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.
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).
- Lacrimal gland enlargement
- 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).
- Restricted eye movement
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).