Rhabdomyosarcoma is the most common malignant orbital neoplasm in children. Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder often resulting from germline mutations impairing the antitumor functions of p53.1,2 Li-Fraumeni syndrome is characterized by a marked increase in familial disposition to cancers, including rhabdomyosarcoma. We report, to our knowledge, the first clinicopathologic description of orbital rhabdomyosarcoma in LFS in the ophthalmic literature.
A 23-month-old boy developed progressive left proptosis over 4 days. His medical history was unremarkable, but his family history was positive for cancer in multiple generations. His mother developed Paget disease of the breast at age 31 years, a maternal uncle died of an unknown cancer at age 12 years, a maternal grandmother had bilateral breast cancer at ages 20 and 31 years, and a maternal great-grandmother also had breast cancer. One of 3 maternal half-siblings developed alveolar rhabdomyosarcoma of the tongue at age 4 years. The 2 others, ages 8 and 10 years, were in good health.
Examination revealed proptosis (Figure 1A and B), increased resistance to retropulsion, inferolateral dystopia, and limited vertical ductions of the left eye. The remainder of the ophthalmic examination results were unremarkable. Computerized tomography demonstrated a predominantly intraconal, inhomogeneous mass, 2.8 cm in maximum dimension, in the superomedial aspect of the left orbit (Figure 2A). Magnetic resonance imaging (Figure 2B) confirmed the computerized tomographic findings, including heterogenous contrast enhancement. A transcaruncular orbital biopsy was performed.
Patient with proptotic left eye. A and B, Initial examination. C, Twelve-week follow-up with worsening proptosis.
Radiographic imaging. A, Computed tomographic scan at initial examination demonstrating predominantly intraconal, inhomogeneous mass in the left orbit. B, T1-weighted magnetic resonance image at initial examination demonstrating mass in superomedial aspect of the left orbit. C, T1-weighted magnetic resonance image at 12-week follow-up showing increased tumor size.
Histopathologic Findings. The biopsy specimen showed a moderately cellular spindle cell neoplasm composed of well-formed interlacing fascicles of tumor cells cut in longitudinal and cross sections (Figure 3A). The cells contained pale, indistinct cytoplasm and oval or elongated hyperchromatic nuclei with homogenous chromatin and inconspicuous nucleoli. Scattered throughout were spindled, polygonal, or rounded rhabdomyoblasts with distinct, brightly eosinophilic cytoplasm (Figure 3B). There was moderate nuclear pleomorphism. Mitoses were rare. No necrosis was identified. Distinct immunostaining of the tumor cells, particularly the rhabdomyoblasts, with antibodies against desmin and myogenin was observed (Figure 4A and B). Muscle-specific actin immunoreactivity was also present (not shown). The proliferation marker MIB-1 was positive in most tumor cells (not shown). Immunoreactivity for the tumor suppressor p53 was highly positive in the majority of tumor cells (Figure 4C). A diagnosis of embryonal rhabdomyosarcoma with prominent spindle cell differentiation was made.
Orbital rhabdomyosarcoma. A, Neoplastic cells with spindled, hyperchromatic nuclei arranged in vaguely delineated bundles. Necrosis is absent (hematoxylin-eosin, original magnification × 200). B, Rhabdomyoblasts containing moderate amounts of eosinophilic cytoplasm (arrows). Mitotic figures and marked nuclear pleomorphism are absent (hematoxylin-eosin, original magnification × 360).
Orbital rhabdomyosarcoma. Rhabdomyosarcoma cells are decorated with antibodies to desmin (A), myogenin (B), and p53 (C) (original magnification × 360).
Clinical Course. Low-risk protocol treatment was begun for stage I, clinical group III embryonal rhabdomyosarcoma limited to the orbit. The patient received several cycles of vincristine sulfate, actinomycin, and cyclophosphamide followed by radiotherapy. After 12 weeks of treatment, however, he showed evidence of regrowth on clinical examination (Figure 1C) with a more than 20% increase in tumor size based on magnetic resonance imaging (Figure 2C). Therefore, a relapse protocol with ifosfamide, etoposide phosphate, doxorubicin hydrochloride, and cyclophosphamide was initiated with apparent response.
A diagnosis of LFS was made based on his strong family history of cancer. After informed consent was obtained, a peripheral blood sample was sent to University of Minnesota Physicians Outreach Laboratory, and DNA sequencing of selected exons confirmed the diagnosis by detecting a germline mutation 13203 G>A within exon 5 of the p53 gene, which results in change of amino acid 175 from arginine to histidine (R175H).
Orbital rhabdomyosarcomas are typically sporadic but can occur in the setting of syndromes such as LFS. Li-Fraumeni syndrome is a cancer predisposition syndrome in which soft tissue sarcomas, osteosarcomas, premenopausal breast cancers, adrenocortical carcinomas, brain tumors, and leukemias occur in affected family members.3 Rhabdomyo sarcoma is the most common sarcoma in LFS.3 Criteria for the diagnosis include a proband with sarcoma occurring before age 45 years, a first-degree relative with any cancer diagnosed before age 45 years, and another first- or second-degree relative with any cancer diagnosed before age 45 years or sarcoma diagnosed at any age.3 Studies estimate a cancer risk of 42% by age 16 years and 85% by age 85 years in mutation carriers in LFS.4
Germline p53 mutations are found in approximately 85% of individuals with family histories meeting criteria for LFS1 and up to 23% of patients with rhabdomyosarcoma diagnosed at younger than 3 years.5 A nuclear phosphoprotein, p53 halts progression of the cell cycle in the G1 phase when DNA damage, gamma irradiation, or hypoxia is present6; p53 also plays a role in tumor apoptosis.6 Although mutations have been documented at several loci in the p53 tumor suppressor gene on chromosome 17, codon 175 represents a germline mutational hot spot.1 The p53 R175H mutant has also been shown to impair cellular apoptosis and promote proliferation in mouse models and tissue culture.7,8 Antibodies that bind the R175H mutant p53 protein restore induction of apoptosis and abrogate mutant p53-mediated cellular proliferation.8 Inasmuch as the efficacy of chemotherapeutic drugs and radiotherapy relies on their ability to trigger tumor cell apoptosis, mutation-induced loss of p53 function may reduce tumor sensitivity to apoptosis and, thus, the efficacy of anticancer drugs and radiotherapy.
Based on data from the Intergroup Rhabdomyosarcoma Study, patients treated for embryonal tumors have 5-year survival rates of 87%, and those with primary orbital rhabdomyosarcomas approach 100% survival.9 Our patient's tumor was classified as an embryonal rhabdomyosarcoma with prominent spindle cell differentiation. Among the unusual features of this embryonal tumor, however, were its prominent fascicles imparting a striking resemblance to leiomyosarcoma, reduced cellularity and pleomorphism when compared with typical embryonal rhabdomyosarcomas, and low mitotic rate. These histopathologic characteristics may underlie the poor response to chemotherapy and radiotherapy in this case, similar to the poorer prognosis of adults with a spindle cell subtype.10
Given the high incidence of germline p53 mutations in children with rhabdomyosarcoma who are younger than 3 years,5 it is likely that LFS is present, but not recognized, in some cases of orbital rhabdomyosarcoma. Obtaining a family history of cancer is the best method of detecting LFS, which may then be further supported by genetic analysis of the patient. Immunohistochemical staining is inadequate because mutant p53 may be robustly expressed in orbital rhabdomyosarcomas in LFS but lack tumor suppressor function. The diagnosis of LFS may be life saving in affected patients and their families.
Correspondence: Dr Elner, Department of Ophthalmology, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (firstname.lastname@example.org).
Financial Disclosure: None reported.
Previous Presentation: This study was presented in part at the Combined Ophthalmic Pathology Meeting; April 22, 2006; Philadelphia, Pa.
Chong DY, Demirci H, Ronan SM, Flint A, Elner VM. Orbital Rhabdomyosarcoma in Li-Fraumeni Syndrome. Arch Ophthalmol. 2007;125(4):566-599. doi:10.1001/archopht.125.4.566