Ocular Adnexal Follicular Lymphoma

Etiology

Follicular lymphoma (FL) is the second-most common low-grade B-cell lymphoma after MALT (J Clin Exp Hematop 2014; 54:3).

Tumor cells are malignant counterparts of normal germinal center B-cells.

The tumor is made of closely associated follicles with abnormal architecture and loss of interfollicular space (Hematology 2013; 2013:561).

FL tumor cells in these follicles are associated with normal reactive cells such as dendritic cells, macrophages, fibroblasts, and T-lymphocytes (Leukemia 2014; 28:1388).

Some of these normal reactive cells suppress growth of the tumor cells whereas others support growth of the tumor cells.

Behavior of the tumor cells can differ in various involved organs and nodal versus extranodal disease.

Some FLs are indolent, but 30%­–40% progress to aggressive diffuse large B-cell lymphoma.

Histone modifying genes are frequently mutated in FL, secondary oncogenetic events leading to lymphomagenesis.

• EZH2 — histone-lysine N-methyltransferase — encodes protein complexes that repress gene transcription; adds 3 methyl groups to Lysine 27 of histone 3, which leads to chromatin condensation.
• CREBBP — a coactivator of transcription factors — has histone acetyltransferase activity.
• MLL2 — histone-lysine N-methyltransferase 2D — another histone-modifying protein and a chromatin-remodeling protein
• EPHA7 — ephrin type-A receptor 7 — tyrosine kinase mediates developmental events in the nervous system.
• TNFRSF14 — tumor necrosis factor receptor superfamily member 14 — herpes virus entry mediator; mediates signal transduction pathways that activate the immune system.
• BCL6 — B-cell lymphoma 6 protein — zinc finger transcription factor, sequence specific repressor of transcription, mediates interleukin-4 response of B-cells.

The genetic hallmark is translocation t(14;18)(q32;q21).

• Results in the constitutive overexpression of the BCL2 protein
• Analogous to hallmark translocation of mantle cell lymphoma
• BCL2 = B-cell lymphoma 2 — regulates apoptosis

Tumor cells express IgD and IgM on the cell surface.

Epidemiology

The incidence of FL is roughly 1 case per 24,000 in the US (New Engl J Med 2007; 356:741).

Among 18,830 patients with FL identified through the Surveillance, Epidemiology and End Results program (SEER) of the National Cancer Institute from 1992 to 2009 (Am J Hematol 2014; 89:633):

• 80% were Caucasian; 8% were Hispanic; and 4% were African-American.
• No gender differences
• No particular age predisposition

Among 2,744 FL patients identified through the National LyphoCare study, a multicenter, observational cohort or newly diagnosed FL in the US from 2004-2007:

• 90% were Caucasian; 5% were Hispanic; and 3% were African-American (Cancer 2012; 118:4842).
• Compared with Caucasian patients, Hispanic and African-American patients were diagnosed younger (< 45 years old).

Ocular adnexal FL was studied in 98 patients through a multicenter (six centers) retrospective analysis, including patients from 1980-2010 (JAMA Ophthalmol 2014; 132:851).

• Median age was 63 years (range 32–6 years).
• 70% had primary ocular adnexal FL.
• 10% had an ocular adnexal presentation of relapse.
• Lacrimal gland (28%), orbit (28%), and conjunctiva (28%) were equally involved.
• Ten-year survival was 60% in this cohort.

24 patients from Denmark with follicular lymphoma of the ocular adenexal region were studied (Rasmussen et al, Acta Ophthalmol 2015).

• Median age was 63 years, and 58% were female.
• The most frequently affected sites were the lacrimal gland (38%) and orbit (33%).

In a multicenter retrospective study of 797 patients with orbital lymphoma, follicular lymphoma was the third most common subtype (11%). Compared to diffuse large B-cell and mantle cell lymphoma, extranodal marginal zone B-cell lymphoma and follicular lymphoma had markedly better prognosis (Olsen et al., Am J. Ophthalmol 2018).

History

• Pain
• Epiphora
• Mass
• Chemosis
• Lacrimal gland enlargement
• Proptosis
• Ptosis
• Diplopia

Clinical features

• Lacrimal gland enlargement: Among 27 patients with lacrimal gland lymphoma from 1975-2009 identified through the Danish Registry of Pathology, 37% were MALT and 19% were FL (Arch Ophthalmol 2011; 129:1275).
• Proptosis
• Chemosis
• Mass
• Restricted eye movement
• Ptosis

Testing

Tumor cells are CD20+, CD19+, CD22+, BCL2+, BCL6+, and CD5 negative.

Nine ocular adnexal reactive lymphoid hyperplasias (RLH) were compared with 6 FLs (AJO 2010; 150:412):

• BCL-2 was positive in the follicle centers of FLs but not the RLHs.

Tumor follicles show strong CD10 immunostaining, contrasted with reactive lymphoid follicles.

• “Cluster of differentiation 10” — CD10 — is present on leukemic cells of pre-B phenotype.
• It is a zinc-dependent metalloproteinase.
• CD10 is also a marker for diffuse large B-cell lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia, and angioimmunoblastic T-cell lymphoma.

Testing for staging, fundamental impairment

Staging of FL depends more on grading than on distribution of disease.

• The typical staging from I to IV where local disease is compared with local disease and regional lymphadenopathy, etc., is based on Hodgkins lymphoma and is less relevant for FL.
• Typical staging workup includes whole body CT and PET scan to define the extent of clinically evident disease.
• Treatment decisions, however, are based on grading.

Grading depends on the relative proportion of centrocytes to centroblasts.

• Grade 1: < 5 centroblasts per high power field (HPF)
• Grade 2: 6–15 centroblasts per HPF
• Grade 3A has centrocytes whereas grade 3B has > 15% centroblasts per HPF as solid sheets.

Grade 3B is most aggressive and resembles diffuse large B-cell lymphoma.

• Stage 3B might lose evidence of t(14;18) and CD10 expression and have increased p53 and other oncogenes.

About 75% of patients presenting with FL have indolent disease (grades 1-2, and possibly 3A), with median survival 11 years, while median survival with aggressive disease (grade 3B, and possibly 3A) is 4 years (New Engl J Med 2007; 356:741).

520,000 healthy participants were enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; 100 subsequently developed FL within 2–161 months (J Clin Oncol 2014; 32:1347).

• The t(14;18) translocation imparted a 23 fold higher risk of developing FL; confirming that it is an early initiating event.
• Patients could harbor the translocation for 15 years before presenting with clinical disease.

Vegetable intake, or fruits and vegetables, but not fruit alone, is significantly inversely proportional with the development of FL (Int J Cancer 2013; 133:190).

Postmenopausal women who are using hormone replacement therapy are at decreased risk of FL, but having stopped for more than 2 years eliminates the decreased risk (Ann Oncol 2013; 24:433).

Dark colored hair dyes may increase the risk of FL (Asian Pac J Can Prev 2011; 12:2393).

• IgG-4 lymphoproliferative disease
• Diffuse large B-cell lymphoma
• Mucosa associated lymphoid tumor (MALT)
• Mantle cell lymphoma

Natural history

For patients without symptoms and low tumor burden, expectant watching can be appropriate.

This is a heterogeneous disease and predicting tumor behavior is difficult.

Medical therapy

Prognosis has improved since the introduction of rituximab (J Clin Exp Hematop 2014; 54:31).

• Treatment regimens include R-CHOP, R-CVP, and bendamustine plus rituximab.
• Rituximab monotherapy is sometimes a reasonable option.

Radiation

Local radiotherapy has been a standard treatment.

Radiotherapy is recommended for stage I and II disease (Leukemia 2014; 28:1388).

In the recent multicenter trial cited above (JAMA Ophthalmol 2014; 132:851), patients with primary ocular adnexal FL and isolated ocular relapse were treated with external beam radiotherapy alone or radiotherapy plus chemotherapy.

Newer studies have looked at low dose radiation with 4 Gy in 2 fractions and assessed for response at 3-month intervals and an additional 20 Gy in 10 fractiosn for persistent orbital lymphoma (Pinnix, JAMA Oncology 2024, e242112).

However, the recognition that many patients can be observed, and most should be treated with rituximab has altered the standard of care.

• In a survey of 471 patients with stage I FL, only 127 (27%) were treated with radiotherapy alone, whereas 17% were observed, 12% were treated with rituximab alone, and 28% received rituximab-based chemotherapy (J Clin Oncol 2012; 30:3368).

Surgery

Biopsy leads to diagnosis and aids in decision regarding initial management.

• Decision to observe will be based on limited disease and lower grade histology.
• Rituximab may be added to treat subclinical systemic disease and radiotherapy may be added to control local disease.
• Generally, FL in the ocular adnexa is too infiltrative to allow for definitive surgical excision.

Specimen is submitted fresh to facilitate immunohistochemistry.

If a lesion can be completely excised and is accessible, then surgical management is appropriate.

For lacrimal gland tumors the morbidity of excision often minimizes the benefit; medial treatment or radiotherapy are preferred.

Other management considerations

For recurrent disease, experimental therapies and stem cell transplantation are recommended.

Rather than waiting for relapse, maintenance rituximab might extend duration of remission and possibly improve survival (Hematol Oncol 2013; 31:171).

Common treatment responses, follow-up strategies

Radioimmunotherapy might stabilize and extend remission induced by rituximab based therapy (Clin Develop Immunol 2013; 2013:875343.

Preventing and managing treatment complications

Complications are primarily related to chemotherapeutic regimen.

Five factors predict poor outcome (Am J Hematol 2014; 89:429):

• Age > 60 years
• Hemoglobin <12 g/dL
• Elevated serum lactate dehydrogenase
• Number of involved nodal areas > 4
• Ann Arbor stage III/IV

In 1982 the translocation between chromosomes 14 and 18 was identified in 16 of 19 patients with FL (New Engl J Med 1982; 307:1231).

By 2007 it was found that a majority of healthy persons have, in their normal B-cells, the same t(14;18) translocation that brings together the BCL2 gene and the gene encoding the immunoglobulin heavy chain (New Engl J Med 2007; 356:741).

• The factors that cause B-lymphocyte progenitor cells with this translocation to undergo malignant transformation seem to be a function of antigenic stimulation.

In 1997 rituximab was the first monoclonal antibody approved by the FDA for treatment of relapsed or refractory, low grade FL (New Engl J Med 2008; 359:613).

1. 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.
2. Rasmussen PK, Coupland SE, Finger PT, et al: Ocular adnexal follicular lymphoma: a multicenter international study. Arch Ophthalmol 2014; 132:851.
3. Staudt LM: A closer look at follicular lymphoma. New Engl J Med 2007; 356:741
4. Olsen TG, Holm F, Mikkelsen LH, et al. Orbital lymphoma: An international multicenter retrospective study. Am J Ophthalmol 2018 [Epub ahead of print].
5. Pinnix CC, Dabaja BS, Gunther JR, Fang PQ, Wu SY, Nastoupil LJ, Strati P, Nair R, Ahmed S, Steiner R, Westin J, Neelapu S, Rodriguez MA, Lee HJ, Wang M, Flowers C, Feng L, Esmaeli B. Response-Adapted Ultralow-Dose Radiation Therapy for Orbital Indolent B-Cell Lymphoma: A Phase 2 Nonrandomized Controlled Trial. JAMA Oncol. 2024 Jul 11:e242112.
6. Rasmussen PK, Ralfkiaer E, Prause JU, et al. Follicular lymphoma of the ocular adnexal region: a nation-based study. Acta Ophthalmol 2015; 93:184-91.