Diffuse large B-cell lymphoma: clinical implications of
extranodal versus nodal presentation – a population-based
study of 1575 cases
(NHL) arise in tissue other than the lymph node, spleen,
Waldeyer’s ring and thymus, and are referred to as primary
extranodal NHL (Otter et al, 1989; d’Amore et al, 1991).
Numerous studies have elucidated clinical differences between
nodal and extranodal NHL, including differences in aetiology,
presentation, behaviour and outcome. However, the extensive
literature on extranodal NHL is mainly comprised of smaller,
retrospective series of cases from almost every organ of the
body. Often these series were assembled by selective referral,
and only a few studies have reported consecutively collected
data from population-based registries (d’Amore et al, 1994;
Møller et al, 1994; Pedersen & Pedersen, 1996; Krol et al, 1997;
Hansen et al, 1998; Krogh-Jensen et al, 1998; Gurney et al,
1999; van der Sanden et al, 2002). The number of studies
investigating extranodal NHL as a group is more limited
(Freeman et al, 1972; Rudders et al, 1978; Otter et al, 1989;
d’Amore et al, 1991; Glass et al, 1997; Newton et al, 1997; Krol
et al, 1998; Krol et al, 2003). These studies are generally
hampered by suboptimal histopathological classification as the
studies either do not classify the lymphomas histologically, use
older classification systems, or do not report the clinicopath-
ological correlations within each NHL type. This literature is
therefore often inconclusive and contradictory. Thus, it is still
an open question whether identified clinical differences
between lymphomas presenting at different sites are attribut-
able to the presenting site per se or to differences in the
spectrum of histological subtypes at each site.
Diffuse large B-cell lymphoma (DLBCL) is the largest
subtype of NHL, comprising 30% of all lymphomas in the
West (Chan et al, 1997), and a subtype with frequent
extranodal presentation. Molecular studies have indicated
significant molecular differences between nodal and extranodal
DLBCL, suggesting that both have different genetic origins and
arguably could be regarded as separate entities (van Krieken
et al, 1990; Raghoebier et al, 1991; Clark et al, 1992; Jacobson
Michael B. Møller,1,2Niels T. Pedersen1,2
and Bjarne E. Christensen2,3
1Department of Pathology, Odense University
Hospital,2Institute of Clinical Research,
University of Southern Denmark, and
3Department of Haematology, Odense University
Hospital, Odense, Denmark
? 2004 Blackwell Publishing Ltd, British Journal
of Haematology, 124, 151–159
Received 18 August 2003; accepted for
publication 14 October 2003
Correspondence: Michael B. Møller MD, DMSc,
Department of Pathology, Odense University
Hospital, Winsløwparken 15, DK-5000
Odense C, Denmark.
Differences in genetic origin between nodal and extranodal diffuse large
B-cell lymphomas (DLBCL) exist. Using population-based data from the
registry of the Danish Lymphoma Group, the present study is the first to
analyse clinical implications of nodal versus extranodal presentation of
DLBCL. Of 4786 newly diagnosed non-Hodgkin’s lymphoma patients in a
16-year period, 1575 (33%) had DLBCL. The annual incidence rate was 2Æ9
per 100 000; 40% were extranodal. The clinical profile of patients with
extranodal DLBCL was different from the nodal DLBCL patients. Extranodal
DLBCL was associated with older age and poorer performance score, but also
lower tumour burden. In extranodal DLBCL, 51% of the cases were stage I
and 36% were stage IV, whereas the patients were relatively equally
distributed between the four stages in nodal DLBCL. For stage I patients,
extranodal DLBCL was independently associated with poor survival
(P ¼ 0Æ003). In contrast, among stage IV patients those with extranodal
DLBCL survived longer (P ¼ 0Æ009). We conclude that there are important
clinical differences between nodal and extranodal DLBCL. The addition of
these clinical results to the existing aetiological and genetic data suggests that
the distinction between nodal and extranodal DLBCL is not only
pathogenetically but also clinically important.
Keywords: non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma,
extranodal, prognosis, incidence.
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 124, 151–159
et al, 1993; Offit et al, 1994; Houldsworth et al, 1996; Kramer
et al, 1996, 1998; Grønbæk et al, 1998; Rao et al, 1998).
Clinical data specifically addressing this issue have not been
reported. Using prospectively collected population-based data
from the Danish lymphoma registry (Danish Lymphoma
Group, LYFO), the present study addresses clinicopathological
differences between 1209 nodal and extranodal DLBCL
Patients and methods
Since 1983 all new cases of primary adult NHL have been
prospectively included in the population-based LYFO registry
of the Danish Lymphoma Group covering western Denmark
(2Æ9 million inhabitants). Excluded from registration were
cases of acute lymphoblastic leukaemia, chronic lymphocytic
leukaemia and multiple myeloma. Staging procedures inclu-
ded clinical history, physical examination including all
lymphoid regions and ear–nose–throat examination, biopsy
from involved tissue, bone marrow aspirate and biopsy,
complete blood cell count, serum chemistry analysis, chest
X-ray and/or thoracic computed tomography (CT) scan,
abdominal CT scan and/or lymphangiography and abdominal
ultrasonography. The Ann Arbor staging system was used
(Carbone et al, 1971). In the rare cases with involvement of
one extranodal site but with multicentric disease, i.e. in the
skin, it was considered to be a localized disease if the
involved area was within one radiotherapy field and stage IV
otherwise. Patients were defined as having extranodal DLBCL
when the disease after the staging procedures was confined to
one or more extranodal sites and with no (or only minor)
nodal involvement (d’Amore et al, 1991; Krol et al, 2003).
Waldeyer’s ring was considered a nodal site (d’Amore et al,
1991; Krol et al, 2001). Complete response was defined as the
resolution of all pretreatment clinical and laboratory evidence
of disease for at least 1 month. Three haematopathologists
centrally review all cases entered in the LYFO registry. As of
31 December 1998, 4786 patients aged 15 years or older were
included. All cases of DLBCL (Jaffe et al, 2001) of centrob-
lastic or immunoblastic morphology diagnosed in the period
1983–98 were included in the present study. No patients were
lost to follow-up.
The patients were treated following common general LYFO
guidelines. The majority of cases with localized disease were
treated with involved-field radiotherapy (30 Gy in 15 fractions
over 3 weeks) supplemented with six to nine courses of CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone) or
CHOP-like regimens (doxorubicin was substituted with less
cardiotoxic anthracyclines such as epirubicin or mitoxantrone
in patients with a left ventricular ejection fraction of 50% or
less). A minority were treated locoregionally only (radiother-
apy and/or surgery). The standard treatment of patients with
disseminated disease was nine courses of CHOP or CHOP-like
regimens. Additional radiotherapy was given for bulky
tumours (>5 cm) or persistent lesions after chemotherapy.
Dichotomized data were compared with the chi-square test,
groups of continuous data were compared with the Wilcoxon
rank sum test, and groups of ordinal data were compared with
the Kruskal–Wallis test. The primary end-point for statistical
survival analysis was overall survival, which was defined as the
duration between the date of histological diagnosis and the
date of death of any cause or date last known alive. All analyses
were performed on an intent-to-treat basis. Overall survival
was estimated with the Kaplan and Meier method. Survival
curves were compared with the log-rank test. Factors inde-
pendently affecting overall survival were identified using a Cox
proportional hazards regression model. All P-values are two-
sided and were considered significant when <0Æ05. The
Statistical Package for the Social Sciences (SPSS) for Windows,
version 11.0.0 (SPSS Ltd, Chicago, IL, USA), was used for all
In the 16-year period between 1983 and 1998, 1575 (32Æ9%) of
4786 newly diagnosed adult NHL patients in the LYFO registry
had DLBCL. This corresponded to a mean annual incidence
rate for DLBCL of 2Æ9 per 100 000 (age-standardized to world
population 2000) aged 15 years or older. Excluded from
further analysis were cases diagnosed at autopsy, cases with
incomplete staging or incomplete data for calculation of the
International Prognostic Index (IPI) (Shipp et al, 1993), and
cases not treated with curative intent. Using these criteria, a
total of 1209 patients remained for further study. The median
age at diagnosis of the 1209 patients was 65 years. A total of
663 (55%) patients presented with localized disease. A
complete remission was achieved in 811 (67%) patients and
393 patients were alive at the end of the observation period
3Æ0–18Æ8 years). The median survival among all patients was
38 months and the 5-year overall survival was 44%.
time of7Æ8 years(range
Influence of extranodal disease on presentation
Patient characteristics according to nodal or extranodal pres-
entation are presented in Table I. In general, there was no
difference in IPI risk group allocation between patients with
nodal or extranodal disease (P ¼ 0Æ879). However, differences
emerged when individual IPI variables and other clinical factors
were analysed. Patients with extranodal disease were older (P <
0Æ001) and had poorer performance score (P ¼ 0Æ006) than
nodal cases. In contrast, tumour burden was lower, as indicated
by the lower rate of lactate dehydrogenase (LDH) elevation
(P < 0Æ001) and B symptoms (P < 0Æ001). There was also a
marked difference in Ann Arbor stage distribution (P < 0Æ001).
Whereas nodal cases where relatively equally distributed
between stages I and IV, half of the extranodal cases were
stage I and most of the remaining cases were stage IV.
M. B. Møller et al
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Comparison of Nodal and Extranodal DLBCL
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