Rhabdomyosarcoma
Key Points
Rhabdomyosarcoma (RMS) is an aggressive tumor that develops from mesenchymal cells of uncertain origin
It can occur in any anatomic location of the body where there is skeletal muscle
The most common subtype is embryonal, which accounts for about 60% to 70% of cases
It is believed that the embryonal subtype arises from undifferentiated mesenchymal progenitor cells that have the capacity to differentiate into striated muscle
Embryonal RMS may show allelic gains in chromosomes 2, 7, 8, 11, 12, 13, 17, 18, and 20, losses in chromosomes 10, 14, 15, and 16, and 35% contain mutant NRAS or KRAS genes
For ophthalmic RMS, only 3% occur in the eyelids and most cases represent subcutaneous extensions from anterior orbital tumors
Clinically, eyelid RMS presents as a firm, immobile, nontender mass with eyelid swelling and occasional ulceration, chemosis, superficial bleeding, and ecchymosis
Treatment is with radiation therapy and systemic chemotherapy
Embryonal RMS carries a favorable prognosis if the tumor remains localized, with a 5-year overall survival of about 70%-80%
Rhabdomyosarcoma (RMS) is an aggressive tumor that develops from mesenchymal cells of uncertain origin.1 While RMS can occur at any age, and case reports occur in patients ranging from 3 weeks to 78 years of age,2,3 this tumor is far more common in children. It represents 3% to 5% of all childhood cancers and accounts for about 40% to 50% of pediatric soft tissue sarcomas in childhood and adolescence.1,4,5,6 RMS can occur in any anatomic location of the body where there is skeletal muscle, as well as at sites without skeletal muscle, such as the urinary bladder and common bile duct.7,8 These tumors occur most commonly in the head and neck (35%), genitourinary tract (24%), extremities (19%), and at other locations (22%).9
Ophthalmic RMS accounts for about 10% of all localizations.10 In a series of 33 ophthalmic RMS cases examined by Shields and coworkers, the tumor had an orbital epicenter in 75%, conjunctival in 12%, intraocular in 9%, and palpebral in 3% of cases.10 Of the 30 cases of extraocular RMS in the Shields et al study, “all had an orbital component, despite apparent tumor origin in the conjunctiva or eyelid.”10 About 90% of RMS are diagnosed in patients less than 25 years of age, and 60% to 70% less than 10 years old.11 In the head and neck area, RMS occurs most commonly in the orbit, the nasopharynx, middle ear, paranasal sinuses, and infratemporal and pterygopalatine fossae, and in the larynx, oropharynx, oral cavity, parotid gland, cheek, and scalp.7,8 Eyelid involvement is uncommon and most cases represent extension from anterior orbital tumors. Primary isolated RMS of the eyelid is exceedingly rare with only 13 cases described. In the early stages, they may be misdiagnosed as a benign lesion, such as chalazion, hordeolum, or an epithelial tumor.12,13
RMS has been categorized into several subtypes according to histopathological differences. The most common subtype is embryonal, which accounts for about 60% to 70% of cases in children less than 10 years of age.5 About 350 new RMS cases are diagnosed per year in the United States,14 and the estimated incidence is 4.5 cases per million population among individuals aged 0 to 14 years.5,11 This subtype occurs most commonly in the head and neck region and genitourinary tract.14 Embryonal RMS has been further subdivided into a botryoid subtype. Botryoid RMS represents 10% of embryonal RMS and characteristically occurs in mucosal-lined organs such as the bladder, vagina, nasopharynx, and respiratory tract and carries a better prognosis than other types.15
Alveolar RMS is the second most common subtype and accounts for about 20% to 25% of RMS cases.4 It is equally distributed among all age groups but is the most common type in teenagers and young adults.14 This subtype is most common in the extremities and less commonly in the head and neck or on the torso.14
The World Health Organization now includes pleomorphic and spindle cell/sclerosing RMS as rare but distinct subtypes of RMS. Pleomorphic RMS is most common in adults in their 50s and often involves the legs.14 Adult pleomorphic RMS has a poor prognosis with a median overall survival of about 13 months for people with localized disease.14 Spindle cell/sclerosing RMS accounts for 3% to 10% of RMS, affects all age groups of both sexes, and is most common in the head and neck region followed by the extremities.16 Congenital and infantile spindle cell/sclerosing RMS have a favorable prognosis when gene fusions are present but a poor prognosis if there is an MYOD1 mutation.16
Etiology and Pathogenesis
RMSs are generally thought of as skeletal muscle tumors, mainly because they usually arise in or near muscle beds and show features of myogenic differentiation.17 They exhibit diverse phenotypes that may reflect differences in their genetic mutations and cells of origin.18 While the specific cell lineage of origin remains uncertain for all subtypes, the pleomorphic subtype is thought to originate from muscle stem cells,19,20 whereas the alveolar subtype has been proposed to originate from mature differentiating skeletal muscles cells, not satellite cells.21,22 It is believed that the embryonal subtype arises from undifferentiated mesenchymal progenitor cells that can differentiate into striated muscle,17 although it has also been suggested that it may develop from a range of muscle lineage cells, including muscle satellite cells and downstream myogenic progenitors such as maturing myoblasts.23,24
Environmental risk factors have been associated with RMS. These include paternal smoking, maternal recreational drug use, advanced maternal age, and radiation exposure in utero.5 Genetic risk factors include several hereditary syndromes including neurofibromatosis type 1 and Li-Fraumeni, Beckwith-Wiedemann, nevoid basal cell carcinoma, Rubinstein-Taybi syndromes, as well as hereditary retinoblastoma.1,5 Oncogene mutations have been identified in 28% of embryonal and 3.5% of alveolar RMS. Embryonal RMS shows an increased incidence in syndromes with RAS/MAPK pathway and BRAF mutations, including cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome.25,26,27,28
Eighty percent of alveolar RMS exhibit a translocation between chromosomes 2 and 13 (t(1;13)(q35;q14) (PAX3-FOX1A).1,4,26,29,30,31,32 Embryonal RMS often shows allelic gains in chromosomes 2, 7, 8, 11, 12, 13, 17, 18, and 20, losses in chromosomes 10, 14, 15, and 16,33,34 and translocations in the 1p11-1q11 region.33 Moreover, studies have shown that 35% (5 of 14) of embryonal RMS samples contain mutant NRAS or KRAS genes.35 P53, RAS, Hedgehog, and PI3K pathways are potentially necessary for the pathogenesis of embryonal RMS and could thus be important for targeted therapy.35
 FIGURE 143.1 A, Child with a rhabdomyosarcoma of the left upper eyelid presenting as eyelid swelling and ecchymoses. B, Rhabdomyosarcoma of the medial canthus and upper eyelid. (A, Courtesy of Dr. Ilya Leingold. B, Courtesy of Dr. Antonio Augusto Cruz.) |
Clinical Presentation
For ophthalmic RMS, 76% occur in the orbit, 12% in the conjunctiva, and 3% in the eyelids.10 Localized eyelid involvement is quite rare and most cases represent subcutaneous extensions from anterior orbital tumors.10 Conjunctival and subconjunctival lesions appear as a fleshy, pink lesion often in the fornix. Early stages of eyelid RMS in children may be misdiagnosed as a benign lesion. For periorbital lesions, the size can vary considerably, from pimple size to 6 cm or more.36
Eyelid RMS occurs at all ages with a mean of 11.3 years, a median of 8.0 years, and a range of 1 day to 54 years. Males and females are equally affected, and there is a slight predilection for the right side (70%). All subtypes are represented, with 58% embryonal, 25% anaplastic, and 17% alveolar. The specific localizations are upper eyelid (64%), lower eyelid (18%), caruncle (9%), and medial canthus (9%). Eyelid RMS usually present as a firm, immobile, nontender mass with eyelid swelling and occasional ulceration, chemosis, superficial bleeding, and ecchymosis (Figure 143.1).
Differential Diagnosis
Eyelid RMS usually grows rapidly so that suspicion for a neoplastic process is common. But initially, these tumors can be small, associated with ptosis, dilated vessels, and sometimes
inflammation. They can initially be confused with a variety of benign lesions such as chalazion, hordeolum, epithelial cyst, an epithelial tumor, vascular lesions such as hemangioma, or a subcutaneous hematoma. As they enlarge, they are confused with other primary cutaneous malignancies, lymphoma, or metastases particularly in a patient with a history of prior systemic malignancy. Histologically, RMS can be mistaken for round cell and spindle cell tumors such as leukemia, lymphoma, metastatic neuroblastoma, extraocular spread of retinoblastoma, Ewing sarcoma, peripheral ectodermal tumors, fibrosarcoma, and rhabdoid tumor. Immunohistochemistry and electron microscopy are required for definitive diagnosis.37
inflammation. They can initially be confused with a variety of benign lesions such as chalazion, hordeolum, epithelial cyst, an epithelial tumor, vascular lesions such as hemangioma, or a subcutaneous hematoma. As they enlarge, they are confused with other primary cutaneous malignancies, lymphoma, or metastases particularly in a patient with a history of prior systemic malignancy. Histologically, RMS can be mistaken for round cell and spindle cell tumors such as leukemia, lymphoma, metastatic neuroblastoma, extraocular spread of retinoblastoma, Ewing sarcoma, peripheral ectodermal tumors, fibrosarcoma, and rhabdoid tumor. Immunohistochemistry and electron microscopy are required for definitive diagnosis.37
Treatment
Treatment for RMS of the head and neck has evolved significantly since 1965. Previously, the gold standard was a primary, often radical, surgical excision in all cases, followed by radiation therapy when complete excision could not be achieved. The survival rate was only 5% to 9%. Since 1965, radiation therapy and systemic chemotherapy have become the standard primary treatment, based on the guidelines set forth by intergroup RMS studies. Metastasis from orbital RMS is uncommon because lymphatics are very sparse in the orbit. However, conjunctiva and eyelid RMS are exposed to lymphatic vessels so that metastasis to preauricular or cervical lymph nodes can occur more easily.
Chemotherapy consists of combinations of vincristine, dactinomycin, and cyclophosphamide.38 Success has been reported with low- and intermediate-risk RMS patients, but the 5-year failure-free survival for high-risk groups has not changed very much over the past 25 years.4,39 For patients with disseminated tumor having the worst prognosis, chemotherapy with subsequent autologous myogenic stem cell transplantation has been proposed.40,41
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