Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

incidence•Follicular lymphomas are the second most frequent subtype of nodal lymphoid malignancies in Western Europe.•The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5–7/100 000 recently.diagnosis•Diagnosis is only based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be performed in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of follicular lymphoma grading difficult to appreciate on core biopsies. Fine needle aspirations are inappropriate for a reliable diagnosis.•The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is performed according to the number of blasts/high power field (Table 1). Follicular lymphoma grade 3B (with sheets of blasts) is considered an aggressive lymphoma and treated alike (see clinical recommendation DLBCL) [1.Ott G. Katzenberger T. Lohr A. et al.Cytomorphologic, immunhisto-chemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood. 2002; 99: 3806-3812Crossref PubMed Scopus (232) Google Scholar].Table 1Grading of follicular lymphomaGradeDescription1≤5 blasts/high power field26–15 blasts/high power field3A>15 blasts/high power field, centroblasts with intermingled centrocytes3B>15 blasts/high power field, pure sheets of blasts Open table in a new tab •When possible, additional biopsy material should be stored fresh frozen to allow additional molecular (currently still investigational) analyses.staging and risk assessment•Since treatment substantially depends on the stage of the disease, initial staging should be thorough particularly in the small proportion of patients with early stages I and II (5–10%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy. An additional positron emission tomography (PET) scan is not recommended according to the updated consensus [2.Cheson B. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3685) Google Scholar]. In rare cases PET scan may be useful to confirm localized stage I/II [IV, C].Table 2Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a single localized extralymphatic site (IIE) on the same side of the diaphragmIII (IIIE, IIIs)Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localized extranodal site (IIIE) or spleen (IIIS)IVDiffuse or disseminated extralymphatic organ involvementA, no symptoms.B, unexplained fever of >38°C, drenching night sweats or loss of <10% body weight within 6 months. Open table in a new tab •A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as screening tests for human immunodeficiency virus (HIV) and hepatitis B and C are required.•The staging is given according to the Ann Arbor system (Table 2) with mention of bulky disease, when appropriate.•For prognostic purposes, a Follicular Lymphoma-specific International Prognostic Index (FLIPI, Table 3: >4 involved nodal sites, elevated LDH, age >60 years, advanced stage III/IV, hemoglobin <12 g/dl) should be determined [I, A] [3.Solal-Celigny P. Roy P. Colombat P. et al.Follicular lymphoma international prognostic index.Blood. 2004; 104: 1258-1265Crossref PubMed Scopus (1376) Google Scholar, 4.Buske C. Hoster E. Dreyling M. Hasford J. et al.The Follicular Lymphoma International Prognostic Index (FLIPI) separates high risk from intermediate or low risk patients with advanced stage follicular lymphoma treated front-line with Rituximab and the combination of Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) with respect to treatment outcome.Blood. 2006; 108: 1504-1508Crossref PubMed Scopus (176) Google Scholar]. A revised FLIPI2 (incorporating β2 microglobuline, diameter of largest lymph node, bone marrow involvement and hemoglobin level) has been recently suggested for patients requiring treatment [5.Federico M. Bellei M. Marcheselli L. et al.Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.J Clin Oncol. 2009; 27: 4555-4652Crossref PubMed Scopus (487) Google Scholar].Table 3FLIPI risk factorsParameterDefinition of risk factorsFLIPI 1FLIPI 2Nodal sites>4 lymph node regionsLong diameter of largest lymph node >6 cmAgeAbove 60 yearsAbove 60 yearsSerum markerElevated lactate dehydrogenaseElevated β2 microglobulinstageAdvanced (III–IV according to Ann Arbor)Bone marrow involvementHemoglobin<12 g/dl<12 g/dlWith 0–1 risk factors, low risk; 2, intermediate risk; 3–5, high risk. Open table in a new tab •RNA expression analysis suggests a more favorable clinical course in cases with infiltrating T cells in comparison with cases with unspecific macrophage bystander cells [6.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Crossref PubMed Scopus (1151) Google Scholar]. However, this technique is not yet applicable in clinical routine, and immunohistochemistry studies have reported conflicting data recently.treatment planfirst linestage I–II.•In the small proportion of patients with limited non-bulky stages I–II, radiotherapy (involved or extended field, 30–36 Gy) is the preferred treatment having a curative potential [II, B] [7.MacManus P.M. Hoppe R.T. Is radiotherapy curative for stage I and II low grade follicular lymphoma? Results of a long term follow-up study of patients treated at Stanford University.J Clin Oncol. 1996; 14: 1282-1290Crossref PubMed Scopus (356) Google Scholar]. In selected cases a watchful waiting may be discussed to avoid the side effects of radiation (e.g. cervical, sicca syndrome; abdominal, myeloablative suppression) [8.Advani R. Rosenberg S.A. Horning S.J. Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy.J Clin Oncol. 2004; 22: 1454-1459Crossref PubMed Scopus (201) Google Scholar].•In patients with large tumor burden or adverse prognostic features, systemic therapy as indicated for advanced stages should be applied and the role of radiation consolidation is not proven [IV, B].stage III–IV.induction.•In the majority of patients with advanced stage III and IV disease, no curative therapy is yet established. Since the natural course of the disease is characterized by spontaneous regressions in up to 25% of cases and varies significantly from case to case, therapy should be initiated only upon the occurrence of symptoms including B-symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma progression [I, A]. In four randomized trials an early initiation of therapy in asymptomatic patients did not result in any improvement of disease-specific survival or overall survival (OS) [9.Ardeshna K.M. Smith P. Norton A. et al.Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.Lancet. 2003; 362: 516-522Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. In a recent study, early initiation of rituximab resulted in improved progression-free survival (PFS; 80% vs 48%, P <0.001), but the benefit on long-term outcome has to be determined [10.KM Ardeshna P Smith W Qian. An intergroup randomised trial of rituximab vs a watch & wait approach in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma. ASH 2010 Congress, December 2010; abstract 6.Google Scholar].•If complete remission and long PFS are to be achieved, rituximab in combination with chemotherapy [such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), purine analog-based schemes: FC (fludarabine and cyclophosphamide) or FM (fludarabine and mitoxantrone) or Bendamustine] should be used [I, B] [11.Rummel M.J. Niederle N. Maschmeyer G. et al.Bendamustin plus ritxuiamb is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the STIL.Blood. 2009; 110Google Scholar]. In cases with (histologically or clinically) suspected transformation to aggressive lymphoma, an anthracycline-based regimen should be preferred. Four prospective first-line trials and two salvage trials as well as a systematic meta-analysis confirmed an improved overall response, PFS and OS when rituximab was added to chemotherapy (Table 4) [12.Hiddemann W. Kneba M. Dreyling M. et al.Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone—results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG).Blood. 2005; 106: 3725-3732Crossref PubMed Scopus (1113) Google Scholar, 13.Herold M. Haas A. Srock S. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.J Clin Oncol. 2007; 25: 1986-1992Crossref PubMed Scopus (444) Google Scholar, 14.Marcus R. Imrie K. Solal-Celigny P. et al.Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.J Clin Oncol. 2008; 28: 4579-4586Crossref Scopus (493) Google Scholar, 15.Salles G. Mounier N. de Guibert S. et al.Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study.Blood. 2008; 112: 4824-4831Crossref PubMed Scopus (276) Google Scholar, 16.Schulz H. Bohlius J.F. Trelle S. et al.Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2007; 99: 706-714Crossref PubMed Scopus (322) Google Scholar].Table 4Combined chemoimmunotherapy in follicular lymphoma (first line)StudyTotal no. of patientsMedian follow-upOverall responseTime to treatment failure (months)Overall survivalMarcus 2008 [14.Marcus R. Imrie K. Solal-Celigny P. et al.Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.J Clin Oncol. 2008; 28: 4579-4586Crossref Scopus (493) Google Scholar] R-CVP32153 months81% (P <0.0001)27 (P <0.0001)83% (4 years) (P = 0.029)Hiddemann 2005 [12.Hiddemann W. Kneba M. Dreyling M. et al.Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone—results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG).Blood. 2005; 106: 3725-3732Crossref PubMed Scopus (1113) Google Scholar] R-CHOP42858 months96%NR (P <0.001)90% (2 years) (P = 0.0493)Herold 2007 [13.Herold M. Haas A. Srock S. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.J Clin Oncol. 2007; 25: 1986-1992Crossref PubMed Scopus (444) Google Scholar] R-MCP20148 months92% (P = 0.0009)NR (P <0.0001)87% (P = 0.0096)Salles 2008 [15.Salles G. Mounier N. de Guibert S. et al.Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study.Blood. 2008; 112: 4824-4831Crossref PubMed Scopus (276) Google Scholar] R-CHVP-Ifn35860 months81% (P = 0.035)NR (P <0.0001)(high FPLIPI: P = 0.025)Rummel 2009 [11.Rummel M.J. Niederle N. Maschmeyer G. et al.Bendamustin plus ritxuiamb is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the STIL.Blood. 2009; 110Google Scholar] Bendamustine-R27934 months92.7%NR84% (4 years)P, significance levels in comparison with chemotherapy only. Open table in a new tab •Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remains an alternative in patients with low risk profile or contraindications for a more intensive chemoimmunotherapy [III, B] [17.Kaminski M.S. Tuck M. Estes J. et al.131I-Tositumomab therapy as initial treatment for follicular lymphoma.N Engl J Med. 2005; 352: 441-449Crossref PubMed Scopus (639) Google Scholar, 18.Martinelli G. Schmitz S.F. Utiger U. et al.Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98 J Clin Oncol. 2010; 28: 4480-4484Google Scholar].•In hepatitis B patients, specific recommendations (HBV monitoring, antiviral therapy) should be followed [19.Ziakas P.D. Karsaliakos P. Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance.Haematologica. 2009; 94: 998-1005Crossref PubMed Scopus (69) Google Scholar].consolidation/maintenance.•Meta-analysis of the pre-rituximab era suggests a potential benefit of interferon-α maintenance therapy that has to be balanced against toxicity [20.Rohatiner A.Z. Gregory W.M. Peterson B. et al.Meta-analysis to evaluate the role of interferon in follicular lymphoma.J Clin Oncol. 2005; 23: 2215-2223Crossref PubMed Scopus (169) Google Scholar].•Rituximab maintenance for 2 years improves PFS (75% vs 58% after 3 years, P <0.0001) [I, B] [21.Salles G. Seymour J.-F. Offner F. et al.Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.Lancet. 2010; 377: 42-51Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar].•Radioimmunotherapy consolidation prolongs PFS after chemotherapy but its benefit following rituximab combinations has not been established [I, B] [22.Morschhauser F. Radford J. van Hoof A. et al.Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma.J Clin Oncol. 2008; 26: 5156-5163Crossref PubMed Scopus (381) Google Scholar].•Myeloablative radiochemotherapy followed by autologous stem cell transplantation prolongs PFS but not OS in four randomized trials and therefore represents no standard of care outside of trials [I, A] [23.Lenz G. Dreyling M. Schiegnitz E. et al.Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma—results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group (GLSG).Blood. 2004; 104: 2667-2674Crossref PubMed Scopus (259) Google Scholar, 24.Sebban C. Mounier N. Brousse N. et al.Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA).Blood. 2006; 108: 2540-2544Crossref PubMed Scopus (201) Google Scholar, 25.Ladetto M. Ed Marco F. Benedetti F. et al.Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage.Blood. 2008; 111: 4004-4013Crossref PubMed Scopus (207) Google Scholar, 26.Gyan E. Foussard C. Bertrand P. et al.High dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS. Final results with a median follow-up of nine years.Blood. 2009; 113: 995-1001Crossref PubMed Scopus (128) Google Scholar]relapsed diseaseTable 5Recommended treatment strategies outside of clinical studiesLow tumor burdenHigh tumor burdenStage I/IIStage III/IVStage III/IV (<65 years)Stage III/IV (>65 years)Radiotherapy (involved field) 30–36 GyIn selected cases: watchful waitingWatch and waitIn symptomatic cases: consider rituximab monotherapyChemoimmunotherapy (e.g. R-CHOP, R-CVP, BR)In selected cases: rituximab monotherapyChemoimmunotherapy (e.g. R-CVP, BR, R-CHOP)In selected cases: R-chlorambucil Rituximab monotherapyCR/PR:Rituximab maintenance (single application every 2 months up to 2 years)CR/PR:Rituximab maintenance (single application every 2 months up to 2 years)Insufficient response: consider radioimmunotherapy consider ASCT after salvageInsufficient response: consider radioimmunotherapyRelapse/progressChemoimmunotherapyIn selected cases: palliative radiation (e.g. 2×2 Gray)Chemoimmunotherapy (e.g.. R-CHOP, R-CVP, BR)In selected cases: Rituximab monotherapyDependent on first-line regimen and remission duration: Chemoimmunotherapy: e.g. BR, R-CHOP, R-FCDiscuss high dose consolidation with autologous ASCTRituximab maintenance (single application every 3 months, up to 2 years)Alternatively radioimmuntherapy In selected cases: discuss allogeneic transplantationDependent on first-line regimen and remission duration: Chemoimmunotherapy: e.g.. BR, R-CHOP, R-FCRituximab maintenance (single application every 3 months, up to 2 years)Alternatively radioimmuntherapy Open table in a new tab response evaluation•Adequate radiological tests should be performed midterm and after completion of chemotherapy. Patients with insufficient or lacking response should be evaluated for early salvage regimens.•PET scan-CT to evaluate response quality remains investigational in this disease, until future study confirms its predictive value [33.Trotman J. Fournier M. Lamy T. et al.Result of FDG PET-CT imaging after immunochemotherapy induction is a powerful and independent progsnotic indicator of outcome for patients with follicular lymphoma.Blood. 2010; 116 (#855): 372Crossref Google Scholar].•Minimal residual disease (MRD) analysis at the end of the treatment has some prognostic impact, but should not guide therapeutic strategies outside of clinical studies [34.Rambaldi A. Carlotti E. Oldani E. et al.Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma.Blood. 2005; 105: 3428-3433Crossref PubMed Scopus (100) Google Scholar].follow-upThe following recommendation are based on consensus rather than on evidence:•History and physical examination every 3 months for 2 years, every 4–6 months for an additional 3 years, and subsequently once a year with special attention to transformation and secondary malignancies including secondary leukemia [V, D].•Blood count and routine chemistry every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms.•Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years.•Minimal adequate radiological or ultrasound examinations every 6 months for 2 years and annually thereafter. Regular CT scans are not mandatory outside of clinical trials.•MRD screening may be performed in clinical studies but should not guide therapeutic strategies. incidence•Follicular lymphomas are the second most frequent subtype of nodal lymphoid malignancies in Western Europe.•The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5–7/100 000 recently. •Follicular lymphomas are the second most frequent subtype of nodal lymphoid malignancies in Western Europe.•The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5–7/100 000 recently. diagnosis•Diagnosis is only based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be performed in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of follicular lymphoma grading difficult to appreciate on core biopsies. Fine needle aspirations are inappropriate for a reliable diagnosis.•The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is performed according to the number of blasts/high power field (Table 1). Follicular lymphoma grade 3B (with sheets of blasts) is considered an aggressive lymphoma and treated alike (see clinical recommendation DLBCL) [1.Ott G. Katzenberger T. Lohr A. et al.Cytomorphologic, immunhisto-chemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood. 2002; 99: 3806-3812Crossref PubMed Scopus (232) Google Scholar].Table 1Grading of follicular lymphomaGradeDescription1≤5 blasts/high power field26–15 blasts/high power field3A>15 blasts/high power field, centroblasts with intermingled centrocytes3B>15 blasts/high power field, pure sheets of blasts Open table in a new tab •When possible, additional biopsy material should be stored fresh frozen to allow additional molecular (currently still investigational) analyses. •Diagnosis is only based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be performed in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of follicular lymphoma grading difficult to appreciate on core biopsies. Fine needle aspirations are inappropriate for a reliable diagnosis.•The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is performed according to the number of blasts/high power field (Table 1). Follicular lymphoma grade 3B (with sheets of blasts) is considered an aggressive lymphoma and treated alike (see clinical recommendation DLBCL) [1.Ott G. Katzenberger T. Lohr A. et al.Cytomorphologic, immunhisto-chemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood. 2002; 99: 3806-3812Crossref PubMed Scopus (232) Google Scholar].Table 1Grading of follicular lymphomaGradeDescription1≤5 blasts/high power field26–15 blasts/high power field3A>15 blasts/high power field, centroblasts with intermingled centrocytes3B>15 blasts/high power field, pure sheets of blasts Open table in a new tab •When possible, additional biopsy material should be stored fresh frozen to allow additional molecular (currently still investigational) analyses. staging and risk assessment•Since treatment substantially depends on the stage of the disease, initial staging should be thorough particularly in the small proportion of patients with early stages I and II (5–10%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy. An additional positron emission tomography (PET) scan is not recommended according to the updated consensus [2.Cheson B. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3685) Google Scholar]. In rare cases PET scan may be useful to confirm localized stage I/II [IV, C].Table 2Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a single localized extralymphatic site (IIE) on the same side of the diaphragmIII (IIIE, IIIs)Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localized extranodal site (IIIE) or spleen (IIIS)IVDiffuse or disseminated extralymphatic organ involvementA, no symptoms.B, unexplained fever of >38°C, drenching night sweats or loss of <10% body weight within 6 months. Open table in a new tab •A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as screening tests for human immunodeficiency virus (HIV) and hepatitis B and C are required.•The staging is given according to the Ann Arbor system (Table 2) with mention of bulky disease, when appropriate.•For prognostic purposes, a Follicular Lymphoma-specific International Prognostic Index (FLIPI, Table 3: >4 involved nodal sites, elevated LDH, age >60 years, advanced stage III/IV, hemoglobin <12 g/dl) should be determined [I, A] [3.Solal-Celigny P. Roy P. Colombat P. et al.Follicular lymphoma international prognostic index.Blood. 2004; 104: 1258-1265Crossref PubMed Scopus (1376) Google Scholar, 4.Buske C. Hoster E. Dreyling M. Hasford J. et al.The Follicular Lymphoma International Prognostic Index (FLIPI) separates high risk from intermediate or low risk patients with advanced stage follicular lymphoma treated front-line with Rituximab and the combination of Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) with respect to treatment outcome.Blood. 2006; 108: 1504-1508Crossref PubMed Scopus (176) Google Scholar]. A revised FLIPI2 (incorporating β2 microglobuline, diameter of largest lymph node, bone marrow involvement and hemoglobin level) has been recently suggested for patients requiring treatment [5.Federico M. Bellei M. Marcheselli L. et al.Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.J Clin Oncol. 2009; 27: 4555-4652Crossref PubMed Scopus (487) Google Scholar].Table 3FLIPI risk factorsParameterDefinition of risk factorsFLIPI 1FLIPI 2Nodal sites>4 lymph node regionsLong diameter of largest lymph node >6 cmAgeAbove 60 yearsAbove 60 yearsSerum markerElevated lactate dehydrogenaseElevated β2 microglobulinstageAdvanced (III–IV according to Ann Arbor)Bone marrow involvementHemoglobin<12 g/dl<12 g/dlWith 0–1 risk factors, low risk; 2, intermediate risk; 3–5, high risk. Open table in a new tab •RNA expression analysis suggests a more favorable clinical course in cases with infiltrating T cells in comparison with cases with unspecific macrophage bystander cells [6.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Crossref PubMed Scopus (1151) Google Scholar]. However, this technique is not yet applicable in clinical routine, and immunohistochemistry studies have reported conflicting data recently. •Since treatment substantially depends on the stage of the disease, initial staging should be thorough particularly in the small proportion of patients with early stages I and II (5–10%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy. An additional positron emission tomography (PET) scan is not recommended according to the updated consensus [2.Cheson B. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3685) Google Scholar]. In rare cases PET scan may be useful to confirm localized stage I/II [IV, C].Table 2Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a single localized extralymphatic site (IIE) on the same side of the diaphragmIII (IIIE, IIIs)Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localized extranodal site (IIIE) or spleen (IIIS)IVDiffuse or disseminated extralymphatic organ involvementA, no symptoms.B, unexplained fever of >38°C, drenching night sweats or loss of <10% body weight within 6 months. Open table in a new tab •A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as screening tests for human immunodeficiency virus (HIV) and hepatitis B and C are required.•The staging is given according to the Ann Arbor system (Table 2) with mention of bulky disease, when appropriate.•For prognostic purposes, a Follicular Lymphoma-specific Internation