Editors: Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry
M.Title: Hematology in Clinical Practice, 4th EditionCopyright 2005
McGraw-Hill> Table of Contents > Part II - White Blood Cell
Disorders > Chapter 22 - Non-Hodgkin's Lymphomas
Chapter 22
Non-Hodgkin's LymphomasThe non-Hodgkin's lymphomas (NHLs) are a
heterogeneous group of disorders characterized by malignant
proliferation of B or T lymphocytes. From a clinical standpoint,
lymphomas generally present as solid tumors of the lymphoid
systemthe lymph nodes, Waldeyer's ring, spleen, blood, and marrow.
Because of the functional heterogeneity of lymphocytes and because
lymphocytes by their nature have access to nearly every anatomic
site, these diseases may involve any organ and are very
heterogeneous. Despite multiple attempts to improve the
classification of NHL, it remains difficult to predict the course
of the disease in an individual patient based on prognostic
factors. Perhaps more than any other malignant disease, the
treatment of the patient must be individualized based on the
behavior of the patient's own disease.The importance of accurate
diagnosis and effective management of lymphomas has been heightened
by their increasing incidence, the association of lymphomas with
immune deficiency states, and improvements in therapy. The
incidence in Western countries has more than doubled in the last 20
years and should increase even further because of the association
of B-cell lymphomas with AIDS. The rising incidence may also
reflect greater exposure to chemical agents in the environment.NHL
in general is very responsive to therapy, and in most cases the
physician can offer the patient with NHL both improved survival and
improved quality of life. It is an unusual fact that the NHL
patient with the most aggressive form of the disease can be offered
the possibility of a cure, whereas the patient with indolent
lymphoma may never be cured despite a relatively long
survival.Because lymphoma cells tend to be very mobile, silently
involving not only lymphoid organs but nearly every part of the
body, concepts of staging, remission, and relapse are less useful
and less important than in other malignancies. With increasingly
sensitive means of detecting lymphoma cells, it is frequently
possible to demonstrate their presence throughout the body in
patients previously thought to have localized disease. Similarly,
it is frequently possible to detect lymphoma cells in patients who
appear by usual criteria to be in complete remission. Patients with
lymphoma will sometimes undergo prolonged periods of quiescent
disease punctuated by periods of increased disease activity. In
general these patients must be followed up carefully, with a
constant suspicion that minor symptoms may indicate progression or
relapse.
DIAGNOSISUltimately, a diagnosis of lymphoma depends on finding
abnormal numbers of lymphocytes that are destroying the normal
architecture of the lymphoid tissues or invading nonlymphoid
tissues or both. Detection of lymphoma in its early stages can be
more of a challenge. It is difficult, probably impossible, to
recognize a single malignant lymphocyte based on morphology alone,
because lymphocytes are capable of dedifferentiation,
proliferation, and differentiation in the course of a normal immune
response. A reactive lymph node contains activated lymphocytes that
look as malignant as any lymphoma cell.Thus, in order for one to
accurately diagnose lymphoma, an adequate tissue biopsy is
absolutely required. Lymphoma can be suspected on the basis of
cytologic examination of blood, marrow, effusions, and aspirates,
but the physician should always make every attempt to obtain a good
surgical biopsy of involved lymphoid or nonlymphoid tissue in order
to be certain of the diagnosis. When multiple sites are available
for biopsy, one should avoid those sites where normal reactive
nodes are frequently found, such as the groin and the axilla.With
the availability of immunologic and genetic tests for clonality,
one can make a strong presumptive diagnosis of lymphoma on the
basis of the finding of clonal lymphocytes involving multiple
sites, such as marrow and blood, but the finding of clonality does
not absolutely prove malignancy, and clonality tells us nothing
about prognosis. Therefore, a diagnosis based solely on these
criteria should be viewed with caution.
CLASSIFICATIONOver the years, several different classifications
of lymphomas have been popularized: the Rappaport classification,
the Lukes-Collins classification, the International Working
Formulation, the Revised European American Classification (REAL),
and most recently a consensus classification sponsored by the World
Health Organization (WHO), which closely follows the REAL system.
The Working Formulation and WHO/REAL classifications are compared
in Table 22-1. The Working Formulation and previous systems were
based almost entirely on morphologic criteria. The Working
Formulation was an advance because it emphasized the clinical
behavior of the various lymphomas, grouping them into low-,
intermediate-, and high-grade based on their aggressiveness. The
REAL system, for the first time, incorporated immunologic and
genetic criteria in classifying the lymphomas, and this has been
extended in the WHO system.
Table 22-1. Lymphoma classification.
Revised European American (REAL) and WHO Consensus
Classification
Working FormulationB-Cell NeoplasmsT-Cell Neoplasms
Low-Grade
Small lymphocyticB-cell CLL/SLLMarginal zone, mucosa associated
(MALT)Mantle cellT-cell CLLLarge granular lymphocyticAdult T-cell
lymphoma/leukemia
PlasmacytoidLymphoplasmacyticMarginal zone (MALT)
Follicular, small-cell, and mixed-cellFollicular, grades I and
IIMantle cellMarginal zone (MALT)
Intermediate-Grade
Follicular, large-cellFollicular, grade III
Diffuse, small-cellMantle cellFollicular center, diffuse
small-cellMarginal zone (MALT)T-cell CLLLarge granular
lymphocyticAdult T-cell
lymphoma/leukemiaAngioimmunoblasticAngiocentric
Diffuse, mixed-cellLarge B-cell lymphomaFollicular center,
diffuse small-cellLymphoplasmacytoidMarginal zone (MALT)Mantle
cellPeripheral T-cell lymphomaAdult T-cell
lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell
lymphoma
Diffuse, large-cellDiffuse large B-cell lymphomaPeripheral
T-cell lymphomaAdult T-cell
lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell
lymphoma
High-Grade
Large-cell immunoblasticDiffuse large B-cell lymphomaPeripheral
T-cell lymphomaAdult T-cell
lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell
lymphomaAnaplastic large cell
LymphoblasticPrecursor B-cell lymphoblasticPrecursor T-cell
lymphoblastic
Burkitt lymphomaBurkitt lymphomaPeripheral T-cell lymphoma
The WHO/REAL classification should hold promise in the design of
future therapies. However, as can be seen in Table 22-1, it is
difficult to correlate the WHO/REAL system with the Working
Formulation. As long as the concept of tumor aggressiveness is
preserved in the classification, there is extensive overlap and
duplication. For example, the B-cell, marginal zone (MALT)
lymphomas can present as follicular or diffuse small- or mixed-cell
tumors with low to intermediate growth potential. It is likely that
with more experience, the clinical classification and the
immunogenetic classification will converge, and the situation will
become clearer.The frequencies with which the more common forms of
lymphoma will be encountered in practice are indicated in Table
22-2. When a patient presents with lymphoma it is important to
obtain as much prognostic information as possible on the basis of
whatever can be measured. This can be divided into histologic
features, cytologic features, immunologic features, cytogenetics,
and stage or extent of disease.
Histologic FeaturesThe normal architecture of a lymph node and
the phenotypic and cytologic features of the lymphocytes found in
various regions are illustrated in Figure 22-1. The histologic
description of lymphoma focuses on the overall architecture of a
lymphoid or nonlymphoid tissue. Perhaps the most useful histologic
finding is whether there is nodular (or follicular) versus diffuse
morphology (see Color Plates 54,55,56). Those lymphomas showing the
formation of nodules, reminiscent of normal lymphoid follicles,
tend to be more indolent and have a better prognosis than those
showing diffuse infiltration. This distinction is true regardless
of the details of the individual cells and regardless of the
immunologic type of the lymphoma. Therefore, the first question the
clinician should ask of NHL is whether it is nodular (follicular)
or diffuse in histology. This distinction can only be made on the
basis of an adequate biopsy.
Cytologic FeaturesThe cytologic classification of a lymphoma
depends on the appearance of the individual cells. Cells may be
described as well versus poorly differentiated (Rappaport
classification) or as large versus small, with folded or cleaved
nuclei (Luke-Collins classification and International Formulation).
In general, small, well-differentiated cells are seen with more
indolent lymphomas, whereas large, poorly differentiated cells are
typical of high-grade, aggressive lymphomas. However, this
classification is weakened by the frequent presence of cells of
many descriptions scattered throughout the lesion. Overall, the
cytologic description of the cells is not as strongly associated
with prognosis as is the histologic description (nodular versus
diffuse).
Immunologic FeaturesThe immunologic classification of the
lymphomas requires use of immunologic markers, genetic analysis, or
both (see Chapters 19 and 21) to determine whether the cells are of
B- or T-cell origin and to indicate clonality. Most (approximately
80%) NHLs are of B-cell origin. Clonality in a B-cell lymphoma can
be indicated by uniform expression of a single light chain class of
surface immunoglobulin ( or ) or by the presence of a single
immunoglobulin gene rearrangement pattern. Clonality of the T-cell
lymphomas is suggested by the expression of a single functional
class marker (CD4 or CD8) or by a characteristic pattern of
expression and deletion of other T-cell markers, but it is best
demonstrated by genetic analysis for T-cellreceptor gene
rearrangement.
Table 22-2. Frequencies of non-Hodgkin's lymphomas.
DiagnosisFrequency (%)
Diffuse large B-cell lymphoma31
Follicular lymphoma22
Small lymphocytic lymphoma6
Mantle cell lymphoma6
Peripheral T-cell lymphoma6
Marginal zone B-cell lymphoma, MALT type5
Mediastinal large B-cell lymphoma2
Anaplastic T-cell lymphoma2
Lymphoblastic lymphoma2
Burkitt-like lymphoma2
Marginal zone B-cell lymphoma1
Lymphoplasmacytic lymphoma1
Burkitt lymphoma< 1
Figure 22-1. The normal architecture, histology, and phenotype
of a lymph node. The major lymphocyte subsets are distributed
through the lymph node in characteristic regions. Follicular
centers contain predominantly large proliferating B cells, whereas
the mantle zones of the follicles contain smaller B cells in the
resting state. Interfollicular regions and the paracortex contain
predominantly T cells. Macrophages are located in the follicular
centers and in the medulla of the node. Antigen, and circulating T
cells, enter via the cortical afferent lymphatics.
Antigen-stimulated T cells reenter the circulation via the efferent
lymphatics. Disruption of the normal lymph node architecture is one
of the major causes of immunodeficiency in lymphoma.
Immunologic analysis of lymphomas is particularly useful in
distinguishing between a reactive process and a lymphoma. It is not
uncommon for a lymph node biopsy to show a lymphocyte proliferation
that could be a normal reactive process rather than a lymphoma.
Since the reactive process is characterized by a heterogeneous
collection of T and B cells arising from multiple clones of
different progenitor cells, it is easy to distinguish
immunologically from a lymphoma, where most cells are of one
phenotype and belong to one clone.
Cytogenetic FeaturesSpecific NHL subtypes can also be classified
based on nonrandom chromosomal translocations (Tables 22-3 and
22-4). Most share one common feature in that they involve the genes
responsible for the coding of the immunologic receptors for antigen
on the lymphocytes. For the B cells these are located on chromosome
14 (the immunoglobulin heavy chains) and on chromosomes 2 (
immunoglobulin light chain) and 22 ( immunoglobulin light chain).
For the T cells, the T-cellreceptor genes are usually involved.
Most of these mutations result in the juxtaposition of an
immunologic receptor gene and its controlling elements next to a
protooncogene, resulting in overexpression of the oncogene product.
The best examples are the t(14;18) (q32;q21) translocation, which
brings the immunoglobulin heavy chain locus next to the BCL-2
protooncogene, and the translocations that bring the c-myc oncogene
next to immunoglobulin genes on chromosomes 14, 2, or 22. The BCL-2
abnormality occurs in at least 80% of nodular lymphomas, and the
c-myc translocation is characteristic of Burkitt lymphoma. BCL-2 is
a gene associated with the inhibition of programmed cell death
(apoptosis). Thus, its over expression in lymphomas leads to
prolongation of the lifespan of the cells and their accumulation to
the detriment of the patient. The expression of bcl-2 has also been
associated with poor overall survival. Deregulation of BCL-6 in
large B-cell lymphomas and c-myc in Burkitt lymphoma is associated
with uncontrolled cell proliferation. In a study of the expression
of CD10, bcl-6, and MUM1 by immunohistochemistry, diffuse large
cell lymphomas could be subclassified as germinal-center cell and
nongerminal center cell derived disease, with the latter showing a
significantly poorer survival.Table 22-3. Immunologic and
cytogenetic features in the REAL classification of B-cell
neoplasms.
DiseaseMorphologyImmunophenotypeGenotype
Small lymphocytic, CLLSmall, round lymphocytesDim sIgM,
sIgDCD19, 20, 5, 23+CD10-Ig rearrangementsTrisomy 12
(3040%)Deletion 13q14 (50%)
LymphoplasmacytoidSmall lymphocytes with plasmacytoid
featurescIg+,CD19, 20+CD5, 10-Ig rearrangementst(9;14) (50%)
Mantle cellSmall to medium irregular lymphocytessIgM, sIgD+CD19,
20, 5+CD10, CD23-Ig rearrangementst(11;14) (70%)involves BCL-1
Follicular center cellSmall, medium, or large, irregular,
cleaved cellssIgM, sIgD+CD19, 20+CD10, 23CD5+Ig
rearrangementst(14;18) (7095%)involves BCL-2
Marginal zone (MALT)Small or large, monocytoid lymphocytessIgM,
sIgD+CD19, 20+CD5, 10, 23-Ig rearrangementsTrisomy 3t(11;18)
Hairy-cellSmall lymphocytes with cytoplasmic projectionssIgM,
sIgD+CD19, 20, 11b, 103+FMC7+, CD5, 10, 23-Ig rearrangements
Diffuse large B-cellLarge, irregular lymphocytessIgM, sIgDCD19,
20+CD5, 10Ig rearrangementsRearrangements of 3q27 (BCL-6) (30%)
Burkitt lymphomaMedium round cells with abundant
cytoplasmsIgM+CD19, 20, 10+CD5, 23-t(8;14), t(2;8), ort(8;22)
involves c-myc
Table 22-4. Significance of some chromosomal translocations
associated with B-cell neoplasms.
DiseaseTranslocationsFrequencyImmunoglobulin
Gene(s)ProtooncogeneMechanism
Lymphoplasmacytoidt(9;14)50%IgHPAX-5 (9q13)A transcription
factor controlling B-cell proliferation and differentiation
Mantle cellt(11;14)95%IgHBCL-1 (11q13)The gene for cyclin D1
that regulates the cell cycle
Follicular cellt(14;18)t(2;18)t(18;22)80%IgH or IgLBCL-2
(18q21)A gene that inhibits apoptosis
Diffuse large-cellt(3;14)510%IgH or IgLBCL-6 (3q27)A gene that
appears to control some aspect of germinal center formation
Burkitt lymphomat(8;10)t(2;8)t(8;22)100%IgH or IgLc-myc (8q24)A
transcription factor controlling proliferation, differentiation,
and apoptosis
MALT lymphomat(11;18)30%IgHAPI2, MLTGenes involved in inhibition
of apoptosis
Since immunoglobulin and T-cellreceptor genes are always
rearranged as a part of the normal differentiation process of B and
T lymphocytes (see Chapter 19), it is reasonable to conclude that
the defect in lymphoma is often owing to abnormal rearrangement.
This is confirmed by the observation that most of the
translocations in B-cell lymphomas involve the J and S sequences of
the immunoglobulin genes that are the sites of normal
rearrangements. Most of the common genetic alterations seen in
lymphomas can be detected by polymerase chain reaction (PCR)
techniques or by fluorescence in-situ hybridization.Gene-expression
profiling using microarray technology is now being explored as an
even more sophisticated way of understanding lymphoid tumorogenesis
and classifying the non-Hodgkin's lymphomas. For example, it has
been reported that small cell lymphocytic lymphoma, marginal zone
B-cell lymphoma, and mantle cell lymphoma can be reliably
distinguished using a 44 gene microarray more than 95% of the time,
a considerable improvement over traditional histopathology. Large
B-cell lymphomas can also be divided into good and bad prognostic
groups using a cDNA microarray analysis. In one series, the
measurement of six genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL-2)
was reported to reliably identify patients with very poor 5-year
survivals (< 27%).
CLINICAL FEATURESThe clinical manifestations of lymphoma can be
considered under several general categories, which are discussed
further under Laboratory Studies. The first category is those
effects caused by enlargement of lymphoid tissues; second is the
immunologic sequelae of the lymphoma; third is those effects caused
by invasion of nonlymphoid tissues, particularly marrow; and last,
the metabolic and humoral effects of the lymphoma.Enlargement of
Lymphoid TissuesMost patients with lymphoma present with painless
enlargement of lymph nodes or spleen or both. The effects of node
enlargement vary from the cosmetic to such complications as
obstruction of airway or major vessels, compression of the stomach,
or obstruction of the intestines. In general the node enlargement
is gradual and painless. Lymphomatous infiltration seldom results
in an inflammatory response, and thus symptoms such as fever,
weight loss, and night sweats are less common than in Hodgkin's
disease.A common clinical situation is the patient who presents
with one or more enlarged nodes and a history compatible with a
recent viral infection. Although the only way to confidently rule
out lymphoma is to take a biopsy of the node, one is usually
reluctant to do this immediately. If the node enlargement has been
sudden or painful (tender), then a reactive process is more likely
than a lymphoma. If the node is very hard to palpate or fixed to
underlying tissues, suspect carcinoma rather than lymphoma. In
general a reactive process will subside over a few weeks. A node
that persists longer than this, and is painless, firm, or grows in
size, must undergo biopsy. Lymphomatous nodes can undergo
fluctuating enlargement. A history of recurrent enlargement of a
node is as compatible with lymphoma as is persistent enlargement.
It is also possible to obtain a history of previous node biopsies
that were read as reactive followed by a biopsy read as lymphoma.
Thus a previous benign biopsy should not weigh against taking a
biopsy of a suspicious node.
Multifocal versus Localized DiseaseNodal involvement in NHL is
usually multifocal, with involved nodes separated by groups of
normal nodes, and early dissemination throughout the body. Thus the
concept of metastasis with orderly progression of disease from one
node group to another, although useful in Hodgkin's disease, has
little use in NHL.However, a few patients do present with localized
disease, often in unusual locations. High-grade B-cell lymphomas
can present in one node area or present as solitary brain tumors or
osteolytic bone tumors. Gastrointestinal lymphomas can be localized
and, if disseminated, tend to preferentially involve gut-associated
lymphoid tissue.Interestingly, low- and intermediate-grade
lymphomas are almost always disseminated at the time of
presentation. Although the tumor masses associated with B-cell
lymphomas tend to follow the anatomic distribution of the lymph
nodes and lymphatics, T-cell malignancies are more likely to show a
wider tissue distribution. T-cell malignancies resulting from
clonal expansion of CD4-positive T cells generally involve the
skin, sometimes with their major manifestation being skin
infiltrations (mycosis fungoides). This situation reflects the
natural propensity of T cells to migrate through the subepidermal
layers of the skin. Both T- and B-cell lymphomas can have a blood
(leukemic) component. The T-cell lymphomas and B-cell chronic
lymphocytic leukemia (CLL) (see Chapter 21) are the most likely to
result in high circulating lymphocyte counts, whereas other
lymphomas usually have a minor circulating component that may not
be reflected in the absolute lymphocyte count.
Other Clinical FeaturesA detailed history and a physical
examination are very important in evaluating the NHL patient.
Exposure to toxic chemicals, chemotherapeutic or immunosuppressive
agents, or ionizing radiation can have epidemiologic importance,
especially in the younger patient. HIV infection is a clear risk
factor. A careful physical examination to look for other enlarged
lymph nodes is essential for any patient presenting with a
suspicious node. In addition to the common sites, involvement of
retroclavicular nodes, Waldeyer's ring, and thoracic and
retroperitoneal nodes should be sought by physical examination,
x-ray, and CT scan. Renal and hepatic function tests should be
done; however, in the absence of obstruction, involvement of these
organs with lymphoma is frequently not reflected by
chemistries.
Laboratory StudiesAs mentioned in the preceding section, Other
Clinical Features, a detailed history and physical examination are
important in identifying many manifestations of NHL. Renal and
hepatic function tests should also be done. The evaluation of
patients suspected of having lymphoma should include examination of
blood and marrow for the presence of lymphoma cells as judged by
morphology, cell surface markers, and genetic analysis. Sixty
percent to 80 percent of lymphoma patients have involvement of
blood, marrow, or both when sensitive techniques are used. This is
true even when the complete blood count is perfectly normal
A. BLOOD AND MARROW TESTS FOR IMMUNOLOGIC EFFECTSMost patients
with NHL do not develop profound marrow dysfunction even when the
marrow is partially infiltrated with malignant cells. Immunologic
testing of blood and marrow is best performed after the disease has
been diagnosed by biopsy so that specific immunologic
characteristics of the lymphoma are known. For example, if the
lymphoma is of B-cell origin and is expressing immunoglobulin light
chains, this information can be used to increase the sensitivity of
the tests in blood and marrow.Most patients with lymphoma have or
soon develop an immune deficiency that is characterized by diffuse
hypogammaglobulinemia or by a poor response to new antigens and to
infections (or both). However, a significant number of these
patients, particularly those with T-cell lymphomas, may have
diffuse or specific hypergammaglobulinemia, and a minority (about
5%) have a monoclonal serum immunoglobulin (M protein). Increased
susceptibility to viral infection, and reactivation of viruses such
as herpes zoster, may occur even prior to the onset of overt
symptoms of lymphoma. This situation is owing to depression of
cell-mediated immunity. Some lymphomas, particularly low-grade
B-cell and CLL, may demonstrate autoantibodies directed against red
blood cells or platelets, resulting in hemolytic anemia or immune
thrombocytopenia.
B. TESTS FOR LYMPHOMATOUS INFILTRATION OF NONLYMPHOID ORGANSThe
possibility of lymphomatous infiltration of nonlymphoid organs
should always be suspected. Because lymphoma seldom elicits an
inflammatory response as it invades, the involvement can be
extensive before the patient becomes symptomatic. The most common
involvement is seen in skin (especially T-cell lymphomas), lung,
the gastrointestinal (GI) tract, the liver, bone and marrow, the
kidney, and the central nervous system (CNS). Attention should be
paid to all of these sites in evaluating a patient with lymphoma,
and any otherwise unexplained findings should be fully evaluated by
chemical and radiologic techniques. Liver involvement, for example,
may be revealed by CT scan despite normal liver chemistries.
Because the patient with lymphoma is subject to unusual and
opportunistic infections, one is often faced with a difficult
clinical distinction between infection and lymphomatous
infiltration, for example, in the lung. These distinctions may
require biopsy to resolve. Positron emission tomography (PET
scanning) is being increasingly used in the initial staging and
followup of lymphoma patients. Because it detects regions of
increased metabolic activity it is sometimes more sensitive than CT
or MRI in locating sites of lymphoma and in distinguishing between
active tumor and residual scarring following treatment.
C. SERUM ASSAY TESTS FOR METABOLIC AND HUMORAL EFFECTSSome
patients with lymphoma develop profound marrow dysfunction even
when the marrow cannot be shown to be heavily involved with
lymphoma. However, more common is the presence of significant
numbers of lymphoma cells in the marrow with relatively normal
blood counts. Anemia and thrombocytopenia are more often seen as
side effects of therapy than as presenting features. Because
lymphocytes produce a variety of cytokines with diverse effects on
other cells, patients with lymphoma can display generalized
metabolic and systemic symptoms. Most common are unexplained fever,
weight loss, night sweats, and chills; less common are
hypercalcemia and hypoglycemia. The availability of serum assays
for lymphocyte-produced cytokines and their receptors may be useful
in evaluating patients for these effects.
CHARACTERISTICS OF INDIVIDUAL LYMPHOMASSome types of lymphoma
have relatively specific profiles of clinical presentation,
histology, cell phenotype, and cytogenetic abnormalities. The
following descriptions highlight the more important disease states
as classified in the Working Formulation or REAL classification.
Tables 22-3 and 22-5 summarize the features of many of these
lymphoma types.
Low-Grade LymphomasThe nodular, or follicular, lymphomas
dominate this class. In fact, they make up one-third or more of all
cases of NHL. Follicular lymphomas typically occur in middle-aged
or elderly adults. They usually present as a slow-growing, non
tender enlargement of lymph nodes, taking months to years to appear
and evolve. More than 75% of patients have disseminated disease at
presentation, and 50% or more have marrow involvement. They tend to
be resistant to curative chemotherapy, but even so, have a median
survival of 7 years as compared with survival of 1- 2 years for the
intermediate- and high-grade lymphomas that fail to respond to
curative chemotherapy or transplantation. With time, the follicular
lymphomas can exhibit a change in histology and behavior to a more
high-grade tumor class with a concomitant reduction in
survival.Once a diagnosis is made from a node or tumor mass biopsy,
a search for evidence of disseminated disease should be undertaken,
using studies of blood and marrow for cell morphology, immunologic
markers, and gene rearrangements. These studies will usually be
positive. More complex staging (staging laparotomy or organ biopsy)
is unnecessary unless it appears that the disease may in fact be
localized.These tumors are usually of B-cell origin, and their
nodular pattern of growth is reminiscent of their origin in the
germinal center. The presence of larger cells and mixtures of
diffuse as well as nodular architecture suggests a more aggressive
variant of the disease. The characteristic cell phenotypes are
summarized in Figure 22-2. These cells correspond to the phenotype
of maturing lymphocytes of both T- and B-cell type (see Chapter
19). The presence or absence of CD5 is important because it is
characteristic of B-cell CLL and its presence suggests a less
aggressive variant. In addition, there is a rough positive
correlation between the intensity of expression of surface
immunoglobulin and the aggressiveness of the disease.
Table 22-5. Immunologic and cytogenetic features in the REAL
classification of T-cell neoplasms.
DiseaseMorphologyImmunophenotypeGenotype
T-cell CLLSmall lymphocytes or prolymphocytesTdT-CD2, 3, 5,
7+CD4+8- > CD8+4+ > CD4-8+CD25-TCR rearrangementsInv14
(q11;q32) (75%)
Cutaneous T-cellSmall and large cells with cerebriform
nucleiTdT-CD2, 3, 5+, 7CD4+8-, CD25TCR rearrangement
Large granular lymphocyteLymphocytes with abundant cytoplasm and
azurophilic granulesTdT-CD2, 3+, 5CD8, 16, 57+CD4, 56, 25-TCR
rearrangement
Peripheral T-cellSmall to medium-sized irregular
lymphocytesTdT-CD2, 3, 5, 7CD4 and/or 8+TCR rearrangement
Adult T-cellHighly variableTdT-CD2, 3, 5, 25+CD7-, CD4+8-TCR
rearrangementIntegrated HTLV-1
Anaplastic large-cellLarge blastic pleomorphic cellsTdT-CD2, 3,
5, 7CD25, CD30+TCR rearrangementt(2;5) (ALK)
Precursor T lymphoblasticMedium-sized blastic cellsTdT+CD7+CD2,
3, 5CD4, 8+ or CD4, 8-Variable TCR and IgG rearrangement
The cells display the characteristic immunoglobulin gene
rearrangements seen in B cells. In addition, most will display a
t(14:18) chromosomal translocation, which places the BCL-2
protooncogene under the influence of the immunoglobulin heavy chain
gene locus. The use of PCR technology to detect immunoglobulin gene
rearrangements and the BCL-2 translocation permits the detection of
very small numbers of malignant cells in clinical specimens.
A. TISSUE-BASED VARIANT OF B-CELL CLLAnother low-grade lymphoma
is characterized by a diffuse infiltration of small, noncleaved
lymphocytes. The tissue-based variant of B-cell CLL is almost
always associated with a leukemic phase of varying degree. The
presence of the CD5 marker and low levels of surface immunoglobulin
are characteristic. Its presentation and response to therapy are
identical to that of CLL. In many cases it evolves over time to a
more aggressive variant of lymphoma.
B. LYMPHO-PLASMA-CYTOID VARIANTThe lymphoplasmacytoid variant is
frequently associated with an IgM component that leads to its being
considered along with multiple myeloma as a plasma cell neoplasm
(see Chapter 25). However, the biology and clinical behavior of
this disease more closely resemble that of the low-grade
lymphomas.
C. MARGINAL ZONE LYMPHOMASAn additional variant of low- to
intermediate-grade lymphomas has been brought to the fore front by
the REAL classification the marginal zone lymphomas. Three clinical
presentations have now been described, including nodal marginal
zone, splenic marginal zone, and extranodal with masses in the
respiratory or GI system, involving subepithelial,
mucosa-associated lymphoid tissue (MALT tumors). Patients with MALT
tumors generally have a history of autoimmune disease or chronic
antigenic stimulation. Sites of presentation include the GI tract,
especially the stomach, salivary glands, skin, lung, thyroid, and
orbit. Gastric MALT lymphoma (see Color Plate 58) commonly presents
with symptoms of dyspepsia, anorexia, epigastric pain, and GI
bleeding. Its pathogenesis is related to Helicobacter pylori
infection, and some 70% of cases will show regression of the tumor
with antibiotic therapy alone. This has led to the use of
antibiotic and acid blockade as first line therapy. Sustained
responses are seen reliably in patients with stage I diseases
(endoscopic appearance of gastritis), whereas chemotherapy and
gastrectomy may be needed in patients who present with more
advanced disease.
Splenic marginal zone lymphoma appears to be another distinct
entity, although much less common. It is distinguished by variable
lymphocytosis (10,000 - 40,000/L) with the appearance of villous
lymphocytes in both blood and marrow, moderate to marked
splenomegaly, and the presence of a small M component (either IgG
or IgM) of less than 30 g/L. B symptoms are rare and the lactic
dehydrogenase (LDH) level tends to be normal at presentation.
Spleen histology shows giant follicles with some red pulp
infiltration but not to the degree seen in hairy-cell leukemia. By
immunophenotype, the tumor cells are usually positive for sIg and
CD22, 24, and 25 (unlike hairy cells, which are CD24 and 25
negative), and negative for CD5, 23, and 76b. No consistent or
unique chromosomal abnormalities have been
reported.Intermediate-Grade LymphomasThe intermediate-grade
lymphomas share characteristics of the low- and high-grade tumors.
Patterns of disease histology include nodular large-cell lymphoma;
a small cell or mixed small and large-cell tumor with diffuse
histology; and a diffuse large-cell lymphoma. The latter may be
classified as high-grade if the cells are poorly differentiated.
The classification of lymphomas as intermediate-grade is done more
on the basis of what the tumor is not, rather than on specific
characteristics. Thus, when a lymphoma does not fit the profile of
either a low- or high-grade lymphoma it is assigned to the
intermediate-grade class.Most of the intermediate-grade lymphomas
are of B-cell origin. There are no unique characteristics to the
clinical presentation or course other than an intermediate level of
aggressiveness of the tumor growth. The physician must observe the
patient to determine the pattern and course of the disease over
time in order to derive the prognosis for the individual patient.
For treatment purposes, intermediate-grade lymphomas are generally
considered in the same category as high-grade lymphomas.Another
class of B-cell lymphomas, which has been emphasized by the REAL
classification, is mantle cell lymphoma (see Color Plate 55). This
lymphoma variant is characterized immunophenotypically by the
presence of CD5 (like CLL), but, unlike CLL, it does not express
CD23. Most mantle cell lymphomas have a t(11;14) translocation that
involves the BCL-1 protooncogene (see Table 22-3). Patients with
this lymphoma respond poorly to therapy and relapse early.
Therefore, these lymphomas are clinically very distinct from the
low-grade lymphomas, which they otherwise resemble.
High-Grade LymphomasSeveral diseases with unique profiles fall
into the high-grade lymphoma category. It is also common to see
tumors of both B- and T-cell origin within this grouping. Four of
the more important node-based high-grade lymphomas are diffuse
large-cell lymphoma, formerly referred to as diffuse histiocytic
lymphoma; large-cell immunoblastic lymphoma; lymphoblastic
lymphoma; and a very aggressive small-cell tumor called Burkitt
lymphoma. In general, these are all very rapidly growing tumors
with a poor prognosis when left untreated.
A. DIFFUSE LARGE-CELL LYMPHOMAThe large-cell lymphoma patient
frequently presents with one or more rapidly developing tumor
masses involving nodal or extranodal sites. As is typical of most
lymphomas, the mass is not tender and does not cause inflammation
or interfere with organ function except by compression.
Retroperitoneal disease can obstruct venous drainage of the legs,
resulting in edema and thrombophlebitis.Staging studies should
involve a large-volume biopsy of the tumor for histology and cell
phenotype studies. Marrow and blood studies for morphology,
immunophenotype, chromosomal analysis, and T- and B-cell gene
rearrangements should be obtained to prove disseminated disease.
Cerebrospinal fluid examination and imaging of the CNS are
indicated in patients with neurologic findings. Patients can
present with localized involvement of the brain or widely
disseminated lymphoma involving the CNS. Ten percent to 20 percent
of the large cell lymphomas may be limited to a single node or
extranodal site such as bone, Waldeyer's ring, thyroid, lachrymal
glands, or the gastrointestinal tract.The typical large-cell tumor
mass shows complete effacement of normal lymphoid architecture with
a monotonous infiltrate of large lymphocytes (see Color Plates 56
and 57). These cells are usually of B-cell origin with a phenotype
not distinctly different from that of other lymphomas except for an
increased expression of surface immunoglobulin in many cases. Many
of these lymphomas have chromosomal rearrangements that involve
BCL-6, either alone or in combination with involvement of BCL-2
and, in some cases, c-myc (see Tables 22-3 and 22-4). In addition,
mutations of the p53 tumor-suppressor gene are seen. This complex
genetic background may explain the clinical heterogeneity that
characterizes this disease.
B. LARGE-CELL IMMUNOBLASTIC LYMPHOMASome of the diffuse
large-cell lymphomas are composed of so-called immunoblasts, that
is, cells with abundant basophilic cytoplasm and nuclei with a
large central nucleolus. Some of these cells resemble plasma cells
or plasma blasts. This form is referred to as immunoblastic
lymphoma and may be of either T- or B-cell origin. It is most
commonly seen in older patients, often with pre-existing
immunologic disease such as Sjgren syndrome, thyroiditis, or celiac
sprue or a previous lymphoproliferative disease such as CLL,
myeloma, or angioimmunoblastic lymphadenopathy. In those patients
with a T-cell angioimmunoblastic lymphoma, leukopenia and
polyclonal hypergammaglobulinemia are often seen.
Angioimmunoblastic lymphoma has an extremely poor prognosis,
especially in older patients.
C. LYMPHOBLASTIC LYMPHOMAPrecursor lymphoblastic lymphoma
represents another high-grade malignancy with diffuse histology.
This condition is a disease of younger individuals and children. It
often presents with a bulky, rapidly growing mediastinal mass. The
marrow and CNS are frequently involved. On biopsy, the mass
consists of a diffuse infiltrate of cells with convoluted nuclei
and little cytoplasm. The phenotype of the cells is most often that
of a preB or T cell. This tumor shares characteristics with acute
lymphocytic leukemia (ALL) and is treated with a similar regimen.
Patients presenting with lymphoblastic lymphoma frequently have a
leukemic component to their disease and may rapidly progress to
overt ALL.
D. BURKITT LYMPHOMABurkitt lymphoma, another disease in the
high-grade category, is a very aggressive tumor of immature B-cell
origin. The characteristic histology is that of a diffuse
infiltrate of small noncleaved lymphocytes interspersed with large
cells imparting a starry sky appearance under low-power
magnification (see Color Plate 60). The vacuoles in these cells
responsible for the starry sky appearance stain positively for fat
using the oil red O stain (see Color Plate 61). The tumor is
associated with a unique chromosomal rearrangement involving the
c-myc protooncogene on chromosome 8 moving to one of the
immunoglobulin gene loci, the most common being t(8;14) (see Tables
22-3 and 22-4).A form of Burkitt lymphoma occurs endemically in
children in Africa. It usually presents as a tumor mass localized
to the jaw or retroperitoneum with involvement of bone, kidney,
ovaries, and CNS. This endemic form is strongly associated with
Epstein-Barr virus infection. In Western countries, Burkitt
lymphoma is a nonendemic disease of children and young adults with
no clear connection to the Epstein-Barr virus. It most often
presents as a rapidly growing tumor of abdominal lymph nodes,
although marrow involvement is generally present at the time of
diagnosis.
E. B-CELL LYMPHOMA IN AIDS PATIENTSAn increasing incidence of
B-cell lymphomas is being seen in AIDS patients. They are strongly
associated with Epstein-Barr virus and may also show rearrangements
involving c-myc and mutation of p53. Many of these involve the
brain. Clinical staging is important in planning treatment and
should be carried out without delay. Patients with a single tumor
mass and low LDH indicating a small tumor mass have the best
prognosis. Bulky tumor in the abdomen imparts a worse prognosis,
and involvement of either marrow or the CNS together with a high
LDH predict a high failure rate even with multidrug chemotherapy.
The incidence of AIDS-related lymphoma has not changed with the
introduction of highly active antiretroviral therapy. This is in
contrast to the marked reduction in the incidence of Kaposi
sarcoma.
F. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERSPost-transplant
B-cell lymphomas are seen in organ transplant patients receiving
chronic immunosuppressive therapy. They generally arise in
extranodal sites and are extremely aggressive. Early onset
lymphomas are usually related to Epstein-Barr virus infection and
are polyclonal or oligoclonal, whereas late-onset lymphomas are
true monoclonal malignancies of the diffuse large B cell and
Burkitt-like type. Most of the monoclonal B-cell lymphomas derive
from germinal center B cells.
T-CELL LYMPHOMA CLASSIFICATIONAs techniques for diagnosing
clonal lymphoid malignancies have improved, especially the ability
to detect rearrangements of the B- and T-cell antigen receptor
genes, an increasing number of tumors of T-cell origin have been
identified. Clinical clues to the presence of a T-cell malignancy
include the presence of B symptoms, leukopenia or aplastic anemia
(or both), disseminated disease with marrow involvement,
hepatosplenomegaly, and lung and skin involvement. Several subtypes
of T-cell disease have been identified. These are defined largely
by their clinical profiles; however, the ultimate diagnosis of a
T-cell lymphoma requires study of cell surface markers and an
analysis for T-cellreceptor gene rearrangement. The latter is the
only certain way of proving a clonal origin for T cells. The array
of surface markers can be helpful in that frequently T-cell
lymphomas will express some, but not all, of the characteristic
T-cell markers. The unexpected absence of a T-cell marker on a
population of T cells can be a clue to their malignant nature. In
addition, the presence of CD4, CD8, or both provides some help in
predicting the signs and symptoms related to lymphomas of T-helper
(CD4+) or T-cytotoxic/ suppressor (CD8+) subtypes.Histologic
subclassifications of T-cell lymphoma distinguish between
peripheral T-cell lymphoma, several angiocentric forms, and a
Hodgkin's diseaselike form (see Table 22-5). Many T-cell lymphomas
are characterized by a pleomorphic cell population, often including
large numbers of macrophages. This diverse cell population is
probably recruited to the site of the tumor by production of
cytokines by the malignant T cells. In addition, production of
these cytokines explains the common occurrence of inflammatory
signs and symptoms.Peripheral T-Cell LymphomaMost patients present
with peripheral T-cell lymphoma, which is a diffuse small- or
large-cell lymphoma with the phenotype of mature T cells. More than
one-half of these patients have B symptoms (fever, chills, weight
loss) suggesting active cytokine production by the malignant cells.
Widespread lymphadenopathy is the rule, and many patients have
involvement of extranodal sites, marrow, blood, liver, spleen,
lung, and skin.Large Granular Lymphocyte DiseaseLarge granular
lymphocyte (LGL) disease is a distinct disorder arising from a
clonal proliferation of a granular lymphocyte, derived from a CD3+,
CD8+ T cell. Although sometimes confused with an NK cell, these are
true T cells. The disease presents clinically as a low-grade
lymphoproliferative disorder with splenomegaly but little or no
lymphadenopathy, pancytopenia complicated by recurrent bacterial
infections, and, in a quarter of cases, an autoimmune disorder such
as rheumatoid arthritis. LGL disease in patients with rheumatoid
arthritis can be indistinguishable from Felty syndrome.
Proliferation of LGL cells has also been reported in association
with other hematologic malignancies (monoclonal gammopathy of
undetermined significance, multiple myeloma, and myelodysplasia)
and with both marrow and organ transplantation.The diagnosis of LGL
leukemia can usually be made from the appearance of large numbers
of granular lymphocytes (GL) in the peripheral blood and bone
marrow. Most patients demonstrate GL levels greater than 2000/L,
although when the other clinical features are present, a GL count
greater than 500/L is acceptable (normal GL count 223 - 699/L).
True NK-cell disease is very uncommon and often presents as a
leukemia with a very aggressive course.Lymphomatoid Granulomatosis
& Polymorphic ReticulosisLess common, angiocentric types of T
cell lymphoma include two entities: lymphomatoid granulomatosis and
polymorphic reticulosis (lethal midline granuloma) of the upper
respiratory tract. The latter is characterized by destructive
lesions of the nose, sinuses, and nasopharynx. Patients with
lymphomatoid granulomatosis complain of fever, weight loss,
shortness of breath, cough, and hemoptysis. They have single or
multiple lung nodules or masses on chest x-ray. Recently
lymphomatoid granulomatosis has been reclassified as a mixed B- and
T-cell lymphoma in which the B cells are EBV
positive.Angioimmunoblastic LymphadenopathyAngioimmunoblastic
lymphadenopathy is a disease of the elderly that presents with
generalized lymphadenopathy, hepatosplenomegaly, B symptoms,
polyclonal expansion of B cells with hypergammaglobulinemia, and,
in some cases, autoantibodies resulting in hemolytic anemia or
thrombocytopenia. It is an aggressive disease that progresses to
either overt T- or B-cell lymphoma.
HISTIOCYTIC MEDULLARY RETICULOSIS & LENNERT
LYMPHOMAHistiocytic medullary reticulosis HMR is primarily a
disease of the marrow that results in profound pancytopenia with
infiltration of phagocytic cells that characteristically ingest
erythrocytes. As with other T-cell lymphomas, it is usually
accompanied by fever, weight loss, lymphadenopathy, and
hepatosplenomegaly. Lennert lymphoma is characterized by the
appearance of large numbers of epithelioid cells mixed with
lymphoid cells, often forming granulomas.Hodgkin's Disease like
T-Cell LymphomaHodgkin's disease like T-cell lymphoma, as implied
by its name, mimics the presentation and histology of Hodgkin's
disease. However, the T-cell infiltrate of the involved nodes is
clonal. It is important to distinguish this variant since its
prognosis is significantly poorer than that of Hodgkin's
disease.Other PresentationsT-cell malignancies can also present as
CLL (see Chapter 21), ALL (see Chapter 24), or as skin disease
(cutaneous T-cell lymphoma/mycosis fungoides/Saezary syndrome; see
Color Plates 52 and 59). The presenting skin lesions of mycosis
fungoides vary from an eczematous or psoriatic-appearing lesion to
plaques with sharply demarcated margins. With time these cutaneous
lesions develop into painless nodules that can ulcerate and become
infected. Severe itching is the rule, and many patients will
develop generalized erythroderma progressing to exfoliation.
Survival can range from a few months to several decades, depending
on extent of blood, nodal, and visceral disease. When disease is
limited to the skin, median survival is in excess of 10 years.
However, most patients will in time progress to stage IV with
involvement of lymph nodes and visceral organs. Blood and marrow
involvement is characterized by the appearance in the circulation
of small or large lymphocytes with highly convoluted (cerebriform)
nuclei. These cells are acid phosphatase positive and CD4 positive.
Their presence signifies progression from mycosis fungoides to
Saezary cell leukemia.On skin biopsy the CD4 T-helper cell
lymphomas typically show a lymphocytic or mixed cell infiltrate
immediately under the epidermis. In some patients the epidermis is
actually invaded by clusters of lymphocytes producing unique
lesions called Pautrier microabscesses (see Color Plate 59). This
pattern is quite different from that seen with B-cell lymphomas,
where the cells tend to congregate in the lower dermis, leaving a
clear subepidermal zone. T-cell receptor gene rearrangement
analysis can be used to identify the clonal T-cell nature of the
infiltrate in unclear cases.Table 22-6. WHO classification of
cutaneous lymphomas.
Mycosis fungoides/Szary syndromeAnaplastic large cell lymphoma,
primary cutaneous typePeripheral T-cell lymphomaNK/T-cell
lymphomaSubcutaneous pannicilitis-like T-cell lymphomaExtranodal
marginal zone lymphoma of MALT typeFollicular lymphomaDiffuse large
B-cell lymphomaExtramedullary plasmacytoma
Lymphomas of the skin are not all T-cell malignancies; B-cell
lymphomas and Hodgkin's disease can also initially present with
cutaneous involvement. As a reflection of this, classification
schemes for the cutaneous lymphomas have been proposed by the WHO
and the EORTC (European Organization for Research and Treatment of
Cancer). The newer WHO classification is summarized in Table
22-6.
THERAPY & CLINICAL COURSEThe success rate in treating
lymphoma is of course related to grade of disease as well as many
other prognostic factors. For both high-grade and low-grade
lymphomas the most important prognostic indicators are summarized
in Table 22-7, and the outcomes associated with combinations of
these factors are shown in Table 22-8. Patients with low-grade
lymphomas often have a good prognosis in terms of their long-term
survival but are very rarely cured, ultimately dying of their
disease. Conversely, patients with high-grade lymphomas, who have a
very poor prognosis when untreated, and a much shorter average
survival, can often be cured by aggressive therapy (Figure 22-3).
Thus, NHL therapy must be tailored to the disease and to the
patient. In many institutions these patients will be treated
according to research protocols. This permits continuous
improvement in therapy as new regimens for radiotherapy, multidrug
chemotherapy, and marrow transplantation are introduced. Successful
treatment of the lymphoma also requires a high-quality blood
transfusion service to provide red blood cell and platelet support
and an aggressive approach to the control of infection in these
immunocompromised patients.Table 22-7. Prognostic indices in high-
and low-grade lymphomas.
Adverse Factors for High-Grade LymphomaAdverse Factors for
Low-Grade Lymphoma
Age > 60 yrAge > 60 yr
Serum LDH elevatedSerum LDH elevated
Performance status 2 - 4B symptoms or ESR > 30
Stage III or IVMale sex
Extranodal involvementExtranodal involvement
Table 22-8. Survival according to prognostic indices.
High-Grade Lymphoma Low-Grade Lymphoma
2-yr Survival5-yr Survival5-yr Survival10-yr Survival
Low risk: 0 - 1 factor84%73%89%70%
Intermediate risk: 2 - 3 factors60%47%71%49%
High risk: > 3 factors34%26%47%8%
Radiation TherapyRadiation therapy is very effective in
destroying sites of bulky disease. Relatively low doses (2000 cGy)
will result in spectacular regression of a tumor mass. However,
since most patients have widely disseminated disease at
presentation, the role of radiotherapy is only palliative, and
limited to the treatment of a restricted site of symptomatic
disease. The only situation in which radiotherapy may be undertaken
with curative intent is in localized (stage I or II) disease, where
cures have been reported in high-, low-, and intermediate-grade
lymphomas. However, radiotherapy alone can only be recommended
after an exhaustive search using radiologic, immunologic, and
molecular techniques has failed to find any evidence of
dissemination of the lymphoma. Even when there is no evidence for
blood, marrow, or other organ involvement, up to 50% of apparent
stage I lymphomas will relapse at a distant site and need multidrug
chemotherapy with or without transplantation.
Treatment of Low-Grade LymphomasLow-grade lymphomas are
frequently extremely indolent, with long periods of regression or
stable disease interrupted by periods of increased disease
activity. No evidence exists that aggressive chemotherapy can cure
these patients. Thus a conservative therapeutic approach is
indicated, ranging from no therapy at all during quiescent periods
to the use of minimal chemotherapy or radiotherapy designed to
control flare-ups and eliminate symptoms. Some of these patients
will survive for 5 - 10 years, requiring only brief periods of
treatment or none at all. The usual treatment for these patients is
local radiotherapy to bulky symptomatic disease and a mild regimen
of chemotherapy such as oral chlorambucil or cyclophosphamide or a
cyclophosphamide-vincristine-prednisone regimen (Table 22-9).
Chemotherapy should be continued until the disease has regressed
and appears quiescent, and then should be stopped and the patient
closely observed. Such patients may gradually become more resistant
to treatment with shorter periods of remission, or they may convert
to a higher grade of lymphoma with a more rapid growth
pattern.Recently there have been reports of a high level of
responsiveness in patients with low-grade lymphoma to the newer
agents such as fludarabine and 2-chlordeoxyadenosine (2-CdA). These
agents, which are proving very effective in the treatment of the
CLLs (see Chapter 21), now have roles in the therapy of other
low-grade lymphomas. These agents are highly immunosuppressive,
especially in combination with corticosteroids, and their use
increases the risk of opportunistic infections.Some patients with
low- or intermediate-grade lymphoma will show a pattern of
continual slow growth of the disease despite therapy (unresponsive
disease) or will have brief responses followed by rapid resumption
of growth. These patients have a markedly poorer prognosis. In this
case more aggressive chemotherapy protocols are justified in an
attempt to achieve longer remissions. Such protocols include
chemotherapy capable of crossing into the CNS, such as high-dose
methotrexate with leucovorin rescue, cytosine arabinoside, or both.
Such multidrug protocols involve a high level of treatment-related
morbidity and mortality (up to 5 - 10%) but do result in prolonged
disease-free survival in up to 50% of patients. Because of a
tendency to see late relapses it is unclear what proportion of
these may be considered cures.Immunotherapy has shown considerable
promise in the treatment of the low-grade lymphomas. Several
different approaches are being studied. Monoclonal antibodies
against B cell epitopes-for example, CD19 or CD20 together or
alone, coupled with toxins or radioisotopes have been produced.
Rituximab, a chimeric anti-CD20 monoclonal antibody with
specificity for the late preB stage to plasma cell differentiation,
is now being used in various combinations with chemotherapy and
stem cell rescue strategies. Patients with follicular histology
show the best response; 80% of patients who fail on chemotherapy
alone respond to rituximab with minimal toxicity. Although the best
use of this agent is still a matter of study, it is typically given
in doses of 375 mg/m2 as a weekly infusion for up to 8 weeks. Its
use as an up front part of combination chemotherapeutic regimens is
also being studied. Another approach to immunotherapy involves
coupling a radionuclide, such as 131I or 90Y, to an anti-CD20
antibody (131I tositumomab and 90Y ibritumomab). When given in
myeloablative doses followed by stem cell rescue, this approach is
well tolerated and can produce prolonged remissions in more than
50% of relapsed patients.
Table 22-9. Some typical chemotherapeutic regimens for
lymphoma.
RegimenDrug Dosage and Schedule
Single agent
Cyclophosphamide or100 PO qd
Chlorambucil412 mg PO qd
Fludarabine25 mg/m2/IV days 15
CVP Repeated q3 weeks
Cyclophosphamide400 mg/m2 PO days 15
Vincristine1.4 mg/m2 IV day 1
Prednisone100 mg/m2 PO days 15
CHOP Repeated q3 weeks
Cyclophosphamide750 mg/m2 IV day 1
Adriamycin50 mg/m2 IV day 1
Vincristine1.4 mg/m2 IV day 1
Prednisone100 mg PO days 15
R-CHOP Repeated q3 weeks
Rituximab375 mg/m2 IV day 1
CHOP (as above)Beginning day 3
Chemotherapy with autologous marrow support
BCNU112 mg/m2 IV days 14
Cyclophosphamide900 mg/m2 IV q12h days 14
Etoposide (VP-16)250 mg/m2 IV q12h days 14
Infusion of autologous marrow cellsAt least 2 106 CD34+ cells/kg
IV day 7
Lymphoma vaccine therapy is another potentially useful approach.
Typically the vaccine is custom-made using a sample of the
patient's own tumor cells to derive an idiotype protein, which is
unique to the patient's lymphoma. This tumor-derived protein is
then combined with an imunnostimulant, such as keyhole limpet
hemocyanin, and injected subcutaneously on a monthly schedule for
up to 2 years. Simultaneous treatment with G-CSF may help magnify
the immune response. Patients with the lowest tumor burden appear
to do the best; therefore, candidate patients should be pretreated
with combination chemotherapy.
Treatment of High-Grade LymphomasPatients with high-grade
lymphomas have a poor prognosis when left untreated and should
receive aggressive chemotherapy without waiting to see how the
disease responds to milder therapy. A high-dose, multidrug
protocol, such as
cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) should
always be used in these patients. Even more aggressive chemotherapy
with autologous stem cell transplantation offers a significantly
better chance of survival in selected patients; long-term survivals
approach 60%. An international index of prognostic factors has been
applied to these patients and has demonstrated that age (greater
than 60 years), elevated LDH, poor performance status, the presence
of stage III or IV disease, and the presence of more than one site
of extranodal involvement are the most significant factors.
Patients with 0 to 1 risk factor show 5-year survivals of greater
than 70%, whereas patients with four or more risk factors have
survivals of 20 - 30%.There is also evidence that patients with
intermediate-risk lymphomas achieve significantly better survivals
when treated with high-dose therapy and stem cell transplantation,
rather than conventional CHOP. However, the simple addition of
rituximab to the CHOP regimen has now provided greatly improved
results and has become the standard of care for these patients. To
date, the rituximab-CHOP combination has not been randomly tested
against transplantation. For patients with low-risk lymphomas,
conventional and high-dose therapy with transplantation seems to
offer equivalent results.Patients with high-grade lymphomas who
relapse after conventional chemotherapy are routinely treated with
very high-dose chemotherapy regimens, sometimes including total
body irradiation, followed by peripheral stem cell transplantation.
The success of this salvage therapy has been reported by several
centers to range from 30% to 50% long-term disease-free survival.
Radioimmunotherapy is another promising approach for relapsed
high-grade lymphomas. Recently, the proteosome inhibitor
bortezomib, which is active in myeloma, has shown some activity in
non-Hodgkin's lymphomas as well. Thus, the addition of this new
agent to existing regimens is now being studied.
Marrow Transplantation/Peripheral Blood Stem Cell
SupportAllogeneic transplantation has curative potential in the
patient with a matched sibling. Success depends on the
responsiveness of the tumor to chemotherapy and the patient's age
and overall state of health. Compared to autologous transplantation
(ABMTx), it is associated with higher transplantation related
mortality, but a better chance of long-term disease-free survival,
approaching 70 - 80% at 5 years. Unlike acute leukemia, the outcome
does not appear to correlate with the antitumor effect of
GVHD.Because many more patients are eligible, ABMTx has become a
major treatment option for patients with high-grade lymphomas and
relapsed Hodgkin's disease. The procedure has undergone a gradual
transition so that it is now more correctly referred to as
high-dose chemotherapy with peripheral blood stem cell (PBSC)
support. Most transplant protocols now make use of autologous
peripheral blood stem cells collected by apheresis, rather than
bone marrow. The rate of recovery of the patient's blood counts,
especially the platelet count, is more rapid with the peripheral
stem cell method.In essence ABMTx/PBSC support is not a transplant
in the usual sense of the word, but is really a strategy for
overcoming the major dose-limiting toxicity of chemotherapy, marrow
failure, by supporting the patients with infusions of marrow cells,
blood progenitor cells, or both. The fundamental rationale is that
it may be possible to achieve cures of some diseases by increasing
the dose of chemotherapy to 5 - 10 times that which could be given
without replacement of hematopoietic progenitor cells. This has
proved to be the case for some diseases. It must be remembered,
however, that the procedure cannot be successful if the disease is
not responsive to very high-dose chemotherapy. ABMTx/PBSC support
has the advantage that it can be used in patients who do not have
an HLA-compatible family or unrelated donor, it can be applied to
older patients with much greater safety than allogeneic
transplantation, and it does not have the complication of
graft-versus-host disease. Its major disadvantage is the risk of
relapse due to small numbers of tumor cells in the autologous
marrow or PBSC collection. There is increasing evidence that this
is indeed a serious consideration that limits the success of this
strategy.
A. PROCEDUREABMTx/PBSC protocols now involve the collection of
PBSCs instead of marrow (Figure 22-4). PBSCs are collected from the
patient by repeated leukapheresis, usually one to five times over
as many days. The timing of these collections is critical since for
them to be successful. In order to obtain adequate numbers of stem
cells it is necessary to increase the proportion of circulating
progenitor cells in the blood. This may be done either by
collecting the cells during the period that the patient is
recovering from conventional chemotherapy or when the granulocyte
count is rising in response to either granulocyte
colony-stimulating factor (G-CSF) or granulocyte macrophage
colony-stimulating factor (GM-CSF). In either case it is preferable
to begin collections when the count is rising sharply, either at
the level of 1000 - 2000/L following chemotherapy or after 4 - 5
days of daily colony-stimulating factor injections. The leukocytes
from these collections are frozen until needed by the patient.
Usually between 1 and 10 1010 cells are collected. Enumeration of
the CD34+ cells, which include all of the hematopoietic progenitor
cells, has improved the ability to determine how many cells are
required for successful engraftment. Between 2 and 5 106 CD34+
cells/kg are adequate, and in some patients this goal may be
reached in a single apheresis session.
The patient is then admitted for high-dose chemotherapy, which
may contain any of a number of different combinations of drugs
according to specific protocols (see Table 22-9). Some ABMTx
regimens include total body irradiation in addition to
chemotherapy. The doses of drugs are chosen so as to result in
total ablation of the marrow while avoiding lethal toxicity to
other organs such as lung, liver, and heart. Within 1 - 4 days
following chemotherapy, patients receive intravenous infusions of
their PBSC and begin receiving daily injections of G-CSF or
GM-CSF.Following reinfusion of the progenitor cells, there is a
period of 5 - 10 days in which the patient is absolutely
pancytopenic, with essentially no leukocytes, and dependent on
platelet support. After this latent period, there is, under the
influence of the myeloid growth factors, a rapid rise in the
leukocyte count. Platelet recovery usually lags behind the white
blood cells, and the patients may require platelet support for
weeks to months, although the use of PBSC hastens platelet
recovery.The management of these patients is essentially the same
as that of any patient receiving high-dose, marrow-ablative
chemotherapy. They are at high risk for severe infections and must
receive intensive antibiotic coverage (see Chapter 17). In
addition, the chemotherapy may result in reversible toxicity to
other organs that would not be seen with lower doses.
B. OUTCOME AND PROGNOSISThe ultimate outcome of ABMTx/PBSC
therapy depends on three factors. First, there is a significant
treatment-related mortality, which is usually less than 5%. Second,
and most likely, is the possibility that the patient's tumor could
not be ablated completely by the chemotherapy and radiation. A
fairly high percentage of patients relapse within the first 1 - 2
years. For most protocols in the treatment of high-grade
non-Hodgkin's lymphomas, this is in the range of 30 - 50% of
patients. Third, there is the possibility that the marrow and PBSC
collections contain small numbers of tumor cells that will regrow.
Since ABMTx/PBSC therapy involves the reinfusion of more than 1010
cells, and since even the most sensitive detection methods permit
the identification of only about 1 tumor cell in 106 cells, it is
possible that the patient can receive as many as 104 tumor cells
even if they are undetectable. It has been shown in the case of
non-Hodgkin's lymphoma that the risk of relapse is higher in
patients who have such very small numbers of cells detectable in
their stem cell collections.Strategies for depleting these tumor
cells, which involve treating the marrow with monoclonal
antibodies, in vitro chemotherapy, or immunotoxins (purging), have
been evaluated but do not yet offer a consistently clear
improvement in outcome. Recently, devices for purification of the
CD34+ stem cells using immunoabsorptive columns based on the
ability of monoclonal antibodies to bind to the CD34 antigen have
become available. There is hope that this procedure will
simultaneously enrich for the desired stem cells and deplete
unwanted tumor cells. It is striking that successful engraftment
can be achieved by infusion of as few as 1 to 2 106 purified CD34+
cells, with exactly the same engraftment kinetics as infusion of
10,000 times more unenriched marrow or blood cells.The prognosis
for the patient with relapsed or refractory non-Hodgkin's lymphoma
who undergoes a modern ABMTx protocol is 30 - 50% long-term
disease-free survival. Although far from perfect, this represents a
significant improvement over conventional chemotherapy for this
patient group. Treatment with rituximab post-transplant may improve
survival, although optimal dosing needs to be defined.
Treatment Regimens for T-Cell LymphomasEarly-stage mycosis
fungoides with disease limited to the skin is best treated with
topical therapy. Barely perceptible skin lesions (plaques, papules,
or eczematous patches) will usually respond to topical steroids,
alone. PUVA therapy (oral psoralen with UVA irradiation) or topical
nitrogen mustard (mechlorethamine) applied as an aqueous solution
or ointment will induce complete remission, lasting more than a
year, in most patients with skin-limited disease. Hypersensitivity
reactions are, however, seen in up to 50% of patients treated with
mechlorethamine. If topical therapy does not work, total-skin
electron-beam irradiation can be used, usually in combination with
maintenance PUVA, interferon-, or oral methotrexate to prevent
rapid relapse.Patients with cutaneous tumors and nodal involvement
are treated with local-field electron beam and PUVA maintenance or,
in the case of refractory or visceral disease, single-agent
(methotrexate, 2-CdA, fludarabine, or pentostatin) or combination
chemotherapy (EPOCH). Patients with generalized erythroderma should
receive photophoresis, together with low-dose interferon- or
methotrexate when the response is poor. Photophoresis involves
collecting the patient's leukocytes by leukopheresis after the oral
administration of methoxypsoralen and then exposing them to UV
light. When the treated leukocytes are reinfused they somehow
stimulate a host response to the tumor cells and significant
improvement in the patient's erythroderma. Photophoresis has also
been used as an adjuvant to chemotherapy in Szary cell leukemia
patients.LGL disease in otherwise asymptomatic patients may best be
simply observed. Survivals can exceed 10 years. The principal
indications for treatment are recurrent infections secondary to
severe neutropenia and B symptoms. Patients may respond to
prednisone alone or in combination with Cytoxan, or to low-dose
oral methotrexate. Combination chemotherapy (CHOP-like regimen) has
been used in patients with aggressive disease with only limited
success.
BIBLIOGRAPHYDiagnosisArgatoff LH et al: Mantle cell lymphoma: A
clinicopathologic study of 80 cases. Blood 1997;89:2067.Berger F et
al: Non-MALT marginal zone B-cell lymphomas: A description of
clinical presentation and outcome in 124 patients. Blood
2000;95:1950.Capello D et al: Molecular histogenesis of
posttransplantation lymphoproliferative disorders. Blood
2003;102:3775.Catovsky D, Matutes E: Splenic lymphoma with
circulating villous lymphocytes/splenic marginal-zone lymphoma.
Semin Hematol 1999;36:184.Coiffier B et al: Indolent nonfollicular
lymphomas: Characteristics, treatment, and outcome. Semin Hematol
1999;36:198.Franco V et al: Splenic marginal zone lymphoma. Blood
2003;101: 2464.Frederico M et al: Prognosis of follicular lymphoma:
A predictive model based on a retrospective analysis of 987 cases.
Blood 2000;95:783.Hans CP et al: Confirmation of the molecular
classification of diffuse large B-cell lymphoma by
immunohistochemistry using tissue microarray. Blood
2004;103:275.Harris NL et al: A revised European-American
classification of lymphoid neoplasms: A proposal from the
international lymphoma study group. Blood 1994;84:1361.Harris NL et
al: The World Health Organization classification of hematological
malignancies report of the clinical advisory committee meeting,
Airlie House, Virginia, November 1997. Mod Pathol
2000;13:193.Hiddeman W et al: Lymphoma classification: The gap
between biology and clinical management is closing. Blood 1996;88:
4085.Lossos IS et al: Prediction of survival in diffuse largeB-cell
lymphoma based on the gene expression of sic genes. N Engl J Med
2004;350:2828.Sanchez-Beato M et al: Cell cycle derregulation in
B-cell lymphomas. Blood 2003;101:1220.Semenzato G et al: The
lymphoproliferative disease of granular lymphocytes: Updated
criteria for diagnosis. Blood 1997;89: 256.Thieblemont C et al:
Small lymphocytic lymphoma, marginal zone B-cell lymphoma, and
mantle cell lymphoma exhibit distinct gene-expression profiles
allowing molecular diagnosis. Blood 2004;103:2727.Tilly H et al:
Prognostic value of chromosomal abnormalities in follicular
lymphoma. Blood 1994;84:1043.Willis TG, Dyer MJS: The role of
immunoglobulin translocations in the pathogenesis of B cell
malignancies. Blood 2000; 96:808.Zucca E et al: The gastric
marginal zone B cell lymphoma of the MALT type. Blood
2000;96:410.TherapyAppelbaum FR: Treatment of aggressive
non-Hodgkin's lymphoma with marrow transplantation. Marrow
Transplant Rev 1993; 3:1.Armitage JO: Treatment of non-Hodgkin's
lymphomas. N Engl J Med 1993;328:1023.Cheson BD: Radioimmunotherapy
of non-Hodgkin's lymphomas. Blood 2003;101:391.Fisher RI et al:
Comparison of a standard regimen (CHOP) with three intensive
chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J
Med 1993;328:1002.Ghielmini M et al: Prolonged treatment with
rituximab in patients with follicular lymphoma significantly
increases event-free survival and response duration compared with
the standard weekly X 4 schedule. Blood 2004;103:4416.Milpied N et
al: Initial treatment of aggressive lymphoma with high-dose
chemotherapy and autologous stem-cell support. N Engl J Med
2004;350:1287.Pittaluga S et al: Clinical analysis of 670 cases in
two trials of the European organization for the research and
treatment of cancer lymphoma cooperative group subtyped according
to the revised European-American classification of the lymphoid
neoplasms: A comparison with the working formulation. Blood
1996;87:4358.Press OW et al: A phase I/II trial of iodine
131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and
autologous stem cell transplantation for relapsed B-cell lymphomas.
Blood 2000;96:2934.Rowe JM et al: Recommended guidelines for the
management of autologous and allogeneic bone marrow
transplantation. Ann Intern Med 1994;120:143.Shipp MA et al: A
predictive model for aggressive non-Hodgkin's lymphoma: The
international non-Hodgkin's lymphoma prognostic factors project. N
Engl J Med 1993;329:987.Steinbach G et al: Antibiotic treatment of
gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern
Med 1999; 131:88.The non-Hodgkin's lymphoma classification project:
A clinical evaluation of the international study group
classification of non-Hodgkin's lymphoma. Blood 1997;89:3909.The
international non-Hodgkin's lymphoma prognostic factors project: A
predictive model for aggressive non-Hodgkin's lymphoma. N Engl J
Med 1993;329:987.Van Besien et al: Comparison of autologous and
allogeneic hematopoietic stem cell transplantation for follicular
lymphoma. Blood 2003;102:3521.Verdonck LF et al: Comparison of CHOP
chemotherapy with autologous bone marrow transplantation for slowly
responding patients with aggressive non-Hodgkin's lymphoma. N Engl
J Med 1995;332:1045.