Follicular lymphoma (FL) is the second most common subtype of lymphoma in Western Europe, as it represents 22-25% of non-Hodgkin´s lymphomas (NHL), according to the WHO histological classification [1
]. The annual incidence of FL increased from two to three per 100,000 persons/year during the 1950s to five to seven per 100,000 persons/year in 2009, with a prevalence of 40 cases per 100,000 people [3
FL originates in follicular-centre B cells, usually in the lymph nodes, and maintains the phenotypic characteristics and gene expression of these cells. Approximately 85% of FL patients present with chromosomal translocation t(14;18), which leads to overexpression of the BCL-2 oncogene and results in resistance to apoptosis. t(14,18) is not specific for FL, as it is present in 30% of diffuse large B-cell lymphomas (DLBCL) and even in some healthy individuals [4
Morphologically, FL is composed of small B-cells (centrocytes) and large B-cells (centroblasts) that are clonally related. The morphological distribution follows a nodal growth pattern similar to that of the germinal centres observed in secondary lymphoid follicles. Neoplastic follicles may be prevalent in tumoural tissue; the rest of the tumour exhibits a diffuse growth pattern [1
]. FL is classified into three grades according to the number of centroblasts present in the tumour tissue (Table ). In grades 1 and 2, centrocytes prevail; in grade 3 large cells are more numerous. Grade 3 is divided into 3A (when centrocytes are still present) and 3B (characterised by the presence of solid sheets of centroblasts). Although grade 3B FL has a worse prognosis and its natural history and treatment are similar to those of DLBCL, the genetic characteristics and clinical behaviour suggest that grade 3A FL exhibits indolent behaviour very similar to that of grade 1-2 FL [5
Follicular lymphoma grading according to the WHO classification1
FL is the most common indolent lymphoma accounting for 70% of all indolent lymphomas. The treatment used for FL has been generally accepted for other less frequent indolent lymphomas. Usually the first symptom is the asymptomatic presence of enlarged peripheral nodes in the neck, and in the axillary or inguinal areas.
Occasionally, adenopathies increase and decrease in size for prolonged intervals before diagnosis. Some patients present a bulky abdominal mass not associated with urinary/intestinal obstruction. Although patients only present with one or two node areas that are clinically affected, the staging study showed dissemination affecting the spleen, liver or bone marrow in 40%, 50% and over 60% of patients, respectively. Extranodal involvement is infrequent [6
Once a diagnosis of FL is confirmed, the pretreatment evaluation determines the extent of the disease and provides information about the individual's comorbidities that are likely to have an impact on treatment options. Of particular importance is the information gathered from this evaluation, as it is used to determine the patient's Follicular Lymphoma International Prognostic Index (FLIPI) [7
] and FLIPI 2 [8
] scores, which determines whether the patient is at risk for progression (Table ) [7
Follicular Lymphoma International Prognostic Index (FLIPI) and Follicular Lymphoma International Prognostic Index 2 (FLIPI 2)
Most patients are diagnosed with FL when they have an advanced stage of the disease (less than 20% present with stages I or II), although a significant percentage of patients just present with an enlarged node noted by palpation (asymptomatic FL).
FL is characterised by a chronic remission/relapse pattern. FL natural history is characterised by alternating periods of treatment, achievement of a partial/total remission, and periods free of disease and relapse or progression of the lymphoma, which requires additional treatment. With each new treatment remissions are less frequent and progression-free periods are shorter. Occasionally, partial and short spontaneous remissions can occur. Finally, patients die after developing refractory FL, FL transformation to a more aggressive lymphoma (10-70% of cases), acute toxicity, or of causes unrelated to the disease. However, FL is not necessarily an incurable disease. A randomized study with a long follow-up period, conducted in the pre-rituximab era, showed that about 15-20% of patients never relapse or die without known disease at nearly 20
years after treatment [9
With the treatments that were applied 10-15
years ago in the so-called pre-rituximab era, the median survival ranged from 9 to 10
years and no treatment was shown to increase overall survival [10
]. The aim of the treatment was to improve patients’ quality of life. Therefore, asymptomatic patients were not treated until the disease was progressive (watch-and-wait strategy). Thus, patients were spared the acute and late toxic effects of the treatment.
In the past 15
years, the introduction of rituximab into the treatment of patients with FL has resulted in a significant change in the diseases’ prognosis and natural history. The median survival has increased to approximately 14
], and progression-free survival periods without treatment have been extended to nearly 5
]. All this has been achieved with just a slight increase in toxicity.
Unfortunately, advanced-stage FL is still incurable for the majority of patients. Thus, current therapies are aimed at achieving optimal palliation by inducing long periods of durable remissions with assumable acute and late toxicity, which limit the potential development of shared "cross-resistance" to other therapies in the future [13
In this new setting and in the light of recent evidence, application of the “watch and wait” policy to asymptomatic patients should be reviewed.