Epstein-Barr virus-associated smooth muscle tumor of the iris in a patient with transplant: a case report and review of the literature.
Abstract: * Epstein-Barr virus infection has been linked to the development of smooth muscle tumors in immunocompromised patients with organ transplants and acquired immunodeficiency syndrome. A 52-year-old female recipient of a renal transplant presented with enlarging masses of the left iris. Incisional biopsy of the mass revealed a smooth muscle tumor of the iris. Epstein-Barr virus infection was confirmed by in situ hybridization for Epstein-Barr virus-encoded, small RNA in tumor cells. Eight months after total iridectomy the patient was free of disease. Although the prognosis and classification of Epstein-Barr virus-associated smooth muscle tumors are controversial, mortalities caused by these tumors are rare.

(Arch Pathol Lab Med. 2009;133:1238-1241)
Article Type: Clinical report
Subject: Epstein-Barr virus diseases (Development and progression)
Epstein-Barr virus diseases (Case studies)
Epstein-Barr virus diseases (Care and treatment)
Muscle tissue tumors (Development and progression)
Muscle tissue tumors (Case studies)
Muscle tissue tumors (Care and treatment)
Iris (Eye) (Medical examination)
Smooth muscle (Medical examination)
Kidneys (Transplantation)
Kidneys (Complications and side effects)
Authors: Yu, Le
Aldave, Anthony J.
Glasgow, Ben J.
Pub Date: 08/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: August, 2009 Source Volume: 133 Source Issue: 8
Topic: Canadian Subject Form: Muscle tissue tumours; Muscle tissue tumours; Muscle tissue tumours
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230247109
Full Text: Iris smooth muscle tumors have been reported to comprise between 2.3% and 14% of all iris tumors. (1,2) Epstein-Barr virus (EBV)-induced smooth muscle tumors have been associated with acquired immunodeficiency syndrome as well as with organ transplantation. A case is presented of EBV-associated smooth muscle tumors involving the iris of a patient with kidney transplant taking topical steroids.

REPORT OF A CASE

A 52-year-old woman was referred for evaluation of 2 iris lesions in the left eye (Figure 1, A). Sixteen years before, the patient had undergone a cadaveric renal transplant and was treated with immunosuppressive medications, including mycophenolate mofetil, cyclosporine, and prednisone. Trabeculectomy, cataract surgery, and corneal transplant of the left eye had been performed 10 years earlier, with continuous, subsequent, topical steroid use in the left eye since that time. Her best-corrected visual acuity was 20/20 in the right eye and 20/200 in the left eye. The 2 iris masses were noted to have enlarged rapidly during a period of 2 months to 4.2 x 3.8 mm at the 4 o'clock position and 4.0 x 3.8 mm at the 8 o'clock position (Figure 1, B). Ultrasound biomicroscopy did not demonstrate evidence of ciliary body involvement.

A fine-needle aspiration biopsy of the iris lesion produced insufficient material for diagnosis. Histologic examination of the incisional biopsy specimen revealed a tumor composed of intersecting fascicles of nonpigmented, spindle-shaped cells, with blunt ended and occasionally vesicular nuclei and eosinophilic cytoplasm (Figure 2, A). Nuclear pleomorphism, occasional pyknotic cells, and rare mitotic figures were observed (Figure 2, B). Immunohistochemistry was performed on paraffin-embedded sections of the iris biopsy. Antibodies directed against smoothmuscle actin and desmin strongly reacted to tumor cells (Figure 3). The tumor cells were not reactive to anti-Melan-A, HMB-45, neurofilament, and S100. Electron microscopy of the tumor cells revealed numerous thin filaments, micropinocytotic vesicles emanating from the cell membrane, dense bodies, and glycogen (Figure 4). Sections hybridized to EBV-encoded, small RNA were positive in approximately 30% to 50% of the tumor cell nuclei (Figure 5). Given continued rapid growth of the iris lesions with posterior displacement of the intraocular lens and increasing intraocular pressure, a complete iridectomy, removal of the dislocated intraocular lens, placement of a Morcher 67B iris-reconstruction lens, and corneal transplantation were performed. The excised, bilobed mass measured 14 x 6 x 5 mm in greatest dimensions and demonstrated the same histologic features as those noted in the incisional biopsy specimen. The patient did not demonstrate any clinical signs or symptoms of metastasis. The lack of clear criteria for the diagnosis of malignancy in this location resulted in a diagnosis of smooth muscle tumors of uncertain malignant potential. She has not had a recurrence of the iris tumor in the 8 months of follow-up.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

COMMENT

Seventy-eight cases of EBV-associated smooth muscle tumors have been reported in a variety of organs, including liver, lung, and brain. (3-11) Although EBV-associated iris smooth muscle tumors have not been previously described in immunosuppressed, organ-transplant recipients, EBV-associated leiomyosarcoma of the iris has been described in a patient with acquired immunodeficiency syndrome. (6) Of the 37 additional cases published of iris smooth muscle tumors, 33 (89%) were reported before 1975 and were not confirmed by either immunohistochemistry or electron microscopy. (1,2,6,12-18) Neither immune status nor EBV association were invoked as the cause in any of the 4 remaining cases (11%; Table). (6,15-18)

[FIGURE 3 OMITTED]

Other neoplasms, including Burkitt lymphoma, Hodgkin disease, nasopharyngeal carcinoma, and posttransplant lymphoproliferative disease, have been associated with EBV infection. (19) Expression of latent EBV genes and aberrant cellular signaling are involved in oncogenicity, although the precise mechanism for the genesis of EBV-associated smooth muscle tumors in an immunocompromised setting is not known. (19)

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

Our patient had been immunosuppressed at the time of detection of the tumor, within the range (8-348 months) described for 28 immunosuppressed patients with organ transplant and EBV smooth tumors in other organs. (4,5,8,10,11) In addition, topical corticosteroids had been administered continuously to the left eye for 10 years at the time of tumor detection. A single case of exogenous corticosteroid use for 5 years was previously reported for an EBV-related leiomyoma of the abdominal wall. (8)

The classification and prognosis of EBV-related smooth muscle tumors are controversial. In the 78 reported cases, the diagnoses included leiomyoma (7%), smooth muscle tumor of unknown malignant potential (12%), leiomyosarcoma (28%), and simply EBV-associated smooth muscle tumor

(53%).3-11 Three of 78 patients (4%) died with multiple organ involvement, including the liver and lungs. (8,10,11) Two of the three patients (67%) were found to have well-differentiated tumors and were diagnosed with EBV-associated smooth muscle tumors, and 1 (33%) was diagnosed with leiomyosarcoma. (8,10,11) Although EBV-associated smooth muscle tumors generally show mild to moderate atypia and low mitotic activity, 46 of the 78 cases (59%) manifested multiple lesions. (3-11) Southern blot and microsatellite analysis suggest that multiple tumors represent independent primary tumors rather than metastatic disease. (8) Our case showed moderate atypia and only rare mitotic figures. The only other EBV-related smooth iris tumor was diagnosed as leiomyosarcoma, and the patient subsequently died of unknown causes. (6) Four additional cases of leiomyosarcomas of the iris have been reported; however, neither immunohistochemical nor electron microscopy analyses were employed to verify smooth muscle origin. (2) However, these patients were treated by iridectomy and / or enucleation, and all were free of disease at follow-up time between 3 and 5 years. The rarity of the tumor has precluded the establishment of tested cytologic criteria for malignancy. Treatment of EBV-associated smooth muscle tumors has included reduction of immunosuppression, chemotherapy, antiviral treatment, and radiation therapy. (3-11) As in our case, most of these tumors reviewed in the literature were treated by surgical resection, with or without other forms of adjuvant therapy. (3-11) Of the reported cases treated with surgical resection, regardless of additional therapy, 33% were disease-free at 1 year follow-up. In contrast, no cures were reported without surgery. (3-11)

Because EBV infects 95% of the world's population, the possibility of latent infection should be considered in evaluating smooth muscle tumors of the eye, particularly in immunocompromised hosts and/or when multiple lesions are present. (19)

References

(1.) Duke JR, Dunn SN. Primary tumors of the iris. AMA Arch Ophthalmol. 1958;59(2):204-214.

(2.) Ashton N. Primary tumours of the iris. Br J Ophthalmol. 1964;48:650-668.

(3.) Litofsky NS, Pihan G, Corvi F, Smith TW. Intracranial leiomyosarcoma: a neuro-oncological consequence of acquired immunodeficiency syndrome. J Neurooncol. 1998;40(2):179-183.

(4.) Cheuk W, Li PC, Chan JK. Epstein-Barr virus-associated smooth muscle tumour: a distinctive mesenchymal tumour of immunocompromised individuals. Pathology. 2002;34(3):245-249.

(5.) Ferri L, Fraser R, Gaboury L, Mulder D. Epstein-Barr virus-associated pulmonary leiomyosarcoma arising twenty-nine years after renal transplantation. J Thorac Cardiovasc Surg. 2003;126(3):877-879.

(6.) Tulvatana W, Pancharoen C, Mekmullica J, et al. Epstein-Barr virus-associated leiomyosarcoma of the iris in a child infected with human immunodeficiency virus. Arch Ophthalmol. 2003;121(10):1478-1481.

(7.) Kumar S, Santi M, Vezina G, Rosser T, Chandra RS, Keating R. Epstein-Barr virus-associated smooth muscle tumor of the basal ganglia in an HIV+ child: case report and review of the literature. Pediatr Dev Pathol. 2004;7(2):198-203.

(8.) Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of29 tumors from 19 patients. Am J Surg Pathol. 2006;30(1):75-82.

(9.) Gallien S, Zuber B, Polivka M, et al. Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature. Oncology. 2008;74(3-4):167-176.

(10.) Moore Dalal K, Antonescu CR, Dematteo RP, Maki RG. EBV-associated smooth muscle neoplasms: solid tumors arising in the presence of immunosuppression and autoimmune diseases. Sarcoma. 2008;2008:859407. doi: 10.1155/ 2008/859407.

(11.) Timmons CF, Dawson DB, Richards CS, Andrews WS, Katz JA. Epstein-Barr virus-associated leiomyosarcomas in liver transplantation recipients: origin from either donor or recipient tissue. Cancer. 1995;76(8):1481-1489.

(12.) Erdbrink WL, Harbert F. Leiomyoma of the iris: report of a case and review of literature. AMA Arch Ophthalmol. 1955;53(5):643-648.

(13.) Brown WC, Kellenberger RE, Hudson KE, Matthews JL. Leiomyoma of the iris: report of a case. Am J Ophthalmol. 1957;43(3):457-460.

(14.) De Buen S, Olivares ML, Charlin C. Leiomyoma of the iris: report of a case. Br J Ophthalmol. 1971;55(5):353-356.

(15.) Okamoto N, Sotani T, Shimo-Oku M, Sashikata T. A case with leiomyoma of iris extirpated with cryosurgery and its pathological findings. Acta Ophthalmol. (Copenh). 1982;60(2):183-189.

(16.) Jellie HG, Gonder JR, Willis NR, Green L, Tokarewicz AC. Leiomyoma of the iris. Can J Ophthalmol. 1 989;24(4):169-171.

(17.) Eide N, Farstad IN, Roger M. A leiomyoma of the iris documented by immunohistochemistry and electron microscopy. Acta Ophthalmol Scand. 1997; 75(4):470-473.

(18.) Tuncer S, Peksayar G, Demiryont M, Gozum N. Longterm follow-up of a patient with iris leiomyoma treated with partial lamellar iridocyclectomy. Acta Ophthalmol Scand. 2004;82(1):112-114.

(19.) Baumforth KR, Young LS, Flavell KJ, Constandinou C, Murray PG. The Epstein-Barr virus and its association with human cancers. Mol Pathol. 1999;52(6): 307-322.

Le Yu, MD; Anthony J. Aldave, MD; Ben J. Glasgow, MD

Accepted for publication March 20, 2009.

From the Jules Stein Eye Institute (Drs Yu, Aldave, and Glasgow) and the Department of Pathology and Laboratory Medicine (Dr Glasgow), David Geffen School of Medicine, University of California, Los Angeles.

Reprints: Ben J. Glasgow, MD, Jules Stein Eye Institute, Room B-279, University of California, 1 0833 Le Conte Ave, Los Angeles, CA 90095 (e-mail: bglasgow@mednet.ucla.edu).

The authors have no relevant financial interest in the products or companies described in this article.
Iris Smooth Muscle Tumors With Diagnosis by Immunohistochemistry
and/or Electron Microscopy (a)

Source, y                   Age, y/Sex   Immunosuppression

Okamoto et al, (15) 1982       44/M             ...
Jellie et al, (16) 1989        77/F             ...
Eide et al, (17) 1997          43/M             ...
Tulvatana et al, (6) 2003      4/F              Yes
Tuncer et al, (18) 2004        40/F             ...
This case                      52/F             Yes

Source, y                   Presentation   Treatment    Follow-up, mo

Okamoto et al, (15) 1982    ACR            Iridectomy
Jellie et al, (16) 1989     Incidental     Biopsy
Eide et al, (17) 1997       EU             Iridectomy     ANED, 7
Tulvatana et al, (6) 2003   Pain           Iridectomy     DUC, 12
Tuncer et al, (18) 2004     EU             Iridectomy     ANED, 144
This case                   Incidental     Iridectomy     ANED, 8

Abbreviations: ACR, anterior chamber reaction; ANED, alive, no
evidence of disease; DUC, dead of unknown cause; EM, electron
microscopy; EU, ectropion uvea; I, inferior; IN, inferonasal;
IT, inferotemporal; N, nasal; ST, superotemporal; STUMP, smooth
muscle tumor of uncertain malignant potential.

(a) Epstein-Barr virus-encoded small RNA detected by in situ
hybridization.

Table. Extended

Tumor Location   Size, mm       Diagnosis

  ST                5       Leiomyoma
  I                ...      Leiomyoma
  N                 3       Leiomyoma

  I                 4       Leiomyosarcoma (a)

  IN                8       Leiomyoma

  IN, IT           4, 4     STUMP (a)

Tumor Location   Immunohistochemistry   EM

  ST                        ...         Yes
  I                         ...         Yes
  N              Smooth muscle          Yes
                 [actin.sup.+];
                 [desmin.sup.+]

  I              Muscle specific        ...
                 [actin.sup.+];
                 [desmin.sup.+];
                 [S100.sup.-];
                 [HMB-45.sup.-];
                 [NF.sup.-]

  IN             Smooth muscle          ...
                 [actin.sup.+]+;
                 [vimentin.sup.+]+;
                 [S100.sup.-];
                 [HMB-45.sup.-]

  IN, IT         Smooth muscle          Yes
                 [actin.sup.+];
                 [desmin.sup.+];
                 [S100.sup.-];
                 [Melan-A.sup.-];
                 [HMB-45.sup.-];
                 [NF.sup.-]
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