Rhabdomyosarcoma: Review for the Ophthalmologist**

A. Definition 

Rhabdomyosarcoma is a malignant neoplasm that is composed of cells with histologic features of striated muscle in various stages of embryogenesis.27, 59, 87 It can occur in several sites in the body, including the ocular region.59, 87, 103 Ocular rhabdomyosarcoma is defined as the occurrence of this tumor in the area of the eye. Most ocular rhabdomyosarcomas arise in the soft tissues of the orbit but they can rarely occur in other ocular adnexal structures and even within the eye.25, 32, 102, 103, 131, 134

B. Historical aspects 

The historical aspects of rhabdomyosarcoma have been reviewed.59 Weber is generally credited with providing the first acceptable description of rhabdomyosarcoma, which occurred in the tongue of a 21-year-old man.59 The report of Bayer, in 1882, is probably the first published description of an orbital rhabdomyosarcoma.9, 59 The first comprehensive histopathologic study of rhabdomyosarcoma was published in 1946.118 Subsequently, several authors expanded on the clinical and histopathologic features of orbital rhabdomyosarcoma.11, 26, 59, 87, 117 In recent years, the clinical diagnosis of rhabdomyosarcoma has been facilitated by imaging studies like computed tomography (CT) and magnetic resonance imaging (MRI).20, 70 More recently, emphasis has been placed on improved methods of management, particularly adjunctive chemotherapy and irradiation.

C. Incidence 

Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric population, accounting for approximately 5% of all childhood cancers and for about 20% of all malignant soft tissue tumors. Approximately 250 new cases of rhabdomyosarcoma are diagnosed in the United States each year.18, 127, 135

D. Demographics 

The pleomorphic type more often occurs in adults but the embryonal and alveolar types mainly occur in infants and children, frequently in the head and neck region. Head and neck rhabdomyosarcomas usually appear in the first decade of life.59, 127 There is a slight predilection of males, with a male: female ratio of 1.3 to 1.27 There appears to be no major predilection for race, although some studies have suggested that it may have a slightly greater incidence in whites than in African-Americans.127

E. Anatomic locations 

The primary sites of rhabdomyosarcoma include head and neck area (45%), trunk (40%), and extremities (15%).27 About 25%–35% of head and neck rhabdomyosarcomas arise in the orbit, 50% in other parameningeal sites, and 25% in other locations such as the scalp, face, buccal mucosa, oropharynx, larynx, and neck.79, 127 The features of rhabdomyosarcoma in extraocular locations are thoroughly described elsewhere in the literature.21, 22, 27

F. Pathology 

Microscopically, the four major histopathologic types of rhabdomyosarcoma are pleomorphic, embryonal, alveolar, and botryoid.27, 46 There may be overlap of these types and pure classification can occasionally be difficult. The majority of orbital rhabdomyosarcomas are of the embryonal type. Alveolar rhabdomyosarcoma is considerably less common in the orbital region. Immunohistochemistry and electron microscopy can provide assistance in the diagnosis of rhabdomyosarcoma and in its differentiation from other spindle cell tumors.27, 59 Histopathology, immunohistochemistry, and electron microscopy findings are discussed subsequently in the section on orbital rhabdomyosarcoma.

A. Primary ocular rhabdomyosarcoma 

Although ocular rhabdomyosarcoma usually originates in the orbit, it can occasionally arise in the conjunctiva, eyelid, or in the anterior uveal tract.25, 32, 102, 103, 131, 134

1. Orbit 

The main goal of this review is to provide an update on orbital rhabdomyosarcoma. However, a brief review of nonorbital ocular rhabdomyosarcoma will be covered first.

2. Eyelid 

Rhabdomyosarcoma confined to the eyelid is rare. However, orbital rhabdomyosarcoma frequently presents as a visible and palpable subcutaneous mass deep in the eyelid. It is likely that some reported cases of “eyelid” rhabdomyosarcoma actually represent subcutaneous extension of anterior orbital rhabdomyosarcoma.62, 100, 133 The management of eyelid rhabdomyosarcoma includes surgical excision and consideration of radiotherapy and/or chemotherapy, as discussed in the section on orbital rhabdomyosarcoma.

3. Conjunctival Rhabdomyosarcoma 

Rhabdomyosarcoma confined to the conjunctiva is rare.12, 52, 68 In the authors' series of 33 cases of ocular rhabdomyosarcoma, there were 4 that presented initially in the forniceal conjunctival and all had contiguous anterior orbital involvement.102 It is also likely that some reported “conjunctival” rhabdomyosarcomas actually represent subconjunctival extension of primary anterior orbital tumors.68 Occasionally, however, there are cases that are confined to the conjunctiva or subconjunctival tissues, without orbital involvement.52 Conjunctival or subconjunctival rhabdomyosarcoma usually appears as a fleshy pink mass in the forniceal conjunctiva, most often in the superior fornix. In the authors' 4 cases that presented initially as a visible conjunctival mass, 3 were located in the superior fornix and 1 in the inferior fornix. It can appear as a papillomatous or botryoid (grapelike) mass (Fig. 1) or as a deep, circumscribed epibulbar lesion (Fig. 2).52 A child who presents with such findings should have orbital imaging studies to exclude more posterior involvement and the tumor should be managed by methods discussed subsequently under orbital rhabdomyosarcoma.

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Fig. 1. Rhabdomyosarcoma presenting as a superior conjunctival forniceal mass in an 8-year-old boy.

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Fig. 2. Rhabdomyosarcoma presenting as a circumscribed subconjunctival mass in an 8-year-old boy. The posterior margin of the mass could be palpated and the mass was removed intact.

4. Anterior Uvea (Iris and Ciliary Body) Rhabdomyosarcoma 

Rhabdomyosarcoma can rarely arise in the iris or ciliary body.25, 32, 102, 131, 134 It generally presents in an infant or young child as a solitary, fleshy iris mass that shows slow growth (Fig. 3, left). Early in it course, iris rhabdomyosarcoma can become loosely cohesive and diffusely seed the anterior chamber (Fig. 3, right), producing secondary glaucoma. It must be differentiated from iris melanoma, juvenile xanthogranuloma, leukemia, lymphoma, and endophytic retinoblastoma.

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Fig. 3. Primary rhabdomyosarcoma of the iris in a 2-year-old girl. Left: Lesion when first recognized, showing circumscribed iris mass inferiorly. Right: Lesion several weeks later showing more loose arrangement of the tumor. The diagnosed was made histopathologically after enucleation of the affected eye. (Courtesy of Dr. Frederick Elsas).

The pathogenesis of anterior uveal rhabdomyosarcoma is uncertain, because skeletal muscle is not present in the human iris. However, striated muscle is normally present in birds and amphibians and it has been speculated that its occurrence as an embryonal tumor in humans may represent a rhabdomyoblastic progonoma.131 It is well known that teratoid medulloepithelioma of the ciliary body may contain skeletal muscle as well as other heteroplastic tissues.137 It is possible that some reported rhabdomyosarcomas of the ciliary body may actually represent medulloepithelioma with total rhabdomyosarcomatous differentiation.131 Perhaps a more likely explanation is that anterior uveal rhabdomyosarcoma arises from undifferentiated mesenchymal cells of the uveal stroma that exhibit rhabdomyoblastic differentiation, similar to the mechanism of development of orbital rhabdomyosarcoma.32

Because anterior uveal rhabdomyosarcoma is rare, its management is not well established. Most cases have come to enucleation but it is quite possible that a small, localized tumor could be removed by iridectomy or iridocyclectomy. The tumor is probably radiosensitive, although recurrence after radiotherapy has been observed in one case32 The systemic prognosis for anterior uveal rhabdomyosarcoma appears to be excellent. We are not aware of cases that have metastasized.

B. Secondary orbital rhabdomyosarcoma 

Rhabdomyosarcoma can also gain access to the orbit by direct extension from paranasal sinuses or nasopharynx. The patient with sinus or nasopharyngeal rhabdomyosarcoma often presents with signs of sinusitis, nasal congestion, or epistaxis. Proptosis, globe displacement, or visual loss can occur later (Fig. 4). Nasopharyngeal rhabdomyosarcoma can be more difficult to diagnose and affected patients can sometimes present with rapid, bilateral visual loss due to invasion of the orbital apices, leading to optic nerve compression.10

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Fig. 4. Secondary orbital rhabdomyosarcoma originating in the ethmoid sinus. Left: There is slight proptosis and lateral displacement of the right eye, with limitation of adduction and supraduction. Right: Computed tomogram showing mass in right ethmoid sinus. The orbital component is not seen in this image.

The management of secondary orbital rhabdomyosarcoma should consist of a generous biopsy, histopathologic confirmation of the diagnosis, and combined radiation and chemotherapy, as described subsequently for primary orbital rhabdomyosarcoma.

C. Orbital metastasis from extraocular rhabdomyosarcoma 

Rarely, the orbit can be the site of metastasis from a primary neoplasm in other parts of the body, including the paravaginal area28 and the maxillary sinus, without direct communication to the orbit.125 The tumor generally presents as a rapidly progressive orbital mass in a child with a known primary rhabdomyosarcoma at a nonocular location. The best management is biopsy confirmation followed by combined orbital irradiation and systemic chemotherapy under the direction of a pediatric oncologist.

A. General considerations 

2. Age, Sex, and Race 

As mentioned earlier, orbital rhabdomyosarcoma is primarily a disease of young children with a mean age at diagnosis of 8 years.5, 34, 53, 54, 87 However, it can occur at any age, with cases reported in newborns,15, 24, 50 infants,76, 115 and adults.19, 56, 71, 85 It has been diagnosed in a 78-year-old patient.56 It has also been diagnosed during pregnancy in two Nigerian women.84 There is a slight predilection for males, with roughly a 5:3 male to female ratio.53, 54 There appears to be no racial predisposition. The tumor is invariably unilateral.

B. Clinical features 

Most publication on orbital rhabdomyosarcoma have not provided statistics as to presenting features and precise location of the neoplasm in the orbit. However, based on reports where that information is provided, the patient with orbital rhabdomyosarcoma generally presents with proptosis (80–100%), globe displacement (80%), blepharoptosis (30–50%), conjunctival and eyelid swelling (60%), palpable mass (25%), and pain (10%).53, 54, 102 The blepharoptosis is often the first sign in a patients with a superior orbital tumor (Fig. 5). Slightly more advanced cases show downward and lateral displacement of the globe due to the usual superior or superonasal location of the mass in 70% (Table 1, Fig. 6).

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Fig. 5. Blepharoptosis and slight proptosis of the left upper eyelid in a 7-year-old boy with orbital rhabdomyosarcoma.

Table 1. Primary Orbital Rhabdomyosarcoma in 30 Consecutive Patients: Primary Tumor Location

	Tumor Location	Number (%)
	Quadrant location
	Superior	10 (33)
	Inferior	3 (10)
	Nasal	2 (7)
	Temporal	0 —
	Superonasal	11 (37)
	Superotemporal	0—
	Inferonasal	3 (10)
	Inferotemporal	1 (3)
	Anteroposterior location
	Anterior orbit	11 (37)
	Mid orbit	13 (43)
	Posterior orbit	6 (20)

Modified from Shields et al.102

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Fig. 6. Inferior and temporal displacement of the right eye in a 12-year-old girl with orbital rhabdomyosarcoma.

Ophthalmoscopy can occasionally reveal choroidal folds, retinal venous tortuosity, and optic disk edema.102 Although the symptoms and signs usually have a rather rapid onset, some cases have a slower onset, with chronic eyelid and conjunctival edema being present before proptosis and globe displacement.75 Pain is a symptom in about 10% of cases, and it usually occurs in more advanced cases.53, 54 Visual impairment in usually minimal until the tumor becomes advanced.102 A firm mass is palpable in subcutaneous tissues in about 25% of cases53, 54 and a fleshy conjunctival component is sometimes visible (Fig. 1). Rhabdomyosarcoma in the orbit anteriorly and nasally has been known to initially produce nasolacrimal duct obstruction, which can lead to a delay in diagnosis.8

The proptosis secondary to orbital rhabdomyosarcoma can develop more rapidly in newborns and infants with rhabdomyosarcoma (Fig. 7). In older children and adults, it tends to have a slower course and rarely attains a large size (Fig. 8). In regions where medical care is not readily available, rhabdomyosarcoma can attain immense proportions and destroy the eye Fig. 9, Fig. 10.

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Fig. 7. Marked proptosis of the left eye in a newborn with orbital rhabdomyosarcoma. Congenital rhabdomyosarcoma is rare. (Courtesy of Dr. Mohamad Jaafar).

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Fig. 8. Rhabdomyosarcoma presenting in the conjunctiva in a 39-year-old man.

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Fig. 9. Advanced rhabdomyosarcoma of orbit with destruction of the globe and metastasis to preauricular lymph node. (Courtesy of Dr. Ellen Anker, South Africa).

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Fig. 10. Markedly advanced rhabdomyosarcoma of the left orbit. (Courtesy of Dr. Eugen Meyer, South Africa).

C. Mechanisms of spread 

As orbital rhabdomyosarcoma progresses, Fig. 9, Fig. 10, it can invade orbital bone and even extend into the cranial cavity. Metastatic disease from orbital rhabdomyosarcoma has become relatively uncommon in recent years. When it does occur, it has a tendency to metastasize most often to lung and bone.59, 87, 90, 91 Metastasis generally occurs via hematogenous dissemination. Regional lymph node metastasis from orbital rhabdomyosarcoma is rare, perhaps because the orbit is largely void of lymphatics.87 However, tumors that extend from the orbit anteriorly into the conjunctiva or eyelid can gain access to lymphatic channels and can metastasize to regional lymph nodes. Distant metastasis from rhabdomyosarcomas is usually fatal, in spite of intensive chemotherapy and symptomatic treatment.7, 73, 90

D. Pathology 

As mentioned earlier, embryonal rhabdomyosarcoma is by far the most common variant found in the head and neck region, including the orbit.33, 87 The alveolar and botryoid types are less common, and the pleomorphic type is extremely rare in the orbit.

Grossly, orbital rhabdomyosarcoma is a well circumscribed tumor in the early stages. Larger, more aggressive tumors have an irregular border as a result of tumor invasion though the pseudocapsule. In fresh sections, the tumor has a light gray to pink color and may show areas of hemorrhage and cyst formation.

Embryonal rhabdomyosarcoma is characterized histopathologically by spindle to round cells that show features characteristic of skeletal muscle in various stages of embryogenesis.27, 59, 87 The predominant cell is an elongated spindle cell that can assume a variety of arrangements and degrees of differentiation (Fig. 11, left). The cytoplasm is generally highly eosin- ophilic and cross striations can sometimes be identified on routine histopathologic sections (Fig. 11, right) or with special histochemical stains. The alveolar type appears as loosely arranged, malignant cells with septae that are reminiscent of the alveoli of the lung (Fig. 12). The botryoid type may be a variant of the embryonal type that assumes a papillary configuration.

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Fig. 11. Histopathology of embryonal rhabdomyosarcoma of the orbit. Left: Elongated spindle-shaped cells with prominent cytoplasm and nuclear pleomorphism (Hematoxylin-eosin × 200). Right: Cross striations in the cytoplasm of a cell from orbital embryonal rhabdomyosarcoma (arrow) (Hematoxylin-eosin × 300). (Courtesy of Ralph C. Eagle, Jr., MD)

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Fig. 12. Histopathology of alveolar rhabdomyosarcoma of the orbit. Left: Low magnification showing free-floating tumor cells with fine connective tissue septae (Hematoxylin-eosin × 25). Right: Higher magnification showing large anaplastic tumor cells (Hematoxylin-eosin × 200). (Courtesy of Ralph C. Eagle, Jr., MD)

3. Immunohistochemistry 

Immunohistochemical studies have provided great assistance in the diagnosis of rhabdomyosarcoma and in its differentiation from other spindle cell tumors.27, 59 Today, immunohistochemical studies have become the main approach to establishing the diagnosis. The most useful immunohistochemical markers include antibodies against desmin, muscle-specific actin, and myoglobin, that typically show positive reaction in rhabdomyosarcoma. Although vimentin shows a positive reaction in most cases, it is less specific and can be positive in a variety of other neoplasms.27, 59

4. Electron Microscopy 

There has been some controversy as to the diagnostic value of electron microscopy for rhabdomyosarcoma. In certain cases where the histopathologic diagnosis is uncertain, ultrastructural studies can demonstrate the parallel arrays of thick myosin filaments which are quite characteristic of skeletal muscle, thus lending support to the diagnosis. However, in most cases cytoplasmic banding has not been easy to demonstrate.45, 55, 86, 122

5. Histopathology Differential Diagnosis 

A number of round cell and spindle cell tumors of soft tissue can be similar histopathologically to rhabdomyosarcoma. These include neuroblastoma, Ewing's sarcoma, lymphoma, fibrosarcoma, fibrous histiocytoma, leiomyosarcoma, malignant Schwannoma, alveolar soft-part sarcoma, hemangiopericytoma, granulocytic sarcoma, osteogenic sarcoma, nodular fasciitis, rhabdoid tumor, and other conditions.59, 103, 111 The clinical and pathologic features of most of these tumors are well described in the literature.27 As mentioned earlier, immunohistochemical studies can be helpful in differentiating these lesions from rhabdomyosarcoma and electron microscopy can be employed in selected cases.

E. Pathogenesis 

There was once a misconception that orbital rhabdomyosarcoma arose from extraocular muscles, similar to pleomorphic rhabdomyosarcoma of adulthood. In 1962, Porterfield and Zimmerman refuted the prevailing assumption that embryonal rhabdomyosarcoma originates from preformed muscle.87 Subsequent authors agreed with their observations, and it is now widely accepted that embryonal rhabdomyosarcoma arises independent of the muscles and probably develops from undifferentiated mesenchymal cells that possess the capacity to differentiate into striated muscle.59 Conceivably, rhabdomyosarcoma could arise in any part of the body where such primitive pleuripotential cells exist, even if that area did not contain skeletal muscle.

It is possible that some cases of orbital rhabdomyosarcoma may be related to prior radiation. Orbital rhabdomyosarcoma has occurred as a second tumor in patients who had ocular irradiation therapy for retinoblastoma,2, 41, 113, 130 and after irradiation for squamous cell carcinoma of the eyelid.78 Otherwise, there appears to be no recognizable environmental, viral, or chemical influence in the pathogenesis of rhabdomyosarcoma.

F. Genetics 

Concerning rhabdomyosarcoma in general, the tumor has been seen in patients with certain familial syndromes like neurofibromatosis and Li-Fraumeni syndrome.69 The latter has been associated with germline mutations of the p53 tumor suppressor gene.127

In general, there appears to be no hereditary tendency for orbital rhabdomyosarcoma. Orbital rhabdomyosarcomas has been observed in brothers, both of whom died in spite of orbital exenteration and attempts at irradiation.47 Orbital rhabdomyosarcoma has been described in a patient who had prior rhabdomyosarcoma of the kidney.58 As with other cancers, it is possible that future studies will define genetic abnormalities that predispose patients for orbital rhabdomyosarcoma.

G. Differential diagnosis 

Rhabdomyosarcoma should be considered in the initial differential diagnosis in any child who presents with proptosis. The main lesions that may simulate rhabdomyosarcoma clinically are orbital cellulitis, idiopathic orbital inflammation, dermoid cyst, capillary hemangioma, lymphangioma, Langerhans cell histiocytosis (eosinophilic granuloma), myeloid-sarcoma, metastatic neuroblastoma, and lymphoma.103 In many instances, these conditions can be easily differentiated from rhabdomyosarcoma by clinical features and imaging studies. The precise incidence of these conditions, as compared to rhabdomyosarcoma is unclear, because many benign tumors and infectious and inflammatory conditions do not come to biopsy and most studies have been based on material received in pathology laboratories. Nevertheless, the following conditions represent the most important entities in the differential diagnosis of orbital rhabdomyosarcoma.

1. Orbital Cellulitis 

Orbital cellulitis is considerably more common than rhabdomyosarcoma. It usually occurs in young children with ethmoid or frontal sinusitis and is heralded by rapid onset of proptosis, associated with fever and leukocytosis. CT and MRI usually show sinus inflammation, diffuse orbital inflammation, and often a classic subperiosteal abscess near the medial wall of the orbit.103, 126 On occasion, a localized orbital abscess without sinusitis can simulate rhabdomyosarcoma.16

2. Idiopathic Orbital Inflammation 

Idiopathic orbital inflammation (“inflammatory pseudotumor”) can sometimes occur in children and be difficult to differentiate from rhabdomyosarcoma.82 Inflammatory conditions accounted for about 8% of biopsied childhood orbital tumors in the Mayo Clinic series and rhabdomyosarcoma accounted for 7%.61 In the Wills Eye Hospital series, inflammatory lesions accounted for 16% and rhabdomyosarcoma for 4%.107 Idiopathic orbital inflammation generally shows more inflammatory signs and pain, as compared to rhabdomyosarcoma. In some instances a soft tissue mass is seen and MRI and CT cannot satisfactorily distinguish the two. The myositis variety, often seen in children, shows a characteristic enlargement of one muscle, a finding that would be highly unlikely with rhabdomyosarcoma. Inflammation confined to the lacrimal gland (dacryoadenitis) can be circumscribed and similar to rhabdomyosarcoma. However, it is usually painful and can be bilateral, findings that would mitigate against rhabdomyosarcoma. If idiopathic orbital inflammation is strongly suspected, a trial of corticosteroids is warranted and if there is no response, biopsy should be considered to rule out rhabdomyosarcoma or other neoplasm.

3. Dermoid Cyst 

Dermoid cyst usually is located near the superotemporal orbital rim and has typical clinical features.108 Dermoid cyst is much more common than orbital rhabdomyosarcoma. Cystic lesions, mostly dermoids, accounted for about 23% of biopsied childhood orbital tumors in the Mayo Clinic series.61 In the Wills Eye Hospital series, cystic lesions accounted for 52%.107 In some cases, a deeper orbital dermoid cyst can rupture, leading to signs and symptoms similar to rhabdomyosarcoma. Imaging studies characteristically show a cystic component to the lesion, a finding that is considerably less likely with rhabdomyosarcoma. In addition, many dermoid cysts show bone involvement, particularly a fossa in the adjacent bone. Such bony changes would be less likely in a comparable-sized orbital rhabdomyosarcoma.

4. Capillary Hemangioma 

Capillary hemangioma can also occur in the anterior aspect of the orbit and simulate rhabdomyosarcoma. Vascular lesions, mostly capillary hemangiomas, accounted for about 18% of biopsied childhood orbital tumors in the Mayo Clinic series.61 In the Wills Eye Hospital series, capillary hemangioma accounted for 4%.107 Capillary hemangioma is clearly more common than reflected in those histopathologic series, but many cases do not undergo biopsy. Orbital capillary hemangioma generally appears in infants during the first few months of life, whereas the great majority of orbital rhabdomyosarcomas are diagnosed in somewhat older children. It may be sometimes associated with an ipsilateral cutaneous eyelid component of the lesion which should suggest the diagnosis of capillary hemangioma.39, 105

5. Lymphangioma 

Orbital lymphangioma can occasionally be difficult to differentiate from rhabdomyosarcoma. Like the latter, it is generally diagnosed in the first decade of life, and is characterized by a rapid onset of proptosis.95, 105 This usually results from hemorrhage into a preexisting lesion, often after orbital trauma or upper respiratory infection. Other areas of the body, particular the palate, may show a lymphangioma, which should suggest the diagnosis. Imaging studies frequently reveal blood levels in the larger cystic spaces that comprise the mass. Such hemorrhagic cysts would be unlikely in rhabdomyosarcoma, which usually appears as a solid mass. However, occasionally a rhabdomyosarcoma can develop cavitary changes and masquerade as a lymphangioma.29

6. Langerhans Cell Histiocytosis 

The most common form of Langerhan's cell histiocytosis is the eosinophilic granuloma, which can occur as a solitary lesion in the orbit. It can occur as a rather rapid onset of proptosis, sometimes with mild inflammatory signs. In contrast to rhabdomyosarcoma, it generally arises in bone and produces atypical bone destructive changes, which would be rare for orbital rhabdomyosarcoma.80, 110

7. Myeloid Sarcoma 

Myeloid sarcoma (chloroma) is a soft tissue mass secondary to myelogenous leukemia. Although many affected patients have a prior history of leukemia, this tumor can sometimes appear as a circumscribed orbital lesion as the first manifestation of leukemia.136 The orbital mass can be similar to rhabdomyosarcoma clinically and radiographically. Orbital myeloid sarcoma is frequently bilateral, whereas rhabdomyosarcoma in invariably unilateral. Children with a rapidly expanding orbital mass should have a white blood count and other appropriate studies to exclude leukemia. Excised tissue in such instances should be subjected to appropriate histopathologic studies to exclude the possibility of myeloid sarcoma.

8. Lymphoma 

Although lymphoma is the most common malignant orbital tumor of adulthood,19 orbital lymphoma is rare in children except in areas of Africa, where Burkitt's lymphoma is the most common orbital tumor of childhood.1, 121 It can also occur in a non-African patient as a solitary orbital mass that may closely resemble rhabdomyosarcoma clinically and radiographically.23

H. Diagnostic approaches 

Any child in the first two decades of life who presents with symptoms and signs of an orbital mass should be considered to have rhabdomyosarcoma until proven otherwise. The child should have a detailed history, office examination, and imaging studies, particularly CT or MRI. Prompt biopsy should be considered whenever rhabdomyosarcoma is a reasonable possibility.

1. History 

A medical and ocular history should be taken on any child with suspected rhabdomyosarcoma. Inquiry should be made regarding pain, visual loss, and signs of sinusitis. Parents will sometimes recall an incident of ocular trauma at the time of the first symptoms.6 This history can be misleading and can cause a delay in diagnosis. Most orbital rhabdomyosarcomas do not produce early pain, a symptom more likely to be seen with orbital cellulitis or idiopathic orbital inflammation. A history of acute or chronic sinusitis would be more consistent with orbital cellulitis. A long history of mild proptosis followed by an acute exacerbation should suggest a lymphangioma.

2. Office Examination 

A careful ocular examination in the office may also assist in the diagnosis of rhabdomyosarcoma. The clinician should look specifically for those clinical features discussed earlier. As mentioned, the child with rhabdomyosarcoma usually has proptosis and/or inferior or inferotemporal displacement of the globe due to the usual location of the tumor in the superior or superonasal aspect of the orbit anteriorly103, 109, 111, 112 However, the globe displacement can occur in any direction.

3. Computed Tomography 

Today, most children with signs of symptoms of an orbital mass undergo CT, MRI, or both. These studies can suggest the diagnosis, determine the size and extent of the tumor, and facilitate surgical planning. With CT, the tumor appears in the early stages as a well-circumscribed, homogeneous, round to ovoid mass that is isodense to muscle (Fig. 13). It is usually extraconal in location and is most often found in the superonasal aspect of the orbit. It is usually confined to the orbital soft tissues and does not appear to arise from the extraocular muscles. In general, the earlier tumors do not invade bone, but larger tumors tend to erode bone and occasionally extend to the sinuses or nasopharynx. It does not usually show the more extensive bony involvement that characterizes eosinophilic granuloma or metastatic neuroblastoma. The extraocular muscles are sometimes displaced by the tumor, but the belly of the muscle is not enlarged by the tumor.114 Orbital rhabdomyosarcoma shows moderate to marked enhancement with contrast agents.70, 114

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Fig. 13. Computed tomography of orbital rhabdomyosarcoma in patient shown in Fig. 6. Left: Axial section. Right: Coronal section. Note that the mass has irregular margins and is located superonasally.

4. Magnetic Resonance Imaging 

Like CT, MRI is a valuable method for diagnosis and surgical planning in patients with suspected rhabdomyosarcoma (Fig. 14).20, 70, 114 On T1-weighted image, the tumor appears in the early stages as a round to ovoid mass that is usually located in the orbital soft tissue superonasally. It usually has a hypointense signal with respect to orbital fat, but is isointense with respect to extraocular muscles (Fig. 14, top left). It generally shows moderate to marked enhancement with gadolinium and is best delineated with fat suppression techniques. (Fig. 14, top right). On T2-weighted image, the lesion is hyperintense to extraocular muscles and orbital fat.20 (Fig. 14, bottom). It is usually noncystic but rare cavitary rhabdomyosarcoma may resemble a cystic lesion.29

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Fig. 14. Magnetic resonance imaging of orbital rhabdomyosarcoma. Top left: T1-weighted image, Top right: T1-weighted image with contrast enhancement and fat suppression. Bottom: T2-weighted image.

5. Biopsy 

Some type of biopsy is generally necessary in cases of suspected rhabdomyosarcoma in order to establish the diagnosis before initiation of therapy.42, 57, 94, 103 Based on the findings of clinical examination and imaging studies, the clinician must decide whether to perform an excisional or incisional biopsy, a subject to be discussed in the subsequent section on management.

The question sometimes arises as to whether fine needle aspiration biopsy (FNAB) should be used to establish the diagnosis of orbital rhabdomyosarcoma. Although there are occasional indications for FNAB of orbital tumors, particularly in the diagnosis of lymphoma and orbital metastasis, there is a limited role for FNAB in the primary diagnosis of rhabdomyosarcoma.83 The scanty tissue obtained by FNAB is often insufficient for the cytopathologist to establish a diagnosis. In addition, the best management is generally to remove as much of the tumor as possible and this cannot be achieved with FNAB. Therefore, FNAB should rarely, if ever, be used to make the primary diagnosis of rhabdomyosarcoma.

6. Histopathology 

The ultimate diagnosis of orbital rhabdomyosarcoma depends on recognition of the typical histopathologic features, using routine methods combined with immunohistochemistry and, if necessary, electron microscopy. This subject was discussed previously in the section on pathology.

I. Management 

2. Intergroup Rhabdomyosarcoma Study (IRS) 

In 1972, the Intergroup Rhabdomyosarcoma Study (now called IRSG) was established to increase knowledge and to improve therapeutic results for rhabdomyosarcoma from all locations. Four consecutive clinical trials have been conducted and reported and several studies based on IRSG studies were subsequently published.7, 17, 18, 73, 74, 128, 129 Although these studies have usually been directed to rhabdomyosarcoma from all locations, some investigators have retrieved data that pertains only to orbital rhabdomyosarcoma.

A staging classification of rhabdomyosarcoma, employed by the IRSG, is summarized in Table 2, Table 3. In brief, group I is defined as localized disease, completely resected. Group II is microscopic disease remaining after biopsy. Group III is gross residual disease remaining after biopsy. Group IV is distant metastasis present at onset. This classification can assist in selecting treatment and in predicting prognosis. This classification can also be applied to cases of orbital rhabdomyosarcoma.102

Table 2. Staging of Rhabdomyosarcoma by the Intergroup Rhabdomyosarcoma Study Group Staging Classification

	Group	Description
	I	Completely resected localized disease implying both gross impression resection and microscopic confirmation of complete resection and absence of regional lymph node involvement
	Ia	Confirmed to muscle or organ of origin
	Ib	Contiguous involvement outside the muscle or organ of origin
	II	Residual disease and/or regional lymph node involvement
	IIa	Grossly resected localized tumor with microscopic residual disease and no evidence of gross residual tumor or regional lymph node involvement
	IIb	Completely resected regional disease with no microscopic residual tumora
	IIc	Grossly resected regional disease with microscopic residual tumora
	III	Incomplete resection with biopsy or gross residual disease
	IV	Distant metastatic disease present at onset

aRegional disease implies involvement of the regional lymph nodes.

Table 3. Primary Orbital Rhaddomyosarcoma in 30 Consecutive Patients: Staging by the Intergroup Rhabdomyosarcoma Study Classification

	Group	Description	Number (%)
	I	Completely resected	2 (7)
	II	Residual microscopic disease	11 (37)
	III	Residual gross disease	16 (53)
	IV	Distant metastasis present at onset	1 (3)

Modified from Shields et al.102

3. Current Treatment 

The management of orbital rhabdomyosarcoma should include any combination of surgery, irradiation, and chemotherapy Table 4, Table 5. Although details regarding treatment are well described for rhabdomyosarcoma in general, details are scanty regarding management of orbital rhabdomyosarcoma. However, specific recommendations for management of orbital rhabdomyosarcoma have been proposed (Table 4) using various regimens of radiation and chemotherapy depending upon the IRSG stage. The following discussion of current management of orbital rhabdomyosarcoma is based on results of the aforementioned studies combined with the authors' personal experience.102

Table 4. Intergroup Rhabdomyosarcoma Study Group IV: Current Recommendations for Treatment of Orbital Rhabdomyosarcoma (Groups I, II, and III)

	Group	Radiation Therapya	Chemotherapy
	I	None	VA × 32 weeks (regimen 44, VA)
	II	4,140 cGy CFI	VA
	III	5,040 cGy CFI or 5,940 cGy HFI	VA + C × 52 weeks (regimen 41, VAC) or VA + I × 52 weeks (regimen 42, VAI) or VI + E × 52 weeks (regimen 43, VIE)

Radiotherapy should begin at week 9. CFI = conventional fractionated irradiation; HFI = hyperfractionated irradiation; V = Vincristine; A = Actinomycin D; C = Cyclophosphamide; I = Ifosfamide; E = Etoposide. From Wexler and Helman127 and Lanzkowsky.64

Table 5. Primary Orbital Rhabdomyosarcoma in 30 Consecutive Patients: Local and Systemic Tumor Outcomes

	Outcome	Number (%)
	Local tumor outcome
	Regression, no recurrence	24 (80)
	Recurrencea	6 (20)
	Regional outcome
	No lymph node spread	28 (94)
	Lymph node spreadb	2 (6)
	Systemic outcome
	No distant metastasis	28 (94)
	Distant metastasisc	2 (6)
	Final Status
	Alive	29 (97)
	Dead of metastasis	1 (3)

aLocal recurrence was managed sucessfully with debulking + chemotherapy in all 6 cases, with additional external beam radiotherapy in 1 case, gamma knife radiosurgery in 1 case, and exenteration in 2 cases. bLymph node spread was documented at presentation in 1 case and upon follow-up after therapy in 1 case. Lymph node spread was successfully managed with debulking + chemotherapy in both cases and additional radiotherapy in 1 case. cDistant metastasis was documented at presentation in 1 case and upon follow-up after therapy in 1 case. Metastasis was successfully treated with debulking + chemotherapy + radiotherapy in 1 case. One patient with overwhelming lung metastasis died despite chemotherapy. Modified from Shields et al.102

a. Surgery 

The final diagnosis of orbital rhabdomyosarcoma should be made on the basis of histopathologic findings following surgery, usually by excisional or incisional biopsy. Regardless of the type of biopsy, the excised tissue should be submitted immediately for routine histopathologic examination. There is usually no need for frozen sections except when the surgeon is uncertain whether representative tumor tissue is biopsied. When such diagnostic frozen sections are ordered, the surgeon should realize that the pathologist may not be able to provided a definitive diagnosis, since it may sometimes be difficult to differentiate rhabdomyosarcoma from several other neoplasms and inflammatory processes by that technique alone. Processing for light microscopy and immunohistochemical studies should be expedited so that a diagnosis should be finalized within 24 to 48 hours if possible.

Several approaches to surgery have been advocated, including orbital exenteration, excisional biopsy, and incisional biopsy. As mentioned earlier, orbital exenteration is rarely used today as a primary treatment.

i. Excisional biopsy 

There is a general belief in ophthalmology that orbital rhabdomyosarcoma should be managed by biopsy followed by irradiation and chemotherapy. However, there are few details in the literature that address the planned approach and the type and extent of the biopsy. It has been our impression that many ophthalmologists, in keeping with traditional teaching, perform a small biopsy to establish the diagnosis, so that the patient can then be referred for irradiation and chemotherapy. Some investigators believe that only a small biopsy is necessary, since orbital rhabdomyosarcoma has a favorable prognosis following radiation and chemotherapy, regardless of the amount of tissue removed.65 However, we believe that it is more prudent to manage orbital rhabdomyosarcoma by complete, or near complete, surgical removal when that can be achieved without major damage to vital structures like the optic nerve and extraocular muscles. Most early rhabdomyosarcomas are well circumscribed, located in the superonasal aspect of the orbit, and do not directly affect the optic nerve or extraocular muscles. Therefore, complete removal is occasionally possible.

In each case of suspected rhabdomyosarcoma, the surgeon should carefully review the axial and coronal CTs or MRIs to determine whether it is possible to attempt complete removal of the mass. If the tumor is very anterior in the orbit and presenting in the conjunctival fornix, a forniceal conjunctival approach can be considered. However, most tumors are located more posteriorly or are palpable through the eyelid. In such instances, a cutaneous approach is preferable, choosing the most direct route as determined by a review of the axial and coronal CTs or MRIs. A trans-septal, rather than an extraperiosteal approach is preferable. An attempt should be made to leave the orbital periosteum intact, because it is a natural barrier to future local spread of the tumor. The surgery should be done meticulously in order not to disrupt the pseudocapsule that often encases the mass.

An important unanswered question is whether complete surgical excision of rhabdomyosarcoma eliminates the need for subsequent irradiation and or chemotherapy. In cases where an anteriorly located rhabdomyosarcoma has been completely removed clinically and histopathologically, it may be tempting to recommend cautious observation only, rather than subjecting the patient to irradiation and chemotherapy. In such cases, pediatric oncologists usually advocate chemotherapy and irradiation because of the malignant nature of the disease. Because orbital rhabdomyosarcoma is rare and most cases cannot be excised completely, clinical trials to address that question may not be feasible.

ii. Incisional biopsy 

In most cases, the suspected rhabdomyosarcoma is large and located more posteriorly in the orbit, making complete excision difficult to impossible without damage to the vital orbital structures. In such instances, an incisional biopsy is appropriate. The incisional biopsy in these circumstances should be sufficiently large to debulk as much of the tumor as possible, without damage to the optic nerve and extraocular muscles. Although it has not been clearly proven, it seems possible that such debulking would relieve the tumor burden, facilitate subsequent treatment with irradiation or chemotherapy, and provide the pathologist with sufficient tissue of for routine and special studies. The surgical approach should be planned according the clinical and radiographic findings as described above.

2. Irradiation 

The poor prognosis for patients with orbital rhabdomyosarcoma following orbital exenteration prompted the use of orbital irradiation (later combined with chemotherapy) for selected patients. As early as 1956, Lederman reported favorable results in adjunctive irradiation in 7 patients with orbital involvement by rhabdomyosarcoma.66 Subsequent reports further attested to the role of radiotherapy in controlling this disease.14, 36, 63, 97, 98, 99 Enthusiasm for radiotherapy gained momentum as techniques continued to improve.

Studies published in 1995 of rhabdomyosarcomas at all sites suggested that patients with microscopic residual disease had satisfactory tumor control using 4,000 cGy in fractionated doses.13, 92 Although those studies were not limited to orbital disease, the results are important in treatment of orbital disease, since the ocular structures are particularly sensitive to irradiation.

Radiation currently employed for orbital rhabdomyosarcoma (4,000 to 5,000 cGy) can be associated with ocular complications (Table 6).43, 81, 102 Most notable are radiation cataract (55%), dry eye (36%), orbital hypoplasia (24%), blepharoptosis (9%), and radiation retinopathy (90%).102 Orbital malignant melanoma has been observed 45 years after irradiation for orbital. rhabdomyosarcoma and may represent a radiation side effect.67 It is anticipated that with continued improvement in radiation techniques, that complications will be fewer and less severe. Some investigators have shown enthusiasm for new techniques of proton irradiation therapy for orbital rhabdomyosarcoma.48, 77 The fine details of irradiation are beyond the scope of this review and are described in the literature7, 14, 36, 63, 73, 92, 97, 98, 99, 129 and outlined in Table 4.

Table 6. Primary Ocular Rhabdomyosarcoma in 30 Consecutive Patients: Complications of Management

	Complication	Number (%)
	Orbit
	Orbital hypoplasia	8 (24)
	Strabismus	1 (3)
	Restriction of ocular motility	1 (3)
	Diplopia	1 (3)
	Eyelid
	Blepharoptosis	3 (9)
	Ocular surface
	Dry eye	12 (36)
	Radiation keratopathy	1 (3)
	Intraocular
	Radiation cataract	18 (55)
	Radiation retinopathy	3 (9)
	Phthisis bulbi	1 (3)
	Face
	Second malignant neoplasm	1 (3)

Modified from Shields et al.102

Irradiation is often necessary following orbital exenteration for tumor recurrence after standard irradiation and chemotherapy have failed to control the tumor. Although external beam irradiation has generally been employed in such cases, implant brachytherapy using a specially designed radioactive plaque has been rarely used.4

3. Chemotherapy 

In the late 1960s and early 1970s, systemic chemotherapy was incorporated into protocols for treatment of rhabdomyosarcoma. This was usually combined with radiotherapy with continued success.123 In 1974, Heyn and associates reported results of a prospective, randomized trial of childhood rhabdomyosarcoma of all sites and demonstrated a substantial benefit of chemotherapy. Patients who underwent tumor excision and radiotherapy had 82% 2-year disease-free survival if they received a year of chemotherapy, compared to 53% if they did not. The agents employed were vincristine and actinomycin D.44 In 1979, a review of orbital rhabdomyosarcoma treated with combined surgery, irradiation, and chemotherapy demonstrated control of the primary tumor and salvage of the eye in over 90% of cases.3 Encouraged by results with newer methods of chemotherapy, some investigators have suggested that radiation be reserved for patients who do not achieve a complete response to chemotherapy.96 The results of one of the latest reports has indicated that the addition of newer chemotherapeutic agents, particularly ifosfamide and etoposide, may be beneficial. However, the authors of that study chose to use only vincristine and actinomycin for orbital rhabdomyosarcoma, because tumors in that location are known to have a very favorable outcome with those agents.88 Further discussion of chemotherapy is beyond the scope of this review and is covered in detail in the recent literature.3, 30, 31, 36, 132 and summarized in Table 4.

4. Current Management of Orbital Rhabdomyosarcoma (Authors' Experience) 

As mentioned earlier, recommendations that have been proposed for the management of rhabdomyosarcoma in general can also be applied to orbital rhabdomyosarcoma (Table 4). In a recent study 33 cases of ocular rhabdomyosarcoma diagnosed by our group and managed systemically by pediatric oncologists, mainly at Children's Hospital of Philadelphia, there were 30 tumors that apparently arose in the orbital area.102 The tumor was staged as IRSG group I in 2 cases (7%) group II in 11, (37%) group III in 16 (53%), and group IV in 1 (3%) (Table 3). Treatment included surgical debulking and regimens of chemotherapy and radiotherapy as described above. Local and systemic outcomes are depicted in Table 5. There was local tumor recurrence in 6 patients (20%), and orbital exenteration was necessary in 2 patients (6%). Regional lymph node metastasis occurred in 2 patients (6%) and distant metastasis occurred in 2 patients (6%). With a mean follow-up of 8.3 years, tumor-related death occurred in 1 patient (3%). This seems to support the fact that the overall prognosis is better when the rhabdomyosarcoma is confined to the orbit. Long-term visual outcome in the 28 patients who maintained the globe was 20/20 to 20/40 in 11 (39%), 20/50–20/100 in 5 (18%), and 20/200 to no light perception in 12 (43%).

5. Follow-Up Procedures 

In addition to follow-up by the pediatric oncologist, the ophthalmologist has a continued role in following patients who have been treated for orbital rhabdomyosarcoma. After completion of chemotherapy and irradiation, the child should have a comprehensive ocular examination every 3–4 months initially, with a visual acuity examination, external ocular examination for dry eye, proptosis, and motility disturbance. Slit-lamp biomicroscopy should be done to detect cataract and ophthalmoscopy should be performed to rule out radiation retinopathy. Orbital CT or MRI should be performed shortly after completion of the treatment and the size and extend of any residual tumor should be recorded. It has been our experience that radiologists and pediatric oncologists often express concern about residual tumor and they recommend an additional orbital biopsy. However, we believe that biopsy should generally be withheld until there is a sufficient suggestion of tumor regrowth as determined by clinical findings and serial CT or MRI. Biopsy of small, residual orbital tumor in a child is often surgically difficult and complications can ensue. Furthermore, the viability of residual tumor can be difficult to interpret for the pathologist. After the first year the child should be examined every 4–6 months for several years and then on a yearly basis with periodic orbital CT or MRI, depending on the clinical findings.

K. prognosis 

Early reports showed that the prognosis for orbital rhabdomyosarcoma was poor even following radical surgery by orbital exenteration and early attempts at radiotherapy.53, 59, 116 In 1976, Knowles and associates59 reviewed combined survival data on four reported series of orbital rhabdomyosarcoma.5, 35, 53 They found that of 162 cases only 49 patients (30%) were alive without evidence of disease at 3 years and only 39 patients (25%) survived more than 3 years.

As mentioned earlier, the prognosis for orbital rhabdomyosarcoma has improved greatly in recent years.35, 40, 51, 60, 93, 119, 120, 124 Factors that appear responsible for the better prognosis for rhabdomyosarcoma in the orbital region include the more favorable anatomic location, the earlier stage of the disease at the time of diagnosis, more favorable tumor morphology, and perhaps patient age. Each of these may be interrelated.

Concerning anatomic location, rhabdomyosarcoma in the orbit produces early ocular symptoms and signs as compared to tumors in more occult locations and his permits earlier recognition of the tumor.35, 40, 51 In addition, there are few lymphatic channels in the orbital area and, therefore, early lymph node metastasis rarely occurs.

Tumor morphology also appears to be an important prognostic indicator, with embryonal rhabdomyosarcoma, the most common type in the orbit, carrying a more favorable prognosis. Patients with alveolar cell type show 74% 5-year survival whereas those with embryonal cell type demonstrate 94% 5-year survival. 60 The great majority of orbital rhabdomyosarcomas are of embryonal cell type (80%) as compared to rhabdomyosarcoma at any site (54%). From another perspective, 44% of children who die from orbital rhabdomyosarcoma have alveolar cell type. Even though age at diagnosis has not proven to be a predictor of tumor-related death, infants under 1 year of age with orbital rhabdomyosarcoma have a worse prognosis with death in 46%. 60 The reason for more aggressive behavior of rhabdomyosarcoma in infancy is unknown.