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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4708-4714
Follicular Lymphomas Contain a Clonally Linked But Phenotypically
Distinct Neoplastic B-Cell Population in the Interfollicular Zone
By
Ahmet Dogan,
Ming-Qing Du,
Antonella Aiello,
Tim C. Diss,
Hong-Tao Ye,
Lang-Xing Pan, and
Peter G. Isaacson
From the Department of Histopathology, UCL Medical School, London, UK
and the Divisione di Anatomia Patologica, Instituto Nazionale Tumori,
Milano, Italy.
 |
ABSTRACT |
Follicular lymphomas are thought to arise from the follicle center B
cells and are characterized by follicular structures that recapitulate
many features of normal secondary lymphoid follicles. The neoplastic B
cells of follicular lymphoma reside not only in follicles but also in
the interfollicular zone in which they form a diffuse infiltrate. We
have investigated the frequency, extent, and biological characteristics
of this interfollicular component in 30 cases of follicular lymphoma.
An interfollicular B-cell infiltrate of variable extent (minimal,
moderate, or prominent) was present in all cases. Morphologically
interfollicular neoplastic B cells were small centrocyte-like cells
with lower grade cytology and lower proliferation fraction compared
with the neoplastic follicles. The neoplastic phenotype of these cells
(CD20+, light chain restricted) was confirmed in 18 cases. Clonal identity between the follicular and interfollicular
components was shown in five cases using microdissection and PCR
amplification of immunoglobulin heavy chain genes. Analysis of Ig heavy
chain gene sequences showed identical variants of tumor subclones in
both follicular and interfollicular compartments, indicating active
tumor cell traffic between the two. In six cases in which frozen tissue
was available, the immunophenotype of follicular and interfollicular
tumor cells were compared using immunohistochemistry. Activation
markers such as CD10, CD38, and CD95 and T-cell costimulatory molecules
CD80 and CD86, which were expressed by neoplastic follicles, were
either downregulated or absent in the interfollicular component in most
of the cases. The low-grade cytological features, low proliferation
fraction, and downregulation of activation markers in the
interfollicular neoplastic B cells suggests that these are resting
cells analogous to memory B cells of normal lymphoid tissues. The
presence of such a resting tumor cell subpopulation in the majority of
follicular lymphomas may partly account for the remarkable resistance
to therapy of this disease.
| |
INTRODUCTION |
FOLLICULAR LYMPHOMA is the most common
variety of non-Hodgkin's lymphoma in the West, accounting for 40% to
50% of all cases in the United States1-4 and 35% in
England and Wales.5 Although histologically low grade and
clinically indolent, follicular lymphoma is incurable and most patients
die of the disease within 7 to 10 years from the time of
diagnosis.6-8 Recent attempts to devise successful
therapies for follicular lymphoma have focused on ablation of the
malignant B-cell clone using both radiotherapy and chemotherapy followed by bone marrow transplantation,7,8 or biological therapy based on antibodies to tumor immunoglobulin or B-cell antigens.9 In either case an understanding of the cell
biology of the disease is essential because it is necessary to identify the target (ie, which cells need to be killed). In this context it has
long been assumed that the neoplastic cells of follicular lymphoma
constitute a homogeneous population of follicle center cells
(centrocytes and centroblasts) that reside in neoplastic follicle
centers. It is, therefore, these cells that comprise the neoplastic
follicles that constitute the therapeutic "target."
In follicular lymphomas, the presence of a separate interfollicular
neoplastic B-cell population that infiltrate in a diffuse pattern
between the follicles was first noted by Rappaport.10 The
neoplastic nature of these cells was confirmed by Harris et al11,12 using immunohistochemistry to show light chain
restriction in cryostat sections. These interfollicular neoplastic B
cells should not be confused with the diffuse component that has often been described complicating follicular lymphoma, which is essentially an expression of focal high-grade transformation.13
Although this interfollicular population has been recognized for some
time, it has never been characterized in any detail. This could be an important omission because it is conceivable that these interfollicular cells may be relevant to the therapeutic resistance of follicular lymphoma. We have, therefore, investigated the frequency, extent, and
biological characteristics of the interfollicular component of
follicular lymphoma.
| |
MATERIALS AND METHODS |
Tissues.
Paraffin-embedded blocks from 30 cases of classical follicular lymphoma
were retrieved from the archives of the Department of Histopathology,
UCL Medical School, London, UK. Frozen tissue blocks were available in
6 of the cases studied.
Histology.
Routine hematoxylin and eosin (H&E) stained sections were prepared in
each case. The morphological features of follicular lymphoma were
confirmed and the cytological features of any interfollicular component
noted.
Immunohistochemistry.
Immunohistochemistry was performed on both paraffin sections and frozen
sections using an avidin-biotin-peroxidase technique preceded by heat
retrieval of antigenicity where required.14 The list of
antibodies used for immunostaining is shown in
Table 1. A sequential double immunostaining
technique was used to show proliferating T (Ki67/CD3) and B (Ki67/CD20)
cells in frozen sections.15
The extent of the interfollicular neoplastic (CD20+,
IgD ) B-cell component was estimated in serial paraffin
sections and confirmed where possible in serial sections stained for
immunoglobulin (Ig) light chains. In two cases in which the tumor cells
expressed IgD, the extent of the neoplastic interfollicular component
was estimated in sections stained for Ig light chains. The
interfollicular component was estimated as minimal (+) when less than
10% of all neoplastic B cells were in the interfollicular zone,
moderate (++) when between 10% to 30% of all neoplastic B cells were
in the interfollicular zone, and prominent (+++) when more than 30% of
all neoplastic B cells were in the interfollicular zone.
The proliferation fraction of follicular and interfollicular components
was determined semiquantitatively by estimating the percentage of cells
expressing the Ki67 antigen in respective compartments as follows:
( ), if there is no expression of Ki67; (+/), if 0% to 5% of the
cells express Ki67; (+), if 5% to 15% of the cells express Ki67;
(++), if 15% to 30% of the cells express Ki67; and (+++), if more
than 30% of the cells express Ki67.
Molecular genetics.
The Ig genes were polymerase chain reaction (PCR) amplified from
framework (Fr)2 or Fr3 to the joining (JH) region with a seminested PCR protocol16 using DNA extracted from
microdissected follicles and interfollicular tissue identified by
appropriate immunostaining of cryostat sections with either CD10, CD21,
or both. Microdissection was performed using the method of Pan et al.17 All PCR reactions were performed using a hot start
procedure18 and appropriate positive (a B-cell lymphoma)
and negative controls (without template DNA) were included in each
experiment. All samples were analyzed in duplicate.
PCR products were purified on Sephacryl S-400 MicroSpin columns
(Pharmacia, St Albans, UK), ligated to TA cloning vector pCR II, and
transfected into One Shot competent cells (INVaF') according to the
manufacturer's protocol (Invitrogen, Leek, The Netherlands). The
transfected cells were plated onto LB-ampicillin agar plates containing
X-gal. White colonies were transferred to a fresh LB-ampicillin agar
plate containing X-gal and grown overnight for secondary selection.
Confirmed white colonies were then transferred into 150 µL of LB
medium containing 50 g/mL ampicillin and cultured at 37°C for 4 hours. The cultures (100 µL) were centrifuged, resuspended in 20 µL
of water, and heated at 98°C for 10 minutes. After centrifugation, the resulting supernatants were used for PCR with vector primers Sp6
and T7.
The PCR products showing the expected insert size were sequenced using
an ABI sequencer with dye terminators (Perkin Elmer, Warrington, UK).
In each case, at least six PCR clones from each follicular or
interfollicular cell population were sequenced. All sequencing was
performed in both orientations.
The identification of VH and JH germline sequences
was performed by sequence comparison with the V BASE, which is a
comprehensive database of human immunoglobulin germline gene sequences
compiled from the published sequences by
Tomlinson,19 using online DNAPLOT. Mutations in VH
were identified by comparing the tumor sequence with the closest
published germlines, whereas mutations in the CDR3 region were recorded
according to the most closely related PCR clone.
| |
RESULTS |
The majority of follicular lymphomas contain an Ig light chain
restricted neoplastic B-cell population in the interfollicular zone.
Examination of the H&E stained sections from 30 cases of follicular
lymphoma showed that all cases contained varying degrees of
interfollicular tissue between the neoplastic follicles
(Fig 1A, C, and E). Cytologically, this
tissue comprised small lymphocytes and a variable population of
slightly larger cells with dense euchromatic nuclei showing slight to
moderate irregularity of their nuclear outline (Fig 1G and H). These
cells resembled the intrafollicular small centrocytes (small cleaved
cells) but were, nevertheless, cytologically distinctive. Only
occasional centroblasts (large noncleaved cells) were present.
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| Fig 1.
Interfollicular neoplastic B cells in follicular
lymphoma. (A-F) Three cases of follicular lymphoma with minimal (case
8; A, B), moderate (case 13; C, D), or prominent (case 2; E, F)
CD20+ interfollicular neoplastic B-cell component. (G, H)
High-power view of follicular (G) and interfollicular (H) components
showing lower-grade cytology of interfollicular cells in case 13. (A, C, E, G, and H, H&E; B, D, and F, immunoperoxidase)
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A significant proportion of the interfollicular cells were
CD20+ (Table 2 and Fig 1B, D,
and F) including a minor component of IgD+ small
lymphocytes (mantle zone cells) around follicles and scattered in the
interfollicular zone (Fig 2A and B).
Immunostaining for Ig light chains showed identical light chain
restriction in the follicular and interfollicular compartments in 18 cases (68%) including 2 cases in which the neoplastic cells were
IgD+ (Fig 2C and D). The extent of interfollicular B-cell
component varied between the cases (Table 2). It was minimal in 3 cases (Fig 1A and B), moderate in 15 cases (Fig 1C and D), and
prominent in 12 cases (Fig 1E and F).
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| Fig 2.
Immunophenotype of interfollicular neoplastic B cells in
paraffin sections of follicular lymphoma. (A-F) Serial sections of a
follicular lymphoma (case 13) immunostained for CD20 (A), IgD (B), Ig
 light chain (C), Ig  light chain (D), Ki67 (E), and bcl-2
protein (F). There are numerous CD20+ B cells both in the follicles and
the interfollicular zone. IgD+ cells are concentrated in a narrow
follicular mantle and scattered in the interfollicular area. There is
Ig light chain restriction both in the follicular and
interfollicular B cells showing the neoplastic nature of both cell
populations. Immunostaining for Ki67 antigen shows that follicular neoplastic B cells have a much higher proliferation fraction than the
interfollicular component (E) and Bcl-2 immunostaining shows that bcl-2
is expressed by both follicular and interfollicular neoplastic B cells
(F). (A-F, immunoperoxidase)
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Immunostaining also showed numerous CD3+ small lymphocytes
(T cells) in the interfollicular zone with a CD4:CD8 ratio of
approximately 4 to 3:1. Both T-cell subsets were also present within
neoplastic follicle centers in which CD4+ cells
predominated.
The proliferation fraction determined with the antibody MIB-1 was
significantly higher in the follicles, although lower than expected for
reactive follicles, than in the interfollicular compartment (Table 2
and Fig 2E). Double immunohistochemical staining with CD20 or CD3 and
MIB-1 showed that in contrast to the follicles, the majority of cells
expressing the Ki67 antigen in the interfollicular compartment were T
cells. In all cases both follicular and interfollicular components
showed bcl-2 expression (Table 2 and Fig 2F).
The neoplastic B cells in the interfollicular zone have a resting
phenotype compared with the activated phenotype of follicular
neoplastic B cells.
The expression of cell surface molecules that are known to be
induced in normal follicle center B cells were examined in frozen sections of six cases, all of which contained a light chain restricted interfollicular neoplastic B-cell component
(Table 3 and
Fig 3A, C and D). CD10 was
expressed by the follicular component in all six cases but was either
downregulated or absent in the interfollicular component in four of the
six cases (Table 3 and Fig 3B). CD38 was expressed by the neoplastic
follicles in all six cases and downregulated in the interfollicular
B-cell component in five (Table 3 and Fig 3E). T cells both in the
interfollicular and follicular compartments were also labelled with the
CD38 antibody. Staining for CD95 (fas antigen) showed weak expression
in neoplastic follicles in all cases. The interfollicular B cells were
CD95 negative in 4 cases but stained with similar intensity to the follicles in the remaining 2 cases (Table 3 and Fig 3F). The T-cell
costimulatory molecules CD80 and CD86 were both expressed, albeit
weakly, in the neoplastic follicles in all cases. In the interfollicular component the expression of CD80 was either
downregulated or absent in 5 cases whereas CD86 was downregulated in
all cases (Table 3 and Fig 3G and H). In some cases the dendritic cells in the interfollicular zone expressed CD80 and CD86.
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Table 3.
Differences in the Intensity of Staining in
Interfollicular Component Compared With Follicular Component in Six
Cases in Which Frozen Tissue Was Available
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| Fig 3.
Immunophenotype of interfollicular neoplastic B
cells in frozen sections of follicular lymphoma. (A-F) Serial sections
of case 6 immunostained for CD20 (A), CD10 (B), Ig light chain (C),
Ig light chain (D), CD38 (E), and CD95 (F). The interfollicular zone contains an Ig light chain restricted B-cell population. CD10,
CD38, and CD95 are expressed by the neoplastic follicle but not by the
neoplastic B cells of the interfollicular zone. (G,H) Sections of case
1 immunostained for CD80 (G) and case 2 for CD86 (H) show that CD80 and
CD86 are expressed in the follicles but are downregulated in the
interfollicular zone. (A-H, immunoperoxidase)
|
|
Analysis of rearranged Ig heavy chain genes confirms the clonal
identity of interfollicular and follicular components.
The clonal identity of follicular and interfollicular components
was confirmed by analysis of rearranged Ig heavy chain genes from Fr2
to JH with PCR amplification in 5 of the 6 cases in which frozen material was available. PCR amplification of microdissected fragments from follicular and interfollicular areas showed
identical-sized dominant bands from either site in each of these cases.
In case 5, the rearranged Ig heavy chain gene could not be amplified
with either Fr2 or Fr3 primers. The PCR products from cases 1, 2, and 3 were cloned and sequenced. In each case the dominant clone from either
site had the same CDR3 sequence (Fig 4).
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| Fig 4.
Intraclonal Ig sequence variations in case 1. Identity
with the germline sequence is shown by dashes, replacement mutations are shown by uppercase letters, and silent mutations are shown by
lowercase letters. Sequence variations are highlighted in bold. The
primer sequences are not included. F, follicular neoplastic B cells;
IF, interfollicular neoplastic B cells. s prefix indicates clones
analyzed from a separate tissue block; and * indicates nucleotide
deletions.
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Mutation analysis indicates active traffic between follicular and
interfollicular compartments.
In each of the three cases sequenced, cell populations of both
follicular and interfollicular compartments showed frequent intraclonal
Ig gene sequence variations (Fig 4, Table
4), which were well above the PCR error rate (<0.2%) in the system
used. There was no significant difference in the frequency of
intraclonal variations between the two neoplastic cell populations
(Table 4). In addition, identical variants of the tumor subclones were observed between the two compartments in each case, such as follicular clones sF6, sF16, and interfollicular clone sIF4, as well as follicular clone sF19 and interfollicular clone IF4 in case 1 (Fig 4 ). Similar results were observed when cell populations of follicular and interfollicular compartments from independent blocks were examined (performed in case 1; Fig 4).
| |
DISCUSSION |
This study shows that significant numbers of B cells are present
between the follicles in most cases of follicular lymphoma. Because
these cells express the same light chain and harbor the same rearranged
Ig heavy chain gene as the neoplastic follicle center cells, they are
clearly part of the same neoplastic clone. These interfollicular tumor
cells are dispersed diffusely between the neoplastic follicles, without
disturbing the overall follicular architecture of the tumor, and often
constitute a substantial component of the lymphoma. This together with
the observation of identical variants of tumor subclones in both
follicular and interfollicular compartments, indicates that there is
tumor cell traffic between the two compartments. Because there is no
difference in the degree of intraclonal sequence variation between the
two compartments and somatic mutations of the Ig gene are introduced only in the follicle,20 the tumor cell traffic must be
active. Thus, it appears that the tumor cells, which originate from the follicle center B cells, constantly travel from the follicle to the
interfollicular region, then return back to the follicle. Similar
events are also observed in other low-grade B-cell lymphomas such as
the lymphomas of mucosa-associated lymphoid tissue
(MALT).21,22 The neoplastic B cells of MALT lymphomas
normally diffusely infiltrate between the reactive follicles
characteristically present in this disease and have the phenotypic and
genotypic features of postfollicular B cells. However, they may
selectively colonize reactive follicle centers and can closely resemble
follicle center B cells. This interaction between the two compartments
in both follicular lymphoma and MALT lymphoma may represent an
important mechanism underlying the tumor progression.
Despite the presence of active traffic between the follicular and
interfollicular compartments, the phenotypic features remain distinct
between the follicular and interfollicular neoplastic cell
populations. The interfollicular tumor cells are small- to medium-sized
cells that resemble the follicle center centrocytes, but are
cytologically of lower grade. Importantly, this population is not
related to the diffuse component of so-called mixed follicular and
diffuse lymphoma in which the diffuse component is usually composed of
cytologically higher-grade cells.13
When compared with the cells comprising the neoplastic follicles,
the immunophenotype of the interfollicular cells is consistent with
their lower cytological grade and, in keeping with this, significantly
fewer of these cells are in cell cycle. The immunophenotype of the
neoplastic interfollicular cells is similar to that of a subpopulation
of postfollicular B cells observed outside the follicles in normal
lymphoid tissue.8,23-25 Like the neoplastic interfollicular
cells these have downregulated expression of follicle center activation
markers such as CD10, CD38, and CD95. They are thought to be memory B
cells that have differentiated from the follicle center B cells. It is
possible, therefore, that the interfollicular neoplastic B cells in
follicular lymphoma are an analogous population that is the result of
differentiation of neoplastic follicle center cells. It appears that
differentiation towards a cell with a more mature phenotype and a lower
proliferation fraction is a normal occurrence in follicular lymphoma.
Distinct phenotypic differences between the follicular and
interfollicular components suggests that responses of these two cell
populations to various treatment regimes could be different. The
interfollicular neoplastic B cells are likely to be less sensitive to
chemotherapy and radiotherapy than the intrafollicular cells with their
larger nuclei and higher proliferation fraction.26 Based on
clinical observations, Longo27 has suggested that there are
two tumor cell populations in follicular lymphoma with different sensitivities to chemotherapy and radiotherapy. Our study supports this
notion but suggests that the two populations are comprised of
follicular and interfollicular cells rather than small and large
intrafollicular cells (centrocytes and centroblasts) as proposed by
Longo.
Downregulation of expression of T-cell costimulatory molecules, CD80
and CD86, in tumor cells has been proposed as a possible mechanism
developed by follicular lymphomas to escape immune
surveillance.25 Expression of CD80 and CD86 is even lower
in the interfollicular component than the follicular component, which
suggests that the interfollicular tumor cells are likely to be even
more resistant to natural or induced T-cell mediated antitumor immunity
than their follicular counterparts.
Given that there is a two-way traffic of neoplastic B cells
between follicular and interfollicular compartments as shown by the
analysis of Ig heavy chain genes, then it is likely that the interfollicular tumor cells have the capacity to acquire an activated phenotype when the conditions are right. Thus, the interfollicular component could provide a reservoir of tumor cells for the progression of the follicular lymphoma after treatment, which may account for the
remarkable therapeutic resistance of this disease. Conceivably, it is
these cells that constitute the optimum target for the treatment of
follicular lymphoma.
| |
FOOTNOTES |
Submitted September 22, 1997;
accepted February 10, 1998.
Supported by the Cancer Research Campaign and the Leukaemia Research
Fund.
Address correspondence to Professor Peter G. Isaacson, Department of
Histopathology, UCL Medical School, Rockefeller Building, University
St, London WC1E 6JJ, UK; e-mail: p.isaacson{at}ucl.ac.uk.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract