Follicular Lymphoma

t(14;18) and the anti-apoptotic lesion

• The t(14;18)(q32;q21) translocation places BCL2 on chromosome 18 under the control of the immunoglobulin heavy chain enhancer on chromosome 14, producing constitutive BCL2 overexpression
• BCL2 is an anti-apoptotic protein. Germinal centre B cells are normally programmed to die unless rescued by successful antigen selection; overexpressed BCL2 removes that checkpoint, allowing cells to persist indefinitely
• The result is accumulation, not proliferation — hence the indolent tempo, the low Ki-67, and the relative chemoresistance of a tumour whose cells are largely not cycling
• t(14;18) alone is insufficient. The translocation is detectable in circulating B cells of healthy people; additional lesions — CREBBP, KMT2D (MLL2), EZH2, TNFRSF14 — are required for overt lymphoma
• The tumour remains dependent on its microenvironment: follicular dendritic cells, follicular helper T cells and macrophages support survival, which is why immunomodulatory therapy works well

Transformation

• Acquisition of TP53 loss, CDKN2A deletion or MYC deregulation converts follicular lymphoma into diffuse large B-cell lymphoma
• Rate is approximately 2-3% per year, and appears to plateau in patients surviving many years
• Announced clinically by rapid asymmetric nodal growth, new B symptoms, a sharply rising LDH, hypercalcaemia, or a discordantly high SUV on PET

• Age — median at diagnosis around 60; uncommon under 40 and rare in children (paediatric-type follicular lymphoma is a distinct, localized, BCL2-negative entity with excellent outcome)
• Slight female predominance; more common in white populations in North America and Western Europe than in Asia
• Family history of non-Hodgkin lymphoma confers a modest increase in risk
• Autoimmune disease and chronic immune stimulation, particularly Sjögren syndrome and rheumatoid arthritis
• Occupational exposure to certain pesticides, herbicides and organic solvents is reported, with modest and inconsistent effect sizes
• Cigarette smoking shows a weak association in some series
• No infectious agent is established as causative, in contrast to the marginal zone lymphomas

• Painless, slowly progressive lymphadenopathy, often peripheral and symmetrical, characteristically waxing and waning over months to years — a history of nodes that enlarge then shrink spontaneously is highly suggestive
• Many patients are entirely asymptomatic, the disease found incidentally on examination or imaging
• Advanced stage (III-IV) in 80-90% at diagnosis, with bone marrow involvement in around half — often in a characteristic paratrabecular pattern
• B symptoms are uncommon and their appearance should raise concern for transformation
• Splenomegaly and, less commonly, hepatomegaly
• Cytopenias from marrow infiltration or hypersplenism
• Extranodal involvement is less frequent than in other lymphomas; the gastrointestinal tract (particularly duodenal-type follicular lymphoma, a localized indolent variant) and skin may be involved
• Compressive symptoms from bulky retroperitoneal or mesenteric disease — ureteric obstruction, lymphoedema, bowel compression
• Features suggesting transformation: one nodal area growing far faster than others, new fevers or weight loss, rising LDH, hypercalcaemia, new extranodal disease

Tissue

• Excisional lymph node biopsy is required. Core or needle biopsy frequently cannot establish grade or assess architecture, both of which change management
• Histology: a nodular (follicular) growth pattern effacing nodal architecture, composed of centrocytes (small cleaved cells) and centroblasts (large non-cleaved cells)
• Grading is by centroblast count per high-power field: grades 1-2 and 3A behave indolently; grade 3B is treated as diffuse large B-cell lymphoma

Immunophenotype — the single most useful diagnostic point

• CD20, CD19, CD10 and BCL6 positive, with monotypic light chain — a germinal-centre phenotype
• BCL2 positive, and this is the discriminator: normal reactive germinal centres are BCL2-negative, because normal germinal-centre B cells are meant to be apoptosis-competent. A BCL2-positive germinal centre is neoplastic
• CD5 and cyclin D1 negative, separating it from CLL/SLL and mantle cell lymphoma
• Low Ki-67, consistent with indolent biology

Staging and prognostic assessment

• PET-CT and bone marrow biopsy; contrast CT where PET is unavailable
• FLIPI (Follicular Lymphoma International Prognostic Index): age over 60, stage III-IV, haemoglobin below 12 g/dL, elevated LDH, and more than four nodal sites. FLIPI-2 uses beta-2 microglobulin, marrow involvement, largest node diameter, haemoglobin and age
• POD24 — progression within 24 months of starting immunochemotherapy — identifies a poor-risk group with substantially reduced survival and is among the strongest available prognostic markers
• Biopsy any discordant or rapidly growing site to exclude transformation; a high focal SUV on PET should be targeted

Watchful waiting is a real treatment decision

• For asymptomatic patients with low tumour burden, observation is standard. Randomized data show no survival advantage to early treatment, and patients avoid toxicity, sometimes for many years
• Burden is assessed with the GELF criteria: nodal mass over 7 cm, three or more nodal sites each over 3 cm, symptomatic splenomegaly, organ compression, ascites or pleural effusion, cytopenias, or leukaemic phase
• Explaining "we are not treating because treating now would not help you live longer" takes time and is essential — untreated disease is deeply counterintuitive to most patients

Limited stage

• Stage I-II disease is potentially curable with involved-site radiotherapy, and a substantial minority achieve durable remission. This is the one setting where cure is a realistic goal

Advanced, symptomatic or high-burden disease

• Bendamustine with rituximab or R-CHOP are the standard immunochemotherapy backbones; obinutuzumab-based combinations offer improved progression-free survival at the cost of more toxicity (GALLIUM)
• Rituximab monotherapy is appropriate for lower-burden symptomatic disease and older or frailer patients
• Rituximab maintenance after induction prolongs progression-free survival without a proven overall survival benefit (PRIMA), and is a shared decision weighing remission duration against infection risk and hypogammaglobulinaemia

Relapsed disease

• Re-biopsy at each relapse to exclude transformation before choosing therapy
• Lenalidomide with rituximab ("R-squared") is effective and chemotherapy-free (AUGMENT)
• Tazemetostat for EZH2-mutant disease, and in EZH2 wild-type patients without other options
• CAR T-cell therapy — axicabtagene ciloleucel, tisagenlecleucel — produces high response rates in multiply relapsed disease
• Mosunetuzumab, a CD20/CD3 bispecific antibody, is active and off-the-shelf
• Autologous stem cell transplantation is considered particularly for POD24 patients; allogeneic transplantation is reserved for selected younger patients
• PI3K inhibitors were widely used and have largely been withdrawn after confirmatory trials failed to demonstrate benefit
• Transformed disease is treated as DLBCL, with anthracycline-based immunochemotherapy and consideration of transplantation or CAR-T

• Histologic transformation to DLBCL at roughly 2-3% per year — the principal cause of lymphoma-related death, converting an indolent disease into an aggressive one
• Progressive marrow infiltration with anaemia, thrombocytopenia and neutropenia
• POD24 — early progression after immunochemotherapy — marking a group with markedly worse survival
• Compressive complications from bulky nodal masses: ureteric obstruction with hydronephrosis, bowel obstruction, lymphoedema, superior vena cava obstruction
• Recurrent infection from disease-related and treatment-related hypogammaglobulinaemia, compounded by prolonged rituximab or obinutuzumab exposure
• Hepatitis B reactivation after anti-CD20 therapy in unscreened patients
• Secondary myelodysplastic syndrome and acute myeloid leukaemia, particularly after alkylating agents and after autologous transplantation
• Anthracycline cardiotoxicity where R-CHOP is used, and cumulative neuropathy from vincristine
• Autoimmune cytopenias, including immune thrombocytopenia and autoimmune haemolytic anaemia
• Psychological burden of surveillance — living with a known, untreated, incurable malignancy is genuinely difficult and deserves explicit support

• t(14;18) places BCL2 under the IgH enhancer — the lesion blocks apoptosis rather than driving proliferation, which is why the disease accumulates slowly, has a low Ki-67, and behaves indolently
• A BCL2-positive germinal centre is neoplastic; reactive germinal centres are BCL2-negative. This is the most useful single immunohistochemical discriminator in nodal pathology
• Most patients present at stage III-IV and feel perfectly well — advanced stage does not carry the same meaning here as in aggressive lymphoma
• Watchful waiting is standard for asymptomatic low-burden disease; early treatment does not prolong survival. Use the GELF criteria to define burden
• Stage I-II disease is potentially cured by radiotherapy — the one curative setting
• Advanced disease is treatable but not curable, with median survival now beyond 18-20 years
• Transformation to DLBCL runs at 2-3% per year. Suspect it with rapid asymmetric nodal growth, new B symptoms, rising LDH, hypercalcaemia, or a discordantly high PET SUV — and re-biopsy rather than assume
• B symptoms are unusual in untreated follicular lymphoma and should prompt a search for transformation
• Grade 3B follicular lymphoma is treated as DLBCL, unlike grades 1-3A
• FLIPI: age over 60, stage III-IV, haemoglobin under 12, raised LDH, more than four nodal sites
• POD24 — relapse within two years of immunochemotherapy — is the strongest adverse prognostic marker and should prompt consideration of transplantation or cellular therapy
• Rituximab maintenance improves progression-free but not overall survival — a genuine trade-off against infection risk, not an automatic choice
• Screen for hepatitis B before any anti-CD20 antibody
• Excisional biopsy, not a needle — grading and architecture both change management, and a needle core often cannot provide them