Optometry (2010) 81, 528-532

Recurrent subconjunctival hemorrhages leadingto the discovery of ocular adnexal lymphoma

Dave Hicks, O.D.,a,b and Andrew Mick, O.D.b

aVeterans Affairs Palo Alto Health Care System, Palo Alto, California; and bSan Francisco Department of Veterans AffairsMedical Center, San Francisco, California.

KEYWORDS Abstract

He

152

doi:

Conjunctivalneoplasms;

Eye hemorrhage;

Lymphoma, B-cell

BACKGROUND: Subconjunctival hemorrhages commonly occur idiopathically or from causes includ-ing ocular surgery, trauma, anticoagulation medications, or a Valsalva maneuver. When a hemorrhagepersists or recurs, a more extensive list of differential diagnoses must be considered. This report detailsa case in which persistent subconjunctival hemorrhages led to the discovery of ocular adnexal lym-phoma.CASE REPORT: A 68-year-old white man presented with a 7- to 8-month history of a recurrent red lefteye. There was no associated pain, discharge, or change in vision over that time. The right eye wasnever involved. An ocular examination of the left eye found a mild nasal subconjunctival hemorrhageand a salmon-pink–colored lesion involving the superior conjunctiva. Clinical findings, photos, mag-netic resonance images, and histopathology results are presented and reviewed. The signs, symptoms,incidence, pathophysiology, treatment, and prognosis of ocular adnexal lymphoma are also discussed.CONCLUSION: Lymphomas can occur in a variety of sites in the body. It is well documented that pri-mary tumors can originate in the ocular adnexa. Although not typical, the first sign in this case was arecurrent subconjunctival hemorrhage. The importance of a thorough ocular examination is paramountfor a patient’s ocular health and possibly the patient’s life.Optometry 2010;81:528-532

Subconjunctival hemorrhages commonly occur idiopath-ically or from causes including ocular surgery, trauma,anticoagulation medications, or a Valsalva maneuver. Asidefrom minor irritation and pronounced redness, subconjun-tival hemorrhages are benign and only require patienteducation, palliative care, or monitoring. More important,clinical investigation should focus on discovering andrectifying the underlying cause. When a hemorrhage per-sists or recurs, a more extensive list of differential diagnosesmust be considered. This report details a case in which theclinical finding of persistent and recurring subconjunctival

Corresponding author: Dave Hicks, O.D., Veterans Affairs Palo Alto

alth Care System, 3801 Miranda Ave., Palo Alto, California 94304.

E-mail: davehicks.OD@gmail.com

9-1839/$ -see front matter–This is a U.S. government work. There are no restrictions on

10.1016/j.optm.2009.11.008

hemorrhages led to the discovery and diagnosis of ocularadnexal lymphoma.

Case report

A 68-year-old white man presented to the eye clinic at theSan Francisco Department of Veterans Affairs MedicalCenter with the chief complaint of a recurrent nonpainfulred left eye. He was a new patient to the clinic, and noprevious records were available. The patient recalled thathis left eye had been persistently red for about 7 to 8months prior with some episodes of resolution and recur-rence. During the 6 months before presentation, the patientreported that he was evaluated twice and each time had asubconjunctival hemorrhage diagnosed. There was no

its use. Published by Elsevier Inc. on behalf of the American Optometric Association.

Figure 2 Raised salmon-pink–colored lesion, superior bulbar conjunc-

tiva, left eye.

Hicks and Mick Clinical Care 529

associated pain, discharge, or change in vision over thatperiod, and the right eye was never involved. Medicalhistory was remarkable for hypertension, hepatitis C, livercirrhosis, and benign prostate hypertrophy. The patient wasnot using blood-thinning medications. Clotting status lab-oratory tests had not been performed at presentation, but1 month later, his platelet count was low. Social history waspositive for alcohol abuse and smoking, although he ceasedsmoking more than 25 years ago.

Best-corrected visual acuities in each eye were 20/20.Pupils, extraocular motility, confrontation visual fields, andintraocular pressure (by Goldmann tonometry) were normalin each eye. The anterior segment of the right eye wasunremarkable. Slit lamp examination of the left eye found amild resolving subconjunctival hemorrhage nasally withengorgement of the overlying conjunctival vessels (seeFigure 1). The nasal conjunctiva appeared yellowish-redand was not chemotic or elevated.

Elevation of the superior lid revealed a raised, salmon-pink–colored lesion approximately 12 mm in length,involving the majority of the superior conjunctiva (seeFigures 2 and 3). This large lesion was immediately adja-cent to the yellow-red nasal conjunctiva, was homogeneousin color, was not deeply vascularized, and extended about 3clock hours. The rest of the anterior segment of the left eyewas unremarkable. Dilated fundus examination of botheyes found no intraocular involvement or other lesions.

With a preliminary diagnosis of ocular lymphoma, thepatient was referred for neuroimaging and a conjunctivalbiopsy. Magnetic resonance imaging (MRI) of the brain andorbits found asymmetric enlargement of the anterior portionof the left medial rectus muscle with poorly defined margins.The enlarged area involved the musculotendinous junctionand extended to the ocular insertion (see Figure 4). Althoughthe pattern of involvement was nonspecific, because of thepoor definition and association with adnexal and orbital tis-sue, the lesion was suspected to be a neoplasm (seeFigure 5). No intracranial masses or abnormal enhancementswere found with the MRI, indicating a localized growth.

Figure 1 Injection of nasal bulbar conjunctiva, left eye.

After the MRI studies, the patient returned to the eyeclinic for a conjunctival biopsy. Histopathologic analysis ofthe specimens found atypical proliferation of mature lym-phoid cells (see Figures 6 and 7). Based on the clinical pre-sentation, MRI results, and histopathology, a diagnosis oflow-grade B-cell lymphoma was made.

To investigate the level of systemic involvement, thepatient underwent liver sonograms and computed tomog-raphy (CT) scans of the chest, abdomen, and pelvis.Multiple soft tissue deposits were found throughout thesubcutaneous fat of the chest and abdomen, with the largestlesions appearing in the buttocks. This confirmed that thelymphoma was disseminated and not confined to the orbit.

The Veterans Medical Center Tumor Board reviewed thefindings from all imaging, pathology, and clinical studiesand confirmed a diagnosis of systemic marginal zone B-cell, non-Hodgkin’s lymphoma. A decision was made tostart systemic lymphoma treatment before hepatitis Ctherapy. The patient was treated with 800 mg intravenousrituximab each week. A decrease in ocular and systemictumor sizes was noted after 2 months of therapy, and nearly1 year later there has been no recurrence.

Figure 3 Raised salmon-pink–colored lesion, superonasal bulbar con-

junctiva, left eye.

Figure 4 Transverse MR image. Arrow indicates enlargement of the left

medial rectus muscle.

Figure 6 Low-magnification histopathology of conjunctival biopsy

shows proliferation of lymphoid cells.

530 Optometry, Vol 81, No 10, October 2010

Incidence

According to the National Cancer Institute, in the year2005, non-Hodgkin’s lymphoma had an estimated annualincidence of 22.2 cases per 100,000 people in the UnitedStates.1 It has been further estimated that 1% to 2% of alllymphomas and nearly 8% of extranodal lymphomas

Figure 5 Coronal MR image. Arrow indicates enlargement of the left

medial rectus muscle.

originate in the ocular adnexa.2 Extranodal refers to lym-phomas that do not arise from the spleen or lymph nodes,as in this case.3

Non-Hodgkin’s lymphoma is commonly regarded as themost prevalent type of orbital malignancy and can invade avariety of orbital structures.2,3 In a 30-year longitudinalstudy of 1,264 patients, Shields et al.4 found 36% of alllesions to be malignant. In their sample of patients referredfor an orbital mass, lymphoid tumors were identified to bethe most prevalent subtype with 139 cases (11%). Baireyet al.5 reviewed the records of 187 patients with confirmednon-Hodgkin’s lymphoma and found 5.3% of those hadorbital or adnexal involvement or both.

Demographics

The majority of patients with all types of non-Hodgkin’slymphoma are older than age 65 (mean age of 74) and havean average 5-year survival rate of 67.7%.1 Among individ-ual population groups, whites were found to have the high-est rates of incidence (27.6 per 100,000 men) and mortality.

Figure 7 High-magnification histopathology of conjunctival biopsy

also demonstrates proliferation of lymphoid cells.

Hicks and Mick Clinical Care 531

Blacks, Asians, and Hispanics had lower rates than whitesin both categories. Prevalence rates between men andwomen differ among studies.1,2,6 Overall incidence inadults has trended upward in recent years with an agingUnited States population. Ocular adnexal lymphoma is un-common in children. As a 68-year-old white man, the pa-tient in this case meets the main expected demographiccriteria for new diagnosis of lymphoma.

Signs/symptoms

One of the most common presenting symptoms of ocularlymphoma is a visible or palpable mass or the awareness ofswelling around the eye (64% to 68%).2,7 Patients may alsoreport redness (32%), irritation (28%), diplopia (16%), tear-ing (16%), blurred vision (11%), and pain (3%).7,8 Theduration of symptoms before diagnosis ranges from 4 to11 months with an average of 6 months.3,6

Adnexal lymphomas may exhibit several or few signs inthe early stages. Ptosis (20%) and proptosis (18% to 27%)are relatively common.7,8 Conjunctival tumors are the mostfrequently observed and often are salmon colored, forminga smooth mass. Less commonly, other orbital tissues, suchas the lacrimal system and eyelids, may be involved. Extra-ocular muscle involvement, which was present in this case,has been reported only rarely.9 Bilateral involvement occursin approximately 10% to 17% of cases.3,8,10

Pathophysiology

Ocular lymphomas can be categorized broadly as adnexalor intraocular, primary or secondary, and low grade or highgrade. Adnexal lymphomas are those that invade the orbitalfat, conjunctiva, eyelids, extraocular muscles, lacrimalglands, or lacrimal sac but do not involve the intraocularstructures. Primary diseases are first discovered in oraround the eye, whereas secondary ocular lymphomasoriginate as an identical cell type at another primary sitein the body. The proliferation of malignancies often isbroadly referred to as either low or high grade to aid instatistical analysis because of limited sample sizes of somemore specific cell types.

Two major systems have been used to subcategorize thevarious types of lymphomas: the World Health Organiza-tion (WHO) and the Revised European and AmericanLymphoma (REAL) classifications. These schemes labellymphomas based on cell type and immunohistology. Themost common subtype of ocular adnexal lymphoma isextranodal marginal zone B-cell lymphoma, whichaccounts for 52% to 67% of cases.2,11,12 REAL considersthese tumors to be low-grade malignancies that can be pri-mary or secondary in origin. In a large case series, Ferryet al.2 reported 84% to 92% of all ocular adnexal lympho-mas to be primary. Primary ocular adnexal lymphomas arethought to have a low rate of dissemination to other sites in

the body because of the lack of lymphatic drainage chan-nels from the eye.3

Marginal zone B-cell lymphomas are composed ofsmall, slightly irregular lymphoid cells that occasionallyhave a distinct rim of pale cytoplasm.7 When this type oflymphoma occurs in the parotid or thyroid gland, it is oftenassociated with an autoimmune condition.2 Gastric cases ofmarginal zone lymphoma are frequently related to Helico-bacter pylori infections. Ocular adnexal B-cell lymphomasdo not have that association but have been linked withChlamydia psittaci and hepatitis C.2,3,13 Although the exactmechanism for development of adnexal lymphomas is stilluncertain, the patient in this case was hepatitis C positive.

Differential diagnosis

A variety of benign and malignant lesions can arise in theocular adnexa including basal and squamous cell carcino-mas, melanoma, hemangioma, Kaposi’s sarcoma, granulo-mas, pingueculae, and pterygia. Recurrent subconjunctivalhemorrhages could result from these lesions and warrantinvestigation for an underlying cause, including toxic,infectious, inflammatory, traumatic, or metabolic etiolo-gies. A recent report identified the primary causes ofsubconjunctival hemorrhages to be traumatic or contactlens–related injury (77.7%).14 Hypertension (39.5%) anddiabetes (13.1%) are risk factors for patients older than61 years, but unknown etiology still accounts for nearly40% of cases.14 To date, there appears to be only 1 pub-lished report linking systemic lymphoma with a subcon-junctival hemorrhage.15 In this case, the lymphoma itselfor the ocular surface irritation from the growing lesioncould have led to the subconjunctival hemorrhage.

Histology and imaging

Once lymphoma is suspected, laboratory and radiologictesting must be used to specify the cell type and directtreatment. Clinical determination of malignancy is notoften possible.16 Differentiation of lymphomas from non-lymphomas and characterization of specific cell types canbe reliably performed with molecular analysis.17 Althoughmarginal zone B-cell lymphomas are the most commonsubtype in the ocular adnexa, follicular, Mantle cell, andBurkitt’s lymphomas can also occur.

Conjunctival biopsy in this case found multiple maturenuclei that densely stained with hematoxylin, which is char-acteristic of a diffuse small B-cell lymphoproliferative disor-der.2,10 Histopathology (see Figure 6) was also consistent withothers published by Ferry et al.2 CT scans and MR images arerequired to identify lesion sites and classify the lymphoma asprimary or secondary. Some investigators have also suggestedthat a positron emission tomography (PET) scan should be per-formed in all cases.18 These scans are essential to directingtreatment either locally or systemically.

532 Optometry, Vol 81, No 10, October 2010

Treatment

When a patient presents with a new adnexal lesion, it isimportant to determine if there is malignancy potential toproperly direct therapy. If lymphoma is suspected, referraland consultation with a hematologist and oncologist arerequired. In most cases, a complete blood count; chest x-ray;CT and/or MRI of chest, abdomen, and pelvis; bone marrowbiopsy; and possibly a PET scan should be performed.10

Once the extent of lymphoma has been identified throughthese measures, appropriate treatment can be selected.

External beam radiotherapy is preferred for localizedocular adnexal lymphoma because surgical excision does nottypically remove all of the tumor cells.7,10 Steroids have beenfound to be ineffective.10 For disseminated lymphoma, sys-temic chemotherapy is required. The recommended treat-ment for this patient was rituximab, which is a monoclonalantibody that acts against the CD20 cell surface antigen.Because up to 90% of malignant B-cells in non-Hodgkin’slymphomas express the CD20 antigen, drugs like rituximabhave proven efficacious in reducing tumor size and growth.19

However, this therapy also has a 50% relapse rate.19

Prognosis

Extranodal marginal zone B-cell lymphomas frequentlyremain localized to one site for many years before dissem-ination. At the time of diagnosis, 60-80% of ocular adnexallymphomas are found to be primary only, but systemicinvolvement can develop within the first 6 months.10 Ratesof dissemination can range from 17-68% and have beenestimated at 30% for primary ocular adnexal lymphomas.10

Overall survival rates for adnexal lymphomas are high,with 94% of patients being disease free at 5 years and 85%disease free at 10 years.7 Conjunctival lesions have the bestprognosis, followed by lacrimal glands, extraocular muscles,and orbital fat.20 Fung et al.7 reported no deaths from lym-phoma in those same survival groups, indicating disease-free survival of 100%. Although survival rates are excellent,relapses were common in this cohort, with 25% relapsing in5 years and 55% recurrence at 10 years. Median relapsetime was 40 months.7 Other investigators have noted arelapse-free survival rate of 64.6% at 5 years.18 It has beenrecommended that systemic evaluation of patients with ocularlymphoma be performed every 6 months for the first 5 years.10

Conclusion

Ocular adnexal lymphoma can induce a variety of present-ing signs and symptoms. Although not typical, the first signthat compelled the patient to seek care in this case was anonpainful, recurrent subconjunctival hemorrhage. Lym-phomas can occur in a variety of sites in the body, and it iswell documented that primary tumors can originate in theocular adnexa. A thorough ocular examination, properancillary testing, and a correct diagnosis are paramount

for the patient’s ocular health, vision, and possibly thepatient’s life. With timely diagnosis and treatment, ocularadnexal lymphoma is rarely fatal, but routine follow-up isnecessary because of the high recurrence rates.

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