GENERAL CONSIDERATIONS


Pathophysiology

•well-differentiated mast cells contain cytoplasmic granules which enlarge as the mast cell matures

•cytoplasmic granules contain:

•vasoactive substances (i.e., histamine, leukotrienes, prostaglandins, and platelet activating factor)

•heparin-proteoglycan matrix (i.e., chondroitin sulfate and heparin)

•chemotactic factors (i.e., eosinophilic and neutrophilic chemotactic factors)

•proteolytic enzymes (i.e., α-tryptase, β-tryptase, chymase, carboxypeptidase, cathepsin, acid hydrolases, phospholipase A 2, aminopeptidase, and hexosaminodase)

•serotonin

•canine MCT is associated with significantly higher histamine and lower gastrin serum concentrations than normal dogs (with gastrin levels lower due to negative feedback associated with increased gastric acid secretion)

•degranulation results in increased vascular permeability, smooth muscle spasm, mucus secretion, eosinophil and neutrophil chemotaxis, pruritis, vasodilation, anticoagulation, and tissue destruction

•degranulation can be caused by physical injury (i.e., heat, cold, and trauma) and associated with handling, cryosurgery, radiation therapy, and hyperthermia

•poorly differentiated MCT have no cytoplasmic granules

•other paraneoplastic syndromes identified include hypergammaglobulinemia and inflammatory glomerular disease

•steroid receptors have been identified in the cytosol of canine MCT (i.e., progesterone, estrogen, and glucocorticoid) and these may provide diagnostic and therapeutic benefits

•mutations of c-kit have been identified in grade II and III canine MCT and may contribute to development ± progression of MCT


Signalment

•MCT account for 7%-21% of all skin tumors and 11%-27% of malignant skin tumors in dogs

•mean age 8-9 years (range, 3 weeks to 19 years)

•breeds include Boxer (odds ratio 11.3), Staffordshire Bull Terrier (odds ratio 6.1), Boston Terrier, Bulldog, Labrador Retriever (odds ratio 4.2), Golden Retriever, Beagle, Scottish Terrier, Weimaraner, Rhodesian Ridgeback, German Short-Haired Pointer, Chinese Shar-Pei, and Schnauzer

•Boxers tend have well-differentiated MCT

•no sex predisposition

•MCT primarily arise from the dermis and subcutaneous tissues in dogs, but oral and visceral sites are reported


Site and Appearance

•locations: trunk and perineum (50%), extremities (40%), and head and neck (10%)

•primary MCT also reported in oral cavity, larynx, trachea, mediastinum, GI, nasopharynx, and hepatopancreatic lymph node

•solitary MCT is more common, but multiple sites simultaneously or staged are reported in 11%-14% dogs

•appearance: firm, well-circumscribed, raised plaque ± erythema or ulceration

•MCT can be ill-defined, soft, and edematous due to collagen breakdown from mast cell products and can frequently be misdiagnosed as lipomatous

•rate of growth of MCT correlates with histologic grade

•palpation of MCT can lead to degranulation of mast cells with erythema and swelling and, if severe, anaphylaxis and hypotension (= Darier's sign)


Metastasis

•MCT metastasize along hematogenous and lymphatic routes

•coagulopathies including DIC can occur secondary to effect of vasoactive amines (i.e., heparin)

•inguinal and perineal MCT recur and metastasize more frequently than other areas in dogs

•metastatic sites include regional lymph nodes followed by spleen (46%) and liver (41%)

•other sites include lungs (rare), bone marrow, peripheral blood, skin, kidney, and heart

•pleural and peritoneal effusions containing abundant mast cells can be seen with visceral or systemic mastocytosis


Effects of Mast Cell Tumor Degranulation


Gastroduodenal Ulceration

•histamine stimulates H2 receptors on gastric parietal cells increasing gastric acid secretion

•plasma histamine levels are initially increased in dogs with gross MCT and progressively increase in dogs with poor tumor control and MCT-associated GI signs, whereas dogs with adequate tumor control have normal plasma histamine concentrations

•plasma gastrin levels are decreased in dogs with MCT, usually released secondary to increased hydrogen chloride as a negative-feed back mechanism on gastric acid production

•GI motility is also increased

•histamine damages vascular endothelium of arterioles and venules and results in release of plasminogen activator

•histamine may also damage gastric submucosal vasculature by causing small venule and capillary dilation, increased endothelial permeability, and resulting in intravascular thrombosis, decreased gastric blood flow, and ischemic necrosis of mucosa

•gastric ulceration is the result of vascular damage, increased gastric acid, and gastric hypermotility

•35%-83% of dogs with MCT have some evidence of GI ulceration at necropsy or endoscopy with 15% perforated


Delayed Wound Healing

•delayed wound healing due to local effects of proteolytic enzymes and vasoactive amines

•histamine binds to H1 and H2 receptors on macrophages resulting in the release of fibroblastic suppressor factor which decreases normal fibroplasia and delays wound healing in mice


Hypotension

•histamine and other vasoactive amine release by MCT degranulation may cause potentially fatal hypotension

•prostaglandin D may also be involved in MCT-induced hypotension


Local Hemorrhage

•local hemorrhage common after FNA, biopsy, and excessive manipulation

•hemorrhage is caused by release of heparin from MCT granules

•coagulation times are increased from blood collected adjacent to MCT but not systemic blood



DIAGNOSIS


General Considerations

•diagnostic technique can vary depending on clinical signs and results of FNA

•wide surgical excision with histologic grading and margin assessment recommended if MCT is located in an amenable surgical site and no negative prognostic factors are present

•staging (i.e., abdominal ultrasound with splenic and hepatic aspirates, bone marrow aspirate, and regional lymph node aspirate) is recommended if incomplete excision or high-grade MCT

•incisional biopsy and staging are recommended if site not amenable to wide surgical excision or negative prognostic factors are present


Fine Needle Aspiration

•premedication with H 1 antagonist (diphenhydramine 2-4 mg/kg q 12 hrs PO) to prevent platelet degranulation, anaphylaxis, and hypotension during handling (i.e., Darier's sign)

•MCT usually easily diagnosed on FNA but confirmed with histopathology

•small-to-medium sized cell with abundant, small, metachromatic, and uniform cytoplasmic granules

•mast cell cytoplasmic granules contain several vasoactive substances including histamine and heparin

•toluidine blue stain: histamine stains blue (high in immature cells) and heparin stains red

•poorly differentiated MCT have no cytoplasmic granules

•other stain: Romanovsky or other rapid hematological stains

•eosinophils are attracted to MCT and their presence assists in differentiating other round cell tumors


Regional Lymph Node

•palpation and FNA

•FNA is recommended as nodal metastasis has been documented in normal sized and unfixed nodes

•> 10% mast cells is considered consistent with metastatic disease

•tumor cells tend to become less differentiated as they metastasize

•up to 76% MCT are metastatic to regional lymph nodes at the time of diagnosis


Hematology


General Considerations

•anemia with gastroduodenal ulceration

•mild regenerative anemia in acute stages and microcytic hypochromic anemia in late stages

•dogs with systemic mastocytosis will have eosinophilia, basophilia, and circulating mast cells

•eosinophilia and basophilia caused by release of eosinophil chemotactic factor during mast cell degranulation

•peripheral mastocytemia has also been reported in acute inflammatory disease (especially parvovirus), regenerative anemia, non-MCT neoplasia, allergy, and trauma

•eosinophilia is present in 13%, basophilia in 31%, and mast cells are evident in 37% of buffy coat smears and 56% of bone marrow aspirates from dogs with visceral MCT


Buffy Coat Smears

•buffy coat smears or bone marrow aspirates may be more sensitive for circulating mast cells, however, 95.5% of blood smears with mast cells are from dogs with disease other than MCT, including inflammatory disease (28.2%), regenerative anemia (27.0%), neoplasia other than MCT (25.9%), and trauma (11.8%)

•buffy coat smear: > 2-3 circulating mast cells suggestive but not specific for systemic mastocytosis

•normal Beagles: mast cells in 24% lymph nodes, 4% bone marrow aspirates, and 0% buffy coat smears


Survey Radiographs

•metastasis to the lungs is rare and usually presents as diffuse interstitial pattern rather than discrete nodules

•intrathoracic lymph node involvement common if the axillary or superficial cervical lymph nodes are involved

•abdominal radiographs may show lymph node involvement, especially with inguinal and perineal MCT

•organomegaly may be evident on either abdominal radiography or ultrasonography


Other Tests


Urinalysis

•methylated metabolites of histamine in urine may be a valuable diagnostic technique for mastocytosis


Bone Marrow Aspirate

•bone marrow aspirate is generally recommended, but some recommend staging only in dogs with grade III MCT or if other negative prognostic factors are present

•bone marrow aspirate more sensitive for systemic involvement than peripheral blood and buffy coat analysis

•normal bone marrow: 0-1 mast cells per 1,000 nucleated cells

•systemic mastocytosis: > 10 mast cells per 1,000 nucleated cells


Incisional Biopsy

•incisional biopsy to determine grade of MCT


Ultrasound

•ultrasound and CT increase the extent of local tumor margins by 19% and 65% of cases, respectively

•ultrasound-guided aspirates of spleen and liver used for staging purposes

•10.2% (7/73) positive liver aspirates in grade II and some III MCT

•0% grade I, 2% grade II, and 19% grade III MCT have positive splenic or liver aspirates



GRADING SYSTEMS


General Considerations

•grading system is based on cellularity and nuclear and cytoplasmic cellular features

•3 grades: well differentiated, moderately differentiated, and poorly differentiated or anaplastic

•other histologic features: destruction of collagen bundles, collagen degeneration, hyalinization, hemorrhage, lymphangiectasia, and eosinophilic infiltration























Grade I Mast Cell Tumor

•grade I MCT have a low metastatic potential (< 10%) and account for 34%-54% of all MCT

•cellular characteristics: well-defined cytoplasmic boundaries, regular spherical-to-ovoid nuclei, rare mitotic figures, and large cytoplasmic granules


Grade II Mast Cell Tumor

•grade II MCT have moderate metastatic potential and account for 26%-43% of all MCT

•cellular characteristics: closely packed with indistinct cytoplasmic boundaries, lower nucleus-to-cytoplasmic ratio, infrequent mitotic figures, and more granules

•grade II MCT with regional or distant metastasis have a biologic behaviour similar to grade III MCT

•11% local recurrence rate following complete resection of grade II MCT

•management of incompletely excised grade II MCT is difficult as recurrence and metastatic potential are unknown and cannot currently be identified

•treatment options include repeat surgery, radiation therapy, or management with prednisone ± chemotherapy


Grade III Mast Cell Tumor

•grade III MCT have a high metastatic potential (55%-96%) and account for 19%-39% of all MCT

•cellular characteristics: highly anaplastic, highly cellular with undifferentiated cytoplasmic granules, irregular nuclei size and shape, frequent mitotic figures, and low number cytoplasmic granules

•diagnosis can be difficult with routine light microscopy because of the low number of granules and diagnosis may require immunohistochemistry (i.e., vimentin and α-1-antitrypsin) ± electron microscopy

•anaplastic cells contain more histamine and less heparin due to decreased sulfation


World Health Organization Staging System
















SURGICAL MANAGEMENT


General Considerations

•treatment decisions are based on prognostic factors and clinical stage

•surgical resection and radiation therapy are the most successful single agent protocols

•multimodality approach is recommended by some as up to 50% recurrence rate following surgical resection

•however, local tumor recurrence rate is low for grade I and II MCT with appropriate surgery:

•0% local tumor recurrence rate and 100% survival rate at 1- and 3-years for grade I MCT

•0%-11% local tumor recurrence rate for grade II MCT with a median time to local recurrence of 62 days to 21 months

•11%-39% de novo tumor development with a median time to 2nd tumor development of 240-362 days

•0%-22% distant metastasis rate with a median time to metastasis of 158 days to 18.5 months

•84%-89% dogs with grade II MCT are cured with surgery alone

•MST > 603-1,605 days

•local tumor recurrence is often more aggressive as recurrent tumor infiltrates more deeply and grows more rapidly


Surgical Resection

•surgery should be performed with cutaneous or subcutaneous lesions in a site amenable to wide excision

•wide surgical excision includes a minimum 3-4 cm margin of normal tissue around the tumor if grade is unknown

•however, if histologic grade in known from preoperative biopsy, 1 cm margin is adequate for grade I MCT and 2 cm margins are adequate for grade II MCT

•deep margins are important and fascial and muscle layers should be included

•margins (i.e., lateral and deep) should be histologically examined for completeness of excision

•incisional biopsy should be considered in sites not amenable to wide surgical excision

•treatment options for MCT on distal extremities includes limb amputation, radiation therapy, or combined surgery and radiation therapy

•2nd surgical excision (of scar) or adjunctive radiation therapy recommended if incomplete excision

•recurrence rate following incomplete excision is unknown



MEDICAL MANAGEMENT


Gastric Protectants

•gastric protectants are required to protect against MCT degranulation and systemic effects of granule contents

•gastric protectants are indicated for dogs with systemic signs, excessive intraoperative handling, residual macroscopic disease, and when degranulation is suspected or likely

•H1 blockers (diphenhydramine 2 mg/kg q 8 hrs PO) prevent suppressive effects of histamine on fibroblast activity during wound healing

•H2 blockers: cimetidine (5 mg/kg q 6-8 hrs PO) or ranitidine (0.5 mg/kg q 12 hrs PO)

•cimetidine is preferred as it may alter immune response to MCT and activate alkylating agents

•proton pump inhibitors (i.e., omeprazole 0.5-1.0 mg/kg q 24 hrs PO)

•sucralfate (500-1,000mg q 8 hrs PO) or misoprostol (2-4 mg/kg q 8 hrs PO)

•sucralfate interferes with cimetidine absorption and hence cimetidine is administered 45 minutes before sucralfate

•others: cyproheptadine (antiserotonin agent) and sodium chromoglycate (stabilizes mast cells)


Chemotherapy

•indications: dogs with metastatic grade II and III MCT, and systemic mastocytosis

•multiagent protocols probably offer higher response rate and better prognosis than single agent protocols

•chemotherapy agents include prednisone, vinblastine, CCNU ± vincristine, doxorubicin, mitoxantrone, and L-asparaginase

•L-asparaginase is cytotoxic to canine mast cells in vitro

•daunorubicin and chlorambucil are directly cytotoxic to human mast cells but have not tested in animals






















RADIATION THERAPY


Indications

•radiation therapy can be used in palliative, curative-intent, or adjunctive setting

•mast cells are very sensitive to the effects of radiation therapy

•radiation therapy is not recommended for grade III MCT due to high rate of systemic involvement

•however, good to excellent local tumor control and survival times have been reported for incompletely resected grade III MCT treated with radiation therapy alone

•responsiveness of MCT to radiation therapy is dose-dependent


Protocols

•palliative radiation therapy: 6-10 Gy fractions either weekly for 3-4 weeks or day 0, 7, and 21

•curative-intent and adjunctive radiation therapy: daily (Monday-Friday) protocol with total dose between 45-57 Gy

•adjunctive iridium 192 interstitial brachytherapy following incompletely resected MCT

•radiation field should include mass and 5 cm margins

•± prophylactic irradiation of cytologically-negative regional lymph nodes, but no known survival advantage

•complications include massive degranulation and release of proteolytic enzymes and vasoactive amines


Prognosis

•prognostic factors: radiation dose, location, clinical stage, and histologic grade

•MCT on extremities have significantly longer DFI and MST than MCT on trunk

•median DFI 32.7 months to > 5 years, with:

•12-month DFI 78.8%-97.0%

•24-month DFI 73.2%-88.0%

•3-5 year DFI 88.0%-93.0%

•DFI depends on age, residual disease, and histologic grade:

•median DFI for dogs > 7.5 years is 15 months v 62 months for dogs < 7.5 years

•median DFI for dogs with gross disease is 12 months v 54 months for microscopic disease

•grade I median DFI is 123 months, grade II median is DFI 21.6 months, and grade III median DFI is 9.6 months

•MST 19 months to > 5 years, with:

•12-month survival rate 76.2%-100%

•2-5 year survival rate 96.0%

•MCT in regional lymph nodes and bone marrow are more resistant than skin

•however, median DFI is 1,240 days for dogs with MCT metastatic to the regional lymph node treated with surgical debulking, irradiation of the primary MCT and regional lymph node, and oral prednisone

•good to excellent local tumor control and survival times have been reported for incompletely resected grade III MCT treated with radiation therapy alone (Hahn et al, JAVMA, 2004):

•median DFI 27.7 months with 1-year DFI 65% and 2-year DFI 26%

•good prognostic factors for local tumor control include MCT on the pinna, perineum, or prepuce (median DFI 27.7 months v 14.4 months)

•MST 28.0 months with 1-year survival rate 71% and 2-year MST 39%

•prognostic factors for survival include tumor size ≤ 3 cm (MST 31 months v 24 months)

•palliative radiation: CR 27% and PR 36%, and median DFI 60 days

•interstitial radiation therapy: local tumor recurrence rate 45% with median DFI 1,391 days and MST 730 days



PROGNOSIS


Breed

•Boxers have well-differentiated MCT and hence better prognosis


Age

•median DFI for dogs > 7.5 years treated with radiation therapy is 15 months v 62 months for dogs < 7.5 years

•older dogs have a significantly shorter survival time ± time to local recurrence or de novo tumor development following surgical resection of grade I-III MCT and treatment of inguinal and perineal MCT


Sex

•male dogs are significantly more likely to have recurrent MCT

•male dogs have a shorter survival time when treated with chemotherapy


Systemic Signs

•vomiting, melena, and GI ulceration are associated with grade II-III MCT or visceral MCT

•MST for visceral MCT 90 days


Location

•poor prognosis with preputial, subungual, perianal, oral, and mucocutaneous junctions as most are grade III MCT

•however, the biologic behavior of MCT of the muzzle is not different to other cutaneous sites except for a 64% metastasis rate at presentation in dogs with MCT of the muzzle:

•1-year DFI 70% and 3-year DFI 50%

•histologic grade is prognostic for local tumor recurrence

•MST 30 months with 1-year survival rate 78% and 3-year survival rate 63%

•metastasis at the time of diagnosis, clinical stage, and histologic grade are prognostic for survival

•furthermore, the biologic behavior of MCT of the inguinal and perineal region is not different to other sites:

•mean DFI 1,635 days with 1-year DFI 79% and 2-year DFI 71% (median not reached)

•MST 1,111 days with 1-year survival rate 79% and 2-year survival rate 61%

•grave prognosis with visceral or bone marrow involvement

•extremity MCT have longer MST than truncal MCT when treated with radiation therapy alone


Growth Rate

•grade I are more likely to remain localized and be present for prolonged period (i.e., months to years)

•MCT present for > 28 weeks had more favorable prognosis


Histologic Grade

•cure is possible for low grade MCT but tumor-related deaths are common in high grade MCT

•grade I MCT: 100% survival rate at 12-, 18-, and 24-months

•grade II MCT: 71% 12-month survival rate, 56% 18-month survival rate, and 44% 24-month survival rate

•grade III MCT: 24% 12-month survival rate, 19% 18-month survival rate, and 7% 24-month survival rate


Clinical Stage

•dermal MCT without regional lymph nodes or distant metastasis involvement (i.e., stage 0 or 1) has a better prognosis than metastatic MCT

•solitary or multiple MCT may not make any difference in prognosis


AgNOR Counts

•argyrophilic nuclear organizer regions (AgNOR) count indirect measure of cellular proliferation

•AgNOR uses silver colloid staining of paraffin-embedded sections

•AgNOR counts are predictive for postoperative outcome with higher counts having a higher grade, increased risk of local tumor recurrence and metastasis, and worse prognosis

•AgNOR > 2.25 per cell associated with poor prognosis

•AgNOR counts from FNA correlate with AgNOR counts from biopsy samples and is significantly associated with histologic grade


Proliferating Cell Nuclear Antigen

•PCNA count is an indirect measurement of tumor proliferation

•mean number of PCNA-positive nuclei/1,000 tumor nuclei is significantly higher in dogs with MCT-related deaths

•PCNA count > 261 in 5 HPF correlates with poor postoperative outcome


Ki-67

•Ki-67 count is an indirect measurement of tumor proliferation

•mean number of Ki67-positive nuclei/1,000 tumor nuclei is significantly higher in dogs with MCT-related deaths

•Ki-67 correlates with histologic grade with:

•31 Ki-67-positive nuclei/1,000 tumor nuclei for grade I MCT

•93 Ki-67-positive nuclei/1,000 tumor nuclei for grade II MCT

•204 Ki-67-positive nuclei/1,000 tumor nuclei for grade III MCT

•Ki-67-positive nuclei/1,000 tumor nuclei < 93 and ≥ 93 is significantly associated with outcome in grade II MCT:

•88% survival rate with < 93 Ki-67-positive nuclei/1,000 tumor nuclei

•37% survival rate with ≥ 93 Ki-67-positive nuclei/1,000 tumor nuclei


DNA Ploidy

•flow cytometric analysis

•aneuploid cells associated with grade III MCT and shorter survival times

•light microscopy has greater predictive value and more economic


c-kit

•c-kit expression is more common in high grade MCT

•juxtamembrane duplication of c-kit occurs in 10% of MCT, but only in grade II and III MCT


Local Tumor Recurrence

•MCT tumor is unlikely to recur if recurrence not evident by 6 months

•recurrence rate 11% following complete resection and 30% following incomplete excision of grade II MCT

•local tumor recurrence is considered more aggressive as infiltrates deep structures and grows more rapidly and associated with significantly shorter survival time

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Grade I

Grade II

Grade III

Confined to dermis

Dermis and subcutaneous

Deeply invasive

Low cellularity

Moderate cellularity

High cellularity

Well differentiated cells

Moderately pleomorphic cells

Increased cellular pleomorphism

Monomorphic nuclei

Minimal nucleolar pleomorphism and single nucleoli

Giant nuclear forms, multi-nucleated cells and prominent nuclei

No mitoses

0-2 mitoses per high power field

3-6 mitoses per high power field

Minimal necrosis

Minimal edema and necrosis

Marked edema and necrosis

Ample granulated cytoplasm

Variable granulated cytoplasm

Poorly granulated cytoplasm

1,500-day survival 93%

1,500-day survival 44%

1,500-day survival 6%

Stage

Description

0

Incompletely excised solitary MCT without regional lymph node involvement

I

Solitary MCT without regional lymph nodes involvement without (a) or with (b) systemic signs

II

Solitary MCT with regional lymph node involvement without (a) or with (b) systemic signs

III

Multiple MCT or large infiltrating MCT without (a) or with (b) systemic signs

IV

Distant metastasis or local recurrence

Overall

Prednisone

20%

Vincristine

7%

CCNU

44%

Prednisone-Vinblastine

47%

Prednisone-Vinblastine-Cyclophosphamide

78%

COP-Hydroxyurea

59%

Drug

Response Rate

Complete

4%

0%

6%

33%

0%

23%

Partial

16%

7%

38%

13%

78%

35%

Duration

NR

NR

79 days

154 days

NR

53 days