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About Lymphoma > Types of Lymphoma > Follicular (Center Cell) Lymphoma
Grade 3 and First Line Treatment - Comments from Experts

Last update: 06/07/2005

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]

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