Hodgkin Lymphoma: Diagnostic and Biological Insights
Moderators: Dr. Philippe Gaulard and Dr. Nancy Lee Harris
Section 2 -
Nodular Lymphocyte Predominant Hodgkin's Lymphoma and T-cell rich/
Histiocyte-rich Large B-cell Lymphoma
Chris De Wolf-Peeters
Nodular lymphocyte predominance Hodgkin's lymphoma (NLPHL), is a particular subtype of Hodgkin's
lymphoma (HL) characterized by distinct morphologic, phenotypic and clinical features. It has been
recognized for almost 70 years. In 1944 it was designated as "paragranuloma" by Jackson and Parker.
Later on a nodular and a diffuse type were described, which were grouped together as lymphocyte
predominance Hodgkin's disease (LPHD) at the Rye conference. In Europe the term "paragranuloma" has
remained in use to indicate the nodular form of LPHD. In the REAL classification LPHD was listed as a
distinct clinico-pathological entity, separately from all other subtypes of Hodgkin's disease (HD) that
were termed "classic HD" (cHD).
 In the
World Health Organization (WHO) Classification, the term
Hodgkin's disease was changed to Hodgkin's lymphoma (HL), in recognition of the fact that this is now
known to be a lymphoid neoplasm. 
NLPHL affects the B follicle resulting in its nodular growth pattern, in contrast to cHL, which
localizes in the extra-follicular compartment. The aberrant, enlarged follicles show fragmentation of
their germinal centre. These centers are supported by a disrupted follicular dendritic network that can
be visualized by CD21 staining. The atypical cells of NLPHL display a particular morphology by which
they are referred to as "popcorn" cells; these atypical cells are rather distinct from the Reed Sternberg
cells in cHL. Moreover these popcorn cells express B cell antigens (e.g. CD20), which are either not
expressed or expressed weakly and variably on classic Reed Sternberg cells. Furthermore, popcorn cells
lack expression of CD15 and CD30, two markers characteristically expressed by classic Reed Sternberg
Besides these features of the atypical cells, the stromal component is of equal interest in NLPHL. It
is quite distinct from that found in cHL as the majority of the small lymphocytes are B cells. As in cHL
the atypical cells are surrounded by T cells. Together with some small clusters of T cells within the
expanded nodules, they express CD57, a finding that can be of diagnostic help. Further studies on the
stromal T cells in NLPHL demonstrated that these CD4+ T cells, in particular those rosetting around the
popcorn cells, express nuclear BCL6 while they lack CD40L expression. T cells surrounding classic Reed
Sternberg cells, on the other hand, lack expression of BCL6 whereas they do express CD40L.  There is
some variability within the morphological features of NLPHL, which largely results from the occasional
presence of small clusters of epitheloid cells and from the number of T cells within the affected B
follicles. As such the picture may resemble T cell rich/histiocyte rich large B cell lymphoma (THRLBCL)
as discussed below.
Despite these distinctive features, the disease has several mimics and/or morphological variants. In
a European task force study on LPHL, supposed to include a large number NLPHL cases, collected from
different centers in Europe and the United States, the diagnosis could be confirmed on review in only 56%
of the cases.  One of the main mimics/variants shares with NLPHL a nodular growth pattern and a
stromal reaction, predominantly composed of B cells. The atypical cells however express a classical
phenotype, showing CD15 and CD30 positivity without CD20 staining. This mimic/variant has been
designated as nodular lymphocyte-rich classic HL (NLRCHL) and has formerly been described as follicular
HL. In NLRCHL, atypical cells occur within an expanded mantle of the B follicle sparing out a residual
atrophic germinal centre. In addition a diffuse variant of NLPHL sharing all features with NLPHL, except
for the nodular growth pattern, was recognized.
NLPHL and NLRCHL have several clinical and behavioral features in common, distinguishing them from
other subytpes of cHL.  Both predominantly affect male patients leading to early-stage disease with
low risk factors at presentation. They infrequently have B symptoms, a bulky disease or a mediastinal
mass. Overall survival and disease free survival are similar and mainly stage-dependent. Complete
remission is obtained in 95% of both types. Relapses, based on clinical parameters and radiological
imaging, are reported to occur in almost one third of the patients suffering from NLPHL. Nevertheless
lymphadenopathy occurring in these patients may result from the presence of progressively transformed
follicles without proven disease recurrence.
Whether NLPHL is a monoclonal or a polyclonal proliferation has been debated for a long time. Indeed
only few studies could demonstrate a monoclonal immunoglobulin gene rearrangement most probably due to
the admixture of numerous stromal, reactive, polyclonal B cells associated with the atypical cells.
Molecular genetic studies on single, microdissected Reed Sternberg cells have demonstrated that these
cells are clonally related, transformed B cells with somatically mutated immunoglobulin genes.
The latter feature is very characteristic for germinal centre B cells and their descendants. The
expression of BCL6 by popcorn cells is in line with this concept.  This nuclear protein is
considered to be rather specific for germinal centre cells.
The differential diagnosis of NLPHL and NLRCHL from THRLBCL is the most problematic. The recognition
of THRLBCL as a clinico-pathological entity is still a matter of debate. The presence of high numbers of
T cells within follicular centre lymphomas has been indicated as a caveat for pathologists  and has
resulted in the introduction of the name "T cell rich B cell lymphoma".
In 1992 Delabie et al.  described a particular B cell lymphoma rich in histiocytes as well as T
cells and mimicking NLPHL by morphology; the term, T-cell-rich/histiocyte-rich large B-cell lymphoma
(THRLBCL) has been applied to this tumor. This lymphoma is characterized by a diffuse or vaguely nodular
growth pattern, a background of non-epitheloid histiocytes and reactive T cells, and a limited number of
scattered large atypical B cells. The atypical B cells display some features of popcorn cells though
being somewhat smaller in size. They express B cell markers but are negative for CD15 and CD30. Small B
cells or remnants of B follicles are nearly absent and no underlying follicular dendritic cell meshwork
is found to support the neoplastic proliferation. This lymphoma does not occur within the B follicle but
affects the extra-follicular compartment while T cells around the atypical B cells are CD57 negative.
 The disease affects mainly elderly male patients. They frequently present with stage III and IV
disease, splenomegaly, hepatomegaly and bone marrow involvement. It is a very aggressive behavior with
virtually no response to therapy.  In some of these patients splenomegaly is the main symptom. In
these cases, splenectomy will reveal a unique morphologic image referred to as "micro-nodular" THRLBCL.
 A particular subtype of large B cell lymphoma characterized by a "host inflammatory response" has
been identified recently. Some cases of this particular subtype featured characteristics of THRLBCL by
morphology and by clinical parameters. 
THRLBCL should be recognized from B cell lymphomas rich in stromal T cells on the one hand, and from
NLPHL on the other. In the former situation the T cell rich stroma might suggest the presence of
peripheral T cell lymphoma. Such pseudo-T cell lymphomas should be correctly diagnosed as B cell
lymphoma. In most cases the precise subtype of B cell lymphoma can be given.
The differentiation of THRLBCL from NLPHL can be more problematic. Several authors have speculated
that THRLBCL evolves from NLPHL.
In one of these studies  both disorders were compared by
evaluating a series of 218 cases: in that series 17 cases were considered to belong to a gray zone
between both lymphomas. These cases were characterized by neoplastic nodules comprising the atypical B
cells and as such simulating THRLBCL. These nodules were however supported by a dendritic cell network
and almost depleted of small B cells. Of interest, cases with this "gray zone" morphology show a high
stage disease and B symptoms at presentation but behave like NLPHL. These findings illustrate the
existence of a morphological continuum between both disorders. It can be questioned if this reflects a
biological continuum as high numbers of T cells within the neoplastic nodules of NLPHL can occur.
The molecular genetic background of NLPHL and THRLBCL is difficult to explore, as the number of
atypical B cells in both conditions is very low. Karyotyping was successful in a limited number of cases
only and no recurrent abnormalities have been described. Comparative genomic hybridization performed on
DNA obtained from microdissected tumor cells demonstrated that chromosomal imbalances are more numerous
in NLPHL as compared to those found in THRLBCL. This finding argues against the hypothesis that THRLBCL
develops from NLPHL, as tumor progression mostly goes together with an increased number of chromosomal
abnormalities. Of interest the atypical B cells in NLPHL and in THRLBCL share imbalances on chromosome
4q and 19 suggesting a similar precursor for both disorders.  Both disorders may develop into more
typical large B cell lymphoma; in NLPHL this large B cell lymphoma will be less aggressive than de novo large B cell lymphomas. Large B cell lymphomas developing from THRLBCL,
on the contrary, herald a short term adverse outcome. 
Given the bad prognosis of THRLBCL further characterization of its inflammatory host response will be
helpful to identify new and more appropriate therapeutic approaches.
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