Epstein-Barr Virus–Associated Leiomyosarcoma of the Iris in a Child Infected With Human Immunodeficiency Virus FREE

Children with human immunodefiency virus (HIV) infection have a higher risk of developing a malignant neoplasm, the most common of which is non-Hodgkin lymphoma, followed by leiomyosarcoma.^{1 - 2} Most leiomyosarcomas in children with HIV infection have been found in various anatomical locations, including the gastrointestinal tract, liver, spleen, and lung.^{3 - 4} The association between leiomyosarcoma and Epstein-Barr virus (EBV) infection in HIV-infected patients is known.⁵

Reports from 1964⁶ and 1972⁷ described smooth muscle tumors in the iris. Foss et al, ⁸ using immunohistochemical analysis, have reclassified previous reported cases as melanocytic lesions. As a result, stricter pathologic criteria for diagnosing intraocular neoplasms of smooth muscle were established in 1994.⁸ Since then, there has been only one well-documented example of iris leiomyoma reported.⁹ We report an HIV-infected girl with an iris neoplasm, histologically and immunohistochemically proven to be leiomyosarcoma.

A 4-year-old Thai girl with vertically acquired HIV infection was born at our hospital in 1996. She was asymptomatic until age 2 years, when she developed dermatitis, dilated cardiomyopathy, hepatosplenomegaly, lymphadenopathy, and parotitis. The CD4 count was 1%. At 3 years of age, treatment with zidovudine and dideoxycytidine was started, but the adherence to antiretroviral agents was poor. Her subsequent course was complicated by pneumonia, leading to several hospital admissions.

At the age of 4 years 10 months, she experienced pain in her right eye. Ophthalmologic examination revealed a whitish mass located on the lower half of the iris, 4 mm in diameter. There was vascular dilatation on the anterior stromal surface. The lower part of the anterior chamber was shallow, with peripheral anterior synechiae. There were no signs of inflammation seen in the anterior chamber. The lens was normal. Computed tomography (CT) did not demonstrate any other intraocular lesions, but CT of the brain showed a 3-cm cystic mass in the parenchyma of the left frontal lobe. Aspiration of the cyst revealed numerous red cells, some mononuclear cells, and no malignant cells.

Inferior sector iridectomy was carried out, and the iris mass was surgically removed by an inferior limbal incision. The entire tissue was fixed in 10% formalin, routinely processed, and embedded in paraffin wax. In addition to routine staining, immunohistochemical analysis was performed with antibodies against the following proteins: S100, HMB45, muscle-specific actin, smooth-muscle actin, desmin, and EBV latent membrane protein. In situ hybridization for EBV was also performed, using EBV-encoded RNA oligonucleotide probe. Both the immunohistochemical analysis and in situ hybridization were done in the presence of adequate controls.

Microscopically (Figure 1 and Figure 2), the lesion consisted of plump spindle-shaped tumor cells forming interlacing fascicles. The neoplastic nuclei were hyperchromatic, and some of them possessed distinct small nucleoli. There are scattered mitotic figures, approximately 5/10 per high-power field. Tumor cells strongly expressed muscle-specific actin and smooth-muscle actin, supporting the smooth muscle origin of the lesion. Desmin, S100 protein, and HMB45 were nonreactive. The above findings are characteristics of leiomyosarcoma. Evidence of EBV infection was revealed by in situ hybridization but not by immunohistochemical analysis.

At the age of 5 years 3 months, she was admitted to the hospital with persistent and severe abdominal pain. Duodenal tissue biopsy showed acid fast bacilli in the mucosa, and Mycobacterium gordonae were later isolated. She died at the age of 5 years 6 months.

Leiomyosarcoma has been well-documented to be associated with HIV infection, and usually occurs in the visceral organs. The tumor rarely arises in the uveal tract. A literature search, using the keywords "iris, " "uvea, " "uveal tract, " and "leiomyosarcoma" from major electronic databases (MEDLINE, EMBASE, BIOSIS, and CINAHL), did not reveal any previous cases of histologically and immunohistochemically proven iris leiomyosarcoma.

Before the advent of immunohistochemical analysis, intraocular leiomyomas and their malignant counterparts, leiomyosarcomas, have been a frequent subject of debate.^{6 - 7} Spindle cell melanoma is the main differential diagnosis. Immunohistochemical study is therefore particularly important. Foss et al⁸ proposed that immunohistochemical and/or electron microscopic investigation are crucial in establishing the correct diagnosis of ocular smooth muscle tumors. In our case, the positive staining for smooth muscle markers (smooth-muscle actin and muscle-specific actin) and the absence of immunolabeling for melanoma markers (S100 protein and HMB45) strongly support the diagnosis of smooth muscle tumor and rule out the possibility of melanocytic lesion.^{8 - 9} Although histologic criteria for the distinction of benign and malignant smooth muscle neoplasms outside the uterus are not well established, the high mitotic index favors the diagnosis of leiomyosarcoma.

The presence of the cystic lesion in the left frontal lobe raises questions concerning the possible relationship between the cyst and the iris tumor and whether both represent leiomyosarcoma. If this was the case, it would be difficult to determine the primary site of the tumor. However, most reported HIV-associated intracranial leiomyosarcomas are dura-based, solid (noncystic) masses.^{10 - 12} We consider both of these lesions to be unrelated. Unfortunately, no tissue was obtained from the cyst for definite histologic evaluation.

Regarding the histogenesis, smooth muscle tumors of the iris are thought to originate from its sphincter or dilator muscle, but the concept that neoplasms can affect the iris is dubious.⁸ Our case has confirmed that a cellular progenitor of smooth muscle tumors does exist in this location. The association between EBV and smooth muscle tumors in HIV-infected subjects has been well documented, ⁵ as evident in our patient. In addition to the reduction in tumor surveillance cells and the inability to remove EBV in immunocompromised subjects, it has been shown that EBV receptors are unregulated and thus may enhance viral entrance into and transformation of the human cells.^{5 ,12} The discrepancy between EBV-encoded RNA in situ hybridization and immunohistochemical characteristics of EBV latent membrane protein is the same as for previously reported EBV-associated smooth muscle tumors.^{10 ,13} Failure to detect EBV latent membrane protein may be due to the absence or subthreshold level of the antigen in this tumor cell type.¹³

This case is the first immunohistochemically verified leiomyosarcoma of the iris that has occurred in an HIV-infected child, to our knowledge. Although the association between the tumor and EBV in immunosuppressive patients has been previously determined, this report reiterates that HIV infection facilitates the development of this tumor, even in an unusual location such as the iris.

The authors have no relevant financial interest in this article.

Corresponding author and reprints: Wasee Tulvatana, MD, Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University Hospital, 1873 Rama IV Rd, Bangkok 10330, Thailand (e-mail: wasee.t@chula.ac.th).