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Canine Mast Cell Tumors

Mast cell tumors (MCT) in dogs are very common, accounting for approximately 20% of all skin tumors in dogs.

For most dogs, the underlying cause promoting the development of the tumor is not known. Mast cells are specialized cells derived from stem cells in the bone marrow and play an important role in helping an animal respond to inflammation and allergies. They are found distributed throughout the body, predominantly near blood vessels, nerves, and beneath the skin. Mast cells become activated when antigens bind to receptors on their surface and subsequently release several biologically active chemicals stored in their granules when stimulated including histamine, heparin, serotonin, prostaglandins, proteolytic enzymes, and other pro-inflammatory molecules. Although these chemicals are vital to normal bodily function, they can be very damaging to the body when released in chronic excess. These chemicals can cause systemic problems that include gastric ulcers, internal bleeding, and a range of allergic manifestations.

Mast cell tumors can arise from any skin site on the body and can have a variety of appearances. MCT most commonly are seen as solitary lumps or masses in or underneath the skin; occasional dogs can have multiple masses. MCT can look like just about anything ranging from benign-appearing lumps, to more angry or ulcerated lumps, masses with a stalk, or focal thickenings in the skin. MCT may change quickly in size because of reactions around the mass and release of their vasoactive compounds. In most cases, evidence of an MCT is easily generated by examination of a fine-needle aspirate of the suspect mass, and aspiration is advised before removal of a mass to determine if it is an MCT, a finding that would demand a more aggressive surgical removal than for other more benign skin masses. Often, obtaining blood for a complete blood count and biochemical profile, buffy coat analysis, and a urinalysis will be advised as these can help assess overall health and provide information that potentially influences treatment recommendations. The CBC may reflect low or high white blood cell count, low platelet count, and/or elevated mast cell counts. The buffy coat is diagnostic (although subject to false-positives) and reflects mast cells circulating in the bloodstream where they are ordinarily not found in large numbers. A positive buffy coat suggests bone marrow involvement. Other tests may include lymph node aspirate, bone marrow aspirate, x-rays, and ultrasound evaluation.

As mentioned previously, canine mast cell tumors are among the most common skin tumors, which occur in dogs. Boxers, Rhodesian ridgebacks, Pugs, Boston terriers, Pit-bull terriers, and Weimaraners are at high risk (4 to 8 times more than the population) for developing MCT. Shar-Peis, particularly young dogs, are predisposed to developing MCT, and these tumors are often poorly differentiated and act more aggressively biologically than in other breeds.

One characteristic of mast cell tumors is the tendency for them to change in size, even on a daily basis. A tumor that gets bigger and smaller, seemingly on a whim, maybe an MCT. Another idiosyncrasy is the potential of the tumor to produce “Dariers sign” if poked and prodded. Handling these tumors – even a routine veterinary palpation or needle aspirate – can cause a heavy release of histamine that results in swelling, redness, itchiness, and/or hives. Symptoms are variable, depending on the location of the tumor and the degree to which it has developed and/or spread. Signs of systemic involvement may include: loss of appetite, vomiting, bloody vomit, diarrhea, abdominal pain, dark or black feces, itchiness, lethargy, anorexia, irregular heart rhythm and blood pressure, coughing, labored breathing, various bleeding disorders, delayed wound healing, enlarged lymph nodes.

Most mast cell tumors are considered locally invasive and can be difficult to remove completely because of the extent of local spread. The behavior of mast cell tumors is a reflection of their grade. When evaluating the tissue sample obtained from surgical removal of the mast cell tumor, the diagnosis of mast cell tumor will be confirmed, the mast cell tumor will be staged, and the width of the tissue margins, which are free of tumor will be measured. Staging and the width of the tissue margins which are free of tumor cells together with the location of the mass, the health of the dog, and the grade of the mast cell tumor will determine whether further treatment with radiation therapy or chemotherapy will be recommended.

Mast cell tumors have 3 grades. Tumor grade is associated with the degree of differentiation of the mast cells. Grade I tumors are well differentiated and are the least aggressive and least likely to metastasize (spread to other organs). Complete surgical excision of Grade 1 MCT is usually curative. Grade 2 tumors are moderately differentiated and the prognosis and treatment options are perhaps the most complicated and difficult to predict. Grade 3 tumors are poorly differentiated, very aggressive with a high likelihood of metastasis. They carry the poorest prognosis but are fortunately the least common grade encountered. Mast cell tumors show a predilection to spread to regional lymph nodes, liver, spleen, and bone marrow.

Grading of mast cell tumors, however, is very subjective. In one study, mast cell tumors were graded by a group of pathologists, and frequently, there was disagreement regarding the grade even amongst board-certified pathologists. In many cases, perhaps a better method of determining how malignant or benign a mast cell tumor will behave is to have a proliferative study performed. This includes PCNA (proliferating cell nuclear antigen), AgNOR (agyrophilc nuclear organizing regions), and Ki67. Tyrosine kinase receptors (a receptor for mast cell growth factor) are also important and tests related to this include cKIT mutations and KIT staining patterns.

Because mast cell tumors prefer to metastasize the above-mentioned sites, staging a dog with a mast cell tumor entails collecting cells from the regional lymph nodes for microscopic examination, imaging the thorax and abdomen (radiographs, abdominal ultrasound, ) for evidence of enlargement of the mesenteric lymph nodes, liver or spleen, and an assessment of potential bone marrow involvement, either via a bone marrow aspirate for microscopic examination, or examination of the white blood cells for circulating mast cells.

Surgical removal is the mainstay of treatment of canine mast cell tumors. Presurgical treatment with histamine blockers and/or steroids is recommended to prevent complications of mast cell degranulation during manipulation of the tumor mass for the duration of its removal. Because of their locally invasive behavior, wide margins of what appears to be normal tissue around the tumor needs to be removed to increase the likelihood that the tumor has been completely removed. Approximately 2-3 cm margins and one fascial plane of depth are attempted as surgical margins.  Recent research has shown that 1-2 cm clean margins of a grade 1 or 2 mast cell tumor can be curative.  For mast cell tumors that were not or because of location could not be completely removed with wide surgical margins, radiation therapy is often the best treatment for residual disease. Radiation therapy after surgical removal appears to be beneficial and may reduce the incidence of reoccurrence and increase survival rates. Radiation is most useful when the tumors have not spread to multiple areas of the body. Radiation therapy, however, is expensive and there may not be a facility able to offer this option within a convenient distance in many locations. Chemotherapy is sometimes used to treat mast cell tumors, but chemotherapy is usually reserved for dogs with grade 3 tumors. Mast cell tumors are notoriously unpredictable tumors with regards to response to chemotherapy, and chemotherapy for metastatic mast cell neoplasia does not offer consistent results. If the mast cell tumors have spread to multiple areas, combinations of anti-cancer drugs are commonly used along with surgery and radiation. These include vinblastine, lomustine, vincristine, doxorubicin, mitoxantrone, cyclophosphamide, and L-asparginase. These are all heavy-duty chemotherapy drugs with potential side-effects that include severe immunosuppression, vomiting, diarrhea, and/or liver damage. Palladia is a tyrosine kinase receptor blocker; the proliferative panel may be helpful to determine if the patient will respond to this type of medication. The tumor should be positive for cKIT mutations for this drug to be potentially effective. Unfortunately, mast cell tumors do not respond well to these drugs and several recent studies seem to demonstrate very limited efficacy in conjunction with surgery. It is important to remember that, while radiotherapy and chemotherapy are potentially useful adjuvant forms of therapy, aggressive surgery remains the mainstay of treatment for canine MCT and is sufficient to successfully treat the majority of MCT encountered in practice.

In addition to surgery, radiation therapy, and/or chemotherapy management of the tumors, many dogs will benefit from the administration of medications that tend to help fight the secondary local and systemic effects of the tumor. These usually include steroidal drugs like prednisone, and anti-histamines like Benadryl, Pepcid, or Zantac. These medications prevent the undue side-effects of histamine release commonly encountered in dogs with MCT.

Several prognostic factors (in addition to grade or stage) have been identified. Boxers have a higher percentage of low-grade tumors compared to most other breeds (It is important to recognize, though, that a high-grade mast cell tumor will behave just as aggressively in a boxer as in any other breed.) Smaller tumors and tumors that remain relatively static in size for prolonged periods (months or years) carry a better prognosis. Tumors that remain confined to the skin without metastasis to regional lymph nodes or distant sites carry a better prognosis. The presence of multiple cutaneous tumors does not affect long-term prognosis. Systemic illness (anorexia, vomiting, melena, gastrointestinal ulceration) is usually a reflection of a larger tumor burden and therefore carries a worse prognosis. Tumors located on the muzzle have a higher rate of spread to regional lymph nodes and therefore carry a more guarded prognosis. Historically, it has been suggested that tumors located in the inguinal area, perineum, and scrotum carry a more guarded prognosis, but this is based solely on anecdotal evidence, and two recent studies have refuted this claim.

The prognosis for completely removed grade I and grade II tumors is excellent. Even with complete surgical removal, however, because of the tendency of MCT to exhibit multicentric origination, new lesions may appear elsewhere, which are not the result of actual metastatic spread. For this reason, multiple surgeries over time may be necessary to control the disease process. The prognosis for incompletely removed grade I and II tumors treated with radiation therapy after surgery is also excellent with approximately 90-95% of dogs having no recurrence of tumor within 3 years of receiving radiation therapy. The prognosis for dogs with grade III tumors is considered guarded as local recurrence and/or spread is likely in most dogs. If your dog is diagnosed with a grade III MCT, most likely chemotherapy will be recommended as at least part of the protocol and a guarded prognosis is warranted.


Multiple Myeloma

Multiple myelomas or plasma cell myeloma is a neoplasm of well-differentiated B cell lymphocytes typically originating from the bone marrow.

Neoplastic cells can metastasize widely, having a predilection for bone and resulting in osteolysis. The malignant transformation of a single B cell can secrete a homogenous immunoglobulin product known as paraprotein, which will mimic the structure of normal immunoglobulins. Overabundant production of paraprotein, consisting of any of the immunoglobulin classes, will appear as a sharp, well-defined peak or monoclonal gammopathy on serum electrophoresis.

The most frequently encountered multiple myelomas secrete IgG or IgA paraproteins; however, IgM myelomas (macroglobulinemia) have also been diagnosed in companion animals. Light chain disease is caused by plasma cell overproduction of the light chain segment of the immunoglobulin complex, consisting of either the lambda or kappa light chain. These proteins are referred to as Bence-Jones proteins and are the most commonly observed immunoglobulin fragments in the monoclonal gammopathies. There are rare instances where a malignant plasma cell neoplasm will be nonsecretory. These tumors occur in approximately 1% of all cases of multiple myeloma and are referred to as nonsecretory multiple myeloma. In this type of neoplasm, malignant plasma cells produce either fragments or intact monoclonal immunoglobulins but do not secrete them from the cell. In rare cases of nonsecretory multiple myeloma, recognizable immunoglobulins are not produced.

Multiple myelomas have been described most commonly in dogs, humans, and cats. They account for

< 1% of all malignant canine tumors, ~ 8% of all malignant hematopoietic tumors in dogs, and 3.6% of all primary and secondary bone tumors diagnosed by biopsy. There is no current evidence suggesting any age, sex, or breed predilection; however, older dogs are most commonly affected with a mean age of 8 to 9 years. Multiple myeloma is even less common in cats with a median age of 12 to 14 years and possible male predisposition. The cause of multiple myeloma in companion animals is largely unknown although genetics, viral infections, chronic immune stimulation, and exposure to carcinogens have been identified as possible contributing factors.

The clinical manifestations of multiple myeloma are highly variable and may affect multiple organ systems. The pathologic conditions associated with multiple myeloma are related to the effects of the circulating paraprotein as well as organ or bone marrow dysfunction due to neoplastic infiltration. The presentation of a patient with multiple myeloma will depend on the type of neoplastic cell, type of immunoglobulin produced, location of the tumor, and severity of growth and infiltration. Affected dogs can exhibit signs of lethargy, weakness, lameness, bone pain, hemorrhage (e.g, petechiae on mucous membranes, gingival bleeding, and epistaxis), polyuria / polydypsia, and/or neurologic deficits. Other presenting signs of disease may include hypertension, ophthalmic abnormalities (e.g., venous dialation with sacculation, retinal hemorrhages, and retinal detachment), neurologic dysfunction (including seizures), organomegaly, and suggestion of multiple organ failure.

Hyperviscosity syndrome.
Hyperviscosity syndrome is an increase in the viscosity of the blood secondary to the high concentrations of circulating paraprotein, clinically manifesting in neurologic signs, retinopathy, and cardiomyopathy. IgA and IgM are most often associated with hyperviscosity syndrome because of their structure and size (IgA dimers and IgM pentamers). Cardiomegaly and cardiac disease may result secondary to increased cardiac workload and myocardial hypoxia caused by hyperviscosity. In a study of cats with multiple myeloma, two-thirds of the cats had cardiomegaly on thoracic radiographs and nearly half had a heart murmur.

Osteolysis.
Bone lesions associated with multiple myeloma include discrete radiolucent lytic areas (punched-out appearance) or diffuse osteopenia and commonly affect the axial skeleton and long bones. These lesions may be associated with severe bone pain, spinal cord compression, pathologic fracture, and hypercalcemia. However, only 50% of dogs have radiographic evidence of bone disease. And although cats are reported to have skeletal lesions (8% to 67%), the true incidence of lytic lesions in cats is unknown.

Bone lesion detection improves with focused imaging on specific regions or bones vs. routine survey abdominal and thoracic radiographs. In people, conventional radiography remains the gold standard imaging technique. Computed tomography and magnetic resonance imaging may also be useful; however, nuclear scintigraphy is generally not recommended since myeloma patients have inadequate skeletal uptake of technetium-99 secondary to osteoblast dysfunction.

Hemorrhagic diathesis.
Patients with multiple myeloma can manifest unique hemostatic disorders that predispose them to hemorrhage. Mechanisms include paraprotein-induced thrombocytopath, in which protein coating of platelets leads to platelet dysfunction and paraprotein interference with clotting factors. Other potential causes of bleeding include abnormalities in the formation and polymerization of fibrin, tissue fragility associated with amyloidosis, hypervolemia secondary to hyperviscosity syndrome, and thrombocytopenia. About one-third of dogs and cats with multiple myeloma have clinical signs of bleeding, most commonly epistaxis, intraocular hemorrhage, and gingival bleeding. These patients may have prolonged prothrombin and partial thromboplastin times and about 50% of cats and 30% of dogs are thrombocytopenic.

Cytopenias.
Patients with multiple myeloma can develop anemia from a variety of causes including chronic disease, hemorrhage due to coagulopathy, myelophthisis, and red blood cell destruction. Normocytic, normochromic, and nonregenerative anemia is one of the most common findings on a complete blood count (CBC); two-thirds of dogs and cats are affected. Pancytopenia may be seen in patients with marked bone marrow infiltration with neoplastic cells.

Hypercalcemia.
Hypercalcemia in cases of multiple myeloma can result from osteoclastic bone resorption, hypercalcemia of malignancy, or hyperglobulinemia. Bone stores of calcium can be released by osteoclasts secondary to cytokine secretion by myeloma cells (e.g. lymphotoxin, tumor necrosis factor alpha, interleukins 1, 3, and 6). Myeloma cells can also secrete parathyroid hormone-related peptide, resulting in paraneoplastic hypercalcemia of malignancy. Hyperglobulinemia results in calcium binding by the paraprotein increasing the total calcium concentration while the ionized calcium concentration remains normal. Ionized calcium measurement is, therefore, needed to confirm true hypercalcemia in patients with multiple myeloma.

Renal disease.
Renal disease occurs in about one-third of dogs and cats with multiple myeloma. Renal insufficiency is most commonly associated with excessive light chain production or hypercalcemia. First, excessive light chain production overwhelms the catabolic capacity of the renal tubular cells and the free light chains complex with proteins to form tubular casts leading to renal tubular obstruction. Endocytosis of light chains by tubular cells also induces cytokine release and inflammation resulting in further renal damage. Second, hypercalcemia can lead to prerenal azotemia secondary to antidiuretic hormone inhibition and eventual renal mineralization. Other potential causes of renal disease include amyloidosis, pyelonephritis, and decreased renal perfusion secondary to hyperviscosity syndrome.

Bacterial infection.
Increased susceptibility to bacterial infection is common in patients with multiple myeloma and infections can be life-threatening if not addressed. Immunodeficiency can be secondary to myelophthisis (which results in leukopenia), decreased production of functional immunoglobulin, and compromised B cell function.

Clinical signs and symptoms may be present for up to 1 year before a definitive diagnosis of multiple myeloma is made. Patients can also present with recurrent infections, non-regenerative anemia, pathologic bone fractures, and/or seizures. Complications secondary to multiple myeloma may include renal failure, infections secondary to immunosuppression, clotting disorders, chronic anemia, cardiac insufficiency, and neurologic dysfunctions such as senility.

A diagnosis of multiple myeloma may be made if there is radiographic evidence of osteolysis, there is a population of greater than 20% plasma cells in bone marrow aspirates or biopsies, a monoclonal gammopathy on serum electrophoresis exists, and/or Bence-Jones protinuria is present. Recent studies suggest that in cats’ visceral organ infiltration be included in the diagnostic criteria. Further studies suggest a primary extramedullary origin for neoplastic transformation in cats with multiple myeloma vs. primary intramedullary neoplastic transformation as accepted in the dog myeloma model.

Multifocal radiolucent lesions within the bone may be seen in ~ 40% of dogs suffering from multiple myeloma. In contrast, osteolytic lesions rarely are seen in cats. The bones most commonly involved in canine multiple myeloma include the spine, pelvis, ribs, skull, and proximal extremities. Malignant plasma cell tumors present in the bone marrow are often osteolytic. The presence of these tumors directly induces bone resorption by production of osteoclastic-activating factor from neoplastic cells. Osteolysis is also induced secondary to paraprotein binding of ionized calcium, which initiates secretion of parathormone (PTH) from the parathyroid gland. PTH acts directly on the bone to increase serum calcium concentration.

Survey radiographs may reveal focal, multifocal, or diffuse osteoporosis-type lesions approximately 3-4 weeks after bone changes have occurred. Clinically, the patient may present with pathologic fractures, rear limb lameness or paresis, or bone pain. Myelograms are an effective means of visualizing the changes to vertebral bodies, especially when the patient presents with rear limb lameness or paresis. Most commonly, the myelogram will show extradural compression of spinal cord in the area of the lesion. Plasma cell tumors producing IgM often infiltrate the spleen, liver, and lymph tissue rather than bone. Whole body survey radiographs may detect enlargement of these organs and tissues.

Dogs and cats with multiple myeloma may experience moderate to severe pain, and eliminating it should be a priority. Pain may be relieved by treating the underlying cancer and providing various analgesic therapies and supportive care. Antibiotic therapy may be needed to treat concurrent infections, such as urinary tract infection or bacterial pyoderma, as these can progress to life-threatening infections if left untreated. Intravenous fluid therapy is often needed initially to correct dehydration, improve cardiovascular status, and manage hypercalcemia and azotemia. Treatment with isotonic saline solution is preferred over other crystalloid replacement fluids in the initial management of hypercalcemic patients. Bisphosphonates, such as pamidronate, may be useful in managing hypercalcemia as well as reducing bone pain and decreasing osteoclastic bone resorption. Evaluation of blood urea nitrogen and creatinine concentrations in conjunction with urine specific gravity should be performed before using this medication since it is potentially nephrotoxic. The recommended dose of pamidronate is 1 to 2 mg/kg given intravenously in dogs and, anecdotally, 1 mg/kg given intravenously in cats every 21 to 28 days. This medication should be diluted in saline solution and administered as a slow infusion over two hours to minimize renal toxicosis. Bisphosphonates are an essential component of therapy for multiple myeloma in people, and their use is associated with significantly reduced skeletal-related events and improved survival times. Plasmapheresis is the best immediate treatment for hyperviscosity syndrome. Although rarely performed in veterinary medicine, this procedure involves withdrawing anticoagulated blood, separating blood components, removing the plasma, and reinfusing the remaining components with crystalloid fluids. Packed red blood cells or platelet-rich plasma transfusions may be required if marked hemorrhage or thrombocytopenia is present, respectively. Neoplastic plasma cells are sensitive to irradiation, and radiation therapy is a highly effective palliative treatment for multiple myeloma since it can relieve discomfort and decrease the size of the mass or tumor burden. Indications for radiation therapy include painful bone lesions, spinal cord compression, pathologic fracture (after fracture stabilization), or a large soft tissue mass.

Although a cure is unlikely, multiple myeloma can be a rewarding disease to treat since chemotherapy can greatly extend the quality and duration of life. The chemotherapy drugs most often used are alkylating agents, usually melphalan, combined with prednisone. However, eventual relapse during therapy is anticipated. In dogs, the recommended treatment protocol is melphalan administered orally once daily at a dose of 0.1 mg/kg for 10 days and then 0.05 mg/kg once daily until the disease relapses or myelosuppression occurs. Prednisone is given concurrently at a dose of 0.5 mg/kg given orally once daily for 10 days and then 0.5 mg/kg every other day for 30 to 60 days, at which time prednisone is discontinued. Pulse-dose therapy with melphalan has also been described, in which melphalan, at a dose of 7 mg/m2, is given orally once daily for five consecutive days every 21 days. The most common side effects associated with melphalan therapy are myelosuppression and delayed thrombocytopenia. A CBC should be performed every two weeks for the first two months of treatment and then monthly.

Combined melphalan and prednisone therapy can also be used in cats; however, cats appear to be much more susceptible to myelosuppression. The recommended treatment protocol is 0.1 mg/kg (or 0.5 mg total dose) melphalan given orally once daily for 10 to 14 days and then every other day until clinical improvement or leukopenia develops. A maintenance dose of 0.5 mg given every seven days is then recommended. Prednisone or prednisolone is given concurrently at a dose of 0.5 mg/kg orally once daily. If leukopenia develops, melphalan therapy should be discontinued until white blood cell counts return to normal; then, maintenance therapy may be attempted at the same or a lower dose.

Other chemotherapy agents used to treat multiple myeloma include chlorambucil and cyclophosphamide either alone or in combination with melphalan. In sick myeoma patients, in which a faster response to treatment is needed, cyclophosphamide may be administered intravenously at a dosage of 200 mg/m2 once at the time that oral melphalan therapy is initiated. Lomustine (CCNU) has also been used in combination with prednisone to treat multiple myeloma in cats.

In dogs with relapsing multiple myeloma or resistance to alkylating agents, single agent doxorubicin or the VAD (vincristine, Adriamycin [doxorubicin], and dexamethasone) protocol can be considered. This protocol combines vincristine (0.7 mg/m2 intravenously on days 8 and 15), doxorubicin (30 mg/m2 intravenously every 21 days), and dexamethasone sodium phosphate (1 mg/kg intravenously on days 1, 8, and 15); however, the reported duration of response to this protocol is only a few months.

The overall response rate for dogs treated with melphalan and prednisone chemotherapy is 92%, with 43.2% of dogs achieving a complete response and 48.6% achieving a partial response. The median survival time of dogs treated with this drug combination is 540 days, which is significantly longer than the survival time of 220 days in dogs treated with prednisone alone. Negative prognostic factors in dogs include hypercalcemia, light chain proteinuria, and extensive lytic bone lesions.

Response to therapy and duration of response appear to be more variable in cats. Factors associated with a more aggressive form of the disease and poor prognosis include bone lesions with pathologic fracture, anemia, light chain proteinuria, azotemia, and poor response to treatment. When treated with melphalan and prednisone chemotherapy, four cats classified as having aggressive disease had a median survival time of five days, whereas the median survival time of five cats with less aggressive disease was 387 days. Other studies have shown overall less promising results with a shorter duration of response to treatment and a survival time of six months or less in treated cats. In cats with multiple myeloma and other related disorders, the degree of plasma cell differentiation is significantly correlated with survival. Cats with well-differentiated tumors (< 15% plasmablasts) have a median survival of 254 days, whereas cats with poorly differentiated tumors (≥ 50% plasmablasts) have a median survival of 14 days.

In summary, multiple myeloma is a rare neoplasm in both cats and dogs. Conditions associated with multiple myeloma include hyperviscosity syndrome, bone lesions, hypercalcemia, renal disease, cytopenias, hemorrhagic diathesis, and increased susceptibility to bacterial infection. Multiple myeloma does not appear to have the same biologic behavior in dogs and cats and is best viewed as a heterogeneous disease with a different prognosis, clinical course, and response to therapy both within and between species. Although a good clinical response may be achieved with chemotherapy, eventual relapse of disease is to be expected.