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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-07-2298.
 Previous Article | Table of Contents | Next Article 
Blood, 15 March 2003, Vol. 101, No. 6, pp. 2363-2367
NEOPLASIA
A significant diffuse component predicts for inferior survival in
grade 3 follicular lymphoma, but cytologic subtypes do not predict
survival
Christine P. Hans,
Dennis
D. Weisenburger,
Julie M. Vose,
Lynette M. Hock,
James C. Lynch,
Patricia Aoun,
Timothy C. Greiner,
Wing C. Chan,
Robert G. Bociek,
Philip J. Bierman, and
James O. Armitage
From the Departments of Pathology and Microbiology,
Internal Medicine, and Preventive and Societal Medicine, University of
Nebraska Medical Center, Omaha, NE.
 |
Abstract |
Grade 3 follicular lymphoma (FL3) is thought to have an aggressive
clinical course. On the basis of possible biologic differences, the new
World Health Organization (WHO) classification of lymphoma suggests further subdivision of FL3 into grades 3a and 3b and states
that the percentage of involvement by diffuse large B-cell lymphoma
(DLBCL) should also be reported. However, the clinical implications of
these features are unclear. Therefore, we studied 190 newly diagnosed
patients with lymph node-based FL3 who received anthracycline-containing combination chemotherapy. The follicular component was subclassified as grade 3a (FL3a) or grade 3b (FL3b) according to the WHO criteria, or as follicular large cleaved cell type
(FLC). The percentage of a diffuse component, if present, was also
recorded. Of the 190 cases, there were 107 FL3a (56%), 53 FL3b (28%),
and 30 FLC (16%) cases. Diffuse areas were seen in 72 cases (31 FL3a,
28 FL3b, and 13 FLC). There were no significant differences in the
clinical characteristics, overall survival, or event-free survival
between patients with grades FL3a, FL3b, or FLC. However, those cases
with a predominant diffuse component (> 50% diffuse) had a
significantly worse overall survival (P = .0037) and
event-free survival (P = .012). Therefore, we conclude that the subdivision of FL3 into cytologic subtypes does not appear to
be important clinically. However, patients with FL3 having a diffuse
component of more than 50% have an inferior survival that is similar
to the survival of those with DLBCL.
(Blood. 2003;101:2363-2367)
© 2003 by The American Society of Hematology.
| |
Introduction |
Grade 3 follicular lymphoma (FL3) accounts for
approximately 6% of all non-Hodgkin lymphomas.1 Compared
with lower-grade follicular lymphoma, FL3 is thought to be a more
aggressive disease and should be treated accordingly.2-11
However, there is controversy regarding the curability of FL3 with
aggressive therapy.12
Both the Revised European and American Lymphoma (REAL) classification
and the new World Health Organization (WHO) classification recommend
subdividing follicular lymphoma into 3 grades.13,14 The
REAL classification does not provide criteria for grading, but the WHO
recommends using the cell counting method of Mann and
Berard.15 In addition, the WHO classification suggests
further subdivision of FL3 into grades 3a and 3b, based on the presence or absence of small cleaved cells (centrocytes), respectively. In FL3a,
the neoplastic follicles have more than 15 centroblasts per high-power
field in a background of centrocytes. In FL3b, the neoplastic follicles
are composed of sheets of centroblasts without admixed centrocytes.
Thus, FL3 appears to be a heterogenous disorder, and cytologic
subdivision may help to define potential biologic and clinical
variants.16 However, the clinical importance of this
subdivision has not been investigated in a large cohort of patients
with FL3.
The WHO classification also recommends the reporting of pattern in
low-grade follicular lymphoma, and 3 patterns are suggested based on
the percentage of the follicular component.14 The WHO classification also states that any involvement by diffuse large B-cell
lymphoma (DLBCL) should be identified, estimated by percentage, and
reported as a separate diagnosis. However, investigations of the
prognostic value of DLBCL areas in patients with FL3 have yielded
conflicting results. Although some studies have found differences in
overall survival7,17 or failure-free
survival,6 most studies have found no difference in
survival for patients with DLBCL areas.2-4,9,10,18
The goals of this study are 2-fold: first, to evaluate the
clinical significance of the subdivision of FL3 into grades 3a and 3b,
and, second, to evaluate the clinical significance of DLBCL areas in FL3.
| |
Patients and methods |
Between June 1985 and December 2000, 252 patients with FL3 were
treated with anthracycline-containing combination chemotherapy by the
Nebraska Lymphoma Study Group. During this time, follicular lymphoma
represented 22% of non-Hodgkin lymphoma diagnoses in our database,
with FL3 accounting for 8.3% of non-Hodgkin lymphoma and 37% of
follicular lymphoma. The University of Nebraska Institutional Review
Board approved this study and informed consent was obtained in
accordance with the Declaration of Helsinki. Eight cases were excluded
from this study because the original biopsy slides were unavailable for
review, and 10 cases could not be subclassified because of inadequate
material for review (ie, needle biopsy or small sample size). An
additional 31 cases were excluded because the disease was primarily
extranodal, ie, not lymph node-based disease. Nine cases were excluded
because they were reclassified on review (low-grade follicular
lymphoma, 4; diffuse large B-cell lymphoma, 3; small lymphocytic
lymphoma, 1; mantle cell lymphoma, 1). One patient was excluded because
of a previous history of lymphoma, and 3 patients were excluded because
documentation of informed consent was lacking. Therefore, this series
consists of 190 patients with newly diagnosed, node-based FL3, all of
whom underwent an excisional lymph node biopsy. Clinical features, including the components of the International Prognostic Index (IPI)
and the IPI score, were recorded.19 Therapy for 108 patients (57%) consisted of combination chemotherapy, including
cyclophosphamide, doxorubicin or mitoxantrone, procarbazine, bleomycin,
vincristine, and prednisone or dexamethasone (CAP-BOP),20
whereas 75 patients (39%) received cyclophosphamide, mitoxantrone,
vincristine, prednisone (CNOP),21 and 7 patients (4%)
received cyclophosphamide, doxorubicin, vincristine, and
prednisone (CHOP).
The diagnosis of FL3 was based on counting more than 15 transformed
lymphoid cells (centroblasts) on average in 10 × 40 high-power fields
(hpf = 0.159 mm2) of 10 neoplastic
follicles.14,15 The cases were then subclassified as grade
3a (FL3a) if the follicular component contained more than 15 centroblasts/hpf in a background of small cleaved cells (centrocytes), grade 3b (FL3b) if there were solid sheets of
centroblasts without small centrocytes, or grade 3b with small
centroblasts (FL3bs) if there were solid sheets of small centroblasts
without centrocytes (Figure 1). On
review, some of our cases did not meet the WHO counting criteria for
FL3. Our database includes a category of FL3 that consists
predominantly of large cleaved cells, as defined in the Working
Formulation.22 In these cases, the neoplastic follicles
contained a predominance of large cleaved cells (large centrocytes or
multilobated cells) with irregular nuclei that were 2 to 3 times the
size of a small lymphocyte and fine chromatin with absent or
inconspicuous small nucleoli. These cases were classified as follicular
large cleaved type (FLC) if a predominance (> 50%) of the cells in
the neoplastic follicles were large cleaved cells but there were less
than 15 centroblasts/hpf (Figure 1D). A diffuse component was defined
according to the WHO recommendation as an area lacking follicular
architecture (not including interfollicular involvement).14 The percentage of a diffuse component, if
present, was estimated by morphologic review of all of the slides in
each case and recorded at the time of diagnosis.
View larger version (194K):
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| Figure 1.
Subtypes of grade 3 follicular lymphoma.
(A) Grade 3a contains more than 15 centroblasts/hpf in a background of
centrocytes; (B) grade 3b consists of sheets of centroblasts with no
admixed centrocytes; (C) grade 3bs consists predominantly of small
centroblasts with no admixed centrocytes; a large centroblast (arrow)
is shown for comparison; and (D) large cleaved cell lymphoma consisting
of intermediate-sized to large cells with irregular, cleaved, or
twisted nuclei, fine chromatin, and inconspicuous nucleoli; a large
centroblast (arrow) and small centrocyte (arrowhead) are shown for
comparison (H&E stains, original magnification,
× 400).
|
|
For comparison purposes, a group of 530 patients with DLBCL was
retrieved from the Nebraska Lymphoma Study Group Registry. These
patients were treated with similar combination chemotherapy regimens
(53% received CNOP, 46% CAP-BOP, and 1% CHOP) and had clinical
follow-up data. In addition, a group of 186 patients with low-grade
follicular lymphoma (grades 1 and 2) was retrieved from the Nebraska
Lymphoma Study Group Registry. These patients were also treated with
similar combination chemotherapy regimens (61% received CNOP and 39%
CAP-BOP) and had clinical follow-up data. These data were used to
generate survival curves that were compared with the curves for the FL3
study population.
Fisher exact test was used to compare the clinical
characteristics of the various histologic groups. Median ages were
compared using the Wilcoxon rank-sum test. The Kaplan-Meier
method23 was used to estimate overall and event-free
survival distributions. Overall survival was defined as the time from
the start of treatment to the date of death or last contact. Patients
alive at last contact were treated as censored for overall survival
analysis. Event-free survival was defined as the time from the start of
treatment to either the date of disease progression, death, or last
contact. Patients who were alive at last contact and had not progressed were treated as censored for event-free survival analysis. The log-rank
test was used to compare the survival distributions of the various
groups.24 Cox regression was used for multivariate analysis of factors predictive of overall survival.25,26
| |
Results |
Of the 190 patients, 107 had FL3a (56%), 51 had FL3b (27%), 2 had FL3bs (1%), and 30 had FLC (16%). The 2 patients with FL3bs included a 72-year-old man with stage III disease who achieved a
complete remission but died secondary to a cerebral vascular accident 5 years after diagnosis, and a 54-year-old man with stage IV disease who
died of progressive lymphoma 3 years after diagnosis. Given the small
number of patients with FL3bs, they were combined with the FL3b cases
for all subsequent analyses. The median follow-up for the entire group
was 5.9 years (range, 1-17.6) and the 5-year overall survival (OS) and
event-free survival (EFS) were 59% and 38%, respectively.
There were no differences in the clinical characteristics between
patients with FL3a, FL3b, or FLC (Table
1). The 5-year OS was 65% for those with
FL3a, 52% for FL3b, and 54% for FLC, and there were no significant
differences in OS (Figure 2A) or EFS
(P = .72) between patients with grades FL3a, FL3b, or FLC. There is a separation between the OS curves for FL3a and FL3b after 1 year of follow-up (Figure 2B), but this separation is of borderline
statistical significance (P = .10). However, when comparing only the cases without diffuse areas (ie, cases that are
100% follicular), the difference in OS between grades FL3a and FL3b is
not significant (Figure 2C). The FLC group was compared with a group of
similarly treated patients with low-grade follicular lymphoma and had a
worse OS (P = .054), but there was no significant difference in EFS (P = .69). The 5-year OS for the
low-grade follicular lymphoma group was 74% compared with only 54%
for the FLC patients.
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| Figure 2.
Overall survival by subtypes of grade 3 follicular lymphoma.
(A) Grade 3a versus 3b versus FLC; (B) grade 3a versus 3b, all cases;
(C) grade 3a versus 3b, only 100% follicular cases.
|
|
Areas consisting of DLBCL, ranging from 10% to 95%, were seen
in 72 cases (38%). Twelve cases had diffuse areas of more than 80%.
Of the cases with diffuse areas, 31 were FL3a, 28 were FL3b, and 13 were FLC. Diffuse areas were present in 29% of FL3a, 58% of FL3b, and
43% of FLC. Therefore, diffuse areas are more likely to be identified
in FL3b. The cases that were 100% follicular (FL) were clinically
similar to those with diffuse areas (DFL), with the exception of stage
(Table 2). The patients with pure FL were
more likely to be of higher stage than those with diffuse areas
(P = .0054). The patients with DFL had a 5-year OS of
54%, which is significantly worse than the 63% OS for those with pure FL (Figure 3A). When we used the WHO
recommendations for pattern reporting in low-grade follicular
lymphoma,14 the patients with diffuse areas more than 75%
had a significantly worse OS (Figure 3B). The cases were also analyzed
by deciles and quartiles, and a cut-point of 50% was confirmed as
being optimal for prediction of survival by using a survival tree
method.27 The patients with a diffuse component of more
than 50% diffuse had a significantly worse OS than those with a
diffuse component less than or equal to 50% (Figure 3C). In addition,
the EFS between these 2 groups was also significantly different
(P = .012). This predominantly diffuse (> 50%) group
also had an OS and EFS similar to that of a group of 530 cases of DLBCL
that were treated similarly (Figure 3D).
View this table:
[in this window]
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|
Table 2.
Clinical characteristics of grade 3 follicular
lymphoma patients with 100% follicular lymphoma (FL) and those
with diffuse areas (DFL)
|
|
View larger version (33K):
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| Figure 3.
Overall survival according to diffuse areas in grade 3 follicular lymphoma.
(A) Cases with 100% follicular (FL) versus cases with diffuse areas
(DFL); (B) all cases divided according to WHO-recommended pattern
reporting; (C) all cases that are 50% or less diffuse versus cases
that are more than 50% diffuse; (D) FL3 that is more than 50% diffuse
compared with a group of 530 similarly treated DLBCL
patients.
|
|
Multivariate analysis was performed using Cox
regression25,26 to determine which factors were predictive
of OS when controlling for other factors found to be significant in
univariate analysis. The variables included were age, sex, stage,
performance score, extranodal sites, LDH level, IPI score, and
diffuse areas more than 50%. For OS, only a high IPI score (3-5) and
diffuse areas more than 50% were independent predictors. Patients with
high IPI scores had a relative risk of death of 2.2 (P = .0022) when compared with those with low IPI scores
(0-2), and patients with more than 50% diffuse areas had a relative
risk of death of 1.8 (P = .022) when compared with those
with less than or equal to 50% diffuse areas.
| |
Discussion |
The WHO has recommended the subdivision of FL3 into grades 3a and
3b based on the number of centroblasts and the presence or absence of
centrocytes. The current study is the first to analyze the clinical
relevance of this subdivision in a large group of patients with nodal
FL3 who received aggressive chemotherapy at the time of presentation. A
recent study of follicular lymphoma suggested that this morphologic
subdivision has biologic and possibly clinical
significance.16 However, that study included only 27 patients with FL3, and a subset of the patients were studied at relapse. Although that study found differences in cytogenetic alterations between FL3a and FL3b, there were no differences in OS or
EFS between those 2 groups.16 On the basis of our data, this subdivision does not appear to be clinically significant when
patients are treated with anthracycline-containing chemotherapy. Our
patients with FL3a and FL3b were clinically similar, and there were no
differences in OS or EFS. Although there was a separation of the
survival curves when comparing FL3a and FL3b (Figure 2B), with the FL3b
cases showing a trend toward inferior survival, this separation did not
reach statistical significance (P = .10). This difference
is most likely due to the fact that diffuse areas were more frequent in
FL3b. In fact, when evaluating only those cases that were 100%
follicular, ie, cases lacking diffuse areas, there was no survival
difference between FL3a and FL3b (Figure 2C).
Follicular large cleaved cell lymphoma is not recognized as an entity
in the current WHO classification. However, the Working Formulation22 did recognize large cleaved cells in
defining follicular large cell lymphoma. The 30 cases of FLC in our
study had a clinical presentation and survival similar to the FL3a and FL3b cases, suggesting that FLC is a morphologic subtype of FL3. Furthermore, when we compared our FLC group with a group of similarly treated patients with low-grade follicular lymphoma, the FLC group had
a significantly worse OS. A study of follicular large cell lymphomas by
Horning et al18 also found no difference in OS when
comparing cases composed of large noncleaved cells versus large cleaved
cells. Many FLC cases may actually be misclassified as low-grade
follicular lymphoma because they usually do not meet the strict WHO
criteria for FL3. Although FLC represents a minority subtype (16%) of
FL3, it is important to recognize this category because it appears to
behave similarly to FL3, and, therefore, the diagnosis has important
treatment implications. However, additional studies to further define
this subtype of FL3 and confirm our findings are necessary.
In the Working Formulation,22 follicular lymphoma composed
of small centroblasts (small noncleaved cells) had a more aggressive course. Nathwani et al28 also found that follicular
lymphomas with more than 10 small noncleaved cells per hpf had a
significantly worse overall survival. However, we identified only 2 cases with FL3 having a predominance of small centroblasts in our
study. Because this type of grade 3b follicular lymphoma is quite rare, multi-institutional studies will be needed to delineate whether such
cases are more aggressive.
Studies evaluating the significance of diffuse areas in
follicular large cell or FL3 have yielded conflicting results. In most
studies, the presence of diffuse areas had no effect on OS or
EFS.2-4,9,10,18 One study6 found that diffuse
areas predicted for EFS but not OS, and 2 studies7,17
found that diffuse areas were associated with a worse OS. In the study
by Bartlett et al,7 increasing percentages of diffuse
areas were associated with a significantly worse OS in univariate
analysis. In the study by Warnke et al,17 the cases with
more than 25% diffuse areas had a significantly worse OS. In the
current study, diffuse areas of more than 50% predicted for inferior
OS and EFS in both univariate and multivariate analysis. Previous
studies2-4,6,7,9,10,17,18 had populations ranging from 16 to 107 patients, and the median follow-up ranged from 47 to 67 months.
However, our current study is considerably larger (190 patients) and
also has the longest median follow-up (71 months). In addition, the
current study is restricted to patients with node-based disease. It is
not clear if other studies excluded primary extranodal cases. Finally,
17% of our study population had diffuse areas that were more than 50%. If the cases with diffuse areas included in the other series were
predominantly those with less than or equal to 50% diffuse areas, the
survival difference may not have been evident because cases with less
than or equal to 50% diffuse areas behave similarly to those without
diffuse areas. These factors may also account for our ability to find a
difference between cases with diffuse areas versus those that are
purely follicular.
It is difficult to compare our current study with previous studies
because most used the Rappaport Classification or the Working Formulation. Only 3 studies6,7,10 have used the counting criteria of Mann and Berard.15 Bartlett et
al7 also found a significantly worse OS for patients with
areas of diffuse histology. Interestingly, this was an expansion of an
earlier study18 that did not find any differences in OS in
cases with diffuse areas. Apparently, the inclusion of additional
patients and longer follow-up resulted in a significant survival
difference. In the study by Anderson et al,6 the
researchers found that diffuse areas predicted for a worse EFS but did
not predict OS. However, that study did not include patients that had
diffuse areas more than 80%, which may account for their inability to
detect a difference in OS. A third study10 found no
difference in OS for cases with diffuse areas. Although the percentage
of patients with diffuse areas (30%) in that study is similar to the
current study (38%), the researchers did not quantitate the diffuse
areas, thus making it difficult to compare the current study with their findings.
In conclusion, the subdivision of FL3 into the cytologic subtypes of
3a, 3b, and FLC does not appear to be clinically important. However, to
prevent its misclassification as a low-grade follicular lymphoma, FLC
should be recognized and considered as a morphologic subtype of FL3 for
clinical purposes. Finally, patients with FL3 with a significant
diffuse component (> 50%) have an inferior survival that is similar
to the survival of those with DLBCL. Future studies focusing on the
molecular genetic events associated with these differences would be of
great interest.
| |
Footnotes |
Submitted July 31, 2002; accepted October 25, 2002.
Prepublished
online as Blood First Edition Paper, November 7, 2002; DOI
10.1182/blood-2002-07-2298.
Supported by grant CA36727 from the National Cancer Institute,
Department of Health and Human Services.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Dennis D. Weisenburger, Department of
Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE
68198-3135; e-mail: dweisenb{at}unmc.edu.
| |
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M. Ghielmini, O. Mora, P. McLaughlin, P. Solal-Celigny, and on behalf of the Scientific Committee of the FLIPI
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Top
Abstract
Introduction