What are the key features and treatment options for follicular lymphoma?

Follicular Lymphoma: Key Features and Treatment Options

Follicular lymphoma is the second most frequent subtype of nodal lymphoid malignancies with heterogeneous clinical outcomes, requiring stage-appropriate treatment strategies ranging from watchful waiting to combined chemoimmunotherapy depending on disease burden and symptoms.

Epidemiology and Pathobiology

• Follicular lymphoma (FL) represents approximately 20-25% of all new non-Hodgkin lymphoma diagnoses in western countries 1
• Incidence has increased over recent decades, rising from 2-3/100,000/year in the 1950s to 5-7/100,000/year recently 2
• Originates from germinal center B-cells (centrocytes and centroblasts) of lymphoid follicles 3
• Tumorigenesis begins with t(14;18)(q32;q21) chromosomal translocation in precursor B-cells, with additional genetic alterations acquired as cells mature in germinal centers 3, 4

Diagnostic Features

• Diagnosis requires surgical specimen/excisional lymph node biopsy with adequate material for fresh-frozen and formalin-fixed samples 2
• Fine-needle aspirations or core biopsies are inappropriate for proper diagnosis except in emergency situations 2
• Histologically characterized by follicular (nodular) growth pattern of centrocytes and centroblasts 4
• Immunophenotyping shows expression of germinal center-associated antigens 3
• PET scan is recommended as FL is FDG-avid in more than 90% of cases, with sensitivity higher than 95% 2

Clinical Presentation and Staging

• Most patients present with peripheral lymphadenopathy, often with involvement of spleen, bone marrow, and peripheral blood 3
• Staging follows the Ann Arbor system and should include 2:
  • CT scan of abdomen, pelvis, and chest
  • Bone marrow aspirate and biopsy
  • Complete blood count and routine blood chemistry including LDH, beta2-microglobulin and uric acid
  • Screening for HIV and hepatitis B and C
• PET scan should be included in staging of patients with limited-stage disease who are candidates for radiotherapy 2
• Follicular Lymphoma International Prognostic Index (FLIPI) should be determined in all patients 2

Treatment Approach by Stage

Early Stage (I-II) Disease

• Involved field radiotherapy (IF-RT) is the treatment of choice with curative potential 2
• 24 Gy radiotherapy is as effective as higher doses (40-45 Gy) 2
• In selected patients with large tumor burden, systemic therapy as used for advanced stages may be considered 2
• Watchful waiting is not recommended in stage I-II disease except in patients with short life expectancy due to comorbidities 2

Advanced Stage (III-IV) Disease

• Treatment initiation criteria for stage III-IV disease include 2:
  • Systemic symptoms
  • High tumor burden (>3 lymph nodes >3 cm or single lymph node >7 cm)
  • Extranodal disease
  • Cytopenia due to marrow involvement
  • Spleen involvement (>16 cm by CT)
  • Leukemic phase
  • Serous effusion
  • Symptomatic or life-threatening organ involvement
  • Rapid lymphoma progression
  • Consistently increased LDH levels
• For asymptomatic patients with advanced disease, watchful waiting remains the standard of care 2
• For symptomatic patients with low tumor burden, rituximab monotherapy may be considered 2

First-line Treatment Options

• Combined chemoimmunotherapy is standard for advanced symptomatic disease 2
• Common regimens include 2:
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • R-CVP (rituximab, cyclophosphamide, vincristine, prednisone)
  • Single agents such as rituximab, fludarabine, or chlorambucil
• Rituximab maintenance for up to 2 years after initial therapy prolongs progression-free survival 2

Prognostic Factors and Risk Assessment

• Progression of disease within 2 years (POD24) after diagnosis is associated with poor outcomes and lower 5-year overall survival (82% vs. 93.3% for non-POD24) 5
• FLIPI includes five adverse prognostic factors 2:
  • Age >60 years
  • Stage III-IV
  • Hemoglobin <12 g/dL

  • 4 nodal sites

  • Elevated LDH

Follow-up Recommendations

• History and physical examination every 3 months for 2 years, every 6 months for 3 more years, then annually 2
• Blood count and LDH at 3,6,12, and 24 months, then as needed 2
• Radiological or ultrasound examinations at 6,12, and 24 months after end of treatment 2
• Evaluation of thyroid function in patients with irradiation to the neck at 1,2, and 5 years 2

Treatment of Relapsed Disease

• Options for relapsed disease include 2:
  • Rituximab-containing regimens
  • Radioimmunotherapy (90yttrium-ibritumomab-tiuxetan)
  • High-dose chemotherapy with autologous stem cell transplantation (ASCT) for patients with short-lived first remissions
• Rituximab maintenance for up to 2 years substantially prolongs progression-free survival and overall survival in relapsed disease 2

Common Pitfalls to Avoid

• Inadequate initial biopsy leading to misdiagnosis - always obtain excisional lymph node biopsy 2
• Overtreatment of asymptomatic patients with advanced disease - watchful waiting remains appropriate 2
• Failure to perform comprehensive staging, which may lead to suboptimal treatment selection 2
• Not screening for hepatitis B before rituximab therapy, which can lead to hepatitis B reactivation 6