Outcome in dogs with surgically resected oral fibrosarcoma ( )

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1 See discussions, stats, and author profiles for this publication at: Outcome in dogs with surgically resected oral fibrosarcoma ( ) Article in Veterinary and Comparative Oncology March 2012 DOI: /j x Source: PubMed CITATIONS 4 READS authors, including: Allison Zwingenberger University of California, Davis 58 PUBLICATIONS 490 CITATIONS Michael S Kent University of California, Davis 85 PUBLICATIONS 752 CITATIONS SEE PROFILE SEE PROFILE Carlos O Rodriguez 58 PUBLICATIONS 920 CITATIONS SEE PROFILE Michele Steffey University of California, Davis 39 PUBLICATIONS 428 CITATIONS SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Available from: Carlos O Rodriguez Retrieved on: 21 August 2016

2 Original Article DOI: /j x Outcome in dogs with surgically resected oral fibrosarcoma ( ) S. A. Frazier 1, S. M. Johns 2, J. Ortega 1, A. L. Zwingenberger 3, M. S. Kent 3, G. M. Hammond 1, C. O. Rodriguez Jr. 3, M. A. Steffey 3 and K. A. Skorupski 3 1 William R. Prichard Veterinary Medical Teaching Hospital, University of California-Davis, Davis, CA, USA 2 School of Veterinary Medicine, University of California-Davis, Davis, CA, USA 3 Department of Surgical and Radiological Sciences, University of California-Davis, Davis, CA, USA Keywords canine, fibrosarcoma, mandibulectomy, maxillectomy, oral tumour Abstract Oral fibrosarcoma (FSA) is a common oral tumour in dogs, and historically reported survival times after surgical excision range from 7.0 to 12.2 months with local recurrence rates of 32 57%. The purpose of this retrospective study was to report outcome in a cohort of dogs with oral FSA treated with surgical excision with or without adjuvant radiation therapy. Twenty-nine dogs with a histological diagnosis of FSA arising from the oral cavity that underwent surgical resection of their oral FSA were included in this study. Twenty-one dogs were treated with surgical excision alone and eight dogs with both surgery and radiation therapy. The median progression-free interval was >653 days. The median survival time was 743 days. The 1- and 2-year survival rates were 87.7 and 57.8%, respectively. Seven (24.1%) dogs developed local recurrence. Seven dogs (24.1%) developed metastasis. Correspondence address: S. A. Frazier Department of Surgical and Radiological Sciences University of California-Davis, 2112 Tupper Hall Davis, CA 95616, USA sdfrazier@ucdavis.edu Introduction Oral neoplasia accounts for approximately 6% of all canine cancers, and fibrosarcoma (FSA) is the third most common oral tumour in the dog. 1 Canine oral FSA is reported to be locally aggressive with a low rate of metastasis. 2 7 Surgery has historically played a major role in the control of these tumours, either alone or in combination with radiation therapy. 2 6 Outcomes reported in the published literature are variable, but high recurrence rates and relatively short survivals have been common findings Presented in part at the 28th Annual Veterinary Cancer Society Annual Meeting, Seattle, WA, USA, October Present address: Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, Davis, CA, USA Present address: Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, USA Present address: Facultad de Veterinaria, Universidad CEU Cardenal Herrera, Valencia, Spain Present address: Sacramento Veterinary Referral Center, Sacramento, CA, USA There have been multiple published reports of outcome in dogs with oral FSA treated with surgery alone. Withrow reported survival times of 2, 6 and 32 months after mandibulectomy in three dogs with FSA of the mandible. 11 Salisbury et al. reported nine dogs with FSA of the mandible treated with partial mandibulectomy with a median survival time of 7 months. 4 Forty-four percent of these dogs experienced local recurrence of their tumours. 4 Schwartz et al. reported a 31% rate of recurrence for mandibular FSA after mandibulectomy and a 57% rate of recurrence for maxillary FSA after resection. 2,3 This group reported median survival times of 11 months for mandibular FSA and 9.5 months for maxillary FSA. 2,3 Kosovsky et al. reported on the results of partial mandibulectomy in which 19 dogs with FSA had a median survival time of 10.6 months and a 47.3% rate of local recurrence. 7 The longest published survival times in dogs with oral FSA were reported by Wallace et al. after hemimaxillectomy with 15 dogs experiencing a median survival time of 12.2 months and a 33% local recurrence rate Blackwell Publishing Ltd 33

3 34 S. A. Frazier et al. Radiation therapy has also been used as a firstline therapy for oral FSA as well as in the postoperative setting. Thèon et al. reported on 28 dogs with oral FSA treated with a definitive megavoltage radiation protocol. These dogs experienced a progression-free survival (PFS) time of 26 months with a 76% of dogs progression-free at 1 year. 8 Dogs with a lower stage (i.e. smaller tumours without evidence of metastasis) at diagnosis experienced longer progression-free intervals. Overall survival time was not reported in this study and all of these dogs had gross disease at the time of radiation. 8 Brewer and Turrel reported a median survival time of 398 days with hyperthermia combined with orthovoltage radiation in dogs with gross disease. 9 Thrall reported on 17 dogs treated with orthovoltage radiation in 10 fractions given 3 days a week with a 6.8-month median survival time. 10 Three of these 17 dogs had a surgical debulking of their tumour prior to irradiation. 10 In 2000, Forrest et al. reported on postoperative radiation therapy for canine soft tissue sarcomas, including seven dogs with oral FSA with incomplete surgical margins. 12 These seven dogs experienced a median survival time of 540 days and while the number of dogs in this study is low, the median survival time reported is higher than in the previous reports described above, excluding Theon et al. 8,12 Owners and veterinarians may be more likely to consider aggressive surgical resection of oral tumours if they have a reasonable expectation of a good long-term outcome for their pet or patient. The purpose of this retrospective study was to report outcome in a recent cohort of oral FSA bearing dogs treated with surgical excision with or without adjuvant radiation therapy and to determine prognostic factors for these patients. Materials and methods Study population Dogs with histologically confirmed FSA of the oral cavity that underwent surgical excision by a board-certified surgeon or dentist that were seen at the University of California Davis Veterinary Medical Teaching Hospital between January 1997 and January 2008 were included in this study. Signalment, staging tests, pre-operative imaging, tumour location and size, method of surgery, surgical margins, adjunctive therapy and outcome were extracted from medical records. Only those cases with follow-up of at least 30 days postoperatively were included in this study. Diagnosis and staging Primary diagnosis of FSA was made from tissues obtained through curative-intent surgical excision. All tumours had been previously biopsied to confirm tumour type. Surgical reports were reviewed by a board-certified surgeon (M. A. S.) to evaluate surgical technique and pre-operative surgical margin intent. Surgical intent and pre-operative margin intent must have been explicitly stated in the medical record or surgery report for evaluation. Tumours were staged according to the World Health Organization Tumour Node Metastasis system for classification of tumours in domestic animals (Table 1). 13 Histopathology slides were reviewed whenever possible by a single board-certified pathologist (J. O.) to confirm the diagnosis. Histological criteria for grading oral FSA have not been standardized, thus the Kuntz et al. classification for soft tissue tumours was used with combination of grade 1 and 2 tumours into one category. 14 Tumours that were well differentiated (low number of fibrocytes with minimal cellular anaplasia, minimal nuclear pleomorphism and abundant collagenous matrix), with occasional small areas of necrosis and <20 mitoses per 10 high power fields (HPF), were classified as low grade (combining grades 1 and 2 from the Kuntz classification). Tumours with the features of marked cellular anaplasia, marked nuclear pleomorphism, large areas of necrosis and 20 or more mitoses per 10 HPF were classified as high grade (grade 3 in Kuntz classification). The degree of invasiveness of the tumour was also noted. 14 Dogs with tumours not clearly arising in the oral cavity, whose tumours were not clearly classified as a FSA on histopathology, whose histopathology showed more than one type of neoplasia or whose primary surgery was not performed by a boardcertified veterinary surgeon or veterinary dentist were excluded from the study. The degree of invasiveness of the tumour was also noted. The intent of

4 Canine oral fibrosarcoma 35 Table 1. World Health Organization TNM system for classification of tumours in domestic animals T = primary tumour T1 T2 T3 N = regional lymph nodes N0 N1 N2 N3 N1a N1b N2a N2b Tumour <2cmmaximumdiameter Tumour 2 4 cm maximum diameter Tumour >4cmmaximumdiameter Regional lymph nodes not palpable Movable ipsilateral nodes Nodes not considered to contain tumour growth Nodes considered to contain tumour growth Moveable contralateral or bilateral nodes Nodes not considered to contain tumour growth Nodes considered to contain tumour growth Fixed nodes M = distant metastasis M0 M1 No evidence of distant metastasis Distant metastasis present Stage grouping I T1 N0,N1aorN2a M0 II T2 N0, N1a or N2a M0 III T3 N0, N1a or N2a M0 IV Any T N1b, N2b or N3 M0 Any T Any N M1 classification of tumours as low grade was to aid in the identification of histologically low-grade, biologically high-grade FSA. Tumours were classified as histologically low-grade, biologically high-grade tumours if they had a low-grade appearance on histopathological review but an aggressive clinical behaviour of the tumour was described in the medical record (i.e. rapid growth and progression of tumour, quick regrowth after biopsy). Golden Retriever breed dogs were analysed separately from other breeds because of a published report by Ciekot et al. that up to 52% of dogs with histologically lowgrade, biologically high-grade tumours are of the Golden Retriever breed. 15 Variable methods have been reported for localization of oral tumours. There are multiple reports that divide the oral cavity into rostral, middle and caudal locations and multiple reports of rostral versus caudal locations. 2 4 We chose simply to use rostral versus caudal locations in this study. The space between PM2 and PM3 was chosen as the rostral/caudal demarcation, as no standardized cutoff has been reported for rostral versus caudal oral tumours. Location of the tumour was determined based on the physical exam notes, surgical report and/or computed tomography (CT) images. CT scans were reviewed by a single boardcertified radiologist (A. L. Z.) and tumour volume was calculated using hand-drawn regions of interest on transverse images and three-dimensional reconstruction of the tumour (Osirix, Geneva, Switzerland). Tumour volume as well as the longest measurement of the tumour were recorded for analysis on prognosis and staging. If a clinical measurement of the longest diameter of the tumour was not recorded in the medical record, then the longest measurement of the tumour was calculated via the CT images. CT scans were evaluated for evidence of bone destruction. If a CT scan was not performed, then dental radiographic evaluation, if available, was used to determine if evidence of bone destruction was present. For patients that underwent radiation therapy, medical and radiation therapy records were searched for the following information: type of machine used, planned course of therapy, actual course of therapy, dates of therapy, field size,

5 36 S. A. Frazier et al. number of fields, noted radiation-induced side effects, therapy of radiation side effects and timing of radiation (pre- or postoperative radiation). Statistical analyses Endpoints evaluated were PFS and overall survival (OS) times. PFS time was defined as the time between surgery and detection of measurable local recurrence, detection of regional or distant metastasis or death. Overall survival was defined as the time between surgery and death related to the tumour. Dogs alive without evidence of tumour progression (i.e. local recurrence or metastasis) were censored at the time of their last follow-up examination for calculation of PFS or OS. Dogs that died of unrelated causes to the tumour (confirmed via necropsy) were censored on their date of death. Dogs that died or were euthanized because of local tumour recurrence or metastasis or that died of unknown causes were assumed to be dead because of their oral FSA. Variables examined for their effect on prognosis included: age, sex, breed (Golden Retriever versus other breeds), weight, clinical stage, margin status (complete versus incomplete), grade (low versus high), location (rostral mandible, caudal mandible, rostral maxilla, caudal maxilla; cranial versus caudal locations; maxilla versus mandible), local recurrence, metastasis, whether or not the patient had a pre-operative CT scan, tumour volume calculated via CT, longest diameter of the tumour as measured clinically or via CT and whether or not the patient received radiation therapy. Time to local recurrence, PFS and OS were estimated using the Kaplan Meier product-limit method. To look for differences between categorical variables, a log-rank test was performed. To look for differences in continuous variables (weight and age), these variables were coded to be above or below the mean and then a log-rank test was performed. To evaluate if there were differences in the rate of metastasis and local recurrence between categorical variables either a chi-square or Fisher s exact test was carried out based upon sample size. P-values <0.05 were considered significant. Statistical analysis was performed using a commercially available statistics program (Stata 10.0, Stata, College Station, TX, USA). Results Patient characteristics Twenty-nine dogs met the criteria for inclusion in this study. Fifteen (51.7%) were spayed females, nine (31.0%) were castrated males and five (17.2%) were intact males. Seven dogs (24.1%) were mixed breed, 10 (34.5%) dogs were Golden Retriever or Golden Retriever mix breed dogs and 12 (41.3%) dogs were other purebred dogs. The mean age was 9.4 years (range years) and the mean weight was 30.7 kg (range kg). Five (17.2%) tumours were located on the rostral mandible, 11 (37.9%) on the caudal mandible, 6 (20.7%) on the rostral maxilla and 7 (24.1%) on the caudal maxilla. Staging, treatment and complications Overall, 10 dogs (34.4%) were classified with stage I disease, 11 (37.9%) with stage II disease and 8 dogs (27.5%) with stage III disease. Fourteen dogs did not have a pre-operative CT scan. Seven of these were dogs with stage I disease (primary tumour <2 cmindiameter)andsevenhadstageiidisease (primary tumour 2 4 cm in diameter). Fifteen dogs underwent a pre-operative CT scan for surgical planning. In these dogs that underwent CT, three were classified with stage I tumours (<2 cm), four had stage II tumours (>2 but<4 cm)and eight had tumours >4 cm (stage III). Dogs with larger tumours were more likely to have a CT scan (P = 0.006). Eight of these 15 dogs had complete surgical excision of their tumours. Neither tumour volume nor longest tumour diameter were found to be predictive of outcome (P = 0.73 and 0.94, respectively). There was no statistical difference in outcome between dogs that had a pre-operative CT scan and those that did not have a pre-operative CT scan (P = 0.39; see Table 2). Fourteen dogs had dental radiographs performed and 7 of these dogs also had a CT scan performed prior to surgery allowing evaluation of bone involvement in 23 dogs. Twenty-two of these 23 dogs had evidence of bone involvement/destruction either in the CT scan and/or dental radiographs. In seven dogs, we were unable to determine the presence or absence of bone involvement because of

6 Canine oral fibrosarcoma 37 Table 2. Variables assessed for effect on OS and local recurrence Variable Overall survival Local failure Number of dogs Days P-value Days P-value Golden Yes No NR Stage NR NR Margin Complete NR Incomplete Unknown 3 Grade Low NR High NR Location Rostral mandible Caudal mandible 10 NR Rostral maxilla Caudal maxilla Location Maxilla NR Mandible NR Pre-operative CT Yes NR No NR Radiation therapy Yes No NR NR, not reached. either lack of imaging or unknown status of imaging (i.e. patients that had imaging performed elsewhere or for which imaging results were unavailable). Treatments included surgery alone or surgery in combination with radiation therapy. All dogs had a pre-operative histopathological diagnosis of tumour type prior to surgery via incisional biopsy. Twenty-one dogs (72.4%) had surgical excision alone and eight dogs (27.6%) had surgery and radiation therapy. Fifteen (51.7%) had histopathological margins free of tumour (complete excision), 11 (37.9%) had tumour cells evident at the edge of the biopsy (incomplete surgical excision) and in 3 cases (10.3%) completeness of excision could not be determined from the pathology report or on histopathological review. Twenty-one dogs had surgical reports available for review. Only 13 of these 21 reports had data on intra-operative margin intent, that is, the gross margins that the surgeon was attempting to obtain via excision. Three cases required cheliotomy to obtain adequate surgical exposure. Intra-operative (gross) margins in these 13 dogs were as follows: 4caseswithmargins 15 mm (two maxilla, two mandible; with upper limit of margins not defined) with 1 out of 4 having incomplete margins on histopathology; 5 cases with margins mm (two maxilla, three mandible) with 3 out of 5 having incomplete margins on histopathology; 2 cases with margins 5 9 mm (one maxilla, one mandible; both completely excised); and 2 cases with margins <5mm(onemaxilla,onemandible) with 1 of these having incomplete excision on histopathology. In retrospective evaluation, the intra-operative margin intent appeared to be limited by surrounding anatomical structures. Surgical complications included oronasal fistula (three), dehiscence (three), mandibular drift (two), haemorrhage (one), aspiration pneumonia (one), infection (one), minor suture reaction (one), esophagitis (one) and difficulty prehending soft food (one). Among the three patients that developed oronasal fistulas postoperatively, only one required surgical repair and two resolved with medical management alone. Dehiscence was managed with surgical repair in one case and via second intention healing in two cases. Haemorrhage occurred in one patient postoperatively after left lateral and rostral maxillectomy. In this patient, serisanguineous discharge and subcutaneous haemorrhage were noted for 48 h postoperatively and was managed with conservative medical management and supportive care and resolved without surgical intervention. This dog did not require a blood transfusion. Infection occurred in one patient on the mesial border of the buccal flap and resolved with oral antibiotics. Difficulty prehending food in one patient had resolved by a 1-month post-surgery recheck examination. All complications eventually resolved without long-term adverse effects. Eight dogs underwent radiation therapy in addition to surgery. Two of these dogs had complete excision and six had incomplete excision. Radiation therapy techniques varied with both

7 38 S. A. Frazier et al. coarse fractionation and definitive radiation therapy incorporated in this cohort of dogs. All dogs underwent megavoltage irradiation with a 4-MV linear accelerator. One dog had pre-operative radiation and seven dogs had postoperative radiation. Six dogs received 48 gray (Gy) delivered in 16 fractions on a 5-day per week fractionation schedule. In one dog, the plan was for the dog to receive 48 Gy delivered in 16 fractions, however, this dog received 46 Gy delivered in 15 fractions because of owner inability to complete the planned course of therapy. One patient received a palliative course of radiation consisting of 32 Gy delivered in four once weekly 8 Gy fractions because of owner preference (the owner declined definitive therapy) despite only microscopic disease remaining. Seven (87.5%) dogs developed mild to moderate mucositis. Five (62.5%) dogs developed moist desquamation in the radiation field. In four dogs this was mild, and in one dog this was moderate to severe. None of the dogs experienced a treatment delay due to adverse effects. Twenty-eight dogs had slides available for review by a single pathologist (J. O.). In the one case in which the specimen was not available, the biopsy report was available for review and was consistent with a diagnosis of FSA. Thirteen dogs had tumours classified as low grade. Of these, six dogs were classified as having histologically lowgrade, biologically high-grade tumours. Two of these were Golden Retriever or Golden Retriever mix breed dogs and four were other purebred dogs. Treatment response, prognostic factors, survival and outcome data Table 2 shows the variables assessed for effect on OS and time to local recurrence. Seven (24.1%) dogs experienced local recurrence. In the dogs that experienced local recurrence, the median time to recurrence was 282 days. Golden Retriever or Golden Retriever mixed breed dogs were more likely to experience local recurrence than other breeds (P = 0.03). Five of the seven dogs with local recurrence had incomplete margins, one had unknown margins and one had margins assessed histologically to be free of tumour. Two of the dogs with local recurrence had received curative-intent radiation therapy after incomplete surgical excision. In comparison with dogs with complete excision, dogs with incomplete surgical excision were also more likely to experience local recurrence (P = 0.002). The seven dogs with local recurrence had variable treatment at the time of recurrence. Three underwent re-excision of their tumours at the time of local recurrence and four did not. In the dogs that underwent re-excision, one was lost to follow-up immediately after re-excision, one died a year later because of hepatic carcinoma and one recurred 8 months after re-excision. In the four dogs that did not undergo re-excision, survival times were 1, 5, 6, and 8 months. Seven dogs (24.1%) developed metastasis: three to regional (mandibular) lymph node only, three to lung only and one to both regional lymph node and lung. In the dogs that developed metastasis, the median time to metastasis was 282 days. No variables were found to be predictive of the development of metastasis. The median survival time of the seven dogs that developed metastasis was 391 days. Three of the dogs that developed pulmonary metastasis also experienced local recurrence. The median PFS was not reached, but was >653 days [95% confidence interval (CI), range 316- upper limit not reached] (Fig. 1). The 1-year PFS rate was 71.9% (95% CI ) and the 2-year PFS rate was 50.3% (95% CI, range ). There were no prognostic variables predictive of PFS other than the Golden Retriever breed. The median survival time (MST) of all dogs was 743 days (95% CI days) (Fig. 2). The 1- and 2-year survival times were 87.7% (95% CI Figure 1. Kaplan Meier curve of disease-free interval for 29 dogs with oral FSA treated with surgery with or without radiation therapy. Black ticks indicate censored dogs.

8 Canine oral fibrosarcoma 39 Figure 2. Kaplan Meier curve of OS for 29 dogs with oral FSA treated with surgery with or without radiation therapy. Black ticks indicate censored dogs ) and 57.8% (95% CI ), respectively. The median survival times of dogs treated with surgery alone or with surgery and radiation therapy were not statistically different (1024 days and 576 days, respectively; P = 0.40). The MST for dogs with complete excision was not statistically different from those with incomplete excision (1598 days versus 576 days, respectively; P = 0.09); however, dogs with incomplete margins were more likely to experience local recurrence (P = 0.002). There were no variables predictive of survival and Table 2 lists the variables that were evaluated for effect on survival. Dogs that developed metastasis experienced lower survival times (P = 0.002). Biologically highgrade histologically low-grade classification did not affect outcome in this study (MST = 1063 versus 1460 days, P = 0.61). Discussion Results of this study show better local control and survival than previous reports of surgically treated canine oral FSA. Previous studies report median survival times between 7.0 and 12.2 months after surgical excision 2 7 compared with an OS of 24.8 months reported herein. There are several possible reasons for this finding, including the inclusion of a greater number of patients in this study compared with previous publications. Previous studies reported on 3 19 dogs treated with surgery alone and 7 28 dogs treated with radiation therapy. Many of the previous reports of oral FSA are from the 1980s to 1990s, and it is possible that oral surgical experience and techniques have improved in this time. Another possible reason for the improved survival reported here may be due to recent advancements in diagnostic imaging. Fifteen dogs in this study underwent a pre-operative CT scan which may have aided in removal of all or a larger portion of the tumour in these patients. However, the use of a pre-operative CT was not prognostic in this study. It is important to note that the 12 of the 15 dogs that underwent a pre-operative CT had stage II and III tumours, and statistical evaluation confirmed that dogs with smaller tumours were less likely to undergo a CT scan. Perhaps the low number of overall dogs and the high number of low stage (stage I and II) dogs that did not have a CT contributed to this factor not affecting outcome in this study. Another interesting finding was that 12 of the 15 dogs that had a CT had caudally located tumours. Perhaps selection bias also contributed to failure to find a correlation with CT and surgical outcome most of the dogs that underwent CT had caudally located tumours, which are more challenging to excise. Ideally, all dogs with oral tumours should undergo CT evaluation of their tumours to optimize surgical planning and assist in obtaining the widest margins possible. This recommendation is supported by the fact that 5 out of 12 dogs with known margins that did not have a CT used for pre-operative planning had incomplete excision of their tumours. In 2003, Lascelles et al. reported on a combined dorsolateral and intra-oral approach to the maxilla in the dog. 16 In this report of 20 dogs, seven had oral FSA. Whereas this paper 16 was aimed at describing a surgical technique for tumours of the maxilla, this was the first oral tumour paper including routine pre-operative CT scans. Several dogs in this study experienced prolonged survival times and similar to other oral surgery publications, all of the dogs in this study by Lascelles underwent surgery at a referral institution. In 2004, Lascelles reported another surgical technique for tumours of the maxilla via bilateral rostral maxillectomy and nasal planectomy. 17 Only three dogs in the study reported herein that underwent caudal maxillectomies had surgery reports available for review and only one of the three reports describes the use of the combined

9 40 S. A. Frazier et al. dorsolateral and intra-oral approach. All three caudal maxillectomies obtained complete excision, and thus little information can be gained from this data. The data reported in this manuscript shows a lower rate of local recurrence (24.1%) compared with previous studies, which reported recurrence in 32 57% of dogs with FSA. 2 7 This improved outcome should encourage oncologists and surgeons to consider surgical resection of oral FSA. Only 21 dogs in this study had surgical reports available for review and in only 13 of these were intra-operative margin intent recorded, thus information on surgical margin intent was very limited. There are currently no definitive standards for intra-operative margins for oral tumours; however, 1cmhasbeenproposedasaguidelinewithmodifications made as necessary based on the tumour type as recommended by Salisbury; 18 another source suggests 2 cm margins for malignant oral tumours. 1 Margin intent in the oral cavity is usually restricted to anatomical planes and expected patient functionality postoperatively. Since FSA is known to be locally invasive, margins wider than 1 cm should be considered when possible. Intra-operative margin intent was only available retrospectively in 44.8% of the cases in this manuscript and only 30.7% of these had the statement that the incision was made at least mm from the tumour recorded in their surgical report. The upper limit of the surgical margin was not recorded in these cases, thus in these four cases we can only state that intra-operative margin intent was >15 mm. Despite the possibility that most of these dogs had a narrow excision of their tumours, outcome in these dogs was quite good, indicating that many of these patients may indeed do well despite the anatomical limitations of oral surgery. Thus, the goal of surgical excision when planning resection of oral FSA should always be to obtain the widest margins possible but these results suggest that surgical excision should still be considered even if surgical margins are expected to be <2cm. Many of the variables evaluated in this study did not have a statistically significant association with PFS or OS. Variables that were evaluated in this study included breed, age, sex, tumour location, tumour volume, tumour grade, surgical margins, stage, histologically low-grade, biologically high-grade tumours 15 and whether or not the patient received a pre-operative CT scan or radiation therapy. Interestingly, factors previously reported to predict outcome were not significant in this study: location, whether the patient received radiation therapy, and grade of tumour (specifically, histopathologically low-grade, biologically high-grade FSA versus other oral FSA). These factors may have proven significant had there been a larger cohort of patients in this study. Golden Retrievers and dogs with incomplete margins were more likely to experience local recurrence (P = 0.03 and P = 0.002, respectively). The role of radiation in the treatment of oral FSA has not been adequately studied and the outcome of dogs treated with radiation in this study should be interpreted cautiously. With only eight dogs undergoing radiation therapy, there is low power of statistical evaluation and these data are difficult to interpret. Six of the 11 dogs with incomplete resection were treated with radiation therapy. Three of these six (50%) dogs experienced local recurrence at a median time to recurrence of 282 days post-surgery. The data suggest that the dogs that underwent radiation may have had larger or more invasive tumours with five of the eight cases that underwent radiation therapy having stage III tumours, two with stage II tumours and only one with a stage I tumour. Their survival, PFS and time to local recurrence were numerically shorter than dogs with surgery alone, as expected in dogs with higher stage tumours. Although the data reported herein suggests that radiation may not have a benefit in the treatment of oral FSA, other studies have shown that radiation may benefit these patients and radiation has been shown to benefit patients with incompletely excised soft tissue sarcomas. 8 10,12,19 A larger cohort of patients may have shown a significant difference in patients that were treated with adjuvant radiation therapy and further study is needed before drawing any conclusions regarding the role of radiation in the treatment of oral FSA. Histologically low-grade, biologically high-grade tumours are a recognized subset of oral FSA in the dog. 15 These tumours have a very low-grade appearance histopathologically but act very aggressively biologically. Ciekot et al. reported that 52% of cases with histologically low-grade, biologically

10 Canine oral fibrosarcoma 41 high-grade FSA are of the Golden Retriever breed. 15 In this study, Golden Retriever and Golden Retriever mix breed dogs were more likely to experience local recurrence, however histologically low-grade, biologically high-grade tumours were not found to predict local recurrence. Only two of the six tumours in this study classified as histologically low-grade, biologically high-grade tumours occurred in Golden Retriever or Golden Retriever mix breed dogs, making statistical evaluation difficult. Tumours were classified as histologically low-grade, biologically high-grade based on a lowgrade appearance on biopsy with an aggressive clinical behaviour described in the medical record. This method of classification is less than ideal, as some medical records may have omitted clinical behaviour of the tumour or owner recollection of the rapidity of tumour growth may be distorted. Perhaps Golden Retriever breed dogs with histologically low-grade, biologically high-grade tumours were not identified in the retrospective evaluation of the medical records leading to misclassification of their tumours but making local recurrence more likely in this breed. It is also possible that tumours were not considered low-grade in the histopathological review of these tumours if tumour invasion into adjacent structures was noted, leading to classification of the tumour as more aggressive because of invasion. Grade was not found to be prognostic in this study. Histological criteria for grading oral FSA have not been standardized, thus the Kuntz et al. classification for soft tissues tumours was used with combination of grades 1 and 2 tumours into one category separated from grade 3 tumours. 14 The decision to combine grades 1 and 2 was an attempt to separate less aggressive tumours from very aggressive (i.e. grade 3) tumours which, for soft tissue sarcomas, is predictive of metastatic behaviour. However, no difference in metastasis or outcome was found in these dogs based on grade. The pattern of metastasis to the local lymph nodes and lung in this study is similar to many previous reports of oral FSA. 2 5,7,15 The highest rate of metastasis (71.4%) was reported by Schwarz et al. in 1991 after mandibular resection and based on necropsy reports in 32 dogs dying with oral FSA. 3 Other reports have historically reported low rates of metastasis from oral FSA, ranging from 0 to 20%. 2,4,5,7,11,15 The metastatic rate in this study was 24.1%, and it is possible that the higher rate of metastasis in clinical patients reported here is, in part, due to prolonged survival which would allow more time for metastasis to develop. This higher metastatic rate suggests that routine monitoring for development of metastatic lesions should be considered in dogs with oral FSA. Perhaps, this indicates that investigation into a possible role for adjuvant chemotherapy for oral FSA should be considered; however, the time to metastasis is relatively long at 282 days and a role for adjuvant chemotherapy has not been defined for oral FSA. With a metastatic rate of <25% reported widely across studies, the focus of therapy for these dogs should remain on local control. The limitations of this retrospective study include the small number of cases and the variability in case management and follow-up along with the lack of cytological or histopathological confirmation of metastasis, conservative censoring and lack of margin quantification. This was a small retrospective study of 29 cases which likely limited the power necessary to discover prognostic factors; however, it included a larger cohort of dogs than in past reports. Most data in this study were extrapolated from medical record notes or via contact with the referring veterinarian and/or owner. All patients did not receive consistent monitoring for recurrence or metastasis. Not all metastatic lesions were biopsy-confirmed and not all patients underwent necropsy confirmation of cause of death, which forced assumptions in these cases. Censoring was conservative in this study. Specifically, patients were considered dead because of their FSA if the cause of death could not be confirmed, thus the reported PFS and OS times may be low. Pulmonary lesions were considered to represent metastasis even without histological confirmation which may have falsely elevated our reported rate of metastasis. The lack of histopathological margin quantification is an additional limitation of this study. The authors attempted to quantify all margins but were limited by the sectioning of tissues during the original evaluation postoperatively. Many of the older cases only had clean/complete or dirty/incomplete margins reported on the initial

11 42 S. A. Frazier et al. histopathology report without quantification of the margin. Quantified margins would have been ideal to evaluate in relation to PFS and OS; however, quantification of the margins retrospectively was hindered by the original sectioning of the tissues and thus we were unable to quantify margins. This significantly limits our ability to study optimal margin of resection in cases of oral FSA. Given that the surgical (i.e. gross) margin intent was <15 mm in 69.2% (8 of 13 cases) in which this information was available, and the prolonged PFS in many of these dogs suggests that even narrow excision can still potentially provide these dogs with a good long-term outcome. An additional limitation of this study includes the biased population reported here all of these patients underwent surgery by a board-certified surgeon or dentist, potentially biasing our population of patients for a better outcome. It would be ideal to compare this population to a similar population that underwent surgery by non-boardcertified veterinarian. Although the limitations are numerous in this study, the authors feel that the data reported in this study is potentially useful to veterinarians contemplating therapy for a patient with oral FSA. In summary, the results of this study show a better outcome in dogs with oral FSA treated with surgical excision when compared with previously published reports. Thus, the dogs reported in this study experienced lower rates of recurrence and longer survival times than those previously reported. We were unable to define a role for radiation therapy and further study is required to more clearly define the role of radiation in the treatment of oral FSA. On the basis of these results, local control should remain the focus of therapy for oral FSA and these dogs may experience prolonged survival times even when surgical excision is narrow. Thus, surgical excision should still be considered even when margins are expected to be narrow, however the surgical intent should be to obtain the widest margins possible. References 1. Liptak JM and Withrow SJ. Cancer of the gastrointestinal tract. In: Withrow and MacEwen s Small Animal Clinical Oncology,4 th edn., SJ Withrow and DM Vail, eds., St. Louis, Saunders Elsevier, 2007: Schwarz PD, Withrow SJ, Curtis CR, Powers BE and Straw RC. Partial maxillary resection as a treatment for oral cancer in 61 dogs. Journal of the American Animal Hospital Association 1991; 27: Schwarz PD, Withrow SJ, Curtis CR, Powers BE and Straw RC. Mandibular resection as a treatment for oral cancer in 81 dogs. Journal of the American Animal Hospital Association 1991; 27: Salisbury S, Richardson D and Lantz G. Partial maxillectomy and premaxillectomy in the treatment of oral neoplasia in the dog and cat. Veterinary Surgery 1986; 15: Wallace J, Matthiesen DT and Patnaik AK. Hemimaxillectomy for the treatment of oral tumors in 69 dogs. Veterinary Surgery 1992;21: White R. Mandibulectomy and maxillectomy in the dog: long term survival in 100 cases. Journal of Small Animal Practice 1991; 32: Kosovsky JK, Matthiesen DT, Marretta SM and Patnaik AK. Results of partial mandibulectomy for the treatment of oral tumors in 142 dogs. Veterinary Surgery 1991; 20: Theon AP, Rodriguez C and Madewell BR. Analysis of prognostic factors and patterns of failure in dogs with malignant oral tumors treated with megavoltage irradiation. Journal of the American Veterinary Medical Association 1997; 210: Brewer W and Turrel J. Radiotherapy and hyperthermia in the treatment of fibrosarcomas in the dog. Journal of the American Veterinary Medical Association 1982; 181: Thrall DE. Orthovoltage radiotherapy of oral fibrosarcomas in dogs. Journal of the American Veterinary Medical Association 1981; 179: Withrow SJ. Mandibulectomy in the treatment of oral cancer. Journal of the American Animal Hospital Association 1983; 19: Forrest LJ, Chun R, Adams WM, Cooley AJ and Vail DM. Postoperative radiotherapy for canine soft tissue sarcoma. Journal of Veterinary Internal Medicine 2000; 14: Owen L. TNM Classification of Tumors in Domestic Animals,1 st edn., Geneva, World Health Organization, Kuntz CA, Dernell WS, Powers BE, Devitt C, Straw RC and Withrow SJ. Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases ( ). Journal of the American Veterinary Medical Association 1997; 211: Ciekot PA, Powers BE, Withrow SJ, Straw RC, Ogilvie GK and LaRue SM. Histologically

12 Canine oral fibrosarcoma 43 low-grade, yet biologically high-grade, fibrosarcomas of the mandible and maxilla in dogs: 25 cases ( ). Journal of the American Veterinary Medical Association 1994; 204: Lascelles BDX, Thomson MJ, Dernell WS, Straw RC, Lafferty M and Withrow SJ. Combined dorsolateral and intraoral approach for the resection of tumors of the maxilla in the dog. Journal of the American Animal Hospital Association 2003; 39: Lascelles BDX, Henderson RA, Seguin B, Liptak JM and Withrow SJ. Bilateral rostral maxillectomy and nasal planectomy for large rostral maxillofacial neoplasms in six dogs and one cat. Journal of the American Animal Hospital Association 2004; 40: Salisbury SK. Maxillectomy and mandibulectomy. In: Textbook of Small Animal Surgery,3 rd edn., DH Slatter, ed., Philadelphia, Saunders, 2003: McKnight JA, Mauldin GN, McEntee MC, Meleo KA and Patnaik AK. Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. Journal of the American Veterinary Medical Association 2000; 217: