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G. Cartron and J. Trotman
countries The median age at diagnosis is 63 years and the male/female ratio is around 1.2.4 The incidence is 2.7 per 100,000 people, such that there are approximately 13,200 new cases of FL in the USA each year. Most patients (54.8%) are aged 55 - 75 years whereas patients younger than 40 and older than 85 represent a minority (2.4 and 4.8%, respectively). Epidemiological data from outside the USA remain sparse, but a French report charted a sim- ilar incidence and median age.5
A family history of non-Hodgkin lymphoma (odds ratio [OR]: 1.99), high body mass index in young adult- hood (OR: 1.15) and Sjögren syndrome in young women (OR: 3.37) increase the risk of FL.6 Among environmental factors, smoking (especially heavy smoking in women, OR: 1.41) also correlated with FL.7 Prolonged agriculture exposure to pesticides increases the risk of FL8 (OR: 2.9- 5.0 according to the type of pesticide), a situation also associated with both circulating B cells harboring the ini- tiating t(14;18) and genetic alterations linked to malignant progression.9
Clinical features and diagnostic approach
Most patients with FL present with asymptomatic dis- ease and the diagnosis is often suspected incidentally dur- ing a clinical or radiological examination performed for symptoms unrelated to FL. When symptomatic, the clini- cal presentation is dominated by lymphadenopathy or less frequently disease-related complications, such as abdominal pain (mesenteric lymphadenopathy) or respi- ratory signs (cough, shortness of breath, pleural effusion) in the event of thoracic lymphadenopathy. The general “B” symptoms (recurrent fever >38°C, drenching sweats, weight loss >10%) associated with lymphoma only occur in about 20% of patients and should raise the suspicion of histological transformation.
Laboratory investigations look for the existence of cytopenia, particularly anemia. While bone marrow infil- tration is the most common cause, the possibility of autoimmune cytopenia should not be underestimated. The presence of circulating lymphoma cells, found in fewer than 10% of cases, is associated with a shorter pro- gression-free survival (PFS).10 The lactate dehydrogenase and b2-microglobulin levels are important prognostic markers, and serum electrophoresis should be systemati- cally requested in the search for an associated monoclonal protein and viral serology (hepatitis B and C, human immunodeficiency virus) should be determined before any treatment using anti-CD20 monoclonal antibody.
The diagnosis of FL is made on a lymph node or, in the uncommon extranodal FL, organ biopsy. Initial diagnosis by fine needle aspiration or needle biopsy is not recom- mended due to the importance of architectural examina- tion in diagnosis and the risk of missing histological trans- formation. Multiple core needle biopsies, guided by ultra- sonography or a computerized tomography (CT) scan, using a 14- or 16-gauge needle, may be informative but should be reserved in the context of disease to abdominal or extranodal sites. If it remains debated, when clinical findings suggest a possible hidden histological transfor- mation, a 18F-fluorodeoxyglucose (FDG) positron emis- sion tomography, coupled with low-dose CT (PET) may assist in identifying sites where a repeat biopsy could identify such. There are however no prospective data to
support re-biopsy on the basis of baseline quantitative PET metrics alone. Indeed, a large body of data from the GALLIUM study suggests no association of maximum standardized glucose uptake value (SUVmax) with either histological transformation11 or PFS.12 There is marked heterogeneity in FDG uptake within patients which reflects metabolic activity of the malignant B cells as well as that of the microenvironment.13 Likewise, the isolated analysis of bone marrow or blood infiltration is not appropriate for the diagnosis of FL.
Histopathology
FL is an entity well-defined in the World Health Organization (WHO) classification.14 The macroscopic appearance of lymph nodes involved by FL is usually vaguely nodular with a predominantly follicular organiza- tion microscopically. Thus, tumors frequently maintain a normal germinal center architecture forming enlarged lymphoid follicles with centroblasts and centrocytes ran- domly distributed with a loss of the polarization usually seen in reactive lymph nodes. On immunochemistry, FL cells typically express a germinal center pattern (CD10, BCL6), B-markers (CD19, CD20, SIg) and BCL2. Although absent in 10 to 15% of cases, BCL2 overexpres- sion, secondary to t(14;18), is the hallmark of FL and can be useful in distinguishing FL from reactive follicles. It is important to note that t(14;18) (q32;q21), placing BCL2 under the transcriptional regulation of IGH regulatory regions leading to the overexpression of this anti-apoptot- ic protein, is a lymphoma-initiating event. In cases lacking BCL2 expression, the usual BCL6 and CD10 expression helps to distinguish FL from other lymphoproliferative diseases. Present at low level in 70% of healthy individu- als, lymphoid cells harboring t(14;18) require additional genetic events for the development of FL.
A grading system based on counting the absolute num- ber of centroblasts in ten neoplastic follicles per high power field is used to characterize FL into grades 1 and 2 (grade 1: 0-5 centroblasts per high power field, grade 2: 6- 15) which represent the majority of cases (80%). Grade 3 FL has >15 centroblasts per high power field and is fur- ther subdivided into FL 3A (centrocytes still present) and FL 3B (composed exclusively of centroblasts). FL grade 3B is now managed as an aggressive lymphoma similar to diffuse large B-cell lymphoma. Considering the therapeu- tic impact of distinguishing between FL3A/3B, an expert review of histological classification may be useful. Rare entities including testicular FL, duodenal-type FL, pedi- atric FL and in situ follicular neoplasia are also character- ized in the WHO classification. These entities are not dis- cussed in this review.
Staging
At diagnosis, staging is mandatory to determine the dis- tribution and burden of the lymphoma. Staging is an important factor in guiding treatment decisions - influenc- ing both choice and timing of therapy- and re-staging is important to assess disease response after treatment and at times of progression requiring treatment. The current stag- ing procedures include physical examination, blood inves- tigations (full blood count, renal function and liver function
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haematologica | 2022; 107(1)