Hodgkin Lymphoma: Diagnostic and Biological Insights
Moderators: Dr. Philippe Gaulard and Dr. Nancy Lee Harris
Section 5 -
Hodgkin Lymphoma: Diagnostic and Biological Insights
Institute of Pathology
Charité Campus Benjamin Franklin
The mystery which surrounded Hodgkin lymphoma (HL) for more than 150 years is dissipating although new
findings raise new questions. Today we know the following:
An important question which is not yet clarified is why HLs respond so well to polychemotherapy and
Non-Hodgkin lymphomas not.
- The cytokine
receptor CD30 of the TNF-receptor family is the most specific molecular marker for Hodgkin- and
Reed-Sternberg cells. However, CD30 is not restricted in its expression to Hodgkin- and Reed-Sternberg
cells. It also occurs on the tumor cells of anaplastic large cell lymphomas, diffuse large B-cell
lymphomas of the anaplastic variant, enteropathy-type T-cell lymphomas with anaplastic differentiation
and others. Outside the lymphoid systems CD30 is expressed on embryonal carcinomas. In normal lymphoid
tissues CD30 is only detectable on few perifollicular blasts. In germinal centres CD30 might be
expressed by blastoid cells located at the margin of the light zone.
- HLs are composed of two
different disease entities i.e. nodular lymphocyte predominant HL (nLPHL) and classical HL. These
two HL entities can be – thanks to differences in the immunophenotype of the tumour cells –distinguished
from each other with 100% reliability in all instances. The atypical cells of classical HL, i.e. the
Hodgkin- and Reed-Sternberg cells, are positive for CD30, CD15 and lack B-cell antigens in all or most
instances respectively. In contrast, the dysplastic cells of nLPHD (usually termed as L&H or popcorn
cells) express CD20, CD75, Oct2 and J-chain and are devoid of CD30 and CD15 in all or most instances
respectively. There are also differences in the growth patterns which can be highlighted by
immunohistochemical reactions for follicular dendritic cells using anti-CD21 antibodies.
- A novel subtype of
classical HL: In the late 90ies a new subtype of classical HL has been identified by
immunophenotyping, i.e. nodular lymphocyte-rich classical HL (LRCHL). The knowledge of the diagnostic
criteria of this subtype is important since it is easily confused with nLPHL on H&E histology. The
separation of LRCHL from nLPHL is only reliably possible by immunophenotypting. 
- Differential diagnostic
aspects: The major differential diagnosis of classical HL is its separation from anaplastic large
cell lymphoma (ALCL), diffuse large B-cell lymphoma of anaplastic variant and primary mediastinal B-cell
lymphoma. Most helpful for the differential diagnosis between classical HL and ALCL are the B-cell
lineage maintenance transcription factor PAX5, CD43 and the anaplastic lymphoma kinase (ALK). PAX5 is
expressed - although at a lower level as in reactive B cells - on Hodgkin- and Reed-Sternberg cells of
more than 95% of classical HL cases in difference to ALCL where PAX5 is consistently absent. CD43 and
ALK do not occur on Hodgkin-and Reed-Sternberg cells but are expressed on most or at least half of the
ALCL respectively. The Hodgkin- and Reed-Sternberg cells of classical HL differ immunophenotypically
from diffuse large B-cell lymphomas of analplastic variant and primary mediastinal B-cell lymphoma in
that the latter consistently express B-cell antigens as well Oct2 and BOB.1. A very important
differential diagnosis is between classical HL which has only focally affected lymphoid tissue and
reactive increase of CD30-positive blasts. Classical HL should be diagnosed only if the CD30-positive
cells have the morphological features of mononuclear Hodgkin or multinuclear Reed-Sternberg cells.
- Clinical behaviour:
Classical HL was a fatal disease till the 60ies. Over 90% of the patients died within 3 to 4 years.
This has dramatically changed with the introduction of polychemotherapy. The most advanced
polychemotherapy regimen BEACOPP has increased the long-term remission rate to over 90% even in advanced
stages. nLPHL is an indolent disease which tends to repetitious relapses. Its treatment with anti-CD20
antibodies proved to be efficient. A major advantage of this treatment modality is the avoidance of the
side effects of polychemotherapy. It appears as if patients with nLPHL were over-treated in the
- Clonality of the atypical
cells in HL: Both types of HD are a clonal lymphoproliferative disorders which start with one
single transformed lymphoid cell. This finding induced the WHO to regard Hodgkin's disease as a true
lymphoiod neoplasm and rename Hodgkin's disease into Hodgkin lymphoma (HL).
- Cellular derivation:
Single cell studies have demonstrated that the tumour cells of LPHL are derived from B-cells in 100% and
of classical HL in 98-99% of the cases. In the residual classical HL cases the tumour cells originate
from T cells.
- The differentiation stage
of the B cells from which LPHL and classical HL of B-cell type originates has been identified as
that of the germinal centre B cells. 
- Lack of immunoglobulin
expression: The tumour cells of classical HL have lost their capacity to express immunoglobulin
(Ig) in all and B-cell antigens in most instances and instead express B-cell inappropriate antigens like
GATA3, T-bet, CD2, CD3, CD4, and others in varying frequencies.
- Cause of the non-expression
of Ig : This is due to a defect in the transcription machinery in which down-regulation of the
transcription factors Oct2, BOB.1, PU.1 and epigenetic factors are involved.
- Extinction of the B-cell
expression program. This in conjunction with the expression of B-cell inappropriate proteins is –
at least partially – due to intrinsic inhibition of the transcription factor E2A by HLH proteins ABF-1
and Id2. 
pathways: Several pathways are dregulated, e.g. CD30, NF-kB, AP-1 and Notch-1.
- Effects of deregulated
pathways: The result of the deregulated pathways is the up-regulation of several anti-apoptotic
molecules (e.g. TRAF1, XIAP, cIAP2, c-FLIP, pro-proliferative molecules cyclin D2 and certain chemokine
receptors, e.g. CCR7.
- Preferential dissemination
in lymph nodes: The up-regulation of the chemokine receptor CCR7 in Hodgkin and Reed-Sternberg
cells appears to be mainly responsible for growing in lymph nodes and not in extranodal sites.
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- Hopken UE, Foss HD, Meyer D, Hinz M, Leder K, Stein H, Lipp M. Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. Blood. 2002 Feb 15;99(4):1109-16