Orbital Rhabdomyosarcoma

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Disease Entity

Disease

Rhabdomyosarcoma (RMS) is a rare childhood cancer with an estimated 250-350 new cases per year. The head and neck region and in particular, the orbit, represent a major anatomic site for RMS. Orbital RMS is the most common primary orbital malignancy in children with approximately 35 new cases per year.[1] The advances in imaging including computed tomography (CT) and magnetic resonance imaging (MRI) as well as significant strides in treatment utilizing chemotherapy and radiation as determined by the Intergroup Rhabdomyosarcoma Study (IRSG) have made orbital RMS a pediatric cancer with a relatively good prognosis. Because most cases of orbital RMS present initially to ophthalmologists, a thorough understanding of the disease process, diagnosis, and treatment are of significant importance.

Primary Orbital RMS is mainly a disease of young children, with 90% occurring before the age of 16 years old with a mean age of onset of 5-7 years old.[2] While presentation within this age group is the most common, case reports have documented newborns and elderly patients with orbital RMS. There is a slight male to female predilection with a male:female ratio of 5:3.[3] Most authors agree that there is no racial predisposition for this malignancy.

RMS can primarily involve the orbit, eyelid, conjunctiva, and rarely, the uveal tract. Further, RMS can gain access to the orbit secondarily by direct extension from the paranasal sinuses or nasopharynx. Very rarely, RMS can metastasize to the orbit from distant sites. Overwhelming however, the majority of ophthalmic RMS arises from the orbit. In a retrospective review by Shields et al, the primary site of ophthalmic RMS was the orbit in 76%, eyelid in 3%, conjunctiva in 12%, and the uveal tract in 9%.[4]

Etiology

RMS initially was believed to originate directly from striated muscle. While this may be true for the pleomorphic histopathologic variant, it is now believed that most types including primary orbital RMS originate from primitive pleuripotential mesenchymal cells that possess the ability to differentiate into striated muscle. This theoretically explains the known occurrence of ocular RMS at sites where no skeletal muscle is present including the conjunctiva and uveal tract.[5]

There are currently no known specific genes suggesting direct hereditary transmission of RMS. There are however multiple associations of RMS with diseases with known genetic mutations including retinoblastoma (RB1 gene on chromosome 13q14), Li-Fraumeni syndrome (p53 gene on chromosome 17p13.1), Neurofibromatosis type I (NF1 gene on chromosome 17q11.2), Costello Syndrome (HRAS gene on chromosome 11p15.5), Beckwith-Wiedemann Syndrome (multiple genes on chromosome 11p15), Nevoid Basal Cell Carcinoma Syndrome (PCTH gene on chromosome 9q), and Rubinstein-Taybi Syndrome (CREBBP gene on chromosome 16p).[3][6] [7] [8] [9] [10] [11] [12] There are multiple reports in the literature of orbital RMS occurring as a secondary tumor after treatment with radiation for retinoblastoma and squamous cell carcinoma of the eyelid.[3] Otherwise, there are no known environmental associations with RMS.

General Pathology

The four histopathologic types of RMS include embryonal, alveolar, pleomorphic, and botyroid. Histologic subtype has been shown to affect long-term prognosis and therefore tissue diagnosis is critical. Orbital RMS is generally a well-circumscribed homogenous tumor with rare areas of hemorrhage or cyst formation.[13] In a comprehensive report of 264 patients from the Intergroup Rhabdomyosarcoma Study (IRSG), the tumor type was classified as Embryonal in 84%, Alveolar in 9%, and Boyroid in 4%. Pleomorphic RMS is very rare in the orbit and generally occurs in adults.[14]

Embryonal RMS is the most common histopathologic type seen in the orbit and generally has a favorable prognosis. Embryonal RMS is composed of alternating cellular and myxoid areas. The tumor cells are elongated with a centrally located hyperchromatic nucleus surrounded by a considerable amount of eosinophilic cytoplasm. The rhabdomyoblastic cells may show cross striations on light microscopy representing cytoplasmic bundles of actin and myosin filaments in approximately 30%.[15]

Alveolar RMS, named because of its similar histologic appearance to lung alveoli, is the least common variety and carries the worst prognosis. It consists of eosinophilic rhabdomyoblasts that are loosely adherent within a thin hyalinized septa. The tumor cells at the periphery of the alveoli are often well preserved while those free floating at the center are loosely arranged and poorly preserved. Only 10% will show cross striations histologically.[15]

Botyroid RMS, often considered a variant of embryonal RMS, most often appears as a fleshy grape-like or papillomatous mass in the forniceal conjunctiva. Histologically it appears similar to embryonal RMS.[15]

Immunohistochemical stains including desmin, muscle specific actin, and myoglobin have become the main histopathologic approach to establishing the diagnosis of RMS and differentiating it from other spindle cell tumors. In difficult cases, electron microscopy may further aid in the identification of cross striations.[15]

Further, cytogenetics is important in the diagnosis of RMS and differentiation between alveolar and embryonal variants. Alveolar RMS is distinguished from Embryonal RMS by the presence of one or two recurrent chromosomal translocations including t(2;13)(q35;q14) and t(1;13)(p36;q14). Embryonal RMS does not have recurrent structural chromosomal rearrangements but rather has frequent chromosomal gains and losses. In particular, there is a higher frequency of loss of one or two alleles often at chromosome 11 loci particularly in the 11p15.5 region.[1] [3]

Diagnosis

History

The most characteristic presentation for primary orbital RMS is the rapid onset of unilateral proptosis and inferior or inferiotemporal displacement of the globe. Proptosis can develop rapidly within a few days, or less commonly, present insidiously as a gradual painless process. Further, patients may present with a history of worsening eyelid edema and erythema, chemosis, ophthalmoplegia, blepharoptosis, or a palpable mass. Interestingly, ocular and orbital pain are less common presenting symptoms ranging from 10-20%. A history of trauma is sometimes associated with the clinical presentation of the tumor, which may confound the diagnosis. In a review of paranasal sinus and orbital RMS by Gandhi et al, approximately 11% of patients presented after trauma.[1]

Paranasal sinus RMS with secondary orbital invasion often presents similarly to primary orbital RMS but with additional symptoms including nasal or sinus congestion and epistaxis. Rarely, nasopharyngeal RMS can invade the orbital apices with resultant rapid, bilateral visual loss secondary to optic nerve compression.

Eyelid and conjunctival RMS often present as a gradually enlarging, well circumscribed mass, that may have associated eyelid edema and erythema as well as chemosis.

Primary uveal RMS most commonly presents as a slow growing, solitary, fleshy iris mass which may rarely seed the trabecular meshwork resulting in a secondary glaucoma.

Physical examination

A detailed ophthalmic examination aids in the initial diagnosis of orbital RMS. Examination findings correlate with the size and location of the orbital tumor. The most common location for orbital RMS is the superior or superonasal orbit and therefore the most important examination findings are proptosis and inferior or inferotemporal displacement of the globe.[4] Superior tumors are also commonly associated with blepharoptosis. Anteriorly located tumors are commonly associated with edema and erythema of the eyelids as well as conjunctival congestion and chemosis. Further, these are typically associated with a palpable subcutaneous mass. Tumors located anterior and nasal have been shown to be associated with nasolacrimal duct obstruction. Posteriorly located tumors are more commonly associated with choroidal folds, retinal detachment, retinal vessel tortuosity, and optic disc edema with optic neuropathy. Larger tumors are more likely to cause extraocular motility restriction, severe proptosis, and optic nerve compression. As discussed previously, conjunctival RMS usually appears as a fleshy pink grapelike mass in the conjunctival fornix. Uveal RMS most commonly appears as a single fleshy iris mass that may be associated with seeding of the anterior chamber with secondary glaucoma.

Signs

As noted above

Symptoms

As noted above

Clinical diagnosis

Diagnostic procedures

Orbital RMS should be considered in the differential diagnosis of any child with a progressive unilateral proptosis. Diagnosis consists of a detailed history, ocular examination, imaging studies including CT or MRI, and biopsy. History and examination were discussed in the preceding sections. Imaging is of particular importance in the diagnosis of orbital RMS and subsequent management including surgical planning.

Orbital RMS most commonly appears as a well-circumscribed, albeit irregular, solitary superior or superonasal mass that enhances with contrast on CT. The tumor is non-calcified and most frequently appears isointense to the extraocular muscles and is separate from them. In more advanced cases, there may be bony erosion or invasion into the surrounding paranasal sinuses or nasopharynx. There is almost never hyperostosis of the orbital bones.[16] [17] Similarly, MRI shows a well-circumscribed mass that typically enhances with gadolinium. On T1-weighted imaging, the tumor usually appears isointense to extraocular muscles but hypointense to orbital fat. On T2-weighted imaging, the lesion appears hyperintense to extraocular muscles and orbital fat. The lesion usually appears homogenous on both imaging modalities, but rarely may resemble a cystic lesion and have areas of hemorrhage.[16][18]


The ultimate diagnosis of RMS requires biopsy for histopathologic evaluation. CT or MRI imaging studies guide appropriate surgical planning for incisional or excisional biopsy of the orbital tumor. Fine needle aspiration biopsy (FNAB) is generally not recommended because it provides an insufficient amount of tissue for adequate diagnosis of RMS. The Intergroup Rhabdomyosarcoma Study (IRSG) found that patients with primary orbital RMS localized to the orbit (group II or III) fared well regardless of the extent of the initial resection. This important finding has shifted the surgical approach from maximal excisional biopsy and debulking to the more recent utilized approach of incisional biopsy and closure.[19] [20] [21] [22] [23] [24] The biopsy specimen is sent for routine histopathologic examination with light microscopy, immunohistochemical studies, and rarely electron microscopy. Further, it is important to send tissue for cytogenetic studies which aid in the differentiation of embryonal and alveolar RMS. Occasionally, frozen sections may be utilized to ensure an appropriate biopsy specimen was achieved.

Differential diagnosis

The differential diagnosis for orbital RMS includes a group of childhood neoplastic, vascular, inflammatory, and infectious conditions that result in proptosis.

These include:

Management

General treatment

Staging of RMS is essential to the treatment approach. The most commonly utilized staging classification system was established by the Intergroup Rhabdomyosarcoma Studies (IRSG). The current postsurgical grouping classification by IRSG and further modified by Shields et al defines Group I as completely resected, no microscopic, localized disease. Group II is defined as microscopic disease remaining after biopsy. Group III is defined as gross residual disease after biopsy. Group IV is defined as distant metastatic disease at presentation. Because a small incisional biopsy is most commonly performed at the time of surgery, most patients with localized disease are staged in Group III. Further the IRSG classified primary RMS lesions using risk groups A through C (low, intermediate, and high, respectively). These groups are based on histology, site, group and stage, and the presence or absence of metastatic disease. The orbit is considered a favorable site. Additionally, the embryonal variant, which is the most common form in the orbit, is considered favorable as compared to the alveolar variant which is considered unfavorable.[3] [24] Other institutional studies have recommended utilizing the preoperative TNM (tumor, node, metastasis) classification system to aid in the staging of RMS.

The treatment of orbital RMS typically includes a combination of surgery, irradiation, and chemotherapy. Prior to the IRSG studies, complete excision, often with orbital exenteration, was the primary treatment modality. With primarily surgical management, survival was generally low, with 3-year survival rates often quoted in the 30-40% range. Secondary to the findings of the IRSG studies, there has been a significant paradigm shift in the treatment of RMS with drastic improvement in survival. The treatment for orbital RMS groups I to III are summarized in the findings of the IRS-IV. Group I patients are treated with chemotherapy (vincristine + actinomycin D) without radiation. Group II patients are treated with chemotherapy (vincristine + actinomycin D) and a reduced dose of 41.4-Gy conventional fractionated irradiation. Group III patients are treated with chemotherapy (vincristine + actinomycin D + cyclophosphamide or vincristine + actinomycin D + ifosfamide or vincristine + actinomycin D + etoposide) and 50.4-Gy conventional fractionated irradiation. In patients with low-risk RMS, which includes group III orbital RMS, reduced doses of radiation (45.0-Gy conventional fractionaed irradiation) are used. Group IV patients by definition have metastatic disease and therefore are treated only with palliative regimens.[25] [26] For nasal and paranasal sinus RMS that has secondarily invaded the orbit, a similar treatment algorithm based on postoperative IRS-IV staging may be used.[3] However, unlike orbital RMS, studies suggest that maximum tumor excision prior to adjunctive chemotherapy and radiation may offer a survival benefit.[27]

Medical therapy

Medical follow up

Close follow-up by the pediatric oncologist and the ophthalmologist are essential during and after treatment for orbital RMS. After completion of treatment, the patient should be monitored closely for the development of recurrences of RMS as well as complications secondary to treatment with chemotherapy and radiation.


Complications

The wide utilization of the IRSG treatment guidelines for RMS has led to a significant increase in the number of patients surviving and leading longer tumor-free lives. Secondarily, there is an increasing need for health care providers, in particular the ophthalmologist caring for these patients, to have a thorough understanding of the ophthalmic comorbidities associated with these tumors and specifically their treatment. The chemotherapeutic agents used for the treatment of RMS are known to have ophthalmic complications. For example, cyclophosphamide is most commonly associated with keratoconjunctivitis sicca and blepharoconjunctivitis as well as, albeit less frequently, lacrimal duct stenosis and cataract. Similarly, ifosfamide is associated with conjunctivitis and blurred vision. Etoposide has been associated with central retinal artery occlusion. Lastly, doxorubicin has been associated with acute reversible maculopathy.[28] While chemotherapy side-effects occur in the treatment of RMS, most of the treatment associated morbidity is believed to be secondary to the local effects of radiation on the orbital soft tissues and globe. The most commonly documented complications include punctate epithelial keratitis, conjunctival injection, cataract, orbitofacial bony hypoplasia, and enophthalmos secondary to orbital fat atrophy. These can generally be managed with minimal patient morbidity. Less frequently, vision-threatening complications may occur including dense corneal scarring, radiation retinopathy, macular scarring, and phthsis bulbi.[1] Further, the IRSG studies reported, albeit rarely, the development of secondary malignancies including basal cell carcinoma, bone and soft tissue sarcomas, and acute nonlymphoblastic leukemias.[4][28][29] [30] [31]

Prognosis

The prognosis for RMS, including primary orbital RMS, has improved significantly in the past 30 years secondary to the shift to chemotherapy and radiation regimens determined by the IRSG studies. Survival rates when utilizing surgery alone, primarily exenteration, were as low as 30% for primary orbital RMS.[32] With the recommendations based on post-operative staging for primary orbital RMS, the IRS-IV study showed a 3-year failure-free survival rate of 91%, 94%, and 80% for group I, II, and III disease respectively. Histopathology also plays an important role in prognosis. There is a definite survival advantage to the embryonal variant compared to the alveolar variant of orbital RMS. A review of orbital RMS in the IRSG studies show a 94% and 74% 5-year survival for the embroyonal and alveolar variants, respectively. Orbital RMS presenting in infants less than one year of age follows a more aggressive course with poor survival rates of 54%.[33] Survival rates for paranasal RMS that secondarily invades the orbit is considered lower than for primary orbital RMS.

Additional Resources

References

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