Conjunctival Reactive Lymphoid Hyperplasia (CRLH) is a benign lymphoproliferative disorder characterized by a polyclonal proliferation of lymphoid tissue in the conjunctiva. It most often occurs in young to middle‑aged adults and typically presents as a unilateral, painless, red or orange swelling on the bulbar conjunctiva. Histologically, CRLH displays a mixed population of B and T lymphocytes forming well‑organized follicles with germinal centers, reflecting an exaggerated but non‑neoplastic immune response to antigenic stimulation. NCBIPMC
Conjunctival Reactive Lymphoid Hyperplasia (CRLH) is a benign overgrowth of immune cells—both B and T lymphocytes—in the conjunctiva, the clear membrane covering the white part of the eye. It typically presents in young to middle‑aged adults as a painless, salmon‑pink, fleshy patch that may slowly enlarge. Histologically, CRLH is characterized by a polyclonal proliferation of lymphoid follicles in response to chronic antigen stimulation, such as inflammation or infection. Although it can mimic malignant lymphoma clinically, CRLH lacks the monoclonal cell patterns seen in cancer and usually carries an excellent prognosis once properly diagnosed and managed NCBIPMC.
CRLH lesions usually grow slowly over weeks to months and may mimic the salmon‑pink patches seen in conjunctival lymphoma, making accurate diagnosis critical to avoid overtreatment. Clinically, they are often firm but mobile, can occur anywhere on the conjunctiva (though most commonly on the nasal side), and rarely cause systemic symptoms. Despite their alarming appearance, these lesions carry minimal risk of malignant transformation—reported in fewer than 1% of cases—but warrant careful follow‑up. PMC
Types of Conjunctival Reactive Lymphoid Hyperplasia
CRLH is classified histologically into three main patterns—follicular, diffuse, and sheet‑like—each reflecting a distinct arrangement of the reactive lymphoid cells. PMC
Follicular Type: In this form, well‑formed lymphoid follicles with prominent germinal centers are present beneath the conjunctival epithelium. The follicles are encapsulated by a mantle zone of small lymphocytes, and there is usually preservation of normal follicular architecture. Patients with the follicular type may present with multiple discrete, nodular lesions. PMC
Diffuse Type: The diffuse pattern shows a uniform infiltration of lymphocytes throughout the substantia propria without clearly demarcated follicles. This type may appear as a more confluent, flat patch rather than discrete nodules. Despite its name, the diffuse type remains benign and shows polyclonality on immunohistochemical studies. PMC
Sheet‑Like Type: In the sheet‑like pattern, dense sheets of lymphoid cells fill the conjunctival stroma, sometimes obscuring normal tissue architecture. Germinal centers may be less distinct, and immunohistochemistry reveals a mixed population of B and T cells, confirming reactive (non‑malignant) proliferation. PMC
Causes
While the exact etiology of CRLH remains uncertain, it is widely thought to arise from chronic antigenic stimulation that triggers a reactive proliferation of lymphoid cells. Commonly implicated factors include chronic inflammation, infection, mechanical irritation, and systemic immune dysregulation. PMC
Chronic Antigenic Stimulation: Persistent exposure to antigens—such as environmental allergens or microbial proteins—can provoke a continuous immune response in the conjunctiva, leading to reactive lymphoid proliferation. PMC
Chronic Conjunctivitis: Long‑standing bacterial or viral conjunctivitis may stimulate lymphoid follicles in the conjunctiva, predisposing to hyperplasia. PMC
Allergic Conjunctivitis: Repeated allergic reactions, such as in vernal or seasonal allergic conjunctivitis, can maintain chronic inflammatory signaling and follicle formation. PMC
Dry Eye Syndrome: Tear film instability and epithelial damage in dry eye can chronically activate conjunctival immune cells, contributing to lymphoid aggregation. PMC
Ocular Trauma: Mechanical injury to the ocular surface—whether accidental or surgical—may release antigens and incite a reactive lymphoid response. PMC
Ocular Surgery: Procedures such as pterygium excision or cataract surgery can introduce local inflammation and antigen exposure, occasionally leading to CRLH. PMC
Contact Lens–Related Irritation: Chronic mechanical rubbing or lens‑related hypersensitivity can perpetuate low‑grade inflammation and lymphoid proliferation. PMC
Local Infection: Infections like Chlamydia psittaci or Herpes simplex may act as chronic antigen sources in the conjunctiva. PMC
Systemic Infection (e.g., EBV): Epstein–Barr virus and other systemic infections have been associated with reactive lymphoid lesions in various mucosal tissues, including the conjunctiva. PMC
Immunosuppression: Paradoxically, immunosuppressed patients (e.g., HIV) may develop exaggerated reactive hyperplasia due to altered immune regulation. PMC
Autoimmune Disorders (e.g., Sarcoidosis): Systemic granulomatous diseases can involve conjunctival lymphoid tissue, promoting CRLH. PMC
Environmental Irritants (e.g., Smoke, Dust): Chronic exposure to airborne irritants can lead to sustained conjunctival inflammation. PMC
Ultraviolet (UV) Light Exposure: UV radiation may damage conjunctival epithelium and underlying immune cells, triggering reactive changes over time. PMC
Pterygium: The presence of pterygium reflects chronic UV and inflammatory insults, sometimes coinciding with adjacent lymphoid hyperplasia. PMC
Idiopathic Factors: In many cases, no clear trigger is identified, suggesting individual immune predisposition or unrecognized antigen exposures. PMC
Symptoms
CRLH often remains asymptomatic aside from the visible lesion, but patients may report mild ocular discomfort or cosmetic concerns. NCBIEyeWiki
Visible Conjunctival Lesion: A salmon‑pink or orange‑colored patch or nodule is the most common presenting feature, noticed by the patient or physician. NCBIEyeWiki
Painless Swelling: Unlike infectious conjunctivitis, CRLH lesions are typically painless, reflecting their non‑infectious, reactive nature. NCBIEyeWiki
Foreign Body Sensation: Mild scratchiness or sensation of something in the eye may occur if the lesion disrupts the tear film. EyeWiki
Itching: Some patients experience intermittent itching, especially if an allergic component is present. EyeWiki
Dryness: Local inflammation can impair tear distribution, leading to sensations of dryness. EyeWiki
Excessive Tearing (Epiphora): Irritation from the lesion can reflexively increase tear production. EyeWiki
Cosmetic Disfigurement: The visible mass may cause self‑consciousness or concern over eye appearance. EyeWiki
Upper Eyelid Ptosis: Large lesions near the lid margin can mechanically weigh down the eyelid. EyeWiki
Diplopia: Rarely, extensive lesions encroaching on the fornix may restrict eye movement, causing double vision. EyeWiki
Conjunctival Irritation: Redness and mild inflammation around the lesion may lead to general ocular discomfort. EyeWiki
Diagnostic Tests
Physical Examination Tests
1. Slit‑Lamp Examination: Under high magnification, the clinician identifies a salmon‑pink, subepithelial lesion, assesses its size, borders, and relation to surrounding structures, and rules out epithelial defects. EyeWiki
2. Visual Acuity Assessment: Standard vision testing confirms that the lesion itself has not impaired central vision, helping differentiate CRLH from lesions affecting the cornea or globe. EyeWiki
3. Conjunctival Color Inspection: Direct observation under white light allows evaluation of lesion hue (red, orange, yellow) and surface changes, providing clues to lymphoid versus epithelial pathology. EyeWiki
4. Ocular Motility and Lid Evaluation: Assessment of eye movements and eyelid position can detect subtle restrictions or ptosis caused by larger or posteriorly extending lesions. EyeWiki
Manual Tests
5. Lesion Palpation: Gentle palpation of the conjunctival mass helps determine consistency (firm vs. cystic), mobility, and tenderness, distinguishing CRLH from cysts or foreign bodies. EyeWiki
6. Regional Lymph Node Palpation: Examination of preauricular and submandibular nodes assesses for reactive lymphadenopathy or systemic spread suggestive of lymphoma. EyeWiki
Laboratory and Pathological Tests
7. Conjunctival Biopsy with Histopathology: Excisional or incisional biopsy remains the gold standard, revealing polyclonal B‑ and T‑cell proliferation with preserved follicular architecture under hematoxylin‑eosin staining. PMC
8. Immunohistochemistry (IHC): Staining for CD20 (B cells), CD3 (T cells), and germinal center markers such as BCL6 confirms reactive (polyclonal) versus neoplastic (monoclonal) lymphoid expansion. PMC
9. Flow Cytometry: Fresh tissue analysis quantifies cell populations and light chain expression, demonstrating a mixed κ and λ profile characteristic of polyclonality. PMC
10. Polymerase Chain Reaction (PCR) for Clonality: PCR‑based assays detect immunoglobulin heavy chain gene rearrangements, with absence of a dominant clone supporting a reactive process. PMC
11. Complete Blood Count (CBC) with Differential: A basic hematologic evaluation screens for systemic lymphoproliferative disorders and assesses overall immune status. PMC
12. Serum Protein Electrophoresis: This test evaluates for monoclonal gammopathies that could indicate systemic lymphoma rather than localized reactive hyperplasia. PMC
13. Serologic Testing for Infectious Agents: Targeted serologies (e.g., EBV, Chlamydia psittaci) help identify potential antigenic triggers. PMC
14. Serum Immunoglobulin Levels: Quantification of IgG, IgM, and IgA can reveal hypergammaglobulinemia associated with chronic immune stimulation. PMC
Electrodiagnostic Tests
15. Visual Evoked Potential (VEP): Although not routine, VEP can assess optic nerve function if posterior extension of the lesion is suspected.
16. Pattern Electroretinography (pERG): Used rarely to evaluate retinal ganglion cell integrity when lesions encroach on adjacent structures.
17. Electrooculography (EOG): May help assess retinal pigment epithelium function in cases with extensive ocular surface involvement.
Imaging Tests
18. High‑Resolution Anterior Segment Optical Coherence Tomography (HR‑OCT): HR‑OCT provides an “optical biopsy,” showing a subepithelial, hyporeflective lesion with a normal overlying epithelium, aiding differentiation from lymphoma and amyloidosis. PMC
19. Ultrasound Biomicroscopy (UBM): UBM measures lesion depth and extent, guiding biopsy planning and monitoring treatment response. EyeWiki
20. Orbital Magnetic Resonance Imaging (MRI): MRI evaluates posterior and orbital extension, particularly when clinical exam suggests deeper involvement, and offers superior soft tissue contrast. mehdijournal.com
21. Computed Tomography (CT) Scan: CT is useful for detecting calcifications, bone involvement, or subtle orbital infiltration in extensive or atypical cases. mehdijournal.com
Non‑Pharmacological Treatments
While medical and surgical therapies are often central to management, supportive, non‑drug strategies can help modulate immune activity, reduce inflammation, and improve patient comfort.
Exercise Therapies
Physical activity stimulates protective factors and reduces harmful inflammation in the eye. A recent review highlights how regular exercise enhances blood flow, reduces oxidative stress, and modulates immune responses in various ocular diseases PMC.
Blink Exercises
Gently close and open your eyes 20 times, three sessions daily. This strengthens the orbicularis oculi muscle, promotes tear film distribution, and flushes inflammatory debris.Saccadic Training
Focus quickly between two points 10 cm apart, 30 repetitions twice daily. Improves ocular microcirculation and reduces lymphoid congestion by stimulating small blood vessels in the conjunctiva.Pencil Push‑Ups
Hold a pencil at arm’s length and slowly bring it toward your nose, focusing until it blurs, then refocus. Repeat 10 times per session. Enhances ocular muscle coordination, indirectly supporting immune cell clearance.Palming and Stretching
Rub your hands together, place them gently over closed eyes for one minute, then perform gentle neck and shoulder stretches. Relieves tension that can impair ocular blood flow.Neck and Postural Exercises
Chin tucks and shoulder blades squeezes, 10 reps each session. Correct posture reduces strain on ocular vessels and lymphatics.Aerobic Exercise
Brisk walking or cycling for 30 minutes, five times weekly. Lowers systemic inflammatory markers (e.g., TNF‑α, IL‑6), supporting conjunctival immune balance.Yoga Asanas for Ocular Health
Practices like “Trataka” (steady gazing) for 5 minutes daily. Improves tear film stability and ocular blood flow through focused practice.
Mind‑Body Therapies
Stress hormones can fuel inflammation. Mind‑body interventions help reset the nervous‑immune axis and reduce harmful cytokines Karger.
8. Guided Imagery
Listen to a 10‑minute stress‑reduction audio daily. Eases sympathetic overdrive, lowering inflammatory mediators in ocular tissues.
9. Progressive Muscle Relaxation
Tense and release muscle groups from head to toe, 15 minutes nightly. Decreases systemic cortisol, which can exacerbate lymphoid proliferation.
10. Mindfulness Meditation
Focus on breath for 10 minutes each morning. Boosts parasympathetic tone and reduces chronic inflammation.
11. Biofeedback
Use a simple device to monitor muscle tension around the eyes and learn to relax. Lowers local tissue stress.
12. Yoga Nidra
A guided deep‑relaxation practice for 20 minutes. Provides restorative rest, aiding immune regulation.
Educational Self‑Management
Empowering patients with knowledge fosters early detection, better adherence, and reduced complications.
13. Structured Education Workshops
Small‑group sessions led by an eye care professional covering CRLH basics, treatment options, and self‑care strategies.
14. Symptom‑Tracking Journals
Daily logs of lesion size, redness, and comfort levels. Helps tailor treatment and detect changes early.
15. Lifestyle Counseling
One‑on‑one sessions on diet, sleep hygiene, and stress management to support ocular immunity.
16. Digital Health Apps
Mobile apps reminding patients to perform eye exercises, track symptoms, and schedule follow‑ups.
17. Personalized Action Plans
Written plans outlining when to seek care, medication schedules, and self‑care tasks.
18. Peer Support Groups
Regular meetings—online or in person—to share experiences and coping strategies.
19. Goal‑Setting Consultations
Collaborative setting of realistic targets for exercise, self‑monitoring, and therapy adherence.
20. Tele‑ophthalmology Check‑ins
Virtual visits for symptom review and early intervention when needed.
Pharmacological Treatments
First‑line medications focus on reducing lymphoid proliferation with corticosteroids or modifying immune responses with immunosuppressants.
Oral Prednisolone (Corticosteroid)
Dosage: 1 mg/kg daily, tapered over 6–8 weeks.
Purpose: Rapid suppression of lymphoid expansion.
Mechanism: Binds glucocorticoid receptors to inhibit pro‑inflammatory gene transcription.
Side Effects: Weight gain, hypertension, hyperglycemia, osteoporosis EyeWiki.Intralesional Triamcinolone Acetonide (Corticosteroid)
Dosage: 20 mg injected around lesion every 4 weeks.
Purpose: High‑local steroid delivery with minimal systemic exposure.
Mechanism: Reduces local cytokine release and lymphocyte proliferation.
Side Effects: Elevated intraocular pressure, cataract formation Karger.Topical Prednisolone Acetate 1% Eye Drops (Corticosteroid)
Dosage: Four times daily for 1–2 weeks, then taper.
Purpose: Surface immune modulation for superficial lesions.
Mechanism: Inhibits local inflammatory cell infiltration.
Side Effects: Ocular hypertension, risk of cataracts PubMed.Cyclosporine Ophthalmic Emulsion 0.05% (Calcineurin Inhibitor)
Dosage: Twice daily.
Purpose: Alternative for steroid‑resistant or steroid‑intolerant cases.
Mechanism: Blocks T‑cell activation by inhibiting calcineurin.
Side Effects: Burning, stinging EyeWiki.Doxycycline (Tetracycline Antibiotic)
Dosage: 100 mg twice daily for 4–6 weeks.
Purpose: Anti‑inflammatory and anti‑matrix metalloproteinase effects.
Mechanism: Inhibits MMPs, reducing tissue remodeling and inflammation.
Side Effects: Photosensitivity, gastrointestinal upset EyeWiki.Interferon Alfa‑2b (Biologic)
Dosage: 1×10⁶ IU subconjunctival weekly for 4 weeks.
Purpose: Immunomodulation in refractory cases.
Mechanism: Enhances NK cell activity and shifts cytokine balance.
Side Effects: Flu‑like symptoms, fatigue EyeWiki.Rituximab (Anti‑CD20 Monoclonal Antibody)
Dosage: 375 mg/m² IV weekly for 4 weeks.
Purpose: Targets B lymphocytes to reduce lesion size.
Mechanism: Depletes CD20+ B cells via complement‑mediated cytotoxicity.
Side Effects: Infusion reactions, increased infection risk.Methotrexate (Antimetabolite)
Dosage: 25 mg orally once weekly.
Purpose: T‑cell and B‑cell proliferation blockade.
Mechanism: Inhibits dihydrofolate reductase, impairing DNA synthesis.
Side Effects: Hepatotoxicity, bone marrow suppression.Azathioprine (Purine Synthesis Inhibitor)
Dosage: 1–2 mg/kg daily.
Purpose: Maintenance immunosuppression.
Mechanism: Incorporates into DNA/RNA to inhibit lymphocyte proliferation.
Side Effects: Leukopenia, hepatotoxicity.Mycophenolate Mofetil (Inhibitor of Lymphocyte Proliferation)
Dosage: 1 g twice daily.
Purpose: Alternative or adjunct to other immunosuppressants.
Mechanism: Selectively inhibits inosine monophosphate dehydrogenase in lymphocytes.
Side Effects: Diarrhea, increased infection risk.
Dietary Molecular Supplements
Nutrition can fine‑tune immune responses and support tissue health.
Omega‑3 Fatty Acids (EPA/DHA 1000 mg daily)
Anti‑inflammatory by shifting eicosanoid production away from pro‑inflammatory mediators.Vitamin D3 (2000 IU daily)
Balances innate and adaptive immunity; deficiency linked to lymphoproliferative disorders.Curcumin (500 mg twice daily)
Inhibits NF‑κB pathway, reducing inflammatory cytokine release.Epigallocatechin Gallate (EGCG 300 mg daily)
Antioxidant that downregulates IL‑6 and TNF‑α production.Lutein (10 mg daily)
Filters blue light; protects conjunctival cells from oxidative damage.Zeaxanthin (2 mg daily)
Synergizes with lutein to stabilize cellular membranes.Selenium (100 μg daily)
Cofactor for glutathione peroxidase, reducing oxidative stress.Zinc (15 mg daily)
Essential for thymic function and T cell maturation.Vitamin C (500 mg twice daily)
Supports collagen synthesis and has antioxidant properties.Quercetin (500 mg twice daily)
Stabilizes mast cells and inhibits histamine release.
Regenerative and Stem Cell Drugs
Cutting‑edge therapies aim to restore healthy conjunctival tissue.
Autologous Limbal Stem Cell Transplants
Dosage: Individualized graft of limbal epithelial stem cells.
Function: Reconstitutes normal epithelial barrier.
Mechanism: Repopulates conjunctival surface with healthy cells.Recombinant Epidermal Growth Factor (EGF) Eye Drops
Dosage: 10 μg/mL three times daily.
Function: Stimulates epithelial healing.
Mechanism: Activates EGFR signaling to promote cell proliferation.Platelet‑Rich Plasma Eye Drops
Dosage: 20% dilution, four times daily.
Function: Delivers a cocktail of growth factors (PDGF, TGF‑β).
Mechanism: Accelerates wound healing and reduces inflammation.Mesenchymal Stem Cell–Derived Exosomes
Dosage: 100 μg topical application daily.
Function: Paracrine delivery of anti‑inflammatory signals.
Mechanism: Modulates macrophage phenotype to a reparative state.Nerve Growth Factor (NGF) Eye Drops
Dosage: 20 μg/mL twice daily.
Function: Supports ocular surface innervation.
Mechanism: Promotes trophic support for epithelial cells.Bone Marrow Mononuclear Cell Infusion
Dosage: 1×10⁶ cells/kg IV.
Function: Systemic immunomodulation.
Mechanism: Releases anti‑inflammatory cytokines and growth factors.
Surgical Options
Definitive procedures provide tissue diagnosis and remove persistent lesions.
Excisional Biopsy with Cryotherapy
Complete lesion removal followed by freezing margins; low recurrence risk.Conjunctival Resection
Surgical excision of affected conjunctiva with primary closure; rapid healing.Amniotic Membrane Transplantation
Graft placed over resected area; promotes epithelial growth and reduces scarring.Cryoexcision
Combines excision and cryotherapy in one step; targets deep tissue while preserving healthy conjunctiva.Conjunctival Flap Reconstruction
Mobilizes adjacent healthy tissue to cover defect; supports surface restoration.
Prevention Strategies
Minimizing risk factors can reduce recurrence and new lesion formation.
Maintain gentle ocular hygiene.
Wear UV‑protective sunglasses outdoors.
Avoid chronic eye rubbing or pressing.
Control allergic conjunctivitis promptly.
Manage systemic inflammatory diseases (e.g., rheumatoid arthritis).
Eliminate smoking and secondhand smoke exposure.
Schedule routine eye exams every 6–12 months.
Use protective eyewear in dusty or chemical environments.
Follow an anti‑inflammatory diet rich in fruits, vegetables, and healthy fats.
Stay well‑hydrated to support mucosal barriers.
When to See a Doctor
Prompt evaluation is critical if you experience:
A persistent salmon‑pink patch lasting longer than two weeks.
Rapid growth beyond a few millimeters.
Vision changes (blurriness, double vision).
Pain, bleeding, or unusual discharge.
Systemic “B” symptoms such as weight loss or night sweats.
What to Do and What to Avoid
What to Do:
Track lesion appearance and symptoms in a diary.
Shield your eyes from glare and irritants.
Clean eyelids gently with approved wipes.
Take medications exactly as prescribed.
Report any new or worsening signs promptly.
What to Avoid:
Rubbing or forcibly touching the lesion.
Using over‑the‑counter drops without professional advice.
Smoking or exposure to pollutants.
Sharing contact lenses or eye cosmetics.
Skipping scheduled follow‑up visits.
FAQs
What is Conjunctival Reactive Lymphoid Hyperplasia?
A benign, polyclonal proliferation of lymphoid tissue in the conjunctiva.Is it cancer?
No—unlike lymphoma, CRLH is polyclonal and usually non‑progressive NCBI.What triggers it?
Chronic antigen exposure from infections or inflammation.How is it diagnosed?
Slit‑lamp exam followed by biopsy and histopathology.Can it resolve spontaneously?
Some small, asymptomatic lesions may remain stable without intervention.What are first‑line treatments?
Corticosteroids (topical, intralesional, or systemic) and surgical excision.What are the risks of steroids?
Elevated eye pressure, cataracts, systemic side effects with oral use.Are immunosuppressants necessary?
Used when steroids fail or are not tolerated.When is surgery indicated?
For lesions unresponsive to medication or those causing discomfort.Can lifestyle changes help?
Yes—exercise, stress reduction, and diet support immune balance.Is recurrence common?
Recurrence is rare with complete excision and adjuvant therapy.Can it transform into lymphoma?
Extremely rare, but ongoing monitoring is essential.What follow‑up is needed?
Every 4–6 weeks during active treatment, then every 3–6 months.Are there experimental therapies?
Yes—stem cell and growth factor–based treatments are under study.How is vision affected?
Most patients maintain normal vision, though large lesions can cause discomfort or mild visual changes.
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The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: July 20, 2025.
