[CANCER RESEARCH (SUPPL.) 52, 5447s-5452s. October I. 1992|
An Overview of the Classification of Non-Hodgkin's
of Morphological and Phenotypical Concepts1
Lymphomas: An Integration
Elaine S. Jaffe,2 Mark Raffeid, L. Jeffrey Medeiros, and Maryalice Stetler-Stevenson
Hematopathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20982
Abstract
An analysis
of trends in the incidence
of non-Hodgkin's
lymphoma
requires an understanding
of individual disease entities within this
broad group. The non-Hodgkin's lymphomas represent a diverse group
of malignancies that have in common an origin from lymphoid cells.
Nevertheless, these disorders are heterogeneous in their clinical behav
ior, morphological appearance, cellular origin, etiology, and pathogenesis. A modern classification of non-Hodgkin's lymphomas must include
an integration of morphological, immunophenotypical,
and molecular
concepts in order to delineate individual diseases within this broad
group. Existing classification schemes such as the working formulation,
while they may be useful in providing a guide to clinical management,
cannot provide this information in the absence of other data.
This point is most readily made with the low-grade B-cell lymphomas
which include follicular lymphomas, mantle cell lymphomas, small lymphocytic lymphomas, immunosecretory
disorders, and lymphomas of
mucosa-associated
lymphoid tissues. Each of these malignancies has a
distinct phenotype and genotype, and indubitably each has a different
etiology. The postthymic T-cell tumors are equally diverse. Analysis of
epidemiológica! data from cancer registries must include a recognition
that our ability to recognize individual diseases from historical data is
limited. Studies of trends in the non-Hodgkin's lymphomas should at
tempt to delineate biological markers that may be of relevance to pathogenesis in both historical
Introduction
The non-Hodgkin's
and prospectively
lymphomas
accrued cases.
are not a single disease
but represent a diverse group of clinicopathological and biolog
ical entities. The modern approach to lymphoma diagnosis
should include both morphological and phenotypic techniques.
The Rappaport classification is not in current use; however,
when this classification scheme was proposed in the 1960s, it
immediately became popular among clinicians and is the ter
minology that has been most widely utilized in the Surveillance
Epidemiology and End Results program (SEER) data base (Ta
ble 1)(1).
The classification of non-Hodgkin's lymphomas, as proposed
by Rappaport (1), first divided lymphomas according to their
architectural pattern, nodular or diffuse, and then according to
the cytological cell type. If the cells were small, they were
termed "lymphocytic," or if large, "histiocytic." However, dur
ing the 1970s when the field of immunology was undergoing a
rapid expansion, the scientific basis for this scheme came into
question. It became apparent that the large cell tumors that
Rappaport termed histiocytic were, in fact, composed of trans
formed lymphoid cells. Furthermore, the Rappaport scheme
did not take into consideration the phenotypic heterogeneity of
the immune system as it related to the classification of lympho
mas (2).
1 Presented at the National Cancer Institute Workshop, "The Emerging Epi
demic of Non-Hodgkin's Lymphoma: Current Knowledge Regarding Etiological
Factors," October 22-23, 1991, Bethesda. MD.
2 To whom requests for reprints should be addressed, at Hematopathology Sec
tion, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20982.
As a result of this dissatisfaction, a variety of classification
schemes were proposed. Two of them, the Lukes and Collins
Classification (3) and the Kiel Scheme (4), as proposed by Lennert and colleagues, are shown in Table 1. The complexity of
this terminology is obvious. All of these terms have been in
International Classification of Diseases for Oncology, and
probably all are reflected in the SEER data at one point or
another. Moreover, if one tries to discern individual disease
entities from these data, it is virtually impossible.
The National Cancer Institute responded to this problem by
funding a study to test the six major classification schemes
proposed at this time. They examined 1175 cases of lymphoma
that had been prospectively staged and treated in a uniform
manner at one of four major treatment centers (5). Not surpris
ingly, all six classification schemes could identify tumors of
low- or high-grade clinical behavior, and no one scheme seemed
to work significantly better than any other.
Consequently, the investigators involved in that study pro
posed a working formulation for non-Hodgkin's lymphoma di
agnosis, and they divided the tumors into morphological groups
ranked according to their clinical behavior in these 1175 cases
(Table 2). At the time that the working formulation was pub
lished, the authors (5) of it stated that it was "not proposed as
a new classification, but as a means of translation among the
various systems." Unfortunately, this subtle distinction has not
always been appreciated.
The working formulation categories do not identify individ
ual disease entities. The terms that it uses are microscopic
descriptors. They describe the cellular population that the pa
thologist sees in the histológica! section, but one cannot infer
that each category is an individual disease. In fact, we have very
good evidence today that most of these categories do not rep
resent individual diseases. If one wishes to understand the ep
idemiology of lymphomas and to understand time trends, one
must step away from this approach and look at individual dis
eases rather than morphological categories.
Essential to this process is the use of immunological ap
proaches. The malignant lymphomas are tumors of the immune
system, and the malignant cells retain both the phenotypic and
functional properties of their precursors. Using the tools of
immunology, we can begin to dissect out individual diseases
among the malignant lymphomas.
The development of monoclonal antibodies has been invalu
able in providing us with a battery of reagents that can be
consistently used among different laboratories. Most of these
reagents have to be applied to freshly isolated cells, either in cell
suspension or in frozen sections, but increasingly, monoclonal
antibodies are available that can be used on routinely processed
paraffin-embedded sections (6). These reagents provide an im
portant step in permitting the use of these techniques on a
routine basis for most lymphomas.
The vast majority of non-Hodgkin's lymphomas diagnosed in
the United States and in Europe are of B-cell origin and fall into
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CLASSIFICATION OF NON-HODGKIN'S LYMPHOMAS
Table 1 Comparison of commonly used classifications for non-Hodgkin's lymphomas
Modified Rappaport
classification
Nodular
Lymphocytic, well differentiated
Lymphocytic, poorly
differentiated
Mixed, lymphocytic and histiocytic
Histiocytic
Diffuse
Lymphocytic, well differentiated
without plasmacytoid features
Lymphocytic, well differentiated
with plasmacytoid features
Lymphocytic, poorly
differentiated
Lymphoblastic, convoluted
Lymphoblastic, nonconvoluted
Mixed, lymphocytic and histioytic
Histiocytic without sclerosis
Histiocytic with sclerosis
Burkitt's tumor
Undifferentiated
Malignant lymphoma, unclassified
Composite lymphoma
Working
formulation"
A
B
C
D
A
A
E
I
I
F
G
G
J
J
Lukes and Collins
classification
Working
formulation
Undefined cell type
T-cell type, small lymphocytic
T-cell type, Sézary-mycosisfungoides
(cerebriform)
T-cell type, convoluted lymphocytic
T-cell type, immunoblastic sarcoma
(T-cell)
B-cell type, small lymphocytic
B-cell type, plasmacytoid lymphocytic
Follicular center cell, small cleaved
Follicular center cell, large cleaved
Follicular center cell, small
noncleaved
Follicular center cell, large
noncleaved
Immunoblastic sarcoma (B-cell)
Subtypes of follicular center cell
lymphomas
1. Follicular
2. Follicular and diffuse
3. Diffuse
4. Sclerotic with follicles
5. Sclerotic without follicles
Histiocytic
Malignant lymphoma, unclassified
A
I
H
A
A
B-E
D-G
J
D-G
H
Kiel classification
Low-grade malignancy
Lymphocytic, chronic lymphocytic/
leukemia
Lymphocytic, other
Lymphoplasmacytoid
Centrocytic
Centroblastic-centrocytic, follicular
without sclerosis
Centroblastic-centrocytic, follicular
with sclerosis
Centroblastic-centrocytic, follicular
and diffuse, without sclerosis
Centroblastic-centrocytic, follicular
and diffuse, with sclerosis
Centroblastic-centrocytic, diffuse
Low-grade malignant lymphoma,
unclassified
High-grade malignancy
Centroblastic
Lymphoblastic, Burkitt's type
Lymphoblastic, convoluted cell type
Lymphoblastic, other (classified)
Immunoblastic
High-grade malignant lymphoma,
unclassified
Malignant lymphoma, unclassified
(unable to specify "high grade"
or "low grade")
Working
formulation
A
A
A
E
B, C
D
F
G
J
I
H
Composite lymphoma
" Letters indicate equivalent or related category in the working formulation as shown in Table 2.
Table 2 National Cancer Institute working formulation of non-Hodgkin's
lymphomas for clinical usage (Ref. 5)
Follicular lymphoma is the prototype of the low-grade B-cell
lymphomas and is the single largest group of non-Hodgkin's
Low grade
A. Small lymphocytic
B. Follicular, predominantly small cleaved cell
C. Follicular, mixed small cleaved and large cell
Intermediate grade
D. Follicular, predominantly large cell
E. Diffuse, small cleaved cell
F. Diffuse, mixed small cleaved and large cell
G. Diffuse, large cell
High grade
H. Large cell, immunoblastic
I. Lymphoblastic
J. Small noncleaved cell
Miscellaneous
Composite
Mycosis fungoides
Histiocytic
Extramedullary plasmacytoma
Unclassifiable, other
the midstage of B-cell differentiation (6). At this stage of dif
ferentiation, cells express monoclonal surface immunoglobulin,
most often IgM, with or without IgD, and usually express the
pan-B-cell antigens, CD 19, CD20, and CD22.
Low-Grade
B-Cell Lymphomas
Within the working formulation, virtually all low-grade lym
phomas are of B-cell origin, but one can begin to recognize
different disease entities among the low-grade B-cell lympho
mas that are not readily apparent in the pure working formu
lation approach. First and foremost among these is follicular
lymphoma, which is well recognized in the working formulation
but spans three separate clinical groups, in both the low-grade
and intermediate-grade categories. Other disease entities are
less readily identified in the working formulation (Table 3). For
example, mantle zone lymphoma, or mantle cell lymphoma,
falls within several different working formulation groups. Con
versely, the small lymphocytic lymphoma group (A) includes
several different disease entities.
lymphomas, accounting for approximately 45% of all cases (5).
It is a disease of adult life and occurs equally in males and
females. The neoplastic cells form follicular aggregates, which
tend to mimic normal lymphoid follicles. Cytologically, the cell
types that we see within follicular lymphomas resemble the cells
within the normal germinal center, as described by Lukes and
Collins (3) and Gerard-Marchant et al. (4). Follicular lympho
mas are subclassified according to the proportion of these var
ious cytological cell types (7). In the working formulation, the
small cleaved and mixed small cleaved and large cell categories
are in the low-grade group, whereas the follicular large cell type
is in the intermediate-grade group, based on its more aggressive
clinical behavior. However, all of these cells exist in all follic
ular lymphomas, and the Kiel classification takes the approach
of considering all tumors centrocytic/centroblastic, without the
identification of cytological subgroups.
The follicular lymphomas are monoclonal B-cell neoplasms;
the cells express monoclonal surface immunoglobulin and are
frequently confined to the neoplastic nodules (8, 9). In fact, in
early lymph node involvement, one can show that the neoplastic
cells selectively home to or colonize the germinal centers,
focally involving these structures within the lymph node (10,
11).
The cells seem to be held together within these follicles by
dendritic reticulum cells, which are a normal structural and
functional component of the germinal center. These cells are an
invariant component of follicular lymphomas but are not con
sidered neoplastic. When the dendritic reticulum cells are lost,
the process tends to become diffuse, although these events may
not be causally related. Follicular lymphomas usually present
with generalized lymphadenopathy and frequent involvement
of the bone marrow with paratrabecular lymphoid aggregates
(5, 12, 13). In approximately 10% of patients, neoplastic cells
are identified morphologically in the peripheral blood.
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CLASSIFICATION
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Table 3 A disease-oriented approach to lymphoma classification
Low-grade B-cell lymphomas
Follicular lymphoma
Mantle cell lymphoma
IDL"/centrocytic/mantle zone
Small lymphocytic lymphoma/CLL
Immunosecretory disorders
Waldenström's macroglobulinemia
MALT
Monocytoid B-cell lymphoma
Working formulation
B.C. D
A, B, E
A
A, F
A, E
' IDL, lymphocytic lymphoma of intermediate grade of differentiation.
When more sensitive molecular techniques are used, even a
higher proportion of patients can be shown to have peripheral
blood involvement. Follicular lymphomas are characterized by
a consistent cytogenetic abnormality; the t(14;18) is found in
90% of cases of follicular lymphoma (14). This translocation
involves the immunoglobulin heavy chain locus on chromo
some 14 and the bcl-2 gene on chromosome 18. Probes to the
bcl-2 gene can be used to detect this translocation at the mo
lecular level, using either Southern blot hybridization or the
polymerase chain reaction technique (15).
Mantle cell lymphoma is a distinct clinicopathological entity,
equivalent morphologically to lymphocytic lymphoma, inter
mediate grade of differentiation (IDL) of the modified Rappaport scheme (16); centrocytic lymphoma of the Kiel classifica
tion; and mantle zone lymphoma, a term popularized by
Weisenburger et al. (17). This form of lymphoma was originally
called intermediate because it was believed to be intermediate in
its cytological characteristics between the well-differentiated
and poorly differentiated lymphocytic lymphomas of the Rappaport scheme (18). The cells are slightly cleaved and angulated
with an atypical appearance.
In contrast to follicular lymphoma, in which selective in
volvement of germinal centers is seen, in mantle cell lymphoma,
residual normal germinal centers are often uninvolved by the
neoplastic process (16). This mantle zone growth pattern can be
seen in the small intestine, bone marrow, and other extranodal
sites and provides evidence for a mantle zone derivation of the
malignant cells.
In fact, this tumor can have a vaguely nodular growth pattern,
which derives from its propensity to grow as an expanded man
tle around residual germinal centers. As such, (mis)diagnosis as
follicular small cleaved in the working formulation may occur.
Such an error may be avoided if careful cytological criteria are
utilized. For example, follicular lymphomas always have a mix
ture of cell types, so-called "centrocytes" and "centroblasts,"
whereas mantle cell lymphomas are much more homogeneous
cytologically. In addition, in contrast to follicular lymphomas,
in which one finds a tight meshwork of dendritic reticulum
cells, in mantle cell lymphomas, the dendritic reticulum cells
are often disorganized, correlating with the vaguely follicular
growth pattern (19). Another distinguishing feature of this lym
phoma and one that is useful from a diagnostic standpoint is
that this tumor, like chronic lymphocytic leukemia, is almost
always CDS positive (20, 21). CDS is an antigen expressed on
normal T-cells but also expressed on a subset of B-cells. True
follicular lymphomas are always CDS negative.
Mantle cell lymphomas are unique in that a greater propor
tion of these cases express monoclonal X-light chain than mon
oclonal K.For most of the non-Hodgkin's lymphomas, there is
LYMPHOMAS
positive (20, 21). Like normal mantle zone cells, the tumor cells
also often coexpress IgM and IgD.
In the working formulation, mantle cell lymphomas fall into
the diffuse small cleaved category, which is in the intermediategrade group. However, unlike all other intermediate-grade lym
phomas, the survival curve does not show a plateau or evidence
of a cured population (20). In this regard, they resemble lowgrade lymphomas. However, the median survival is only 5
years, somewhat less than other low-grade lymphomas (20).
Recent studies have shed light on the pathogenesis of mantle
cell lymphomas. They are often associated with the t(ll;14)
involving the bcl-l breakpoint region (22, 23). Recently, an
oncogene, PRAD\, located near this breakpoint has been shown
to be overexpressed in centrocytic or mantle cell lymphomas
(24).
A third category of low-grade B-cell lymphoma is the small
lymphocytic malignancies, which include chronic lymphocytic
leukemia (25, 26). These tumors are composed of cells that are
relatively uniform in their appearance, resembling normal lym
phocytes, and thus in the Rappaport classification they were
called well-differentiated lymphocytic lymphomas. Small lym
phocytic malignancies can present either as chronic lympho
cytic leukemia or, less commonly, with primarily lymph node
disease, as a lymphoma. In the latter case, there is usually
generalized lymphadenopathy and only focal bone marrow in
volvement. However, whether the presentation is leukemic or
lymphomatous, the process is identical phenotypically and
morphologically and represents different clinical presentations
of the same neoplastic population. Like mantle cell lympho
mas, this B-cell neoplasm also expresses CDS in most cases.
Small lymphocytic malignancies may represent a block in the
terminal maturation of a B-cell toward a plasma cell. These
patients often have hypogammaglobulinemia and humoral im
munodeficiency (10).
Waldenström's macroglobulinemia represents one step fur
ther in the maturation of a B-lymphocyte (27). In this disease,
the cells express surface and cytoplasmic IgM and secrete im
munoglobulin resulting in a monoclonal paraproteinemia.
Morphologically, the cells also appear more plasmacytoid.
Waldenström's macroglobulinemia usually presents as lym
phoma with generalized lymphadenopathy, although in about
10% of patients it may present as chronic lymphocytic leukemia
with a lymphocytosis (27). In tumors with plasmacytic differ
entiation, there is often a change in the antigenic phenotype
(28). The cells may lose many of the pan-B-cell antigens at this
late stage of B-cell differentiation. In addition, there is eventu
ally a loss of surface immunoglobulin and a predominance of
cytoplasmic immunoglobulin in these secretory B-Iymphocytes.
The last category of low-grade B-cell lymphomas, which has
been recently proposed by Isaacson and Spencer (29, 30), is
lymphomas of MALT3. MALT lymphomas usually occur in
extranodal sites, such as the stomach and the lung. Many of
these tumors were called pseudolymphomas prior to the devel
opment of the MALT lymphoma concept because they fre
quently contain hyperplastic germinal centers. However, inumi
nophenotypic studies have revealed a monoclonal pattern of
light chain expression in the small lymphocytic component.
The reclassification of these lesions because of a change in
diagnostic criteria might provide a partial explanation for the
recently observed increase in the incidence of lymphoma.
a predominance of Kbecause there is a predominance of normal
K-bearing cells in the peripheral blood. But centrocytic lympho
mas or mantle cell lymphomas are more often Xpositive than K
' The abbreviation used is: MALT, mucosa! associated lymphoid tissue.
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CLASSIFICATION
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LYMPHOMAS
Table 5 Classification ofpostthymic T-cell malignancies
T-cell "chronic" lymphocytic leukemia
Clinically, the MALT lymphomas have a unique and often
indolent behavior. They tend to recur in extranodal sites but
usually do not disseminate widely to bone marrow or to lymph
nodes (31 ). In the working formulation, most would fall into the
small lymphocytic group, but their often heterogeneous cellular
composition might place them in other categories as well (Table
3). In contrast to the other small lymphocytic lymphomas, they
are CDS negative rather than CDS positive (31). Monocytoid
B-cell lymphomas, originally described in lymph nodes, appear
to be the nodal counterpart of MALT lymphomas and show a
high frequency of extranodal disease (32-34).
CD4 positive (prolymphocytic)
CDS positive/large granular lymphocytes
Mycosis fungoides-Sezary syndrome
Lymph node-based peripheral T-cell lymphomas
IBL-like" T-cell lymphoma
Large cell anaplastic lymphoma (KÕ-1+)
Adult T-cell leukemia/lymphoma
Subcutaneous panniculitic T-cell lymphoma
Angiocentric immunoproliferative disease
IBL, immunoblastic lymphadenopathy.
Aggressive B-Cell Lymphomas
The small noncleaved cell lymphomas fall into two groups.
Small noncleaved cell lymphoma of the Burkitt's type is a dis
Recognition of distinct disease entities within the aggressive
lymphomas is more difficult. The more high-grade lymphomas
can occur de novo, or they can occur as a consequence of histological transformation of a low-grade lymphoma (35-37).
The diffuse aggressive B-cell lymphomas fall into four catego
ries in the working formulation: diffuse mixed small and large
cell, diffuse large cell, large cell immunoblastic, and small noncleaved cell. In the working formulation, diffuse large cell and
small noncleaved cell lymphomas are almost always of B-cell
origin. By contrast, diffuse mixed, or diffuse large cell immu
noblastic lymphomas are phenotypically heterogeneous and can
be derived from either B- or T-lymphocytes (38).
The diffuse aggressive lymphomas differ from the low-grade
lymphomas in their biological and clinical manifestations (Ta
ble 4) (11). Rather than demonstrating homing to microscopic
compartments of the lymphoid system, these tumors more of
ten spread as large masses. In addition, these tumors have a
greater propensity to involve privileged sites, such as the testes
and in particular the central nervous system. Virtually all cen
tral nervous system lymphomas are of aggressive histológica!
grade.
Cytologically, many diffuse aggressive lymphomas resemble
the large follicular center cells encountered in follicular
lymphomas—large cleaved, large noncleaved, and immuno
blastic. Moreover, if one looks for evidence of the bcl-2 translocation characteristic of follicular lymphoma, one can find
bcl-2 translocations in approximately 35% of patients with dif
fuse aggressive B-cell lymphomas presenting de novo (39, 40).
Either these tumors arose as follicular lymphomas and trans
formed prior to clinical presentation or they represent another
manifestation of the bcl-2 translocation.
The aggressive B-cell lymphomas also can represent trans
formations of other low-grade disorders. For example, small
lymphocytic lymphomas or chronic lymphocytic leukemias can
transform into large cell lymphomas, so-called Richter's syn
tinct clinicopathological entity, both in its endemic form in
Africa and in its sporadic form in the United States and else
where (42, 43). In the working formulation, Burkitt's lym
drome. While such cases may not be recognizable on purely
morphological grounds, the neoplastic cells may retain the CDS
antigen characteristic of small lymphocytic malignancies (41).
Table 4 Clinical, pathological, and experimental characteristics oflowand high-grade malignant lymphomas
Low grade
Indolent clinical course
Relatively long survival
Not curable with chemotherapy
Nondestructive growth pattern
Absence of cellular atypia
Respect privileged sites
Respond to regulatory influences
Fail to grow in culture
Nontransplantable
High grade
Aggressive clinical course
Short survival without therapy
Potential for long remission (cure)
with modern chemotherapy
Destructive growth pattern
Presence of cellular atypia/anaplasia
Invade privileged sites
Autonomous
Immortalized in culture
Transplantable in immunodeficient host
phoma is called small noncleaved because the nuclei of the
tumor cells approximate in nuclear diameter the nuclei of the
admixed starry histiocytes. This tumor is very uniform in its
cytological composition and has a very high-growth fraction
(44).
Burkitt's lymphoma usually presents in extranodal sites. In
the United States, the most common presentation is as an ab
dominal mass involving the ileocecal region. In women, it may
present with ovarian or even breast involvement. Burkitt's lym
phoma is primarily a disease of young children with, of course,
sporadic cases occurring in older age groups. Burkitt's lym
phoma is also commonly seen in association with human im
munodeficiency virus infection (45).
By contrast, small noncleaved (or undifferentiated) lympho
mas of the non-Burkitt's type are much more heterogeneous
and do not represent a disease entity. They exhibit a wide age
distribution, ranging from children to adults (5, 44). Morpho
logically, these tumors are heterogeneous. While some cells
closely resemble those of Burkitt's lymphoma, others are more
pleomorphic in terms of nuclear size and shape.
The non-Burkitt's cell lymphomas also differ from classic
Burkitt's at the molecular level. Whereas Burkitt's lymphomas
are frequently associated with c-myc translocations, this translocation is uncommonly seen in the non-Burkitt's lymphomas
(46). In fact, some of these tumors contain bcl-2 translocations,
suggesting that they may be more closely related to the diffuse
follicular center cell neoplasms.
Postthymic
T-Cell Lymphomas
The postthymic T-cell malignancies represent a heteroge
neous group of disease entities that can present as leukemia or
lymphoma (Table 5). They also range in their clinical behavior
from low to high grade. Some clinicopathological entities, such
as mycosis fungoides-Sézarysyndrome, are considered sepa
rately from the other non-Hodgkin's lymphomas and are listed
in the "miscellaneous" group (Table 2).
Lymphomas with a mature T-cell phenotype are relatively
uncommon and account for only 10-15% of all non-Hodgkin's
lymphomas. The neoplastic cells express one or more of the
pan-T-cell antigens, as well as one of the major subset antigens,
CD4 or CDS, in most cases (47). Virtually all of the postthymic
T-cell lymphomas are clinically aggressive and fall into inter
mediate- and high-grade categories in the working formulation.
Peripheral T-cell lymphomas have a high incidence of involve
ment of skin and/or mucosal sites, in addition to frequent gen
eralized adenopathy. Clinically, they have an aggressive natural
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CLASSIFICATION
OF NON-HODGKIN'S
history but will respond to multiagent chemotherapy, with
long-term remission in some cases.
Unfortunately, the working formulation is not helpful in de
lineating the different categories of T-cell malignancy or in
identifying distinct clinicopathological entities. For example,
adult T-cell leukemia-lymphoma, a distinct disease associated
with human T-cell leukemia virus, type 1, is not separately
identified in the working formulation (48). Morphologically, it
might fall into the diffuse mixed small and large cell or large
cell immunoblastic groups. In fact, most peripheral or postthymic T-cell lymphomas are classified in these two categories in
the working formulation. However, even these working formu
lation groups are not phenotypically homogeneous and include
both B- and T-cell lymphomas.
Recent studies have shed light on the spectrum of diseases
included in the broad group of T-cell lymphomas, and newly
emerging entities have been identified (Table 5). It is also ap
parent that these diseases vary in their pathogenesis, a fact that
is of great importance in understanding lymphoma trends. For
example, the angiocentric lymphomas appear to be associated
with Epstein-Barr virus, whereas the large cell anaplastic lym
phomas are frequently found to contain the t(2;5)(p23;q35)
translocation (49-53). The recognition of distinct disease enti
ties in the T-cell lymphoma group requires a multidisciplinar)
approach using clinical, pathological, immunophenotypic, mo
lecular, and virological data.
LYMPHOMAS
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13. Anderson. T., Chabner, B. A., Young, R. C.. Berard, C. W., GarvÃ-n,A. J.,
Lymphoblastic
Malignancies
The last category to be considered in the non-Hodgkin's lym
phomas are the lymphoblastic malignancies; these include lymphoblastic lymphomas and acute lymphoblastic leukemias. The
morphological criteria that distinguish lymphoblastic lym
phoma from other lymphomas have been clearly delineated,
and lymphoblastic lymphoma is a morphological entity (54,
55). The nuclei of the neoplastic cells have finely distributed
chromatin and resemble the lymphoblasts of acute lymphoblas
tic leukemia.
Most lymphoblastic lymphomas have an immature T-cell
phenotype; they are usually terminal transferase positive and
CD7 positive and express one or more of the pan-T-cell anti
gens. Less commonly, these tumors have a precursor B-cell
phenotype comparable to what one would see in common acute
lymphocytic leukemia or precursor B-cell leukemia. The pre
cursor B-cell type differs from the precursor T-cell type clini
cally in that it often presents in skin and/or bone, with an
absence of a mediastinal mass (56-58). Morphological criteria
are not helpful in identifying the immunophenotypic subtypes
of lymphoblastic malignancies; consequently, immunological
methodologies must be used.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Conclusion
The working formulation is a useful scheme for the clinician
in providing guidance for the clinical management of nonHodgkin's lymphomas. It also permits the pathologist to inter
pret the material in the absence of immunophenotypic studies.
However, the working formulation is an imperfect scheme for
identifying individual disease entities. The identification of in
dividual disease entities is crucial for epidemiological analysis
of disease incidence and trends. Other approaches including
immunophenotypic and molecular studies should be attempted
whenever possible.
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5452s
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An Overview of the Classification of Non-Hodgkin's
Lymphomas: An Integration of Morphological and Phenotypical
Concepts
Elaine S. Jaffe, Mark Raffeld, L. Jeffrey Medeiros, et al.
Cancer Res 1992;52:5447s-5452s.
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