Follicular Lymphoma 

Non-Hodgkin lymphoma (NHL) 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 are usually referred to as primary extranodal lymphomas. Microscopically, follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers (see the image below). 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.^[1]

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 (CNS), and they cause detrimental effects by organ invasion and by obstruction of anatomic structures by a tumoral mass.^{[2, 3]} For example, ureteral obstruction by enlarged lymph nodes can lead to renal failure.

Acquired nonrandom chromosomal translocations

The most common acquired nonrandom chromosomal translocation in patients with follicular lymphomas is the t(14;18) translocation, which is found in more than 80% of cases.^[4] This chromosomal translocation brings the bcl2 protooncogene under the transcriptional influence of the immunoglobulin heavy-chain gene, leading 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 homologues is felt to determine the likelihood of a cell undergoing apoptosis.

The detection of the t(14;18) product by polymerase chain reaction (PCR) 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 and chemicals

Viruses have been implicated as etiologic factors for lymphomas, including the Epstein-Barr virus (EBV), human T-cell lymphotropic virus (HTLV) type I, and the herpesvirus associated with Kaposi sarcoma (ie, human herpesvirus [HHV]-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 (HIV). Most lymphomas associated with HIV are intermediate-grade or high-grade lymphomas.

Patients who have been on immunosuppressant drugs after organ transplantation may develop lymphoma. Most of these lymphomas are diffuse or high-grade lymphomas.

Non-Hodgkin lymphoma (NHL) is the fifth most frequently diagnosed malignancy in the United States. Estimates indicate that more than 66,000 cases of non-Hodgkin lymphoma were diagnosed in 2008. Of those, 15-20% were follicular lymphomas.^[5] No sex preponderance is seen.

In general, age-adjusted incidence rates of non-Hodgkin lymphoma are higher in more developed countries. The incidence of follicular lymphomas increases with age; these conditions are extremely rare in children. The median age at diagnosis is 60-65 years. The age-adjusted incidence rates of non-Hodgkin lymphoma varied from 3.7-14 cases per 100,000 person years from 1983-1987 in different countries.

Variations in racial incidence are found throughout the world. The incidence of follicular lymphomas is low in China and Japan, but people of Jewish ancestry have a higher incidence of lymphoma. In the United States, the incidence is 2-3 times higher in white individuals than in black persons.

Follicular lymphoma most commonly presents as a painless, slowly progressive adenopathy. 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 also be observed in the later stages of the disease.

During the physical evaluation, all lymph node areas and the reticuloendothelial system 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.

In addition, the throat should be examined for involvement of the oropharyngeal lymphoid tissue (ie, Waldeyer ring), and particular attention should be given to the abdominal examination (eg, liver and spleen), as splenomegaly is present in approximately 50% of patients at presentation and hepatosplenomegaly may occur.

Most patients with follicular lymphoma present at an advanced stage, and most patients have bone marrow involvement at diagnosis. Staging is as follows:

• 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 (CNS) involvement

See also Pathologic classification systems under Histologic Findings.

Autoimmune disorders and chronic infections as well as the following conditions should be evaluated as part of the differential diagnosis of follicular lymphomas:

• Chronic Lymphocytic Leukemia
• Lymphoma, Diffuse Large Cell
• Lymphoma, Diffuse Mixed
• Lymphoma, Lymphoblastic
• Mucosa-Associated Lymphoid Tissue

A complete blood cell (CBC) count should be obtained, including examination of the peripheral blood smear. Frequently, abnormal lymphocytes can be identified in the blood smear.

Blood chemistries, including lactate dehydrogenase (LDH) levels, uric acid levels, liver function tests, and creatinine measurements should be assessed. LDH is an indicator of tumor load, and an elevated level 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 levels can be observed in patients with renal obstruction caused by lymphadenopathy, and increased alkaline phosphatase and bilirubin measurements can be observed in patients with biliary obstruction due to lymphadenopathy.

A chest radiograph should be performed, but a computed tomography (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. This imaging modality 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, such a finding will not change management.^[6] This is in contrast to Hodgkin lymphoma and intermediate-grade lymphoma in which a positive PET scan might prompt salvage chemotherapy or radiation.

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 before performing the biopsy.

Pathologic diagnosis from biopsy specimen

Biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy of an involved node. Note that a needle aspiration is not adequate for the initial diagnosis of lymphoma.^[7] 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 should also be performed. It can detect an abnormal clone of B cells, which also can help establish the diagnosis.

Polymerase chain reaction (PCR) for bcl-2 in bone marrow also can help establish the diagnosis, because the majority of follicular lymphomas are positive for bcl-2.

The most common diagnostic 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.

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 (see the following images).

Pathologic classification systems

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, such as the following^{[8, 9, 10]} :

• 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.
• 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. See the following image.

A study by Camacho et al found that several immunohistochemical markers are associated with differences in overall survival in univariate analyses. These include Cyclin E, Mdm2, CD10, p21, IgD, Bcl-xL, CD30, and E2F6. A combination of the Follicular Lymphoma International Prognostic Index score and Cyclin E, Mdm2, and CD10 expression revealed a subset of patients with a good clinical course.^[11]

Most patients with follicular lymphoma do not require hospitalization during the early stages of the disease. However, patients with bulky disease at the time of treatment should be followed closely for tumor lysis syndrome. Allopurinol should be considered in these patients.

Physicians who have training and/or experience in antineoplastic agents should be the ones to order the following:

• Alkylating agents (eg, chlorambucil, cyclophosphamide): These agents inhibit cell growth and proliferation.
• Antimetabolites (eg, fludarabine): These agents interfere with metabolic pathways necessary for the survival of target cells.
• Anthracyclines (eg, doxorubicin, mitoxantrone): These drugs inhibit DNA synthesis.
• Vinca alkaloids (eg, vincristine): These drugs inhibit cell growth and proliferation at the mitotic phase of the cell cycle.
• Corticosteroids (eg, prednisone): These agents have anti-inflammatory effects in many organ system disorders. Corticosteroids are also lympholytic and modify the body's immune responses to diverse stimuli.
• Monoclonal antibodies (eg, rituximab, tositumomab and iodine-131, ibritumomab tiuxetan): These agents bind to target cells and recruit immune-effector functions to mediate target-cell lysis.^[12]

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.

The rare patient who presents with localized disease should be treated with radiation therapy with curative intent; approximately half of these patients will be cured with radiation alone. Unfortunately, fewer than 10% of patients with follicular lymphoma present with localized disease.

The treatment for advanced stage disease is considered palliative, because most follicular lymphomas are disseminated and incurable at the time of diagnosis. Many experts recommend observation until the patient develops systemic symptoms, such as fever, weight loss, or bulky lymphadenopathy, because early therapy has not been shown to impact overall survival.^[13] 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 chemotherapy is an option for patients with symptomatic disease.^[14] Single agents tend to have lower response rates and provide a shorter duration of disease control than do combination chemotherapy regimens. Nonetheless they are appropriate for selected patients, because they may be simpler to administer, induce less toxicity, and palliate symptoms.

Chlorambucil

Chlorambucil is an oral alkylating agent that is often reserved for elderly patients with a poor performance status or those who wish to defer intravenous therapy. Few patients will have a complete response, and there is no impact on overall survival.

Fludarabine

Single-agent fludarabine must be administered intravenously; this agent causes a significant degree of myelosuppression and immunosuppression, and there is also some concern that therapy with fludarabine may impair the ability to collect hematopoietic stem cells for an autologous stem cell transplantation. Fludarabine is associated with higher response rates than single-agent chlorambucil is, but it has no impact on overall survival.

Rituximab

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. It is generally well tolerated but is significantly more expensive than most other therapies; there has been no definitive improvement found in overall survival when rituximab is administered as a single agent. Clinical trials using rituximab as maintenance therapy have suggested that this strategy prolonged progression-free survival in patients who had an objective response or stable disease following rituximab monotherapy.^{[15, 16, 17, 18]}

Patients treated with single-agent rituximab who also received maintenance therapy had a longer disease-free survival. Patients who benefited the most from this approach were previously untreated patients.^[19]

A study by Vidal et al concluded that rituximab maintenance remains the standard of care for refractory or relapsed follicular lymphoma.^[20]

Combining multiagent chemotherapy and rituximab is the most common first-line treatment strategy in the United States. Several studies have compared combination chemotherapy with and without rituximab; the rituximab containing regimens generally produce a higher response rate and a more durable response. A meta-analysis confirmed an improvement in overall survival in patients with follicular lymphoma, associated with the addition of rituximab to combination chemotherapy regimens.

Combination chemotherapy regimens vary and include the following:

• Rituximab, cyclophosphamide, vincristine, prednisone (R-CVP)^[21]
• Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)^[22]
• Fludarabine, cyclophosphamide, rituximab (FCR)
• Rituximab, fludarabine, cyclophosphamide, mitoxantrone (R-FCM)
• Fludarabine, rituximab (FR)

Rituximab has been evaluated as maintenance chemotherapy in patients with follicular lymphoma after initial chemotherapy. In a large study European study, rituximab given every 2 months for 2 years increased disease-free survival, but not survival in this population of patients.^[23]

A study by Fowler et al found a combination of rituximab, bendamustine, and bortezomib to be highly active in treating relapsed or refractory follicular lymphoma.^[24]

Hematopoietic stem cell transplantation has a role in the treatment of follicular lymphoma, especially in younger patients with relapsed or recurrent disease.^[25] Allogeneic hematopoietic stem cell transplantation can induce long-term remissions in patients with follicular lymphoma, but transplant-related mortality is high.^[26]

Autologous hematopoietic stem cell transplantation has a low transplant-associated mortality and prolongs progression-free survival; in a randomized, controlled trial, improvement in overall patient survival was observed.^[27] However, most patients eventually relapse after undergoing this therapy, and there is an increased rate of secondary malignancies. Hematopoietic stem cell transplantation is generally reserved for patients with relapsed or refractory disease.

A study by Al Khabori et al determined that available evidence indicates autologous transplantation in first remission is not indicated; however, the best time for transplantation is unclear.^[28]

Follicular lymphoma is inherently radiosensitive, so the development of targeted radioimmunotherapy^[29] to the CD20 marker expressed on B cells has been a significant advance.^[30] This technique enables the delivery of cytocidal doses of radiation to all sites of disseminated disease. There are 2 agents available for this type of treatment: iodine-131 (¹³¹ I)–labeled tositumomab (Bexxar) and yttrium-90 (⁹⁰ Y)–labeled ibritumomab tiuxetan (Zevalin).^[31] Both agents have produced high response rates in patients with relapsed or refractory and treatment-naive follicular lymphoma.^{[32, 33, 34]}

¹³¹ I–labeled tositumomab and⁹⁰ Y–labeled ibritumomab tiuxetan have demonstrated improvements in progression-free survival but not in overall patient survival. In an attempt to achieve a complete response in a higher proportion of patients, ongoing clinical trials are utilizing these agents in consolidation therapy following an initial chemotherapy regimen or as part of a hematopoietic stem cell transplantation regimen.

The use of radioimmunoconjugate agents is limited in the United States by the need for highly trained staff and specialized equipment, the expense of therapy, the risk for secondary malignancies, and the relatively short duration of follow-up.

Because radiation therapy with curative intent should be used in patients with stage I disease, although this represents a minority of cases of follicular lymphoma, seek consultation with a radiation oncologist. 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 is usually 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.

It is recommended that surgeons consult with pathologists before obtaining excisional biopsy specimens to discuss the proper handling of the specimen and the special tests required, because the biopsy might require special handling.

Institute close follow-up of renal function and electrolyte balance. Patients should be monitored periodically to facilitate avoidance or early treatment of complications of the disease, and those 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.

See also Clinical Evaluation for follow-up evaluation in patients.

The overall survival rate of patients with follicular lymphoma is 72-77% at 5 years. Median survival is approximately 8-10 years.^[35]

The Follicular Lymphoma International Prognostic Index (FLIPI) is predictive of survival in patients with follicular lymphomas.^[36] Patients who have 4 or more of the following adverse prognostic factors have a 10-year survival rate of approximately 36% (compared with 71% for those with 1 or none of these variables)^[36] :

• Age 60 years or older
• Ann Arbor Stage III or IV
• Lactate dehydrogenase (LDH) level above the upper limit of normal at diagnosis
• Hemoglobin less than 12 g/dL
• Presence of more than 4 nodal sites of disease