Mast Cell Cancer
MAST CELL CANCER seems to be a particularly aggressive and troublesome
problem in the Shar-Pei breed. The following discussion hopefully will provide you
with some useful information.
Ultrasonography can also be used to evaluate abdominal organs (spleen, liver, GI
tract and lymph nodes for metastatic mast cell disease
- CAUSE: Mast cells are a normal component of the body. These cells contain
granules in their cytoplasm which contain heparin (an anticoagulant), serotonin
(an inflammatory mediator), histamine, bradykinins, TNF-α and a number of
other substances. The release of these vasodilator, nociceptive and proinflammatory
molecules cause inflammation, itching, edema, vasodilation and
attract other cells such as macrophages and white blood cells to the area. This
response is usually helpful in responding to allergic reactions, foreign objects,
infection, etc. This also explains why mast cell tumors tend to be swollen,
inflamed, ulcerated and itchy. Often a "blush" or skin redness around the
tumor is apparent (Darier's sign). Shar-Pei have a higher than normal
population of mast cells in their subcutaneous tissue which may partially explain
the frequency and aggressiveness of these tumors in our breed. Due to the
increased mucin in the subcutaneous tissues of Shar-Pei spread of mast cells may
occur more easily as well — the mucin may also hinder the identification of the
tumor margins and thus the complete surgical removal of mast cell tumors.
There appears to be an inherited or genetic aspect to mast cell cancer as well as
it appears more often in some lines of Shar-Pei. There also seems to be a
connection between eosinophilic granulomas and mast cell cancer in some
individuals. I have removed masses which on histopath read out as eosinophilic
granulomas and recurred as mast cell tumors. The ultimate cause of this type of
cancer is unknown. It is the most common skin tumor in dogs accounting for
about 20% of all reported skin tumors. Dogs with mast cell tumors have
increased levels of circulating histamine, which may lead to GI ulcers and
- SIGNS: Owners may report seeing a mass that grows and shrinks repeatedly -
this is usually due to local histamine release that leads to intermittent swelling.
Some dogs have a recent rapid tumor growth while others have a tumor that has
been present and unchanged for months to years. There is not one characteristic
appearance for mast cell tumors - often skin nodules are reddened, itchy and
ulcerated. These can be confused with histiocytomas, a benign growth which
often regresses on its own in 4-8 weeks and which are often seen in Shar-Pei at
any age. In Shar-Pei cutaneous mastocytosis may be seen in which large areas of
skin are involved without an actual tumor being present - often this is confused
with allergic skin disease or demodecosis. The importance of fine-needle
aspiration and cytology cannot be over-emphasized. Subcutaneous nodules
(under the skin) can be confused with lipomas, benign fatty tumors.
- DIAGNOSIS: Any lump or bump on a Shar-Pei is suspicious. Mast cell tumors
are often confused with histiocytoma, a benign tumor of the skin which also has
a high incidence in the Shar-Pei. If the mass is large enough a fine-needle
aspirate may be done to identify the mast cells. Often the tumor must be
identified after it is removed. A particularly troublesome variation of mast cell
tumor known as AGRANULAR SPINDELOID MAST CELL or ANAPLASTIC
MAST CELL is seen in the Shar-Pei and is characterized by mast cells with few
or no granules. This is a very aggressive form of mast cell and can be confused
with other tumor types. The most commonly used grading system for mast cell
has a Grade 1 which indicates a well-differentiated mast cell type and is
considered least malignant, Grade 2 which is an intermediate type and which I
consider malignant in the Shar-Pei and a Grade 3 which is an undifferentiated
type of mast cell and definitely considered malignant.
- TREATMENT: Surgical removal of the tumor with wide normal margins is the
current recommended treatment. Obviously the smaller the tumor the more
easily this is accomplished. Location of the mass also determines how successful
surgery will be. I often recommend referral to a veterinary oncologist (cancer
specialist) or a veterinary cancer center. At the cancer center there is usually a
group consisting of a veterinary surgeon, veterinary oncologist and often,
radiation treatment facilities. The chemotherapeutic approach for mast cell
cancer is not well worked out at this time and is an area of active research. Mast
cells are radiation-sensitive and radiation therapy is often used as an adjunct to
surgery. The Shar-Pei owner must decide early on how aggressive an approach
they will seek. Local recurrence and spread of mast cell cancer often occurs
within 4-6 months after surgery alone. The prognosis in the Shar-Pei is guarded
to poor. I have seen mast cell cancer in Shar-Pei as young as 10 months.
Chemotherapy often includes prednisolone in combination with other agents.
Currently tyrosine kinase inhibitor therapy appears to be useful in the treatment
of mast cell cancer.
- MASTOCYTOSIS: This is a form of mast cell cancer which is systemic and
involves internal organs such as the liver, spleen, lymph nodes and GI tract.
This can have a much poorer prognosis.
- PARANEOPLASTIC SYNDROME: This term denotes systemic signs which
accompany certain types of cancer. The inflammatory response which often
accompanies mast cell cancer can result in GI tract ulceration with vomiting and
diarrhea, often with blood, as a consequence. Sometimes excessive manipulation
of a mast cell tumor can result in massive degranulation of the tumor cells which
can lead to a life-threatening systemic shock reaction. Most common is the
localized swelling, draining and itching at the tumor site.
- PROGNOSIS: Mast cell tumors have extremely variable biologic behavior.
Some are relatively benign and curable with local excision while others may be
very aggressive, spread rapidly (metastasis) and are fatal. Sites for metastasis
include regional lymph nodes, spleen, liber, bone marrow and skin - they rarely
involve the lung. Negative prognostic factors:
- Recent, rapid growth
- Deep, fixed mass
- Systemic signs: tarry stools, vomiting,etc.
- Tumor location - poorer prognosis for tumors on the muzzle,
inquinal/preputial areas and mucocutaneous junctions (mouth, anus, nail
- Regional lymph node metastasis
- Internal spread
- Histologic features - high grade tumor (grade3), high mitotic index (>5
mitotic figures/10 hpf), presence of c-kit mutation, high Ki-67 score
Research conducted over the last several years has concentrated on the genetic
aspects of mast cell cancer. KIT is a receptor protein located on mast cells which is
encoded by the proto-oncogene c-kit. A gene normally encodes for a protein product
which performs a specific function in the body and in many genetic diseases a gene
mutation occurs which results in no protein being produced or an abnormal protein
product which is either non-functional or has an abnormal function. In normal
mast cells KIT signaling is critical for the normal development and function of mast
cells. Mutations in c-kit result in KIT dysregulation which may promote
uncontrolled growth or survival of mast cells. These mutations in c-kit have been
discovered and consistent of tandem duplications in exons 11 and 12 of the gene.
These exons encode for the juxtamembrane domain which prevents activation of
KIT. It acts as an "on-off" switch if you will. These mutations cause a continuous
"on" signal for KIT and appear to be associated with more aggressive mast cell
tumors. Another study has demonstrated loss of intron 11 which is the region
between exon 11 and 12 which occurs in canine mast cell tumors. This suggests that
canine mast cell disease is probably the result of several different mutations in the ckit
Additional research has looked at the serine proteases α-chymase and tryptase
which are selectively concentrated in secretory granules of mast cells. These serine
proteases may potentially serve as markers of the biological aggressiveness of mast
- London CA, Chien MB, Pfieff J, Downing S, Grahn RA. Genes, Dogs and Cancer: Emerging
Concepts in Molecular Diagnosis and Therapy. Conference May, 2001.
- Reguera MJ, Ferrer L, Rabanal RM. Evaluation of an intron deletion in the c-kit gene of canine
mast cell tumors. Am J Vet Res 63.9:1257-1261.
- Downing S, Chien MB, Kass PH, Moore PF, London CA. Prevalence and importance of internal
tandem duplications in exons 11 and 12 of c-kit in mast cell tumors of dogs. Am J Vet Res
- Dank G, Chien MB, London CA. Activating mutations in the catalytic or juxtamembrane domain
of c-kit in splenic mast cell tumors of cats. Am J Vet Res 63.8:1129-1133.
As a direct result of some of the above research projects some therapeutic trials
have been initiated. Since KIT is classified as a receptor tyrosine kinase it can be
inhibited by agents called kinase inhibitors. Several of these drugs are in the
pipeline. One has been developed for humans called Gleevac® (STI571) which
blocks the ATP binding site of KIT and inhibits KIT signaling. Liver toxicity has
been a problem in animals with this drug. Another class of kinase inhibitors called
the indolinone kinase inhibitors (SU5416, SU6668) are currently being studied in
humans. These agents are capable of disrupting the function of all forms of mutant
KIT. Remissions of up to 6 months have been induced by these agents in some cases
of mast cell cancer in dogs but relapses occur6.
- Serine Proteases in Mast Cell Disease. Timothy M. Fan, DVM, DACVIM, Proceedings of the 20th
Annual AVCIM Forum, Dallas TX, May 2002, pages 414-415.
Another recent article has looked at mast cell cancer and plasma histamine
concentrations. Mast cell granules contain histamine, heparin and proteolytic
enzymes. Release of these granule substances can cause gastroduodenal
ulceration/perforation, delayed wound healing, hypotensive shock, local
ulceration/swelling and coagulation abnormalities. Hyperhistaminemia is a major
factor contributing to gastroduodenal ulceration and perforation. Histamine release
from mast cell tumors can occur due to spontaneous release, aggressive
manipulation (especially during surgery), chemotherapy and radiation therapy.
Plasma histamine concentration is one factor related to mast cell disease
progression. It also appears related to tumor dissemination. Up to 80% of dogs
with progressive mast cell cancer have gastroduodenal ulceration. Lastly, dogs that
don't respond to H2 -blockers have marked hyperhistaminemia. This study
concludes that plasma histamine concentrations may provide useful diagnostic,
prognostic and therapeutic information7.
- Kinase Inhibitors in Cancer Therapy. Dr. Cheryl London, DVM, PhD, DACVIM. Proceedings of
the 20th Annual ACVIM Forum, Dallas TX, May 2002, pages 436-438.
The drug company Pfizer has plans to release a tyrosine kinase inhibitor for the
veterinary market called Palladia® in late 2009 or early 2010. It will be labeled for
use in mast cell cancer in the dog. No further information is available at this time.
- Ishiguro T, Kadosawa T, Takagi S, Kim G, Ohsaki T, Bosnakovski D, Okumura M, Fujinaga T.
Relationship of Disease Progression and Plasma Histamine Concentrations in 11 Dogs with
Cell Tumors. J Vet Intern Med 2003; 17.2:194-198.
Another potential modality in the treatment of mast cell cancer involves the use of
mast cell stabilizers. One such drug is cromolyn sodium (Gastrocrom®). Another
drug which inhibits mast cell histamine secretion is pentosanpolysulfate (Elmiron®,
This is a synthetic, sulfated polysaccharide that has been approved for the treatment
of interstitial cystitis (IC) - it may help replenish the defective glycoseaminoglycan
layer in the bladder in this condition. A research paper indicates
pentosanpolysulfate has a powerful dose-dependent inhibitory effect on mast cell
release of histamine8.
- Chiang G, Patra P, Letourneau R, Jeudy S, Boucher W, Green M, Sant GR, Theoharides TC.
Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an
alternative explanation of its beneficial effect in interstitial cystitis. Department of Pharmacology
and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts,
Palladia® (toceranib phosphate) has been around for about 3 years now and here
are some insights from the specialists who use it:
- Palladia® will be effective only in Grade II or Grade III mast cell tumors
that are positive for the c-kit gene mutation. It is important when a mast cell
tumor is removed that it be tested for this genetic mutation. Only 28% of
mast cell tumors are positive for this mutation
- Palladia® should be used with the same precautions as any other
chemotherapeutic drug. It can be nephrotoxic, may cause pancreatitis, low
serum albumin levels, anemia, low white blood cell counts, etc. Dogs should
be seen weekly for the first 6 weeks with CBC, blood panel and urine samples
checked. The dosage of the drug should be adjusted or the drug
discontinued if any of these side-effects are seen.
- Often it is best to start with a dosage about 25% less than the original dosage
proposed by the manufacturer and often other drugs are added such as
prednisone, antihistamines and H2-receptor antagonists such as Tagamet-
HB®, Pepcid-AC® and others to minimize side effects.
- Another drug calledMasivet® (masitinib) is currently in clinical trials in
Europe. This drug appears to have fewer side effects than Palladia®. It is
now available in the U.S. as Kinavet®
- I have seen some promising results with the use of Palladia® in some of the
mast cell cases I've personally referred to oncologists who have used it. It is
an oral medication and can be given by owners at home - a distinct
advantage over other chemotherapies.
- Masivet® is the brand name for the tyrosine kinase inhibitor masitinib.
- It specifically targets stem cell receptor c-kit, PDGFR α and &beta, and LYN.
- Particularly effective in controlling the proliferation, differentiation and
degranulation of mast cells.
- Useful in the treatment of mast cell dysfunctions.
- In mast cell cancer treatment it is only used if the presence of a mutated of
the receptor protein c-kit in the tumor has been confirmed. Excessive action
of c-kit results in uncontrollable mast cell proliferation. Masivet® blocks
receptors for c-kit.
- Dogs on Masivet® took longer for the tumor to get worse (median of 241days
in treated dogs vs. median of 83 days in untreated dogs).
- Survival rates at 12 and 24 months were significantly improved in dogs
receiving this drug.
- Tumor response at 6 months was predictive of long-term survival at 12 and
- First-line treatment with masitinib was more effective than placebo
regardless of whether a c-kit mutation was present. Dogs that had received
other therapy prior to masitinib, however, only responded if the c-kit
mutation was present.
- Masitinib effective in dogs with metastases.
- Also significantly reduces the emergence of nodal and visceral metastasis.
- Prevents the proliferation of tumor mast cells
- Inhibits the phosphorylation of PDGF-α and &beta receptors as well as PDGFdependent
- Inhibits mast cell degranulation modulates inflammatory and immune
- Tablet sizes = 50mg. and 150mg.
- Common side effects are diarrhea, vomiting and alopecia.
- Dose is 12.5 mg/kg once a day.
- Kinavet-CA1® -- ABScience (in the United States)
- Inhibits LYN kinase activity. Lyn has been associated in certain forms of
TKI resistance and is associated with several different cancers.
- Side-effects include non-regenerative anemia, decreased white blood cell
counts, protein-losing nephropathy
- Particularly effective in controlling the proliferation, differentiation and
degranulation of mast cells.
- Useful in the treatment of mast cell dysfunctions.
- They play a key role in chronic inflammatory diseases such as allergies,
atopic dermatitis, asthma and arthritis
- Kinavet-CA1®Tablet sizes = 50mg. and 150mg.
More mast cell stuff:
- c-kit is a receptor tyrosine kinase for stem cell factor (SCF). Stem cell factor
stimulates mast cell growth.
- Mutations in c-kit are: internal tandem duplications (ITD) within exons 11 and
12 of the c-kit gene. This is known as the exon 11 mutation.
- When SCF binds to unmutated c-kit, the cytoplasmic portion of the receptor
undergoes autophosphorylation. In the presence of the exon 11 ITD, the receptor is
constitutively phosphorylated, regardless of whether SCF is present or not. The
presence of the mutation is directly responsible for the uncontrolled proliferation of
- Other c-kit mutations: 12-base pair ITD in exon 8, single base pair change in
exon 9, additional single base changes and rare deletions and insertions detected in
exon 11 and exon 17.
- Current methodology will not detect single base pair changes (false negatives?).
- The standard methodology requires approximately 10% of the cells in the sample
to be mast cells - not useful for detecting mets in draining lymph nodes or for
residual disease detection.
- First-line treatment with masitinib was more effective than placebo regardless of
whether a c-kit mutation was present. Dogs that had received other therapy prior
to masitinib, however, only responded if the c-kit mutation was present.
- In another study, dogs with recurrent mast cell disease responded better to
Palladia if they carried the exon 11 c-kit mutation than if they did not.
- c-kit mutations can be used as a tumor fingerprint - determines if recurrent mast
cell tumors are from the same clone (the same mutation).
- Possibility of creating tumor-specific PCR primers based on the mutated
sequence which could detect distant metastases and the presence of neoplastic cells
in the blood and can even be used to quantify tumor cells.
- c-kit mutations present in gastrointestinal stromal cell tumors (GISTs) also.
- Detection of c-kit mutations in mast cell tumors is now routinely used for
prognosis and guiding treatment. Most commonly, mutation status is determined
together with immunohistochemical staining to examine proliferation markers and
the cellular location of c-kit. These factors help establish prognosis and the need for
Avery AC. Molecular Diagnostics of Hematologic Malignancies in Small Animals. Vet
Clin Small Anim 42 (2012) 97-110
I realize much of this new information will mean little to the reader but four points
need to be made. First, the Chinese Shar-Pei Club of America Charitable Trust has
been actively involved in funding much of this research in mast cell disease. I
believe this function of the Charitable Trust is critical for our breed and I believe
your continued donations to the Trust are critical for our breed as well. You won't
see breakthroughs in cancer research unless you have funding of that research.
Second, there is a great deal of information sharing in the scientific community
concerning cancer research. Much of the work I share here has application to
human cancer as well. Third, much of this research information is applicable to
other cancers as well. This means that progress in the studies of other cancer types
will be much more rapid. Lastly, as dog enthusiasts, understanding the genetics of
cancer will allow us to develop tests and breeding programs to avoid those types of
cancer which may have a hereditary aspect to them.
Jeff Vidt, DVM