Follicular B-cell lymphoma

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Follicular (Center Cell) Lymphoma

Last update: 01/03/2018

About Lymphoma

B-lymphocyte

Lymphoma is a cancer

About Lymphoma - general

Characteristics
Cell type | Histology   Grading | Staging

Ann Arbor Staging
Extranodal notations

Diagnosis

Host/tumor interaction and the microenvironment

Lymphatic System

Overview of genes
and cancer

Risk Factors

Statistics

Staging

Symptoms

Transformation

Guidelines at diagnosis

Treatment Decisions

When to treat?

Treatments

Watch & Wait

Lymphomas versus "solid" cancers

It's common to be diagnosed with lymphoma at an advanced stage (III or IV) and with bone marrow involvement. While this might seem alarming, you should know that advanced stages of lymphoma can be treated successfully, and that lymphoma in the bone marrow is as reversible as lymphoma anywhere in the body.

One way to understand this is to compare lymphoma with a so-called solid tumor, such as a prostate cancer. Here the cell of origin does not normally exist anywhere but in the prostate. So when you find malignant prostate cells in the lymph nodes, or in the bone marrow, you have a big problem. Compare with blood cells that we expect to move anywhere in the lymphatic or circulatory system, including the nursery for these cells, the bone marrow.

Another favorable aspect of blood cancers is that they are generally much more sensitive to treatment than "solid" tumors, probably because blood cells are more poised to self- destruct, and they can also regenerate more readily from stem cells in the marrow. Consider that the main side effect of chemotherapies is a drop in blood counts, but not the destruction of normal prostate or breast cells ...

We're not suggesting that lymphoma is not a life-threatening disease. It is. But we know that many types of lymphomas can be managed well, other types can be cured, and the potential to make additional progress against this family of diseases is real.

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Lymphoma is a blood cell cancer affecting lymphocytes - immune cells that normally protect our health by fighting infection. Sometimes these specialized blood cells develop defects (mutations) that cause them to divide or persist longer than they should - forming tumors. The malignant lymphocytes may be t-cells (uncommonly) or b-cells. One important role of normal b-cell lymphocytes is to make antibodies to fight infection.

See for details: Lymphoma Simplified and Encouragement

Follicular lymphoma (FL) arises from defective b-cell lymphocytes. B-cells arise from the bone marrow and mature (differentiate) into many cell types that tend to migrate to different areas of the body in order to defend against pathogens (viruses, bacteria, etc.).

Natural history

Follicular lymphoma (FL) is the most common type of indolent lymphoma. How the FL will behave over time and responds to treatment varies considerably from patient to patient.

The average time to initial therapy is about 3 years for patients with advanced stage FL, which is the most common stage at diagnosis. Bone marrow involvement is also common, and is potentially reversible with treatment. The literature notes that some few patient never require therapy (the lymphoma never progresses significantly or causes symptoms) and it sometimes regresses spontaneously; while others may require therapy when first diagnosed.

FL is an indolent lymphoma but some of the indolent cells can transform - behaving and resembling Diffuse Large B-cell lymphoma. Patients diagnosed with localized FL (stage I/II) are often treated with radiotherapy with intent to cure. When to start therapy and choosing the type of initial therapy is a source of anxiety and stress for patients as is the potential of this indolent lymphoma to transform.

See also for general guidelines on the need to treat: GELF | NCCN

Initial response to standard Rituxan-based chemotherapy is very good for most patients. Complete and durable remissions are often achieved with initial therapy - the long remissions suggesting that perhaps a significant fraction of patients with advanced FL may be cured (although this notion is controversial and is not possible to validate without very long follow up).

The PRIMA study evaluating maintenance Rituxan compared to observation after Rituxan-based chemo has not yet shown an advantage in survival at 6 years (both study arms with very good survival) despite a strong advantage for Progression Free Survival (See graph).

Overall, survival is long for FL and is improving -- as are the opportunities to improve care based on insights into the pathways of the disease and how they can be targeted by therapy (see Agents that Target Disease Pathways) such as ibrutinib, Idelalisib, and ABT199.

An important challenge is the slow enrollment in clinical trials due to the number of promising investigational approaches competing for patients to participate in the studies - but also the very good results achieved with regular care. A second major challenge is the need for biomarkers that can reliably predict patients with lower- or higher- risk disease who are appropriate candidates for novel approaches to treatment; and biomarkers that predict response to specific treatment agents.

The observation period (watch and wait) seems an excellent research opportunity to identify potential biomarkers and evaluate targeted therapies or immunotherapies with lower expected toxicity - such as the RESORT study that evaluated Rituxan as a single agent in FL with low tumor burden.

* Natural history of follicular lymphoma -
related articles: http://1.usa.gov/1hcgbRB

"Follicular" describes the type of lymphocyte that has become malignant. Normal follicular b-cells reside in the germinal center of lymph nodes, however, being blood cells they can migrate anywhere in the body and therefore can also present in the bone marrow, spleen, blood, skin -- virtually anywhere in the body. For this reason, lymphoma is called a systemic (body-wide) condition.

As noted, FL has a variable clinical course, meaning the lymphoma you have might not behave like it does in another. It often behaves indolently (the cells can accumulate very slowly) but it can progresses steadily. How it is managed over time depends on its behavior and how it has responded to prior therapies. It is generally treatment-sensitive, however response and duration of response tend to decrease over time.

Age and patient preference can be part of the decision of when to treat and the desired approach - management versus intent to achieve a durable complete remission. The approach can range from single agent antibody therapy (Rituxan) to combination chemotherapy with antibody. Radioimmunotherapy is another important option.

We recommend at least one consult with an expert for a second opinion - and a second opinion with an expert prior to treatment .. if it is feasible for you, to discuss and consider also clinical trials. We also recommend a second evaluation of the biopsy sample to make sure the diagnosis is correct.

(The above is a layperson's perspective) ~ KarlS

See Getting a Second Pathology Evaluation

More technical information: Clinical Features, Prognosis and Treatment of
Follicular Lymphoma, Gilles A. Salles

http://asheducationbook.hematologylibrary.org/content/2007/1/216.full.pdf

Please read also Guidelines at Diagnosis

In the News / New Resources:

Indolent Treatment Survey results:

Follicular | Marginal Zone

M7FLIPI: A Follicular Lymphoma Prognostic Model for the 21st Century
Ann S. LaCasce, MD, MSc hematology.org

Survival outcomes for various treatment modalities in advanced-stage grade 3 follicular lymphoma (FL3): A National Cancer Database (NCDB) study. | 2017 ASCO Annual Meeting Abstracts http://bit.ly/2qKJGHU

Role of consolidation with Zevalin radioimmunotherapy in patients with advanced-stage follicular lymphoma http://1.usa.gov/1UQFGQB

Aug 2015
Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance) http://bit.ly/1hfqhXU

Aug 2015:
Blood Journal | Cell-of-origin of transformed follicular lymphoma http://bit.ly/1fGoVnS

Polatuzumab Vedotin (PoV) is an antibody that binds to cd79b that delivers a drug payload.

* ASCO 2015: Durable responses: polatuzumab vedotin (CD79b antibody-drug conjugate) in relapsed/refractory follicular lymphoma http://bit.ly/1K6TuPM

* PAL query for Polatuzumab Vedotin (PoV)
For trials see: http://1.usa.gov/1sd80LK

Drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells http://1.usa.gov/1zAB8RG

snip: In summary, we identified a novel CSC (cancer stem cell) population in FL and its signalling mechanism of interaction with the niche cells. Current treatments for FL are not curative for the majority of patients and were designed and deemed successful based on the response of the bulk population of tumour cells (Reya, et al 2001). Effects on a rare CSC population or on cells in the supportive microenvironment are unknown but presumed to be inadequate given the rates of relapse in FL. Understanding the essential signals for tumour chemoresistance and survival produced by FDC in FL may help develop novel therapeutic strategies (Burger, et al 2009). FL-SC biomarkers may also serve as prognostic markers to classify patients at higher risk of transformation or suggest alternative treatments.

The overall limitation of the current study is the considerable reliance on cell line-based studies with confirmation of the results using patient specimens. Given the limited availability of clinical specimens and the rare CSC population, it is a reasonable strategy to use a cell line model for exploratory experiments but requiring confirmation in clinical specimens. In future studies of FL, a much larger effort would be required to perform lymph node biopsies rather than fine needle aspirations in FL patients in order to collect a larger number of cancer cells to perform FL-SC studies. We believe that our studies, which identify and characterize the FL-SC and its interactions with the tumour microenvironment, are an important step in the development of biologically-based, curative treatments for FL.

Technical / Feb 2014
Integrated genomic analysis identifies recurrent mutations and evolution patterns driving follicular lymphoma http://1.usa.gov/1sleWJ8

We identified recurrent mutations in linker histones, JAK-STAT signaling, NF-κB signaling and B-cell development genes. Longitudinal analyses revealed chromatin regulators (CREBBP, EZH2 and MLL2) as early driver genes, whilst mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation.

In summary, we report the most comprehensive sequencing effort in FL to date. The mutational landscape of FL is predominantly epigenetically �addicted� but highlights co-occurring aberrations of genes involved in B-cell development, JAK-STAT and NF-κB signaling. By longitudinal profiling, we provide unequivocal evidence for a reservoir ancestral population, enriched in early driver genes, that propagates successive disease events.

We did not identify a single compelling genetic event responsible for transformation but instead demonstrate that acquisition of distinct genetic alterations may prompt the onset of aggressive disease.

* The frequency of relapses suggests that the CPC (common progenitor clone) is resistant to our standard therapies and that adopting a stratified treatment approach targeting specific early genetic lesions identified within the putative CPC may ultimately offer the best chance of eradicating these cells and cure of FL.

Technical:
Nature and importance of follicular lymphoma precursors http://1.usa.gov/1qIAoD8

Cheson, Hiddemann - Leukemia 2014:
How we manage follicular lymphoma http://bit.ly/TSQD5P

... the hope is justified that the long-term perspectives of patients suffering from the disease will be further improved in the near future.

Sonali Smith, 2013:
Dissecting follicular lymphoma: high versus low risk http://bit.ly/1koraMi

ASCO 2014
Alliance: A phase II trial of lenalidomide plus rituximab in previously untreated follicular lymphoma. http://bit.ly/1tPiMbg

ASCO 2014:
Value of PET-CT after frontline therapy in follicular lymphoma: A pooled analysis http://bit.ly/SQmPa4

ASH 2012 Paper: The Bruton�s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma http://bit.ly/VkVB9p

Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Studyhttp://1.usa.gov/1hcnEA1

Clinical Oncology 2013:
Bruce Cheson, MD: How I Treat Follicular Lymphoma�Part II http://bit.ly/1dpk5Xz

Front Oncology 2012: Backgrounder
Therapy of newly diagnosed follicular lymphoma http://1.usa.gov/1dZEIJi

IMPORTANT * Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party

In the absence of randomized controlled trials (RCT) addressing these questions, systematic reviews inevitably fail to provide conclusions helpful for clinical decision making, whereas traditional narrative reviews are prone to be biased by the individual view and expertise of the authors.

Therefore, the European Group for Blood and Marrow Transplantation (EBMT) launched a project to define indications for HDT-ASCR and for allogeneic transplantation in patients with FL in the rituximab era in Europe following a RAND-modified Delphi consensus method.

Leuk Lymph: Higher grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy. http://1.usa.gov/10BLkIk

JCO, 2013 - Dr. Oliver. Press: Selection of First-Line Therapy for Advanced Follicular Lymphoma http://bit.ly/17ZENKq

Medscape: Choice of First-Line Therapy in Follicular Lymphoma Debated http://bit.ly/12KGg52

Follicular Lymphoma ASH 2012 Abstracts

2012, Shuangge , Associate Professor of Biostatistics, Yale University: Risk factors for the etiology and prognosis of follicular lymphoma

ASCO 2012 - compiled links to follicular lymphoma abstracts

FL -Bendamustine clear winner over R-CHOP in randomized study

OncLive: Dr. Rummel on Treanda Plus Rituxan in Indolent Lymphoma

OncLive: Bendamustine Superiority in Lymphoma Regimen Confirmed

Blood: "mini" allogeneic transplantation with or without Zevalin is potentially curative for relapsed follicular lymphoma: 12-year results.

Natural History - treated and untreated

TOPIC SEARCH: Scholar | PubMed

The "natural history" of a lymphoma refers to the expected clinical course of the disease if it is untreated. Along with the availability of effective treatments, the natural history provides the context that guides the most appropriate timing and approach to treatment. For example, a type of lymphoma with a very short natural history would require prompt and effective therapy - with curative intent; while a less aggressive type might be observed and treated (managed) as needed with less aggressive therapy.

"The course of follicular lymphoma is quite variable. Some patients with widespread disease have no symptoms or signs of progression for years and do not require immediate therapy, while others cases demonstrate rapid tumor growth and need early treatment." Source towercancerfoundation.org/

"[Advanced] Follicular lymphoma (FL) is considered incurable [or challenging to cure] with currently available therapies, and no chemotherapy agent or combination regimen prior to the introduction of rituximab had been shown to prolong overall survival.

... As a result, the selection, timing, and sequencing of available therapies have been a matter of continuing debate. " (Olin, et al nih.gov )

So when to treat follicular lymphoma, and with what therapy, is individualized based on the clinical behavior of the lymphoma (including sensitivity to initial therapy) - such as if it is causing symptoms and if it is growing steadily, remaining stable, or even regressing spontaneously - but it is also based on patient characteristics - such as one's age and fitness or if there are any secondary medical conditions.

At this time, in large part because of the variable natural history of follicular lymphoma - there is no gold standard treatment that applies to all patients. However, this is not meant to suggest that all approaches to treatment are equally appropriate for each clinical circumstance. For example, if the behavior of a follicular lymphoma becomes aggressive it will often be best to treat it accordingly.

See Summary of factors that can influence the timing and
choice of therapy

Which illustrates the complexity of treatment decisions and how the factors that guide therapy can interact; how each case and lymphoma can be unique, thus treatments need to be tailored accordingly - the reason professional guidance is required.

Incidence

Follicular non-Hodgkin's Lymphoma (NHL) is a very common type lymphoma, approximately 30% of all cases. There are about 61,000 new cases of NHL diagnosed annually. Therefore, there are approximately 18,300 new cases of follicular NHL diagnosed annually. Follicular lymphomas account for 70% of indolent (slow growing) lymphomas.

Diagnosis of follicular lymphoma in children is very rare (emedicine.medscape.com). The mean age at diagnosis is about 60 to 65 years.

Diagnosis

To diagnose a lymphoma, a biopsy must be performed by the surgical removal (resection) of a lymph node. A fine needle aspiration may be performed if a lymph node is not accessible, but this is not considered a definitive way to determine the diagnosis.

A series of tests will then be performed on the sample to determine the characteristics of the cells. If a malignancy is determined, these discovered characteristics will allow your doctors to recommend appropriate treatments to use when needed.

Resources:

	Indolent Lymphomas: Classic Subtypes and Newer Entities moffitt.org
	Identification of B-cell lymphoma ibms.org pdf
	Differential diagnosis (technical), Stanford

Workup (adapted from NCCN Guidelines 2010)

Staging tests:

CT of Chest/abdominal/pelvic with contrast of diagnostic quality

Useful in select cases:

	PET-CT scan
	CT of neck

Bone marrow biopsy + aspirate to document clinical stage I_II disease

Physical exam:

	Examine node-bearing areas, including Waldeyer's ring
	Examine size of liver and spleen
	Performance status
	B symptoms (patient reported)

Labs and tests:

CBC, differential, platelets,

LDH

Comprehensive metabolic panel

Hepatitis B testing

Useful in select cases:

	Hepatitis C test
	Uric acid
	SPEP and/or immunoglobulin levels
	Beta-2-microglobulin

Treatment, age and gender specific:

	MUGA scan / echocardiogram" (prior to anthracycline-based therapy)
	Discuss fertility issues
	Pregnancy testing in women of child-bearing age if chemo is planned

Staging

Staging refers to the how widespread the disease is. Imaging tests (CT MRI, PET) and bone marrow biopsies are commonly done to estimate this. See Staging for more detail.

Value of PET imaging in Follicular Lymphoma: Discussion http://www.medscape.com/viewarticle/583796_4

Common symptoms

	fatigue (anemia)
	loss of appetite
	feeling of fullness or discomfort due to enlarged liver or spleen
	enlarged lymph nodes - painless swelling in the neck, armpit or groin - often in more than one group

Other symptoms may include night sweats, unexplained high temperatures and weight loss. These are known as B symptoms.

Prognostic indicators

The variable natural history

	Indolent grade "Follicular lymphomas are characterized by relatively long median survivals and a continuous pattern of relapse. The heterogeneity (variable clinical courses) in these diseases is increasingly appreciated, leading to concerted efforts to define prognostic factors and risk-adapted strategies."
	Grade 3

Prognostic Indicators

FLIPI Follicular Lymphoma International Prognostic Index

NEW 2012, Shuangge , Associate Professor of Biostatistics, Yale University: Risk factors for the etiology and prognosis of follicular lymphoma

Resources

	Clinical Oncology News 2013: Bruce D. Cheson, MD: How I Manage Follicular Lymphoma: Part I http://bit.ly/1iNRISj
	NCCN Guidelines for Follicular Lymphoma - Patient friendlier
	Clinical Features, Prognosis and Treatment of Follicular Lymphoma Gilles Andre Salles, MD, PhD, Centre Hospitalier Lyon-Sud, 165, Ch du Grand Revoyet, asheducationbook.hematologylibrary.org 2007 The therapeutic strategies in follicular lymphoma have been transformed by monoclonal antibodies, used alone or in combination with chemotherapy. Treatment options should be adapted to the clinical features at diagnosis and appear to be able to modify the overall survival of some subgroups of patients. Further efforts may focus on strategies that can alter the natural history of this disease.

Reports Archive

	PET imaging response after rituximab-containing induction therapy in follicular lymphoma predictor of OS http://bit.ly/2c9vrYa
	Cancer: Racial differences in presentation and management of follicular non-Hodgkin lymphoma in the US Interesting findings: "The National LymphoCare Study is a multicenter, longitudinal, observational cohort study collecting data on treatment patterns and outcomes for patients with newly diagnosed FL in the United States between 2004 and 2007 without any predefined, study-specific intervention."
	Rev. Bras. Hematol. Hemoter. S�o Paulo 2012: Follicular lymphoma - treatment and prognostic factors
	Early stage - Strahlentherapie Und Onkologie: Radiotherapy in stage I-III follicular non-Hodgkin lymphoma: Retrospective analysis of a series of 50 patients RT is a curative option in the treatment of limited stage FL. If RT of microscopically uninvolved area is necessary, a reduction in the radiation dose should be carefully weighed against the risk of in-field recurrences.
	Video - Dr. Kahl interview: Results of the RESORT Trial for Follicular Lymphoma: Questions for Patients and Their Physicians Interview by Patient Power - in association with Patients Against Lymphoma NOTE: Excellent description of the study by Dr. Kahl ... However, we anticipate that his closing comment on evidence of a lack of resistance to Rituxan will be controversial.
	FL - Weill Cornell: ASH: What is the role of rituximab maintenance in patients with low tumor burden follicular lymphoma?
	Indolent - Monthly Prescribing Reference: Bendamustine Plus Rituximab Provides Superior Progression-Free Survival Benefit to Patients With Relapsed Follicular, Indolent, or Mantle Cell Lymphomas vs. Fludarabine Plus Rituximab
	Indolent - Oncology Times: Bendamustine + rituximab offers new standard first-line treatment option for lymphoma
	Follicular - ASH 2011: CHOP + Rituxan versus CHOP - Bexxar
	Management of Follicular Lymphoma in the Up-Front and Relapsed Settings http://bit.ly/mjsYzy snip: �This paper reviews recent practice patterns in the broad context of the published findings from major phase III randomized trials; it documents potential gaps between trial results and actual practice, and the implications of these for continuing education of oncologists."
	Novel Agents for Follicular Lymphoma Lymphoma: Translating Basic Science into Therapy Leonard, Martin http://bit.ly/hY59Bl
	Treatment Approaches for Follicular Lymphoma Continue to Evolve -- An Interview with Dr. Andre Goy http://bit.ly/fbfIfm Free login registration required
	Aiming at a Curative Strategy for Follicular Lymphoma caonline.amcancersoc.org Maurizio Bendandi,MD, PhD One clear fact is that no patients will ever be cured by adopting a palliative treatment approach. The assumption that patients with follicular lymphoma are incurable is certain to be a self-fulfilling prophecy. Here the author summarizes the large and growing body of knowledge that suggests an expectant approach to management is not appropriate for all patients. (CA Cancer J Clin 2008;58:305�317.) � American Cancer Society, Inc., 2008. http://caonline.amcancersoc.org:80/cgi/reprint/58/5/305?eaf
	Evolving Paradigms in Follicular Lymphoma: Re-Evaluating Prognostic Factors and Challenging Treatment Dogmas molecularonc.com Cara A. Rosenbaum, MD Current clinical indices and molecular markers in follicular lymphoma must be re-evaluated and incorporated actively into prospective trials to allow development of risk-adapted treatment guidelines and novel targeted therapies. The results of such studies will help to further recommendations regarding the effective timing of therapeutic intervention (ie, watchful waiting versus active treatment) and the efficacy of various chemotherapeutic regimens in different patient populations.
	Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology � v.1.2006 nccn.org pdf
	Low grade Lymphoma asheducationbook.org /2004 full text
	Follicular NHL, overview asheducation \| emedicine
	Follicular NHL, technical Umdnj.edu \| Cancer Genetics Web \| infobiogenl

Subtypes of Follicular Lymphoma

Subtypes of Follicular non-Hodgkin's lymphomas

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Categorized by cell size:

"The cells of follicle center lymphomas are derived from the germinal center cells of the normal lymph node. This category in the Working Formulation encompasses three different tumor types:

Follicular Mixed-Cell / Small-cell / cleaved

Most common cell-size subtype of follicular lymphoma. An indolent (slow growing) lymphoma.

	PubMed abstracts for: Review \| Therapy \| Diagnosis
	PubMed abstracts for: Review \| Therapy \| Diagnosis
	follicular predominantly small-cleaved (generally slower growing)
	follicular mixed small-cleaved and large-cell, and
	follicular predominantly large-cell (generally faster growing).

In the Kiel classification, these tumors are included within the centroblastic/centrocytic and follicular centroblastic classifications."
source: cancernetwork

Extranodal Follicular Lymphoma - a Retrospective Review and Comparison with Localized Nodal Follicular Lymphoma. Session Type: Poster Session 529-I - ASH 2004 | Terms of Use

It's common to find a mix of cell-sizes in the diagnosis of follicular lymphoma.

Follicular Lymphoma of the Thyroid Gland

About - full text ncbi.nlm.nih.gov

Predictive signatures came from immune cells:

" Two signatures [in follicular lymphomas] -- one which indicated poor prognosis, the other good--had strong synergy and together predicted survival better than any other model tested.

Unexpectedly, both came from nonmalignant immune cells infiltrating the tumors. The good prognosis signature genes reflect a mixture of immune cells that is dominated by T cells. T cells react to specific threats to the body's health. In contrast, the poor prognosis signature genes reflect a different group of immune cells dominated by macrophages and/or dendritic cells--which react to nonspecific threats--rather than T cells. http://www.cancer.gov/

Also see Host/tumor interaction and the microenvironment

See more on each subtype below.

Follicular Large-Cell (Grade 3)

Follicular Large-Cell
(Grade 3)

As tumor classification systems evolve, research using older systems may show different results than newer systems. As insights into genetic and molecular aspects of tumors are discovered it is hoped that treatment strategies more tailored to an individual's tumor will be identified. This will take research and will be facilitated by participation in research trials.

- Anjou NHL-info

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TOPIC SEARCH: Scholar | PubMed

Grade 3 (large cell) Follicular lymphomas make up only a minority of all Follicular lymphomas. Follicular Large cell lymphomas may have a more aggressive clinical behavior, and therefore treatments may be initiated early with intend to cure or induce durable remissions.

Grade 3 confusion?

NCCN GUIDELINES for grade 3: "Follicular lymphoma, grade 3 is an area of controversy. The distinction between follicular grade 3a and 3b has not been shown to have clinical significance to date.

Follicular lymphoma grade 3 is commonly treated according to NCCN guidelines for DLBCL (BCEL-1). Any area of diffuse large B-cell lymphoma (DLBCL) in a follicular lymphoma of any grade should be diagnosed and treated as a DLBCL." - April 2011

Resources and Reports:

	2017: Survival outcomes for various treatment modalities in advanced-stage grade 3 follicular lymphoma (FL3): A National Cancer Database (NCDB) study. \| 2017 ASCO Annual Meeting Abstracts http://bit.ly/2qKJGHU Multiple agent (MA) chemotherapy in pts with advanced-stage FL3 was associated with improved survival compared to single agent (SA) therapy, and radiation does not appear to influence outcomes. Outcomes were superior to what has been previously reported.
	Compiled abstracts: Follicular grade 3 lymphoma
	A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival bloodjournal.hematologylibrary.org The authors conclude that the 3a-3b distinction does not correlate with response to treatment or with clinical outcome. But the presence and extent of a diffuse large-cell component does correlate with behavior of the disease. The latter finding appears to justify the WHO-sanctioned practice of rendering a separate diagnosis of diffuse large B-cell lymphoma in such cases.
	Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas, May 2008 http://www.haematologica.org/cgi/content/full/93/7/1033
	Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology � v.1.2006 nccn.org professionals pdf
	Low-Grade Lymphoma, Hematology 2004 asheducationbooks Jane N. Winter, Randy D. Gascoyne and Koen Van Besien
	Cytologic subtypes of grade 3 follicular lymphoma bloodjournal.hematologylibrary.org The authors conclude that the 3a-3b distinction does not correlate with response to treatment or with clinical outcome. But the presence and extent of a diffuse large-cell component does correlate with behavior of the disease. The latter finding appears to justify the WHO-sanctioned practice of rendering a separate diagnosis of diffuse large B-cell lymphoma in such cases. bloodjournal.hematologylibrary.org
	Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Ann Oncol. 2006 Jun;17(6):920-7. Epub 2006 Mar 8. PMID: 16524969 Full text
	Follicular Lymphoma grade 3B. A separate entity? dissertations.ub.rug.nl Bosga-Bouwer, Annigje Geesje (Technical) - Chapters in English
	Natural history of follicular grade 3 non-Hodgkin's lymphoma. Bierman PJ. Curr Opin Oncol. 2007 Sep;19(5):433-7. Review

Reports

	A Clinicopathologic Evaluation of Follicular Lymphoma Grade 3A Versus Grade 3B Reveals No Survival Differences http://findarticles.com In summary, we present a series of pure FL grade 3. Subtyping into FL grades 3A and 3B subtypes, as proposed by the WHO classification, did not appear to be useful as a prognostic factor for overall survival. Previous lower grade FL or treatment with anthracycline-containing regimens did not appear to confound the analysis. Despite our findings, it may be that important biologic differences between these subtypes exist. Since morphologic clues often provide leads for further investigation, it is premature to argue against the continued practice of subtyping. Further characterization of such cases at the genetic and protein-expression levels may yield clinically important factors that do predict outcome.
	A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood. 2003 Mar 15;101(6):2363-7. Epub 2002 Nov 07. PMID: 12424193 full text \| related abstracts
	PubMed abstracts for Large cell follicular: Review \| Therapy \| Diagnosis
	Follicular Large Cell Lymphoma: An Aggressive Lymphoma That Often Presents With Favorable Prognostic Features bloodjournal.org
	Grade 3 and anthracycline-containing treatments [such as CHOP] Commentary from Experts PAL

Cutaneous - skin (extranodal)

Cutaneous - skin
(extranodal)

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Sometimes follicular lymphomas are first diagnosed in the skin (present there), or spread to the skin later on. When lymphomas that normally present in the lymphatic system moves to other areas it is called extranodal disease. Spreading to the skin is not necessarily considered a negative prognostic indicator.

Also see Extranodal lymphomas

	Follicular Center Cell Lymphomas of the Skin thedoctorsdoctor.com
	Cutaneous follicle center lymphoma: a clinicopathologic study of 19 cases. Mod Pathol. 2001 Sep;14(9):828-35. PMID: 11557777 PubMed
	Cutaneous presentation of follicular lymphomas. Mod Pathol. 2001 Sep;14(9):913-9. PMID: 11557789 PubMed

Treatments

Also see

Questions for your doctor - Patients Against Lymphoma
General, Treatment, Side Effects, and Tests

Factors that determine treatment timing and approach:

The characteristics of the lymphoma at diagnosis as determined by the pathology report, and it's actual clinical behavior, and other factors determine the type of treatment and the timing of treatment you and your doctor will consider.

The good news is that lymphomas are often sensitive and responsive to treatments. Aggressive lymphoma are often cured, and indolent (slow growing) lymphomas are often managed effectively. Importantly, recent advances in the understanding of lymphoma has led to effective new therapies and better therapies are certain to follow.

For indolent lymphomas, treatment is often deferred until the patient becomes symptomatic. For aggressive lymphomas treatment is typically initiated early with intent to cure.

See Factors that influence treatment selection and timing - PAL

Radiation therapy for FL

"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."

Source: emedicine.medscape.com

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"Advanced Follicular lymphoma (FL) is considered challenging to cure with standard therapies ... As a result, the selection, timing, and sequencing of available therapies have been a matter of continuing debate. " (Olin, et al nih.gov )

There is no apparent standard treatment for indolent follicular lymphomas.
Current practices include:

	Watchful waiting until symptoms, marked progression, or transformation occurs,
	Management with single agent chemotherapy and/or Rituxan when needed.
	Numerous Investigational therapies. See below.
	Aggressive early treatments with combination therapies for high-risk disease, such as when the lymphoma is resistant to initial treatments.
	Radioimmunotherapy, with Zevalin or Bexxar
	Stem cell transplants, ablative and mini (non-ablative).
	Radiotherapy, which may cure if treated when in stage I or II
	Clinical trials

TOPIC SEARCH: PubMed: Review | Therapies

General Guidelines for Indolent Lymphomas:

	NEW NCCN Guidelines for Follicular Lymphoma - Patient friendlier
	Adult Non-Hodgkin�s Lymphoma ~ Best Practice Cancer.gov
	Radiation for stage I or stage II with curative intent, and management (See Sidebar)
	Considerations at Relapse PAL
	Treatment decisions - factors that determine PAL
	Watchful waiting PAL
	Elderly ~ treatments for PAL
	Refractory (resistant to treatment) resource page PAL

Transplant for FL?

Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma
Julie M. Vose, MD; Edward A. Faber, Jr., DO, MS

	FL - Oncologist, 2009: Role of Hematopoietic Stem Cell Transplant in the Management of Follicular Lymphoma "This review aims to clarify recently published data on the application of HSCT in advanced FL."
	FL - Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma Julie M. Vose, MD; Edward A. Faber, Jr., DO, MS Full text (Medscape.org requires free registration and login)

	Role of Stem Cell transplant in Follicular lymphoma, Foster, Gabriel, Shea, 2010 ncbi.nlm.nih.gov
	Transformed disease PAL

Related News and Resources

	R-CHOP v. R-CVP in the treatment of follicular lymphoma: a meta-analysis
	Novel Agents for Follicular Lymphoma, Dec 2010 John P. Leonard1 and Peter Martin
	Follicular Lymphoma: Emerging Therapeutic Strategies: Therapy for Untreated FL http://bit.ly/a18BZW Nice overview by Vaishalee P Kenkre1 and Brad S Kahl�1
	R-CHOP versus R-CVP in the treatment of follicular lymphoma: a meta-analysis and critical appraisal of current literature pubmedcentral.nih.gov
	Aiming at a Curative Strategy for Follicular Lymphoma caonline.amcancersoc.org Maurizio Bendandi,MD, PhD One clear fact is that no patients will ever be cured by adopting a palliative treatment approach. The assumption that patients with follicular lymphoma are incurable is certain to be a self-fulfilling prophecy. Here the author summarizes the large and growing body of knowledge that suggests an expectant approach to management is not appropriate for all patients. (CA Cancer J Clin 2008;58:305�317.) � American Cancer Society, Inc., 2008. http://caonline.amcancersoc.org:80/cgi/reprint/58/5/305?eaf
	Cure for fNHL? Radiolabeled and Native Antibodies and the Prospect of Cure of Follicular Lymphoma theoncologist.alphamedpress.org "In this review, we hypothesize that the combination of an optimized biological treatment together with radiolabeled antibodies and chemotherapy early in the disease course of advanced-stage follicular lymphoma may represent the best approach to achieve prolonged disease-free survival and eventually cure."
	Cure word used: Mini-BMT: follicular Non-Hodgkin's Lymphoma Cure? www.webmd.com 83% in Complete Remission 5 to 9 Years After Mini-BMT for Follicular Lymphoma
	Stage I and II Follicular Non-Hodgkin�s Lymphoma: Long-Term Follow-Up of No Initial Therapy ~ Ranjana Advani, Saul A. Rosenberg, Sandra J. Horning 2004 - full text article jco.org
	Treatment of Non-Hodgkin's Lymphoma: Next Steps - Medscape.com 2004 (free login req.) Review of progress for Follicular, SLL, Diffuse Large Cell, and Mantle Cell.
	Follicular Lymphoma, Treatment Policy - Dr. Louise Bordeleau PDF \| PDF-Help
	Treatment overview PAL

ClinicalTrials.gov searches by treatment status:

	Untreated
	Relapsed
	Excluding transplant
	And by Type of Agent

Research News

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	Technical: Atlas of Genetics and Cytogenetics in Oncology and Haematology - Follicular lymphoma http://bit.ly/8LTric
	Molecular pathways in follicular lymphoma nature.com pdf RJ Bende, LA Smit and CJM van Noesel, Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
	Survival Improving for Patients with Stage IV Follicular Lymphoma cancerconsultants.com Researchers from the M.D. Anderson Cancer Center have reported that overall survival and failure-free survival of patients with stage IV follicular non-Hodgkin�s lymphoma (NHL) has significantly improved between 1972 and 2002. The details of this study appeared in the April 1, 2006, issue of the Journal of Clinical Oncology.
	Bcl-2 negative: Follicular center cell lymphoma with the t(14;18) translocation in which the rearranged BCL-2 gene is silent. Leukemia. 1993 Nov;7(11):1834-9. PMID: 7694006 PubMed \| Related Abstracts
	Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte. J Clin Oncol. 1999 Aug;17(8):2499-505. PMID: 10561315 PubMed
	Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. J Clin Oncol. 2002 Dec 1;20(23):4523-30. PMID: 12454108 PubMed
	Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities Eric Jonasch, Frank G. Haluska Massachusetts General Hospital, Boston, Massachusetts, USA alphamedpress.org
	Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: results of a large controlled clinical trial. Eur J Haematol. 2002 Mar;68(3):144-9. PMID: 12068794 PubMed
	High-Dose Therapy for Follicular Lymphoma Oncology Arnold Freedman, MD, Jonathan W. Friedberg, MD , and John Gribben, MD, PhD Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts
	Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003 Jan 1;21(1):5-15. PMID: 12506163 PubMed
	New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma. J Clin Oncol. 2005 Oct 17; PMID: 16230674 \| Related articles

Disclaimer: The information on Lymphomation.org is not intended to be a substitute for
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For all medical concerns, you should always consult your doctor.
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Guidelines at Diagnosis | About Clinical Trials Search Site

About Lymphoma

Lymphomas versus "solid" cancers

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Follicular lymphoma (FL) arises from defective b-cell lymphocytes. B-cells arise from the bone marrow and mature (differentiate) into many cell types that tend to migrate to different areas of the body in order to defend against pathogens (viruses, bacteria, etc.).

Natural history

In the News / New Resources:

M7FLIPI: A Follicular Lymphoma Prognostic Model for the 21st Century Ann S. LaCasce, MD, MSc hematology.org

Survival outcomes for various treatment modalities in advanced-stage grade 3 follicular lymphoma (FL3): A National Cancer Database (NCDB) study. | 2017 ASCO Annual Meeting Abstracts http://bit.ly/2qKJGHU

Role of consolidation with Zevalin radioimmunotherapy in patients with advanced-stage follicular lymphoma http://1.usa.gov/1UQFGQB

Aug 2015 Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance) http://bit.ly/1hfqhXU

Aug 2015: Blood Journal | Cell-of-origin of transformed follicular lymphoma http://bit.ly/1fGoVnS

Technical: Nature and importance of follicular lymphoma precursors http://1.usa.gov/1qIAoD8

Cheson, Hiddemann - Leukemia 2014: How we manage follicular lymphoma http://bit.ly/TSQD5P ... the hope is justified that the long-term perspectives of patients suffering from the disease will be further improved in the near future.

Sonali Smith, 2013: Dissecting follicular lymphoma: high versus low risk http://bit.ly/1koraMi

ASCO 2014 Alliance: A phase II trial of lenalidomide plus rituximab in previously untreated follicular lymphoma. http://bit.ly/1tPiMbg

ASCO 2014: Value of PET-CT after frontline therapy in follicular lymphoma: A pooled analysis http://bit.ly/SQmPa4

ASH 2012 Paper: The Bruton�s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma http://bit.ly/VkVB9p

Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Studyhttp://1.usa.gov/1hcnEA1

Clinical Oncology 2013: Bruce Cheson, MD: How I Treat Follicular Lymphoma�Part II http://bit.ly/1dpk5Xz

Front Oncology 2012: Backgrounder Therapy of newly diagnosed follicular lymphoma http://1.usa.gov/1dZEIJi

Leuk Lymph: Higher grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy. http://1.usa.gov/10BLkIk

JCO, 2013 - Dr. Oliver. Press: Selection of First-Line Therapy for Advanced Follicular Lymphoma http://bit.ly/17ZENKq

Medscape: Choice of First-Line Therapy in Follicular Lymphoma Debated http://bit.ly/12KGg52

Follicular Lymphoma ASH 2012 Abstracts

2012, Shuangge , Associate Professor of Biostatistics, Yale University: Risk factors for the etiology and prognosis of follicular lymphoma

ASCO 2012 - compiled links to follicular lymphoma abstracts

FL -Bendamustine clear winner over R-CHOP in randomized study OncLive: Dr. Rummel on Treanda Plus Rituxan in Indolent Lymphoma OncLive: Bendamustine Superiority in Lymphoma Regimen Confirmed

Blood: "mini" allogeneic transplantation with or without Zevalin is potentially curative for relapsed follicular lymphoma: 12-year results.

Natural History - treated and untreated

Incidence

Diagnosis

Resources:

Indolent Lymphomas: Classic Subtypes and Newer Entities moffitt.org

Identification of B-cell lymphoma ibms.org pdf

Differential diagnosis (technical), Stanford

Workup (adapted from NCCN Guidelines 2010)

Staging

Common symptoms

Prognostic indicators

The variable natural history

Grade 3

Prognostic Indicators

FLIPI Follicular Lymphoma International Prognostic Index

NEW 2012, Shuangge , Associate Professor of Biostatistics, Yale University: Risk factors for the etiology and prognosis of follicular lymphoma

Resources

Clinical Oncology News 2013: Bruce D. Cheson, MD: How I Manage Follicular Lymphoma: Part I http://bit.ly/1iNRISj

NCCN Guidelines for Follicular Lymphoma - Patient friendlier

Reports Archive

PET imaging response after rituximab-containing induction therapy in follicular lymphoma predictor of OS http://bit.ly/2c9vrYa

Rev. Bras. Hematol. Hemoter. S�o Paulo 2012: Follicular lymphoma - treatment and prognostic factors

FL - Weill Cornell: ASH: What is the role of rituximab maintenance in patients with low tumor burden follicular lymphoma?

Indolent - Monthly Prescribing Reference: Bendamustine Plus Rituximab Provides Superior Progression-Free Survival Benefit to Patients With Relapsed Follicular, Indolent, or Mantle Cell Lymphomas vs. Fludarabine Plus Rituximab

Indolent - Oncology Times: Bendamustine + rituximab offers new standard first-line treatment option for lymphoma

Follicular - ASH 2011: CHOP + Rituxan versus CHOP - Bexxar

Novel Agents for Follicular Lymphoma Lymphoma: Translating Basic Science into Therapy Leonard, Martin http://bit.ly/hY59Bl

Treatment Approaches for Follicular Lymphoma Continue to Evolve -- An Interview with Dr. Andre Goy http://bit.ly/fbfIfm Free login registration required

Evolving Paradigms in Follicular Lymphoma: Re-Evaluating Prognostic Factors and Challenging Treatment Dogmas molecularonc.com

Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology � v.1.2006 nccn.org pdf

Follicular NHL, overview asheducation | emedicine

Follicular NHL, technical Umdnj.edu | Cancer Genetics Web | infobiogenl

Subtypes of Follicular Lymphoma

Subtypes of Follicular non-Hodgkin's lymphomas

Categorized by cell size:

Follicular Mixed-Cell / Small-cell / cleaved

PubMed abstracts for: Review | Therapy | Diagnosis

PubMed abstracts for: Review | Therapy | Diagnosis

Follicular Lymphoma of the Thyroid Gland

About - full text ncbi.nlm.nih.gov

Predictive signatures came from immune cells:

Follicular Large-Cell (Grade 3)

Follicular Large-Cell (Grade 3)

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Resources and Reports:

Compiled abstracts: Follicular grade 3 lymphoma

Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas, May 2008 http://www.haematologica.org/cgi/content/full/93/7/1033

Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology � v.1.2006 nccn.org professionals pdf

Low-Grade Lymphoma, Hematology 2004 asheducationbooks

Jane N. Winter, Randy D. Gascoyne and Koen Van Besien

Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Ann Oncol. 2006 Jun;17(6):920-7. Epub 2006 Mar 8. PMID: 16524969 Full text

Guidelines at Diagnosis | About Clinical Trials

Search Site

M7FLIPI: A Follicular Lymphoma Prognostic Model for the 21st Century
Ann S. LaCasce, MD, MSc hematology.org

Aug 2015
Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance) http://bit.ly/1hfqhXU

Aug 2015:
Blood Journal | Cell-of-origin of transformed follicular lymphoma http://bit.ly/1fGoVnS

Technical:
Nature and importance of follicular lymphoma precursors http://1.usa.gov/1qIAoD8

Cheson, Hiddemann - Leukemia 2014:
How we manage follicular lymphoma http://bit.ly/TSQD5P

... the hope is justified that the long-term perspectives of patients suffering from the disease will be further improved in the near future.

Sonali Smith, 2013:
Dissecting follicular lymphoma: high versus low risk http://bit.ly/1koraMi

ASCO 2014
Alliance: A phase II trial of lenalidomide plus rituximab in previously untreated follicular lymphoma. http://bit.ly/1tPiMbg

ASCO 2014:
Value of PET-CT after frontline therapy in follicular lymphoma: A pooled analysis http://bit.ly/SQmPa4

Clinical Oncology 2013:
Bruce Cheson, MD: How I Treat Follicular Lymphoma�Part II http://bit.ly/1dpk5Xz

Front Oncology 2012: Backgrounder
Therapy of newly diagnosed follicular lymphoma http://1.usa.gov/1dZEIJi

FL -Bendamustine clear winner over R-CHOP in randomized study

OncLive: Dr. Rummel on Treanda Plus Rituxan in Indolent Lymphoma

OncLive: Bendamustine Superiority in Lymphoma Regimen Confirmed

Clinical Oncology News 2013:
Bruce D. Cheson, MD: How I Manage Follicular Lymphoma: Part I http://bit.ly/1iNRISj

Novel Agents for Follicular Lymphoma Lymphoma:
Translating Basic Science into Therapy Leonard, Martin http://bit.ly/hY59Bl

Treatment Approaches for Follicular Lymphoma Continue to Evolve -- An Interview with Dr. Andre Goy http://bit.ly/fbfIfm
Free login registration required

Follicular NHL, overview
asheducation | emedicine

Follicular NHL, technical
Umdnj.edu | Cancer Genetics Web | infobiogenl

Follicular Large-Cell
(Grade 3)

Follicular Lymphoma grade 3B. A separate entity? dissertations.ub.rug.nl
Bosga-Bouwer, Annigje Geesje (Technical) - Chapters in English

PubMed abstracts for Large cell follicular:
Review | Therapy | Diagnosis

Grade 3 and anthracycline-containing treatments [such as CHOP]
Commentary from Experts PAL

Cutaneous - skin
(extranodal)

Cutaneous presentation of follicular lymphomas.
Mod Pathol. 2001 Sep;14(9):913-9. PMID: 11557789 PubMed

Also see

Questions for your doctor - Patients Against Lymphoma
General, Treatment, Side Effects, and Tests

Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma
Julie M. Vose, MD; Edward A. Faber, Jr., DO, MS

FL - Oncologist, 2009: Role of Hematopoietic Stem Cell Transplant in the Management of Follicular Lymphoma

"This review aims to clarify recently published data on the application of HSCT in advanced FL."

FL - Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma
Julie M. Vose, MD; Edward A. Faber, Jr., DO, MS
Full text (Medscape.org requires free registration and login)

Role of Stem Cell transplant in Follicular lymphoma,
Foster, Gabriel, Shea, 2010 ncbi.nlm.nih.gov

Novel Agents for Follicular Lymphoma, Dec 2010
John P. Leonard1 and Peter Martin

Follicular Lymphoma: Emerging Therapeutic Strategies: Therapy for Untreated FL http://bit.ly/a18BZW

Nice overview by Vaishalee P Kenkre1 and Brad S Kahl�1