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Home » Resources » Mast Cell Tumors: Current Diagnosis, Treatment, and Prognosis

Mast Cell Tumors: Current Diagnosis, Treatment, and Prognosis

Mast Cell Tumors: Current Diagnosis, Treatment, and Prognosis
Stephen Stockdale, DVM
Seattle Veterinary Specialists
Kirkland, WA

Overview
The skin and subcutis are the most common sites for tumors to occur in dogs, with mast cell tumors (MCT) representing the most common malignant tumor type (18.8%).1 Mast cell tumors are primarily a disease of older dogs (median 8.5 years) but have a wide reported age range.2 Pugs, Boston Terriers, Boxers, Labrador Retreivers, Beagles, and Schnauzers are all reported to have higher MCT incidence.1-4 Interestingly, while brachycephalic breads are at a higher risk than most breeds for development of MCT, they appear to develop more well differentiated, low grade tumors relative to their mesaticecephalic and dolichocephalic counterparts.1 There is no identified sex predilection.

Normal mast cells are derived from hematopoietic stem cells in the bone marrow under the control of “stem cell factor”, also known as KIT ligand (or c-kit) via the KIT receptor (CD117) on mast cells. The development of normal mast cells is multifactorial, but there is a strong suspicion for dysregulation of the KIT receptor in provoking MCT development and progression. Cell precursors move from the bone marrow, through the circulation, then to the tissues where they mature into effector mast cells. The skin, GI tract, respiratory tract, and lymphoid tissues are densely populated with mast cells where they play an important role in mediating inflammation. Mast cells respond to stimuli by releasing a variety of substances from their cytoplasmic granules such as vasoactive amines (histamine, seratonin), enzymes (acid hydrolyses, cathepsin G, phospholipase A, chymase, tryptase, carboxypeptidase), proteoglycans (heparin, chondroiten sulfate), and cytokines.5 Mast cells function to promote hypersensitivity reactions, modulate immune responses by stimulating T cell activation and promotion of leukocyte migration during both acute and chronic inflammation.5

Mast cell tumors can develop in any tissue but are most common within connective tissue near epithelial surfaces. Cutaneous and subcutaneous forms are far more common than visceral forms. All MCT are considered malignant but their behavior with respect to risk of local recurrence and spread after resection is often grade dependent. Using the Patnaik 3-tier grading scheme, grade I tumors metastasize less than 10% of the time, grade II tumor metastasize 5-22%, and grade III tumors metastasize 55-96% of the time.14,15,40 The metastatic pattern typically occurs via the reticuloendothelial system with spread to local then distant lymph nodes, followed by the liver, spleen, bone marrow and blood in the most aggressive cases.

History and Clinical Signs
Any skin or subcutaneous nodule can be a MCT regardless of location or appearance. Often these masses are disregarded as a lipoma without further investigation. Characteristics of MCT disease are the result of substances liberated from the cytoplasmic granules within each mast cell such as heparin and histamine. Owners that describe a lump that waxes and wanes with time with or without evidence of pruritis, erythema, ulceration, or bruising should raise the suspicion for a MCT. Patients may have poor wound healing from proteolytic enzymes and vasoactive substances. Local hemorrhage can occur due to local effects of heparin. Gastrointestinal upset or ulceration can occur due to histamine binding of H2 receptors of the gastric parietal cells which stimulates acid release.5 Histamine also increases gastrointestinal motility. More severe cases of marked histamine release may experience intermittent hypotension due to histamine binding of blood vessels, cardiac muscle, and smooth muscle.

Diagnostics
There are several diagnostic tests that can be executed in the work-up for a suspected MCT. Mast cell tumors tend to be easily diagnosed on fine needle aspiration due to their characteristic round cell or “fried egg” appearance and the presence of cytoplasmic granules. [Figure 1] The draining lymph node, even if normal in size, should be aspirated for evidence of metastasis, as it can affect prognosis or change the ultimate treatment plan if there is evidence of metastasis.6 It is important to remember that a normal feeling lymph node does not imply lack of metastasis. If local lymph nodes are negative for metastatic disease, there is controversy whether staging beyond local lymph node assessment is necessary. In a study of 220 dogs with mast cell tumors, none of the dogs with tumor free local lymph nodes had distant metastasis.7 Complete blood counts are often normal but can show eosinophilia, basophilia, or anemia secondary to gastrointestinal blood loss or anemia of chronic disease. Buffy coat assessment has been shown to lack sensitivity and specificity for mast cell disease and therefore is rarely utilized in staging procedures.8 Specifically, dogs with non-mast cell disease tended to have more buffy coat mast cells than dogs with mast cell disease. Abdominal ultrasound and ultrasound guided aspirates of the liver and spleen should be considered regardless of gross appearance for high-grade tumors and those with local metastasis.9,10 Thoracic radiographs are more often indicated to screen for unrelated cardiopulmonary disease rather than for assessment of MCT spread to the lungs since mast cell tumors rarely metastasize to the pulmonary parenchyma. Bone marrow aspiration rarely yields mast cell presence except in visceral or high grade forms of MCT. Since visceral MCT has a uniformly poor prognosis, the presence or absence of mast cells within the bone marrow does not significantly alter the treatment plan and thus is rarely indicated.11

Histopathology is used to determine tumor grade. Historically, as briefly mentioned above, a 3-tiered grading system has been used to determine prognosis.2 Patnaik found that grade correlated with prognosis. The percent of animals alive at 1500 days after removal of a solitary mass was 83% for grade I, 44% for grade II, and 6% for grade III tumors. The fault in this grading scheme is that grade II MCT show significant variability in biological behavior; some behave more like grade I tumors, and others rapidly progress and spread similar to grade III tumors. The historical dilemma has been associated with how to interpret the diagnosis of intermediate grade (Grade II) tumors which comprise the majority of MCT. In order to address this limitation of the 3-tier system, several subsequent classification schemes have been developed to improve prognostication within this group. Kiupel and colleagues proposed a 2-tiered system to eliminate the “gray area” of the grade II tumor distinction. This group reported a 96.8% consistency rate between pathologists when comparing on a 2-tiered system. “Low grade” tumors had a median survival of 2 years whereas “high grade” tumors had a median survival of 4 months.24

Which staging tests should you perform in a general practice setting?
The extent to which staging procedures are performed should be based on the apparent tumor resectability and prognostic factors present. [Figure 2 and Table 1] Fine needle aspiration should be the first diagnostic test performed to determine the presence of a MCT. As discussed above, the local draining lymph node should be aspirated in all cases based on the unpredictable nature of MCT, especially when histological grade is unknown. Once the diagnosis of MCT has been made based on cytology, the next step is to determine if the tumor has the ability to be removed with margins. If the tumor can be completely removed with margins, it should be submitted for histopathologic grading, mitotic index evaluation, and margin determination. The vast majority of grade I tumors and most grade II tumors are cured with complete excision alone. Additionally, contrary to previous dogma, many of these low and intermediate grade tumors do not recur even after incomplete resection. [Figure 3]

There are numerous factors in addition to tumor grade that have been utilized to help predict biological behavior and prognosis. These additional factors are particularly useful in differentiating aggressive from more “benign” grade II MCT. Location has been linked to biologic behavior. Mast cell tumors of the oral mucosa, mucocutaneous junction, and perioral skin have a 59% reported metastatic rate to local lymph nodes.41 For this reason, regardless of grade, all tumors in these locations should be regarded as aggressive. In another study, dogs with perineal and inguinal MCT, had a reported incidence of metastasis at presentation of 48%.25 In the same study, the disease free interval for dogs with perineal or inguinal MCT was 9.6 months compared to 34 months for animals in other cutaneous locations.25 Numerous studies have shown that distant metastasis carries a worse prognosis. Tumors that are larger than 3 cm in diameter at diagnosis, have shown recent rapid growth, or are ulcerated all carry a worse prognosis due to correlation with high grade, undifferentiated tumors.19,21,23,33 In contrast, the presence of multiple concurrent cutaneous MCT have not been shown to negatively affect prognosis.23,34 According to the World Health Organization staging scheme, dogs with multiple cutaneous mast cell tumors would be considered a higher stage than animals with a single MCT or animals with a single MCT and concurrent lymph node metastasis. This brings into light that the current staging system is flawed and needs updating based on current literature. Boxers, bulldogs, pugs, and other brachycephalic breeds tend to have well differentiated tumors at a higher proportion than the general population.1 Tumor recurrence after surgical excision has a poorer prognosis.21,23 Mitotic index is the number of mitoses seen per 10 high power fields on histopathologic analysis. Mitotic index has been highly correlated with survival where animals with a mitotic index less than or equal to 5 had a median survival of 70 months whereas a mitotic index greater than 5 had a median survival of only 2 months.29

Many immunohistochemical tests can be performed on tumor biopsies to help prognosticate. As stated above, KIT is a growth factor receptor that promotes the formation of mast cells. KIT staining pattern has been correlated with MCT recurrence rate and mortality.31 KIT staining is based on a three-level staining pattern. Staining level I, II, and III showed a local recurrence rate of 2.4, 14.0, and 23.1% respectively. The same staining levels showed distant recurrence in 14.3, 31.0, and 38.5% respectively. Mast cell tumor mortality rate was 2.4, 25.6, and 38.5% based on KIT staining pattern. The determination of KIT mutation status has also been correlated with tumor grade, cellular proliferation, and response to tyrosine kinase inhibitor medications.30,31,42, Ki-67, an immunohistochmical marker for proliferation, has been significantly correlated with survival. The 1, 2, and 3 year survival probabilities for dogs with grade II MCT and Ki-67 scores (score being defined as the percentage of positively staining cells) less than 1.8 were 0.92, 0.86, and 0.77, respectively. The corresponding survival probabilities for dogs with grade II MCTs and Ki-67 scores greater than 1.8 were 0.43, 0.21, and 0.21, respectively.43 Argyrophilic staining of nucleolar organizer regions (AgNOR) scoring has been linked to tumor recurrence and survival as well.28,43

The most critical parameters for each mast cell tumor after excision are grade and margins. Grade II tumors tend to be the most difficult to interpret based on the historical wide range of behavior. If a tumor is determined to be a grade II tumor, mitotic index, Ki-67, and KIT should be determined to differentiate grade II-low (less aggressive and more similar in behavior to a grade I) from grade II-high (more aggressive and similar in behavior to a grade III). For grade II-low tumors, they can follow a similar treatment plan as grade I tumors. [Figure 3] Grade II-high and grade III tumors should have KIT staining and KIT mutation status determined as it affects adjuvant treatment strategy and prognosis. KIT mutation positive would likely be started on Palladia treatment whereas KIT mutation negative would likely be started on vinblastine and prednisone. Colorado Statue University and Michigan State University have comprehensive mast cell tumor panels that tests for mitotic index, Ki-67, KIT IHC staining, and KIT mutation status. AgNOR and p53 can also be performed but in the author’s opinion they are not necessary if grade, margins, stage, mitotic index, Ki-67, and KIT mutation status are available.

Figure 2: Diagnostic algorithm for canine mast cell tumors.11

Table 1: Prognostic Factors associated with canine mast cell tumors

Factor    

Notes

Reference

Location

Mucous membranes, muzzle, scrotum, inguinal, and perineal sites controversial

Sfiligoi25, Cahalane26, Gieger27, O’Keefe37, Thamm21, Thamm39, Hillman41

Stage

LN metastasis or distant metastasis worse prognosis

Krick6, Warland7, Book9, Murphy13, Thamm21, Hillman41

Grade

Grade I (Patnaik) and low grade (Kiupel) have good prognosis and rare recurrence. Grade II (Patnaik) has wide range of behavior. Grade III (Patnaik) and High grade (Kiupel) have high rate of metastasis, local recurrence, and shorter survival time.

Patnaik2, Kiupel24

Tumor Size

>3cm diameter

Hahn19 ,Mullins23

Mitotic Index

<5 mitoses / 10hpf had median survival of 70 months versus 2 months for tumors with >5 mitoses/ 10hpf regardless of grade.

Romanisik29

Clinical signs

More likely high grade or advanced stage; worse prognosis

Mullins23, O’Keefe37

Recent rapid growth/ulcerated

More likely high grade; worse prognosis

Thamm21, Poggiani33

Multiple cutaneous masses

No prognostic value Mullins23 , Kiupel24, Murphy34, Scase 43

Breed

Boxers tend to have well differentiated tumors with a better prognosis Bostock1

Recurrence

Recurrent tumors worse prognosis Thamm21, Mullins23

Argyrophilic Nucleolar organizer regions (AgNOR)

Higher levels = worse prognosis

Thamm21, Simoes28, Webster30, Scase 43

c-Kit

Higher level may have worse prognosis, but higher response to TK inhibitors Webster30, Kiupel31, London42

p53 mutations

p53 correlated to higher tumor grade Jaffe32

ki67

Higher level = higher local recurrence and shorter survival; correlates well with Patnaik grading system

Webster30, Abadie38, Scase 43

 

Surgical Considerations:
Surgical excision is the treatment of choice for local disease. The first surgical attempt offers the best chance to cure. Perioperative H1 blocker therapy (diphenhydramine 2-4mg/kg PO q 12hr) and proton pump inhibition Omeprazole (1mg/kg PO q 24hr) should be administered to antagonize the systemic effects of MCT degranulation in the days prior to surgery and the day of surgery when tumor manipulation will occur.11 Many clinicians choose to treat with neoadjuvant prednisone in order to shrink the size of the tumor, reduce local edema, and reduce intraoperative hemorrhage prior to surgical excision. Historically there has been a 70% response rate and an 80.6% decrease in tumor volume with 1mg/kg/day prednisone therapy.44 All excised samples should be submitted for histopathology and margins determination. Historically, wide margins (3 cm in each horizontal plane and at least 1 fascial plane deep) have been recommended. There is some debate over whether 3 cm margins are needed for grade I and grade II tumors.12 Fulcher et al found 91% clean margins and a median disease free interval of 538 days when 2cm margins and 1 fascial plane was used. All animals were alive at 538 days.12 A proportional margins approach has been investigated where the margin determination is based on the diameter of the mass itself. Results of that study showed promising results with 85% clean margins and no local recurrence in the follow-up period.22

Wide surgical excision comes with important factors to consider once the tumor is “out of the picture.” Oftentimes a large void can be left in an area that may be difficult to close without excessive tension and subsequent dehiscence. Areas that lack excessive tissue to manipulate include the distal extremities, caudal thigh, inguinal region, perineum, or head. Thorough planning prior to surgery can help to avoid complications. A sterile skin marker should be used to mark the proposed surgical margins prior to the initial cut. Skin retracts when it is cut so having a previously determined line ensures accurate margins. Careful attention to known tension lines should be taken into account when determining how the wound will be closed. Circular wounds can be closed by transforming the circular wound into an ellipse (closing from the “corners” as an “X” or “Y”), using a sub-dermal plexus flap, or use of an axial pattern flap. It is important to note however that such reconstruction techniques increase the size of the surgical field and thus should be reserved for cases where complete margins are achieved. The wound should be closed in at least 3 layers with external sutures for added tension relief. A tie-over “Bolster” bandage, soft padded bandage, splint, or half cast can be used based on location to help relieve tension even further. In the author’s experience, if you are questioning if additional tension relief is needed, it likely is.

In areas where wide margins are not feasible (distal extremities, head, or tail), incisional biopsy should be performed to help determine appropriate surgical “dose.” For cases where surgical margins are not attainable on the distal limb, amputation has been performed. This treatment modality is likely too aggressive as a first line approach since many tumors can be controlled with marginal excision alone.14 The addition of adjuvant chemotherapy or radiation therapy can further enhance the chances of local cure for marginally excised MCT.

Incomplete margins does not guarantee a high rate of local recurrence as it was previously reported.1,2 This calls into question the true need for adjuvant therapy. Currently reported recurrence rates with incomplete margins without adjuvant therapy for well, intermediate, and poorly differentiated tumors were 1%, 6%, and 19% respectively.13 In one study, patients who had re-excision due to incomplete initial surgery had no evidence of mast cell disease in the en bloc excised tissue.13 Proposed theories for this phenomenon are that the immune system clears the microscopic disease, cytokines from neoplastic cells recruit normal mast cells to the initial tumor margins, that with well differentiated mast cell tumors it is difficult to differentiate between normal mast cells and neoplastic cells, or that the microscopic disease is missed based on how the biopsy is sectioned. Owners should be warned of this possibility prior to a second surgical procedure so that they do not feel that the second procedure was unnecessary. Recurrence of subcutaneous tumors with incomplete margins was reported at in 12% of cases. Risk for recurrence was related to mitotic index and growth pattern (i.e. circumscribed versus infiltrative).

Complete margins do not promise a cure. Nineteen percent of poorly differentiated tumors with complete margins have been reported to recur.13 Studies have shown that complete resection of grade 1 and 2 tumors with no evidence of metastasis will have local control of 80-90%.13-15 This implies that patients with low to intermediate grade tumors have a good prognosis and are essentially “cured.” These patients should go into a phase of “active surveillance.” [Figure 3]

Grade III tumors with no evidence of systemic dissemination can be treated with surgery +/- radiation therapy as long as the owner is warned of the risk of future dissemination. It is recommended that adjuvant chemotherapy (vinblastine/prednisone) or tyrosine kinase inhibitors be used even if margins are deemed complete. Historical studies have shown a median survival of 13 weeks to 9 months with surgery alone for high grade MCT.1,34 Radiation therapy to the surgical field and regional lymph node beds should be also considered as an adjuvant of surgery and chemotherapy. If margins are incomplete, wide re-excision of the initial surgical site followed by radiation therapy and adjuvant chemotherapy should be administered in a similar fashion. [Figure 4]

Radiation Considerations:
Radiation therapy can be used as a primary modality for local disease (resectable or non-resectable), as an adjuvant to surgery with complete margins for grade II or grade III tumors, or for control of local lymph node metastasis. Radiation works best after surgical cytoreduction to microscopic disease.18 When used as a primary modality there has been reported local control of 44-78%. LaDue et al. reported that low to intermediate grade tumors excised with incomplete margins and treated with follow-up radiation therapy (48 Gy fractionated doses or higher) had long term control (two year control rate in 85-95%).18 The actual effect of radiation on these tumor types is unknown since they are compared to historical controls and recent studies have called into question the likelihood of low to intermediate grade tumors recurring even with incomplete margins.12-15,22 For grade III MCT, the one-year local control rate with radiation alone was 65% and survival rate was 71%.19

Chemotherapy Considerations:
Chemotherapy should be considered as an adjuvant to surgery and radiation therapy for any situation where the MCT has a high risk for metastasis based on histopathology and prognostic indices, (grade III or grade II tumors with known negative prognostic factors such as a mitotic index greater than 5/10hpf or Ki-67 greater than 1.8) has metastasized to local nodes or further, or when there are mast cells in circulation. Chemotherapy has been used in many combinations in the past. Prednisone alone can be used to help reduce tumor burden and associated clinical signs but response is typically short lived. Prednisone and vinblastine together has shown good control of recurrence and metastasis when used in conjunction with surgery. Thamm et al did not reach the median survival for this protocol for grade II tumors with a median followup period of 579 days. For grade III tumors the median survival was 333 days.21 Studies have shown that multi agent therapy has higher response rates than single agent therapy.11 Thamm and colleagues showed a median overall survival of 1374 days when vinblastine and prednisone were used in conjunction with surgery and/or radiation therapy in grade III MCT.39

Tyrosine Kinase Inhibitors (Palladia [toceranib], Masivet or Kinavet [masitinib]):
Tyrosine kinases (TK) are cell membrane-bound growth factor receptors that, when mutated, can result in uncontrolled cellular proliferation (so called proto-oncogenes). Masitinib is a human tyrosine kinase inhibitor that has been conditionally approved by the FDA for use in canine MCT disease. Toceranib is a newer FDA approved TK-inhibitor for approved for treatment of canine MCT. Toceranib has been shown to work on a variety of different tumor types. London and colleagues showed that 90% of animals with KIT mutation status responded to toceranib (veterinary formulation) while 25% of animals without the mutation responded.42 This response to therapy regardless of KIT mutation status suggests that TK inhibitors work by another mechanism other than just tyrosine kinase inhibition. Tyrosine kinase inhibitors in general are “dirty” in the fact that they inhibit more than just the KIT tyrosine kinase. Each TK-inhibitor has a different profile of TK inhibition so it is reasonable to consider another version if one fails. Trials with masitinib have shown significantly prolonged survival in dogs with non resectable grade II and grade III mast cell tumors regardless of KIT mutation status.35,36

Figure 3: Therapeutic approach for clinical stage O and stage 1, low or intermediate grade mast cell tumors.11

Figure 4: Therapeutic approach for high grade canine mast cell tumors.11

References
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9) Book AP, et al. Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors. Vet Rad and Ultrasound. 2011; 52(5):548-554.
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39) Thamm DH, et al. Outcome and Prognostic Factors Following Adjuvant Prednisone/Vinblastine Chemotherapy for High-Risk Canine Mast Cell Tumour: 61 Cases. J. Vet. Med. Sci. 2006; 68(6):581-587.
40) Bostock DE. The prognosis following surgical removal of mastocytomas in dogs. J. Small Anim. Prac. 1973; 14:27-40.
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42) 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;15:3856–3865.
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