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Types of Lymphoma > Follicular Lymphoma > grade 3
Literature search on treatment of

Last update: 04/29/2011

Topic Search: - PubMed Abstracts: Follicular Large Cell

Here are some abstracts on Follicular Grade 3, highlighting the controversy.  Abstracts are listed in chronological order, the top being most recent. 

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

Follicular non-Hodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy

1. J. Shustik1,*, 2. M. Quinn1,  3. J. M. Connors1,  4. R. D. Gascoyne2,  5. B. Skinnider2 and  6. L. H. Sehn1

April 27, 2010.


Background: The revised World Health Organization (WHO) classification maintains a histological grading system (grades 1–3) for follicular lymphoma (FL) and subdivides grade 3 into 3A (FL3A) and 3B (FL3B) subtypes. Optimal therapy of FL grade 3 and its potential curability with anthracycline-based chemotherapy remain uncertain.

Patients and methods: We carried out a retrospective population-based analysis evaluating the clinical characteristics and outcome of FL3A and FL3B as strictly defined by WHO diagnostic criteria.

Using the BC Cancer Agency Lymphoid Cancer Database, 161 patients with FL grade 3 were identified and, following detailed pathology review, composed of 139 with FL3A and 22 with FL3B.

Results: Patients with FL3B had a higher overall International Prognostic Index (IPI) score than FL3A patients (P = 0.03), though no significant difference in individual IPI risk factor frequencies was noted.

More patients with FL3B received front-line anthracycline-containing chemotherapy (82% versus 36%, P ≤ 0.001). With median follow-up of 45 months, no difference in disease-specific survival (P = 0.74) or overall survival (OS) (P = 0.87) was found between FL3A and FL3B and no survival curve plateau was observed.

Analysis limited to FL3A patients showed no OS advantage with front-line anthracycline use (P = 0.33).

Conclusion: Using strict diagnostic criteria, there appears to be no difference in outcome between patients with FL3A and FL3B and no evidence of curability with anthracycline-based therapy.


Oncol. 2008 Mar;19(3):553-9.

The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma.

Overman MJ, Feng L, Pro B, McLaughlin P, Hess M, Samaniego F, Younes A, Romaguera JE, Hagemeister FB, Kwak L, Cabanillas F, Rodriguez MA, Fayad LE.

Source: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.


BACKGROUND: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied.

PATIENTS AND METHODS: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made.

RESULTS: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk.

The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group.

The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034.

CONCLUSION: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.
PMID: 18083690

1: Ann Oncol. 2006 Jun;17(6):920-7. Epub 2006 Mar 8. Links

Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience.

Ganti AK, Weisenburger DD, Smith LM, Hans CP, Bociek RG, Bierman PJ, Vose JM, Armitage JO.
Department of Internal Medicine, Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, USA.

BACKGROUND: The aim of the study was to determine the outcome and clinical features predictive of survival in patients with follicular lymphoma (FL) treated aggressively and to determine the rate of disease-specific mortality in patients with grade 3 FL (FL3). 

MATERIALS AND METHODS: Four hundred and twenty-one patients with FL who were treated with various anthracycline-based chemotherapy regimens were included in this retrospective study. 

RESULTS: Patients with FL3 and a diffuse component of >50% had the worst outcome, with a hazard ratio of dying of 2.2 (95% CI 1.4-3.4) compared with patients with FL1 or FL2, and a ratio of 1.6 (95% CI 1.02-2.5) compared with FL3 with a diffuse component of < or =50% by multivariate analysis (P = 0.0026). 

Patients with FL3a had an outcome similar to those with FL3b. In patients with FL3 and a diffuse component of < or =50%, the overall and event-free survival curves showed a plateau for patients younger than 60 years of age. However, there were no differences in the cumulative incidence of relapse/progression or lymphoma-specific/treatment-related mortality between the two age groups. 

CONCLUSIONS: Less than half of the patients with FL3 and a diffuse component of < or =50% treated with anthracycline-based combination chemotherapy will relapse and relapses are uncommon after 6 years. Older patients should be offered the same aggressive chemotherapy as younger patients.

PMID: 16524969


Letter to the editor from Blood regarding the use of the FLIPI in GRADE # follicular

Blood, 15 June 2005, Vol. 105, No. 12, pp. 4892-4893


Does the FLIPI apply to grade 3 follicular lymphoma?

We welcome the publication of a score (Follicular Lymphoma International Prognostic Index [FLIPI]) assisting in the choice of treatment for patients with newly diagnosed follicular lymphoma (FL).1 

As the authors state, treatment options for this disease range from "watch and wait" to allogeneic bone marrow transplantation, and the selection of the best available option will be favored by a realistic estimation of the expected survival for each particular patient.

The 5 independent prognostic factors retained in the FLIPI reflect important characteristics of the patient (age), of the disease extension and clinical aggressiveness (stage and number of nodal sites involved, lactose dehydrogenase [LDH]), and of the tumor-host interaction (hemoglobin level). 

Surprisingly enough, histology grade, a disease characteristic considered by many clinicians to be of paramount importance for prognosis and choice of treatment, is missing from the index and was not even significant in the univarate analysis.

The absence of this parameter from the index and the omission of any discussion about this fact in the paper could suggest that histologic grade is indeed not relevant to patient survival and should therefore not be taken as an important information.

We believe that this misunderstanding results from a bias that is not sufficiently covered in the article and that should be clarified.

It was long recognized that an important proportion of large cells (centroblasts) at histologic examination (an observation referred to as grade 3 in the current World Health Organization [WHO] classification) does confer to FL a worse prognosis, despite apparently favorable clinical prognostic features.2,3 Nevertheless, the outcome of these cases can be similar to the forms with less centroblasts when they are treated with an anthracycline-containing regimen [ie, CHOP].4,5 

This information was known in 19856 (the year of the start of data collection for the FLIPI) and, although details on treatment are not given in the paper, it is probable that the majority of grade 3 FLs of this data set were treated with anthracyclines, thus
influencing the prognosis.

Even though the article states that "none of the treatments given during the period of inclusion has significantly changed the natural history of the disease,"1(p1264) this only applies to cases with histologic grades 1 and 2, while for WHO grade 3 we have reason to think that treatment did indeed influence survival, and therefore interacted with other prognostic factors.

The FLIPI could have been a more reliable index if grade 3 FLs were not included in the analysis. We believe that for grades 1 and 2 FL, treatment should be selected based on a number of factors, including the FLIPI score, but an anthracycline-containing regimen should still be favored for patients with grade 3 FL, independent of their FLIPI index.

See response below.

Michele Ghielmini, and Oreste Mora
Correspondence: Michele Ghielmini and Oreste Mora, Oncology Institute
of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona,
Switzerland; e-mail: mghielmini@ticino.com 
1. Solal-Céligny P, Roy P, Colombat P, White, et al. Follicular
Lymphoma International Prognostic Index. Blood. 2004;104:
1258-1265.[Abstract/Free Full Text]
2. Martin AR, Weisenburger DD, Chan WC, et al. Prognostic value of
cellular proliferation and histologic grade in follicular lymphoma.
Blood. 1995;85: 3671-3678.[Abstract/Free Full Text]
3. Rodriguez J, McLaughlin P, Hagemeister FB, et al. Follicular large
cell lymphoma: an aggressive lymphoma that often presents with
favorable prognostic features. Blood. 1999;93:
2202-2207.[Abstract/Free Full Text]
4. Nathwani BN, Harris NL, Weisenburger D. Follicular lymphoma. In:
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health
Organization Classification of Tumours. Tumours of haematopoietic and
lymphoid tissues. Albany, NY: WHO Publication Center; 2001: 162-167.
5. Bartlett NL, Rizeq M, Dorfman RF, Halpern J, Horning SJ. Follicular
large-cell lymphoma: intermediate or low grade? J Clin Oncol. 1994;12:
1349-1357.[Abstract/Free Full Text]
6. Glick JH, McFadden E, Costello W, Ezdinli E, Berard CW, Bennett JM.
Nodular histiocytic lymphoma: factors influencing prognosis and
implications for aggressive chemotherapy. Cancer. 1982;49:
840-845.[Medline] [Order article via Infotrieve]


FLIPI in grade 3 follicular lymphoma We agree with Prof Ghielmini that grade 3 follicular lymphoma is in many cases a more aggressive disease than other follicular lymphomas, although this is an area of ongoing controversy.1 

Grade 3b follicular lymphoma especially shares the prognosis of and requires treatment approaches similar to that of diffuse large B-cell lymphoma.2 We welcome the opportunity to comment further on the Follicular Lymphoma International Prognostic Index (FLIPI) observations about grade 3 follicular lymphoma.

First, a central pathology review was not realistic for the 5000 FLIPI cases. Since there are known inter-observer variations in the assignment of histologic grade,3,4 we felt we would introduce a bias if we excluded these cases arbitrarily. Moreover, they represented only 9% of the entire FLIPI population.

Second, the IPI appears to have one of the same shortcomings for grade 3 follicular lymphoma as it does for all follicular lymphomas, namely the identification of only a small (15%-20%) fraction of cases with high risk.5,6 Thus the inclusion of grade 3 cases in the FLIPI, and the applicability of the FLIPI to grade 3 follicular lymphoma, represents a potential benefit to patient management.

But we completely agree with Prof Ghielmini's observation that an anthracycline-containing regimen is favored for patients with grade 3 follicular lymphoma. 

It was beyond the scope of the initial FLIPI project to analyze in any detail the various treatment modalities used. Moreover, such a retrospective analysis would be open to valid criticism. But we agree that the literature supporting the inclusion of anthracyclines in grade 3 follicular lymphoma5,6 is less controversial than the comparable literature in other follicular lymphomas.7 

We thank him for drawing attention to this important topic. The F2 study (coordinated by M. Federico) is ongoing to determine the influence of grade and the impact of diffuse areas on prognosis.

~ Peter McLaughlin, Philippe Solal-Céligny, on behalf of the Scientific Committee of the FLIPI

Correspondence: Philippe Solal-Céligny, Centre J. Bernard, 9 rue
Beauverger, 72000 Le Maur, France; e-mail: celigny@roos.fr 
1. Armitage JO, Cavalli F, Zucca E, Longo DL. Follicular lymphoma. In:
Text Atlas of Lymphomas. Martin Dunitz Ltd; 1999: 13-21.
2. Bosga-Bouwer AG, van Imhoff GW, Boonstra R, et al. Follicular
lymphoma grade 3b includes 3 cytogenetically defined subgroups with
primary t(14;18) 3q27 or other translocations: t(14;18) and 3q27 are
mutually exclusive. Blood. 2003;101: 1145-1154.[CrossRef]
3. Horning SJ. Something old, something new, something subjective,
something déjà vu. J Clin Oncol. 2003;21: 1-2.[Free Full Text]
4. Hans CP, Weisenburger DD, Vose JM, et al. A significant diffuse
component predicts for inferior survival in grade 3 follicular
lymphoma, but cytologic types do not predict survival. Blood.
2003;101: 2363-2367.[Abstract/Free Full Text]
5. Wendum D, Sebban C, Gaulard P, et al. Follicular large-cell
lymphoma treated with intensive chemotherapy: an analysis of 89 cases
included in the LNH87 trial and comparison with the outcome of diffuse
large B-cell lymphoma. J Clin Oncol. 1997;15: 1654-1663.[Abstract/Free
Full Text]
6. Rodriguez J, Mc Laughlin P, Hagemeister FB, et al. Follicular large
cell lymphoma: an aggressive lymphoma that often presents with
favorable prognostic features. Blood. 1999;93: 2002-2007.
7. Rigacci L, Federico M, Martinelli M, et al. The role of
anthracyclines in combination chemotherapy for the treatment of
follicular lymphomas. Leuk Lymphoma. 2003;44:
1911-1917.[CrossRef][Medline] [Order article via Infotrieve]

Related Article in Blood Online:
Follicular Lymphoma International Prognostic Index
Philippe Solal-Céligny, Pascal Roy, Philippe Colombat, Josephine
White, Jim O. Armitage, Reyes Arranz-Saez, Wing Y. Au, Monica Bellei,
Pauline Brice, Dolores Caballero, Bertrand Coiffier, Eulogio
Conde-Garcia, Chantal Doyen, Massimo Federico, Richard I. Fisher,
Javier F. Garcia-Conde, Cesare Guglielmi, Anton Hagenbeek, Corinne
Haïoun, Michael LeBlanc, Andrew T. Lister, Armando Lopez-Guillermo,
Peter McLaughlin, Noël Milpied, Pierre Morel, Nicolas Mounier, Stephen
J. Proctor, Ama Rohatiner, Paul Smith, Pierre Soubeyran, Hervé Tilly,
Umberto Vitolo, Pier-Luigi Zinzani, Emanuele Zucca, and Emili Montserrat
Blood 2004 104: 1258-1265. [Abstract] [Full Text]


Biol Blood Marrow Transplant. 2006 Jun;12(6):641-7. Related Articles, Links

Does follicularity in large cell lymphoma predict outcome after autologous stem cell transplantation?

 Krishnan A, Nademanee A, Fung H, Angelopoulou M, Molina A, Gaal K, Dagis A, Palmer J, Alvarnas J, Slovak M, Kogut N, Popplewell L, Rodriguez R, Schriber J, Wang S, Forman SJ.

Division of Hematology/Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA. akrishnan@coh.org

    The purpose of this study was to evaluate whether follicular histology in large cell lymphoma influences treatment outcomes after autologous stem cell transplantation (ASCT). 

It remains an area of controversy whether the natural history of follicular large cell lymphoma (FLCL) is akin to diffuse large cell lymphoma (DLCL) with curative potential or is more similar to indolent follicular lymphomas with a pattern of late relapses after intensive chemotherapy. 

Although ASCT is a potentially curative treatment for patients with recurrent DLCL, the effectiveness of this approach in patients with FLCL is unclear. 

We undertook a retrospective analysis of 332 patients with large cell lymphoma who underwent ASCT at the City of Hope Comprehensive Cancer Center. With a median follow-up of 31 months, the projected 10-year overall survival and disease-free survival were similar between patients with FLCL and DLCL. Analysis of prognostic factors demonstrated that although age, chemotherapy refractoriness, and disease status at the time of ASCT were predictive of overall survival/disease-free survival, follicularity did not influence the outcome. 

Furthermore, the similar plateau in the survival curve for the DLCL and FLCL patients suggests that the behavior of FLCL is similar to that of DLCL and that FLCL is potentially curable with ASCT.

PMID: 16737937


7 July 2003, Volume 89, Number 1, Pages 36-42  

Outcome of follicular lymphoma grade 3: is anthracycline necessary as front-line therapy?

Chau1, R Jones1, D Cunningham1, A Wotherspoon2, N Maisey1, A R
Norman3, P Jain4, L Bishop1, A Horwich5 and D Catovsky4

Presented at the Eighth International Conference on Malignant Lymphoma, Switzerland, June 2002.


A grading system (grades 1-3) for follicular lymphoma (FL) is used in the WHO classification for lymphoid malignancies based on the absolute number of centroblasts in the neoplastic follicles. Grade 3 FL is further subdivided into 3a and 3b depending on the presence or absence of centrocytes.

A total of 231 patients with FL, referred from 1970 to 2001, were identified from our prospectively maintained database. Original diagnostic materials were available for review on 215 patients and these were reclassified according to the WHO grading system. Follicular lymphoma grades 1, 2 and 3 accounted for 92, 68 and 55 patients, respectively.

No significant overall survival (OS) differences were observed among FL grades 1-3 (log rank P=0.25) or between grades 3a and 3b (log rank P=0.20). No significant failure-free survival (FFS) differences were observed among FL grades 1-3 (log rank P=0.72) or between grades 3a and 3b (log rank P=0.11).

First-line anthracyclines did not influence OS or FFS (log rank P=0.86, P=0.58, respectively) in patients with FL grade 3. There are long-term survivors among patients with FL grade 3 with a continuing risk of relapse. Anthracyclines did not appear to influence survival or disease relapses when given as front-line therapy in our series.

The role of anthracyclines should be further evaluated in large randomized studies.

British Journal of Cancer (2003) 89, 36-42. doi:10.1038/sj.bjc.6601006 www.bjcancer.com


1: Ann Oncol 2000 Dec;11(12):1551-6

Follicular large cell lymphoma: long-term follow-up of 62 patients treated between 1973-1981.

Rodriguez J, McLaughlin P, Fayad L, Santiago M, Hess M, Rodriguez MA, Romaguera J, Hagemeister F, Kantarjian H, Cabanillas F.

University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

PURPOSE: Investigators disagree on whether follicular large cell lymphoma (FLCL) behaves like other follicular lymphomas, with no plateau in the survival curve, or as a more aggressive but potentially curable lymphoma. We reported in 1984 results for 62 FLCL patients treated at our institution; the current report updates those results. 

PATIENTS AND METHODS: Sixty-two patients referred from 1973-1981, including fifteen (24%) patients with Ann Arbor stage I-II and forty-seven (76%) with stage III-IV FLCL. 

Seven patients received radiation (XRT) alone, forty patients XRT and chemotherapy, and fifteen patients received chemotherapy alone. 

RESULTS: The median follow-up was 14.7 years. 

The median survival was 5.1 years, with 21% alive at 15 years. 

The failure-free survival (FFS) at 10 years was 31%. Univariate analysis revealed that age, Ann Arbor stage, and the International Index correlated with survival. Performance status, number of platelets, and LDH correlated with failure-free survival.

CONCLUSIONS: FLCL responds to doxorubicin-based regimens similarly to diffuse large cell lymphoma. Patients with FLCL have the potential for prolonged failure-free survival. Variables that predict the survival in aggressive lymphomas apply as well in this type of lymphoma.

PMID: 11205462 


Effect of follicularity on autologous transplantation for large-cell non-Hodgkin's lymphoma.

J Clin Oncol 1998 Mar;16(3):844-9 (ISSN: 0732-183X) Vose JM; Bierman PJ; Lynch JC; Weisenburger DD; Kessinger A; Chan WC; Greiner TC; Armitage JO 

Department of Internal Medicine, University of Nebraska Medical Center, Omaha 69198-3332, USA. jmvose@m...

PURPOSE: This study evaluated the outcomes of patients who received high-dose chemotherapy (HDC) and autologous hematopoietic stem-cell transplantation (ASCT) for large-cell non-Hodgkin's lymphoma (NHL) and the effect of a follicular versus a diffuse histology. 

PATIENTS AND METHODS: The prognostic factors in 289 patients who underwent HDC and ASCT for large-cell NHL between May 1983 and December 1996 were analyzed. 

RESULTS: With a median follow-up duration of 24 months for surviving patients (range, 3 to 131 months), 

112 of 289 (39%) were alive and 82 of 289 (28%) were failure-free. 

In a multivariate analysis, the factors associated with a poorer failure-free survival (FFS) included a lactic dehydrogenase (LDH) level greater than normal (P < .0001), three or more prior chemotherapy regimens received (P < .01), a mass > or = 10 cm at transplant (P < .01), and diffuse histology at the time of transplant (P = .026). 

Patients who received HDC and ASCT for large-cell NHL in the good-prognosis category (normal LDH, < three prior chemotherapy regimens, no large mass, and not chemotherapy-resistant) had a 5-year survival rate of 45%. Within the good-prognosis group, patients with diffuse large-cell NHL had a 5-year survival rate of 42% compared with 58% for patients with follicular large-cell (FLC) lymphoma (P = .05). 

CONCLUSION: Good-prognosis patients with FLC histology who receive HDC and ASCT have an improved survival compared with good-prognosis patients with a diffuse large-cell histology.

2: Blood 1999 Apr 1;93(7):2202-7 Related Articles, Links

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

Rodriguez J, McLaughlin P, Hagemeister FB, Fayad L, Rodriguez MA, Santiago M, Hess M, Romaguera J, Cabanillas F.

University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

It is debated whether follicular large cell lymphoma (FLCL) has a clinical behavior that is distinct from indolent follicular lymphomas, and whether there is a subset of patients who can be potentially cured. 

We report here our experience with 100 FLCL patients treated at our institution since 1984 with three successive programs. We evaluated the predictive value of pretreatment clinical features, including two risk models, the Tumor Score System and the International Prognostic Index (IPI). 

With a median follow-up of 67 months, the 5-year survival is 72% and the failure-free survival (FFS) is 67%, with a possible plateau in the FFS curve, particularly for patients with stage I-III disease. 

Features associated with shorter survival included age >/=60, elevated lactic dehydrogenase (LDH) or beta-2-microglobulin (beta2M), advanced stage, and bone marrow involvement. 

Stage III patients had significantly better survival than stage IV patients (P <.05). By the IPI and Tumor Score System, 80% of the patients were in the lower risk groups; both systems stratified patients into prognostic groups. 

Patients with FLCL have clinical features and response to treatment similar to that reported for diffuse large cell lymphoma. 

Prognostic risk systems for aggressive lymphomas are useful for FLCL. A meaningful fraction of patients may possibly be cured when treated as aggressive lymphomas.

PMID: 10090928 

Full text: http://www.bloodjournal.org/cgi/content/full/93/7/2202

3: J Clin Oncol 1997 Apr;15(4):1654-63

Follicular large-cell lymphoma treated with intensive chemotherapy: an analysis of 89 cases included in the LNH87 trial and comparison with the outcome of diffuse large B-cell lymphoma. 

Groupe d'Etude des
Lymphomes de l'Adulte.

Wendum D, Sebban C, Gaulard P, Coiffier B, Tilly H, Cazals D, Boehn A, Casasnovas RO, Bouabdallah R, Jaubert J, Ferrant A, Diebold J, de Mascarel A, Gisselbrecht C.

Services d'Anatomie et Cytologie Pathologiques, Hopital Saint-Antoine, Pessac, France.

PURPOSE: The aims of this study were as follows: (1) to analyze clinical, histopathologic characteristics, treatment outcome, and prognostic factors of patients with follicular large-cell lymphoma (FLCL); and (2) to compare them with those of patients with diffuse large B-cell lymphoma (DLCL) treated in the same therapeutic trial.

PATIENTS AND METHODS: Eighty-nine FLCL patients who were histologically reviewed and who received an intensive chemotherapy regimen according to the LNH 87 protocol were analyzed and compared with 1,096 B-cell DLCL patients included in the same protocol. 


After intensive induction treatment, 59 patients (67%) achieved a complete remission [CR]. 

Estimated 5-year survival was 59%, and estimated 5-year freedom from progression (FFP) was 39%. 

Prognostic factors associated with shorter FFP were 
  age greater than 60 years (P = .02), 
  advanced clinical stage (P = .01), 
  abnormal lactic dehydrogenase (LDH) level (P = .02), 
  abnormal beta-2 microglobulin (P = .02), 
  B symptoms (P = .03), 
  bone marrow involvement (P = .04), 
  and high expression of bcl-2 protein (P = .05). 

When compared with B-cell DLCL patients, FLCL patients were younger (P = .02), had a better Eastern Cooperative Oncology Group (ECOG) status (P = .05), less bulky mass (P = .04), more advanced clinical stages (P < .001), and more bone marrow involvement (P = .02). 

No significant difference was observed between FLCL and DLCL patients for response to therapy (67% v 67% of CR), 5-year overall survival (58% v 51%), 5-year disease-free survival (53% v 57%), or FFP survival (39% v 43%). 


FLCL patients have a favorable response rate and survival when treated with intensive chemotherapy. Their outcome is similar to that of B-cell DLCL patients, and a long-term FFP is observed for a substantial number of patients.

Some adverse prognostic factors (including those of the International Prognostic Index, bone marrow involvement, and beta-2 microglobulin) have been identified to define a subset of patients who require other therapeutic approach.

PMID: 9193366 [PubMed - indexed for MEDLINE]

4: J Clin Oncol 1994 Jul;12(7):1349-57

Follicular large-cell lymphoma: intermediate or low grade?

Bartlett NL, Rizeq M, Dorfman RF, Halpern J, Horning SJ.

Department of Medicine, Stanford University School of Medicine, CA.

PURPOSE: To evaluate the benefit of anthracycline-based chemotherapy, identify prognostic factors, and determine the value of the International Prognostic Factors Index for patients with follicular large-cell (FLC) lymphoma. 

PATIENTS AND METHODS: This retrospective study includes 96 patients with FLC lymphoma treated at Stanford University Medical Center between 1969 and 1991. 

Fifty-five patients received doxorubicin plus cyclophosphamide-containing chemotherapy regimens, 
  21 patients received other chemotherapy  regimens, 
  15 patients received radiotherapy only, 
  and five patients received no initial therapy. 

Thirty-four patients had stage I or II disease and 62 patients had stage III or IV disease. 


With a median follow-up duration of 5.2 years (range, 1 to 18), the actuarial 5- and 10-year
overall survival rates were 75% and 54%, with actuarial 5- and 10-year freedom from progression (FFP) rates of 53% and 42%, respectively. 

Patients treated with chemotherapy regimens that contained both doxorubicin and cyclophosphamide had a superior actuarial 10-year FFP rate (55% v 25%, P = .06) and overall survival rate (65% v 42%, P = .04) compared with patients treated with other chemotherapy regimens. 

Only one patient treated with doxorubicin plus cyclophosphamide relapsed after 3 years. In the multivariate analysis, discordant lymphoma and treatment with chemotherapy regimens not containing both cyclophosphamide and doxorubicin predicted for worse FFP and overall survival rates. 

In addition, poor performance status and increasing areas of diffuse histology predicted for a worse survival, while anemia and male sex predicted for a worse FFP. The age-specific International Index was useful in predicting outcome; however, few patients with FLC lymphoma had high-risk features. 


The plateau in FFP implies that patients with FLC lymphoma enjoy sustained remissions after standard anthracycline-based chemotherapy. FLC lymphoma should continue to be approached as an intermediate-grade lymphoma with curative intent.

PMID: 8021725

5: J Clin Oncol 1993 Feb;11(2):218-24

Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group.

Anderson JR, Vose JM, Bierman PJ, Weisenberger DD, Sanger WG, Pierson J, Bast M, Armitage JO.

Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha 69198-4350.

PURPOSE: Our purpose was to describe the treatment outcome of patients with follicular large-cell lymphoma (FLCL) and to identify prognostic factors that affect the treatment outcome. 

PATIENTS AND METHODS: Between 1980 and 1991, 107 newly diagnosed, previously untreated
patients with FLCL were prospectively treated using treatment plans of the Nebraska Lymphoma Study Group (NLSG). 

Most stage I/II patients received two to three cycles of one of four closely related six-drug combination chemotherapy regimens (cyclophosphamide, doxorubicin or mitoxantrone, and procarbazine, plus bleomycin, vincristine, and prednisone or dexamethasone [CAP/BOP I-IV]) plus involved-field radiotherapy; 10 patients received involved-field irradiation only. 

Stage III/IV patients received six to eight cycles of CAP/BOP. 

RESULTS: Forty-four percent of patients had stage I/II disease. Stage I/II patients were older and more often female than stage III/IV patients. Cytogenetic studies were available on 35 patients: seven were normal; the most common abnormality was a translocation involving 14q32. Abnormalities of 1p or 1q were also common, often secondary to a 14q32 abnormality. The median follow-up of surviving patients is 2 years. 

The complete response rates observed were stage I/II, 88%; stage III/IV, 49%. 

Complete response rates were affected by both age and tumor bulk. Failure-free survival (FFS; time to first occurrence of progression, relapse after response, or death from any cause) at 3 years was estimated to be 61% for stage I/II patients and 34% for stage III/IV patients. 

Survival at 3 years was estimated to be 76% and 61%, respectively. 

FFS of stage III/IV patients was poorer for stage IV patients and those with composite lymphomas. Significantly poorer survival was only seen in patients older than 70 years of age. 

CONCLUSION: A proportion of stage I/II FLCL patients may obtain long-term disease control with combination chemotherapy plus radiotherapy. Results for patients with stage III/IV FLCL are similar to those seen for other follicular lymphomas. 

PMID: 8426197

These are two articles on the pathology of Grade 3

Re: Grade 3 FLCL--abstracts for Linda R.

Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.

Blood 2002 May 15;99(10):3806-12 (ISSN: 0006-4971) Ott G; Katzenberger T; Lohr A; Kindelberger S; Rudiger T; Wilhelm M; Kalla J; Rosenwald A; Muller JG; Ott MM; Muller-Hermelink HK Pathologisches Institut and Poliklinik fur Innere Medizin, University of Wurzburg, Germany. path042@m...

Follicular lymphoma (FL) grades 1 and 2 are regarded as a distinct disease entity, whereas data suggest that FL grade 3 might be an inhomogeneous tumor category. 

To define the biologic spectrum of FL,  89 follicular lymphomas were studied for their cytologic composition, antigen expression, mitotic and proliferation indices, cytogenetics, and clinical data. In contrast to the homogeneous appearance of FL  grades 1 and 2 (29 and 33 cases, respectively), 2 types of FL grade 3 were recognized. 

Eleven cases of FL 3a displayed structural features similar to those of FL 1 and 2 and were composed of centroblasts and centrocytes, whereas 16 cases of FL 3b, with (n = 4) or without (n = 12) a diffuse large B-cell lymphoma component (DLBL) (FL 3b +/- DLBL), consisted exclusively of blasts. 

In contrast to FL 3a, FL 3b +/- DLBL were CD10(+) in only 50% of cases and displayed plasmacytoid differentiation in 44% of cases. Although FL3a was t(14; 18)+ in 8 of 11 (73%) cases, only 2 of 16 (13%) FL3b +/- DLBLs  harbored this translocation. 

In contrast, chromosomal breaks at 3q27 were encountered in 7 of 16 (44%) FL 3b +/- DLBL in contrast to only 2 of 11 (18%) FL 3a, and the spectrum of secondary aberrations in FL 3b +/- DLBL was similar to that of diffuse large B-cell lymphoma. 

We conclude, therefore, that FL grade 3 is a heterogeneous disease group and that the distinction proposed in the new World Health Organization classification between FL 3a (with centrocytes) and FL3b (without centrocytes) is of biologic, and possibly clinical, importance. 

Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas. 

Am J Clin Pathol 2001 Jun;115(6):862-7 (ISSN: 0002-9173) Eshoa C; Perkins S; Kampalath B; Shidham V; Juckett M; Chang CC  Dept of Pathology, Medical College of Wisconsin, 9200 W Wisconsin Ave,
Milwaukee, WI 53226, USA.

CD10 expression in various grades and interfollicular infiltrates of follicular lymphoma (FL) has not been well documented. Immunohistochemical staining for CD10 (clone 56C6) was performed on paraffin-embedded tissue from 26 cases of classic FL. 

Negative or weak expression of CD10 was more frequent in grade III (5/6 [83%]) than in grade I FLs (3/15 [20%]). CD10+ interfollicular infiltrates were present in 16 cases. Six (38%) of 16 cases showed that CD10 expression was strong or moderate in follicular areas but weak or negative in interfollicular infiltrates. Our results suggest that CD10 expression is frequently weak to negative in grade III and in interfollicular infiltrates of FLs. 

Therefore, lack of CD10 expression on small specimens, such as from needle core biopsy or fine-needle aspiration, does not preclude the possibility of a diagnosis of FL. Furthermore, lack of CD10 expression in diffuse large B-cell lymphoma does not exclude the possibility that the neoplastic lymphocytes are of follicle center cell origin. 


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