Canine cutaneous mast-cell tumors: Current concepts for patient management

Mast-cell tumors (MCT) often present a therapeutic challenge to practitioners due to their varied biologic behavior. Although many are cured with surgery, some MCTs require additional therapy for local and systemic disease control.

•The mast cell

Mast cells originate in the bone marrow and migrate to peripheral tissues, where they are essential in allergic and inflammatory reactions. When mast cells are activated, they release preformed granules that contain histamine, heparin and proteases; this action is termed degranulation. Degranulation results in pruritus and swelling of the tumor or peritumoral tissue, excessive bleeding from the site of biopsy or fine-needle aspiration, delayed wound healing and gastrointestinal ulceration. The etiology of MCT is unknown. Although MCT are most commonly found in the skin and subcutaneous tissues, reports of primary MCT in visceral tissues and the nervous system exist.

•Initial evaluation

Most dogs with MCT are asymptomatic. Mast-cell tumors are often red, raised and alopecic, but some can clinically mimic subcutaneous lipomas or even insect bites. Some MCT have a history of shrinking and swelling, related to intermittent mast-cell degranulation with histamine release. Uncommonly, MCT are surrounded by bruising or edema related to mast-cell degranulation (termed Darier's sign); this usually indicates a poorly differentiated, aggressive tumor. If a skin or subcutaneous tumor is thought to be MCT based on its clinical appearance, then administration of diphenhydramine (1-2 mg/kg, subcutaneously) 30-60 minutes prior to aspiration of the mass can minimize further swelling and degranulation post-aspirate. Mast-cell tumors are generally straightforward to diagnose cytologically because of their round nucleus and characteristic intracytoplasmic granules (Figure 1); however, in poorly differentiated tumors, granules might not be visualized.

Figure 1: Cytologic appearance of a mast-cell tumor.

A thorough examination of the entire skin surface is indicated in every patient with MCT to ensure that no tumors are overlooked. Ten percent or more of dogs with MCT will develop additional MCT during their lifetime, so it is wise to suggest to clients that any new skin mass in a dog with a history of these tumors should be examined and aspirated as soon as possible. Ideally, patients with a history of MCT should have regularly scheduled recheck appointments (typically every three to six months) to examine for new tumors.

Figure 2: Locally invasive and metastatic body wall mast-cell tumor in a Shar pei. Shar peis tend to develop aggressive mast-cell tumors at a young age. This dog was 5 years old.

•Initial therapeutic plan

For most MCT, excisional biopsy after confirming the diagnosis via cytology is the initial treatment of choice. In dogs with large, infiltrative MCT that appear non-resectable or in patients with signs of mast-cell degranulation, such as peritumoral edema and bruising or gastrointestinal ulceration, additional staging is recommended prior to any attempt at surgical removal (Figures 2 and 3). For tumors not amenable to complete surgical resection or in patients with metastasis at diagnosis, chemotherapy and/or radiation therapy (RT) may be indicated prior to, following, or instead of surgery. In those cases, current therapeutic options should be reviewed, and consultation with an oncologist is indicated when available.

•Tests to consider

What tests should be performed prior to surgery?

Prior to surgical excision, routine bloodwork [complete blood count (CBC)], biochemical profile, urinalysis and a regional lymph node aspirate (regardless of lymph-node size) should be performed. Lymph nodes that contain increased numbers of mast cells and/or "clusters" of normal or poorly differentiated mast cells should be removed at the time of surgical excision of the primary tumor for further evaluation for metastasis on histopathology. Computed tomography scan (CT) or magnetic resonance imaging (MRI) can be indicated prior to surgery for treatment planning of large or invasive tumors, especially if they are located over a body wall.

Figure 3: Periocular mast-cell tumor in a dog. Due to the size, location and invasive nature of this tumor, staging tests for mast-cell metastasis are indicated prior to further treatment in this patient in order to formulate an appropriate treatment plan. This dog had evidence of regional (mandibular) lymph-node metastasis.

Additional staging tests for MCT metastasis should be considered prior to surgery in patients that have cytologic evidence of regional lymph-node metastasis or if tumors are highly infiltrative or nonresectable. If peritumoral edema or bruising is present, or tumors are recurrent or present in locations that are associated with an increased metastatic rate (oral, scrotum, prepuce, digits, muzzle and ear), then staging tests prior to surgery are also indicated. Further staging includes thoracic radiographs, abdominal radiographs and ultrasound, and bone marrow aspirate. Thoracic radiographs are usually normal in dogs with MCT, but pleural effusion that contains mast cells occasionally is seen in dogs with severe intra-abdominal mast-cell disease. Abdominal radiographs and ultrasound are used to examine spleen, liver and mesenteric lymph nodes, which are common sites of MCT metastasis. Aspirates of the liver and spleen are indicated if these organs appear abnormal ultrasonographically.

Although mast cells can be found normally in the spleen and liver, large numbers of mast cells or poorly granulated mast cells in these organs likely indicate metastasis. Increased numbers of mast cells in the bone marrow indicate MCT metastasis. Although the buffy coat smear (BCS) is a sensitive test for mast cells in peripheral circulation, it is non-specific and can be positive with any cause of systemic inflammation. A positive BCS can be supportive of MCT metastasis in dogs with other signs and tests documenting metastasis, and it can be useful as a non-invasive test to monitor efficacy of chemotherapy.

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•Surgery for MCT

Surgery is the primary treatment modality for the majority of MCTs. Intra-operative complications of surgery are usually seen only with large, poorly differentiated MCT and include tissue swelling and excessive hemorrhage during surgery related to histamine and heparin present in mast-cell granules.

Diphenhydramine (1-2 mg/kg) should be administered subcutaneously 30-60 minutes prior to surgery. Post-operative complications including incision dehiscence and delayed wound healing are uncommon except with attempted excision of large, poorly differentiated tumors.

Every MCT has the potential to be incompletely resected, so client education prior to surgery is essential. In a study of 55 dogs with grade II MCT treated with surgery alone, 90 percent had complete surgical margins after an attempt was made to excise 2-3 cm of tissue lateral to as well as tissue deep to the tumor (Seguin, 2001). Based on this and other studies, the surgeon's goal should be excision of the tumor with a 2 cm lateral margin and one fascial plane deep to the tumor.

For large body wall or extremity tumors where complete surgical excision is unlikely, marking the surgical site intraoperatively with hemoclips or stainless steel suture is advocated. If radiation therapy (RT) is indicated post-operatively, these radiographically visible markers will assist the radiation therapist in setting up the treatment plan.

Drain placement rarely is indicated when tumors are being resected because all tissues surrounding the drain are considered contaminated with tumor cells. This can make additional surgeries or RT planning more difficult.

•Help the pathologist help you

All excised tissue should be submitted to the pathologist for evaluation. Marking margins of resected tissue (i.e., deep and lateral margins) with India ink or with the multicolor Davidson marking system (Figure 4) (www.bradleyproducts.com) can assist the pathologist in visualizing the margins and determining if they are free of neoplastic cells. It is best to contact your pathologist to determine his or her preferences regarding margin evaluation.

Figure 4: Histologic appearance of a mast-cell tumor. Note that the tumor extends to the (blue) inked margin. The ink was applied prior to placing tissue in formalin, and should aid the pathologist in determining the completeness of the excision.

•Interpreting the biopsy report

• Tumor grade

Mast-cell tumor grading is based on a histologic classification scheme, and cannot be determined cytologically. The Patnaik grading system, which is the most commonly used grading scheme for canine mast-cell tumors, divides MCT into three categories (grades) based on their histologic appearance and invasiveness (Table 1). After these tumors were categorized based on histologic appearance, clinical follow-up information was obtained to determine if grade affects prognosis. The percentage of dogs surviving 1,500 days after diagnosis were 83 percent, 44 percent and 6 percent for grade I, II and III tumors, respectively (Patnaik, 1984). Tumor grade is the most consistent prognostic indicator of disease-free interval, metastasis and survival time in dogs with MCT.

Table 1: The Patnaik grading system for canine cutaneous mast-cell tumors (Patnaik, 1984)

Incidence of metastasis varies by studies, but in general, a 10 percent or less metastatic rate for grade I and II tumors and a 50 percent or greater metastatic rate for grade III tumors is predicted. The tumor grade should be evaluated with other clinical findings, such as the size and invasiveness of the tumor, the presence of local and distant metastasis, and tumor location.

• Tumor margins

Controversy exists among oncologists as to the definition of "clean" versus "close" margins for MCT. One report defines "clean" margins as a 1-2 mm distance between tumor and normal tissue (Weisse, 2002) but other references are scarce. The author generally defines "clean" margins for MCT as 10 mm or greater between tumor and normal tissue and "close" margins as 1-9 mm between tumor and normal tissue. It is important to remember that tissues shrink and can become distorted in formalin, so it can be difficult for the pathologist to give an accurate assessment of margins.

• Additional treatment

Post-operatively, further treatment options are based on biopsy results including evaluation of margins and tumor grade. For low and intermediate grade MCT (Patnaik grades I and II), if the surgical margins are "dirty" (i.e., tumor cells extend to margins of excision), then further treatment options include RT to the tumor bed or a second surgery if the site is amenable.

In addition, some investigators are trying to determine if chemotherapy administration in this setting of microscopic disease will prevent local tumor regrowth. If surgical margins are "close" in this group of patients, then options include second excision with scar revision, close monitoring of the site for recurrence or RT.

If surgical margins are "clean", frequent follow-up visits and diligent examination of the dog by the owner is indicated because some dogs develop recurrent or additional MCT. For dogs with undifferentiated (Patnaik grade III) tumors, evaluation for systemic metastasis and further therapy (chemotherapy ± RT) always are indicated.

•Which patients should have radiation therapy?

A definitive course of radiation therapy (typically administered daily for four to five weeks) is currently the standard of care for incompletely excised low- and intermediate-grade MCT, and provides long-term tumor control (two to five years or longer) in 75-90 percent of cases. For dogs with undifferentiated tumors that are incompletely excised, RT is a consideration, but it is essential that the client and clinician are aware that the tumor could metastasize despite aggressive local treatment such as RT.

Non-resectable MCT may be irradiated to attempt to shrink tumors and palliate clinical signs. Irradiation of a large volume of MCT should be performed with extreme caution, since rapid degranulation with subsequent hypotension, gastrointestinal ulceration and anaphylactic shock can occur in the post-treatment period.

•Chemotherapy considerations

When is chemotherapy indicated in dogs with MCT?

Chemotherapy should be considered if there is any evidence of metastasis, if an undifferentiated (Patnaik grade III) tumor is present, or in any tumor with negative prognostic indicators present (i.e., peritumoral edema and bruising, tumor in a location associated with increased metastasis). This treatment can improve quality of life and survival time, and might make non-resectable tumors amenable to surgery and/or RT (neoadjuvant chemotherapy). Chemotherapy drugs that are useful to treat mast-cell tumors include prednisone, vinblastine, lomustine (CCNU), cyclophosphamide and chlorambucil. Combination therapy is thought to be most effective. Clinical studies are ongoing to determine the usefulness of combination chemotherapy protocols in prolonging survival in dogs with MCT.

Which patients need histamine blockers?

Treatment with histamine receptor blockers (diphenhydramine=H1 blocker; famotidine, cimetidine, ranitidine=H2 blockers) is indicated in patients with non-resectable or metastatic MCT or prior to surgery in dogs with large, inflamed, edematous tumors. The goal of these therapies is to decrease clinical signs related to mast-cell degranulation. Omeprazole (a proton pump inhibitor) should be considered in patients who have clinical signs of gastrointestinal ulceration because it is a powerful inhibitor of gastric-acid secretion.

•Recent developments

Recent studies have focused on therapy for advanced local and metastatic MCT that previously were thought to be poorly responsive to treatment. Although treatment options are limited and generally unsuccessful in long-term management of dogs with evidence of disseminated MCT, dogs with regional lymph-node metastasis can have a better prognosis than previously thought. In a report of 19 dogs with cutaneous MCT with regional lymph-node metastasis treated with surgery, definitive radiation therapy to the primary tumor site and lymph node, and prednisone, the median disease-free interval was 1,240 days (Chaffin, 2002). This is comparable to other studies of dogs without nodal metastasis treated with radiation alone. In another recent study, 31 dogs with incompletely excised, poorly differentiated MCT with no evidence of nodal or systemic metastasis treated with a definitive course of RT alone had a 71 percent one-year survival rate, and 39 percent two-year survival rate (Hahn, 2004).

•Future directions

Veterinary oncologists are continuing to investigate methods of treatment and predicting outcome in dogs with MCT. In one example, investigators are examining the role of mutations in the proto-oncogene c-kit in the outcome of canine cutaneous MCT. The c-kit gene encodes for stem-cell factor, a cytokine responsible for mast-cell growth and differentiation. Mutations in this gene could theoretically promote development and progression of MCT. Recent studies have documented a higher incidence of c-kit mutations in grades III and II than in grade I MCT and that MCT containing c-kit mutations were twice as likely to recur and twice as likely to metastasize as those that did not have a mutation (Downing, 2002). One of the goals of this ongoing research is to examine the efficacy of an inhibitor of mutated c-kit on the outcome of canine mast-cell disease.

Dr. Gieger is a 1996 graduate of Louisiana State University School of Veterinary Medicine. She completed an internship at the Animal Medical Center in New York, a small animal internal medicine residency at Louisiana State University and a medical oncology residency at the University of California-Davis. She is a diplomate of the American College of Veterinary Internal Medicine in the specialties of small animal internal medicine and oncology. She is currently an assistant professor of oncology and internal medicine at the University of Georgia. Her clinical research interests include mast-cell tumors and nasal tumors.