CANINE MAST CELL TUMORS – TWEETS FROM MY TWITTER PAGE Ken Rassnick, DVM, Dipl. ACVIM (Oncology) Director, Oncology Consultation Services (607) 257-3650 (Monday, Wednesday) (315) 446-7933 (Tuesday, Thursday)
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Mast cell tumors (MCTs) occur frequently in dogs and often present a diagnostic and therapeutic challenge to practitioners. Although many MCTs are cured with surgery, some require additional therapy for local and systemic control. By use of Twitter tweets, this presentation will review diagnosis, staging, prognostic indicators, and treatment recommendations for canine MCTs. So, what is Twitter? Twitter is a social networking and micro-blogging service created in 2006 that enables its users to send and read other user messages called tweets. Tweets are text-based posts of up to 140 characters, often with slang and short-hand. Messages were set to 140-character limit for compatibility with SMS (short message service) messaging on cell phones. Users may subscribe to other author tweets—this is known as following and subscribers are known as followers. Twitter is ranked as one of the 50 most visited websites worldwide. Currently, about 65 million tweets are posted each day, equaling about 750 tweets sent each second. Twitter's usage spikes during prominent events. For example, during the 2010 World Cup when fans wrote 2,940 tweets per second in the 30 second period after Japan scored against Cameroon. 4,064 tweets per second were posted during the final moments of the 2011 Super Bowl. MCTs are so common! Also variable in appearance. Don’t let dogs leave your clinic without documenting all skin & subcutaneous masses MCTs are the most common cutaneous tumors in dogs, accounting for 10-20% of all skin tumors. They are one of the most common malignant tumors found in dogs. Older (i.e. approximately 8-9 years of age) Boxers, Labrador Retrievers, Golden Retrievers, Shar-Peis, Boston Terriers, Bulldogs, and Pugs are at an increased risk - but MCTs can be found in any breed at any age. The clinical appearance of MCTs can vary widely. Dermal MCTs may be well-circumscribed, raised, and firm, or the surface might be erythematous and ulcerated. MCTs arising in the subcutaneous tissue are often poorly circumscribed and may resemble lipomas. It is not possible to identify the type of any skin tumor just by its appearance, especially a MCT. The prognosis for dogs with MCTs can be greatly improved by early diagnosis and a prompt, logical approach to treatment. Obtain fine-needle aspirates (FNA) of all skin and subcutaneous masses so a diagnosis of MCT is not missed! And be sure to document all skin masses in the medical record so you won’t have to FNA it again.
Myth buster: aspirating or biopsying a skin mass will cause it to spread. Not true! There is little evidence that a properly performed FNA or biopsy results in widespread dissemination of the primary tumor or negatively impacts patient survival. It is well-known that tumor cells may disseminate during surgical procedures but implantation is highly inefficient and most circulating tumor cells are rapidly destroyed. Mechanical manipulation of a MCT might induce mast cell degranulation and release of mediators such as histamine, heparin, proteases, and cytokines. When this occurs, MCTs can become more erythematous, edematous, enlarge and bruise. However, this is uncommon during routine FNA. If anything, the most common side-effect of FNA of a MCT is mild, temporary bleeding.
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MCTs can look like lipomas! Did I say that already? The subcutaneous variant of MCT looks and feels just like a lipoma. However, when you do an FNA of a subcutaneous MCT, you won’t get the typical greasy material as you would for a lipoma. Dogs with MCT can be cured if diagnosed early in the course of their disease so every effort should be made for a prompt diagnosis. Document all skin masses in the medical record so you can keep track of the ones you’ve already investigated. Dogs can get multiple MCTs. If you find one, look hard – very, very hard – for more. Roughly 10% of dogs present with multiple MCTs. Don’t let the owner point out other skin lesions when they come to take their dog home after surgical removal of one MCT or at the time of suture removal. That’s terribly disappointing for everyone. If you find and work-up a dog for one cutaneous/subcutaneous MCT, go through the skin and make sure there aren’t any more. Document all skin lesions in the medical record and then move on to staging and treatment.
Bloodwork / UA should be part of a minimum database in dogs with MCT. Complete blood count, biochemistry profile, and urinalysis should be part of a minimum database and included in the work-up of any dog with a MCT. Dogs with MCT might rarely have eosinophilia (due to chemotactic factors and IL-5 produced by mast cells). Anemia might be present secondary to hypersplenism or gastrointestinal bleeding. More often, however, a concurrent, secondary disease unrelated to MCT is identified from the minimum database. This would need to be investigated as a treatment plan is developed for the MCT.
The draining LN is the most common site for MCT metastasis. Do anything you can to FNA accessible LNs - even if you think they feel normal! The regional, draining lymph node (LN) is the most common site for MCT metastasis. It is very uncommon for a MCT to skip the draining LN during metastatic spread - so all accessible regional LNs should be aspirated for cytological examination. Early MCT LN metastasis can be found in LNs of “normal” size - so LNs should be evaluated regardless of their size upon palpation. Some LNs might be difficult to identify, such as the axillary node in a dog with a MCT on the forelimb or thorax or the sublumbar LN in a dog with a MCT on the hindleg. In those cases, ultrasound can be useful to help guide the FNA procedure. Mast cells can be present in normal LNs and are often found in reactive LNs, therefore it can be difficult to determine if mast cells found on FNA cytology are part of a normal immune response or are neoplastic. In general, I am comfortable with LN cytology evaluated by a clinical pathologist to rule out LN metastasis. LNs that show only a few (i.e. 2-3) mast cells in small aggregates (i.e. 2-5) might yield a cytological diagnosis of “possible” or “probable” MCT metastasis. In those cases, the LN should be surgically excised for histopathology to evaluate more tissue, the subcapsular LN sinus, and LN architecture. Don’t bother with a ‘buffy coat’ smear. It’s not helpful. A buffy coat smear is made by spinning peripheral blood in a microhematocrit tube, breaking the tube at the buffy coat layer, and smearing the concentrated leukocytes on a slide. For many years, examining the buffy coat for the presence of mast cells was used to screen dogs with MCTs for the presence of metastatic disease. It is now clear that a buffy coat smear is neither sensitive nor specific for mast cell neoplasia. Dogs with many kinds of disease, including pneumonia, pancreatitis, skin disease (i.e. atopy, food allergy), and GI disease can have positive buffy coats.
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Lung metastases do not occur in dogs with MCT. Chest radiographs are generally indicated as part of staging cancer patients, but pulmonary metastases do not occur in dogs with cutaneous MCTs. In some cases of very advanced disease, pleural effusion or thoracic lymphadenopathy might be found, but pulmonary nodules or masses are extremely rare. Baseline thoracic radiographs to evaluate the cardiac silhouette and lung parenchyma as part of a preanesthetic screen before surgery for a MCT is good practice.
Abdominal ultrasound should be done in dogs with metastatic, nonresectable and grade III MCTs. In dogs with MCT, evaluation of the abdominal cavity might be important because spread to the spleen, liver, and other structures can occur. Before surgery, I recommend abdominal ultrasound be done in dogs with evidence of regional LN MCT metastasis or tumors that are highly infiltrative, nonresectable or have a significant amount of peri-tumoral edema/bruising. After surgery, abdominal staging should be done in dogs with high-grade, poorly differentiated (grade III) tumors. Obtaining aspirates of the liver and spleen is indicated if these organs appear ultrasonographically abnormal. Surgery is the treatment of choice for canine MCT – do it right the 1st time since many dogs can be cured. 3-cm surgical margins are typically recommended for canine MCTs. For lower grade tumors (i.e. Grade I or II) 2-cm lateral margins and a deep margin of one fascial plane might be adequate, but very often, the tumor grade and the degree of infiltration are not known before surgery, so most advocate taking 3-cm margins. All excised tissue should be submitted to a pathologist for evaluation of tumor grade and surgical margins. Ideally, the lateral and deep margins should be accurately labeled with India ink or a multicolor marking system so that the pathologist is able to specifically indentify the margins. Controversy exists regarding the definition of a “clean” microscopic margin for MCT. For grade I MCTs and most grade II MCTs, I generally define a “clean” margin as 4-mm or more between the tumor and normal tissue. For infiltrative grade II MCTs and grade III MCTs, I define a “clean” microscopic margin as 10-mm or more. Histological grade is the best predictor of MCT prognosis … but grade does not predict the behavior of every tumor. Histological grade is the most consistent prognostic indicator of recurrence, metastasis, and survival in dogs with MCTs. The grade of a MCT is determined by characteristics of the neoplastic cells (i.e. degree of granulation, cellular and nuclear pleomorphism), number of mitotic figures, and extent of tumor invasion into underlying tissues. In brief, grade I MCTs are well-differentiated and confined to the dermis. Grade II MCTs are moderately (intermediately) differentiated, with infrequent mitotic figures, and/or infiltrative into subcutaneous tissues. Grade III MCTs are poorly differentiated, with frequent mitotic figures, and/or very invasive into deep tissues such as muscle. Recently a two ‐tiered system for grading canine MCT has been proposed, in which the presence of any one of the following criteria: (1) >7 MFs / 10HPFs; (2) >3 multinucleated cells / 10HPFs; (3) > 3 bizarre nuclei / 10HPFs; and (4) karyomegaly, where at least 10% of neoplastic cells vary by 2-fold, account for classification of a high-grade tumor (Kiupel M et al. Vet Pathol;2011:48:147). Histologic grade does not predict the behavior of every MCT. MCT grading has been well-studied and as mentioned, to date has been the most consistent factor to determine the prognosis of affected dogs. However, histological interpretation is a subjective art and interpathologist variation is known to occur.
MCT grading cannot be determined via cytology. In addition to cellular features, MCT grade is based on tissue invasion, which cannot be evaluated by cytological exam.
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Grade I MCT – excellent prognosis – most dogs are cured. Well-differentiated (grade I) MCTs are considered to behave in a benign manner. Complete surgical excision is curative in 95% of dogs. Rare cases might succumb to mast cell neoplasia because either the biopsy grade did not appropriately predict tumor behavior or the dog developed another MCT later in life that was more aggressive. Grade II MCT, completely excised with a negative regional LN – really good prognosis. Approximately 85% of dogs with completely excised non-metastatic intermediately differentiated MCTs are cured. Why not 100%? Roughly 15% of dogs might suffer local MCT regrowth or dissemination despite the assessment of a “clean” margin or negative lymph node. Also, dogs might develop another, more aggressive primary MCT. Still, 85% long-term control for these patients is considered very favorable, so no further MCT treatment is warranted. Grade II MCT, incompletely excised, negative LN - may not recur – prognosis not so bad - a watch and wait approach may be enough. Maybe. Conflicting information exists regarding the regrowth rate of incompletely excised grade II MCTs. Recurrence rates in the literature have ranged from 20 to 65%. I generally discuss a possible 50% recurrence rate with owners. A wider excision to achieve a clean resection should be considered if the site is amenable. If this is not possible, radiation therapy provides excellent, long-term control in most cases (see next). However, if the owner declines further surgery or radiation, with a 50/50 prognosis, a “wait and see” approach is not unreasonable. In that situation, I stress two important points to owners: (1) If the MCT recurs, a 2nd surgery might not be possible since many tumors regrow deeper and more invasive and; (2) MCT recurrence is associated with a shorter survival time. Right now, there is no good evidence to suggest that using steroids or chemotherapy after surgery delays tumor regrowth. Grade II MCT, incompletely excised, negative LN – consider RT – really good prognosis. Approximately 85% of dogs with incompletely excised non-metastatic intermediately differentiated MCTs are cured with a definitive course of radiation therapy (i.e. prognosis as good as if completely excised). Radiation therapy is a localized form of treatment, so some dogs will succumb to MCT despite the assessment of a negative lymph node. Occasionally dogs will suffer local MCT recurrence despite radiation therapy and as in all cases, dogs will be at risk for development of additional, more aggressive MCTs later in life. Still, 85% long-term control is considered excellent. Grade II MCT, incompletely excised – LN positive for mets! Still consider RT. Radiation therapy still has a significant role for controlling MCTs that are metastatic to regional lymph nodes. Radiation therapy is more effective for MCTs that are microscopic, so the MCT and regional lymph node should be surgically excised (if possible). When the MCT scar and lymph node bed (and often, the next draining lymph node) are irradiated, on average the disease can be controlled for 3 or more years. The role of chemotherapy in addition to surgery/radiation therapy for these cases has not been well defined, but many advocate its use. Grade III MCT – not good. Chemotherapy? Radiation? Local treatment alone is generally considered suboptimal for dogs with high-grade MCTs. Median survival time with resection alone is approximately 6 months. Dogs succumb to local recurrence and/or MCT dissemination. Chemotherapy should be considered in dogs with poorly differentiated MCTs. Current chemotherapeutics for canine MCTs include CCNU, vinblastine, and prednisone. Receptor tyrosine kinase inhibitors (i.e. Palladia®, Kinavet®) are also useful. Both single-agent and combination protocols exist. Due to small, uncontrolled studies, there is no standard of care. In general, combination protocols are likely to be more successful. Estimating a 1-year survival time for dogs with grade III MCTs treated by surgery and chemotherapy is reasonable.
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As previously mentioned, radiation therapy is an excellent treatment modality to control microscopic disease in cases of incompletely excised MCTs. This can include incompletely excised high-grade MCTs. If staging tests are all negative, radiation therapy should be considered. In one small study, survival time of dogs with incompletely excised grade III MCTs treated with radiation therapy approached 2-years. Still, chemotherapy should be recommended, but at this time, it is unclear how much additional control time is added. Non-resectable MCT? – consider chemotherapy. Works. But not for too long. CCNU, vinblastine, steroids, Palladia® and Kinavet® all have efficacy against MCTs. For dogs with macroscopic MCTs, I generally quote 25-50% chance of a remission. Most of these dogs will experience “partial” (i.e. >50% but <100%) regression of their tumors, but “complete” (i.e. 100%) regression is possible. In general, remissions last 2-6 months however longer times are definitely possible. Protocols including all of these drugs in combination are probably are more effective then use of the drugs as single-agents. Don’t forget histamine blockers! Treatment with histamine receptor blockers (diphenhydramine, H1-blocker; famotidine, H-2 blocker) is indicated in dogs with non-resectable or metastatic MCTs or prior to surgery in dogs with large tumors. The goal of these therapies is to decrease clinical signs related to mast cell degranulation (i.e. peritumoral edema/bruising, GI ulceration). Omeprazole should be used in dogs that have evidence of overt GI ulceration
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