Adenocarcinoma (ACA) is the most common non-lymphoid. Article

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1 Article Surgical versus non-surgical treatment of feline small intestinal adenocarcinoma and the influence of metastasis on long-term survival in 18 cats ( ) Michael L. Green, Julie D. Smith, Philip H. Kass Abstract This study retrospectively evaluated long-term outcomes of 18 cats diagnosed with small intestinal adenocarcinoma, based on surgical versus non-surgical treatment and the presence or absence of metastasis at the time of surgery. Ten cats had surgery and histopathologic confirmation of adenocarcinoma and 8 cats did not have surgery but had cytologic diagnosis of adenocarcinoma. Median survival of cats with adenocarcinoma that underwent surgical excision was 365 days and 22 days for those with suspected adenocarcinoma that did not undergo surgery (P = 0.019). Median survival of cats was 843 days for those without evidence of metastatic disease at the time of surgery and 358 days for those that had (P = 0.25). In conclusion, surgical excision is beneficial in the treatment of small intestinal adenocarcinoma in the cat, including those patients with metastasis, and may result in a significantly longer survival time compared with patients which do not have their mass surgically excised. Résumé Comparaison du traitement chirurgical et du traitement non chirurgical d un adénocarcinome du petit intestin félin et l influence de la métastase sur la survie à long terme chez 18 chats ( ). Cette étude a permis une évaluation rétrospective de l évolution à long terme de 18 chats diagnostiqués avec un adénocarcinome du petit intestin, en se fondant sur un traitement chirurgical par opposition à un traitement non chirurgical et sur la présence ou l absence de métastase au moment de la chirurgie. Dix chats avaient subi une chirurgie et une confirmation histopathologique d adénocarcinome et 8 chats n avaient pas subi de chirurgie mais avaient obtenu un diagnostic cytologique de l adénocarcinome. La survie médiane des chats avec un adénocarcinome qui avaient subi l excision chirurgicale était de 365 jours et de 22 jours pour ceux avec un adénocarcinome suspecté qui n avaient pas subi de chirurgie (P = 0,019). La survie médiane des chats était de 843 jours pour ceux sans signe de maladie métastasique au moment de la chirurgie et de 358 jours pour ceux qui en avaient (P = 0,25). En conclusion, l excision chirurgicale est bénéfique pour le traitement de l adénocarcinome du petit intestin chez le chat, incluant les patients avec des métastases et peut se traduire par une durée de survie significativement plus longue comparativement aux patients qui n avaient pas eu la masse excisée par chirurgie. (Traduit par Isabelle Vallières) Can Vet J 2011;52: Introduction Adenocarcinoma (ACA) is the most common non-lymphoid intestinal tumor in cats, with surgical resection being the treatment of choice (1). Birchard et al (2) reported an average survival of 3 d without surgical intervention following diagnosis of small intestinal ACA and a 7-day mean survival following surgical excision. A study by Kosovsky et al (3) was more encouraging with a mean survival time of 15 mo for cats that survived longer than 2 wk following intestinal resection and anastomosis. The same study indicated that 71% of cats had gross or histologically confirmed metastasis at the time of surgery indicating how difficult it is to detect this disease early in its course. This is an important consideration intra-operatively, as many practitioners and clients may elect to euthanize rather than proceed with excision of the mass because of the assumption that the cat will do poorly following surgery if evidence of metastasis is found. This is not necessarily the case, however, as cats with confirmed carcinomatosis have survived 4.5 mo without surgery and 28 mo following surgery (3). The aim of this study was to evaluate a population of cats seen over an 8-year period to determine the long-term outcomes of those cats diagnosed as having small intestinal ACA based on surgical versus non-surgical treatment and the presence or absence of metastasis at the time of surgery. The authors tested the hypothesis that surgical intervention would provide a significantly greater survival time in cats with small intestinal ACA, even in the presence of metastasis. Veterinary Surgical Associates, 1410 Monument Blvd., Concord, California 94520, USA (Green, Smith); and the Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California 95616, USA (Kass). Address all correspondence to Dr. Michael L. Green; mgreen@vsasurgery.com Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere. CVJ / VOL 52 / OCTOBER

2 Table 1. Signalment and duration of clinical signs prior to presentation for each treatment group Median duration of Treatment group Median age (range) Sex Breed clinical signs (range) Cats treated 13.5 y 6 neutered males 6 DSH 30 d surgically (n = 10) (10 to 17 y) 4 spayed females 2 Maine coon (5 to 180 d) a 1 Siamese 1 DMH Cats not treated 15 y 5 neutered males 4 DLH 30 d surgically (n = 8) (11 to 17 y) 3 spayed females 3 DSH (7 to 42 d) b 1 DMH DSH domestic short hair; DMH domestic medium hair; DLH domestic long hair. a As reported in 8 of 10 cats. b As reported in 3 of 8 cats. Materials and methods The medical record databases of Veterinary Surgical Associates (VSA) and Veterinary Medical Specialists (VMS) were searched for feline small intestinal masses diagnosed as ACA over an 8-year period from January, 2000 to December, A total of 22 cats were identified as having small intestinal ACA based upon either histopathology or cytology. In order to be included in this study cats diagnosed with small intestinal ACA must have been treated with resection and anastomosis alone or received no treatment. Three of the 22 cats received post-operative chemotherapy and 1 cat had a mass that was deemed nonresectable due to invasion of the mesenteric root. These 4 cats were excluded from the study. Of the 18 remaining cats 10 had their small intestinal mass excised, and 8 received no treatment for ACA following cytologic diagnosis. The medical records of each of the 18 cats were reviewed to determine signalment, presenting complaint, physical examination findings, pertinent laboratory values, imaging findings, surgical findings, the occurrence of surgical complications, histopathology/cytology results (tumor type, location, margin evaluation, and the presence of metastatic disease), as well as long-term outcome. Those cats that underwent surgical resection of their masses had histopathologic confirmation of their tumor types, whereas the suspected diagnoses of those cats that did not undergo surgery were based upon cytologic evaluation from ultrasound guided fine-needle aspirates of the masses. Several of the cats did not return to VSA or VMS following diagnosis and treatment. A questionnaire was generated and faxed or mailed (or both) to the referring veterinarians of those cases that were lost to our follow-up in order to obtain pertinent information. In the instances that the referring veterinarian was unsure of the ultimate outcome of a case, the owners were called directly and the same questions were asked. Statistical analysis Numeric data were expressed as median and range. Median survival was determined using the Kaplan-Meier method of survival function estimation. Significance was determined via log-rank test and set at values of P # 0.05 for all statistical analyses. Statistical analysis was performed using S-PLUS for Windows Enterprise Developer (TIBCO Software, Palo Alto, California, USA). Results Eighteen cats (Table 1) met the criteria for inclusion in this study. The median age of all cats was 14 y (range: 10 to 17 y). Presenting complaints included vomiting (11), anorexia (11), weight loss (8), lethargy (6), diarrhea (3), decreased defecation (2), hiding behavior (1), and obstruction (1). Eleven of the 18 cats that had a reported duration of clinical signs prior to presentation had signs a median of 30 d (range: 5 to 180 d). Abnormalities found on physical examination included a palpable abdominal mass in 10 cats, and a palpable fluid wave and tender abdomen in 2 other cats. Seven cats were emaciated on physical examination and 4 were dehydrated. All 18 cats had a complete blood (cell) count (CBC) and chemistry performed. Eight cats had a stress leukogram; 5 were anemic; 4 had normal blood work; 4 were hypoalbunemic; 3 had an increased ALP; 3 had electrolyte abnormalities; 3 were hyperglycemic; 2 were azotemic; 2 had thrombocytosis; 1 had a decreased BUN; 1 had thrombocytopenia; and 1 was hypoglycemic. Abdominal radiographs were taken of 12 cats which revealed gas distended bowel in 5, an abdominal mass in 4, loss of serosal detail in 2 and no visible abnormalities in 1. Of 5 cats that had thoracic radiographs taken, 2 cats had focal pulmonary masses and 3 thoracic studies were found to be within normal limits. Abdominal ultrasound was performed in 16 of the 18 cats and a small intestinal mass was seen in all 16 cats, as well as mesenteric lymphadenopathy in 10, abdominal effusion in 4, hepatomegaly in 1, splenomegaly in 1, and adrenomegaly in 1. The 18 cats were divided into 2 groups (Table 1) based on whether or not surgery was pursued to resect their masses. The decision whether or not to pursue surgery was made by the clinician on the case in conjunction with the client after receiving and interpreting pertinent clinical and diagnostic findings. Ten cats underwent surgery for resection of their masses and 8 did not. Information regarding signalment including age, sex and breed, as well as duration of clinical signs for each of the 2 groups is listed in Table 1. Each of the 8 cats that did not have surgery had masses that were confirmed as small intestinal in origin via ultrasound, but exact locations within the small intestine could not be determined. Three of the 8 cats that did not undergo surgery had ultrasonographic findings within the abdomen that were suspicious for metastatic disease at the time the small intestinal mass 1102 CVJ / VOL 52 / OCTOBER 2011

3 Figure 1. Kaplan-Meier survival function depicting the increased survival time (P = 0.019) of cats with ACA that were treated with surgical excision as opposed to those that were not. Figure 2. Kaplan-Meier survival function depicting the survival time (P = 0.25) of cats without gross metastatic disease at the time of their intestinal resection and anastomosis as opposed to those that had. was identified, including 2 with mesenteric lymphadenopathy and 1 with an irregular splenic capsule. Thoracic radiographs identified suspected pulmonary metastasis in the same cat with an irregular splenic capsule. All of the small intestinal masses were aspirated via ultrasound guidance and evaluated cytologically. All 8 cats had fine-needle aspirates that were consistent with small intestinal ACA. Ultrasound guided fine-needle aspirates of both the spleen and lung mass in the same cat were obtained and both found to be consistent with metastatic intestinal ACA. The mesenteric lymph nodes of the other 2 cats were not aspirated. Since surgery was not performed, presumptive metastasis was based upon abdominal ultrasound, thoracic radiographs, and cytologic results of ultrasound guided fine-needle aspiration. None of these cats received chemotherapy or other adjunctive therapy for the treatment of small intestinal ACA. Five of the 8 non-surgical patients were euthanized as a direct result of ACA and 3 died of unknown causes at home. Cats with suspected ACA based upon FNA that did not undergo surgical excision had a median survival of 22 d [95% confidence interval (CI) = 11-non-estimable (NE)/range, 1 to 1260 d]. Surgical exploration of the 10 cats revealed 5 ileocecocolic junction (ICCJ) masses, 4 jejunal masses, and 1 ileal mass. Six cats had mesenteric lymphadenopathy, 3 cats had regionally or diffusely distributed 1 to 4 mm tan nodules in the abdomen, 3 cats had livers with a nutmeg appearance, and 3 cats had clear ascites. All 10 cats underwent resection and anastomosis of their intestinal masses. The only surgical complication encountered occurred in a cat that had previously undergone surgery at the referring veterinarian s clinic and was referred for re-excision due to incomplete resection of ACA near the ICCJ. Upon presentation the cat had a subcutaneous abscess associated with the incision that was cultured and debrided. At the same time a resection and anastomosis of the previous surgical site was performed. The cat responded well to debridement and antibiotic therapy. Seven of the masses excised had margin evaluation. Five were completely excised and 1 was incompletely excised. The remaining mass was the case of the re-excision and no evidence of neoplasia was found in that segment following the second surgery. Three of the pathology reports did not mention whether or not margins were obtained. Six of the surgical patients were euthanized due to clinical signs associated with progressive ACA, 1 was still alive and in good health at the completion of the study, 1 died at home of unknown causes, and 2 were lost to follow-up. Cats with histologically confirmed ACA that had their tumors surgically excised regardless of margins had a median survival of 365 d (95% CI = 210-NE/range: 90 to 1320 d), as opposed to those with suspected ACA based upon FNA that did not undergo surgical excision that had a median survival of 22 d (95% CI = 11-NE/ range, 1 to 1260 d) (Figure 1). Survival times were significantly increased for those cats that had their intestinal ACA surgically excised (P = 0.019). The lone cat that did not have complete margins at the time of surgery survived 60 d, while those that were known to have complete excision had a median survival of 1320 d (95% CI = 358-NE/range: 90 to 1320 d). Five of the 10 cats that underwent surgery had metastatic disease at the time of diagnosis, based on histopathologic confirmation and 1 cat had suspected metastasis to the lungs based on thoracic radiographs. Metastatic locations of the ACA included the mesenteric lymph nodes in 3 cats; omentum in 2; liver in 2; abdominal body wall in 1; mesentery in 1; and lungs in 1. Six of the 10 cats taken to surgery were found to have metastasis at the time of surgery. The median survival time of the 4 cats without evidence of metastatic disease at the time of surgery was 843 d (95% CI = 180-NE/range: 180 to 1320 d). The median survival time of the 6 cats with metastatic ACA was 358 d (95% confidence interval = 210-NE/range: 60 to 540 d) (Figure 2). The survival times of those cats with evidence of gross metastasis at the time of surgery were not significantly different from those cats without evidence of metastasis (P = 0.25). Discussion The data on clinical findings and diagnostics are similar to those which have been reported previously. The median age CVJ / VOL 52 / OCTOBER

4 of cats with ACA (14 y) in this study tended to be older than in other studies, with mean ages ranging from 8.7 to 11.3 y (2 6). Historically, Siamese have been the most common breed diagnosed with ACA, but in this study, DSH cats were the most common (2 7). As in other studies. males were more likely to have intestinal ACA than were females (1,3 7). Vomiting, anorexia, and weight loss were the 3 most common clinical signs associated with small intestinal ACA in our study population, which is similar to other studies (3 6). The median duration of clinical signs in cats in this study was 30 d, which is less than the reported data with mean durations ranging from 60 to 83 d (3 6). A palpable abdominal mass, emaciation, and dehydration were the most common physical examination findings, as in other studies (2 4). The hematologic abnormalities tended to be non-specific, which is a common finding amongst the cats in other studies with small intestinal ACA (2 4). Twelve of the 18 cats had a radiographic abnormality consisting of a mass effect within the abdomen, gas-distended bowel loops, loss of serosal detail or combinations of these findings. Previously published studies report similar radiographic findings (2 4). Several previous studies report the use of barium and its usefulness in identifying or confirming obstructions and strictures within the gastrointestinal tract; however, only 1 of the cats in this study received barium, which did reveal a stricture in the proximal small intestine (2 4,6). In this study, all 16 of the 18 cats that had an abdominal ultrasound had an identifiable small intestinal mass. An added advantage of the abdominal ultrasound was the ability to evaluate for potential regional metastasis. Three of 5 cats suspected of having metastatic disease were confirmed at the time of surgery and 1 of the 8 non-surgical cases was supported with FNA (8). Eight of the 18 cats had both abdominal radiographs and abdominal ultrasound performed. In every case the abdominal ultrasound was more accurate in determining not only the presence of a mass, but the location within the intestine, along with potential metastatic disease. This finding supporting the superiority of ultrasonography is consistent with a previously published report evaluating the ultrasonographic features of intestinal ACA in cats (8). Thoracic radiographs were available for 5 of the 18 cats and 2 were consistent with metastatic disease. Pulmonary metastasis has not commonly been reported in cats that are initially evaluated for intestinal ACA (2 4,9). Masses most frequently occurred at the ICCJ, followed by the jejunum and ileum. Masses that occur at the ICCJ have historically been considered ileal, and therefore small intestinal in origin (1,3,5). Other studies on cats have reported varying locations of ACA in the small intestine (3 7). It appears that the ileum and jejunum have a slightly greater frequency of ACA development than the duodenum. Discrete masses that occur in the small intestines allow for the suggested resection of 4 to 8 cm of grossly normal intestine orad and aborad to the mass to achieve clean margins (10). The number of cats with ACA with confirmed margins that were either complete or incomplete was limited. The lone cat in the study with incomplete resection had recurrence of anorexia and developed abdominal distension 60 d after surgery and was subsequently euthanized without further diagnostics. Only 1 of 6 cats that had clean margins at the time of surgery was known to have developed an additional intestinal mass after the surgery, confirmed 10 mo later, though it is unclear whether this was near the site of the previous mass or not. The only previous study that compared surgical versus nonsurgical outcomes of cats that were treated for intestinal ACA indicated a poor prognosis for either treatment option, as it had an average survival of 3 d for those cats that did not undergo surgery and a mean survival of 7 d for those that did (2). Cats that had their ACA surgically excised in this study had a median survival of 365 d, as opposed to those that did not undergo surgical excision that had a median survival of 22 d (P = 0.019). The average survival of cats treated surgically ranges from 7 d to 150 d in other clinically based studies (2,5). The lone cat that had incomplete margins at the time of surgery lived 60 d, while those that were known to have complete margins had a median survival of 1320 d. While a meaningful comparison of complete versus incomplete margins is not possible given the limited numbers, it is interesting to note that cats that had their mass completely excised lived longer (range 90 to 1320 d ) than did the cat with incomplete margins. Six of the 10 cats in this study that underwent surgery had metastasis based on histopathologic confirmation and/or radiographic findings at the time of diagnosis. Metastasis to one or more of the following sites was identified; mesenteric lymph nodes, omentum, abdominal body wall, mesentery, liver, and lungs. Regional lymph nodes, peritoneum, liver and lungs have consistently been the most frequent sites of ACA metastasis (1 5). The average survival of cats in this study that were treated surgically for ACA that had no gross evidence of metastasis at the time of surgery was 843 d, as opposed to 358 d for those which did. The only other study that compared survival times for metastatic versus non-metastatic disease found a mean survival of 300 d for cats without evidence of metastasis at the time of surgery and 150 d for those with metastasis (4). Two of the 6 cats without evidence of metastatic disease in this study lived at least 1095 d. This indicates that if intestinal ACA in cats can be resected prior to the development of metastasis, long-term disease-free intervals can be achieved. However, even with evidence of metastasis and/or carcinomatosis, survival times appear to be extended with surgical intervention to resect the obstructive lesion. The lack of significance in the face of substantial survival differences between these 2 states, suggests that there was inadequate study power (due to the limited number of cases). One limitation of this study is the low number of cats enrolled and the small sizes of the groups. The number was limited by the source, the low frequency of the disease and the need for follow-up (2,9). A multi-institutional study recruiting a larger number of cases would address the sample size limitation. A second limitation of this study is that it is retrospective and histologic confirmation of cytologic diagnoses made by FNA of cats that did not undergo surgery was unavailable. However, cytology is a valuable diagnostic tool. A study by Cohen et al (11) evaluating cytology samples that were mostly acquired pre-operatively indicated a sensitivity of 76.4% in diagnosing neoplasia when considering complete and partial agreement with histopathology and a specificity of 82.5% CVJ / VOL 52 / OCTOBER 2011

5 A further important limitation of the study concerns the validity of the hypothesis tests performed. Due to the nonrandomized nature of this retrospective study, results of statistical tests, including decisions about statistical significance, must be interpreted with caution due to the near certainty of uncontrolled confounding by indication for clinical treatment. Such bias will result in spuriously underestimated P-values and confidence intervals that fail to achieve nominal coverage, along with Type I error frequencies that will exceed sometimes substantially the level of significance specified. Nevertheless, this study retains value in depicting the potential for long-term disease-free intervals of those patients given the benefit of surgical intervention even in the face of suspected metastatic disease. In conclusion, our hypothesis that the surgical excision of small intestinal ACA would significantly improve survival times in cats compared with those that did not have surgery was confirmed. And while the increased survival times of those cats without metastatic disease at the time of surgery was not statistically significant, there was empirical evidence that early surgical intervention could be prognostically favorable. CVJ 3. Kosovsky JE, Matthiesen DT, Patnaik AK. Small intestinal adenocarcinoma in cats: 32 cases ( ). J Am Vet Med Assoc 1988;192: Cribb AE. Feline gastrointestinal adenocarcinoma: A review and retrospective study. Can Vet J 1988;29: Turk MAM, Gallina AM, Russell TS. Nonhematopoietic gastrointestinal neoplasia in cats: A retrospective study of 44 cases. Vet Pathol 1981;18: Patnaik AK, Liu S-K, Johnson GF. Feline intestinal adenocarcinoma (A clinicopathologic study of 22 cases). Vet Pathol 1976;13: Patnaik AK, Liu S-K, Hurvitz AI, McClelland AJ. Nonhematopoietic neoplasms in cats. J Natl Can Inst 1975;54: Rivers BJ, Walter PA, Feeney DA, Johnston GR. Ultrasonographic features of intestinal adenocarcinoma in five cats. Vet Radiol Ultrasound 1997;38: Selting KA. Intestinal tumors. In: Withrow SJ, Vail D, eds. Withrow and MacEwen s Small Animal Clinical Oncology. 4th ed. St. Louis, Missouri: Saunders Elsevier, 2007: Thomson M. Alimentary tract and pancreas. In: Kuntz C, ed. Textbook of Small Animal Surgery. 3rd ed. Philadelphia, Pennsylvania: Saunders Elsevier, 2003: Cohen M, Bohling MW, Wright JC, Welles EA, Spano JS. Evaluation of sensitivity and specificity of cytologic examination: 269 cases ( ). J Am Vet Med Assoc 2003;222: References 1. Brodey RS. Alimentary tract neoplasms in the cat: A clinicopathologic survey of 46 cases. Am J Vet Res 1966;27: Birchard SJ, Couto CG, Johnson S. Nonlymphoid intestinal neoplasia in 32 dogs and 14 cats. J Am Anim Hosp Assoc 1986;22: CVJ / VOL 52 / OCTOBER