Diagnosis, Workup and Treatment

Based on the clinical history and exam, the differential diagnosis included inflammatory or reactive conditions such as a hematoma; aneurysmal bone cyst; giant cell or cholesterol granuloma; histiocytosis; and idiopathic orbital inflammation. The differential diagnosis also included infectious and neoplastic disorders such as cellulitis, primary bone lesions (benign or malignant), lymphoproliferative or vascular disorders, and secondary neoplasms including sinus-related lesions or distant metastases.1,2

Figure 2. Side-by-side CT coronal images which demonstrate an expansile soft-tissue and osteolytic lesion involving the right zygoma and orbital space.
A CT of the orbits was performed and showed an expansile, moth-eaten and osteolytic lesion involving the right zygoma (See Figure 2). With acquisition of these radiographic findings, a more complete and extensive bone-lesion differential diagnosis was drafted. This included benign processes such as osteoid osteoma, osteoblastoma, enchondroma, chondroblastoma; malignant processes such as a primary sarcoma (i.e., osteosarcoma, chondrosarcoma, Ewing’s sarcoma), metastasis, myeloma, lymphoma and choristoma; and reactive, fibrous or vascular lesions including aneurysmal or unicameral bone cysts, fibrous dysplasia, osteomyelitis, Langherhans’ cell histiocytosis, non-ossifying fibroma and bone hemangioma.1,2

The patient underwent an orbital biopsy. Resulting pathology showed sheets of numerous strap cells with abundant eosinophilic cytoplasm reminiscent of rhabdomyoblasts and scattered mitotic figures (See Figure 3). Immunohistochemistry stains were positive for desmin, myogenin, AE1/AE3 and CAM 5.2.
The patient was diagnosed with orbital spindle cell rhabdomyosarcoma and was referred to the Wills Eye Hospital Ocular Oncology service as well as the Thomas Jefferson University Hospital Otolaryngology and Hematology/Oncology departments. A PET/CT showed that disease was localized to the right orbit. While all options, including observation, chemotherapy, radiotherapy and surgical debulking/resection were discussed, the final recommendation was to pursue a combination of systemic and localized therapy in the form of neoadjuvant chemotherapy (vincristine, adriamycin, and cyclophosphamide) followed by local radiation ±local debulking. Unfortunately, after only one visit in each of the previously mentioned departments, the patient refused further therapy and failed to return for any further visits.


Rhabdomyosarcoma is a neoplasm that develops from undifferentiated mesenchymal cells that have the capacity to differentiate into striated muscle. Based on the widely adopted generalized Horn and Enterline classification system, there are classically four distinct histopathological subtypes, each with its own characteristic and identifying features: embryonal; botyroid variant of embryonal; alveolar; and pleomorphic. Although used in the original Intergroup Rhabdomyosarcoma Studies, in recent years this scheme has been modified and adapted by investigating organizations including the National Cancer Institute with the goal of creating a classification system that would better predict patient outcome.3

Figure 3. Histopathology photograph demonstrating extensive sheets of strap cells with abundant eosinophilic cytoplasm and mitotic figures.
The embryonal subtype is the most common, with a frequency of 50 to 60 percent and a five-year survival of 94 percent. Within the embryonal category, the botyroid (named for its association with a mucous membrane-like conjunctiva and grapelike clinical appearance) and spindle cell variants are deemed favorable histopathologic subtypes due to their superior prognosis and longer survival rates. Embryonal rhabdomyosarcoma usually arises in the superonasal orbit and thus produces inferolateral globe displacement. This is contrasted with the alveolar subtype, which histopathologically resembles pulmonary tissue due to branching, fibrous septae that enclose the tumor cells and create pseudo-alveoli. The alveolar subtype has an approximate frequency of 30 percent, a five-year survival rate of 74 percent, and usually arises in the inferior orbit. Additionally, around 75 percent of alveolar cases have a characteristic genetic translocation involving chromosome 1 or 2 and chromosome 13 [t(1;13) or t(2;13)]. These genetic variations have prognostic significance, with the t(1;13) mutation having a much more favorable survival rate. Finally, the classic pleomorphic variant is now a subset within the anaplastic rhabdomyosarcoma category used in modern classification systems. It represents less than 1 percent of rhabdomyosarcomas and occurs almost exclusively in adults.3-8 In addition to histopathology, immunohistochemistry is critically important in making the diagnosis of rhabdomyosarcoma. Some of the most common markers include desmin; myo-D1; myoglobin; myogenin; muscle-specific actin; skeletal muscle myosin; and vimentin.4,8,9,10

Orbital rhabdomyosarcoma is most commonly a disease of pediatric patients who usually present with symptoms before the age of 10 years. It represents approximately 4 percent of pediatric malignancies and is the most common soft-tissue sarcoma of the head and neck in this patient population. Initial presenting symptoms usually include rapidly developing proptosis, globe displacement, eyelid edema, and ptosis. In contrast, adult cases such as ours are much more rare.
Table 1. IRSG Surgical-Pathologic Grouping System
I Localized tumor, completely removed with pathologically clear margins and no regional lymph node involvement
II Localized tumor, grossly removed with (a) microscopically involved margins, (b) involved grossly  resected regional lymph nodes, or (c) both
III Localized tumor with gross residual disease after grossly incomplete removal, or biopsy only
IV Distant metastases present at diagnosis
Table 1, outlining the intergroup rhabdomyosarcoma post-surgical staging system. (Adapted from: Raney RB, et al.10)
In fact, no more than 20 documented adult cases were found during a literature review spanning a 50-year time period after 1965.4-6 While the orbital location is most common, Carol Shields, MD, found various ophthalmic sites of disease in a 25-year period case review. Specifically, 76 percent were located in the orbit, but the conjunctiva, eyelid, and uveal tract were also found to be primary sites of disease.

In terms of staging, categories are classically defined based on the Intergroup Rhabdomyosarcoma Study post-biopsy system (See Table 1).11 Favorable prognostic factors include an orbital location, younger age (1 to 10 years), female sex, embryonal histology, and low tumor burden (size <5 cm diameter).4-6,12

Treatment approaches usually correlate with the stage of disease. Specifically, patients with stage I disease usually receive chemotherapy with either vincristine or actinomycin. For those with stage II or III disease, some combination of chemotherapy (typical agents being vincristine, actinomycin and cyclophoshamide) and radiotherapy is the standard. Finally, for those with metastatic or stage IV involvement, an intensive chemotherapy and radiation regimen is used, along with intrathecal chemotherapy for patients with intracranial involvement. With advances in chemotherapy and radiotherapy over the past 50 years, surgical treatment is no longer the standard of care, and survival rates have markedly improved from 30 percent to 90 percent. In fact, while surgical excision and exenteration used to be the primary treatment, these approaches are often reserved for cases with recurrent disease.4,11,13

In summary, rhabdomyosarcoma is the most common primary orbital and soft tissue malignancy in children, but can occur in patients of any age. Four distinct histopathological subtypes have different frequency rates and prognoses. Fortunately, due to advances in chemotherapy and radiotherapy over the past fifty years, survival rates have markedly improved and disfiguring procedures such as exenteration are no longer the standard of care.  REVIEW

The author would like to thank Robert Penne, MD, and Michael Rabinowitz, MD, members of the Wills Eye Hospital Oculoplastic and Orbital Surgery Service, for their time and assistance in preparing this case report.

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