Follicular lymphoma C82.9

Follicular lymphoma (FL) is predominantly an indolent lymphoproliferative B-cell disease with transformed follicular center B cells. It is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common, but constitutional symptoms such as fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B-cell lymphoma (Freedman A et al 2020).

Staging: Stages I to IV are classified according to the Ann Arbor classification.

• Stage I: Involvement of a single lymph node region (I/N) or presence of a single, localized extranodal focus (I/E)
• Stage II: Involvement of two or more lymph node regions on one side of the diaphragm (II/N) or presence of an extranodal focus (II/E) and involvement of one or more lymph node regions on one side of the diaphragm (II/N/E).
• Stage III: Involvement of two or more lymph node regions on both sides of the diaphragm (III/N) or involvement of localized extranodal foci and lymph node involvement, so that there is involvement on both sides of the diaphragm (III/E or III/N/E).
• Stage IV: disseminated involvement of one or more extralymphoid organs with or without involvement of lymph nodes.

The stages are completed by the addition of "A" in the absence, "B" in the presence of:

• unexplained fever >38°C
• unexplained night sweats
• unexplained weight loss (> 10% of body weight within 6 months).

Note: Lymphatic tissues include: lymph nodes, spleen, thymus, Waldeyer's ring of pharynx, appendix. Cervical, axillary or inguinal lymph node enlargements and hepatic or splenic enlargements are considered as one region each.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in Western Europe and the USA (FL is very rare in Asia). FL accounts for about 5% of all hematologic neoplasms and about 20-25% of all newly diagnosed non-Hodgkin lymphomas in Western countries (Carbone A et al. 2019). The incidence is 4/100,000/year. M:w=1:1.

The origin of follicular lymphoma lies in the B cells of the germinal centers. In about 90% of patients, a balanced translocation between the immunoglobulin heavy chain gene on chromosome 14 and the Bcl-2 gene on chromosome 18 is detectable. The t(14;18)(q32;q21) leads to overexpression of the intact Bcl-2 protein and thus to inhibition of apoptosis. This constellation conditions a longer survival time of transformed cells and their slow accumulation in lymphoid tissues.

About 70% of the known t(14;18)(q32;q21) translocations are found in the major breakpoint region (MBR) of the Bcl-2 locus, 10-15% in the minor breakpoint region (mbr) of the Bcl-2 locus ((Huet S et al. 2018). Note: Bcl-2 translocations are characteristic but not specific to follicular lymphoma. They can also be detected at low frequency in healthy individuals (bone marrow, lymph nodes). Furthermore, this translocation is a feature of diffuse large B-cell lymphoma (DLBCL) detected in bone marrow and lymphoid tissue.

The following environmental risk factors are discussed:

• exposure to benzene; occupational exposure is recognized as an occupational disease in Germany
• occupational exposure to pesticides
• smoking, also passive smoking

The mean age of onset is between 55-60 years.

More than 80% of follicular lymphomas are diagnosed in advanced stages (stage III/IV). The clinical picture is characterized by the affected region and the onset of general symptoms:

• new, mostly painless enlargement of the lymph nodes
• General symptoms (fever, fatigue and tiredness, weight loss, night sweats = so-called "B symptoms")
• Impairment of haematopoiesis such as anaemia, more rarely thrombocytopenia (thrombocytopenia = indication for therapy). Other laboratory changes are uncharacteristic, LDH is normal in the majority of patients.
• An extralymphatic infestation pattern (can occur as part of systemic spread but also less frequently as primary infestation, e.g. spleen, tonsils (Yu YT et al. 2020), gastrointestinal tract (Shirsat HS et al. 2014), lung, integument) occurred in about 50% of cases (301/613) in a PET study series in non-pretreated follicular lymphoma. 28% (171/613) had splenic involvement (St-Pierre F et al 2019). They cause an independent local pathological clinical symptomatology.

Histological diagnosis should be based on surgical lymph node extirpation whenever possible. In the case of inaccessible lymph nodes, e.g. retroperitoneal lymph nodes, a lymph node biopsy can be performed as an alternative. Fine needle aspiration (cytology) is not sufficient due to possible focal heterogeneity of the lymphoma tissue and the possible need for further immunological and molecular genetic investigations. The histological report should designate the diagnosis according to the WHO classification and determine the grading (grade 1-2, 3A or 3B), as the grading has an impact on therapy. Follicular lymphoma grade 3B is considered aggressive lymphoma and treated accordingly. A detailed diagnosis before starting therapy (staging) is essential, as tehrapy modalities depend on this (S3 guideline of the AWMF 2019).

Laboratory screening:

• Blood count: leukocytes with differential blood count (microscopic differentiation), platelets, hemoglobin, reticulocytes.
• Further laboratory analyses of the blood: ESR, electrophoresis, total protein, GOT, GPT, AP, γ-GT, bilirubin, creatinine, uric acid, blood sugar, LDH, β2-microglobulin.
• Single-white electrophoresis, in case of suspicion of paraproteinemia immunoelectrophoresis
• Surface marker by multiparametric immunophenotyping (only in leukemic course)
• Hepatitis B (HBV), HCV, HIV, (before immunochemotherapy)
• Pregnancy test if necessary (before immunochemotherapy or radiotherapy)
• Bone marrow puncture with bone marrow cytology*, bone marrow histology*.
• Cytogenetics: FISH or PCR) for t(14;18) for differentiation from other indolent NHL**

Imaging program: CT neck / thorax / abdomen

• alternative: Positron emission tomography (PET-CT)
• alternative: sonography for follow-up
• In localized stages I/II, the "Lugano Classification" recommends performing positron emission tomography (PET) as part of the initial staging (Cheson BD et al. 2014). In advanced stages, PET has no therapeutic but prognostic value.

In order to identify patients at increased risk of acute and/or late complications, pulmonary function, cardiac (ECG, cardiac echo) and renal function examinations are mandatory before starting therapy.

Comment: In patients of reproductive age with a desire to have children, fertility-preserving measures should be offered before starting therapy.

Diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferable to needle biopsies to obtain sufficient tissue for grade determination and assessment of transformation. Immunohistochemical staining is positive for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin and for cytoplasmic expression of bcl-2 protein in virtually all cases. The vast majority of cases have the characteristic t(14;18) translocation involving the IgH/Bcl-2 genes (Freedman A et al. 2020).

All inflammatory lymph node enlargements of bacterial or viral origin (e.g. tuberculosis, toxoplasmosis, Epstein-Barr virus, cytomegalovirus, HIV) are considered as differential diagnosis.

Furthermore, other malignant lymphomas, lymph node metastases of solid tumors, or sarcoidosis should be included in the differential diagnostic considerations and excluded if necessary.

The differential diagnosis must also take into account the entities newly defined in the WHO with reference to localization/age/histology:

• Duodenal follicular lymphoma
• Cutaneous follicular lymphoma (Scale SLet al. 2018).
• Pseudolymphoma of the skin (lymphadenosis benigna cutis; see there for differential diagnosis).
• Follicular lymphoma of the pediatric type
• Follicular lymphoma in situ

These entities differ mainly prognostically from the other forms of follicular lymphoma.

The therapy depends on the stage. In stage I, irradiation of the affected lymph node regions has a curative claim. Drug therapy is initiated in the advanced stages when clinical symptoms are present. Remission rates of ≥90% are achieved with the combination of chemotherapy and an anti-CD20 antibody .

Patients with indolent lymphomas should be treated in clinical trials whenever possible. The approach depends on the disease stage, general condition and comorbidities.

Stage I and II (up to 15% of patients): Local irradiation ('involved field') with a total dose of 24-30 Gy is able to achieve long-lasting disease freedom and potential cures. After 10 years, approximately 85% of patients in stage I (or LK <2cm), but only 35% in stage II (or LK > 3-5 cm) remain disease-free. Very low recurrence rates have been observed in the combination of radiation with rituximab (Witzens-Harig M et al (2011).

In localized stage I with bulk (LK ≥5-7 cm) or stage II, immunochemotherapy is a treatment option in addition to radiotherapy. Comparable to the advanced stages, a watch and wait strategy can be advocated in case of contraindications to radiotherapy or systemic induction therapy.

Stage III and IV (up to 85% of patients): In the absence of symptoms, a watch-and-wait strategy is indicated in the advanced stage; treatment is not initiated until the onset of disease-associated symptoms (B symptoms, hematopoietic insufficiency, rapid lymphoma progression, organ compression). This recommendation is based on the fact that there is no study to date that has shown that early chemotherapy or rituximab monotherapy can affect the overall survival of patients with advanced follicular lymphoma (Ardeshna KM et al (2003).

First-line therapy - induction

Standard for induction therapy in 'medically fit' patients is immunochemotherapy (combination of an anti-CD20 antibody with chemotherapy) 1st choice therapy (Hiddemann W et al 2014).

R-Bendamustin / Obi-Bendamustin: good efficacy of bendamustin with overall good tolerability, therefore recommended especially in elderly patients; however, risk of sometimes fatal opportunistic infections both in combination with rituximab and obinutuzumab, therefore recommended under and after chemotherapy antibacterial (Pneumocystis - jirovecii - pneumonia) and antiviral prophylaxis (CMV) with attention to CD4 lymphocytes.

R-CVP4 / Obi-CVP: good efficacy of chemotherapy with good tolerability, option in elderly patients.

Lenalidomide: The combination of rituximab/lenalidomide proved equivalent to the combination of rituximab/standard chemotherapy in terms of progression-free survival at 3 years, complete remission rate (48% vs 53%) and adverse event rate (lenalidomide is not approved in this indication).

Antibody monotherapy: Antibody monotherapy(rituximab) is a therapeutic alternative for those patients who have a low tumor burden or who do not tolerate immunochemotherapy (Taverna C et al (2015).

Oral chemotherapy: In elderly, medically non-fit patients, oral chemotherapy is a therapeutic option (e.g. chlorambucil).

First-line therapy - consolidation/maintenance: Maintenance therapy with rituximab (1 x 375 mg/m2 every 8 weeks for 2 years) in patients with a response to first-line immunochemotherapy results in a significant prolongation of progression-free survival, but not overall survival (Salles G et al. 2011).

Recurrence: Before initiating therapy in recurrence, repeat lymph node extirpation or biopsy for histology should be sought to rule out secondary transformation to aggressive lymphoma. The risk of transformation is about 3%/year. Treatment is only indicated when disease-associated symptoms occur.

Recurrence - Induction: Standard therapy is immunochemotherapy. The choice of regimen depends on the primary therapy. In case of relapse >2 years after the end of therapy, the initial therapy can be repeated. Alternative is a change, e.g. in case of pre-treatment with R-CHOP to a therapy with B-R, in case of initial therapy with B-R to R-CHOP. If relapse after initial rituximab/chemotherapy occurs within 6 months of the last rituximab administration, the combination of obinutuzumab/bendamustine followed by obinutuzumab maintenance therapy is an option (Sehn LH et al. 2016).

In patients with relapse or refractory behavior after one or more prior therapies, the combination of lenalidomide with rituximab versus rituximab monotherapy may result in prolonged progression-free survival (Leonard JP et al 2019).

Recurrence - consolidation / maintenance: As consolidation, myeloablative high-dose therapy followed by autologous stem cell transplantation is an option especially in younger patients and early recurrences within 2 years (Montoto S et al (2013). Alternatively, radioimmunotherapy (RIT) with yttrium-90-ibritumomab-tiuxetan is available in this situation, especially in patients with relapse under rituximab maintenance therapy (Morschhauser F et al. (2013).

The "Follicular Lymphoma International Prognostic Index" (FLIP-Index, [FLIPI] http://bloodref.com/lymphoid/lymphoma/flipi) allows a prognostic differentiation into three patient groups after chemotherapy (Solal-Celigny P et al.(2004) and into two risk groups after rituximab therapy. The clinical picture is characterized by a slowly progressive lymphadenopathy. This may persist for a long time without further clinical symptoms. The clinical course is very variable, survival times range from a few years to over two decades. Approximately 20% of patients have a more aggressive course with progression within 24 months of diagnosis. The vast majority of patients with follicular lymphoma are not diagnosed until the disease is advanced. The Follicular Lymphoma International Prognostic Index (FLIPI) allows the differentiation of three groups with different prognosis.

Patients with early recurrences within 24 months of initiation of standard therapy have a below average overall survival of only about 5 years (Casulo C et al (2015)].

Prognostic factors: The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of worse survival. These are:

• >4 affected lymph node regions.
• LDH elevation
• Age > 60 years
• Stage III or IV
• Hemoglobin <12g/dL

Poorer survival: age > 60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of affected nodal regions >4. The presence of 0-1, 2, and ≥ 3 unfavorable factors defines low, intermediate, and high risk, respectively.

Other factors such as time to relapse of less than 2 years after chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have been shown to improve prognosis (Freedman A et al 2020).

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