Orbital Rhabdomyosarcoma

Geeta Lalchandani, MD · Mark R. Levine, MD · David S. Bardenstein, MD

Introduction

Rhabdomyosarcoma is a malignant neoplasm composed of cells with histologic features of striated muscle tissue at various stages of embryogenesis.¹ It develops from undifferentiated mesenchymal cells that possess the capacity to differentiate into skeletal muscle cells.^1-3 Historically, investigators believed that rhabdomyosarcoma cells were striated muscle tissue.^1,2 Rhabdomyosarcoma has a predilection for the head and neck regions, genitourinary track, extremities, and the trunk in both children and adults. Although it is a rare tumor, orbital rhabdomyosarcoma is the most common primary orbital malignancy among children.

The first account of orbital rhabdomyosarcoma was noted in 1882 by Bayer; however, the first series of cases studied did not occur until 60 years later.^1,2 Previously, most children with the disease died, but this changed dramatically as a result of the Intergroup Rhabdomyosarcoma Study Committee (IRS),^1,4 now renamed the Soft Tissue Sarcoma Committee (STSC).

Reported incidence rates of rhabdomyosarcoma are approximately 5% of childhood cancers, accounting for 4% of orbital masses biopsied from children. This disease is slightly more common in boys than in girls (5:3), occurring on average at 6 to 7 years of age; however, rhabdomyosarcoma can also occur in teenagers and adults (Slide 1A and Slide 1B).

Orbital rhabdomyosarcoma accounts for approximately 10% of all cases of rhabdomyosarcoma. The embryonal and alveolar types are common in children, whereas the pleomorphic type occurs most commonly in adults. The characteristic presenting features of orbital rhabdomyosarcoma are rapid onset proptosis and displacement of the globe, depending on the location.^1,3,5

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Clinical Findings

Unilateral, rapidly evolving proptosis with displacement of the globe is the most common symptom of orbital rhabdomyosarcoma (Slide 2A and Slide 2B).^1,3,5 Other presenting features depend largely on the location of the tumor, with the superior or superior nasal quadrant being the most common locations (Slide 3A, Slide 3B, and Slide 3C).^1,3,5,6 These tumors may also present as a palpable subconjunctival mass or blepharoptosis (Slide 4A and Slide 4B). Inferior or anterior tumors tend to cause chemosis and swelling of the eyelids. Posterior tumors may cause ophthalmoplegia resulting in strabismus. Posterior examination of patients may also reveal optic disc edema, choroidal folds, and/or retinal vein tortuosity. Pain may be the presenting complaint in approximately 10% of cases, usually in patients with advanced stages of the disease. Lastly, rhabdomyosarcoma may cause nasolacrimal duct obstruction with the patient presenting with acute dacryocystitis.⁷

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Orbital rhabdomyosarcoma rarely extends locally through bone intracranially (Slide 5A, Slide 5B, and Slide 5C), though it may extend into the maxillary or ethmoid sinuses (Slide 6A and Slide 6B). A small number of tumors may extend into the orbit from the paranasal sinus, nasal cavity or pterygopalatine fossa.⁷ The disease may metastasize to the lungs, bones, and bone marrow via hematogenous dissemination. Lymphatic spread is rare due to the paucity of lymphatics in the orbit. Rapidly progressive proptosis has been noted in numerous cases of newborns with orbital rhabdomyosarcomas.¹ However, this is in contrast to the slower, more gradual course observed in older children. Delays in diagnosis, which may occur in medically deprived areas, may result in large tumors with total destruction of the orbit and its contents.¹

The differential diagnosis of orbital rhabdomyosarcoma includes lesions that cause proptosis in childhood including orbital cellulitis, idiopathic orbital inflammation, capillary hemangioma, lymphangioma, dermoids, leukemia, neuroblastoma, myeloid sarcoma, and Langerhan’s cell histiocytosis, as well as other rare conditions.^1,3,5

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Diagnostic Approaches

The possibility of rhabdomyosarcoma should always be considered in children with orbital disease and should be promptly evaluated with imaging. Imaging studies can suggest the diagnosis, in addition to determining the extent, size, and location of the tumor. This facilitates surgical removal and adjunctive therapy. Most patients have an orbital computed tomography (CT) scan, magnetic resonance imaging (MRI), or both. Orbital CT scans demonstrate a well-circumscribed, homogenous, rounded mass isodense to muscle, which enhances with contrast administration. Bone destruction with local extension is readily recognized with contrast-enhanced CT imaging.

Tumors appear isointense to hyperintense on T1-weighted MRI with respect to muscle tissue, and hypointense as compared to the orbital fat. Rhabdomyosarcoma enhances moderately to markedly after contrast administration and is best seen with fat suppression techniques.³ On T2-weighted MRI, rhabdomyosarcoma appears hyperintense with respect to muscle and orbital fat. The definitive diagnosis of orbital rhabdomyosarcoma is histopathological. Therefore, a biopsy must be obtained to confirm the diagnosis.¹ A fine needle aspiration biopsy is contraindicated in the setting of a possible diagnosis of rhabdomyosarcoma because the limited tissue obtained may be insufficient to make a diagnosis. A general notion exists that the complete or near complete excisional biopsy without damaging the vital structures of the orbit lends toward a favorable prognosis. The extent of removal at surgery determines the staging of the disease and influences the need for adjunctive therapy, radiation, and chemotherapy.^1,3,6 Once the diagnosis is confirmed with an expedient biopsy, staging is required with a bone marrow biopsy, a chest CT scan, a bone scan, liver function tests, and a complete blood count.

Pathology

Orbital rhabdomyosarcoma is a well-circumscribed tumor with an infiltrative growth pattern. It appears light gray to pink and may contain areas of hemorrhage or cyst formation. Microscopically, rhabdomyosarcoma contains variable appearing cells from small round blue cells that are undifferentiated, to large differentiated rhabdomyoblasts with spindled nuclei and cell bodies.

Three histological types of rhabdomyosarcoma are described. The embryonal type accounts for two-thirds of all cases (Slide 7).^1,5 These tumors consist of either round or polygonal cells that are poorly differentiated and highly pleomorphic with nuclear atypia and hyperchromaticity. On low-power magnification, the cells may appear to form parallel palisading or interlacing bands. Other tumors contain highly differentiated spindle cells, with a centrally located, hyperchromatic nucleus surrounded by varying amounts of spindle-shaped eosinophilic cytoplasm. In highly differentiated cells, muscle cross striations can be seen (Slide 8). The botryoid variety is a clinical variant of embryonal rhabdomyosarcoma, which presents under mucosae such as the conjunctival epithelium, giving it a grape-like appearance.

The second most common type of rhabdomyosarcoma is the alveolar variety, which is the most malignant, having a high incidence of metastases and which often arises in the inferior orbit (Slide 9). It consists of well-preserved undifferentiated round or polygonal cells, which are aligned along connective tissue bands. Between the bands are loosely grouped or free-floating cells, which are often less well preserved, thus creating a pattern resembling that of the trabeculae and alveolar spaces in the lung. The noncohesiveness of the cells causing the alveolar morphology may contribute to the propensity of the alveolar rhabdomyosarcoma to metastasize.⁵ Recently, it was discovered that alveolar cells, the specific PAX3(7)/FKHR-translocation, are not present in the embryonal type,⁸ which has led to the use of chromosome analysis to confirm alveolar histology.

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The differentiated type of rhabdomyosarcoma, which used to be known as pleomorphic, is the least common form in the orbit and occurs more often among adults than children. The cells in this form vary from round undifferentiated cells similar to the other types, but can contain racquet or tadpole shaped cells, while cells with cross striations are rare. As expected, as it is the most highly differentiated form, it has the best prognosis.

The histologic differential diagnosis of rhabdomyosarcoma includes the small round blue cell tumors, neuroblastoma, Ewing’s sarcoma, lymphoma, angiosarcoma, neuroepithelioma, melanoma, granulocytic sarcoma, as well as other round cell and spindle sarcomas.

Immunohistochemistry and Electron Microscopy

The diagnosis of rhabdomyosarcoma used to be challenging, as there were no muscle-specific stains and, in tumors with poor differentiation, diagnosis was frequently uncertain. Electron microscopy represented a major advance, since, in many cases, the ability to identify various degrees of muscle components in tumor cells allowed a definitive diagnosis.¹

Immunohistochemical analysis now represents the gold standard for diagnosis of rhabdomyosarcoma. Most tumors consist of undifferentiated cells, and this modality is less expensive and labor intensive than electron microscopy while it examines a large amount of tissue. Immunohistochemical analysis is currently more available. Antibodies against muscle specific actin, desmin, and myoglobin are the most useful markers. Antivimentin antibodies are less specific for this disease.¹

Molecular Genetics

Recent molecular genetic analyses have identified several alterations that separate embryonal from alveolar types of rhabdomyosarcoma. The t(2:13) (q35;q14) reciprocal translocation and also t(1:13) (q36;q14) affecting PAX3 and PAX7 genes are typical of alveolar rhabdomyosarcoma, while loss of heterozygosity of 11p15.5 is typical of embryonal rhabdomyosarcoma. These findings can be used to separate the two types in cases not diagnosable by other methods.⁹

Classification

In 1972, the Intergroup Rhabdomyosarcoma Study Committee (IRS), now known as the Soft Tissue Sarcoma Committee (STSC), was established to increase the understanding and better the treatment options of patients with rhabdomyosarcoma. The group conducted numerous trials over the past 30 years, greatly increasing both the survival and visual prognosis of patients with the disease. The initial protocol determined that patient prognosis depends on the extent of the disease at diagnosis and therefore devised a staging system. The subsequent protocol incorporated tumor site and size.⁵ This staging system is based on location and measurement of the tumor. Tumors of the orbit fall into the stage 1a category based on a "favorable site" location and a measurement of <5 cm.⁸

An STSC designation is done after the diagnosis has been confirmed by biopsy. The biopsy can be either incisional or excisional, depending on the size, location, and involvement of orbital structures. Most studies recommend excising as much of the tumor as possible during the biopsy stage; however, the vital structures of the eye should remain intact. Ideally, the pseudocapsule should be preserved to minimize microscopic dissemination of the tumor. In a similar manner, the orbital periosteum should be left intact, if possible, because it serves a natural barrier for future regional spread. Routine histopathological examination versus frozen section is adequate for most cases, provided that a surgeon can confirm that the representative tissue has been extracted.

The STSC classification for systemic rhabdomyosarcoma has been adapted to orbital rhabdomyosarcoma by Shields and Shields¹ and is summarized in Table 1.

Table 1. Primary ophthalmic rhabdomyosarcoma in 33 consecutive patients staging by the STSC study classification^1,6

Orbital rhabdomyosarcoma most often falls into group 2 or 3 with some residual tumor. Orbital tumors are responsive to radiation and chemotherapy; therefore, aggressive removal possibly damaging orbital structures is not advocated.

Treatment

The introduction of combined modality treatment with chemotherapy and radiation as the mainstay in addition to surgical debulking of tumor when indicated has led to a tremendous improvement in the prognosis of rhabdomyosarcoma and is now the standard of care. Data from studies by the STSC have led to improved understanding of the role of various modalities in specific tumor stages.

The STSC divided patients into treatment subgroups based on their staging, group, and histopathology. Embryonal or botryoid orbital rhabdomyosarcomas without distant metastases fall into the low-risk subgroups A or B. Subgroup A defines clinically negative lymph nodes and subgroup B defines clinically positive lymph nodes. Tumors of the alveolar type are placed into an intermediate risk subgroup. Surgical reduction of tumors is important for outcome and as much reduction as can be achieved without significant functional or cosmetic loss should be attempted. Frequently, however, some residual tumor and other modalities may be needed. Both radiation and chemotherapy will vary according to the STSC classification. According to the treatment protocol advocated by Shields and Shields patients in all groups should receive chemotherapy; however, only those in groups II, III, and IV should receive irradiation.¹ The following is a summary of the Intergroup Rhabdomyosarcoma Study Committee treatment protocol for patients with low-risk tumors (Table 2).

Table 2. Chemotherapy protocol of subgroups of patients with orbital rhabdomyosarcoma based on the IRS V protocol⁸

The initial Intergroup Rhabdomyosarcoma Study Committee protocols used vincristine and actinomycin D as the primary chemotherapeutic agents.⁴ The more recent protocols showed promising results with cyclophosphamide, etoposide, and ifosfamide, but these newer agents were not used in the treatment of orbital rhabdomyosarcoma. Given the low incidence of adverse side effects of the early agents, the new protocols continue to include vincristine and actinomycin D for low-risk subgroup A orbital rhabdomyosarcomas. Cyclophosphamide is added to the treatment regimen for patients who fall into the low-risk subgroup B category. Chemotherapy is generally continued for 32 to 52 weeks depending on the group but may be discontinued prematurely secondary to toxicity. The chemotherapeutic regimen should be modified to adjust for tolerance and extent of disease.

Irradiation showed no statistically significant improvement for patients with completely resected tumor (group I). Therefore, it is not recommended. For those with residual tumor, a gradual increase in dose delivered via external beam radiation is used depending on the group. Appropriate shielding is necessary to limit damage to surrounding structures, particularly the opposite eye.⁵ Radiation used for orbital rhabdomyosarcomas (4,000 to 5,000 Gy) is associated with various significant ocular complications including, but not limited to, radiation retinopathy, dry eye, radiation cataract, blepharoptosis, and orbital hypoplasia.^1,3 Given the response of the tumor to radiation and improvements in the delivery, radiation will continue to be a mainstay of orbital rhabdomyosarcoma treatment.

Prognosis

In the context of all rhabdomyosarcoma, orbital rhabdomyosarcoma has a generally better prognosis. This relates to the relatively small size at detection and the absence of lymphatic vessels in the orbit, limiting early spread. A 1976 study reported a 25% survival rate beyond 3 years among 162 patients.² Due primarily to improved therapies, survival of patients with orbital rhabdomyosarcoma has improved dramatically. Various prognostic factors have been identified, namely location, tumor morphology, and patient age. Shields and Shields¹ reported a 5-year survival rate in patients with alveolar rhabdomyosarcoma of 74% compared to 94% in patients with embryonal-type tumor. Infants with orbital rhabdomyosarcoma have a much poorer survival rate, regardless of tumor type.¹ The data from the latest STSC study are due in the near future and will help continue to guide the treatment of orbital rhabdomyosarcoma. Additionally, as adjunctive therapies improve, the survival rate of patients with orbital rhabdomyosarcoma will continue to improve.

Conclusion

The survival rate for rhabdomyosarcoma continues to improve with newer therapeutic agents and radiation therapy. Early diagnosis and attention to the latest protocols are most important.

References

1. Shields JA, Shields CL. Rhabdomyosarcoma: Review for the ophthalmologist. Surv Ophthalmol. 2003; 48:39-57.
2. Knowles DM, Jakobiec FA, Potter GD, Jones IS. Ophthalmic striated muscle neoplasms. Surv Ophthalmol. 1976; 21:219-261.
3. Karcioglu ZA, Hadjistilianou D, Rozans M, DeFrancesco S. Orbital rhabdomyosarcoma. Cancer Control. 2004; 11:328- 333.
4. Raney RB, Anderson JR, Barr FG, et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: A selective review of intergroup rhabdomyosarcoma study group experience and rationale for the Intergroup Rhabdomyosarcoma Study V. J Ped Hem/Onc. 2001; 23:215-220.
5. Shields JA, Shields CL. Rhabdomyosarcoma of the orbit. Int Ophthalmol Clin. 1993; 33:203-210.
6. Shields CL, Shields JA, Honavar SG, Demirci H. Clinical spectrum of primary ophthalmic rhabdomyosarcoma. Ophthalmology. 2001; 108:2284-2292.
7. Burkat CN, Lucarelli MJ. Rhabdomyosarcoma masquerading as acute dacryocystitis. Ophthal Plast Reconstr Surg. 2005; 21:456-458.
8. Antranik Bedros. Actinomycin D and vincristine with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal/botryoid rhabdomyosarcoma: IRS-V/STS protocol. Available at: www.cancer.gov/clinicaltrials/COG-D9602.
9. Wachtel M, Dettling M, Koscielniak E, et al. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res. 2004; 64:5539-5545.