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Management of High-Grade Lymphomas

Management of High-Grade Lymphomas

ABSTRACT: High-grade non-Hodgkin’s lymphomas generally refer to immunoblastic lymphoma, lymphoblastic lymphoma, and small-noncleaved-cell lymphoma, three histological subtypes that were associated with the worst prognosis at the time of categorization 16 years ago in the Working Formulation for Clinical Usage. Small-noncleaved-cell lymphoma was classified further into Burkitt’s lymphoma and non-Burkitt’s lymphoma. The treatment of high-grade lymphomas in adults remains somewhat unfavorable today. In children, however, survival rates of 80% to 90% are being achieved with intensive short duration protocols. In this article, the management of Burkitt, Burkitt-like, and lymphoblastic lymphomas is discussed as is the possibility of improved survival in adults using treatment strategies developed for pediatric patients.[ONCOLOGY 12(Suppl 8):40-48, 1998]

Introduction

In the United States “high-grade non-Hodgkin’s
lymphomas” generally refer to three histological subtypes of
lymphoma categorized in the Working Formulation for Clinical Usage,
published over 16 years ago.[1] The classification into low-,
intermediate- or high-grade lymphomas was mainly based on differences
in survival, and the three histological subtypes with the worst
prognosis were defined as high-grade (immunoblastic lymphoma,
lymphoblastic lymphoma, and small-noncleaved-cell lymphoma, which
were associated with 5-year survival rates of 32%, 26%, and 23%,
respectively). Small-noncleaved-cell lymphoma was further classified
into Burkitt’s and non-Burkitt’s lymphomas.

High-Grade Non-Hodgkin’s Lymphoma

The decision to label immunoblastic lymphoma, lymphoblastic lymphoma,
and small-noncleaved-cell lymphoma as high-grade has been criticized
on a number of grounds.

First, the term “grade” is usually used in the context of
specific histopathological criteria rather than clinical outcome.

Second, in the study that led to the Working Formulation for Clinical
Usage, there was little or no attempt to take into consideration
either the treatment used (although most patients received an
anthracycline-containing regimen), or the prognostic factors that we
know to be critically important to the outcome of therapy. Even in
1982, better results than those recorded in the study that led to the
Working Formulation for Clinical Usage had been reported, at least in
children, for small-noncleaved-cell and lymphoblastic lymphoma [2-6],
so that the present, paradoxical situation in which the survival
rates of these high-grade lymphomas are much better than the survival
rates of either low-grade or intermediate-grade lymphomas were, even
then, beginning to become apparent.

Third, although differences in survival among the three grades
defined in the study that led to the Working Formulation for Clinical
Usage were statistically significant, there was clear overlap in the
survival rates of lymphomas classified as high and intermediate
grades, overlap that was not always reflected accurately by the
survival rates at 5 years. Clearly, the decisions as to where to draw
the line between high-grade and intermediate-grade was somewhat
arbitrary, as indeed, is the histological distinction between
small-noncleaved-cell lymphoma of non-Burkitt’s type and
large-cell lymphoma.[7] Chromosomal translocations 8;14(q24;q32)
(which might be considered defining characteristics of Burkitt’s
lymphoma), are also observed in subsets of Burkitt-like lymphoma and
large-B-cell lymphoma, particularly in children.[8]

Identifying High-Grade Lymphomas

The problem of the definition of a high-grade lymphoma has been
compounded by the identification, with the help of
immunohistochemical and molecular analyses, of new entities, some of
which (or some histological variants of which) would be classified as
high-grade in the Working Formulation for Clinical Usage. And,
finally, immunoblastic lymphoma cannot be reproducibly separated from
large-B-cell lymphoma, and there is disagreement among pathologists
as to whether it constitutes a separate entity.[9]

The identification of prognostic groups has been greatly refined
since the early 1980s, particularly by the detailed analysis leading
to the “International Prognostic Index,” and such
prognostic factors work for all histologies. However, there is an
increasing recognition that each entity that can be precisely defined
behaves differently, and that the tendency to lump tumors together
for treatment purposes may not be wise. Certainly there is no a priori
reason to suppose that different biological entities will respond
similarly to the same therapy–the reverse is often the case,
particularly in children. Unfortunately, while histology remains the
dominant means of making diagnoses, distinctions between biological
entities within a histological category will remain difficult at
best, and the hypothesis that genetically different tumors require
different therapies for optimal results will remain untested. Thus,
the use of broad risk groups that encompass multiple entities as a
continuing basis for the determination of therapy is of increasingly
questionable validity.

There can be little doubt that the biological nature of the tumor
cell, in addition to the molecular genetic lesions that have modified
normal cellular behavior during the process of lymphomagenesis, are
the primary determinants of treatment outcome, although research is
urgently needed to determine whether molecular genetic markers
(particularly those that influence proliferation and apoptosis)
provide a more effective basis for treatment decisions than histology
(other factors, such as tumor burden and effective drug
concentrations will, doubtless, remain of significance, too).
Moreover, as novel therapies are introduced, (eg, monoclonal antibody
therapy such as anti-CD20 (rituximab [Rituxan]), or therapies
targeted towards specific molecular lesions or viral proteins present
in the tumor cells), the identification of the presence of specific
therapeutic targets is likely to become at least as important as
histology as a basis for therapeutic decisions.

With these considerations in mind, this article will deal with the
management of the three tumors, 1) Burkitt’s lymphoma, 2) the
B-cell tumors from the Working Formulation for Clinical Usage’s
category of non-Burkitt’s lymphoma (renamed in the more recent
Revised European American Lymphoma (REAL) classification [10]
“Burkitt-like” lymphoma), and 3) lymphoblastic lymphoma.
These tumors were defined on exclusively histological grounds in the
Working Formulation for Clinical Usage, but are specified as B-cell
neoplasms (in the case of Burkitt’s lymphoma and Burkitt-like
lymphoma), or neoplasms of precursor T or B cells in the case of
lymphoblastic lymphoma, in the REAL classification.

It is important to recognize that Burkitt-like lymphoma overlaps
considerably with both Burkitt’s lymphoma and large-B-cell
lymphoma and indeed, the dividing lines between these three
“entities” cannot be reproducibly made. It seems probable
that Burkitt-like lymphoma is not truly a separate diesease, but is
composed of a mixture of Burkitt’s lymphoma and large-B-cell
lymphoma, the relative proportion of large-B-cell lymphoma increasing
with age. However, Burkitt-like lymphoma appears, in general, to have
a clinical behavior pattern and response to therapy similar to
Burkitt’s lymphoma (and will be included with Burkitt's lymphoma
for the purposes of this article) such that its large-B-cell lymphoma
element is likely to consist predominantly of a subtype of
large-B-cell lymphoma. For therapeutic purposes it may remain
appropriate to separate this category from large-B-cell lymphoma in
some way. However, in children, large-B-cell lymphoma has a similar
prognosis to Burkitt’s lymphoma and Burkitt-like lymphoma when
treated with the same chemotherapy regimens.[2-4] Whether this would
apply to the large-B-cell lymphomas of adults is not known. All three
of the neoplasms dealt with in this article have a peak incidence in
the first 2 decades of life and are the predominant non-Hodgkin’s
lymphomas of childhood and adolescence, but account for only a few
percent of cases of adult non-Hodgkin’s lymphoma.

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