Perianal rhabdomyosarcoma in a dog

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Perianal rhabdomyosarcoma in a dog A perianal rhabdomyosarcoma was diagnosed in an 11-year-old neutered male Labrador retriever. Following two incomplete surgical excisions of the tumour, the dog was treated by means of surgery combined with local radiotherapy and systemic chemotherapy using one cycle of vincristine sulphate, doxorubicin and cyclophosphamide (VAC protocol). The dog died 252 days after the first combined therapy. Radiography at this time demonstrated enlargement of the iliac lymph nodes, suggesting metastasis of the tumour. To the authors’ knowledge, this is the first report of treatment of canine perianal rhabdomyosarcoma. H. UENO, T. KADOSAWA, H. ISOMURA*, Y. OKADA , K. OCHIAI , T. UMEMURA, M. OKUMURA AND T. FUJINAGA Journal of Small Animal Practice (2002) 43, 217–220

Laboratories of Veterinary Surgery and Comparative Pathology, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Nishi 9-chome, Kita 18-jo, Kita-ku, Sapporo 060-0818, Japan *Sapporo General Pathology Laboratory, Nishi 18-chome, Minami 12-jo, Chuo-ku, Sapporo 064-0912, Japan JOURNAL OF SMALL ANIMAL PRACTICE

INTRODUCTION Most canine perianal tumours originate from glandular epithelial tissue (Berrocal and others 1989). Canine rhabdomyosarcoma has not been documented previously in the perianal region, but has been reported to occur in the scapular skeletal muscles (White 1966), the myocardium (Krotje and others 1990, Gonin and others 1996, Perez and others 1998), the urinary bladder (Stamps and Harris 1968, Halliwell and Ackerman 1974, Pletcher and Dalton 1981, van Vechten and others 1990, Senior and others 1993, Stone and others 1996), the tongue (Lascelles and others 1998) and the larynx (Block and others 1995). There is limited published information regarding treatment of the condition (Senior and others 1993, Block and others 1995, Lascelles and others 1998). In humans, the perianal region is a recognised, but rare, site for rhabdomyosarcoma (Mihara and others 1983), which is usually treated by means of surgery and adjunctive chemotherapy, together with radiotherapy in many cases (Maurer 1981). The following report documents a case of canine rhabdomyosarcoma originating from perianal skeletal muscle. The neoplasm was treated by means of surgery combined with radiotherapy and chemotherapy.

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CASE HISTORY An 11-year-old neutered male Labrador retriever was referred to the Veterinary Teaching Hospital, Hokkaido University, for postoperative radiotherapy of a perianal tumour following two incomplete surgical excisions. Eighty days before referral to the authors’ hospital, the dog had been presented to the referring veterinarian for the investigation of a mass in the left perianal region (2 × 3 cm). The mass was removed surgically, but not evaluated histopathologically. Sixty-five days after the first excision, the second resection was performed because the tumour had recurred at the same site (3 × 3 cm). The excised tissue was evaluated by histopathological examination and a diagnosis of rhabdomyosarcoma was made. On presentation at the authors’ hospital, the dog appeared in good physical condition. Body temperature, pulse and respiration were normal. At the surgical site, a solid ulcerated lesion was present. A complete blood cell count and blood biochemical analysis showed no abnormalities. Radiographs of the chest and the abdomen were taken and no abnormalities were detected. Ultrasonographic examination of the iliac lymph nodes revealed these to be normal in size and echogenicity. Radiotherapy at the perianal site was performed under sedation using 0·03 mg/kg medetomidine hydrochloride (Domitor; Meiji Seika Kaisha, Tokyo, Japan) intramuscularly (IM) and 0·15 mg/kg midazolam (Dormicum; Yamanouchi Pharmaceutical Co, Tokyo) IM. Orthovoltage radiation (half value layer: 0·9 mmCu) was delivered in 4 Gy fractions on a Monday-Wednesday-Friday basis. The radiation was administered over an 8 × 6 cm field centred on the surgical site. After six fractions of radiation, residual tumour tissue was visible due to the reduction of oedema in the irradiated area. On day 21 after referral, the neoplastic tissue was resected widely. Anaesthesia was induced with 15 mg/kg sodium thiopental 217

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FIG 1. Excision of the tumorous tissue. Surgical margins contained one half circle of the external anal sphincter and the adjacent caudal rectal wall

FIG 2. Histology of the perianal subcutaneous mass. The neoplasm is composed of a diffuse proliferation of small undifferentiated cells, rhabdomyoblasts and multinucleated cells, with round, large nuclei in chains. These large nuclei are hyperchromatic with one distinct nucleolus. Haematoxylin and eosin 310, bar=50 µm. Inset: A multinucleated giant cell with intracytoplasmic cross-striations (arrow-head). Phosphotungstic acid haematoxylin stain 610, bar=10 µm

(Ravonal; Tanabe Pharmaceutical Co, Osaka, Japan) intravenously (IV) and maintained with isoflurane (Forane; DaiNippon Pharmaceutical Co, Osaka, Japan) in oxygen via a 10 mm, cuffed endotracheal tube, following premedication with 0·03 mg/kg atropine sulphate IM and 0·05 mg/kg flunitrazepam (Silece; Eisai Co, Tokyo, Japan) IV. The tumorous tissue involved the external anal sphincter and the surrounding skin. A surgical margin of 2 cm was selected, and resulted in the resection of a left half circle of external anal sphincter and adjacent caudal rectal wall (Fig 1). A two-layer suture closure was performed using 2-0 polyglactin 910 (Coated Vicryl; Ethicon). The first layer apposed the rectal muscularis to the subcutaneous tissues of the skin edge. The second layer apposed the rectal submucosa and mucosa to the skin. Postoperatively, 20 mg/kg cefazolin sodium (Cefamezin; Fujisawa Pharmaceutical Co, Tokyo, Japan) was administered subcutaneously (SC) twice daily for 10 days. Histopathological evaluation of the excised specimen revealed invasion of tumour cells into the superficial dermis down to the subcutis, but the surgical margins did not contain tumour cells. The tumour tissue was predominantly composed of a diffuse proliferation of small, round to oval-shaped cells with small, round hyperchromatic nuclei and poorly eosinophilic cytoplasm. Occasionally, there were multinucleated large cells with chained bizarre nuclei, and fibrillar crossstriations in the cytoplasm (Fig 2). Phosphotungstic acid haematoxylin staining was also performed and striations were found in the large neoplastic cells (Fig 2, inset). Immunohistochemical staining demonstrated that the large neoplastic cells were positive for vimentin, desmin and 218

myoglobin. The small neoplastic cells stained positively for vimentin, but negatively for myoglobin and desmin. The nodule was diagnosed as rhabdomyosarcoma, embryonal type. Twenty-four days after the operation, radiotherapy was restarted, following the same protocol (to a total radiation dose of 44 Gy), while awaiting histopathological confirmation of clear surgical margins. VAC chemotherapy was planned as follows: 30 mg/m2 doxorubicin IV once every 21 days, 150 mg/m2 cyclophosphamide orally once every 21 days, starting on the same day as the first dose of doxorubicin, and 0·75 mg/m2 vincristine sulphate IV, on day 7 and day 14 after the first dose of doxorubicin. Haematological parameters were normal before the chemotherapy was initiated. However, toxic effects of chemotherapy, such as neutropenia (0·13  1010/ litre; reference range 0·6 to 1·7  1010/litre), thrombocytopenia (0·5  1011/litre; reference range 1·6 to 4·3  1011/litre), anorexia, diarrhoea and fatigue occurred one week after the first cycle of chemotherapy, so this treatment was discontinued. The dog was given 0·005 mg/kg recombinant human granulocyte colony-stimulating factor SC

and 20 mg/kg cefazolin sodium (Cefamezin; Fujisawa Pharmaceutical Co, Osaka, Japan) IV twice daily for the neutropenia, and 0·1 mg/m2 vincristine sulphate IV for the thrombocytopenia to promote platelet budding from the megakaryocytes. Intravenous fluid therapy using 1·2 to 2·4 litres of lactated Ringer’s solution was given IV daily. Within one week, haematological parameters and the general physical condition of the dog had returned to normal. Follow-up examinations were performed on days 62, 71, 143 and 205 after the first referral to the authors’ hospital. No abnormalities were detected on physical, haematological, radiographic (thorax and abdomen) and ultrasonographic examination. On day 252, the dog was examined at a neighbouring veterinary hospital because of depression. There was no evidence of local tumour recurrence. Haematological and serum biochemical analysis did not reveal any abnormalities. Abdominal radiography demonstrated enlargement of the iliac lymph nodes, suggesting metastasis of the tumour (Fig 3). No abnormalities were detected on thoracic radiographs. The dog suddenly showed Cheyne-Stokes respiration and died at this time. Cardiopulmonary resuscitation and

FIG 3. Lateral radiographic view of the caudal abdomen on day 252 after the first referral, showing enlarged lumbar lymph nodes (arrow-heads) JOURNAL OF SMALL ANIMAL PRACTICE

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necropsy were not performed, in accordance with the owners’ wishes. The cause of death was unknown.

DISCUSSION Rhabdomyosarcoma arising from the sphincter ani is very rare in all domestic animals. In a previous study, 139 canine perineal tumours were histologically evaluated, and the vast majority (134 tumours; 96·4 per cent) appeared to originate from the perianal glands, the characteristic glandular structures of this region. Only five tumours (3·6 per cent) appeared to originate from other perianal structures comprising a leiomyoma, leiomyosarcoma, basalioma, squamous cell carcinoma and an unclassified tumour (Berrocal and others 1989). Canine perianal rhabdomyosarcoma has not been reported previously. Human cases of perianal rhabdomyosarcoma have been infrequently reported (Sharp and Helwig 1959, McGregor and Jewett 1965, Mihara and others 1983), and some were misinterpreted on initial presentation as a papilloma (Sharp and Helwig 1959), a fibroma (McGregor and Jewett 1965) and a perianal abscess (Mihara and others 1983). In the present case, the referring veterinarian initially considered the tumour to be a lipoma or a perianal glandular tumour, common in older male dogs, and did not submit the tissue for histopathological evaluation. On recurrence, the excised mass was examined histopathologically and diagnosed as rhabdomyosarcoma... With reference to human perianal rhabdomyosarcoma, the Intergroup Rhabdomyosarcoma Study (IRS) has emphasised the importance of clinical staging, both for proposed treatment and as a prognostic indicator (Maurer 1981). This IRS system clinically classifies tumour cases as follows. The type I group has localised disease that is completely resected. The type II group has resection of all visible tumour but there is microscopical residual disease or regional spread, with lymph node involvement. The type III JOURNAL OF SMALL ANIMAL PRACTICE

group has incomplete tumour resection and gross evidence of residual disease following surgery, and the type IV group has distant metastases evident at the time of diagnosis. The paper includes data on 12 patients with perianal-perineal rhabdomyosarcoma in the type II to IV groups. Srouji and others (1976) summarised four childhood cases in the type I group (IRS). They advocate local excision followed by both radiation and chemotherapy, although only two of their cases received this treatment. Long-term survival was noted in two cases out of four. They also presented limited data on 11 patients with perianalperineal rhabdomyosarcoma in clinical groups II to IV. Only three of these cases were given a good prognosis, and seven of the remaining eight died. Median survival was only 82 weeks from the beginning of treatment, which consisted of incisional biopsy, irradiation and chemotherapy (Maurer 1981). Following the human IRS system, the present case can be categorised as group III at the time of the referral, suggesting that the prognosis would be relatively poor even with aggressive anti-tumour therapy, including surgery, radiotherapy and chemotherapy. For rhabdomyosarcomas at various sites in the IRS study, progressively poorer survival time was associated with increasing clinical stage number. The present authors performed an aggressive resection of the tumour lesion, including approximately one half circle of the external sphincter and adjacent rectal wall. In a previous report, wide excision of tumour with sufficient margins was considered to contribute to extended tumour-free survival in a case of canine laryngeal rhabdomyosarcoma (Block and others 1995). In the present case, potential risk of postoperative complications, such as dysfunction of the anal sphincter, may have made the referring veterinarian reluctant to perform an aggressive resection of the mass with a wide margin at the first and second surgery. This delay in effective tumour resection may have allowed distant micrometastasis to the lymph nodes to occur, even though the third aggressive surgery removed the local

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perianal tumour completely. The present authors’ extensive resection did not compromise anal function. For cases of perianal rhabdomyosarcoma, the authors would therefore recommend radical, wide excision at the first attempt in order to achieve clear surgical margins, although the risk of faecal incontinence should be appreciated. The present case was treated using pre- and postoperative radiotherapy. The preoperative radiotherapy was useful to shrink and delineate residual tumour before surgery, thus aiding complete resection. The postoperative radiotherapy was performed until histopathology showed that the margin of surgical excision was complete..... Postoperative systemic chemotherapy using a VAC protocol was selected in the present case. There are few reports discussing chemotherapy for canine rhabdomyosarcoma. Adjuvant chemotherapy using doxorubicin and cyclophosphamide was given to one dog with a urinary bladder rhabdomyosarcoma after an incomplete surgical excision, and there was no evidence of tumour recurrence 21 months after surgery (Senior and others 1993). However, other cases treated with adjuvant chemotherapy had a much poorer outcome (van Vechten and others 1990, Lascelles and others 1998). The present case showed enlargement of the iliac lymph nodes before its death, suggesting metastasis of the primary tumour. The size of these iliac nodes was unchanged for six months following a single VAC therapy. If the lymphadenopathy was a result of metastasis, it is possible that the chemotherapy may have delayed tumour growth at this site. However, the exact cause of the enlarged lymph nodes was not established due to the sudden death of the patient, so it is difficult to comment on the role of this protocol in controlling metastatic disease in this case. In addition, this dog only received a single cycle owing to toxic effects. Conclusions The efficacy of the VAC protocol for canine rhabdomyosarcoma should be assessed in a large number of dogs. 219

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Concurrent prophylactic antibiotics may be advisable due to the severe myelosuppressive effects of such drugs. Acknowledgements The authors would like to thank Dr Yoshinori Suwa of The Hokkaido Guide Dogs for The Blind Association, for his technical assistance in nursing this old guide dog.a References BERROCAL, A., VOS, J. H., VAN DEN INGH, T. S., MOLENBEEK, R. F. & VAN SLUIJS, F. J. (1989) Canine perineal tumours. Zentralblatt für Veterinarmedizin – Reihe A 36, 739-749 BLOCK, G., CLARKE, K., SALISBURY, S. K. & DENICOLA, D. B. (1995) Total laryngectomy and permanent tracheostomy for treatment of laryngeal rhabdomyosarcoma in a dog. Journal of the American Animal Hospital Association 31, 510-513 GONIN, J. D., PAULSEN, D. B. & TABOADA, J. (1996) Pericardial effusion in a dog with rhabdomyosarcoma in the right ventricular wall. Journal of Small

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domyosarcoma in the urinary bladder of a dog. Veterinary Pathology 18, 695-697 SENIOR, D. F., LAWRENCE, D. T., GUNSON, C., FOX, L. E., THOMPSON, J. P. & BUERGELT, C. D. (1993) Successful treatment of botryoid rhabdomyosarcoma in the bladder of a dog. Journal of the American Animal Hospital Association 29, 386-390 SHARP, W. C. & HELWIG, E. B. (1959) Sarcoma botryoides (embryonal rhabdomyosarcoma) of the anus. American Journal of Diseases of Children 97, 845-848 SROUJI, M. N., DONALDSON, M. H., CHATTEN, J. & KOBLENZER, C. S. (1976) Perianal rhabdomyosarcoma in childhood. Cancer 38, 1008-1012 STAMPS, P. & HARRIS, D. L. (1968) Botryoid rhabdomyosarcoma of the urinary bladder of a dog. Journal of the American Veterinary Medical Association 153, 1064-1068 STONE, E. A., GEORGE, T. F., GILSON, S. D. & PAGE, R. L. (1996) Partial cystectomy for urinary bladder neoplasia: surgical technique and outcome in 11 dogs. Journal of Small Animal Practice 37, 480-485 VAN VECHTEN, M., GOLDSCHMIDT, M. & WORTMAN, J. (1990) Embryonal rhabdomyosarcoma of the urinary bladder in dogs. Compendium on Continuing Education for the Practicing Veterinarian 12, 783-793 WHITE, A. E. (1966) Skeletal muscle tumor (rhabdomyosarcoma) in a puppy. Modern Veterinary Practice 47, 74

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