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Metronomic chemotherapy for myxosarcoma treatment in a kori bustard (Ardeotis kori).

Abstract: A 22-year-old, wild-caught male kori bustard (Ardeotis kori) developed a large, slow-growing subcutaneous mass over the keel. The mass was surgically debulked and histopathologically described as a myxosarcoma. Surgical dehiscence and concurrent local tumor regrowth, with no evidence of metastasis, occurred over the subsequent 3 months, necessitating 2 additional surgical procedures to close the wound. At 19 weeks after the initial procedure, a second debulking surgical procedure was performed, at which time carboplatin-impregnated matrix beads were placed in the lesion. Moderate local tumor regrowth was clinically appreciable 4 weeks after surgery, at which time an oral metronomic chemotherapeutic protocol consisting of daily cyclophosphamide (10 mg/[m.sup.2]) and meloxicam (0.1 mg/kg) was initiated. Four months later, the tumor was no longer palpable. While oral therapy was discontinued during the breeding season, mass regrowth was observed, and the mass was surgically debulked before reinitiating oral chemotherapy. Treatment was extended for over 1 year with no hematologic evaluation or serum biochemical abnormalities, and the bird otherwise remained clinically healthy. To our knowledge, this is the first report of a myxosarcoma in a bustard species and the first report of successful clinical application of metronomic chemotherapy in an avian species.

Key words: myxosarcoma, neoplasia, metronomic chemotherapy, Otididae, avian, kori bustard, Ardeotis kori

Clinical Report

A 22-year-old, wild-caught adult male kori bustard (Ardeotis kori), genetically valuable to the captive breeding population, was presented to the Smithsonian National Zoological Park's veterinary hospital with a 2 X 2-cm ventral keel mass. Initial diagnostic tests consisted of hematologic testing and serum biochemical analysis, wholebody imaging, and cytologic evaluation of the mass. Results of the CBC and coelomic ultrasound were unremarkable. Radiographic evaluation revealed a soft tissue density mass over the keel with no associated bony changes and no evidence of metastasis. Results of the serum biochemical analysis showed increases in activities of aspartate dehydrogenase (AST; 729 U/L; reference mean, 292 [+ or-] 80 U/L) (1) and lactate dehydrogenase (LDH; 2740 U/L; reference mean, 837 [+ or -] 158 U/L). (1) Results of cytologic evaluation of a fine needle aspirate of the mass were nondiagnostic, revealing suspect blood contamination. During the subsequent 34 months, the mass would wax and wane in size, measuring as large as 10 X 5 X 6 cm and regressing to as small as 3 X 4 X 2 cm. Given the lack of concurrent systemic clinical signs, inconsistent growth pattern, and concerns that surgical closure after excision of the mass would be at high risk for dehiscence based on the location, the mass was initially monitored for gross pathologic changes. Repeat biochemical panel evaluation 1 month after initial presentation showed resolution of the increase in AST activity and a persistent mild increase in LDH activity over the following months.

At 34 months after initial presentation, the mass measured 9 X 6.5 cm and had ulcerated, with partial necrosis and myiasis, necessitating surgical excision (Fig 1). At surgery, the mass was adhered to the underlying soft tissue and keel by fibrous attachments. As such, surgical margins could not be obtained because of the location and extent of the mass. All necrotic tissue was excised, and advancement flaps were created by extending parallel incisions laterally from the cranial and caudal poles of the primary incision site to minimize tension along the incision line during surgical closure. Results of perioperative hematologic and biochemical analysis were largely unremarkable, revealing only an increase in LDH activity (2081 U/L). (1) Intraoperative treatment consisted of single doses of ceftiofur crystalline free acid (12 mg/kg IM, Excede 200 mg/mL injection, Pfizer Inc, New York, NY, USA), meloxicam (0.13 mg/kg SC), vitamin E (10 IU/kg IM), cefazolin (25 mg/kg IV), and topical 0.1% pyrethrin spray. After surgery, amoxicillin trihydrate with clavulanate potassium (25 mg/kg PO q12h for 42 days, Clavamox, Pfizer Animal Health, New York, NY, USA) and meloxicam (0.13 mg/kg PO q24h for 5 days) were administered. Two additional surgical procedures were performed on days 9 and 30 because of incisional dehiscence and mass regrowth over the same region. During these procedures, a large seroma that had formed over the surgical site after each procedure was drained. Throughout this period, medical management consisted of ceftiofur crystalline free acid (10 mg/ kg IM once), cephalexin (33 mg/kg PO ql2h for 14 days), and ciprofloxacin (17 mg/kg PO ql2h for 14 days) to treat suspected infection and meloxicam (0.13 mg/kg PO q24h for 5 days) as indicated to control inflammation.

On histopathologic evaluation, the mass was characterized as a myxosarcoma (Fig 2). The core of the tumor comprised a homogeneous population of spindle cells with lightly basophilic cytoplasm surrounded by an abundant intracellular matrix that stained blue with Alcian blue special staining. Tumor cells were often accompanied by thin collagen fibers. In some areas, these cells were arranged in relatively dense interwoven bundles. The spindle cells contained moderate anisokaryosis with rounded to fusiform, often vesicular, nuclei; poorly defined cytoplasmic borders; and a low mitotic rate. Neoplastic cells extensively replaced the subcutis, and complete surgical margins were not obtained.

Nineteen weeks after the initial surgery, 600 mL of a cytologically sterile transudate was aspirated from the previous surgical area, and a 9 cm diameter firm, lobulated mass was palpated over the caudal aspect of the keel. At that time, a fourth surgery was performed to debulk the mass and drain the seroma. Additionally, 12 carboplatin-impregnated, calcium-based matrix beads (Matrix III beads, Royer Biomedical Inc, Frederick, MD, USA; each bead containing 4.6 mg of carboplatin; Wedgewood Pharmacy, Swedesboro, NJ, USA) were placed intralesionally, radiating out from the incision, with most beads focused at the cranial and caudal poles of the incision given the moderate tension necessary to close the incision along its central plane. At the time of surgery, a one-time dose of cefazolin (50 mg/kg IV), vitamin E (2 IU/ kg IM), lactacted Ringer's solution (10 mL/kg per hour IV), and meloxicam (0.3 mg/kg SC) were administered. Perioperative diagnostic tests revealed a mild leukopenia (7.20 x [10.sup.3] cells/[micro]L, reference mean, 15.87 [+ or -] 5.50 x [10.sup.3] cells/[micro]L) characterized by a heteropenia (1.70 x [10.sup.3] cells/ [micro]L, reference mean, 9.18 [+ or -] 4.29 x [10.sup.3] cells/[micro]L) (1) and lymphopenia (1.4 x [10.sup.3] cells/[micro]L, reference mean, 5.78 [+ or -] 3.16 x [10.sup.3] cells/[micro]L) (1), suggestive of chronic inflammation or disease. Additional findings were an increase in LDH activity (1530 U/L), (1) which was not considered clinically significant given the normal appearance of the liver on repeated radiographic imaging (most recently performed 1 month prior) and lack of concurrent derangements of other liver or muscle parameters.

One month later (23 weeks after the initial surgery), a wide (approximately 2.2 cm) scab was present along the length of the incision. A small seroma had reformed over the ventral aspect of the incision, and an approximately 5 cm diameter firm mass was again palpable. Results of hematologic testing and serum biochemical analysis showed a mild leukocytosis (21.9 x [10.sup.3] cells/[micro]L) (1) suggestive of inflammation or excitement, but results were otherwise unremarkable. At that time, metronomic chemotherapy with meloxicam (0.1 mg/kg PO q24h) and cyclophosphamide (10 mg/[m.sup.2] PO q24h, Diamondback Drugs, Scottsdale, AZ, USA) was initiated, in addition to a 30-day course of enrofloxacin (10 mg/kg PO q24h, Baytril, BayerHealth Care LLC, Shawnee Mission, KS, USA). Because no conversion scales are validated for this species, body surface area was estimated at 0.58 [m.sup.2] using a body weight of 14 kg and conversion factors used in domestic animals. (2-4) Weight was monitored weekly, and behavior and appetite were assessed daily, with no adverse effects of the oral chemotherapy observed. Seven weeks after initiating chemotherapy (30 weeks after the initial surgery), the bird was manually restrained for a brief physical examination and evaluation of hematologic and biochemical parameters. The ventral scab noted at the previous examination remained, but the seroma had partially resolved, and no mass was appreciable on palpation. The only abnormality on hematologic and serum biochemical testing was a mild increase in LDH activity (1395 U/L). (1) Meloxicam and cyclophosphamide were continued at the same dosages.

The next spring (17 weeks after beginning oral metronomic chemotherapy, 40 weeks after the initial surgery), the bird failed to gain weight or exhibit breeding behavior as would have been seasonally appropriate and consistent with the historic pattern of this proven breeding male. (5,6) There was no palpable recurrence of the mass, and the bird was otherwise eating well and behaving normally. Treatment with meloxicam and cyclophosphamide were discontinued because of concern that the chemotherapy could be suppressing reproductive drive. Lour weeks later, the scab previously identified along the incision site began to tear from the adjacent skin edges, revealing the underlying tissue. Oral prophylactic antibiotic therapy with cephalexin (33 mg/kg PO ql2h for 28 days) and enrofloxacin, and topical application of pyrethrin fly-repellent ointment around the periphery of the wound was started. After an additional 4 weeks (55 weeks after the initial surgery), an 8 X 5-cm firm mass was again appreciable at the cranial aspect of the keel lesion. Results of hematologic testing and serum biochemical analysis performed at that time were unremarkable. The scab was removed, and the mass was debulked during a fifth and final surgical procedure. Treatment was then restarted with continuous meloxicam and cyclophosphamide therapy at the previously prescribed dosages. The incision site healed completely. Lor 16 months after the final surgery, no recurrence of the mass was appreciable, and the bird clinically appeared normal with normal hematologic and serum biochemical values. Treatment with metronomic chemotherapy (meloxicam and cyclophosphamide) has been continued indefinitely, with routine monitoring of weight, hematologic and biochemical values, and breeding ability and assessment of the keel to monitor for mass recurrence.

Discussion

Myxosarcoma is an uncommon tumor of mesenchymal origin that may be pseudoencapsulated with a soft to firm texture. (7) Reports to date in birds are primarily limited to chickens and ducks. (7-10) As with many other soft tissue sarcomas, these tumors have low metastatic potential but are locally aggressive, with a high rate of local recurrence after surgical excision. On histopathologic evaluation, myxosarcomas are often characterized by poorly defined margins, which infiltrate through and along fascial planes. Cytoplasmic borders are difficult to identify, and special staining with Alcian blue dye will highlight the mucopolysaccharides abundant in this tumor type. In other species, these tumors are typically associated with the subcutaneous space of the trunk or limbs. (7) They have been associated with implants (including transponders), local trauma, vaccine administration, radiation exposure, foreign bodies, chronic inflammation, parasitic infections (especially Spirocerca lupi in the domestic dog), and retroviral infections, such as retroendothelial virus and avian leukosis virus in chickens. (7-11) In the case we describe, the kori bustard had a transponder in the left pectoral musculature near the site of the primary mass and a chronic callous over the keel, which is not uncommon for captive adults of this species. Whether either of these factors may have contributed to this bird's risk for tumor development is unknown. No attempts were made to remove the transponder surgically in this case, and its location has remained unchanged radiographically throughout the treatment period.

Treatment recommendations for a myxosarcomatous tumor typically begin with aggressive surgical resection to include at least 3 cm of normal tissue around all tumor edges and penetrating at least 1 fascial layer deep. Based on tumor grade and completeness of surgical margins obtained, subsequent local radiation, chemotherapy, or both may also be indicated. (7) In this case, the histologic grade of the tumor was low, but complete surgical resection was limited because of the location and size of the mass. As such, and given the local tumor recurrence postoperatively, additional antineoplastic therapy was indicated.

There are limited reports of systemic chemotherapeutic use in avian species. Many of these reports have shown anecdotal promise, although not without associated dose-dependent systemic side effects and species variation. (12-21) Few reports of neoplasia in Otididae exist, and none discuss treatment protocols. (22-24) Radiation therapy, repeated intratumoral chemotherapy, and intravenous chemotherapeutic protocols have been documented in other avian species for the treatment of soft tissue sarcoma tumors; however, these strategies were not considered feasible in this case because of the frequent handling required and subsequent high risk of trauma or myopathy for this species. (12-15) Furthermore, reports of systemic chemotherapeutic use in avian species are limited. (12,15-21) Given the lack of established avian protocols that could be utilized within the management constraints of this case, a metronomic chemotherapeutic protocol was developed based on small-animal oncologic principles.

Metronomic chemotherapy is the use of continuous, low-dose pharmaceuticals without prolonged drug-free intervals. (7,25-31) The low drug doses decrease the risk of toxicity and adverse effects (eg, vomiting, inappetence, and hematologic derangements) commonly associated with chemother apeutic protocols. (7,27,30,31) In mammals, metronomic chemotherapeutic protocols have both direct and indirect effects on the host immune system and tumor cells that are not yet fully understood. This treatment modality is believed to down-regulate tumor angiogenesis by targeting vascular endothelial cells vital to the growth and development of tumor cells. (7,27-30) Additionally, metronomic chemotherapy is believed to play a role in immune modulation via the up-regulation of the body's natural anticancer response and initiation of tumor quiescence through suppression of regulatory T-cell function." Regulatory T cells, such as the mammalian CD4+ and CD25+ cells, are increased in many neoplastic conditions and are linked to increased tumor progression and spread, as well as to decreased response to a tumor by the host's immune system. (25,30) In avian species, CD4+ and CD4+CD25F cells are thought to be the avian counterpart to mammalian regulatory T cells. (32,33) These cells play a central role in the avian immune response, and recruitment of these cells has been documented in chickens with lymphoma. (34,35)

Although it is unclear whether the same principles for mammalian metronomic chemotherapy would directly apply to avian species, similar pathways for oncogenesis have been described, suggesting it is possible. (11) Therefore, these principles were applied when developing the chemotherapeutic protocol in this case. Cyclophosphamide is an alkylating chemotherapeutic agent that prevents cell meiosis by causing errors in the cell's DNA. (7) At low doses in mammals, this drug selectively targets and inhibits the regulatory T cells necessary for tumor growth over other T cells in the host's immune system. (26,30) Meloxicam was chosen in this protocol for its activity as a cyclooxygenase-2 (COX-2) inhibitor. (4,7) The COX-2 prostaglandins are involved in carcinogenesis, inflammation, immune response suppression, inhibition of apoptosis, tumor angiogenesis, and metastasis. (7,11,26,36) The inhibition of the COX-2 enzyme is believed to negatively affect the progression and development of tumor cells by selectively inhibiting those prostaglandins. (7,11) Similar metronomic protocols have been used successfully in the treatment of various tumor types in multiple mammalian species. (25,26,29,31,36)

During the course of treatment, the chemotherapy was suspected to have suppressed the bird's testosterone levels, thereby preventing it from developing the weight gain and vocalization behaviors typical of the breeding season. (5,6) Cyclophosphamide has been shown to have a negative effect on testis and epididymal weight, as well as to decrease serum luteinizing hormone and testosterone levels in mice. (37) Furthermore, a reversible decrease in spermatogenesis and sperm motility has been documented in both mice and people undergoing treatment with cyclophosphamide. In these species, a dose-dependent delay in the return of testicular function has been observed after discontinuing cyclophosphamide therapy. (37,38) Based on these findings, any effect on reproduction in this case was likely caused by the cyclophosphamide component of the chemotherapeutic protocol. Within weeks of discontinuing the metronomic chemotherapy, this bird gained weight to within normal ranges of the breeding season, initiated sexual display behavior, and subsequently sired 1 viable chick (although mass recurrence was also noted). Testosterone levels were not measured during this period; thus, any potential effect of chemotherapy on the bird's reproductive capability remains speculative.

Tumor recurrence in this kori bustard was documented after both surgical and intralesional chemotherapeutic interventions, whereas tumor regression occurred after initiating oral therapy with meloxicam and cyclophosphamide. While possible effects on reproductive activity were observed, the bird has tolerated the chronic chemotherapeutic treatment with no significant negative effects. Because no pharmacokinetic data for this species is available to date, all drug dosages used in this case were chosen on the basis of clinician preference and extrapolation from published dosages in other species. To our knowledge, this is the first report of a myxosarcoma in a bustard species and the first report of the successful clinical application of metronomic chemotherapy in any avian species.

Acknowledgments: We thank Curator of Birds, Sara Hallager, as well as the staff and volunteers at the Smithsonian's National Zoo Bird House and Wildlife Health Sciences for the excellent care and monitoring provided to this bustard.

Samantha J. Sander, DVM, Katharine L. Hope, DVM, Conor J. McNeill, DVM, Dipl ACVIM (Oncology), John F. Roberts, DVM, Dipl ACVP, Nancy C. Boedeker, DVM, and Suzan Z. Murray, DVM, Dipl ACZM

From Wildlife Health Sciences, Smithsonian Conservation Biology Institute, PO Box 37012, MRC 5502, Washington, DC 20008, USA (Sander, Hope, Roberts, Boedeker, Murray); and The Hope Advanced Veterinary Center, 140 Park St SE, Vienna, VA 22180, USA (McNeill). Present address (Roberts): Alabama Department of Agriculture and Industries, Thompson Bishop Sparks State Diagnostic Laboratory, 890 Simms Rd, PO Box 2209, Auburn, AL 36831, USA.

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Title Annotation:Clinical Report
Author:Sander, Samantha J.; Hope, Katharine L.; McNeill, Conor J.; Roberts, John F.; Boedeker, Nancy C.; Mu
Publication:Journal of Avian Medicine and Surgery
Article Type:Clinical report
Date:Sep 1, 2015
Words:3949
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