AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Non-Hodgkin lymphoma is a heterogeneous group of malignancies of lymphocyte origin that usually arise or are present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow. Nevertheless, lymphomas can arise in any organ and usually are referred to as primary extranodal lymphomas. Microscopically, follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers. Despite the fact that most follicular lymphomas are advanced at the time of diagnosis, the median survival of patients with follicular lymphomas is approximately 8-10 years, and many patients may not require treatment for prolonged periods of time.

Pathophysiology

Most lymphomas originate from lymph node tissue and frequently metastasize to other organs. Lymphomas can invade any organ, including the skin and central nervous system. Lymphomas cause detrimental effects by organ invasion and by obstruction of anatomical structures by a tumoral mass. For example, ureteral obstruction by enlarged lymph nodes can lead to renal failure.

Frequency

United States

Non-Hodgkin lymphoma is the seventh most frequently diagnosed malignancy in the United States. Estimates indicate that more than 56,000 cases of non-Hodgkin lymphoma were diagnosed in 2005. Of those, 15-20% were follicular lymphomas.

International

In general, age-adjusted incidence rates of non-Hodgkin lymphoma are higher in more developed countries. The age-adjusted incidence rates of non-Hodgkin lymphoma varied from 3.7-14 per 100,000 person years from 1983-1987 in different countries.

Mortality/Morbidity

• The overall survival rate at 5 years is 72-77%. Median survival is approximately 8-10 years.
• The Follicular Lymphoma International Prognostic Index (FLIPI) is predictive of survival in patients with follicular lymphomas. Five adverse prognostic factors have been shown to be correlated with reduced overall survival: age older than 60 years, Ann Arbor stage III or IV disease, hemoglobin less than 12 g/dL, presence of more than 4 nodal sites of disease, and serum lactate dehydrogenase above normal. Patients with 3 or more of the above risk factors have a 10-year overall survival rate of 36% compared with 71% for those with one or none of the above variables.

Race

Variations in racial incidence are found throughout the world. The incidence of follicular lymphomas is low in China and Japan. People of Jewish ancestry have a higher incidence of lymphoma. In the United States, the incidence is 2-3 times higher in Caucasians than in African Americans.

Sex

The male-to-female ratio is approximately 1:1.

Age

Median age at diagnosis is 60-65 years. The incidence of follicular lymphomas increases with age. Follicular lymphomas are extremely rare in children.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

• Painless, slowly progressive adenopathy is the most frequent clinical presentation.
• Some patients have waxing and waning adenopathy.
• Systemic symptoms, such as fever, night sweats, weight loss in excess of 10%, or asthenia, are infrequent at presentation but can be observed in later stages of the disease. Progression to an intermediate-grade or high-grade lymphoma should be considered when a patient develops systemic symptoms.
• Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can be observed in the later stages of the disease.

Physical

• All lymph node areas should be examined, including the retroauricular, submandibular, cervical, supraclavicular, axillary, epitrochlear, inguinal, and popliteal areas.
• Involved nodes typically are nontender, firm, and rubbery in consistency.
• Splenomegaly is present in approximately 50% of patients at presentation.
• The throat should be examined for involvement of the oropharyngeal lymphoid tissue (ie, Waldeyer ring).

Causes

• Acquired nonrandom chromosomal translocations
• • The most common in patients with follicular lymphomas is the t(14;18) translocation, which is found in more than 80% of cases. This chromosomal translocation brings the bcl2 protooncogene under the transcriptional influence of the immunoglobulin heavy-chain gene. This translocation leads to the overexpression of a functionally normal bcl-2 protein. Overexpression of the bcl-2 protein, a protein of the mitochondrial membrane, confers a survival advantage to the cancer cells by inhibiting programmed cell death, or apoptosis. Although the exact mechanism of action of bcl-2 is unclear, its interaction with other homologs is felt to determine the likelihood of a cell undergoing apoptosis.
  • The detection of the t(14;18) product by polymerase chain reaction is used frequently in the diagnosis and follow-up of patients with follicular lymphomas. Nevertheless, this translocation has been detected in healthy patients and in patients with other types of tumors.
• Viruses have been implicated as etiologic factors for lymphomas, including the Epstein-Barr virus, human T-cell lymphotropic virus type I, and the herpesvirus associated with Kaposi sarcoma (ie, human herpesvirus 8). Nevertheless, these viruses have been linked mostly to diffuse or high-grade lymphomas.
• Chemicals, such as pesticides and hair dyes, have been associated with lymphoma.
• Immunodeficiency states
• • Congenital immunodeficiencies have been associated with lymphoma.
  • Acquired immunodeficiencies may include infection with the human immunodeficiency virus. Most lymphomas associated with the human immunodeficiency virus are intermediate-grade or high-grade lymphomas.
  • Patients who have been on immunosuppressant drugs after organ transplantation may develop lymphoma. Most of the lymphomas observed after organ transplantation are diffuse or high-grade lymphomas.

DIFFERENTIALS

Section 4 of 11  

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• Miscellaneous
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Other Problems to be Considered

Autoimmune disorders
Chronic infections

WORKUP

Section 5 of 11  

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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Complete blood count should be obtained, including examination of the peripheral blood smear.
• Frequently, abnormal lymphocytes can be identified in the blood smear.
• Blood chemistries, including LDH, uric acid, liver function tests, and creatinine, should be assessed.
• LDH is an indicator of tumor load.
• • Elevated LDH is a negative prognostic factor.
  • Hyperuricemia can be observed upon presentation or during therapy.
  • Allopurinol should be considered in patients with hyperuricemia and before treatment to prevent uric acid nephropathy.
  • Increased creatinine can be observed in patients with renal obstruction caused by lymphadenopathy.
  • Increased alkaline phosphatase and bilirubin can be observed in patients with biliary obstruction due to lymphadenopathy.

Imaging Studies

• Chest radiograph should be performed.
• CT scan of chest should be considered if the findings from the chest radiograph are abnormal or cause suspicion.
• CT scans of the abdomen and pelvis should be performed to determine if abdominal or pelvic adenopathy is present.
• CT scans allow visualization of the kidneys, ureters, and the hepatobiliary system. At times, these organs are affected by obstruction due to lymphadenopathy or by parenchymal involvement with lymphoma.
• Positron emission tomography (PET) scanning complements standard radiologic testing, but only a minority of patients will be diagnosed with a higher stage of disease.
• PET scanning can distinguish between viable tumor and fibrosis in patients with residual lymphadenopathy after therapy, but because the majority of patients with follicular lymphoma are not curable, this finding will not change management. This is in contrast to Hodgkin lymphoma and intermediate-grade lymphoma where a positive PET scan might prompt salvage chemotherapy or radiation.

Procedures

• Pathologic diagnosis from biopsy specimen
• • Biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy of an involved node.
  • A needle aspiration is not adequate for the initial diagnosis of lymphoma. If the disease is extranodal, a surgical biopsy sample should be obtained from the involved organ.
• Bilateral posterior iliac crest bone marrow aspiration and biopsies
• • Although a diagnosis of follicular lymphoma can be established based on histologic findings from lymph nodes and involvement of the bone marrow can be diagnosed using morphologic criteria, cytogenetic analysis of bone marrow cells should be performed because the t(14;18) translocation is found in the majority of patients with follicular lymphoma and can help establish the diagnosis.
  • Immunophenotyping of bone marrow using flow cytometry also should also be performed. It can detect an abnormal clone of B cells, which also can help establish the diagnosis.
  • Polymerase chain reaction for bcl-2 in bone marrow also can help establish the diagnosis because the majority of follicular lymphomas are positive for bcl-2.

Histologic Findings

Follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers. This follicular pattern of growth contrasts with diffuse lymphomas, which usually are intermediate or high-grade neoplasms.

Several pathologic classification systems have been used since the late 1960s, including the Rappaport, Lukes-Collins, Kiel, Working Formulation, Revised European-American Classification of Lymphoid Neoplasms (REAL), and World Health Organization (WHO). Early classification systems relied solely on the architecture and cytologic appearance of lymph nodes. As more sophisticated tests became available, immunophenotypic, cytogenetic, and molecular criteria were incorporated in the diagnosis of lymphomas. REAL was based on the premise that a classification should attempt to define disease entities using all available information, including morphology characteristics and immunophenotypic, genetic, and clinical features.

More recently, the WHO classification of lymphoid neoplasms adopted the REAL classification and proposed several changes. The WHO classification changed the nomenclature from follicle center cell lymphoma to follicular lymphoma. The WHO classification calls for grading of the follicular lymphoma from grades 1-3 based on the number of centroblasts per high-power field (hpf) and recognizes the importance of reporting on the presence of diffuse areas. In addition, the WHO classification recognizes 2 variants of follicular lymphomas: cutaneous follicle center cell lymphoma and diffuse follicle center lymphoma. Follicular lymphoma according to the WHO classification is staged as grade 1 (0-5 centroblasts per hpf), grade 2 (6-15 centroblasts per hpf), and grade 3 (>15 centroblasts). Variants include cutaneous follicle center cell lymphoma and diffuse follicle center cell lymphoma.

Importantly, progression to diffuse large-cell lymphoma occurs in 10-50% of patients depending on the duration of disease presence. Transformation to diffuse large-cell lymphoma frequently is associated with rapid progression of the disease, including increasing adenopathy, development of systemic symptoms, and infiltration of extranodal sites. Progression to large-cell lymphoma is a poor prognostic factor, and most patients who experience transformation succumb to the disease.

Staging

Most patients with follicular lymphoma present at an advanced stage. Most patients have bone marrow involvement at diagnosis.

• Stage I - One involved lymph node or lymph node area
• Stage II - Two or more involved lymph nodes or lymph node areas on the same side of diaphragm
• Stage III - Involved lymph node or lymph node areas on both sides of diaphragm
• Stage IV - Disseminated disease such as bone marrow, liver, or central nervous system involvement

TREATMENT

Section 6 of 11  

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Medical Care

• The rare patient who presents with localized disease should be treated with radiation therapy with curative intent because as many as 50% of these patients could be cured. Unfortunately, less than 10% of patients with follicular lymphoma present with localized disease.
• Most follicular lymphomas are disseminated and incurable at the time of diagnosis, and the treatment for these lymphomas is considered palliative. Many experts recommend observation until the patient develops systemic symptoms such as fever, weight loss, or bulky lymphadenopathy. Patients in whom treatment is deferred should be followed closely for complications such as ureteral or biliary obstruction. No universally accepted first-line treatment strategy exists for stage III/IV follicular lymphoma.
• Single-agent oral chemotherapy, such as with chlorambucil, is an option that is easy to administer and well tolerated by patients. Although it rarely leads to a durable response, it may palliate symptoms.
  • Fludarabine as a single agent is used less frequently because it must be given intravenously and causes a significant degree of myelosuppression and immunosuppression.
  • Rituximab (Rituxan), a monoclonal antibody targeting the CD20 antigen expressed on the cell surface of most lymphoma cells, has demonstrated efficacy as a single agent and as part of combination chemotherapy regimens. Several phase II clinical trials have demonstrated improved progression-free survival when used as initial therapy and in previously treated patients. Recent studies using rituximab as maintenance therapy suggest that this strategy prolongs progression-free survival in patients who had an objective response or stable disease to rituximab monotherapy. It is generally well tolerated but is significantly more expensive than most other therapies with no definitive improvement in overall survival.
• Combination chemotherapy, such as with cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), is used frequently when patients have recurrence or progression after single-agent chemotherapy or when patients present with rapidly progressive disease. Combination chemotherapy such as CHOP is also used when follicular lymphomas undergo transformation to intermediate or aggressive histology, although the results of therapy for patients who experience transformation to an aggressive histology are poor. Rituximab has also been added to combination chemotherapy regimens, including CVP and CHOP, and has been shown to improve progression-free survival in phase III clinical trials when compared with CVP or CHOP alone.
• Bone marrow/stem cell transplantation is used increasingly as therapy for follicular lymphomas, especially in young patients. Allogeneic bone marrow/stem cell transplantation can induce long-term remissions in patients with follicular lymphomas, but transplant-associated mortality is high. Autologous bone marrow transplantation has low transplant-associated mortality, prolongs progression-free survival, and potentially overall survival in patients with advanced-stage disease, but most patients relapse after this modality of therapy.
• Follicular lymphoma is inherently radiosensitive so the development of targeted radioimmunotherapy to the CD20 marker expressed on B cells has been a significant advance. It enables the delivery of cytocidal doses of radiation to all sites of disseminated disease. Currently, 2 agents are available: iodine-131-labeled tositumomab (Bexxar) and yttrium-90-labeled ibritumomab tiuxetan (Zevalin). In phase III clinical trials, both agents have produced high response rates in patients with relapsed or refractory follicular lymphoma and have demonstrated impressive response rates in treatment-naive patients as well.

Surgical Care

The role of the surgeon is to obtain an excisional biopsy adequate to establish the diagnosis. The surgeon should be instructed about the proper handling of the specimen and the special tests required because the biopsy might require special handling. The surgeon should probably discuss these issues with the pathologist prior to performing the biopsy.

Consultations

Radiation oncologist: Radiation therapy with curative intent should be used in patients with stage I disease, although this represents a minority of cases of follicular lymphoma. Radiation therapy also can be used to treat localized or bulky lymphadenopathy that is causing obstruction or when a more urgent response is desired to relieve obstruction. Radiation therapy usually is tolerated well and, in many instances, can spare the patient the need for additional chemotherapy. The radiation oncologist is also involved in the care of patients receiving radioimmunotherapy.

MEDICATION

Section 7 of 11  

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The treatment of follicular lymphoma varies widely. At present, defining a standard treatment for follicular lymphomas is difficult. Many patients are asymptomatic at the time of diagnosis and are incurable with conventional chemotherapy; therefore, many experts recommend a watch-and-wait approach. This approach is used most commonly in elderly patients and requires close follow-up to avoid complications of the disease, such as organ obstruction by lymphadenopathy.

Most patients eventually require therapy because of systemic symptoms, increasing adenopathy, or splenomegaly or because of low blood counts due to bone marrow involvement by lymphoma. When these patients require treatment, single-agent oral alkylating agents such as chlorambucil with or without steroids (eg, prednisone), has been the initial regimen for many patients. Phase III clinical trials have recently shown significant improvements in progression-free survival, time to retreatment, and in some studies overall survival in patients who were treated with rituximab alone or in addition to combination chemotherapy regimens.

Single-agent chemotherapy: Because most patients with follicular lymphomas experience a recurrence of disease after the initial treatment, additional therapy usually is necessary. If the patient has enjoyed a prolonged remission after treatment with oral alkylating agents, with or without prednisone, this regimen can be used again. Rituximab, a chimeric antibody that recognizes the CD20 antigen present on most follicular lymphoma cells, is being used increasingly for the treatment of patients with relapsed follicular lymphomas. In patients who responded to rituximab as initial therapy, many will benefit from maintenance rituximab to prolong duration of response or from repeating therapy with rituximab at the time of progression. Fludarabine has been used for treatment as well, but, while it will induce remission, it causes significant bone marrow suppression and immunosuppression.

Combination chemotherapy: Because younger patients are more likely to succumb to the disease, a more aggressive therapy, such as combination chemotherapy, is used frequently to obtain more durable remissions. Combination chemotherapy with CVP or CHOP, with or without rituximab, is used frequently in young patients with follicular lymphomas or in those with rapidly progressive disease. At present, no studies demonstrate the superiority of combination chemotherapy over single agents as initial therapy of follicular lymphomas in terms of an overall survival benefit; however, they are associated with improved progression-free survival. Combination chemotherapy also is used in patients with relapsed disease and in those who do not respond to single-agent therapy. Combination chemotherapy also has been used in patients whose condition transforms to the more aggressive diffuse lymphomas.

Allogeneic stem cell transplantation is generally considered in younger patients with aggressive disease because the process has a significant amount of therapy-related morbidity and mortality. Autologous stem cell transplantation, like combination chemotherapy, has been associated with improvements in progression-free survival, but most patients will relapse following this therapy.

Radioimmunotherapy has been proven to induce high rates of complete remission in both heavily pretreated and treatment-naive patients. Further study is needed to determine if this will translate to an improvement in overall survival to evince where these agents fit in the treatment of follicular lymphoma.

All of the medications listed below should only be ordered by physicians who have training and/or experience in antineoplastic agents.

Drug Category: Antineoplastic agent, alkylating agent

These agents inhibit cell growth and proliferation.

Drug Name	Cyclophosphamide (Cytoxan)
Description	Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA is considered cytotoxic. In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T-cell functions.
Adult Dose	CHOP regimen: 750 mg/m2 IV on day 1, repeat q3wk CVP regimen: 750 mg/m2 IV on day 1, repeat q3wk Oral regimens: 50-100 mg/m2/d PO continuously or 400-1000 mg/m2 PO in divided doses for 4-5 d or 400-1800 mg/m2 (30-50 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause sterility; nausea and vomiting are common with intravenous dosing regimen; anorexia, diarrhea, mucositis, and stomatitis are also seen; potentially fatal acute hemorrhagic cystitis may occur; facial flushing, headache, and rash may also occur

Drug Category: Antineoplastic, Antimetabolite

Interfere with metabolic pathways necessary for the survival of target cells.

Drug Category: Antineoplastic agent, anthracycline

These agents inhibit DNA synthesis.

Drug Category: Antineoplastic agent, vinca alkaloid

These agents inhibit cell growth and proliferation at the mitotic phase of the cell cycle.

Drug Category: Corticosteroids

Have anti-inflammatory effects in disorders of many organ systems. Corticosteroids also are lympholytic and modify the body's immune responses to diverse stimuli.

Drug Category: Monoclonal antibodies

Bind to target cells and recruit immune-effector functions to mediate target-cell lysis.

Drug Name	Tositumomab and Iodine 131 (Bexxar)
Description	Murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, found on surface of normal and malignant B lymphocytes. Radiolabeled tositumomab (ie, iodine I131 tositumomab) is administered following nonradiotherapeutic version to direct treatment precisely to the malignancy. Possible mechanisms of action include apoptosis, complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and ionizing radiation. Indicated for CD20 positive non-Hodgkin lymphoma that has relapsed following chemotherapy and is refractory to rituximab.
Adult Dose	Dosimetric step: Tositumomab 450 mg IV infused over 1 h, followed by iodine I-131 tositumomab (5 mCi I-131 and 35 mg tositumomab) IV infused over 20 min Therapeutic step (7-14 d following dosimetric step): Tositumomab 450 mg IV infused over 1 h, followed by iodine I131 (precise dose is dependent on current platelet count)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to tositumomab or murine antibodies
Interactions	Live virus vaccines may not generate an immunologic response; due to frequency and duration of thrombocytopenia, antiplatelets or anticoagulants may cause exacerbation; coadministration with other drugs causing bone marrow suppression may cause additive effects
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause severe or life-threatening cytopenias (ie, 71% experience grade 3 or 4); may cause hypersensitivity, including anaphylaxis; may cause secondary malignancies or hypothyroidism; infusion-related symptoms (eg, fever, rigors, chills, sweating) may occur; 1 d prior to administration, administer protectant SSKI; administer acetaminophen and diphenhydramine on administration day

Drug Name	Ibritumomab tiuxetan (Zevalin)
Description	A murine monoclonal antibody that targets the CD20 antigen, which is chelated to the radioisotopes indium-111 or yttrium-90. Used in conjunction with rituximab to treat B-cell non-Hodgkin lymphoma (NHL) or rituximab-refractory follicular NHL. The regimen consists of 2 low doses of rituximab, an imaging dose, 2-3 whole body scans, and a therapeutic dose, which are all delivered on an outpatient basis over 8 d.
Adult Dose	Day 1: Rituximab (250 mg/m2) IV infused over 4-5 h; followed by ibritumomab 1.6 mg (5 mCi indium111) IV push over 10 min; followed by a whole body scan at 2-24 h Day 3 or 4: Whole body scan at 48-72 h Day 4-5: Whole body scan at 90-120 h (optional) Day 7-9: Rituximab (250 mg/m2) IV infused over 4-5 h; followed by ibritumomab 0.4 mCi/kg of yttrium90 IV push over 10 min; not to exceed 32 mCi Note that the dose of rituximab is lower when used with ibritumomab, than as single agent
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; prior sensitization to murine proteins; greater than or equal to 25% lymphoma bone marrow involvement; prior myeloablative therapies; platelet count <100,000 cells/mm3; neutrophil count <1500 cells/mm3; hypocellular bone marrow (< 15% cellularity of marked reduction in bone marrow precursors); history of failed stem cell collection; breastfeeding
Interactions	Coadministration with antiplatelet or anticoagulant drugs may increase risk of cytopenias and bleeding
Pregnancy	D - Unsafe in pregnancy
Precautions	Therapeutic regimen, which includes rituximab administration may cause severe, and potentially fatal, infusion reactions (typically occur during first rituximab infusion with time to onset of 30-120 min) and may require interruption of drug administration (signs and symptoms of severe infusion reactions may include hypotension, angioedema, hypoxia, or bronchospasm); treatment may cause severe and prolonged thrombocytopenia and neutropenia; do not administer to those with altered biodistribution (according to body scan results); use only as single course of treatment; follow radionucleotide precautions; decrease Y-90 ibritumomab to 0.3 mCi/kg with mild thrombocytopenia (ie, 100,000-149,000 platelets/mm3); severe mucocutaneous reactions, some with fatal outcomes, have been reported with the therapeutic regimen

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Most patients with follicular lymphoma do not require hospitalization during the early stages of the disease.
• Patients with bulky disease at the time of treatment should be followed closely for tumor lysis syndrome. Allopurinol should be considered in these patients. Institute close follow-up of renal function and electrolyte balance.

Further Outpatient Care

• Patients should be monitored periodically to facilitate avoidance or early treatment of complications of the disease.
• Patients should be asked about the development of systemic symptoms such as fever, weight loss, and asthenia. These symptoms may herald progression of the disease or transformation to more aggressive intermediate-grade lymphoma.
• The physical examination should include a complete examination of the lymph nodes and reticuloendothelial system. Particular attention should be given to the abdominal examination, looking for the presence of splenomegaly or hepatosplenomegaly.
• Laboratory evaluation should include complete blood counts and serum chemistries. The serum chemistries should include liver function tests to be able to detect complications such as biliary obstruction and BUN and creatinine to detect ureteral obstruction and metabolic abnormalities such as hyperuricemia and hypercalcemia.

Complications

• Complications due to increased adenopathy causing obstruction, such as biliary obstruction, ureteral obstruction, and bronchial obstruction, should be considered during the follow-up monitoring of patients with follicular lymphomas.

Prognosis

• The overall survival rate of patients with follicular lymphoma is 72-77% at 5 years.
• Median survival is approximately 8-10 years.
• Patients who have 4 or more of the following adverse prognostic factors have a 10-year survival rate of approximately 36%:
• • Age 60 years or older
  • Ann Arbor Stage III or IV
  • LDH above the upper limit of normal at diagnosis
  • Hemoglobin less than 12 g/dL
  • Presence of more than 4 extranodal sites of disease

Patient Education

• Patients should be educated regarding the signs and symptoms of progression of the disease, including new systemic symptoms, new lymphadenopathy, or rapidly enlarging lymphadenopathy.
• Similar to patients with chronic lymphocytic leukemia, patients with follicular lymphoma also are more prone to infections and should be instructed to contact their physician early if they develop signs or symptoms of infection.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• The most common pitfall is to confuse follicular lymphomas with other types of lymphomas. The diagnosis of lymphomas is complex, and tissue biopsies should be reviewed by pathologists with experience in interpreting lymph node biopsies and other diagnostic material.
• Supporting tests, such as immunophenotyping and cytogenetics, should be performed, especially if some doubt exists regarding the diagnosis.

MULTIMEDIA

Section 10 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Follicular lymphoma, low-power view: Note the nodular pattern reminiscent of germinal centers. Photograph courtesy of Aamir Ehsan, MD.
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Media file 2:  Diffuse lymphoma: Note the absence of the nodular pattern observed in follicular lymphomas. Photograph courtesy of Aamir Ehsan, MD.
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Media file 3:  A patient with follicular lymphoma who was diagnosed 6 years earlier presents to his hematologist's office because of rapidly growing lymphadenopathy and a new onset of fever, severe night sweats, and weight loss. In the past, he had been treated with chlorambucil and prednisone when his submandibular lymph nodes became large enough to make him uncomfortable. This treatment had worked well, and he has not required any treatment recently. A biopsy of an involved lymph node is obtained (see image). The diagnosis is transformation to diffuse non-Hodgkin lymphoma.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• American Cancer Society. Cancer facts and figures 2005. American Cancer Society;. 2005.
• Ardeshna KM, Smith P, Norton A. 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. Aug 16 2003;362(9383):516-22. [Medline].
• Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin''s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin''s Lymphoma Classification Project. J Clin Oncol. Aug 1998;16(8):2780-95. [Medline].
• Bordeleau L, Berinstein NL. Molecular diagnostics in follicular non-Hodgkin''s lymphoma: a review. Semin Oncol. Dec 2000;27(6 Suppl 12):42-52. [Medline].
• Fisher RI, Kaminski MS, Wahl RL. Tositumomab and iodine-131 tositumomab produces durable complete remissionsin a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin''s lymphomas. J Clin Oncol. Oct 20 2005;23(30):7565-73.
• Freedman AS, Neuberg D, Mauch P, et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood. Nov 15 1999;94(10):3325-33. [Medline].
• Ghielmini M, Schmitz SF, Cogliatti SB. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. Jun 15 2004;103(12):4416-23.
• Hainsworth JD, Litchy S, Shaffer DW. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin''s lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. Feb 20 2005;23(6):1088-95.
• Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. Dec 1999;10(12):1419-32. [Medline].
• Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. Sep 1 1994;84(5):1361-92. [Medline].
• Hehn ST, Grogan TM, Miller TP. Utility of fine-needle aspiration as a diagnostic technique in lymphoma. J Clin Oncol. Aug 1 2004;22(15):3046-52.
• Hiddemann W, Buske C, Dreyling M. Treatment strategies in follicular lymphomas: current status and future perspectives. J Clin Oncol. Sep 10 2005;23(26):6394-9.
• Hiddemann W, Kneba M, Dreyling M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone. Blood. Dec 1 2005;106(12):3725-32.
• Juweid ME, Cheson BD. Role of positron emission tomography in lymphoma. J Clin Oncol. Jul 20 2005;23(21):4577-80.
• Kaminski MS, Tuck M, Estes J. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. Feb 3 2005;352(5):441-9.
• Marcus R, Imrie K, Belch A. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. Feb 15 2005;105(4):1417-23.
• McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. Aug 1998;16(8):2825-33. [Medline].
• Schouten HC, Qian W, Kvaloy S. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin''s lymphoma: results from the randomized European CUP trial. J Clin Oncol. Nov 1 2003;21(21):3918-27. [Medline].
• Solal-Celigny P, Roy P, Colombat P. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265.
• Swenson WT, Wooldridge JE, Lynch CF. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol. Aug 1 2005;23(22):5019-26.
• Witzig TE, Gordon LI, Cabanillas F. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. May 15 2002;20(10):2453-63. [Medline].
• van Besien K, Sobocinski KA, Rowlings PA, et al. Allogeneic bone marrow transplantation for low-grade lymphoma. Blood. Sep 1 1998;92(5):1832-6. [Medline].
• van Besien K, Loberiza FR, Bajorunaite R. Comparison of autologous and allogeneic hematopoietic stem cell transplantationfor follicular lymphoma. Blood. Nov 15 2003;102(10):3521-9. [Medline].

Article Last Updated: Sep 6, 2006