Ann P. Murchison

BASICS

DESCRIPTION

• Ocular adnexal lymphoproliferative disease (OALD) represents an amalgam of monoclonal and polyclonal lymphocytic proliferations that involve the ocular adnexa (the eyelids, orbit, conjunctiva, and lacrimal apparatus).

• OALD is further divided into 2 sub-categories:

– Lymphoid hyperplasia (LH), a polyclonal, T-cell rich proliferation, which may be reactive. A significant percentage of patients with LH will eventually develop systemic lymphoma.

– Ocular adnexal lymphoma (OAL), a monoclonal, autonomous, self-sustaining lymphocytic malignancy, which is generally of B-cell origin and of the non-Hodgkin type.

– Idiopathic orbital inflammatory syndrome (IOIS) is not in the spectrum of OALD.

• OAL should never be considered a uniform process, but rather a compendium of subtypes of lymphoma, each with its own cytogenetics, therapeutic options, propensity for systemic involvement, and varying prognosis.

• OAL should be classified according to the WHO modifications of the REAL system. The majority of OAL present as 5 subtypes, 3 of which are relatively indolent, and 2 of which are aggressive and potentially fatal (Table 1).

Table 1 Subtypes of OAL

– About 50% of all OAL is extranodal marginal zone lymphoma (EMZL)/mucosa-associated lymphoid tissue (MALT).

– OAL is not associated with intraocular lymphoma, which should be considered a form of central nervous system lymphoma.

EPIDEMIOLOGY

Incidence

• 65,000 cases of non-Hodgkin lymphoma (NHL) per year in the US

• OAL occurs in approximately 5% of all NHL cases and accounts for about 10% of all adult orbital tumors. OAL is rare in the pediatric population.

• OALD has no significant gender predilection.

• The mean age at presentation for OAL is about 67 years, but OALD/OAL may occur in any adult age group.

RISK FACTORS

• Autoimmune disease may predispose to the evolution of LH and OAL.

• Chronic immunosuppression increases the risk of NHL in general.

• Higher rate of NHL in HIV-infected patients.

Genetics

No definite genetic predisposition to OALD.

GENERAL PREVENTION

There is no known effective prevention of LH and OAL. Avoidance of chronic immunostimulation (e.g., chronic infection) and chronic immunosuppression (e.g., HIV infection, long term methotrexate therapy for rheumatoid arthritis) may theoretically be protective.

PATHOPHYSIOLOGY

• The pathophysiology of NHL is not clearly understood.

• The specific subtype of NHL typically mimics the clinical behavior of its mature B-cell progenitor. For example, EMZL arising from marginal zone B-cells will behave indolently, whereas mantle cell lymphoma (MCL) will mimic the more aggressive behavior of a mantle zone B-cell.

• Chronic immune stimulation and chronic infection promote an in situ evolution of lymphoproliferative disease. Examples of this include the formation of gastric EMZL in patients chronically infected with Helicobacter pylori and the proven association between Epstein-Barr virus infection and endemic Burkitt lymphoma.

• Chronic immunosuppression allows for NHL formation, demonstrated by the higher incidence of NHL in HIV infection.

COMMONLY ASSOCIATED CONDITIONS

• Most patients with OALD and OAL have no known associated conditions.

• HIV-infection increases the incidence of NHL.

• Certain autoimmune disease (Sjögren syndrome, possibly rheumatoid arthritis) may increase the risk of NHL.

• Long-term iatrogenic immunosuppression is associated with a higher NHL risk.

• To date, no clear association between OAL and an infectious stimulus has been proven.

DIAGNOSIS

HISTORY

• Most patients with LH and OAL present with slowly progressive, nonspecific symptoms.

• The vast majority of OALD presents without pain. The presence of pain typically signifies an aggressive histopathology.

• Proptosis, ptosis, and eyelid or conjunctival mass are common presenting complaints.

• Diplopia/visual disturbances are infrequent.

• Most patients (78%) have no known history of systemic lymphoma.

PHYSICAL EXAM

• Vision and pupillary examinations are usually normal. Optic neuropathy is uncommon in OALD, and may signify an aggressive histopathology.

• Painless nodularity in the eyelids, conjunctival cul-de-sac, anterior orbit, and lacrimal gland is common. Evert the eyelids to check the tarsal conjunctiva and cul-de-sacs carefully.

• A pink flat or elevated subconjunctival lesion (i.e., “salmon patch”) is a common manifestation of LH and OAL.

• Exophthalmos or other globe dystopia may be present, usually without significant external ophthalmoplegia or diplopia.

• Clinically LH and OAL are indistinguishable.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

Laboratory testing is usually not helpful. An elevated lactate dehydrogenase may be noted in aggressive or disseminated OAL.

Follow-up & special considerations

Serologic testing is performed after pathologic diagnosis. In general, additional testing includes: CBC with differential, serum lactate dehydrogenase, beta-2-microglobulin, protein electrophoresis, renal and hepatic function, and HIV serology.

Imaging

Initial approach

• CT or MRI of the orbits is performed in all cases of suspected OAL, even with presumed clinically localized conjunctival involvement, since 50% of these patients will have deeper, orbital extension.

• About 50% of OAL lesions mold to the native anatomy and 50% are well-circumscribed.

• Bony erosion and adjacent anatomic spread (paranasal sinuses) are uncommon and suggest aggressive histopathology.

Follow-up & special considerations

• Secondary imaging is necessary for staging.

• In OAL, head and body PET/CT is becoming the imaging modality of choice, both for staging and to monitor response to therapy.

• For LH, PET/CT is usually not approved by insurance carriers and CT or MRI of the neck, thorax, abdomen, and pelvis are performed.

• Depending on the chemotherapeutic regimen planned, cardiac function is typically assessed by multigated acquisition (MUGA) scanning.

Diagnostic Procedures/Other

• For OAL, bone marrow biopsy is usually recommended, at the discretion of the oncologist.

• Lumbar puncture is performed in cases of suspected central nervous system lymphoma, usually seen in conjunction with HIV infection.

Pathological Findings

• For OALD, tissue should be sent for histopathology, immunohistochemistry, and flow cytometry. Additional cytogenetic testing may also be necessary. Correct handling of the excised tissue is important.

– Histopathology and immunohistochemistry are performed on formalin-fixed tissue.

– Flow cytometry can only be performed on fresh (non-fixed) tissue. The minimum volume needed for flow cytometry approximates the size of a pea.

DIFFERENTIAL DIAGNOSIS

• Inflammatory conditions (e.g., sarcoidosis, Wegener granulomatosis)

• Metastatic lesions

• Primary conjunctival, eyelid, lacrimal gland (especially pleomorphic adenoma), and orbital lesions

• Sinoorbital aspergillosis

TREATMENT

MEDICATION

• Treatment is highly dependent on several issues:

– LH is usually treated with a course of oral corticosteroids, and refractory cases with low dose radiotherapy.

– For OAL, treatment is guided by the subtype of lymphoma.

– The location of the lesion. In general the best prognosis is for unilateral conjunctival lesions. Negative prognostic features for OAL include location in the eyelids or lacrimal gland, bilateral involvement, bone erosion, and presence of optic neuropathy.

• Localized, indolent disease may be treated with radiotherapy (total dose of 30 Gy).

• Systemic disease or localized, aggressive OAL is typically treated with systemic chemotherapy. The specific protocols are guided by lymphoma subtype, comorbidities, and response to therapy as noted on follow-up PET/CT.

• In cases of localized, indolent OAL in an elderly patient, simple excision and watchful waiting may be all that is necessary.

• Although antibiotic therapy is highly effective in the treatment of H. pylori-associated gastric EMZL, there is to date no evidence that any antibiotic regimen is effective for OAL.

• The use of biologics (e.g., rituximab) is increasing, with impressive early results.

ADDITIONAL TREATMENT

General Measures

Long-term follow-up is indicated in all patients with LH or OAL, since both have a risk for subsequent systemic lymphoma development or recurrence.

Issues for Referral

• Patients with LH can be followed by an ophthalmologist, as long as systemic monitoring is performed on a routine and long-term basis.

• Essentially all cases of OAL are referred to an oncologist for staging and therapeutic options.

• Referral to a radiation therapist may be indicated in some cases of LH and OAL.

SURGERY/OTHER PROCEDURES

The goal of surgery is definitive diagnosis. Complete excision is usually unnecessary and not recommended because of increased local morbidity. Correct handling of the tissue specimen is essential (see Pathologic Findings).

IN-PATIENT CONSIDERATIONS

Admission Criteria

As needed for specific chemotherapeutic regimens and for patient comorbidities

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

As noted, all patients with LH and OAL must be followed for the long term (years to decades) by the ophthalmologist for local disease monitoring and by an oncologist for systemic monitoring.

Patient Monitoring

• Local monitoring of the ocular adnexa is initially performed every few weeks until response to therapy is noted. Thereafter, patients may be monitored every few months during the first year, and subsequently every 6–12 months.

• Long-term systemic monitoring is indicated for all patients. Typically the oncologist performs serial clinical exams and PET/CT or other imaging modalities.

PATIENT EDUCATION

• Depends on subtype of OALD and staging.

• The patient must understand that even with localized disease or systemic disease with complete therapeutic response, long-term systemic monitoring is mandatory.

PROGNOSIS

• For LH, prognosis is excellent.

• For OAL, prognosis is dependent on multiple factors, including OAL subtype, stage at presentation, and response to therapy (Table 2).

Table 2 Ten year mortality of OAL subtypes. Note that this data precedes the use of biologics (e.g. rituximab)

COMPLICATIONS

• Local: Recurrence, radiation injury.

• Systemic: Related to chemotherapy and systemic disease.

• Other: Therapeutic failure, disease recurrence, transformation to more aggressive subtype.

ADDITIONAL READING

• Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: A study of 353 cases. Am J Surg Pathol 2007;31:170–184.

• Jaffe ES. The 2008 WHO classification of lymphomas: Implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523–531.

• Jakobiec FA. Ocular adnexal lymphoid tumors: progress in need of clarification. Am J Ophthalmol 2008;145:941–950.

• Jenkins C, Rose GE, Bunce C, et al. Clinical features associated with survival of patients with lymphoma of the ocular adnexa. Eye (Lond) 2003;17:809–820.

• 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. Ophthal Plast Reconstr Surg 2005;21:177–188.

• Sullivan TJ, Valenzuela AA. Imaging features of ocular adnexal lymphoproliferative disease. Eye (Lond) 2006;20:1189–1195.

CODES

ICD9

• 190.1 Orbital tumor, malignant

• 200.81 Lymphoma malignant specific

CLINICAL PEARLS

• OALD is a spectrum of lymphoproliferation, from polyclonal LH to monoclonal lymphoma.

• Not all OAL is equal. Certain subtypes are indolent and localized, and others are aggressive and systemic.

• EMZL is the most common form of OAL and generally behaves in an indolent fashion.

• Bilateral OAL is a positive predictive factor for eventual systemic lymphoma.

• Regardless of OALD type, all patients require systemic work-up and long term monitoring.

• The treatment of OALD varies and may include systemic corticosteroids, radiotherapy, chemotherapy, or any combination.

• Biologics may improve OAL survival.

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