinarians who have training, and therefore expertise, in herbal medicine for animals. Veterinarians who have not pursued training in herbal medicine are not reliable sources of information on the potential benefits, limitations, dosing and toxicities of these treatments as most veterinary schools do not yet provide consistent training on herbal medicine beyond potential toxicities. It is important to understand that medical schools exist to provide excellent training on the use of pharmaceutical drugs, surgery, and public health. Do not expect your veterinarian to know about these natural medicine treatments unless they have a special interest and have elected to pursue additional training after veterinary school.