Introduction

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma that originates from myoblasts, which are primitive mesenchymal cells capable of differentiating into striated muscle cells.¹ These tumors have been reported in a variety of species including humans, dogs, horses, giraffes, swine, mice, and rats.^2–7 Tumors have been noted in the tongue, oral cavity, skull, heart, genitourinary system, and other areas of skeletal muscle.^2,8 In human medicine, this is the most common soft tissue sarcoma seen in children, adolescents, and young adults, with approximately 35% arising in the head or neck.⁹ Similarly, these appear to be more common in young dogs.^2,8,10–14 A previous literature search reported that 63% of canine rhabdomyosarcomas occur in dogs who are 2 yr or younger.⁸

Histologic subclasses of RMS include embryonal, botryoid (or botryoid embryonal), alveolar, and pleomorphic.^2,8–10 The pleomorphic type occurs primarily in adults.^7–9 The majority of the alveolar and embryonal types occur in young individuals and are thus termed juvenile rhabdomyosarcoma.^8–10 The alveolar type in human medicine tends to be more locally aggressive, has a higher metastatic rate, and has a poorer overall prognosis than the embryonal form.^2,8,9 Metastasis develops in approximately 20% of human oral RMS with major sites including the lung, lymph nodes, and bone marrow; other reported sites of metastasis include the heart, brain, meninges, pancreas, liver, and kidney. Metastatic sites reported in canine RMS include the regional lymph nodes, lungs, and less commonly, other muscles, the spleen, heart, pancreas, adrenal glands, kidney, brain, skin, subcutis, omentum, mesentery, and peritoneal surface.⁸

Treatment of choice in humans with RMS involves a multimodal approach, including surgical removal followed by multiagent chemotherapy, with or without radiation therapy.⁹ The metastatic rate and prognosis in dogs remain unknown because of the low incidence and few reports regarding treatment beyond surgical resection. Treatment has been reported in only a few cases and has consisted of surgical resection, with or without radiation therapy or chemotherapy, with varying successes.^15–18 To the authors' knowledge, there are limited reports of treatment beyond surgery in a maxillofacial juvenile embryonic rhabdomyosarcoma in dogs. A recent report of 18 cases of canine orbital rhabdomyosarcoma described a 1 yr old beagle with embryonal orbital rhabdomyosarcoma who was alive 7 mo post diagnosis following treatment with chemotherapy and palliative radiation therapy. However, the chemotherapy and radiation therapy protocols were not described in detail.¹⁹

The following report describes a case of a metastatic maxillofacial juvenile RMS in a 2 yr old golden retriever treated with multiple-agent chemotherapy and palliative radiation therapy.

Case Report

A 2 yr old male castrated golden retriever was presented to the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania (MJR-VHUP) for treatment options regarding a recently diagnosed oral spindle cell tumor involving the left maxilla. Approximately 4 wk prior to presentation, a swelling was noted below the left eye, and the dog was presented to the primary care veterinarian. A corneal ulceration was diagnosed, and a swelling of the left upper gingiva was noted. The dog was subsequently placed on a topical ophthalmic antibiotic ointment and a 10-day course of an oral antibiotic, clindamycin hydrochloride^a. The corneal ulcer resolved, but the gingival swelling did not improve. The dog was presented to the primary care veterinarian again where he was anesthetized for a dental cleaning, during which biopsies were collected from multiple small masses that were noted near the upper left molars and premolars. Histopathology results were consistent with a malignant spindle cell tumor.

Physical examination at MJR-VHUP revealed a 2 cm-diameter firm swelling ventral to the left eye, mild enophthalmos of the left eye, protrusion of the left nictitating membrane, and a firm, 2.5 cm-diameter left mandibular lymph node. Oral examination revealed a dark pink, ill-defined mass on the palatal surface of the left maxilla, extending from the third premolar to just beyond the second molar. The dog was bright and alert on examination, but mild pain was elicited upon full extension of his jaw. Thoracic radiographs were performed along with fine needle aspiration of the left mandibular lymph node. The radiographs revealed pulmonary lesions, suspicious for metastasis. On the ventrodorsal view, there was a round soft tissue opacity approximately 18.5 mm in diameter superimposed with the proximal aspect of the left fourth rib and a faint, approximately 8 mm-diameter, ill-defined soft tissue opacity within the right seventh intercostal space. On both lateral views, there was a focal round soft tissue opacity superimposed with the costochondral junction of the fourth rib. A computed tomography (CT) scan was recommended to further evaluate the suspected pulmonary metastases. Cytology of the lymph node revealed mixed lymphoid cells and thick aggregates of round cells with distinct cell borders and basophilic cytoplasm (Figure 1). These latter cells were approximately 60 μm in diameter and contained an oval, paracentric nucleus with faintly stippled chromatin. These findings were compatible with nodal metastasis, and biopsy was recommended for further characterization, although this was not performed.

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Based on clinical suspicion of a rhabdomyosarcoma, a second opinion analysis of the original biopsy of the oral mass was requested at MJR-VHUP. Results of histopathology were consistent with a pleomorphic sarcoma with a high mitotic rate, and subsequent immunohistochemical stains were performed for further classification. Many of the neoplastic cells displayed strong cytoplasmic immunoreactivity for desmin but were negative for S100a. These results were compatible with a muscle origin, thus supporting a diagnosis of rhabdomyosarcoma (Figure 2).

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A CT was performed of the head and the thorax for staging and for treatment planning. This revealed a large mass centered at the rostral aspect of the left zygomatic arch, which extended from the level of the fourth maxillary premolar to the level of the frontal process of the zygomatic arch. There was extensive bony lysis. The mass measured 6.7 cm dorsal to ventral × 4.1 cm medial to lateral × 6.5 cm rostral to caudal and caused extensive bony lysis. The mass invaded the rostral aspect of the left orbit, resulting in severe compression of the left globe. Lysis was also noted at the caudal aspect of the right maxillary bone around the roots of both molars. This may have represented an area of skip metastasis or unrelated neoplasia, although a biopsy was not obtained to confirm. Left mandibular lymphadenopathy was noted, consistent with physical examination findings. Mild left medial retropharyngeal, left parotid, right mandibular, and right medial retropharyngeal lymphadenopathy were also evident, which may have represented additional metastatic disease or reactive lymph nodes. Multiple nodules were seen scattered throughout the lung fields, consistent with metastatic pulmonary disease. Because of the extensive nature of the mass and the distant metastatic disease, surgical treatment was not recommended. Instead, chemotherapy and palliative radiation therapy were elected.

The chemotherapy protocol was created based on the published vincristine, actinomycin-D, and cyclophosphamide (VAC) protocols used in humans with rhabdomyosarcoma.^19,20 Doxorubicin was substituted for actinomycin-D due to limited availability and cost constraints to create an alternative vincristine^b, doxorubicin^c, and cyclophosphamide^d protocol, also known as VAC. Palliative radiation therapy using a Three-dimensional conformal radiotherapy computer planning system based on the CT images was intended to be given in four weekly 8 Gray fractions starting at day 7 concurrently with the chemotherapy. The human VAC protocol was also modified to create a less intensive regimen in order to preserve quality of life.

Figure 3 describes the treatment protocol the patient received as well as the associated clinical response to each treatment based on physical examination and imaging when available. Modified Response Evaluation Criteria in Solid Tumors guidelines were used to assess clinical response when measurements were available.²¹ Treatment delays and dose reductions were made at the discretion of the attending veterinarian and were based on toxicity criteria from the Veterinary Cooperative Oncology Group Common Terminology Criteria for Adverse Events v1.1.²² The patient experienced a delay in treatment due to grade 3 neutropenia following the first dose of doxorubicin. The patient also received a total of three of the intended four doses of palliative radiation therapy in 8 Gy fractions intermixed within and starting on day 8 of the chemotherapy protocol. Both the left mandibular lymph node and maxillofacial mass decreased in size after the first chemotherapy treatment based on measurement of the lymph node, oral examination, and visualization of the swelling associated with the left eye. By day 32, the maxillofacial mass was no longer clinically detectable based on palpation around the eye and oral examination, and the left mandibular lymph node had returned to a normal size until the death of the patient. Because of the marked response of the local disease to both chemotherapy and radiation therapy, the radiation therapy protocol was temporarily discontinued after three of the planned four doses with the potential to treat with additional doses upon local disease progression. A repeat CT was not performed during the course of treatment. However, thoracic radiographs performed prior to initiating a second cycle of chemotherapy revealed a mixed response; some of the pulmonary lesions regressed, but multiple new pulmonary nodules also developed. Despite progressive pulmonary disease, the owners elected to try another cycle of chemotherapy because response was noted elsewhere and because the dog was feeling well. The second doxorubicin dose was reduced by 15% due to a grade 3 neutropenia noted after the first dose. On day 70, after completion of the second cycle, thoracic radiographs were repeated, which revealed further progression of the pulmonary metastases. Based on these findings, the VAC protocol was discontinued, and an oral tyrosine kinase inhibitor, toceranib phosphate^e, was dispensed as a rescue chemotherapy protocol. However, prior to initiation of therapy, the dog developed acute vomiting. The toceranib phosphate was not given, and the dog returned 2 days later for re-evaluation. On examination, the left mandibular lymph node was prominent but remained a normal size, and the original maxillofacial tumor was not evident on external palpation nor on oral examination. An abdominal ultrasound examination was performed, which revealed a few hepatic nodules, bilaterally enlarged adrenal glands, and evidence of gastroenteritis. Supportive care was initiated, but the dog developed neurologic signs (head tilt, ataxia, and left-sided hemiparesis) over the next 24 hr. He was re-presented to MJR-VHUP 2 days after his presentation for acute vomiting, at which time he was laterally recumbent and obtunded. Euthanasia was elected at that time, which was 74 days after the initiation of therapy.

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A necropsy examination was performed, in which small residual maxillary masses were evident that had not been noted on oral examinations after chemotherapy and radiation therapy had been initiated. Histopathology confirmed the diagnosis of the residual maxillary masses as rhabdomyosarcoma; the tumor was further classified into the embryonal subclass. Additional immunohistochemical evaluation of the primary tumor was performed, which demonstrated multifocal nuclear immunoreactivity for myogenin, thus confirming a skeletal muscle origin. The tumor was negative for smooth muscle actin, further supporting our diagnosis of rhabdomyosarcoma. The primary tumor expanded the gingiva and infiltrated the subjacent alveolar bone but was notably smaller in size than on original imaging, now appearing as two irregular masses measuring 0.6 × 0.4 × 0.2 cm and 1.4 × 1.1 × 0.5 cm (Figure 3). On gross examination, there was no macroscopic evidence of tumor within the periorbital region. Microscopically, only a small focus of neoplastic cells was detected within the retrobulbar connective tissue. Histopathology of the grossly thickened zygomatic arch revealed extensive bone remodeling but no evidence of neoplasia. Similarly, no neoplastic cells were noted in the medial retropharyngeal and mandibular lymph nodes, with the histopathology, instead, compatible with a reactive lymph node. Metastatic foci were noted in the heart, lungs, liver, brainstem, cerebellum, cerebellar dura mater, and left adrenal gland. Figure 4 depicts the residual primary tumor and metastatic lesions in the lungs, liver, and cerebellum.

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Discussion

Little information is available about rhabdomyosarcoma in veterinary medicine.⁸ However, this tumor type is well documented in human oncology. It accounts for 40% of all soft tissue sarcomas and 7% of all childhood cancer diagnosed annually in the United States.²³ The head and neck is the predominant site of RMS in children.^9,23 These tumors tend to grow in an aggressive manner and have significant potential for metastasis. Thus, the treatment of RMS involves a multimodal approach, often comprising radical surgery with or without radiation therapy and chemotherapy.^9,23,24 Chemotherapy often consists of a combination of vincristine, actinomycin-D, and cyclophosphamide.^9,23 Five yr survival rates have improved for oral RMS, from <10% before the 1960s to 65% today.⁹

Our goal, in this case, was to use a multimodal approach similar to that used in human oncology. However, our chemotherapy protocol substituted doxorubicin for actinomycin-D because the use of the latter was cost-prohibitive. Palliative radiation therapy was also incorporated to treat the primary tumor site and the metastatic mandibular lymph node.

Canine rhabdomyosarcomas are cytologically and histologically similar to their human counterparts and should, therefore, be a differential diagnosis for a solid tumor with a round to spindloid appearance on cytology. Definitive diagnosis involves histopathology and immunohistochemistry. RMS is a locally aggressive tumor with the potential for distant metastasis. The modified multimodal approach incorporated from human protocols was shown to exert clinical efficacy in the patient described in this report. There was a marked regression of the local-regional disease and an overall improved quality of life. Maximal tumor response was noted after radiation therapy, but initial improvements were seen following the first cycle of chemotherapy (prior to initiation of radiation therapy). Although the patient ultimately did succumb to widespread metastasis, minimal disease was identified at the primary tumor site, and no evidence of residual metastatic disease was noted in the local regional lymph nodes on necropsy evaluation.

Based on these clinical findings, a larger study is warranted to determine the best treatment for this rare tumor in dogs. It would also be interesting to assess the response to treatment with an approach similar to that in humans involving aggressive surgery, radiation therapy, and chemotherapy with vincristine, actinomycin-D, and cyclophosphamide in patients without metastatic disease. However, such a study is likely difficult to do because of the low reported incidence. Nevertheless, this case report may offer guidance for therapy for dogs with the same tumor.

Conclusion

This is one of the first case reports describing multimodal treatment of metastatic maxillofacial juvenile RMS in a dog. The combination of radiation and chemotherapy resulted in regression of the local-regional disease and thus improved quality of life. However, the response was only temporary, and the dog ultimately succumbed to widespread metastatic disease. Our patient presented with distant metastasis and therefore had a very grave prognosis. However, based on the observed response to treatment, it is possible that earlier diagnosis and therapy might have resulted in a more favorable outcome.