HELPFUL HINT 1: KNOW TUMOR BIOLOGY
Mast cell tumors are the most common cutaneous tumor in dogs (1). They do not have a specific look or feel (1) – we have diagnosed mast cell tumors that have a similar appearance to that of small pimples, skin tags, large ulcerated lesions, and soft fatty masses. Increased risk is associated with the following breeds: Boxer, Boston Terrier, English Bulldogs, Pugs, Labrador Retriever, Golden Retriever, Cocker Spaniel, Schnauzer, Staffordshire Terrier, Beagle, Rhodesian Ridgeback, Weimaraner, Shar-Pei (1). These tumors occur more often in middle-older aged dogs (1).
Mast cells contain biologically active compounds within the basophilic granules that are seen in the cytoplasm on microscopic evaluation (1). Histamine is the best-known compound; however these granules also contain heparin, proteases, and growth factors (1). These compounds play a role in the localized clinical symptoms and post-operative delay in wound healing seen in some patients with these tumors; specifically, histamine induced inflammation, heparin induced decrease in clot production and prolongation of bleeding, and protease induced protein and tissue breakdown. These granules may also play a role in systemic side effects from mast cell cancer including gastric ulceration induced vomiting, melena, hematochezia, weight loss and diminished appetite.
Mast cell tumors are locally aggressive and often extend beyond what is palpable on the surface (1). Metastasis depends on tumor grade with Grade 1, 2 and 3 tumors (Patnaik Grading Scale) metastasizing less than 10%, less than 20%, and approximately 90% of the time, respectively (2). More recently, a 2-tier grading scale (Kiupel Scale) has been established, with low grade vs high grade (3). The 2-tier scale was established to provide a more objective set of grading criteria for pathologists as the previously used scales may be prone to subjectivity and result in discordant grading results among pathologists (3). Metastatic disease is most often found in regional lymph nodes, liver, spleen, and less commonly the bone marrow (1). Low grade (Grade 1 or Grade 2) tumors typically grow slowly and are relatively quiescent while high grade (Grade 3) tumors have more aggressive behavior with rapid growth and may be associated with ulceration (1-3).
Approximately 20% of dogs will develop multiple cutaneous mast cell tumors (1). Therefore, a dog with prior history of mast cell tumor presenting for a new skin or subcutaneous mass should have that mass aspirated and cytology performed. Several studies have found that dogs with multiple mast cell tumors do not have a poorer prognosis than dogs with just one mast cell tumor (4, 5), although this is somewhat controversial.
EXAMPLES OF WHY IT IS IMPORTANT TO KNOW TUMOR BIOLOGY
- Patient presents for a mass with recent rapid growth. The mass was present for months to years with minimal change but in the past 2 weeks it has doubled in size, growing from a pea to a tennis ball size. The mass is removed and histopathology indicated Grade 1, complete margins. Given the histopathology you may consider this cured with the complete margins and Grade 1 designation; however, the ‘recent rapid growth’ history is concerning and indicates more aggressive tumor behavior. For this reason, a discussion with the pathologist, second opinion pathology review, and/or additional testing on the tumor, such as mast cell tumor proliferation panel, should be considered.
- Tumor biology helps us in our diagnostic plan. The most common staging tests recommended for dogs with mast cell cancer are routine baseline bloodwork (CBC/Chemistry), abdominal ultrasound, needle aspirate of the mass, either needle aspirate and cytology (or more preferred, removal and histopathology) of the regional/draining lymph node, and histopathology with margin assessment of the tumor (1).
- Tumor biology helps us in our treatment plan. With wide roots, 2-3cm margins are generally recommended although for low grade (Grade 1 and Grade 2) tumors, less aggressive margins may be adequate (further discussion below). With incomplete excision (roots left behind), high grade tumors have higher risk for recurrence than low grade, as such adjuvant therapy such as additional surgery or radiation is often recommended (1, 3). Furthermore, high grade tumors have highest risk for metastasis as such adjuvant chemotherapy is recommended in these cases (1, 3, 6). With incomplete excision of low grade (Grade 1 and Grade 2) tumors, additional surgery or radiation is recommended to help reduce risk of recurrence (1).
HELPFUL HINT 2: REVIEW THE MICROSCOPIC DESCRIPTION ON THE HISTOPATHOLOGY REPORT
The microscopic description provides key information in helping predict the behavior of the tumor, aiding in prognostication and treatment planning. Key elements of this description include: mitotic index, presence and number of multinucleated cells, presence and number of bizarre nuclei, presence of karyomegaly, degree of granulation, margins (1-3).
High grade (Grade 3) tumors generally have some of the following characteristics: a mitotic index greater than 5-7 mitotic figures/10 high power field, 3 or more multinucleated cells, 3 or more bizarre nuclei per 10 high powder field, karyomegaly (enlarged cellular nucleus), poorly granulated cells (1-3).
Low grade (Grade 1 and Grade 2) tumors generally have some of the following characteristics: infrequent-rare mitosis (less than 2 mitotic figures/10 high power field), abundant cytoplasmic granules, rare-no multinucleated cells and/or bizarre nuclei (1-3).
In the past, 3cm margins were the standard recommendation. More recent studies are finding 1cm lateral margins and 0.4cm deep margins are sufficient at controlling the tumor in many dogs with low grade (Grade 1 and Grade 2) tumors (7, 8). Wider margins are generally recommended for dogs with high grade tumors due to higher risk for recurrence with this phenotype.
It is important to request and read the microscopic description to get a clear view of the histologic appearance of the tumor and compare this to the historic behavior of the tumor (what your physical exam shows you and what the clients described). For example – if the tumor has been present for months to years with minimal growth and microscopic descriptors are that of low-intermediate grade tumor than this corroborates. If there is discordant data between the history/exam and microscopic description then this warrants further investigation (conversation with pathologist, second opinion pathology review, and/or mast cell tumor proliferation panel).
WHEN TO RECOMMEND THE MAST CELL TUMOR PROLIFERATION PANEL
This panel tests for markers of cellular proliferation, c-kit, AgNOR, KI67, and PCNA, through immunohistochemistry (special stains) and tests for the c-kit mutation through PCR (polymerase chain reaction) (9). This panel is not automatically run on every mast cell tumor and requires additional fee. This panel may be performed on every mast cell tumor if the clinician/client chose; however, this can be cost prohibitive. There are many labs that offer this testing a la carte, so you can pick and choose which tests within this profile you would like performed.
Instances on when to recommend the panel may include:
- Incompletely excised low-intermediate grade tumor, to help further elucidate risk for recurrence (recommend performing the entire panel)
- High grade tumors or tumors with high grade biology, i.e. already metastasized, to help determine chemotherapy protocol (recommend performing the c-kit PCR alone). A recent study demonstrated that tumors with c-kit mutation respond to the small molecule inhibitor Toceranib more often than tumors without the c-kit mutation, as such, Toceranib may be considered as part of the chemotherapy plan in this subset of patients.
HELPFUL HINT 3: TREATMENT RECOMMENDED
The standard of care treatment, first and foremost is surgery (1). If bulky mast cell disease is present, antihistamine (H1 and H2) blockers are recommended including: diphenhydramine or chlorpheniramine (H1 blockers), cimetidine, famotidine, ranitidine (H2 blockers) or proton pump inhibitor omeprazole (instead of H2 blockers). In some cases, surgical pre-treatment with steroid such as prednisone for 1-2 weeks may be recommended to reduce inflammation caused by the tumor and facilitate improved surgical margins (10).
Here are some helpful hints on when to recommend adjuvant therapy or alternative therapy if surgery is not an option.
WHEN TO RECOMMEND RADIATION
There are several common scenarios in which radiation is recommended (not exhaustive list):
- Incompletely excised mast cell tumor if second surgery not feasible (any grade)
- Bulky mast cell tumor that is not amenable to surgery (palliative purposes in this setting)
WHEN TO RECOMMEND CHEMOTHERAPY
There are several common scenarios in which chemotherapy is recommended (not exhaustive list):
- High grade (Grade 3) designation
- Known metastasis to regional lymph node, liver, spleen, etc
- Incompletely excised mast cell tumor (any grade)
- Bulky mast cell tumor that is not amenable to surgery
HELPFUL HINT 4: PROGNOSIS
As with any cancer, outcomes vary depending on stage, grade, treatment chosen, and interpatient variability.
Dogs with low grade (Grade 1 or Grade 2) mast cell tumors, with no evidence of metastasis, receiving surgery with wide and clean margins OR adequate local tumor control (surgery then treat roots with radiation or scar revision surgery) then there is good chance for long term control of this tumor (1). Inform the client that approximately 20% will develop another mast cell tumor in another location so diligent monitoring is recommended.
Dogs with high grade (Grade 3) mast cell tumors, or biologically aggressive tumors (i.e. those tumors with Grade 1 or Grade 2 designation but have known lymph node metastasis), receiving surgery with complete margins, removal of metastatic lymph node, followed by chemotherapy have an average survival time of over 3 years in one study (11).
Dogs with distant metastasis (liver/spleen/bone marrow) may receive radiation and chemotherapy for palliative purposes. Prognosis is generally poor but these treatments may help slow growth and progression as well as palliate clinical symptoms of illness for an estimated 3-4 months, depending on tumor response with therapy.
Dogs with large tumors not amenable to surgery may receive palliative radiation and chemotherapy to help slow growth and metastasis for a median progression free interval of approximately 300 days (12).
Submitted by: Dr. Kate Vickery, VMD, MS, Diplomate ACVIM, CVA
1- Withrow and McEwen. Small Animal Clinical Oncology. 5th ed. Eds Withrow, Vail, Page. Mast Cell Tumors. 335-355.
2 -Patnaik, AK, et al. Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Veterinary Pathology. 1984. 21(5): 469—74. https://www.ncbi.nlm.nih.gov/pubmed/6435301
3- Kiupel, M, et al. Proposal of a 2-tier histologic grading systemi for canine cutanoes mast cell tumors to more accurately predict biological behavior. Veterinary Pathology. 2011. Jan; 48(1): 147-55. https://www.ncbi.nlm.nih.gov/pubmed/21062911
4- Mullins, M, et al. Evaluation of prognostic factors associated with outcome in dogs with multiple cutaneous mast cell tumors treated with surgery with and without adjuvant treatment: 54 cases (1998-2004). JAVMA. 2006. 228(1): 91-95. https://www.ncbi.nlm.nih.gov/pubmed/16426175
5- Thamm, D, et al. Prednisone and vinblastine for canine mast cell tumor – 41 cases. JVIM 1999. 13: 491-97. https://www.ncbi.nlm.nih.gov/pubmed/10499735
6- Stefanello D, et al. Comparison of 2- and 3-category histologic grading systems for predicting the presence of metastasis at the time of initial evaluation in dogs with cutaneous mast cell tumors: 386 cases (2009-2014). JAVMA 2015. 246(7): 765-69. https://www.ncbi.nlm.nih.gov/pubmed/25794126
7- Schultheiss, PC, et al. Association of histologic tumor characteristics and size of surgical margins with clinical outcome after surgical removal of cutaneous mast cell tumors in dogs. JAVAM. 2011. 238(11): 1464-69. https://www.ncbi.nlm.nih.gov/pubmed/21627510
8- Pratschke, KM, et al. Evaluation of a modified proportional margins approach for surgical resection of mast cell tumor sin dogs: 40 cases (2008-2012). JAVMA. 2013. 243(10): 1436-41. https://www.ncbi.nlm.nih.gov/pubmed/24171373
9- Bergman, P, et al. Correlation of histologic grading of canine mast cell tumors with KI67/PCNA/AgNOR/c-kit scores: 38 cases. VCO. 2004. 2: 98. http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5810.2004.0045a.x/abstract
10- Stanclift, RM, et al. Evaluation of neoadjuvant prednisone administration and surgical excision in treatment of cutaneous mast cell tumors in dogs. JAVMA. 2008. 232: 53-62. https://www.ncbi.nlm.nih.gov/pubmed/18167109
11- Thamm, D, et al. Outcome and prognostic factors following adjuvant prednisone/vinblastine chemotherapy for high-risk canine mast cell tumor: 61 cases. J Vet Med Sci. 2006. 68: 581-87. https://www.ncbi.nlm.nih.gov/pubmed/16820715
12- Carlsten, KS, et al. Multicenter Prospective Trial of Hypofractionated Radiation Treatment, Toceranib, and Prednisone for Measurable Canine Mast Cell Tumors. JVIM. 2012. 26: 135–141. https://www.ncbi.nlm.nih.gov/pubmed/22176473