Page 1358 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 74

ORIGIN OF HODGKIN LYMPHOMA

Ralf Küppers

INTRODUCTION is rearranged to one J H gene segment. In the next step, a V H gene
segment is rearranged to a D H-J H joint. A heavy chain can be expressed
More than 150 years ago, Thomas Hodgkin described several cases and the developmental stage of a pre-B cell is reached if the rearrange-
of a lymphoproliferative disease, later named Hodgkin disease. For a ment is in-frame and productive. In the next step, V κ to J κ rearrange-
long time this malignancy, now called Hodgkin lymphoma (HL), has ments occur to generate a κ light chain. If this is not successful, V
been one of the most enigmatic forms of lymphomas. This is due to gene rearrangement processes take place at the λ light chain locus. B
several key features of the disease: First, the pathognomonic and cells expressing a functional (and nonautoreactive) BCR are released
suspected tumor cells of HL, the mononuclear Hodgkin and the into the periphery and express their BCR as IgM and IgD receptors—
bi- or multinucleated large Reed-Sternberg cells, are very rare in the that is, two different classes of the heavy chain constant region. The
tumor tissue, often accounting for only about 1% of the cells. Thus first D H-J H rearrangements are not completely specific for B-lineage
the molecular analysis of these cells was hampered until methods cells, but V H D H J H rearrangements and light chain gene rearrange-
became available to isolate these cells by microdissection from tissue ments are highly specific for B cells. Thus their detection in a cell
sections. Second, the Hodgkin and Reed-Sternberg (HRS) cells have unequivocally defines that cell as a B cell. Moreover, because of the
a very unusual immunophenotype that does not resemble any normal availability of multiple V, D, and J gene segments and additional
cell in the hematopoietic system. Therefore immunophenotyping, diversity generated at the joining sites of the rearranging gene seg-
which was very informative in revealing the cellular derivation of ments, a V(D)J rearrangement (in particular for the heavy chain
most other lymphoid malignancies, did not help to uncover the locus) is unique for each B cell and thus can be used as a clonal marker
cellular origin of HRS cells. Third, only a few cell lines could be for B cells deriving from the same mature B cell.
established from patients with HL, these lines were rather heteroge- If B cells are activated through binding of antigen to their BCR
neous, and for hardly any of these lines was the derivation from the and through cognate help from T-helper cells, the cells undergo a
HRS cells in the patient unequivocally shown. Hence it was initially T-dependent immune response in specific histologic structures, the
difficult to draw firm conclusions from the study of such lines. germinal centers (GC), in lymph nodes or other secondary lymphoid
Although HL still harbors many secrets, exciting novel insights into organs. In these follicles, activated B cells undergo massive clonal
the cellular origin of the HRS cells and the pathogenetic processes in expansion and further diversify their BCR through two processes:
their generation have been obtained in recent years, which will be somatic hypermutation and class switching. The process of somatic
discussed in this chapter. hypermutation introduces point mutations and some deletions and
duplications at a very high rate into the Ig heavy and light chain V
region genes. This randomly modifies amino acids in the V regions,
CLASSIFICATION OF HODGKIN LYMPHOMA and in a selection process involving follicular dendritic cells and
follicular T-helper cells, B cells expressing mutated BCR with
HL is subdivided into classical HL, which accounts for about 95% increased affinity to the stimulating antigen are positively selected,
of cases, and nodular lymphocyte predominant HL (NLPHL). The whereas B cells acquiring unfavorable mutations undergo apoptosis
tumor cells are called HRS cells in classical HL and lymphocyte pre- within the GC microenvironment (Fig. 74.1). Unfavorable mutations
dominant (LP) cells in NLPHL (until recently the tumor cells in include clearly destructive mutations, such as nonsense mutations
NLPHL were called lymphocytic and histiocytic [L&H] cells). Classical and deletions or duplications causing reading frame-shifts that
HL and NLPHL differ in the histologic picture, the morphology and prevent expression of a BCR as such. Other disadvantageous replace-
immunophenotype of the tumor cells, and multiple clinical features. ment mutations still allow BCR expression, but reduce the affinity
Classical HL is further subdivided into four subforms: nodular to the antigen. After multiple rounds of proliferation, mutation, and
sclerosis, mixed cellularity, lymphocyte-rich classical, and lymphocyte selection, positively selected B cells expressing a high-affinity BCR
depletion HL. Again, differences in the histologic picture and HRS differentiate into long-lived memory B cells or plasma cells and exit
cell morphology are the basis for this subtyping (see Chapter 73 for the GC. Many GC B cells also undergo class switching before they
a detailed description). are selected into the memory or plasma cell pool. In class switching,
the originally expressed Cµ and Cδ heavy chain constant region genes
(encoding IgM and IgD, respectively) are replaced by downstream
B-cell Development and Differentiation located Cγ, Cα, or Cε genes, encoding IgG, IgA, and IgE heavy
chains, respectively, so that antibodies with altered effector functions
Because we now know that HRS and LP cells are derived from B cells are generated. At all stages of their development, B lineage cells are
(see later), a brief outline of B-cell development and differentiation selected for expression of the appropriate BCR, and cells failing this
is given first. B cells are generated in the bone marrow from hema- selection are eliminated.
topoietic stem cells in a multistep developmental process. The key
determinant for B-cell development is the generation of a functional
B-cell receptor (BCR) that is composed of two identical immuno- Cellular Origin of Lymphocyte Predominant Cells in
globulin (Ig) heavy chains and two identical light chains, the latter Nodular Lymphocyte Predominant Hodgkin Lymphoma
of which can be of the κ or λ type. B-cell development is initiated
when common lymphoid progenitors undergo gene rearrangements LP cells in NLPHL express multiple typical B cell markers, such as
at the Ig gene heavy chain locus. The variable part of the antibody the surface molecules CD20 and CD79 and the transcription factors
1
heavy chain is composed of three gene segments: variable (V), diver- PAX5, OCT-2, and BOB1 (Table 74.1). LP cells mostly lack expres-
sity (D), and joining (J). First, a randomly selected D H gene segment sion of markers of other hematopoietic cell lineages, thus their

1204