Extraocular Muscle Lymphoma (EOML)
Lymphomas are malignant tumors of lymphoid origin formed by a clonal proliferation of B-lymphocytes, T-lymphocytes, or natural killer (NK) cells. Orbital lymphoma can originate in the conjunctiva, eyelids, lacrimal glands, or extraocular musculature. Orbital lymphomas account for 1% of non-Hodgkins lymphoma cases. They are the most common orbital malignancy in adults, accounting for 10% of cases. Extraocular muscle lymphomas (EOMLs) are rare, accounting for less than 0.2-9.6% of orbital lymphomas. EOMLs are most commonly B-cell lymphomas and the most common subtype is extranodal marginal zone lymphoma. The majority of EOMLs present with involvement of a single muscle but multiple EOM involvement may also occur.
Etiology and Risk Factors
The average age of presentation for EOML is between 57.1 to 64.7 years.  but cases have been reported from ages 13 to 90 years. EOML most commonly presents unilaterally, but has been found to occur bilaterally in 9-12% of cases. The most commonly involved muscles in EOML are the rectus muscles. In one study of 57 EOML cases, the prevalence was highest for the rectus muscles (73%), followed by the oblique muscles (17%) and the levator palpebrae superioris (11%). Another cohort of 25 patients found the highest prevalence for the levator palpebrae superioris (44%), followed by the superior rectus (40%), inferior rectus (40%), lateral rectus (28%), inferior oblique (28%), medial rectus (24%), and superior oblique (16%).
Risk factors for orbital lymphoma include genetic abnormalities, immunosuppressive disorders, and chronic antigen stimulation caused by infectious organisms. Concomitant autoimmune disease has also been described in orbital lymphoma (e.g., Sjogren syndrome, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto thyroiditis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia).
The most common symptoms of EOML are diplopia and edema, but pain is reported in a minority of cases. Patients with EOML however do not typically have afferent complaints and visual loss is uncommon (average visual acuity 20/30).
The most frequent imaging technique, orbital computed tomography (CT), demonstrates enlargement of the affected muscle(s). Orbital magnetic resonance imaging (MRI) also demonstrates enlargement of the affected EOM with enhanced and thickened tendons. Orbital echography can demonstrate thickening of the EOM and involvement of the tendon which is a potential differentiating feature from other more common causes of EOM enlargement (e.g., thyroid eye disease). Surgical orbitotomy and open biopsy of the affected EOM may be necessary however for definitive confirmation of EOML. Positron emission tomography (PET) or combined PET/CT may be useful for staging of disease and guiding treatment options.
Histopathology confirms lymphocytic infiltrate in EOML but further testing is necessary to differentiate benign from malignant (monoclonal) lesions. Immunohistochemistry can confirm the monoclonal nature of the typically B cell neoplasm. Further immunostaining and cell markers (e.g., Ig, CD20, CD3, CD45, kappa, and lambda light chains) confirm the specific subtype of EOML.
The differential diagnosis for EOML includes benign lymphoproliferative lesions, lymphoid hyperplasia, infectious lesions, orbital inflammatory pseudotumor, and other extraocular muscle malignancies (e.g., metastasis).
Radiotherapy is the preferred treatment for low-grade and localized orbital lymphoma. Radiotherapy can be used as monotherapy or can be used in conjunction with other treatment modalities as indicated by oncology. The radiation dosage can vary from 4-80 Gy. The most commonly used radiation dosage is between 20-40 Gy for orbital lymphoma.
Chemotherapy is most commonly used in the treatment of high-grade or disseminated lymphoma. Steroids can be used in conjunction with chemotherapy in the treatment of orbital lymphoma. Immunotherapy with rituximab can also be used in conjunction with chemotherapy. In rare cases, debulking orbital surgery may reduce tumor size.
Overall, the prognosis of EOML depends on stage and cell type but there is a high rate of local remission of the disease. The average time of death however after presentation has been found to be 5.4 years, and the mortality rate may be as high as 14-24%. Ocular complications of radiation retinopathy (average of 3713 Gy radiotherapy) and neovascular glaucoma have been reported in a minority of cases following treatment.
Clinicians should be aware that isolated EOM enlargement can be the presenting or only sign of EOML. Most EOMLs are B-cell in origin and of marginal subtype. Definitive diagnosis typically requires biopsy with histopathology and immunohistochemical studies. Orbital radiation therapy may induce a local remission but consultation with oncology is recommended.
- Yen MT, Bilyk JR, Wladis EJ, Bradley EA, Mawn LA. Treatments for Ocular Adnexal Lymphoma: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018 Jan;125(1):127-136. doi: 10.1016/j.ophtha.2017.05.037. Epub 2017 Jul 14. PMID: 28712656.
- Olsen TG, Heegaard S. Orbital lymphoma. Survey of ophthalmology. 2019;64(1):45-66. doi:10.1016/j.survophthal.2018.08.002
- Ahmed S, Shahid RK, Sison CP, Fuchs A, Mehrotra B. Orbital Lymphomas: A Clinicopathologic Study of a Rare Disease. The American journal of the medical sciences. 2006;331(2):79-83. doi:10.1097/00000441-200602000-00013
- Jakobiec FA. Ocular Adnexal Lymphoid Tumors: Progress in Need of Clarification. American journal of ophthalmology. 2008;145(6):941-950. doi:10.1016/j.ajo.2008.03.013
- Watkins LM, Carter KD, Nerad JA. Ocular Adnexal Lymphoma of the Extraocular Muscles: Case Series From the University of Iowa and Review of the Literature. Ophthalmic plastic and reconstructive surgery. 2011;27(6):471-476. doi:10.1097/IOP.0b013e31822e5c1b
- Sullivan TJ, Whitehead K, Williamson R, et al. Lymphoproliferative Disease of the Ocular Adnexa: A Clinical and Pathologic Study With Statistical Analysis of 69 Patients. Ophthalmic plastic and reconstructive surgery. 2005;21(3):177-188. doi:10.1097/01.IOP.0000159173.42243.AD
- Eade EL, Hardy TG, McKelvie PA, McNab AA. Clinicopathological Features and Outcomes in Lymphoma of Extraocular Muscles. Ophthalmic plastic and reconstructive surgery. 2019;35(6):615-618. doi:10.1097/IOP.0000000000001426
- Guo P, Xian J, Man F, et al. Magnetic Resonance Imaging Features of Extraocular Muscle Lymphoma in Five Cases. Chinese Medical Journal. 2016;129(19):2384-2385. doi:10.4103/0366-6999.190679
- Hornblass A, Jakobiec FA, Reifler DM, Mines J. Orbital Lymphoid Tumors Located Predominantly within Extraocular Muscles. Ophthalmology (Rochester, Minn.). 1987;94(6):688-697. doi:10.1016/S0161-6420(87)33393-7
- Mombaerts, Ilse, MD, PhD, Tousseyn, Thomas, MD, PhD, Van Limbergen, Erik, MD, PhD, Demaerel, Philippe, MD, PhD. Clinically Recognizing Enlarged Extraocular Muscles from Lymphoid Origin. Ophthalmology (Rochester, Minn.). 2015;122(1):217-218. doi:10.1016/j.ophtha.2014.08.018
- Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the Ocular Adnexa: A Study of 353 Cases. The American journal of surgical pathology. 2007;31(2):170-184. doi:10.1097/01.pas.0000213350.49767.46
- Chan-Kai BT, Yen MT. Combined positron emission tomography/computed tomography imaging of orbital lymphoma. Am J Ophthalmol. 2005 Sep;140(3):531-3. doi: 10.1016/j.ajo.2005.02.044. PMID: 16139007.