Follicular lymphomas

https://doi.org/10.1016/j.critrevonc.2008.01.014Get rights and content

Abstract

Follicular lymphomas constitute ∼30% of all non-Hodgkin lymphomas. These lymphomas are characterized by at least partially follicular growth pattern, but diffuse areas may be present. The proportions of follicular or diffuse areas vary also from case to case, which seems to be associated with prognosis. Follicular lymphomas should not be divided into distinct subtypes, but rather shows a continuous gradation in the number of large cells. On the bases of this grading, three groups have been defined: grades 1–3. There is a consensus that grade 3 follicular lymphomas, namely grade 3b, should be discriminated from lower-grade cases. The cells of follicular lymphomas express surface immunoglobulin, more frequently IgM +/− IgD > IgG > IgA, B-cell-associated antigens, CD10+/−; they are CD5−, CD23−/+, CD43−, and CD11c−. Follicular lymphomas express bcl-2 proteins, which is useful in distinguishing reactive from neoplastic follicles. t(14;18) is present in 70–95% of follicular lymphomas, involving rearrangement of bcl-2 gene. Clinical behavior of follicular lymphomas is heterogeneous and differs according to the histologic grade and extension of disease. Moreover, the evaluation of these malignancies is conditioned by therapeutic decision, which is also determined by main prognostic factors. The International Prognostic Index for aggressive lymphomas is not optimal for follicular lymphomas. Conversely, the Italian Lymphoma Intergroup Index and, more recently, the Follicular Lymphoma International Prognostic Index (FLIPI), designed in pre-rituximab era, seem to correlate well with outcome. Several active therapeutic approaches from the “wait and watch” strategy to the allogeneic transplantation are available for management of patients with follicular lymphoma. Therapeutic decision is mostly conditioned by patient's characteristics, stage, histologic grade, tumor burden, and risk-predicting factors.

Section snippets

Definition, incidence and risk factors

Follicular lymphomas are defined as a group of malignancies composed of follicle center cells, usually a mixture of centrocytes (cleaved cells) and centroblasts (large non-cleaved cells). Diffuse areas may be present and, in fact, may even predominate, but follicles exist. This group of lymphomas includes many cases formerly recognized as centroblastic/centrocytic follicular or follicular centroblastic according to the Kiel classification [1], [2] and follicular, small cleaved, mixed or large

Morphology

Follicular lymphomas are characterized by at least partially follicular growth pattern, but diffuse areas may be present [2]. Sclerosis is common in diffuse areas. Centrocytes typically predominate; centroblasts are usually in the minority, but by definition are always present. Rare lymphomas with a follicular pattern consist almost entirely of centroblasts; because the follicular pattern implies a germinal center origin, these cases have been included in the category of follicular center cells

Clinical presentation and natural history

Although not uncommon in the third and fourth decades, follicular lymphomas occur most commonly in middle-aged patients and elderly [20], [21]. Every anatomic district may be involved, but the most common presentation is multiple lymphadenopathy, with or without abdominal or mediastinal masses, splenomegaly, hepatomegaly, and marrow involvement. Leukemic phase is less common than for other indolent lymphomas, and extranodal sites are usually involved with e lower frequency respect to diffuse

Staging procedures

Complete staging work-up for follicular lymphomas is the same that routinely used for other NHL. It includes an accurate physical examination, complete hematological and biochemical exams, total-body computerized tomography, and bone marrow aspirate and biopsy. Bone marrow assessment in follicular lymphoma should follow the general statements for all NHL. Abdominal staging, with evaluation of potential hepatic or splenic involvement in follicular lymphomas should follow the general statements

Prognostic factors

Several groups have described prognostic factors for patients with advanced follicular lymphoma [36], [37], [38]. In the Groupe d’Etude des Lymphomes Folliculaires schema, patients with any one of the following features are considered to have a high tumor burden: systemic symptoms, elevated LDH serum levels, bulky lesion >7 cm, effusion, three or more Ann Arbor sites each 3 cm or greater, circulating lymphoma cells, cytopenias, and splenomegaly [39], [40]. The International Prognostic Index for

“Watch and wait” policy

Treatment can be safely deferred without disadvantage on survival for patients with follicular lymphoma in stages III–IV disease [24], provided that none of the following features occurs: systemic symptoms, high tumor burden, extranodal disease, cytopenia due to marrow involvement, spleen involvement, leukemic phase, serous effusion, high LDH levels. This “watch and wait” policy was evaluated by three trials that randomized to either chemotherapy or watchful waiting (WW) strategy patients with

Umberto Vitolo is chief of the Chemoimmunotherapy Lymphoma Section at the Department of Onco-hematology, S. Giovanni Battista Hospital, Torino Italy.

References (143)

  • R.C. Leonard et al.

    The identification of discrete prognostic groups in low grade non-Hodgkin's lymphoma. The Scotland and Newcastle Lymphoma Group Therapy Working Party

    Ann Oncol

    (1991)
  • J. Rodriguez et al.

    Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features

    Blood

    (1999)
  • J.W. Denham et al.

    The follicular non-Hodgkin's lymphomas. II. Prognostic factors: what do they mean?

    Eur J Cancer

    (1996)
  • M. Ladetto et al.

    High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: a multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

    Blood

    (2002)
  • H. Tilly et al.

    Prognostic value of chromosomal abnormalities in follicular lymphoma

    Blood

    (1994)
  • C.A. Sander et al.

    p53 mutation is associated with progression in follicular lymphomas

    Blood

    (1993)
  • T. Yano et al.

    MYC rearrangements in histologically progressed follicular lymphomas

    Blood

    (1992)
  • K.S. Elenitoba-Johnson et al.

    Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma

    Blood

    (1998)
  • M. Pinyol et al.

    p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas

    Blood

    (1998)
  • M. Federico et al.

    Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi

    Blood

    (2000)
  • P. Solal-Celigny et al.

    Follicular lymphoma international prognostic index

    Blood

    (2004)
  • G. Perea et al.

    Prognostic indexes in follicular lymphoma: a comparison of different prognostic systems

    Ann Oncol

    (2005)
  • K.M. Ardeshna et al.

    Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial

    Lancet

    (2003)
  • S. Pendlebury et al.

    Radiotherapy results in early stage low grade nodal non-Hodgkin's lymphoma

    Radiother Oncol

    (1995)
  • J.F. De Los Santos et al.

    Is comprehensive lymphatic irradiation for low-grade non-Hodgkin's lymphoma curative therapy? Long-term experience at a single institution

    Int J Radiat Oncol Biol Phys

    (1997)
  • P. Soubeyran et al.

    Is there any place for a wait-and-see policy in stage I0 follicular lymphoma? A study of 43 consecutive patients in a single center

    Ann Oncol

    (1996)
  • P. Carde et al.

    Combined radiotherapy-chemotherapy for early stages non-Hodgkin's lymphoma: the 1975–1980 EORTC controlled lymphoma trial

    Radiother Oncol

    (1984)
  • S. Monfardini et al.

    Improved five year survival after combined radiotherapy–chemotherapy for stage I–II non-Hodgkin's lymphoma

    Int J Radiat Oncol Biol Phys

    (1980)
  • S.S. Kamath et al.

    The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma

    Int J Radiat Oncol Biol Phys

    (1999)
  • R.B. Wilder et al.

    Long-term results with radiotherapy for Stage I–II follicular lymphomas

    Int J Radiat Oncol Biol Phys

    (2001)
  • A.D. Murtha et al.

    Long-term follow-up of patients with Stage III follicular lymphoma treated with primary radiotherapy at Stanford University

    Int J Radiat Oncol Biol Phys

    (2001)
  • A. Hagenbeek et al.

    Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant non-Hodgkin's lymphoma

    J Clin Oncol

    (2006)
  • P. McLaughlin 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

    (1998)
  • U. Vitolo et al.

    A brief course of chemo-immunotherapy FND + rituximab is effective to induce a high clinical and molecular response in elderly patients with advanced stage follicular lymphoma (FL) at diagnosis

    Blood

    (2003)
  • W. Hiddemann et al.

    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: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group

    Blood

    (2005)
  • M. Herold et al.

    Results of a prospective randomised open label phase III study comparing rituximab plus mitoxantrone, chlorambucile, prednisolone chemotherapy (R-MCP) versus MCP alone in untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle-cell-lymphoma (MCL)

    ASH

    (2004)
  • P.M. Banks

    Incorporation of immunostaining data in anatomic pathology reports

    Am J Surg Pathol

    (1992)
  • K. Lennert

    Malignant lymphomas: other than Hodgkin's disease: histology, cytology, ultrastructure, immunology

    (1978)
  • N.L. Harris et al.

    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

    J Clin Oncol

    (1999)
  • E.S. Jaffe et al.

    Nodular lymphoma—evidence for origin from follicular B lymphocytes

    N Engl J Med

    (1974)
  • R.S. Stein et al.

    Malignant lymphomas of follicular center cell origin in man. VI. Large cleaved cell lymphoma

    Cancer

    (1987)
  • R.B. Mann et al.

    Criteria for the cytologic subclassification of follicular lymphomas: a proposed alternative method

    Hematol Oncol

    (1983)
  • B.Y. Ngan et al.

    Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation

    N Engl J Med

    (1988)
  • F. Pezzella et al.

    Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation

    Am J Pathol

    (1990)
  • J.J. Yunis et al.

    Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer

    N Engl J Med

    (1987)
  • D.M. Hockenbery et al.

    BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death

    Proc Natl Acad Sci USA

    (1991)
  • Y. Tsujimoto et al.

    Involvement of the bcl-2 gene in human follicular lymphoma

    Science

    (1985)
  • R. Kuppers et al.

    Cellular origin of human B-cell lymphomas

    N Engl J Med

    (1999)
  • J. Limpens et al.

    Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia

    Oncogene

    (1991)
  • K.E. Summers et al.

    Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma

    J Clin Oncol

    (2001)
  • Cited by (39)

    • Follicular lymphoma grade 3: Review and updates

      2014, Clinical Lymphoma, Myeloma and Leukemia
      Citation Excerpt :

      It presents as advanced disease in 80% to 85% of FL Grade 1; 70% to 75% in Grade 2; and 65% to 70% of Grade 3. Systemic symptoms are observed 30% of Grade 3 FL compared with 20% in Grade 1 and 2 FL.2 The Follicular Lymphoma International Prognostic Index (FLIPI) is a prognostic scoring system based on age, Ann Arbor stage, number of nodal sites involved, hemoglobin levels, and serum lactate dehydrogenase levels.36

    • Update in indolent non-hodgkin lymphoma (NHL): Paradigm for Waldenström's macroglobulinemia (WM)

      2011, Clinical Lymphoma, Myeloma and Leukemia
      Citation Excerpt :

      They are characterized by a slow proliferation, but they are almost incurable, with frequent relapses. A careful analysis of biological and clinical prognostic features is mandatory and it is helpful for a better management of the disease.3 As for the treatment of Waldenstrom macroglobulinemia, many therapeutic approaches are available for low-grade lymphomas: watchful waiting, chemotherapy, monoclonal antibodies alone or in association with chemotherapy with or without maintenance treatment, high-dose chemotherapy, and autologous stem cell transplantation.4

    • A rare case of primary conjunctival Follicular Lymphoma grade 3B

      2019, Hematology, Transfusion and Cell Therapy
    View all citing articles on Scopus

    Umberto Vitolo is chief of the Chemoimmunotherapy Lymphoma Section at the Department of Onco-hematology, S. Giovanni Battista Hospital, Torino Italy.

    Andrés J.M. Ferreri is coordinator of the Lymphoma Unit and vice director of the Medical Oncology Unit, San Raffaele Scientific Institute, Milan, Italy.

    Silvia Montoto, trained as a haematologist at the Haematology Department of Hospital Clinic in Barcelona, Spain, is currently a senior lecturer in medical oncology at the Medical Oncology Department, St. Bartholomew's Hospital, London.

    View full text