Follicular Lymphoma

9 Interesting Facts of Follicular Lymphoma

1. Follicular lymphoma is an indolent (low-grade) form of non-Hodgkin lymphoma arising from germinal center B cells
2. Chronic, essentially incurable, illness characterized by a relapsing and remitting pattern of nodal and bone marrow involvement; in a minority of patients, spontaneous prolonged remission may occur
3. Most patients present with advanced disease; however, many patients are relatively asymptomatic
4. Signs and symptoms, when present, may include painless peripheral lymphadenopathy, hepatosplenomegaly, night sweats, fever, and weight loss (B symptoms)
5. Diagnosis is based on history, physical examination findings, and histopathologic examination of a lymph node specimen
6. Additional laboratory tests, imaging, and bone marrow biopsy are required to assess disease burden, stage, and prognosis, and to guide treatment
7. Treatment is highly individualized and influenced by many factors, including disease stage, prior treatment, and prognosis
8. Options include involved-site radiation therapy, chemotherapy, or immunotherapy with rituximab, alone or in combination, or watchful waiting
9. Follicular lymphoma grades 1, 2, and 3A are considered indolent while grade 3B is considered more aggressive. Histologic transformation into more aggressive forms of lymphoma may occur 

Pitfalls

• Some treatment modalities may compromise future treatment options and others carry risks of long-term complications such as secondary cancers, cardiotoxicity, or infertility 

• Follicular lymphoma is an indolent (low-grade) form of non-Hodgkin lymphoma arising from germinal center B cells 
  • Second most common subtype of non-Hodgkin lymphoma, representing up to 35% of cases in North America 

Classification

• Follicular lymphoma is classified by stage and grade
• Staging: Ann Arbor classification for non-Hodgkin lymphoma 
  • Based on distribution of lymph node regions affected
    • Stage I: 1 lymph node region
      • Stage IE: 1 extralymphatic site
    • Stage II: 2 or more lymph node regions on the same side of the diaphragm
      • Stage IIE: at least 1 lymph node region with a single localized extralymphatic site
    • Stage III: lymph node regions or lymphoid structures (eg, thymus, Waldeyer tonsillar ring) on both sides of the diaphragm
      • Stage IIIE: involves extranodal site
      • Stage IIIS: involves spleen
    • Stage IV: diffuse or disseminated extralymphatic organ involvement
    • All stages are further subclassified as “A” or “B” based on presence or absence of symptoms
      • A: asymptomatic
      • B: unexplained fever higher than 38 °C, drenching night sweats, or loss of more than 10% body weight within 6 months 
• Grading: WHO classification 
  • Based on histologic findings, specifically the proportion of centroblasts (large B-cells in the lymphoid follicle undergoing rapid division) found in biopsy specimen
    • Grade 1: 0 to 5 centroblasts per high-power field
    • Grade 2: 6 to 15 centroblasts per high-power field
    • Grade 3: more than 15 centroblasts per high-power field
      • 3A: centrocytes present
      • 3B: pure sheet of blasts, centrocytes absent

What are the Clinical Features?

History

• Many patients, even with advanced disease, are asymptomatic 
• Presenting symptoms may include: 
  • Fatigue
  • Painless peripheral lymphadenopathy involving any lymph node region 
  • Local mass effects of lymph node enlargement
  • Abdominal distention
• Constitutional symptoms (B symptoms for staging purposes) are uncommon, occurring in less than 20% of patients, but may include the following: 
  • Night sweats
  • Fever
  • Weight loss

Physical examination

• Findings may include: 
  • Peripheral lymphadenopathy involving any of the lymph nodes (eg, preauricular, postauricular, submandibular, supraclavicular, cervical, axillary, inguinal, and/or popliteal regions)
    • Lymph nodes are typically firm and nontender
  • Enlarged pharyngeal lymphoid tissue (Waldeyer tonsillar ring)
  • Hepatomegaly
  • Splenomegaly
  • Fever

What causes Follicular Lymphoma?

• No direct cause identified; multiple genetic events may be involved in development 

What are the Risk factors of Follicular Lymphoma?

Age

• Incidence increases with age; median age at presentation is between 60 and 65 years

Gender

• Incidence is slightly higher in men 

Genetics

• Most cases are associated with the characteristic t(14;18)(q32;21) translocation, leading to overexpression of the BCL2 protein 
  • Often accompanied by other genetic aberrations such as disruption of KMT2D (formerly MLL2) and EPHA7 deletion 
• Other mutations reported include H3K27 methyltransferase EZH2 and alterations in genes involved in normal T-cell function such as PMCH, ETV1, and TNFRSF9 

Ethnicity/race

• In the United States, there is higher incidence in the White population compared with Black and Hispanic populations 

Other risk factors/associations

• The following factors have been implicated in other forms of lymphoma, but no specific association with follicular lymphoma has been found:
  • Viruses (eg, Epstein-Barr virus, human T-lymphotrophic virus 1, human herpesvirus 8, hepatitis B and C)
  • Chemicals (eg, Agent Orange, hair dyes before 1980)
  • Immunodeficiencies (congenital or acquired)
  • Immunosuppressive drugs
  • Obesity 
  • Occupational exposures: DDE (dichlorodiphenyldichloroethylene), PCBs (polychlorinated biphenyls), chlorinated solvents 

How is this diagnosed?

Primary diagnostic tools

• Base diagnosis on history, physical examination findings, and histopathologic examination of lymph node specimen 
  • Excisional or incisional biopsy is required for histologic grading
• Assess performance status for all patients 
• Assess for B symptoms in all patients
• Obtain diagnostic tests to assess disease burden, stage, and prognosis, and to guide treatment
  • All patients
    • Laboratory: 
      • CBC with differential, serum lactate dehydrogenase level, uric acid level, and comprehensive metabolic panel
      • Screen for HIV, hepatitis B virus, and hepatitis C virus 
    • Imaging: CT of the chest, abdomen, and pelvis, and/or PET-CT 
    • Excisional or incisional biopsy: 
      • Required for histologic grading (WHO classification)
      • Specimens obtained from fine needle aspiration are not sufficient for histological grading
    • Immunological phenotyping
      • Required to establish diagnosis
  • Useful in selected patients
    • Laboratory: 
      • β₂-microglobulin level, serum protein electrophoresis, and/or immunoglobulin levels
      • Pregnancy testing: women of childbearing age if radiation or chemotherapy is planned 
    • Imaging: additional neck CT scan with contrast 
    • Bone marrow aspirate and biopsy: 
      • May be deferred if initial management is observation
      • Essential in the following cases:
        • Diagnosis of stage 1 or stage 2 disease if radiation therapy is planned
        • Evaluation of unexplained cytopenias
        • If certain therapies (eg, ibritumomab tiuxetan) are being considered
    • Echocardiogram or MUGA (multiple gated acquisition) scan if anthracycline- or anthracenedione-based regimen is planned 
• Use clinical, radiologic, and histologic findings in prognostic scoring systems (eg, FLIPI [Follicular Lymphoma International Prognostic Index]) to assess prognosis; histologic tumor grade also has prognostic utility 

Laboratory

• CBC with differential
  • Decreased hemoglobin level (less than 12 g/dL) in some cases of advanced disease
  • Presence of cytopenia (leukocyte count lower than 1 × 10⁹/L and/or platelet count lower than 100 × 10⁹/L) provides prognostic information and can guide treatment planning
• Comprehensive metabolic panel
  • Evaluate baseline hepatic and renal function
• Lactate dehydrogenase level
  • Elevated in approximately 10% of cases
• Serum β₂-microglobulin level
  • Necessary for calculation of certain prognostic scoring systems (eg, FLIPI-2: Follicular Lymphoma International Prognostic Index 2; PRIMA-PI: PRIMA-prognostic index ) 
  • Elevated levels can be indicative of tumor burden 
  • Not specific to follicular lymphoma, as levels can be elevated in other types of lymphoma, leukemia, and multiple myeloma
  • Like other tumor markers, levels can be used to track disease, but there is no cutoff point for values as related to tumor burden
• HIV:
  • HIV is a known risk factor for non-Hodgkin lymphomas
• Hepatitis B virus
  • Patients have an increased risk of reactivation with immunotherapy and chemotherapy
• Hepatitis C virus 
  • Associated with increased development of non-Hodgkin lymphoma (odds ratio 10.8) compared to healthy controls
• Immunophenotyping of biopsy specimen
  • Immunohistochemistry profile should include: CD20, CD3, CD5, CD10, BCL2, BCL6, CD21, or CD23 with or without additional flow cytometry analysis for kappa/lambda, CD19, CD20, CD5, CD23, and CD10

Imaging

• CT of abdomen, chest, and pelvis with contrast if systemic therapy is planned 
  • Additional neck images are obtained in selected cases
  • Use oral contrast material to differentiate loops of bowel from abdominal nodal masses
  • Use IV contrast material to differentiate blood vessels from lymph nodes
  • Shows extent of disease
• PET-CT (including neck)
  • Required for Stage I or II tumors if radiotherapy is planned or if systemic therapy is planned
  • Shows extent of disease
  • Occult disease sites may be visible
• MRI 
  • May be necessary for rare cases of lymphoma involving the central nervous system and for staging head and neck disease
  • IV gadolinium contrast material increases sensitivity; it is useful in patients with negative MRI findings and a high risk of central nervous system involvement 

Procedures

• Surgical excision of involved lymph node for histologic analysis 
• Needle core biopsy of lymph node is an alternative in patients without accessible lymph nodes, but it is not suitable for histologic grading alone
  • Can be used in conjunction with fine-needle aspirate biopsies and ancillary testing for differential diagnosis when lymph nodes are not easily accessible
• Immunophenotyping using immunohistochemistry and/or flow cytometry for cell surface marker analysis is required to establish diagnosis
  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, CD21, and CD23
  • Flow cytometry for cell surface markers: kappa-lambda ratio, CD19, CD20, CD5, CD23, and CD10
• Persistent lymphadenopathy or suspicion of lymphoma
• Required for definitive diagnosis
• No absolute contraindications
• Definitive diagnosis is based on histopathologic assessment of biopsy specimen by expert hematopathologist
  • Normal follicle center cells are replaced by closely packed neoplastic follicles, uniform in size and lacking tingible body macrophages, with poorly formed mantle zones
  • Architecture of follicular lymphoma can be variable, with a mixture of closely packed and diffuse areas
• Immunophenotyping to confirm diagnosis
  • Common immunophenotype includes: CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+, BCL6+ 
  • Rarely, patients will have CD10- or BCL2- profiles 
• Assessment of tumor grade based on number of centroblasts per high-power field according to WHO criteria 
  • Grade 1: 0 to 5 centroblasts per high-power field
  • Grade 2: 6 to 15 centroblasts per high-power field
  • Grade 3: more than 15 centroblasts per high-power field
    • Distinction between Grade 3A and 3B should be established by expert hematopathologist as the treatment differs significantly between these stages 
      • 3A: centrocytes present
      • 3B: pure sheet of blasts, centrocytes absent
• Identification of transformation to a more aggressive histologic subtype 
• Other investigations may be done in cases of atypical clinical and/or pathologic features 
  • Molecular analysis to detect antigen receptor gene and BCL2 rearrangements
  • Fluorescence in situ hybridization to detect karyotype for t(14;18), IRF4/MUM1, 1p36, and BCL6 rearrangements
  • Immunohistochemistry panel to detect Ki-67 protein, cyclin D1, and IRF4/MUM1 in grade 3 disease
• Hollow cutting needle is used to remove a core of bone containing bone marrow (for core biopsy) and to remove bone marrow fluid (for aspiration biopsy) for histologic, immunohistochemical, and cytogenetic analysis 
  • Aspiration and biopsy are usually performed at the same time
    • Aspiration provides sample of marrow cells
    • Biopsy provides marrow cells and cellular framework of marrow
  • Sample is usually obtained from iliac crest or sternum in adults and from iliac crest, femur, or anterior tibia in children
  • Usually performed under conscious (moderate) sedation and/or local anesthesia
• To determine extent of disease for prognostic purposes 
• Essential in the following cases:
  • Diagnosis of stage 1 or stage 2 disease if radiation therapy is planned 
  • Evaluation of unexplained cytopenias
  • If certain therapies (eg, ibritumomab tiuxetan) are being considered
• Absolute: 
  • Skin infection or osteomyelitis at the biopsy site
  • Hemophilia or similar severe bleeding disorder
  • Uncooperative patient
• Relative
  • Severe obesity
  • Severe osteoporosis
  • Prior radiation therapy to proposed site of biopsy
• Bone marrow involvement with paratrabecular infiltrates is common 
• Positive findings in bone marrow aspirate indicate worse prognosis 

Differential Diagnosis

Most common

• Other subtypes of lymphoma
  • These diseases are also characterized by aberrant proliferation of B cells, T cells, or NK cells
  • Differentiated by cellular origin, with over 60 specific types including:
    • Diffuse large B-cell lymphoma
    • Mucosa-associated lymphoid tissue lymphoma
    • Mantle cell lymphoma 
    • Nodular lymphocyte predominant Hodgkin lymphoma 
    • Burkitt lymphoma
    • Lymphoblastic lymphoma
  • All types are associated with characteristic clinical manifestations of lymphadenopathy, night sweats, and weight loss
  • Differentiate from follicular lymphoma based on histologic examination and immunohistochemical analysis of excised lymph node
• Chronic lymphocytic leukemia
  • Form of leukemia characterized by progressive accumulation of functionally impaired lymphocytes
  • Like that of follicular lymphoma, onset may be insidious, presenting with lymphadenopathy, night sweats, fatigue, and hepatosplenomegaly; many patients are asymptomatic
  • Unlike follicular lymphoma, chronic lymphocytic leukemia may also present with recurrent infections, bruising, and CBC results showing anemia, thrombocytopenia, and lymphocytosis
  • Diagnose based on clinical and laboratory findings and immunohistochemical findings on bone marrow biopsy
• Acute lymphoblastic leukemia
  • Form of leukemia characterized by proliferation of early lymphoid precursors in bone marrow, replacing normal hematopoietic cells in the marrow
  • Like follicular lymphoma, may present with lymphadenopathy, fever, night sweats, and splenomegaly
  • Unlike that of follicular lymphoma, onset is acute and characterized by anemia, bleeding or bruising, bone pain, or infection (eg, pneumonia); in patients with acute lymphoblastic leukemia, CBC results show anemia, thrombocytopenia, and leukopenia
  • Diagnose based on clinical and laboratory findings and immunohistochemical findings on bone marrow biopsy

How is Follicular Lymphoma treated?

• Eradicate tumor
• Sustain remission

Disposition

Admission criteria

• Admission may be required to manage any associated acute medical problems

Recommendations for specialist referral 

• Refer to oncologist for management
• Optimal management involves multidisciplinary lymphoma team, which includes specialists in lymphoma, hematopathology, radiology, nuclear medicine, and radiation oncology

Treatment Options

General overview

• Initial therapy
  • Depends on disease stage; most patients are diagnosed with advanced disease, which is considered incurable; 10% to 15% of patients have stage I to II disease with potential for curative treatment 
    • Stage I and II; low tumor burden
      • ISRT (Involved site radiation therapy) for involved lymph node(s) and/or extranodal sites is preferred treatment with intent to cure 
        • Can be palliative treatment in patients with comorbidity and age considerations
      • Immunotherapy (rituximab) in conjunction with radiation therapy may improve progression-free survival 
        • Choice of initial therapy regimen is highly individualized and influenced by age, performance status, comorbidities, and future treatment possibilities 
      • Watchful waiting or rituximab monotherapy
        • Can be considered in selected patients when the potential toxicity of involved-site radiation therapy outweighs potential benefit and in patients with pediatric follicular lymphoma
      • Patients with stage I or II disease with a large tumor burden or adverse prognostic features are treated systemically as indicated for more advanced disease 
    • Stage III and stage IV
      • There is no curative treatment for most patients with stage III and IV disease 
      • Treatment should only be initiated when patients develop symptoms, since 10% to 20% of patients experience spontaneous regression of disease
        • Indications for treatment include B symptoms, threatened end-organ function, cytopenia, bulky disease per Groupe d’Etude des Lymphomes Folliculaires criteria (3 or more nodal sites with diameter of 3 cm or larger, or any nodal or extranodal tumor mass 7 cm or larger), steady progression, or clinical trial 
      • Choice of regimen is influenced by age, performance status, and comorbidities
        • Immunotherapy (rituximab) in conjunction with chemotherapy is the preferred option if treatment is indicated; offers best outcomes in terms of progression-free survival 
      • First line chemoimmunotherapy regimens 
        • Bendamustine, rituximab
        • Bendamustine, obinutuzumab
        • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
        • CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), obinutuzumab
        • R-CVP (rituximab, cyclophosphamide, vincristine, prednisone)
        • CVP (cyclophosphamide, vincristine, prednisone), obinutuzumab
        • Rituximab monotherapy
        • Lenalidomide, rituximab

Stage (Ann Arbor classification)	Treatment strategy
Stage I/II
Low tumor burden	Preferred therapy: radiation therapy +/- rituximab
	Select cases: watch and wait; rituximab monotherapy
High tumor burden	Consider systemic immunochemotherapy as outlined for advanced, stage III/IV disease
Stage III/IV
Low tumor burden	Preferred therapy: watch and wait
	Select cases: rituximab monotherapy
High tumor burden	Preferred therapy: immunochemotherapy regimen (examples below)
	Obinutuzumab-rituximab + bendamustine Obinutuzumab-rituximab + CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) Obinutuzumab-rituximab + CVP (cyclophosphamide, vincristine, prednisolone)

Caption: Treatment recommendations by Ann Arbor stage, summarized from 2021 European Society for Medical Oncology guidelines.

Citation: Dreyling M et al: Newly diagnosed and relapsed follicular lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 32(3):298-308, 2021

Alternatives for patients with a low risk profile and/or contraindications for more intensive chemoimmunotherapy (eg, elderly or infirm patients), as well as recommendations for second line, third line, and consolidation therapy can be found in the following high-quality clinical practice guidelines: 

National Comprehensive Cancer Network clinical practice guidelines in oncology 

European Society for Medical Oncology clinical practice guidelines 

Asymptomatic patients without extensive disease can be observed, as the disease is characterized by spontaneous regressions in 10% to 20% of cases 

Early initiation of therapy in asymptomatic patients does not improve progression-free survival or overall survival 

Rationale

• Treatment is potentially curative in stage I and II disease
  •  ISRT (Involved site radiation therapy) directed at involved lymph node(s) and/or extranodal sites is the preferred initial treatment, achieving 10-year disease free survival rates of 60% to 80% 
  • Initial observation can be considered in elderly patients or those with comorbid conditions, as aggressive therapy may not alter life expectancy 
• Advanced disease is considered incurable; however, a significant number of patients may achieve prolonged progression-free survival with therapy
  • Immunotherapy (rituximab) in conjunction with chemotherapy offers best outcomes in terms of progression-free survival 
  • Asymptomatic patients without extensive disease can be observed as the disease is characterized by spontaneous regressions in 10% to 20% of cases 

Some treatment modalities may compromise future treatment options and others carry risks of long-term complications such as secondary cancers, cardiotoxicity, or infertility 

Outcomes

• Involved-site radiation therapy in stage I and II disease is associated with 10-year disease-free survival of 60% to 80%, with median survival of 19 years 
  • 5-year overall survival of 95% has been reported in a contemporary series 
• The addition of immunochemotherapy after radiation therapy in localized disease has been shown to improve progression-free survival compared with radiation therapy alone 
• Outcomes in advanced stages of the disease vary according to presence or absence of symptoms, tumor burden, patient age, and comorbidities; median overall survival is more than 12 years 
• Overall survival rates have improved significantly since the introduction of rituximab 

Nondrug and supportive care

Careful IV hydration with induction therapy to avoid tumor lysis syndrome

Manage infectious complications due to immunosuppression 

Procedures

ISRT (Involved-site radiation therapy) 

General explanation

• Ionizing radiation targeted to involved lymph node(s) and/or extranodal sites under direction of a radiation oncologist
• Preferred initial treatment for stage I and II disease
  • 10-year disease-free survival of 60% to 80% 
• Recommended dose of 24 to 30 Gy (with additional 6 Gy in selected patients with bulky disease) 

Indication

• Initial curative therapy for stage I and II (alone or in conjunction with immunotherapy)
• Palliative option for locally symptomatic stage III and IV disease, advanced age, or comorbidities
• Progressive disease that has undergone histologic transformation to diffuse large B-cell lymphoma after initial therapy (alone or in conjunction with immunotherapy)

Comorbidities

• In patients older than 70 years with cardiomyopathy or ventricular ejection fraction less than 50%, do not include anthracyclines in first line therapy regimen 

Special populations

• Children (pediatric follicular lymphoma) 
  • Rare variant can occur in both children and adults
    • Characterized by:
      • Localized disease
      • Lack of hallmark translocation
      • High histologic grade with a high proliferation rate
      • More indolent course
  • Management consists of chemotherapy or excision (with or without radiotherapy), or chemoimmunotherapy 
  • Outcomes are generally favorable 

Monitoring

• Monitor all patients for evidence of recurrence and for therapy-related adverse effects
  • Provide follow-up with history, physical examination, and laboratory tests (eg, CBC, chemistry panel, renal and liver function tests) every 3 to 6 months for 5 years, then annually or as clinically indicated
  • Obtain surveillance imaging (eg, CT, ultrasonography) when indicated for clinically suspected relapse, or every 6 months, for 2 years after completion of treatment, then annually thereafter (up to 5 years) 
    • Obtain CT scan if there is suspicion of relapse that requires therapy
  • In patients with irradiation of the neck, obtain thyroid function tests at 1, 2, and 5 years 
  • Indefinite follow-up is required

Complications

• Histologic transformation into aggressive lymphoma (eg, Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma) 
  • Incidence ranges from 16% to 60% 
• Complications of therapy (eg, tumor lysis syndrome, infertility, cardiac toxicity, secondary malignancy)

Prognosis

• Chronic, essentially incurable, illness characterized by a relapsing and remitting pattern of nodal and bone marrow involvement 
• Spontaneous regression occurs in 10% to 20% of cases 
• Less than 10% of patients have stage I or II disease; most patients have advanced disease at the time of diagnosis 
• Grades 1, 2, and 3A are considered indolent while grade 3B disease is considered more aggressive 
  • 10-year progression-free survival rates for grade 1, 2, and 3A are similar (49% for grade 1-2 and 47% for grade 3A) according to longitudinal cohort data 
• Outcomes in advanced stages of the disease vary according to presence or absence of symptoms, tumor burden, patient age, and comorbidities; median overall survival is more than 12 years 
  • Swedish Lymphoma Registry reports 10-year overall survival of 92% in patients aged 18 to 49 years, 83% in patients aged 50 to 59 years, 78% in the 60- to 69-year age group, and 64% in patients aged 70 years and older 
• Histologic transformation into an aggressive lymphoma with worse prognosis can occur; risk is approximately 2% per year after diagnosis 
  • Median 5-year survival is approximately 26% after histologic transformation of follicular lymphoma 
• Several prognostic models have been developed
  • Follicular Lymphoma International Prognostic Index 
    • Based on the number of factors present, patient is assigned to low (0-1 factor), intermediate (2 factors), or high (3 or more factors) risk; the factors include: 
      • Age older than 60 years
      • Serum lactate dehydrogenase level higher than upper limit of reference range
      • Hemoglobin level less than 12 g/dL
      • Ann Arbor stage III or IV
      • More than 4 nodal sites
    • Overall 5-year survival is 91% in low-risk, 78% in intermediate-risk, and 52% in high-risk patients 
  • Follicular Lymphoma International Prognostic Index-2 
    • Based on number of factors present, patient is assigned to low (0-1 factor), intermediate (2 factors), or high (3 or more factors) risk; the factors include: 
      • Age older than 60 years
      • Bone marrow involvement
      • Hemoglobin level lower than 12 g/dL
      • Diameter of largest node involved is larger than 6 cm
      • Serum β₂-microglobulin level higher than upper limit of reference range
    • Overall 5-year survival is 98% in low-risk, 88% in intermediate-risk, and 77% in high-risk patients 
  • PRIMA-prognostic index 
    • Based on presence of bone marrow involvement and serum β₂-microglobulin level
      • Overall 5-year survival is 93% in low- and intermediate-risk patients and 81% in high-risk patients
  • Groupe d’Etude des Lymphomes Folliculaires criteria for high tumor burden (associated with worse prognosis) 
    • Any site of lymphadenopathy larger than 7 cm
    • 3 or more sites larger than 3 cm
    • B symptoms
    • Spleen below umbilical line
    • Compressive symptoms
    • Pleural or peritoneal effusions with 5000 tumor cells/mm³
    • Absolute neutrophil count lower than 1000/mm³
    • Platelet count lower than 100,000/mm³

References

1: Patel AA et al: Clinical and biological prognostic factors in follicular lymphoma. Hematol Oncol Clin North Am. 34(4):647-62, 2020  Cross Reference