Recurrence Rates and Sites for Grade II Canine Cutaneous Mast Cell Tumors Following Complete Surgical Excision

Introduction

Mast cell tumors are one of the most common cutaneous neoplasms of dogs, but there is still considerable debate concerning the appropriate treatment of these tumors.^1–3 Numerous publications report on the effectiveness of treatment modalities such as surgical excision, radiation therapy, chemotherapy, immunotherapy, and deionized water injection as single modalities or in combination.^24–9 The previous studies that report recurrence rates of these tumors with surgical excision alone are often cited and suggest the need for adjuvant therapy in many situations.³¹⁰ However, these studies have not defined whether the recurrences were local or distant. Furthermore, the recurrences have not been correlated with important prognostic factors such as completeness of the surgical excision, tumor stage, and tumor grade.

Dogs with mast cell tumors may have a good, fair, or poor prognosis.¹² The prognosis in these patients depends on various important factors, including histopathological grade, stage, and completeness of the surgical excision. Surgery and radiation therapy may provide local tumor control, whereas chemotherapy would be indicated in a patient with, or at high risk of, distant metastases. The purpose of this study is to evaluate the recurrence rate in grade II, completely excised, canine cutaneous mast cell tumors. Grade II mast cell tumors are moderately differentiated, as described by Patnaik, et al.³ The hypothesis of the authors of this study was that dogs with complete surgical excision (i.e., clean histopathological surgical margins) were unlikely to have local tumor recurrence. Therefore, radiation therapy may not be warranted in this subset of patients.

Materials and Methods

Medical records of dogs with cutaneous mast cell tumors diagnosed at the Veterinary Hospital of the University of Pennsylvania (VHUP) between January 1994 to December 1998 were reviewed. Inclusion criteria included cutaneous mast cell tumors with a grade II histopathological classification³ and tumor-free surgical margins as identified on the biopsy report. Cases were excluded if the animal was determined to have stage 2 or greater mast cell tumor disease, if the dog had been treated with >2 weeks of corticosteroids or any other chemotherapeutic drug postsurgery, or if the animal had been previously treated for another malignant tumor.

Parameters recorded included signalment, tumor location, tumor size, tumor duration, presence of tumor ulceration, clinical signs, staging criteria performed, surgeon (i.e., referring veterinarian or VHUP), surgery date, local disease-free interval, distant disease-free interval, survival time, postoperative medical therapies, and follow-up. Staging criteria included various combinations of lymph-node aspirates, complete blood counts, serum biochemistry screens, buffy-coat analyses, bone-marrow aspirates, and abdominal ultrasound. Follow-up information was obtained through contact with the owners, the local veterinarians, or both, by phone. End points were tumor recurrence and overall survival. Recurrences were further characterized as local (i.e., at or immediately adjacent to the original tumor) or distant (i.e., in the regional lymph node, other new cutaneous sites, or any other distant sites). Recurrences were diagnosed by fine-needle aspirate and cytopathological examination or by biopsy and histopathological examination. Median survival time was calculated using the Kaplan-Meier product-limit survival method.

Results

Thirty-one of 112 dogs with mast cell tumors fulfilled the criteria for inclusion in this study. Staging diagnostics varied among the 31 dogs and included history and physical examination (31/31; 100%), regional lymph-node aspirates (3/31; 10%), abdominal ultrasound (14/31; 45%), buffy-coat analysis (11/31; 35%), and bone-marrow aspirates (7/31; 23%).

The median age of the dogs in this study was 8 years and 5 months (range, 2 years and 2 months to 14 years and 9 months). Twenty (65%) were females (all neutered), and 11 (35%) were males (four intact, seven neutered). The sex distribution for all dogs admitted to VHUP between 1994 and 1998 was 48% females and 52% males. The 31 dogs included mixed-breeds (n=8), golden retrievers (n=5), boxers (n=3), Labrador retrievers (n=2), Rhodesian ridgebacks (n=2), Portuguese water dogs (n=2), and various other breeds (n=1 each). Three (10%) tumors were located on the head/neck, 19 (61%) were on the trunk/perineum, and nine (29%) were on the extremities. The median tumor size was approximately 2 cm (range, 0.5 to 6 cm). The sizes of five tumors at surgical removal were not reported. Twenty-four (77%) of the tumors were removed at VHUP, and seven (23%) of the tumors were removed by the referring veterinarian. Twenty-seven (87%) dogs were available for follow-up, and four dogs were unavailable. Mean and median follow-up times were 21.7 and 17 months, respectively. Eight of 27 (30%) dogs had recurrence of their tumors; however, six of 27 (22%) dogs had distant tumor recurrence, and three of 27 (11%) dogs had local tumor recurrence. One dog had both local and distant tumor recurrence, although the local recurrence was identified by cytopathology only (designated as “mast cell tumor, probable”). Another dog had a distant tumor recurrence close to the original site but not close enough for the investigator (or the owner) to call the tumor a “local” recurrence.

The three dogs with local tumor recurrence had disease-free intervals of 2 months, 21 months, and 24 months. Mean and median disease-free intervals for local tumor recurrence in these three dogs were 15.6 months and 21 months, respectively. The first dog had both a negative abdominal ultrasound and negative bone-marrow aspirate upon presentation for removal of a mass on the right trunk. The tumor returned locally approximately 2 months later. Incidentally, there was a history of a benign, infiltrative lipoma removed from the same area of the right trunk approximately 5 months previously. The second dog had no staging procedures performed before a mass was removed from the left hind limb. She again presented to the veterinarian 21 months later with cytopathological evidence of local recurrence as well as distant recurrence to the dorsolateral abdominal skin and popliteal lymph node. The third dog had no staging criteria performed before the tumor on the left hind-limb digit was removed. The tumor recurred approximately 2 years later, at which point the original biopsy slides were reviewed to reveal that tumor cells did extend to the surgical margin.

The six dogs (6/27; 22%) with distant tumor recurrence had disease-free intervals of 4, 10, 16, 21, 21, and 27 months. Mean and median disease-free intervals for distant tumor recurrence in these six dogs were 16.5 and 18.5 months, respectively. Five of the six dogs had no staging procedures performed prior to tumor removal, so it is impossible to determine retrospectively whether these were tumor metastases or previously unidentified multicentric disease. The last dog had a negative abdominal ultrasound, negative buffy-coat analysis, and negative bone-marrow aspirate (i.e., only one mast cell was seen), but no lymph-node fine-needle aspirate. Four months later, this dog had both a positive lymph-node fine-needle aspirate and positive buffy-coat analysis. One other dog had a positive buffy coat (i.e., 96 mast cells) 7 months later, but no other evidence of tumor recurrence. This was not considered sufficient criteria to be diagnostic for distant tumor recurrence, because a positive buffy coat may be a nonspecific response to inflammation.¹¹

Median survival time for the 27 dogs available for follow-up was calculated to be 791 days.

Discussion

The small number of animals involved in this retrospective study makes it difficult to draw any statistically significant conclusions. However, there has still only been local tumor recurrence in three (approximately 11%) of the 27 dogs available for follow-up, suggesting that evaluation of the surgical margin accurately predicted adequate local tumor control in 89% of the dogs. For the 24 dogs with biopsy reports from VHUP, “clean surgical margins” are defined as those margins with tumor cells farther than 1 to 2 mm from the tumor edge, evaluated on four lateral margins and four sections through the tumor base. This definition may not apply to the remaining seven biopsies evaluated at other pathology laboratories. Those reports simply stated that the tumor margins were devoid of tumor cells. Furthermore, one of the three dogs with local recurrence had an incorrectly evaluated biopsy specimen initially, and the other dog had a previous benign tumor resected that could potentially have interfered with the complete removal of the subsequent mast cell tumor. It should be noted as well that follow-up information obtained from owners and referral veterinarians can contain bias, and the accuracy of observations may differ.

Six of the 27 (22%) dogs available for follow-up are ≤ 16 months postsurgery. The mean and median disease-free intervals for local tumor recurrence in the three dogs where this occurred were 15.6 and 21 months, respectively, which may suggest that some of these dogs might develop tumor recurrence in the near future. For this reason, the 11% local tumor recurrence rate in this study may actually be an underestimation. Follow-up discussion with these clients over the next few years could potentially yield additional useful information, such as more accurate tumor recurrence rates and survival times.

It is difficult to comment on the distant recurrence rates of these tumors for a number of reasons. Primarily, the majority of these animals were not completely staged, so the tumor may have been present the entire time and not have actually “recurred.” In other words, these tumors may not have been correctly classified as stage 1 mast cell tumors initially, because of incomplete diagnostic workups. The relatively low number of dogs that were completely staged is concerning. Often, a clinical judgment of a solitary mass is considered to be a stage 1 mast cell tumor by the attending veterinarian, and other times the client declines the costly workup to completely stage the dog. Furthermore, results from staging may be difficult to interpret in dogs with mast cell tumors. The presence of mast cells in the draining lymph nodes, buffy coat, and spleen may not necessarily represent metastatic disease but rather an inflammatory response or draining mast cells naturally present in certain tissues, such as lymph nodes and the spleen.¹¹ Regardless of the reason, dogs that are not completely staged will continue to develop “distant tumor recurrences,” and it will remain difficult to provide accurate prognoses for mast cell tumor recurrence.

There is currently little, if any, debate that incompletely excised, grade II mast cell tumors should receive additional tumor treatment, such as radiation therapy or additional surgery. However, there still remains debate as to the appropriate treatment for completely excised grade II, stage 1 mast cell tumors. The initial data from this study reports a local tumor recurrence rate of approximately 11%. Previous studies report of 3-year local control rates of 93% with adjuvant radiation therapy for incompletely resected, cutaneous mast cell tumors.⁵ Eighty-nine percent of the dogs in this study had complete local control with surgery alone. It is therefore unlikely that there would be a significant benefit from adjuvant radiation therapy for these patients, since most cases with completely excised tumors (89%) do not need further local therapy. Furthermore, radiation therapy may be associated with both acute and late side effects in addition to adding a significant financial expense.