Conjunctival Reactive Lymphoid Hyperplasia
1. What is Conjunctival Reactive Lymphoid Hyperplasia?
Section titled “1. What is Conjunctival Reactive Lymphoid Hyperplasia?”Conjunctival reactive lymphoid hyperplasia (CRLH) is a disease in which lymphoid cells of the conjunctiva proliferate benignly. As a result of antigenic stimulation of the conjunctival mucosa-associated lymphoid tissue (MALT), T-cell immune regulation is impaired, triggering a cascade of B-cell proliferation1). It is usually benign, but rarely may progress to malignant lymphoma.
Epidemiology
Section titled “Epidemiology”Approximately one-third of ocular adnexal lymphoid proliferations occur in the conjunctiva1). The mean age at diagnosis is 35 years, with a slight male predominance (54%)1). 75% are unilateral, and over 80% involve the medial bulbar conjunctiva, caruncle, or plica semilunaris1).
Conjunctival reactive lymphoid hyperplasia is a benign disease and is not cancer. However, it can resemble malignant lymphoma in appearance, and there is a rare possibility of progression to lymphoma. Therefore, definitive diagnosis by biopsy and regular follow-up are important. If monoclonality is confirmed, the risk of lymphoma is reported to increase approximately fourfold.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Some cases are asymptomatic, but patients may complain of conjunctival hyperemia, foreign body sensation, eye pain, eyelid swelling, and blurred vision. Palpable masses and cosmetic concerns are also common chief complaints.
Clinical Findings
Section titled “Clinical Findings”Slit-lamp examination reveals a smooth, salmon-pink elevated lesion on the conjunctiva. There is little conjunctival hyperemia and no significant neovascularization. The lesion commonly occurs on the medial bulbar conjunctiva.
On anterior segment OCT, the lesion appears homogeneous and hyporeflective, with thinning of the overlying epithelium. Ultrasound biomicroscopy (UBM) can quantitatively assess the depth and diameter of the lesion.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The exact cause of CRLH is not fully identified, but the following factors are thought to be involved.
- Antigenic stimulation of MALT: Persistent antigen exposure induces T-cell immune dysregulation, leading to B-cell proliferation1)
- Infection: An association with Chlamydia psittaci has been reported
- Autoimmune diseases: Abnormal autoimmune reactions may be involved
- Allergy: May promote chronic inflammation of conjunctival MALT
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Slit-lamp Examination
Section titled “Slit-lamp Examination”Confirm a salmon-pink conjunctival mass. Assess the degree of conjunctival hyperemia, presence of neovascularization, and extent of the lesion.
Imaging Tests
Section titled “Imaging Tests”On anterior segment OCT, it appears as a homogeneous, hypo-reflective lesion. Ultrasound biomicroscopy is useful for quantitative assessment of lesion depth and diameter, and is also used to evaluate treatment response. High-resolution OCT helps differentiate from conjunctival amyloidosis.
Biopsy, Immunohistochemistry, and Flow Cytometry
Section titled “Biopsy, Immunohistochemistry, and Flow Cytometry”Incisional biopsy is recommended for definitive diagnosis. Histopathologically, chronic inflammatory infiltration with normal germinal centers within lymphoid follicles is observed.
If flow cytometry shows polyclonal markers (CD3-positive T lymphocytes + CD20-positive B lymphocytes), benignity is confirmed1). Low Ki-67 expression is also an indicator of benignity. If monoclonality is detected, the risk of progression to lymphoma increases approximately 4-fold1).
Differential Diagnosis
Section titled “Differential Diagnosis”| Differential Diagnosis | Key Differentiating Features |
|---|---|
| Conjunctival lymphoma | Monoclonality, infiltrative pattern |
| Conjunctival amyloidosis | Differentiable by HR-OCT |
| Chronic follicular conjunctivitis | Multiple follicles, hyperemia |
Immunohistochemistry, flow cytometry, and gene rearrangement analysis are essential for differentiating from conjunctival lymphoma.
Salmon-pink conjunctival lesions may be due to conjunctival reactive lymphoid hyperplasia, conjunctival lymphoma, or amyloid deposition. Since it is difficult to distinguish benign from malignant based on appearance alone, it is important to see an ophthalmologist for a thorough examination including biopsy. In particular, evaluation of polyclonality by flow cytometry is key to diagnosis.
5. Standard Treatment
Section titled “5. Standard Treatment”There are no established expert consensus or guidelines for the management of CRLH1).
Observation
Section titled “Observation”If asymptomatic and the patient does not desire active treatment, careful observation is the initial management.
Surgical Excision
Section titled “Surgical Excision”This is the most commonly performed treatment; in a review of 235 cases, 65.9% were treated with excision1). Well-demarcated bulbar conjunctival lesions are the main indication. Adjuvant perilesional steroid injection or cryotherapy may be used.
Medical Therapy
Section titled “Medical Therapy”Oral or topical steroids are used as second-line therapy (12.7%)1). However, long-term use is associated with increased risks of cataract, elevated intraocular pressure, and infection1).
Topical tacrolimus 0.03% ointment (Protopic) has been reported to induce moderate to complete regression of conjunctival lymphoid hyperplasia in two cases. Tacrolimus, a calcineurin inhibitor, is 20 to 100 times more potent than cyclosporine and also suppresses B-cell proliferation. 1)
Other Treatments
Section titled “Other Treatments”Radiation therapy (external beam) is limited to orbital lesions but has also been reported for conjunctival lesions. There are reports of doxycycline, cyclosporine 0.05%, and interferon alpha-2b, but all are in small numbers1). Rituximab (anti-CD20 monoclonal antibody) has been used for orbital lesions, with advantages of avoiding steroid-related side effects and limited suppression of malignant transformation risk.
Yes, follow-up after treatment is very important. There is a recurrence rate of 20-30%, and rarely, it may progress to malignant lymphoma. The risk is particularly high when monoclonality is detected by flow cytometry. Regular check-ups every 6 months for at least 5 years are recommended.
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”Immune Response via MALT
Section titled “Immune Response via MALT”Persistent antigenic stimulation of conjunctival MALT leads to T-cell immune dysregulation 1). Disruption of T-cell function releases suppression of B-cell proliferation, resulting in lymphoid hyperplasia. Polyclonal B-cell proliferation follows a benign course, but accumulation of genetic mutations leading to monoclonality increases the risk of progression to lymphoma.
Continuity with Conjunctival MALT Lymphoma
Section titled “Continuity with Conjunctival MALT Lymphoma”Lymphoproliferative diseases of the conjunctiva are broadly classified into benign reactive lymphoid hyperplasia and malignant lymphoma. Most primary conjunctival malignant lymphomas are B-cell type, with low-grade, slow-growing MALT lymphoma (CALT lymphoma) being common. CRLH lies at the benign end of this spectrum, and acquisition of monoclonality is an indicator of malignant transformation.
7. Latest Research and Future Perspectives
Section titled “7. Latest Research and Future Perspectives”Expert consensus on the management of CRLH has not yet been established 1). Recently, topical administration of tacrolimus (0.03%) has been reported as a steroid-sparing agent to avoid side effects associated with long-term steroid use 1). Tacrolimus has the property of suppressing both T-cell and B-cell proliferation, and together with successful treatment reports in cutaneous lymphoid hyperplasia, accumulation of future cases is expected.
Targeted therapies such as rituximab are mainly being studied for orbital lesions, and expanding their application to conjunctival lesions remains a challenge. Additionally, risk stratification based on the presence or absence of monoclonality and optimization of treatment strategies accordingly are important future research directions.
8. References
Section titled “8. References”- Rivkin AC, Bernhisel AA. Conjunctival lymphoid hyperplasia treated with topical tacrolimus: A report of two cases. Am J Ophthalmol Case Rep. 2025;37:102256.
- Li WJ, Muthu PJ, Galor A, Karp CL. Imaging of Ocular Surface Lesions Using Anterior Segment Optical Coherence Tomography. Clin Exp Ophthalmol. 2026;54(3):341-354. PMID: 41705454.
- Verdijk RM. Lymphoproliferative Tumors of the Ocular Adnexa. Asia Pac J Ophthalmol (Phila). 2017;6(2):132-142. PMID: 28399341.