Mast cell tumors (MCTs) are common cutaneous neoplasms in dogs. This article discusses recent updates in the management of mast cell disease, specifically the use of the MCT prognostic panel; evaluation of regional and sentinel lymph nodes for the presence of metastasis; and local and systemic treatments, including novel therapeutics such as tigilanol tiglate injection and gilvetmab. Ideal scenarios for prognostic panel use and an overview of the implications of lymph node metastasis for survival and systemic therapy are also provided.<\/p>\n
Take-Home Points<\/strong><\/p>\n <\/div><\/div><\/p>\n Mast cell tumors (MCTs) are common cutaneous <\/span>neoplasms in dogs. As treatment recommendations<\/span> and prognostic factors for MCTs continually change, this article aims to demystify the clinical approach to MCTs by reviewing indications for use of the MCT prognostic panel, the clinical <\/span>relevance of regional lymph node metastasis, and various local and systemic therapies.<\/span><\/p>\n An MCT prognostic panel is available through IDEXX and the Michigan State University Veterinary Diagnostic Laboratory. This multifaceted panel is a valuable tool for further characterizing cutaneous and subcutaneous MCTs with equivocal histopathology. The panel includes proliferative indices, c-kit<\/i> mutation status (exons 8 and 11), and KIT localization pattern. These findings are most informative when considered together rather than individually.1,2<\/sup><\/span><\/p>\n For histologically high-grade MCTs, the information gained from the prognostic panel may not change treatment recommendations. The authors feel this tool is best employed when the clinician has reason to suspect that an initial interpretation of low grade is incorrect.<\/span><\/p>\n Possible indications for MCT prognostic panel use include:<\/span><\/p>\n Figure 1. A female Chinese Shar-Pei with diffuse mast cell disease 1 month after presenting for a solitary mast cell tumor.<\/p><\/div>\n Detecting metastatic <\/span>lymph nodes presents a challenge, as not all <\/span>lymph nodes can be palpated or identified as abnormal via physical examination or imaging. For example, 50% of palpably normal <\/span>lymph nodes were found to contain metastasis in a population consisting of 90% low-grade tumors.7<\/sup> Furthermore, the regional (nearest) <\/span>lymph node is not always the sentinel (draining) <\/span>lymph node. A recent study using <\/span>lymph node mapping found that regional and sentinel <\/span>lymph nodes differed in nearly 60% of MCT cases.8<\/sup><\/span><\/p>\n While the presence of <\/span>lymph node involvement is used to stage MCTs (<\/span>TABLE 1<\/b><\/span>), MCT <\/span>lymph node metastasis is not histologically classified as a \u201cyes\/no\u201d binary. Instead, Weishaar\u2019s histologic classification system assesses the number, distribution, and architectural disruption of mast cells within a <\/span>lymph node (<\/span>BOX 1<\/b><\/span>).10<\/sup> This classification describes the extent of nodal metastasis and is increasingly provided on biopsy reports. One study found a difference in survival between patients with HN0<\/span>\u2009<\/span>+<\/span>\u2009<\/span>HN1 <\/span>lymph nodes (60\u00a0months) and those with HN2<\/span>\u2009<\/span>+<\/span>\u2009<\/span>HN3 <\/span>lymph nodes (27 months).10<\/sup> This study included all tumor grades. A more recent study that focused on grade II\/low-grade MCTs with HN2 metastasis found that these patients experienced prolonged survival with surgery alone, with median survival time not reached (median follow-up time, 750 days), suggesting early <\/span>lymph node metastasis (HN2) is insufficient to warrant systemic treatment.11<\/sup><\/span><\/p>\n HN1:<\/strong> Premetastatic<\/p>\n HN2:<\/strong> Early metastasis<\/p>\n HN3:<\/strong> Overt metastasis<\/div><\/div>\n Histologic tumor grade is more predictive of patient outcome than <\/span>lymph node status; however, a common thread has emerged over the past decade: Treatment of metastatic <\/span>lymph nodes has a more significant impact on patient survival than the presence of <\/span>lymph node metastasis.12-14<\/sup> Treatment can include extirpation, chemotherapy, and\/or radiation therapy.<\/span><\/p>\n Patients with <\/span>lymph node involvement (stage II) that do not undergo extirpation have a 5-fold increased risk of tumor progression and a 4-fold increased risk of tumor-related death.13<\/sup> Among patients with grade II (intermediate) MCTs, survival is unaffected by <\/span>lymph node metastasis (stage I versus stage II), assuming the <\/span>lymph node is removed. Extirpation permitted patients a median survival time of \u201cnot reached\u201d (median follow-up time, 409 days) compared with a median survival time of 360 days in patients in which the metastatic <\/span>lymph node was not removed (median follow-up time, 620 days) in 1\u00a0study.13<\/sup><\/span><\/p>\n The value of treating affected <\/span>lymph nodes is not exclusive to intermediate-grade MCTs. In dogs with high-grade MCTs, prophylactic irradiation of regional <\/span>lymph nodes resulted in significantly increased progression-free survival compared with those that did not have <\/span>lymph node extirpation or irradiation.14<\/sup><\/span><\/p>\n Surgery is considered the gold standard for MCT treatment and is often curative. While recommended surgical margins of 3 cm laterally and 1 fascial plane deep were previously applied to all MCTs, recent studies have suggested this may be more tissue than needed to achieve adequate local control of many MCTs.15-17<\/sup> Since most MCTs are low grade and dogs experience low recurrence rates, even with incomplete histologic margins, a smaller surgical dose may be sufficient.17<\/sup><\/span><\/p>\n Several updated recommendations have been proposed. Most prominent is the use of proportional margins. In this approach, a 0.5-cm mass would be removed with 0.5-cm lateral margins, a 1-cm mass with 1-cm margins, and so on up to 2 cm. The recommendation of removing 1 fascial plane deep remains. With this approach, 95% of MCTs were completely excised (all margins histologically clear of mast cell infiltration), regardless of grade, with an overall recurrence rate of 3% in 1 study.17<\/sup> Despite the active components of mast cell granules, these patients do not experience increased incision site complications compared to those with soft tissue sarcomas.18<\/sup><\/span><\/p>\n With recurrence rates for incompletely excised, low-grade tumors at 10% to 30%, several follow-up options exist.15,17,19<\/sup> These may include active surveillance for tumor regrowth, scar revision, or radiation therapy. Scar revision can improve long-term survival (from 24 to 98 months) and decrease recurrence rates (from 38% to 13%).20<\/sup><\/span><\/p>\n Tumor grade and stage may alter the decision to proceed with surgery and associated surgical dose. Cases with negative prognostic factors (see Use of the MCT Prognostic Panel<\/b>) should undergo complete staging preoperatively. This includes cytologic evaluation<\/a> of regional (ideally sentinel) <\/span>lymph nodes and the spleen (plus or minus the liver).8,21<\/sup> Since ultrasonography has poor sensitivity and specificity in identifying MCT metastasis in the liver and spleen, percutaneous fine-needle aspiration with cytologic evaluation is recommended regardless of the ultrasonographic appearance of these organs. While uncommon, viscerally disseminated disease has a considerable impact on expected survival and may alter the decision to proceed with surgery.21<\/sup><\/span><\/p>\n Radiation therapy<\/a> has been used in the adjuvant setting following incomplete resection or in the gross tumor setting for nonresectable tumors.14,20<\/sup> The long-term benefits of radiation therapy for high-grade tumors remain unclear, although radiation therapy is an effective means for reducing the recurrence of low-grade MCTs. A recent study of predominantly low-grade MCTs treated with radiation therapy following incomplete excision demonstrated a recurrence rate of less than 7% and tumor-specific survival time that was not reached.22<\/sup><\/span><\/p>\n Acute toxicity (adverse effects seen during radiation therapy or within 2 weeks of completion) can be seen in MCT patients with gross or microscopic disease. These effects include erythema, desquamation, or other adverse events outlined in the modified Veterinary Radiation Therapy Oncology Group scoring criteria.22,23<\/sup> Concurrent use of supportive medications, particularly prednisone, histamine H1<\/sub> and H2<\/sub> antagonists, or proton pump inhibitors, can help decrease the severity of adverse events.22<\/sup><\/span><\/p>\n Triamcinolone<\/b><\/p>\n Triamcinolone is a long-acting steroid that can be administered intralesionally to decrease or maintain MCT size. In 1 study of 23 dogs, the overall response rate (complete and partial responses) was 67%, including patients receiving concurrent therapies. For patients treated with triamcinolone with or without oral corticosteroids, the median time to progression was 28\u00a0days and 114 days, respectively. The most common adverse effects were gastrointestinal (GI) upset and bleeding at the injection site, which was suspected to be related to degranulation. This therapy is economical and does not require special equipment or training, although the duration of response appears limited.24<\/sup><\/span><\/p>\n Tigilanol Tiglate Injection<\/b><\/p>\n Tigilanol tiglate injection (Stelfonta; Virbac, <\/span>stelfonta.com<\/span><\/a>) is an intralesional treatment labeled for canine cutaneous and subcutaneous MCTs that received full U.S. Food and Drug Administration approval in 2020. Tigilanol tiglate injection uses a multimodal mechanism of action, including causing tumor cell oncolysis, activating an acute inflammatory response, and increasing tumor vascular permeability. Ultimately, tigilanol tiglate injection results in tumor necrosis and tissue sloughing, resulting in wound formation at the tumor site (FIGURE<\/b><\/span><\/span>\u00a02<\/b><\/span>).25<\/sup><\/span><\/p>\n\n
Use of the MCT Prognostic Panel<\/h2>\n
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<\/a>Importance of Lymph Nodes<\/h2>\n
<\/a><\/p>\nLocal MCT Therapy<\/h2>\n
Surgery<\/h3>\n
Radiation Therapy<\/h3>\n
Intralesional Therapy<\/h3>\n
Figure 2A. Cutaneous mast cell tumor on the left lateral thigh immediately before tigilanol tiglate injection administration.<\/span><\/a><\/div><\/div>