Botryoid Rhabdomyosarcoma of the Conjunctiva in a Young Boy.

Primary conjunctival rhabdomyosarcoma (RMS) is a rare entity that can present with or without papillomatous features. A 5-year-old Asian boy was referred for a rapidly growing conjunctival tumor in the superior fornix of the left eye. Surgical excision yielded a 28 mm multilobulated papillomatous specimen that exhibited histopathologic and immunohistochemical features consistent with embryonal (botryoid) RMS. Molecular analysis revealed the absence of the PAX3/FOXO1 fusion gene, indicating favorable prognosis. After surgery, he was promptly treated with systemic chemotherapy and proton beam radiotherapy.

Introduction

Malignant tumors of the conjunctiva in children are rare, accounting for only 3% of conjunctival tumors.[12] Rhabdomyosarcoma (RMS), while more commonly a primary orbital tumor, can present as a primary conjunctival lesion.[34567891011121314151617] In a series of 33 patients with ophthalmic RMS, conjunctival involvement was evident in only 12%.[3] Conjunctival RMS can have papillomatous or smooth features, depending on whether the tumor originates in the conjunctiva or represents extension from orbital disease.[34567891011121314151617]

A review of the 264 ophthalmic RMS cases from the Intergroup RMS Studies (IRS I, II, III, and IV), revealed histopathologic classification as embryonal (n = 221, 84%), alveolar (n = 24, 9%), undifferentiated (n = 11, 4%), and other (n = 12, 4%) subtypes.[1819202122] The 10-year prognosis for survival was more favorable with embryonal (94%) compared to alveolar (62%), undifferentiated (91%), and other (52%) subtypes of RMS.[18] In that review, botryoid variant of RMS was included in the classic embryonal RMS subtype with favorable prognosis.[18]

While clinical and histologic characteristics of RMS have historically guided prognostication, molecular data have recently proven highly effective in RMS risk stratification.[2324252627] Specifically, the presence of the PAX3/FOXO1 fusion gene has been associated with alveolar RMS, thus implying poorer prognosis.[2324252627]

RMS is a life-threatening disease, and early recognition with prompt treatment leads to best outcomes.[1819202122] Ophthalmic RMS generally has a favorable prognosis with an overall survival rate of 93%.[318] Herein, we describe a case of embryonal (botryoid), fusion gene-negative, conjunctival RMS, initially suspected to represent benign papilloma, in a young boy.

Case Report

A 5-year-old Asian boy was referred for a conjunctival mass of the left eye (OS). On examination, uncorrected visual acuity was 20/30 in the right eye (OD) and 20/80 OS. Pupillary examination, motility assessment, and intraocular pressure were normal in both eyes. The OD and orbit were normal. The OS revealed fullness of the upper eyelid with 2 mm blepharoptosis [Figure 1a]. There was no eyelid erythema or tenderness. On eyelid eversion, there was a large 22 mm × 12 mm × 8 mm multilobulated, vascularized papillomatous mass arising within the superior conjunctival fornix [Figure 1b]. The remainder of the anterior and posterior segment was unremarkable. The initial diagnostic considerations included conjunctival giant papilloma versus RMS.

Figure 1

A 5-year-old boy with conjunctival rhabdomyosarcoma of the left eye. (a) External photograph demonstrating left upper eyelid fullness and slight blepharoptosis. (b) Eversion of the left upper eyelid revealing a large multilobulated forniceal mass. (c) At the time of surgery, the conjunctival mass had enlarged. (d) Lateral view of the large pedunculated conjunctival mass. (e) Surgical specimen measuring 28 mm × 20 mm × 8 mm

A few days later, at the time of surgery, there was 6 mm rapid enlargement of the mass [Figure 1c and 1d], suspicious for RMS. Following complete surgical resection and surrounding cryotherapy, the tumor measured 28 × 20 in basal diameter [Figure 1e]. Histopathology revealed an infiltrate of malignant cells [Figure 2a] that were intensely immunoreactive for striated muscle markers, desmin, and myogenin, consistent with RMS [Figure 2b and Figure 2c]. Molecular analysis revealed the absence of the PAX3/FOXO1 fusion gene, suggestive of the embryonal variant. These findings were consistent with conjunctival embryonal RMS, botryoid growth pattern. Systemic staging revealed no metastatic disease (Stage I, favorable site head and neck), Group 2 (microscopic residua), and the patient was treated with vincristine, actinomycin, cyclophosphamide (VAC) plus VA for 4 cycles (protocol ARST0331) and proton beam therapy (36 Gy).

Figure 2

Histopathology and immunohistochemistry of conjunctival rhabdomyosarcoma. (a) The conjunctival substantia propria contained scattered strap cells and rhabdomyoblasts. (b) Intense cytoplasmic immunoreactivity for desmin was seen. (c) Intense nuclear immunoreactivity for myogenin was noted in at least 70% of the tumor cells

Discussion

RMS is the most common soft-tissue sarcoma in children, comprising approximately 3% of all childhood cancers.[28] There have been relatively few reported cases of primary conjunctival RMS or conjunctival extension of orbital RMS.[34567891011121314151617] In 1,258 patients from the Intergroup RMS Study III (IRS-III) and IRS-IV, the primary site for RMS was the head and neck region (42%), trunk (41%), and extremities (15%).[2930] Of those that arose in the head and neck region, 31% occurred in the orbit.[29] In a series of 33 consecutive cases of RMS of the ocular region, Shields et al. noted that all cases were primary orbital malignancies, but 4 (12%) demonstrated secondary conjunctival invasion.[3]

The most common ophthalmic RMS subtype is embryonal, which typically manifests with elongated spindle or strap-like cells and scattered rhabdomyoblasts with eosinophilic cytoplasm. Although cross striations are a characteristic feature, they are absent in many cases.[18] The botryoid variant of embryonal RMS is named for its grape-like appearance and is usually found in the mucous membrane of the urogenital tract or conjunctiva.[31] Botryoid RMS of the conjunctiva with papillomatous features, as seen in our case, has been recognized previously by Polito et al.,[4] Taylor et al.,[5] and Adamopoulou et al.[6] Similar to those cases, our patient displayed a large forniceal papillomatous lesion with rapid growth.

The prognosis for the botryoid variant of ophthalmic RMS is typically favorable. In a 1997 comprehensive review from the Intergroup RMS studies of 264 patients with RMS of the orbit, conjunctiva, and eyelids, the 5-year survival was 94% for embryonal (including botryoid) and 74% for alveolar types.[18] By contrast, embryonal RMS at extraocular locations demonstrated 66% survival estimate.[18]

The prognosis for ophthalmic RMS has drastically improved during the past 40 years to a >90% survival rate based on a combination of surgery, radiotherapy, and chemotherapy.[1819202122] Currently, most therapeutic protocols are based on clinical tumor grouping, combined with histopathology stage and molecular features. The pretreatment staging paradigm from the Intergroup RMS studies includes Stage I (disease involving the orbit, head or neck without parameningeal involvement, biliary tract, or genitourinary without bladder or prostate involvement), Stage II (disease involving the bladder, prostate, extremity, or cranial parameningeal involvement without nodal spread), Stage III (disease involving the bladder, prostate, extremity, or cranial parameningeal involvement with nodal spread), and Stage IV (metastasis).[29] The surgical-pathologic grouping is performed postsurgically and after histopathologic confirmation and includes Group I (no residua), Group II (microscopic residua), Group III (macroscopic residua), and Group IV (metastasis).[29] Our patient exhibited Stage I, Group II RMS. An important molecular feature regarding the presence of PAX3/FOXO1 fusion gene was negative in our patient.[2324252627] Considering these features, the estimated 5-year overall survival rate is 97%.[2932]

Cytogenetic analysis of alveolar RMS in 1993 by Galili et al. revealed a characteristic translocation involving the PAX3 gene on chromosome 2 and a member of the forkhead domain family on chromosome 13 (initially termed PAX3-FKHR and later identified as PAX/FOXO1 fusion gene).[23] When assessing 210 patients with RMS by clinical, histopathologic, and molecular features, Williamson et al. found that PAX3/FOXO1 fusion gene status was a critical factor in risk stratification, irrespective of histopathologic grading.[24] RMSs that were PAX3/FOXO1 gene-negative were clinically and molecularly indistinguishable from embryonal RMS while those that harbored the PAX3/FOXO1 fusion gene were consistent with alveolar RMS and had a poorer prognosis.[24] The status of PAX3/FOXO1 fusion gene is now a key factor in RMS prognostication.[2324252627]

Conclusion

Primary conjunctival RMS is rare and can present as a rapidly evolving papillomatous (botryoid) mass. While the prognosis is usually favorable for ophthalmic RMS, information regarding molecular changes in the PAX3/FOXO1 fusion gene strongly correlate with patient prognosis. In all cases of RMS, prompt diagnosis and management are important.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Support provided by Eye Tumor Research Foundation, Philadelphia, PA (CLS, JAS).

Conflicts of interest

There are no conflicts of interest.