Conjunctival Reactive Lymphoid Hyperplasia

From EyeWiki

Original contributors: Vendantam S, Patadia S, Gugala Jr. Z, Brock DC, Huang A, Yen MT

Disease Entity

Conjunctival Reactive Lymphoid Hyperplasia (CRLH) is the manifestation of uncontrolled proliferation of lymphoid cells in the conjunctiva of the eyes. This hyperplasia is typically benign though in rare instances, it can progress to malignant lymphoma. CRLH comes from a group of Lymphoid Hyperplasia diseases which are characterized by lymphoproliferation and enlargement of the affected tissues which can include the liver and thyroid.

General manifestations of CRLH include tissue swelling, pain, redness, and pink colored lesions in the conjunctival stroma.[1] [2]

Etiology and History

CRLH may arise as a result of antigen stimulation of the conjunctiva mucosa-associated lymphoid tissue (MALT).[3] CRLH is also associated with aberrant autoimmune disease.[4] Chronic or acute MALT inflammation may also arise from allergies or infection with Chlamydia psittaci.[5] [6] However, the exact cause of development remains undetermined. CRLH occurs primarily in adolescents and adults with a higher predisposition in males. Adolescent patients usually present with an otherwise unremarkable history without systemic lymphoma.[5]


Clinical diagnosis

The primary presenting sign of benign CRLH is often a slow growth tumor in the conjunctiva in the form of a salmon-colored lesion, with little conjunctival infection and no significant neovascularization upon slit-lamp examination (Fig. 1).[7]

Figure 1. Slit-lamp photograph of patient’s right eye exhibiting elevated salmon-colored lymphoid tumor in upper bulbar conjunctiva.[7] Open access under terms of the Creative Commons License: Original figures available at:

Ultrasound biomicroscopy may be performed to confirm lesion depth and diameter (Fig. 2).[7] On optical coherence tomography (OCT), the tumor presents as a homogeneous, hyporeflective lesion with thin overlying epithelium (Fig. 3).[2]

Figure 2. Ultrasound biomicroscopy of lesion depth (1.53 mm) and large diameter (10.73 mm).[7] Open access under terms of the Creative Commons License: Original figures available at:
Figure 3. Anterior segment optical coherence tomography scan showing homogeneous, hyporeflective lesion with thin overlying epithelium.[2] Open access under terms of the Creative Commons License: Original figures available at:

Physical examination

As a result of MALT inflammation, patients with CRLH usually present with a “salmon-patch” conjunctival lesion while experiencing symptoms including a palpable mass with swelling, proptosis, conjunctival irritation, diplopia, upper lid ptosis, and pain.[8] Irritation and palpable masses/lesions on the conjunctiva often form the patient’s chief complaint. Lesions are commonly located on the medial bulbar conjunctiva.[5] Many symptoms of CRLH overlap with conjunctival lymphoma and conjunctival amyloidosis. While conjunctival amyloidosis may be differentiated using HR-OCT, conjunctival lymphoma and CRLH are differentiated using histopathological evaluation, immunohistochemistry, flow cytometry and/or gene rearrangement.[9] [10]


Although many may not experience any symptoms, CRLH may present with one or more of the following:[1] [2]

  • Enlarged lymph nodes, specifically in the neck
  • Pain and redness
  • Swelling of the eyelids
  • Difficulty moving the eye
  • Masses and/or lumps
  • Blurred vision
  • Bulging eyes
  • Drooping eyes

Histopathological and Immunohistochemical Diagnosis

Dependent upon symptom presentation and findings from clinical examination, incisional biopsy may be recommended to confirm diagnosis and exclude neoplastic lesions. Histopathology of formalin-fixed tissue typically shows chronic inflammatory process presenting in lymphoid follicles (Fig. 4).[7]

Figure 4. (A) Hematoxylin-Eosin stain, 100x magnification, of conjunctival biopsy showing chronic inflammatory infiltrate.[7] (B) Hematoxylin-Eosin stain, 400x magnification, of conjunctival biopsy.[7] Open access under terms of the Creative Commons License: Original figures available at:

Analysis of fresh, unfixed tissue with flow cytometry for specific immunohistochemical antibodies stains positive for polyclonal markers (e.g., both CD3 T lymphocytes and CD20 B lymphocytes) (Fig. 5A).[7] Immunohistochemistry also reveals low levels of KI-67, a marker of active cell proliferation (Fig. 5B).[7]

Figure 5. (A) Immunohistochemistry staining positive for CD20 B lymphocytes and CD3 T lymphocytes, demonstrating polyclonality.[7] Open access under terms of the Creative Commons License: Original figures available at:
Figure 5. (B) Immunohistochemistry staining positive for KI-67 in low index.[7] Open access under terms of the Creative Commons License: Original figures available at:

Differential diagnosis

Differential diagnosis of CRLH includes conjunctival papilloma, foreign body granuloma, amyloid deposition, chronic follicular conjunctivitis, and other benign ocular surface tumors such as conjunctival pyogenic granulomas.[11] Malignant tumors such as squamous cell carcinoma and conjunctival lymphoma should also be considered and are of paramount importance to exclude early.[11]


Medical therapy

Treatment is dependent on a variety of factors including the extent of symptoms present, comorbidities of other illnesses (e.g., Hodgkin's Lymphoma), and complexity/severity of the disease state. In many instances, careful observation can be the initial management for those who are asymptomatic or are not interested in pursuing further treatment. Historically, the first line of treatment for treating reactive lymphoid hyperplasia has been through administration of oral corticosteroids, such as prednisolone, alongside surgical resection of masses for symptomatic relief.[1] [7] Other forms of treatment include surgical resection with adjuvant perilesional steroid injection, cryotherapy, or external beam radiation therapy. Recent results have shown radiation therapy to be an effective treatment option especially if the condition is confined to only one orbit or for individuals who are contraindicated for corticosteroid use.[1] Studies have also shown that radiation therapy may also limit the extent of recurrence and malignancy development when compared to prednisone treatment alone.[1][12] Other reported forms of treatment have included use of doxycycline, cyclosporine 0.05%, and interferon ɑ-2b.[2][13] Novel treatments have been focusing on targeted-therapy approaches towards managing orbital lymphoid hyperplasia. Rituximab, a monoclonal antibody directed against the CD20 cell surface marker in B-lymphocytes, has been an increasingly popular treatment option for treatment.[1][14] One of the advantages towards using Rituximab over long-term corticosteroids are the decrease in steroid-associated side effects, lack of myelosuppression, and limited malignancy transformation.[1]


Since CRLH is generally benign, the most severe complication is a progression to malignancy as lymphoma. After therapy, there is a 20-30% chance for recurrence of the lesion, typically associated with lesions affecting the lacrimal gland. The incidence of lymphoma appears low across many studies and varies based on the monoclonality of the lesion. Without monoclonality, risk of lymphoma is around 8%. If the cells are derived from a single progenitor, risk for lymphoma increases to about ⅓ of cases. It is recommended that the progression of CRLH even after treatment should be tracked every six months to identify signs of recurrence or lymphoma.[1]


The outcomes for most patients with CRLH are positive. Given the main risk factor of recurring lesions, which affect approximately 20-30% of patients, there have been suggestions to follow up with patients for a minimum of 5 years.[1] The extent of the disease is the most important factor in determining risk of recurrence. There is a small risk for association with non-Hodgkin lymphoma. Additionally, some cases suggest that conjunctival lymphoma may arise from CRLH, emphasizing the need to prevent further malignancy.[15] Some isolated cases report thinning of the sclera along with the “salmon patch” lesion.[16] However, the prognosis for most patients is favorable when appropriate follow-up visits are taken.


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