Jerry A. Shields
BASICS
DESCRIPTION
• Lymphoid tumors comprise a spectrum of neoplasia from benign hyperplasia to malignant lymphoma, based on microscopic features and immunopheno-typic findings. Lymphoma, in general, is classified into 2 major groups, including those of lymph node or splenic origin (nodal) and those that originate at other sites without lymph nodes (extranodal). It has been found that approximately one-fourth to half of lymphomas are extranodal.
• The most common extranodal sites for lymphoma include stomach, tonsils/adenoids, skin, small intestine, and these represent more than 50% of extranodal lymphomas.
• Ocular lymphoma represents only 2% of extranodal lymphoma and the ocular sites include conjunctiva, orbit, eyelid, uvea, vitreous, and retina.
• Ocular lymphoma can be related to the eventual development of systemic lymphoma.
ALERT
A painless, pink conjunctival mass could represent lymphoma and could be the first sign of a life-threatening malignant lymphoma.
Geriatric Considerations
Most conjunctival lymphoma occurs in mid adults or older adults.
Pediatric Considerations
It is rare to find conjunctival lymphoma in children.
Pregnancy Considerations
No relationship to pregnancy.
EPIDEMIOLOGY
Prevalence
• In a large cohort of 1,643 patients with conjunctival tumors from the Wills Eye Institute Ocular Oncology Service, the most common tumors included melanocytic in 53%, epithelial in 11%, lymphoid in 8%, and simulating conditions in 13%.
• The 3 most common conjunctival malignancies include squamous cell carcinoma, lymphoma, and melanoma.
RISK FACTORS
Immunosuppressed patients from organ transplant or human immunodeficiency virus are generally at risk for lymphoma.
Genetics
Most conjunctival lymphoma is of the mucosal associate lymphoid tissue (MALT) type. This represents 8% of all lymphoma and tends to occur in mucous membranes like the intestines and the conjunctival. MALT lymphoma can show t(11;18)(q21;q21) chromosomal translocation giving rise to a AP12-MLT fusion gene. Other genetic alterations are found at the locus 1p22 and 18q21.
GENERAL PREVENTION
PATHOPHYSIOLOGY
• There is some evidence that conjunctival lymphoma might be related to chronic infection with Helicobacter pylori, Chlamydia psittaci, or no infection at all. Data from the US tend to show H. pylori as the cause, data from Italy report C. psittaci, and data from Scandinavia show no organisms.
• It is believed that the chronic infection leads to multiple mutational events that eventuate in lymphoma.
• Patients with chronic immune stimulation like those with autoimmune diseases like Sjögren’s syndrome and Hashimoto’s thyroiditis are at risk for lymphoma.
ETIOLOGY
The exact etiology is not known but it is speculated that chronic infection or immune stimulation can lead to malignant degeneration of the chronic inflammatory cells into lymphoma.
COMMONLY ASSOCIATED CONDITIONS
Most conjunctival lymphoma is unassociated with systemic disease but the patient should be checked for immune deregulatory diseases like HIV, immune suppression with medications, and autoimmune conditions.
DIAGNOSIS
HISTORY
In a review of 117 consecutive cases of conjunctival lymphoid tumors from the Wills Eye Institute Ocular Oncology Service, the main findings noted by the patient included a mass in 30%, irritation in 29%, blepharoptosis in 8%, epiphora in 7%, blurred vision in 5%, proptosis in 3%, diplopia in 3%, and no symptoms in 15%.
PHYSICAL EXAM
• Data from the Wills Eye Institute Ocular Oncology Service has revealed the following findings listed below.
• Tumor location at limbus in 7%, midbulbar in 42%, fornix in 44%, tarsus in 0%, and caruncle or plica semilunaris in 7%.
• Tumor quadrant location was superior in 41%, temporal in 10%, inferior in 21%, nasal in 14%, and multiple sites in 13%.
• Additional lymphoma was found in the eyelid in 3%, orbit in 15%, uvea in 4%, retina in 0%, and vitreous in 1%.
• Systemic lymphoma was present in 31% and absent in 69%.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
Initial lab tests
CBC to rule out leukemia.
Follow-up & special considerations
Repeat CBC as necessary.
Imaging
Initial approach
• Orbital magnetic resonance imaging (MRI) is preferred over computed tomography (CT) because of superior soft tissue resolution.
• Evaluate for orbital invasion
• Evaluate for systemic lymphoma and most oncologists prefer yearly abdominal MRI and physical examination.
Follow-up & special considerations
Repeat above testing annually for life because it may be 30 years before systemic involvement is apparent.
Diagnostic Procedures/Other
• Complete surgical excision is preferred if possible. Cryotherapy to the surrounding margins is often performed to ensure complete removal.
• If the tumor is enwrapping anatomic sites then an incisional biopsy would be preferred to protect the normal tissue. This would be followed by therapy with chemotherapy, monoclonal antibodies, or radiotherapy.
Pathological Findings
• There is a range of findings from reactive lymphoid hyperplasia, atypical lymphoid hyperplasia, to frank malignant lymphoma.
– Reactive lymphoid hyperplasia is composed of diffuse densely cellular polymorphous infiltrate of small bland lymphocytes with reactive germinal centers.
– Atypical lymphoid hyperplasia is an indeterminate lesion with diffuse small lymphocytes with some atypia and no frank cytological malignancy.
– Lymphoma shows malignant lymphocytes often with mitotic activity in monotonous sheets of tumor.
DIFFERENTIAL DIAGNOSIS
• Conjunctivitis
• Conjunctival allergy
• Conjunctival melanoma
• Conjunctival squamous cell carcinoma
• Conjunctival amyloidosis
• Conjunctival sarcoidosis
TREATMENT
MEDICATION
First Line
• Chemotherapy
• Rituximab monoclonal antibody to CD 20 cells
• Many patients use antibiotics for 1 month even if the above agents are used.
Second Line
Interferon alpha 2B injection is another alternative.
ADDITIONAL TREATMENT
General Measures
Radiotherapy with external beam, stereotactic, CyberKnife, or other methods. The usual dose is 2,500 cGy–4,000 cGy. This malignancy is radiosensitive and responds within 1–2 months of treatment.
Additional Therapies
Antibiotics using Prevpac (lansoprazole, amoxicillin, clarithromycin) or doxycycline.
SURGERY/OTHER PROCEDURES
• Complete excision is warranted if the tumor is not enwrapping normal anatomic structures. Otherwise, incisional biopsy is employed.
• The surgical approach depends on the location of the mass. If the mass is relatively small and involves only one quadrant of the eye, then the mass can be unroofed with elevation of the conjunctival epithelium and the stromal mass carefully dissected and removed. Surround cryotherapy is warranted. The spared epithelium is then reposited into normal position and closed with Vicryl.
• If the mass is large and involves multiple quadrants on the surface of the eye then an incisional biopsy is performed with unroofing the tumor and taking a biopsy and then replacing the roof down to the conjunctival bed and suturing with Vicryl sutures.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Conjunctival inspection of both eyes for recurrent lymphoma or new lymphoma
• Orbital and systemic magnetic resonance imaging for evaluation of local orbital disease and to search for systemic lymphoma
Patient Monitoring
Patient should be evaluated minimum twice yearly by ophthalmologist or ocular oncologist.
PATIENT EDUCATION
PROGNOSIS
• The following results were obtained from the Wills Eye Institute Ocular Oncology Service.
• If the conjunctival lymphoma was unilateral, the risk for eventual systemic lymphoma was 17%.
• If the conjunctival lymphoma was bilateral, the risk for eventual systemic lymphoma was 47%.
• Overall, in patients who had no systemic lymphoma at presentation but only had conjunctival lymphoma, systemic lymphoma was eventually found in 7% at 1 year, 15% at 5 years, and 28% at 10 years.
• In that group,<1% died of systemic lymphoma by approximately 3 years average follow-up.
COMPLICATIONS
Following surgery, the patient might have dysmotility, blepharoptosis, double vision, and loss of vision.
ADDITIONAL READING
• Shields CL, Shields JA, Carvalho C, et al. Conjunctival lymphoid tumors: Clinical analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology 2001;108:979–84.
• Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and nonmelanocytic tumors of the conjunctiva. Ophthalmology 2004;111:1747–54.
• Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors. An atlas and textbook, 2nd ed. Philadelphia: Lippincott Williams and Wilkins, 2008:383–391.
CODES
ICD9
• 190.3 Malignant neoplasm of conjunctiva
• 200.50 Primary central nervous system lymphoma, unspecified site, extranodal and solid organ sites
CLINICAL PEARLS
• If possible, complete resection of a conjunctival lymphoma should be attempted.
• Systemic monitoring for life should be used for affected patients to rule out systemic lymphoma.
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