Table of contents :

  • Epidemiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Differential diagnosis
  • Therapy 
  • Prognosis
  • Web resources

  • Epidemiology : average onset : 59 years; the second most frequent lymphoma subtype (35% of all adult NHLs in Western populationsref); only diffuse large B cell lymphoma (DLBCL) is more commonref. Clinically most patients are elderly and present with advanced stage disease.
    Pathogenesis :

    => overexpression of a chimerical BCL2/IgH mRNAref from altered allele. Because the breakpoint is usually located outside the translated portion of the bcl-2 gene, the protein product is identical to the normal BCL-2 proteinref. The function of the BCL-2 protein is to block apoptosis, probably by means of its interaction with other bcl-2-family proteins such as baxref1, ref2, ref3, ref4. The gained expression of BCL-2 at the germinal center stage (where normal counterpart cells down-regulate its expression) inhibits apoptosis and leads to accumulation of B lymphocytes, which might later acquire additional mutations that eventually result in the development of FL
    The frequency of VH family use in FL was found to be similar to that reported for normal peripheral blood lymphocytes (PBLs) and is therefore also roughly proportional to VH family size. Anyway other investigators have observed nonrandom usage by FL of the JH3, JH4, and JH5 joining segmentsref.
    The weight of molecular evidence would favor that the t(14;18) occurs in an immature B cell within the bone marrow at a time when the nuclear enzyme terminal deoxynucleotidyl transferase (Tdt) is active and contact with antigen has not yet occurred. The neoplastic FL cell is left with the capacity to divide and differentiate, exit the bone marrow and seed peripheral lymph nodes primarily. The constitutive expression of Bcl-2 protein resulting from the t(14;18) gives these cells a growth advantage and maintains their extended survival. Now within the germinal center, a hostile microenvironment where the SHM apparatus is active, the FL cells divide and acquire additional molecular alterations resulting in clonal evolution. The degree to which this occurs prior to clinical presentation is extremely variable, as noted earlier. The typical result following repeated cell cycles is characteristically FL. However, in some cases the presentation may be of a de novo DLBCL harboring a t(14;18). The factors that dictate the diversity of cytogenetic alterations and presumed cytogenetic instability are largely unknown.

    The t(14;18) is a rare event occurring in naïve B cells and likely at a time when the RAG complex is active (primary VDJ recombination). These cells are relatively immortalized resulting from overexpression of the Bcl-2 protein and likely seed lymph nodes and reside within follicles. Without significant clonal evolution and independence, these FL cells may require a microenvironment complete with FDCs and reactive T cells. Repeated cycles of proliferation occur (despite the expression of Bcl-2), but at a low rate as is characteristic of FL. With cell divisions the clone expands and secondary cytogenetic alterations occur. If critical cytogenetic events occur early in the evolution of this process, the cells may lose the need for a germinal center (GC) microenvironment and patients may present as de novo DLBCL. Alternatively, patients present with FL characterized by a diverse spectrum of cytogenetic alterations, the majority of which are copy number alterations (chromosomal gains and losses). The presence of FDCs and T cells within the follicle recapitulates the normal secondary follicle, but their presence in FL may be as immune response cells or alternatively, reflect the clonal evolution of the malignant B cells. The development of FL recapitulates the formation of normal lymphoid follicles as evidenced by morphology and immunophenotype. Neoplastic follicles contain the same mix of germinal center B cells and accessory cells, the latter including T cells, macrophages, lymph node stromal elements and FDCs. The latter cell type is not thought to be part of the clone, yet appears to be important in follicular lymphomagenesis, as these cells form an integral component of FL in all sites, including extranodal localizations and bone marrow metastases. A recent publication that raises questions about the nature of the tumor vasculature in FL immediately begs the same question concerning the FDCs and other accessory cells in this tumorref. The typical changes that herald transformation to diffuse large B cell lymphoma (DLBCL) include a loss of the FDC meshwork, reduction in reactive T cells and an increase in centroblasts in proportion to centrocytes. The critical question is whether these non-neoplastic cells in FL are playing a role in immune surveillance, thus maintaining the lymphoma in check, or alternatively merely reflect the milieu required by the FL cells in order to survive. The molecular events that characterize FL appear to represent a combination of background genetic alterations evident at the time of diagnosis and ongoing stochastic events that contribute to clonal evolution. Some data suggest that FL progression may be due to the outgrowth of minor clones present at diagnosis that gain a growth advantage over timeref. The comprehensive cytogenetic database of FL biopsies similarly suggests that the clinical course may be programmed at the time of diagnosis. Moreover, recent microarray gene expression profiling experiments suggest that the molecular features of FL at diagnosis dictate the aggressiveness of the disease and the survival of the patients. Alternatively, the analyses of paired samples of patients with FL and subsequent DLBCL suggest a role for on-going stochastic events occurring over time in the clonal evolution of FL. More than likely, a combination of these hypotheses will prove to be correct. Inhibition of apoptosis resulting from the constitutive expression of Bcl-2 is critical to the pathogenesis of FL. Some data support the notion that for those cases without a t(14;18) and/or Bcl-2 expression, other molecules in the apoptotic signaling cascade may be involved (e.g., Bcl-XL, Bad)ref. Importantly, inhibition of cell death rather than accelerated growth is the hallmark of FL development. Activation-induced cytidine deaminase (AID) has recently been shown to be required for SHM and CSR and is expressed in a subset of FL. Its expression appears to correlate with the presence of ongoing mutation within the FL clone, a finding that would be of interest to correlate with survivalref. Initial gene expression studies in FL used purified malignant B cells and thus failed to appreciate the role of non-neoplastic cells in the biology of FLref. Nonetheless, these studies produced a long list of genes that correlate well with chromosomal gains and losses in FLref. More recent microarray studies using whole frozen tissues have provided important insights into the significance of non-neoplastic cells. In a study of 191 FL diagnostic biopsies, 2 gene expression signatures could be defined, both of which were not derived from the malignant B cellsref : These signatures did not appear to simply reflect absolute numbers of T cells and/or macrophages/FDCs, as other characteristic pan-T cell or macrophage/FDC genes were not associated with survival. Interestingly, some of these genes overlap with genes thought to be associated with resistance to rituximab treatment in FL. High-speed sorting of fresh FL biopsies confirmed the origin of the expressed genes and provided clear evidence that non-neoplastic cells in FL modulate the clinical course of the disease. These data, together with data from animal models of FL, suggest that T cells play an important role in follicular lymphomagenesis. Whether these immune response cells represent an active role for immune surveillance in FL remains unanswered, as does a clear explanation for the marked variation in immune cell signatures in FL. Genetic polymorphisms that govern immune responses in general may modulate the nature and extent of tumor-infiltrating host cells. Alternatively, the malignant cells in FL may dictate the character of the immune infiltrate reflecting nothing more than the degree of clonal evolution of the tumor cells. The length of survival among patients with FL correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis : the molecular features of FL at the time of diagnosis dictated, to a large degree, the aggressiveness of the disease and the duration of survival, suggesting that the random acquisition of oncogenic abnormalities after diagnosis does not have a major effect on survival. In some cases, the lymphoma regresses spontaneouslyref, an observation that has also been made in melanoma and renal-cell carcinoma (RCC) and that may indicate an effective antitumor immune response. The response of follicular lymphomas to idiotype vaccines also highlights the potential of the immune system to recognize and counteract this type of lymphomaref1, ref2, ref3. Although these findings suggest that the clinical course of FL can be modulated by immune responses, this study provides a molecular signature of the type of immune response that is associated with long-term survival. It is also possible that the lymph-node cells responsible for the immune-response 1 signature provide trophic signals that promote the survival or proliferation of the malignant cells. This signature could represent a variant GC reaction that includes T cells, follicular dendritic cells, and the malignant cells. The dependence of the malignant cells on these environmental signals may prevent them from leaving the lymph node, possibly accounting for the association between the immune-response 1 signature and prolonged survival. An understanding of the nature of these trophic signals provided by the microenvironment in follicular lymphoma could provide new targets for therapy. In a pilot study involving 26 patients with FL who were treated with rituximab, the expression of certain genes was associated with responsiveness to this treatmentref, but these genes do not overlap appreciably with our survival-predictor genes and do not predict overall survival in this series. Clearly, future investigations should evaluate these molecular predictors of survival in a prospective fashionref1, ref2, ref3. Benign lymphoma-associated macrophage (LAM) content is an independent predictor of survival in FLref. The dependency of follicular lymphoma cells on their microenvironment is supported by the fact that these cells are very difficult to grow in vitro in the absence of stromal cells and without stimulation of the CD40 receptor, which is a main signaling pathway for interactions between B cells and T cells.

    At some time during the first 10 years following a diagnosis of FL, approximately 30–50% of patients will undergo histological transformation, often heralded by a change in the clinical course of the disease. Repeat biopsies characteristically show a change in the histologic appearance from FL to DLBCL, although less frequent patterns of transformation may be encountered. Like the cytogenetic alterations that characterize FL cells at diagnosis, the molecular events that underlie histologic transformation of FL are also diverse. A number of alterations are associated with transformation to DLBCL, including p53 mutations, loss of p16, upregulated MYC expression resulting from translocation or other mechanisms, +7, gain of 12q13-14, del(6q) and possibly mutations of BCL2 and/or BCL6 genes. Recent microarray studies have also suggested a role for MYC and MYC target genes and possible involvement of p38MAP kinase deregulation in FL transformationref1, ref2. High-resolution array comparative genomic hybridization (CGH) strategies will be important in helping to identify the myriad of molecular changes that underlie FL progression, but may require purified FL cells in order to accurately detect single copy genetic alterations. Important insights into pathogenetic mechanisms should result from these studies, particularly if these data are combined with genome-wide expression profiling.
    Symptoms & signs : very rarely FL may secrete growth hormone (GH) and cause paraneoplastic acromegaly. A growing body of evidence suggests that GH is a paracrine growth factor within the immune systemref. GH has immunomodulatory properties, is required for development and function of the immune systemref1, ref2, ref3, and has a profound influence on both cellular and humoral immunityref. For example, the secretion of thymulin, a hormone produced by thymic epithelial cells, is up-regulated by growth hormoneref. In aging rats, the administration of GH increased the total number of thymocytesref1, ref2. Normal lymphocytes have receptors for GHref1, ref2, and both rodent and human mononuclear cells synthesize and secrete GH–like moleculesref1, ref2, ref3, ref4. GH mRNA has been detected in normal lymphoid tissues and in B-cell and T-cell lymphomasref. These findings support the concept of an autocrine or paracrine effect of GH produced by the lymphoma cells on tumor proliferation. In this context, so-called ectopic GH production by FL is not genuinely ectopic but, rather, a modification of normal cell functionref. The mechanisms by which GH gene expression was up-regulated in the patient's lymphoma are not known. Amplification of the GH gene locus or chromosomal translocation causing gene rearrangement or mutations in the GH promoter could have contributed to the hypersecretion of GH by the GL. The majority of malignant lymphomas express somatostatin receptors and can be visualized by pentetreotide scintigraphyref1, ref2. In that patient, the pentetreotide scan was negative, despite the extensive lymphoma. In addition, the patient's serum GH concentrations did not decrease after the administration of octreotide. The absence of the expression of somatostatin receptors may have contributed to GH excess because of the lack of inhibitory effects of endogenous somatostatinref.
    Laboratory examinations : Differential diagnosis : reactive follicular hyperplasia (RFH). The following significant differences are identified: dimmer CD19 on CD10+ B cells in FL, brighter CD10 and more numerous CD10+ B cells in FL, and brighter CD20 on neoplastic B cells than on other B cells in FL or in RH. In the FL cases, no correlations can be documented between any phenotypic findings. Grade 3 FL has significantly dimmer CD10 expression than lower grades. Visual analysis of CD10+ vs CD10- smaller B cells shows dimmer CD19 on the CD10+ cells in 44% of FL cases and 0% of RFH casesref
    Therapyref1, ref2 : once a simple choice between "watch and wait" and alkylator therapy, decision-making for patients with FL and their physicians has become a complex process in which the pros and cons of many new effective treatment options must be weighed. Within a relatively short period of time, numerous new agents have become available. The current challenge is to devise optimal strategies for individual patients and to select the most pressing questions to be addressed in clinical trials. How to treat FL (grades 1 and 2) (a clinical trial is always the preferred approach!) :

    *Symptoms, cytopenias, rapid growth, of disease, potential organ compromise (e.g., hydronephrosis). Consider collection of peripheral blood progenitor cells for future transplant
    Prognosisref: relatively indolent clinical course and median survivals = 8–10 yearsref. The range is very wide, however, with patients surviving for > 15 years and 10-15% of the patients who run a rapidly fatal course and die within 3 years after diagnosis. 10-year overall survival of 57%, RFS of 43%, and FFS of 30%ref1, ref2, ref3, ref4, ref5. Actuarial survival was 82% at 5 years and 73% at 10 years. The median time until therapy was required was 3 years. Spontaneous regressions occurred in 19 untreated patients (23%), including 30% of patients with nodular, poorly differentiated lymphocytic lymphoma. Histologic transformation to an intermediate-grade or high-grade lymphoma occurred both before and after primary therapy. The actuarial risk of transformation among the initially untreated patients was similar to that in a group of patients treated immediately after diagnosis. Neither the time to histologic transformation nor the incidence of transformation was influenced by when therapy was startedref. FCL transforms to a more aggressive Sometimes patients over 60 years of age and asymptomatic at diagnosis with stage I or II FL can defer treatment until signs of disease progression appear, and many patients do not require treatment for a number of years : in randomized trials, the long-term survival of these patients was similar to the survival of patients treated immediately at time of diagnosisref1, ref2, ref3. Although patients with FL have relatively long median survival times and exhibit dramatic responses to initial therapy, they should be considered affected by a fatal malignancy. Patients tend to relapse over time, their response to salvage therapy is of shorter duration after every relapse, and they eventually die of disease-related causes. Although it is difficult to identify high-risk and low-risk patients at diagnosis, it would be helpful to select those patients who are suitable for experimental therapy and those patients who should avoid undue therapy-related toxicity. In patients with FL, a variety of prognostic factors have been found includingref1, ref2 : More recently some predictive models have been applied to low-grade lymphomas with conflicting results : Series regarding the prognostic importance of Bcl-2 rearrangement in FL :
    reference no. of patients histology  technique to assess t(14;18) prognostic value of bcl-2 rearrangement
    CR rate  DFS  OS 
    Levine,ref 1988  30  FL cytogenetics  NS  NS  NS 
    Yunis,ref 1989  20  FL mixed/large cell  SB  MBR(+) > others NA  MBR(+) > others
    Pezzella,ref 1992  70  FL  SB/PCR  NA  NA NS 
    Tilly,ref 1994  66  FL  cytogenetics NA  NA  NS 
    Johnson,ref 1995  102  FL (52 high-grade)  PCR  NA  NA MBR(+) > others (low-grade)
    Louie DC, Hochauser D, Schluger A, Jaslow R, Roy P, Oliver J, Offit K, Chaganti RSK: BCL6 and BCL2 rearrangement and p53 overexpression as prognostic factors in follicular lymphoma. Ann Oncol 7:16 (051), 1996 (suppl 3) 79  FL  SB/cytogenetics NA NA  NS 
    Lopez-Guillermo,ref 1998  247 indolent FL  PCR mcr(+)/MBR(+) > others mcr(+)/MBR(+) > others  NS
    It is difficult to explain the differences in outcome of the patients according to the bcl-2 rearrangement. In fact, the expression of BCL-2 and BAX proteins, assessed by a semiquantitative immunostaining technique in a significant number of patients, did not show significant differences according to the bcl-2 rearrangement, although the proportion of germline cases with positive or strongly positive bcl-2 expression was higher than that of MBR and mcr casesref
    Several secondary genetic abnormalities have been associated with this histological transformation of FCL, including : High expression of cyclin B1 predicts a favorable outcomeref. The International Prognostic Index (IPI) at transformation correlates with OS : Co-diagnoses : multiple myeloma (Pulini S et al, SIES 2008; P160)

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