Blast those masts! Conquering mast cell tumors in your veterinary patients

Shutterstock.comYour patient has a nasty red nodule on its muzzle. You poke it with a needle and it gets all pissed off.

[Insert expletive here.]

Even before you look at the slide, you know you're going to see a bunch of degranulated, angry mast cells surrounded by those purplish granules. Now what? Staging? Straight to surgery before staging? Referral?

First, calm down. Let's review.

Mast cell tumors are the most common cutaneous tumor in dogs, accounting for 16% to 21% of skin tumors.1 Risk factors include age (there's a higher incidence in older dogs) and breed (boxers, Boston terriers, Labradors, beagles and schnauzers are at higher risk). The cause of mast cell tumors is still largely unknown.

Mast cell tumors are most common in dermal and subcutaneous tissues. Up to 60% of mast cell tumors show up on the trunk and 25% on the limbs, with the head and neck the least common sites. Tumors have a varied appearance. They are typically solitary, but 11% to 22% of cases involve multiple lesions.1,2

The way a mast cell tumor looks to your naked eye in the exam room correlates well with how it looks on a slide. Well-differentiated mast cell tumors are typically single, 1 to 4 cm in diameter, slow-growing, rubbery, non-ulcerated and alopecic. They're most common in dogs older than 6 months of age. Undifferentiated mast cell tumors are large, rapidly growing, ulcerated and irritated. The surrounding tissue is edematous and inflamed, and small satellite nodules may be present.

If a dog with a mast cell tumor is sick when it comes in, blame histamine, heparin and other vasoactive amines. The patient may present with vomiting (possibly with blood), melena, anorexia and abdominal pain due to gastrointestinal (GI) ulceration-in fact, GI ulceration is noted in 35% to 83% of necropsy specimens.1,2 Metastasis is typically to local lymph nodes, the liver, the spleen and bone marrow.

Prognosis for these patients depends on several factors associated with the tumor, including:

• Histologic grade

• Clinical stage

• Location

• Systemic signs

• Recurrence

• Tumor size

• Mitotic index.

Stay tuned for more details on these factors.

Diagnosis and staging

Preliminary diagnosis is made with fine-needle aspiration. On the slide you'll see small to medium-sized round cells, with abundant small uniform cytoplasmic granules that stain purplish-red. Next-step diagnostics can include incisional biopsy to determine grade, fine-needle aspiration of the lymph nodes, complete blood count (CBC), serum chemistry profile and urinalysis.

Why so angry?

Here's a fun fact: Darier's sign refers to the wheal and flare in surrounding tissues after manipulation of a mast cell tumor and is caused by mast cell degranulation.

Additional procedures may include fine-needle aspiration of the liver or spleen, bone marrow cytology, buffy coat smears and abdominal ultrasonography. However, these diagnostics are of questionable value in staging since mast cells are also present in healthy animals. What's more, researchers have not found these procedures useful or definitive in patients with mast cell tumors.3,4

Today, histologic classification is preferred for its superior prognostic capabilities in biological behavior and clinical outcome, and it's an accurate predictor for metastatic behavior. But it's not without controversy either. Let's look more closely.

Three tiers: Old-school but still useful. Here's the classical three-tiered approach to histologic classification:

• Grade 1. Clearly defined cytoplasmic boundaries with regular, spherical or ovoid nuclei, rare or absent mitoses, and abundant large deep-staining cytoplasmic granules.

• Grade 2. Closely packed cells with indistinct cytoplasmic boundaries, nuclear-cytoplasmic ratio lower than with the anaplastic type, infrequent mitoses, and more granules than with the anaplastic type.

• Grade 3. Highly cellular, frequent mitoses, undifferentiated cytoplasmic boundaries, irregularly shaped and sized nuclei, and sparse cytoplasmic granules.

Mitotic index (MI) is an indirect measure of cell proliferation based on the number of mitotic figures present. It can be performed during routine histology and is part of both the three-tier and two-tier (see below) grading scheme. It's a strong prognostic factor for both metastasis and survival. In one study, dogs with a low MI (≤ 5) had a median survival time of 70 months, compared with five months for an MI of more than 5.5 Research is ongoing, as MI cutoff (high versus low) is not consistent from study to study.

It can also be especially difficult to predict which grade 1 and grade 2 mast cell tumors will result in death due to the mast cell tumor. In addition, there's variation among pathologists with the three-tiered system. As a result, experts are questioning the usefulness of the three-tiered staging system.

Three cheers for two tiers. To provide better prognostic significance, researchers have devised a two-tier histologic grading system based on the number of mitoses (less than or more than seven), presence of multinucleated cells or bizarre nuclei, and karyomegaly (increased nuclear size). According to the two-tiered system, high-grade mast cell tumors are significantly associated with shorter time to metastasis or new tumor development and with shorter survival time. In one study, the median survival time was less than four months for high-grade mast cell tumors but more than two years for low-grade mast cell tumors.6

In conjunction with the two-tiered system and MI, several markers are being utilized to better define and predict mast cell tumor disease. Ki-67 determines the number of proliferating cells, and AgNORs correlates with the speed of cell proliferation. c-Kit mutations of exon 11 and 8 of c-Kit have been detected in canine cutaneous mast cell tumors, and aberrant KIT expression patterns have been linked with decreased survival. (Yes, these are the kinds of things we oncologists geek out over-now on to the clinical relevance, which I know is what you're likely waiting for.)

Mast cell tumor grading, cell proliferation analysis (including MI), c-Kit polymerase chain reaction (PCR) testing and KIT immunohistochemistry (IHC) results are all linked to survival and metastasis associated with mast cell tumors.

Michigan State University has a mast cell tumor panel that grades tumors according to the two-tiered system, cell proliferation analysis (Ki-67, AgNORs), c-Kit PCR to detect internal tandem duplication mutations in exon 11 and exon 8, and KIT IHC to analyze expression of this tyrosine kinase receptor. Reference laboratories can send samples to Michigan State for a full panel or just test for the c-Kit mutation.

I recommend running a full mast cell tumor panel on low-grade (grade 1 or 2) mast cell tumors to help with the decision to recommend chemotherapy. For a high-grade (grade 3) mast cell tumor, c-Kit mutation status alone is typically what is needed to help with the decision of which chemotherapy.

Treatment

Most naïve dermal mast cell tumors are intermediate or low-grade and will be cured with surgery alone, provided the site is amenable to wide and clean margins. The recommendations for margins have historically been 3 cm, but 2-cm lateral margins may be adequate for most.7 For small and lower-grade tumors, extensive deep margins are just as crucial; one fascial plane is recommended.

Unfortunately, histologic assessment of margins may be unreliable. Not all incompletely removed mast cell tumors will recur, and recurrence varies study by study. In some studies only 20% to 30% recur and in others incomplete resections are associated with increased recurrence, decreased survival or both. I do recommend additional local therapy to prevent recurrence if surgical margins are incomplete.1

In some locations, such as the distal limb, wide margins are often not possible. In my opinion, amputation is probably too aggressive. But the pet will likely need radiation, chemotherapy or scar revision after surgery. If owners decline postoperative therapy, counsel them on the risks of recurrence.

Consider chemotherapy for patients with:

• High-grade histologic results (grade 3, high grade)

• Distant metastasis

• Lymph node metastasis

• C-Kit-positive results or high proliferation scores

• Nonresectable mast cell tumors

• Multiple mast cell tumors in a short time period.

Toceranib phosphate (Palladia-Zoetis), a novel anti-cancer drug in dogs, is an oral tyrosine kinase inhibitor that blocks activity of multiple receptors and selectively targets the split kinase family of RTKs. It exerts antiangiogenic and antiproliferative effects, and the oral bioavailability is 77%. Palladia is labeled for dogs with grade 2 or 3 recurrent cutaneous mast cell tumors with regional lymph node involvement.

A clinical field study of single-agent Palladia in the treatment of mast cell tumors showed a biologic response rate of 60% for all dogs, although grade 2 mast cell tumors had better outcomes than grade 3, a significantly longer time to progression, and significantly longer response duration.8 GI signs were the most common side effect and neutropenia the most common laboratory abnormality. Based on this study, the recommended label dose for mast cell tumors is 3.25 mg/kg every other day, with dose adjustments downward based on regular assessments.8

Early recognition of side effects is critical with Palladia, so it's important to be vigilant in monitoring. Tell clients that if they note any side effects they should stop the medication, start just-in-case medications and contact a veterinarian. If adverse events occur, drug holidays for up to two weeks are recommended.

In addition to Palladia, some combination therapies have been shown to be effective against mast cell tumors:

• Vinblastine and prednisone: 47% response rate9

• Vinblastine, cyclophosphamide and prednisone: 64% response rate10

• Vinblastine, lomustine and prednisone: 65% response rate11

• Chlorambucil and prednisone: 38% response rate.12

Conclusion

Mast cell tumors are naughty, unpredictable little things. Remember, they can masquerade as other more benign cutaneous neoplasms. Early identification with cytology is key. Don't “just monitor.” Why wait? Aspirate!

Dr. Sue Ettinger is a practicing veterinary cancer specialist, international speaker and book author. Also known as Dr. Sue Cancer Vet, she is most passionate about raising cancer awareness and has developed “See Something, Do Something. Why Wait? Aspirate!” to promote early cancer detection and diagnosis.

References

1. London CA, Thamm DH. Mast cell tumors. In: Small animal clinical oncology. 5th ed. St. Louis Missouri: Elsevier Saunders;2013:335-355.

2. Séguin B, Leibman NF, Bregazzi VS, et al. Clinical outcome of dogs with grade-II mast cell tumors treated with surgery alone: 55 cases (1996-1999). J Am Vet Med Assoc 2001;218:1120-1123.

3. McManus PM. Frequency and severity of mastocytemia in dogs with and without mast cell tumors: 120 cases (1995-1997). J Am Vet Med Assoc 1999;215(3):355-357.

4. Finora K, Leibman NF, Fettman MJ, et al. Cytological comparison of fine-needle aspirates of liver and spleen of normal dogs and of dogs with cutaneous mast cell tumours and an ultrasonographically normal appearing liver and spleen. Vet Comp Oncol 2006;4(3):178-183.

5. Romansik EM, Reilly CM, Kass PH, et al. Mitotic index is predictive for survival for canine cutaneous mast cell tumors. Vet Pathol 2007;44(3):335-341.

6. Kiupel M, Webster JD, Bailey KL. Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Vet Pathol 2011;48(1):147-155.

7. Simpson AM, Ludwig LL, Newman SJ. Evaluation of surgical margins required for complete excision of cutaneous mast cell tumors in dogs. J Am Vet Med Assoc 2004;224(2):236-240.

8. London CA, Malpas PB, Wood-Follis SL, et al. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res 2009;15(11):3856-3865.

9. Thamm DH, Mauldin EA, Vail DM. Prednisone and vinblastine chemotherapy for canine mast cell tumor-41 cases (1992–1997). J Vet Intern Med 1999;13:491-497.

10. Camps-Palau MA, Leibman NF, Elmslie R, et al. Treatment of canine mast cell tumours with vinblastine, cyclophosphamide and prednisone: 35 cases (1997-2004). Vet Comp Oncol 2007;5(3):156-167.

11. Rassnick KM, Bailey DB, Russell DS, et al. A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high-dose vinblastine and prednisone (CVP) for treatment of dogs with high-grade, metastatic or nonresectable mast cell tumours. Vet Comp Oncol 2010;8(2):138-152.

12. Taylor F, Gear R, Hoather T, et al. Chlorambucil and prednisolone chemotherapy for dogs with inoperable mast cell tumours: 21 cases. J Small Anim Pract 2009;50(6):284-289.