PERSPECTIVE
A Revised European-American Classification of Lymphoid Neoplasms:
A Proposal From the International Lymphoma Study Group
By Nancy Lee Harris, Elaine S. Jaffe, Harald Stein, Peter M. Banks, John K.C. Chan, Michael L. Cleary,
Georges Delsol, Christine De Wolf-Peeters, Brunangelo Falini, Kevin C. Gatter, Thomas M. Grogan,
Peter G. Isaacson, Daniel M. Knowles, David Y . Mason, Hans-Konrad Muller-Hermelink, Stefan0 A. Pileri,
Miguel A. Piris, Elisabeth Ralfkiaer, and Roger A. Warnke
T HE HISTOLOGIC categorization of lymphoma has
been a source of frustration for many years for both
clinicians and pathologists. In the last 10 years, much new
information has become available about the lymphomas, re-
sulting in recognition of new entities and refinement of pre-
viously recognized disease categories, raising the question
of whether it is time for a new lymphoma classification. In
this paper we report the result of an international review of
lymphomas, which we hope may clarify some of the confu-
sion surrounding this topic.
This review was conducted at a meeting of 19 hematopa-
thologists with particular interest and experience in lympho-
mas (the International Lymphoma Study Group) in Berlin,
Germany, in April 1993. At previous meetings in Europe
and the United States, we had come to believe that, despite
the variety of classification schemes used, many hematopa-
thologists appeared to agree on a rather large number of
distinct lymphoma entities that they recognize and diagnose
in daily practice. We believed that we could provide a useful
service to both pathologists and clinicians struggling with
the classification of lymphomas by attempting to arrive at a
consensus regarding the categories of lymphoid neoplasia
that can be reliably recognized at present.
What emerged from this meeting was, first, that each of
us had independently evolved ways of viewing these diseases
that were essentially identical. Surprisingly, there was little
divergence between European and US participants. Second,
it was evident that, while many of these lymphoma entities
are recognized in the Kiel Classification,”6the Lukes-Collins
Classification,’ and the Working Formulation,*they often go
by different names in different publications and may have
variable criteria for diagno~is.~ Furthermore, we found that
many of us had doubts about both the practical feasibility
and the scientific validity of distinguishing certain subtypes
in these systems. We also found that while some lymphoma
categories are easy to recognize, others are disturbingly
prone to subjective variability. This feature of lymphoma
diagnosis has not been emphasized in previous schemes for
classification, which imply that all categories are equally
easy for the pathologist to recognize.
Ideally lymphomas, like most other tumors, should be
classified according to their presumed normal counterpart, to
the extent possible. This should provide the best information
about disease biology, natural history, and response to treat-
ment. However, despite extensive study, the definition of
lymphoid compartments in humans and movement of cells
between these compartments still contains many uncertaint-
ies. Furthermore, there are difficulties in defining the full
extent of the neoplastic clone in individual cases of
lymphoma, and some well-defined lymphoma types lack ob-
vious normal counterparts. Consequently, although differen-
tiation schemes provide useful conceptual frameworks for
Blood, Vol 84, No 5 (September l), pp 1361-1392
1994:
understanding lymphomas and suggest important new lines
of research, our current understanding of both the immune
system and the lymphomas appears to be inadequate to sup-
port a biologically “correct” lymphoma classification. Thus,
a classification strictly based on a theoretical relationship of
tumors to normal stages of differentiation is both unrealistic
and unnecessary for the practical categorization of human
lymphomas.
We concluded that the most practical approach to
lymphoma categorization at this time is simply to define the
diseases that we think we can recognize with the currently
available morphologic, immunologic, and genetic tech-
niques.” Thus, a lymphoma classification becomes simply
a list of well-defined, “real” disease entities. Many of these
entities are associated with distinctive clinical presentations
and natural histories, even though treatment options may be
limited. Cases that do not fitinto one of these defined entities
are best left unclassified, reflecting the fact that we do not
yet understand everything about lymphomas or the immune
system.
In this review, we summarize the entities agreed on at the
meeting, giving the major defining histologic, immunologic,
and genetic features, their clinical presentations and course,
and postulated normal counterpart in the immune system. It
is obviously impossible in this space to cover all diseases
completely, and more detailed descriptions of most of these
entities are available in the literature. Thus, we have focused
From the Departments of Pathology, Massachusetts General Hos-
pital, Harvard University MedicalSchool, Boston, MA; The National
Cancer Institute, Bethesda, MD; Klinikum Benjamin Franklin, Free
University of Berlin, Berlin, Germany; University of Texas Health
Science Center, San Antonio; Queen Elizabeth Hospital, Hong Kong;
Stanford University MedicalSchool, Stanford, CA; Faculty of Medi-
cine Purpan, University Paul Sabatier, Toulouse, France; University
of Leuven, Leuven, Belgium: University of Arizona Medical School,
Tucson; University College London Medical School, London, UK:
New York Hospital, Cornell University Medical Center, New York;
University of Wurzburg, Wurzburg, Germany: University of Bolo-
gna,Bologna,Italy; Hospital Virgen de la Salud, Toledo, Spain;
University of Copenhagen, Herlev, Denmark; the University Depart-
ment of Cellular Science, John Radcliffe Hospital, Oxford Univer-
sity,Oxford,UK; and the Institute of Hematology,University of
Perugia, Perugia, Italy.
Submitted December 9, 1993; accepted May 9, 1994.
Supported byA.I.R.C. Milan (S.A.P.,B.F.),CancerResearch
Campaign (P.G.I.), Fondo de Investigacion Sanitaria, Spain
(M.A.P.), Deutsche Krebshilfe and Deutsche Forschungsge-
keinschaft (HS), and Leukemia Research Fund (K.C.G., D.Y.M.).
Address reprint requests to Nancy Lee Harris, MD, Depamnent
of Pathology, Warren 2, Massachusetts General Hospital, Boston,
MA 02114.
0 I994 by The American Society of Hematology.
0006-4971/94/8405-0036$3.00/0
1361
1362
more on some entitiesthanothers,particularlythosefor
which our definitions may differ from those of the major
classifications, or which are recently described or difficult
for nonexperts to understand.
MATERIALS AND METHODS
Disease Categories
We included both Hodgkin’s disease (HD) and non-Hodgkin’s
lymphomas (NHL) and lymphoid leukemias, because both solid and
circulating phases are present inmany lymphoid neoplasms, and
distinction between them is artificial. A proposed list of disease
entities, together with defining histologic, immunologic, and genetic
features and major clinical features, was prepared by three of us
(N.L.H., E.S.J., H.S.). This list was circulated to the group of 19
hematopathologists before the meeting in Berlin, Germany, in April
1993. Participants were assigned one or more ofthe proposed entities
before the meeting, asked to review the literature and their own
experience, and reach a conclusion regarding (1) whether or not there
were sufficient morphologic, immunologic, genetic, and clinical data
to justify its inclusion as a distinct disease entity; (2) what the
defining criteria were; and (3) what subgroups or grades should be
recognized within the entity. Open debate followed each presenta-
tion.
Reproducibility Study: Diffuse Large B-Cell
Lymphoma
To assess the practicality of subclassifying diffuse large cell
lymphomas (as required by both the Kiel Classification and the
Working Formulation), a set of slides of 23 diffuse aggressive B-
cell lymphomas selected from Oxford was circulated to the partici-
pants before the meeting. The cases were confirmed as B-cell
lymphoma by immunophenotyping, and were believed by K.C.G. to
be examples of large cell lymphoma. Participants were asked to
classify each tumor into one of four possible categories: centroblas-
tic, immunoblastic, large cell not classifiable, and other (specify).
The criteria of the updated Kiel Classification6were circulated with
the slides. The scoring sheets were returned to Oxford and collated
before the meeting. The results were presented during the discussion
of diffuse large B-cell lymphoma.
Consensus Development
In a concluding session, a summary of the defining features of
each proposed lymphoma entity was presented in tabular form by
one of the three organizers. Changes were made to the tables until
a final consensus was reached. Only criteria and characteristics that
could be agreed on by a majority of the group were included; features
or entities that were either unpublished, little known or used, or
controversial were not included. The summary tables were used as
a basis for the descriptions of the lymphoma entities. The revised
tables and manuscript were circulated and approved by all partici-
pants.
RESULTS
General Principles
Major Categories
Thegroupwasunanimous in agreeing on three major
categoriesoflymphoidmalignancies:B-cell, T-cell, and
Hodgkin’sdisease (HD) (Table 1). Althoughfor a given
patient, distinction between B-cell andT-cell neoplasia may
not always be clinically relevant, it was the clear consensus
that this distinction is a prerequisite for the recognition of
HARRISETAL
Table 1. List of Lymphoid Neoplasms Recognized by the
International Lymphoma StudyGroup
~~ ~~~ ~~~
B-Cell Neoplasms
I. Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/
lymphoma
II. Peripheral B-cell neoplasms
1. B-cell chronic lymphocytic leukemia/prolymphocytic
leukemia/small lymphocytic lymphoma
2. Lymphoplasmacytoid lymphoma/immunocytoma
3. Mantle cell lymphoma
4. Follicle center lymphoma, follicular
Provisional cytologic grades: I (small cell), I1 (mixed small
and large cell), 111 (large cell)
Provisional subtype: diffuse, predominantly small cell type
5. Marginal zone B-cell lymphoma
Extranodal (MALT-type +/- monocytoid B cells)
Provisional subtype: Nodal (+/- monocytoid B cells)
6. Provisional entity: Splenic marginal zone lymphoma t i / -
villous lymphocytes)
7. Hairy cell leukemia
8. Plasmacytoma/plasma cell myeloma
9. Diffuse Large B-cell lymphoma*
Subtype: Primary mediastinal (thymic) B-cell lymphoma
10. Burkitt‘s lymphoma
11. Provisional entity: High-grade B-cell lymphoma, Burkitt-like*
T-cell and Putative NK-Cell Neoplasms
I. Precursor T-cell neoplasm: Precursor T-lymphoblastic
lymphoma/leukemia
II. Peripheral T-cell and NK-cell neoplasms
1. T-cell chronic lymphocytic leukernialprolymphocytic
leukemia
2. Large granular lymphocyte leukemia (LGL)
T-cell type
NK-cell type
3. Mycosis fungoides/Sezary syndrome
4. Peripheral T-cell lymphomas, unspecified*
Provisional cytologic categories: medium-sized cell, mixed
medium and large cell, large cell, lymphoepithelioid cell
Provisional subtype: Hepatosplenic y6 T-cell lymphoma
Provisional subtype: Subcutaneous panniculitic T-cell
lymphoma
5. Angioimmunoblastic T-cell lymphoma (AILD)
6. Angiocentric lymphoma
7. Intestinal T-cell lymphoma (+/Fenteropathy associated)
8. Adult T-cell lymphoma/leukemia (ATUL)
9. Anaplastic large cell lymphoma (ALCL), CD30’. T- and null-
cell types
10. Provisional entity: Anaplastic large-cell lymphoma,
Hodgkin’s-like
Hodgkin’s Disease
I. Lymphocyte predominance
II. Nodular sclerosis
Ill. Mixed cellularity
IV. Lymphocyte depletion
VI. Provisional entity: Lymphocyte-rich classical HD
* These categories are thought likely to include more than one dis-
ease entity.
biologic entities and should bemade whenever possible, and
particularly for clinicaltrials or other studies for publication.
Within these three groups, three general categories were pro-
posed: definite, provisional, and unclassifiable. Provisional
CONSENSUS LYMPHOMA CLASSIFICATION
categories include entities that have been described in some
detail, but with which we had insufficient experience to be
confident that they represent distinct diseases. We also be-
lieve that it is important to recognize that some cases of
lymphoma do not fitinto one of the well-recognizedor provi-
sional categories, so we includeda separate category for
unclassifiable cases.
Postulated N o m 1 Counterparts
We also agreed that, although understanding lymphomas
may be enhanced by understanding their relationship to the
normal immune system, the normal counterpart ofmany
neoplastic lymphoid cells cannot be defined with certainty
at present, and that these relationships cannot serve as the
sole basis for lymphoma categorization at this time. There-
fore, the putative normal counterpart of each tumor is listed,
but other than separation into B- and T-cell categories, we
have not attempted to organize this list along lines of differ-
entiation within the B- and T-cell systems.
However, we did agree that there are two majorcategories
withinboth B- and T-cell neoplasms: “precursor” neo-
plasms, corresponding to lymphoblastic lymphomas and leu-
kemias, and “peripheral” neoplasms, comprising the re-
mainder of B- and T-cell lymphomas and leukemias. The
peripheral B-and T-cell neoplasms are organizedinthis
report more or less according to histologic grade: that is,
predominant cell size, density of chromatin and proliferation
rate, and entities that morphologically resemble one another
are grouped together. However,they could be sortedac-
cording to a variety of other features, such as clinical aggres-
siveness, treatment category, histologic pattern, and so forth,
depending on the needs of the users.
Nomenclature
For each entity, we proposed a name based either on its
putative normal counterpart, its morphologic features, or es-
tablished usage. Proliferating cells of antigen-independent
stages, which are progenitor cells of the entire lymphoid
system, are called “lymphoblasts,” whereas the cells of later
stages are denoted by prefixes that describe their location in
lymphoid tissues, their cytologic appearance, or their pre-
sumed function in the immune response.
Probable equivalents for each disease entity are given in
the Rappaport, Lukes-Collins and Kiel Classifications, and
in the Working Formulation, based in part on the summary
by Lennert and Fellef; these are summarized in Table 2.
Grade and Aggressiveness
We usethe term “grade” to refer to histologic parameters
such as cell and nuclear size, density of chromatin and prolif-
eration fraction, and the terms “prognostic group” or “ag-
gressiveness” to denote the clinical behavior of a tumor.
One important result of our discussions was the recognition
that many of these distinct lymphoma entities have a range
of morphologic grade and clinical aggressiveness, making it
difficult to arrange them according to a spectrum from low
to high grade or indolent to aggressive behavior. The most
obvious example is that offollicle center (follicular) lympho-
mas,
but also the mucosa-associated lymphoid tissue
1363
(MALT)-type lymphomas, angiocentric lymphoma, and
even mantle cell lymphoma can apparently have relatively
lower and higher grade types. This point may be best under-
stood by analogy to other tumors, such as soft-tissue sarco-
mas or ovarian tumors, where each tumor is recognized as
a distinct entity, withinwhich pathologic criteria can be
established to determine its clinical aggressiveness. This
concept is contrary to the approach in some lymphoma clas-
sifications, which has tended to assume that all lymphomas
are related, can transform into one another, and can be con-
sidered as a single spectrum of disease, from low to high
grade. Although this view has long been known to be incor-
rectin some respects, it still colors muchthinkingabout
lymphomas. We believe it represents an oversimplification
that results in confusion rather than clarity.
Immunophenotypes and Genetic Features
Those given are the most characteristic; variations may
be seen in individual cases. The notations and abbreviations
are as follows: +, over 90% of the cases positive; +/-, over
50% of the cases positive; -/+, less than 50% of the cases
positive; -, less than 10% of the cases positive; TCR-R, T-
cell receptor gene rearrangement; IgH-RandIgL-R,Ig
heavyfight chain genes rearranged; SIg, surface Ig; CIg,
cytoplasmic Ig; CD, cluster of differentiation”; EMA, epi-
thelial membrane antigen. Morphologic, immunologic, and
genetic features that are important in defining the entity or
in differential diagnosis are indicated in boldface type.
B-Cell Neoplasms
Precursor B-Cell Neoplasm: Precursor B-Lymphoblastic
LeukemidLymphoma (B-LBL)
Synonyms. Rappaport: lymphoblastic (formerly diffuse
poorly differentiated lymphocytic [PDL]); Kiel:lymphoblas-
tic, B-cell type; Lukes-Collins: undefined cell; Working For-
mulation: lymphoblastic.
Morphology. Lymphoblasts are slightly larger than
small lymphocytes but smaller than the cells of large B-cell
lymphoma, with round or convoluted nuclei, fine chromatin,
inconspicuous nucleoli, and scant, faintly basophilic cyto-
plasm (Fig 1). Mitoses are frequent; a starry-sky pattern may
be seen. There is no correlation between morphology and B
or Tlineage.’* Thus, immunophenotyping studies are re-
quired to distinguish precursor B- from precursor T-lymph-
oblastic lymphoma (T-LBL). Although histologic features
are usually sufficient to distinguish lymphoblastic from ma-
ture B- or T-cell neoplasms, a differential diagnosis with
mantle cell lymphoma or myeloid leukemia may arise in
rare cases, particularly in adults, and particularly if smears
are not available. In these cases, immunophenotyping and
molecular genetic studies are helpful.
Immunophenotype. Tumor cells are characteristically
TdT+CD19+ CD79a’ CD22+ CD20-’+ CD10+” HLA-Dr+
SIg- cMu”+ CD34+”, and may coexpress CD13 and/or 33
in some c a ~ e s . ’ Antibodies
~-~~ to CD79a (mbl: IgM-associ-
ated protein) are useful in identifying CD19- cases,’6 and
can be used on paraffin-embedded sections. Expression of
TdT and lack of Ig are useful in distinguishing precursor B-
LBL from moremature B-cell neoplasms; CD19, CD22,
 1364 HARRIS ET AL

Table 2. Comparison of the Proposed Classification With the Kiel Classification and Working Formulation
Revised European American
Lymphoma Classification Kiel

B-lymphoblastic Precursor B-lymphoblastic lymphoma/ Lymphoblastic

leukemia
B-Lymphocytic, CLL B-cell chronic lymphocytic leukemia/ Small lymphocytic, consistent with CLL
B-lymphocytic, prolymphocytic leukemia prolymphocytic leukemia/small Small lymphocytic, plasmacytoid
Lymphoplasmacytoid immunocytoma lymphocytic lymphoma

Lymphoplasmacytic immunocytoma Lymphoplasmacytoid lymphoma Small lymphocytic, plasmacytoid

Centrocytic
Centroblastic, centrocytoid subtype
Centroblastic-centrocytic,follicular
Centroblastic, follicular
Centroblastic-centrocytic, diffuse
Diffuse, mixed small and large cell
Mantle cell lymphoma Small lymphocytic
Diffuse, small cleaved cell
Follicular, small cleaved cell
Diffuse, mixed small and large cell
Diffuse, large cleaved cell
Follicular center lymphoma, follicular
-Grade I Follicular, predominantly small cleaved cell
-Grade I1 Follicular, mixed small andlarge cell
-Grade 111 Follicular, predominantly large cell
Follicular center lymphoma, diffuse, small Diffuse, small cleaved cell
cell [provisionall Diffuse, mixed small and large cell

Extranodal marginal zone B-cell lymphoma Small lymphocytic

(low-grade B-cell lymphoma of MALT Diffuse, small cleaved cell
type) Diffuse, mixed small and large cell
Monocytoid, including marginal zone Nodal marginal zone B-cell lymphoma Small lymphocytic
lmmunocvtoma [provisionall Diffuse, small cleaved cell
Diffuse, mixed small and large cell
Unclassifiable
Splenic marginal zone B-cell lymphoma Small lymphocytic
[provisionall Diffuse small cleaved cell
Hairy cell leukemia Hairy cell leukemia -
Plasmacytic Plasmacytoma/myeloma Extramedullary plasmacytoma
Centroblastic (monomorphic, polymorphic Diffuse large B-cell lymphoma Diffuse, large cell
and multilobated subtypes) Large cell immunoblastic
B-lmmunoblastic Diffuse, mixed small and large cell
B-large cell anaplastic (Ki-l+)
"* Primary mediastinal large B-cell lymphoma Diffuse, large cell
Large cell immunoblastic
Burkitt's lymphoma Burkitt's lymphoma Small noncleaved cell, Burkitt's
- High-grade B-cell lymphoma, Burkitt-like Small noncleaved cell, non-Burkitt's
? Some cases of centroblastic and [provisionall Diffuse, large cell
immunoblastic Large cell immunoblastic

T-lymphoblastic Precursor T-lymphoblastic lymphoma/ Lymphoblastic

leukemia
T-lymphocytic, CLL type T-cell chronic lymphocytic leukemia/ Small lymphocytic
T-lymphocytic, prolymphocytic leukemia prolymphocytic leukemia Diffuse small cleaved cell

T-lymphocytic, CLL type Large granular lymphocytic leukemia Small lymphocytic

- "T-cell type Diffuse, small cleaved cell
-NK-cell type
Small call cerebriform (mycosis fungoides, Mycosis fungoides/Sezary syndrome Mycosis fungoides
Sezary syndrome)

T-zone Peripheral T-cell lymphomas, unspecified Diffuse, small cleaved cell

Lymphoepithelioid [including provisional subtype: Diffuse, mlxed small and large cell
Pleomorphic, small T-cell subcutaneous panniculitic T-cell Diffuse, large cell
Pleomorphic, medium-sized and large T-cell lymphoma1 Large cell immunoblastic
T-immunoblastic
- Hepatosplenic y-6 T-cell lymphoma -
[provisionall
Angioimmunoblastic (AILD. Angioimmunoblastic T-cell lymphoma Diffuse, mixed small and large cell
Diffuse, large cell
Large cell immunoblastic
CONSENSUS 1365

Table 2. Comparison of the Proposed ClassificationWkh the Kiel Classification and Working Formulation (Cont'd)
-* Angiocentric lymphoma Diffuse, small cleaved cell
Ditfure, mixed small and large cell
Diffuse, large cell
Large cell immunoblaatic
Intestinal T-cell lymphoma Diffuse, small cleaved cell
Diffuse, mixed small and large cell
Diffuse, large cell
Large cell immunoblastic
Pleomorphic small T-cell, HTLVl+
Adult T-cell lymphoma/leukemia Diffuse, small cleaved cell
Pleomorphic medium-sized and large T-cell, D f i s e , mixed small and large cell
HTLVl + Diffuse, large cell
Large cell immunoblastic
T-large cell anaplastic (Ki-l+) Anaplastic large cell lymphoma, T- and null- Large cell immunoblastic
cell types
When more than one Kiel or Working Formulationcategory is listed, those in boldface type comprise the majority of the cases.
* Not listed in classification, but discussed as rare or ambiguous type.

CD10, and CD79a are useful in distinction from T-LBL and
granulocytic sarcoma.
Genetic features. Ig heavy chain genes are usually re-
arranged; light chain genes may be rearranged.".'* Re-
arrangement of T-cell receptor genes is present in a minority
of the cases''; cytogenetic abnormalities are variable." Anti-
gen receptor gene rearrangements maynotbe helpful in
distinguishing T- from B-precursor neoplasms.
Clinical features. Children are more commonly affected
than adults; this disease accounts for about 80% of acute
lymphoblastic leukemia and probably less than 20% of
lymphoblastic lymphoma. Although the vast majority of pre-
cursor B-cell neoplasms present as acute leukemias, with
bone marrow (BM) and peripheral blood (PB) involvement,
both pathologists and clinicians should be aware that a small
proportion present as solid tumors, most often in skin, bone,
and lymph nodes, with or without BM or peripheral blood
involvement. These solid tumors are histologically indistin-
guishable from precursor T-lymphoblastic lymphoma.2'~22
The disease is highly aggressive but frequently curable with
available therapy. lmmunophenotypic and cytogenetic fea-
tures may be useful in predicting outcome: cases with t( 1; 19)
have a worse prognosis, as do cases with t(9;22) or 1 lq13
abnormalities and those that lack CD10, CD34, or CD24, or
express CD13 and CD33; cases with greater than 50 chromo-
somes have a better p r o g n o s i ~ . ' ~ - ~ ~
Postulated n o m 1 counterpart. BM-derived precursor
B cell.
Peripheral B-Cell Neoplasms
B-Cell Chronic Lymphocytic Leukemia (B-CLL)/
Prolymphocytic Leukemia (B-PLL)/Small Lymphocytic
Lymphoma (B-SLL)
Synonyms. Rappaport: well-differentiated lymphocytic,
diffuse; Kiel, B-CLL, B-PLL, immunocytoma, lymphoplas-
macytoid type; Lukes-Collins: small lymphocyte B, B-CLL;
Working Formulation: small lymphocytic, consistent with
CLL.
Morphology. Enlarged lymph nodes in patients with B-
CLL show a characteristic infiltrate (Fig 2). The predominant
cell is a small lymphocyte, which may be slightly larger than
a normal lymphocyte, with clumped chromatin, usually a
round nucleus, and occasionally a small nucleolus. Larger
lymphoid cells (prolymphocytes and paraimmunoblasts) are
always present, usually clustered in pseudofollicles (prolifer-
ation centers), imparting a pseudofollicular pattern, or less
often, distributed evenly throughout the node.3*23*24Increased
numbers of large cells may be associated with a more aggres-
sive c o ~ r s e . In
~ ,some
~ ~ ~cases,
~ ~ the small lymphoid cells
show moderate nuclear irregularity, which can lead to a dif-
ferential diagnosis of mantle cell lymphoma (see below); if

Table 3. Low-Grade B-Cell Lymphomas: Morphologic Features in Differential Diagnosis

~~

Lymphoma Pattern Small Cells Large Cells

B-CLUSLL Diffuse with pseudofollicles Round (may be cleaved) Prolymphocytes

Paraimmunoblasts
Lymphoplasmacytoid Diffuse Round (may be cleaved) Centroblasts
lymphoma Plasma cells lmmunoblasts
Mantle cell lymphoma Diffuse, vaguely nodular, Cleaved (may
be
round
or oval) None
mantle zone, rarely follicular
Follicle center lymphoma Follicular +/- diffuseCleaved
areas, (centrocytes) Centroblasts
rarely diffuse
Marginal zone B-cell lymphoma Diffuse, interfollicular, marginal Heterogeneous: round(small Centroblasts
zone, occasionally follicular lymphocytes), cleaved lmmunoblasts
(colonization) (marginal zone/monocytoid B
cells), plasma cells
 Fig 1. Precursor lymphoblastic neoplasms. (A) Precursor B-lymph-
blastic lymphomaof lymph node. The tumor cells have irregular nuclei,
dmpersed chromatin,inconspicuousnucleoli,andscantcytoplasm
(Giemsa, original magnification x 872). (B) Precursor T-lymphoblastic
lymphoma of lymph node. The appearance is similar to the Bprecursor
neoplasm (hematoxylinand eosin [HMI, original magnificationx 872).

Fig 3.

Fig 2. Lymph nodefrom a patient with B-cell chroniclymphocytic

leukemia. (A) Low power view showing characteristic pseudofollicles
(proliferation centers) (H&E, original magnification x 22). (B) High
magnificationshowing small lymphocytes, prolymphocytes, and par-
aimmunoblasts (Giemsa, original magnification x 544).
Fig 4.
CONSENSUS LYMPHOMA CLASSIFICATION
pseudofollicles and/or prolymphocytes and paraimmu-
noblasts are present, a diagnosis of B-CLL should be made
(Table 3).9*27 B-PLL is characterized by a predominance
(>50%) of cells with clumped chromatin but with a promi-
nent central nucleolus and more abundant cytoplasm than
typical CLL cell^*^-^^; these cells are best evaluated on
smears of peripheral blood or BM.
Most patients whose lymph nodes contain the characteris-
tic infiltrate associated with B-CLL will prove to have BM
and PB involvement at the time of the diagnosis or shortly
thereafteljSz5; however, some are nonleukemic at presentation
and it is possible that some may not develop leukemia. A
term is needed for these cases, by analogy to granulocytic
sarcoma or lymphoblastic lymphoma. The term small
lymphocytic lymphoma has in the past been used to encom-
pass not only the nodal counterpart of B-CLL, but also many
MALT-type lymphomas and probably also some T-cell neo-
p l a s m ~ . ~ We
, ~ ’ propose that the term small lymphocytic
lymphoma be restricted to tumors that show the characteris-
tic morphology and immunophenotype of B-CLL.
Based on our experience and on the literature, it appears
that some cases with the characteristic morphology and im-
munophenotype of B-CLL can have plasmacytoid differenti-
ation, with cytoplasmic Ig and often a small M - c o m p ~ n e n t . ~ ~ Synonyms. Rappaport: well-differentiated lymphocytic,
These cases correspond to the “lymphoplasmacytoid” im-
munocytoma of the fie1 Clas~ification.~.~~ The clinical
course of these cases does not appear to differ markedly
from B-CLL, and we propose that these tumors not be given
a separate diagnostic category, but rather be regarded as a
variant of B-CLL.
Zmmunophenotype. The tumor cells of B-CLL have faint
SIgM, are SIgD+/-, (CIg”+), B-cell-associated antigen’
(CD19, 20, 79a), CD5’, CD23’ CD43+, CDllc”+ (faint),
and CD10-.31,33.34 CD23 is useful in distinguishing B-CLL/
SLL from mantle cell lymphoma (Table 4). CD22 expression
may beweak or undetectable, particularly by flowcytometry.
Differences in antigen expression (such as CD1 IC) may be
associated with variations in clinical course; further study
of these variants is needed. Cases of B-PLL may be CDY,
have strong SIg, and more often express CD2L3’
Genetics. Ig heavy and light chain genes are rearranged;
trisomy 12 is reported in one third of the and abnor-
malities of 13q are seen in up to 25%. t(11;14) and bcl-l
rearrangement have been reported; these cases mayneed
Fig 3. Mantle celllymphoma. (A) Lowmagnification,showing
mantle zone pattern. This pattern in its pure formis seen in a minority
of the cases (H@, original magnification x 55). (B)High magnifica-
tion, showing smallcells with slightly indented nuclei (Giemsa, origi- These tumors usually lack CD5 and lack characteristic fea-
nalmagnification x 544). (C) Blastoid,orlymphoblastoidvariant,
showing larger cells with dispersed chromatin and deeply indented
nuclei, resembling the lymphoblastic lymphomas in Fig 1 (Giemsa,
original magnification x 544).
Fig 4. Follicle centar lymphoma, follicular.(AI Low magnificetion,
showingwell-definedfollicularpattern. (B) Highmagnification,
showing reactive germinal center at l e f t and neoplastic follicle at
right. Two cell types, centrocytes (cleaved cells) and centroblasts
(large noncleaved cells), are present inboth photographs. Compare
with mantle cell lymphoma (Fig 3, B and Cl, in which only cleaved
cells are present ([AI H&€, original magnification x 22; [B]Giemsa,
original magnification x 872).
1367
further study to rule out the possibility that they are examples
of mantle cell l y r n p h ~ m a . ~ ~ . ~ ~
Clinical features. The majority of the cases occur in
older adults; this disease comprises 90% of chronic lympho-
cytic leukemias in the United States and Europe. Most pa-
tients have BMandPB involvement at diagnosis; tumor
commonly involves multiple nodes, spleen, and liver; extra-
nodal infiltrates may occur.8 A small M-component may be
found in some patient^.^' Occasional patients present with
aleukemic nodal involvement, but most will ultimately be
found to have or develop marrow and blood infiltration. The
clinical course is indolent, and this disease is not usually
considered curable with available therapy. Prolymphocytoid
transformation or transformation to large cell lymphoma
(Richter’s Syndrome), may O C C Uthese ~ ~ ;are usually diffuse
large B-cell lymphomas, but cases resembling HD have been
reported.40 B-PLL presents withanunusuallyhigh white
blood cell (WBC) count and splenomegaly, and has a more
aggressive clinical course than typical B-CLL.28,30
Postulated normal counterpart. Recirculating C D S
CD23+ peripheral B cell.4‘
Lymphoplasmacytoid ~ y m p h o m ~ r m m u ~ o ~ y t o m a
plasmacytoid, diffuse mixed lymphocytic and histiocytic;
Kiel: immunocytoma, lymphoplasmacytic type; Lukes-Col-
lins: plasmacytic-lymphocytic; Working Formulation: small
lymphocytic, plasmacytoid, diffuse mixed small and large
cell.
Morphology. The tumor consists of a diffuse prolifera-
tion of small lymphocytes, plasmacytoid lymphocytes (cells
with abundant basophilic cytoplasm, but lymphocyte-like
nuclei), and plasma cells, with or without Dutcher bodies,
and by definition, lacks features of B-CLL, mantle cell, folli-
cle center cell, or marginal zone lymphomas (Table 3). The
growth pattern is often interfollicular with sparing of the
sinuses.
The terms lymphoplasmacytoid lymphoma, plasmacytoid
lymphocytic lymphoma, or immunocytoma do not appear to
us to define a single entity, as used in the literature. Many
B-cell neoplasms may occasionally show maturation to plas-
macytoid or plasma cells containing CIg, including B-CLL,
mantle cell, follicle center, and marginal zone cell lympho-
mas. We suggest that these cases be classified according to
their major features, and not as lymphoplasmacytoid
lymphomas. There does appear to be a distinct disorder of
small lymphoid cells that show maturation to plasma cells,
without features of other lymphoma types, which corre-
sponds to most cases of Waldenstrom’s macroglobulinemia.
tures of other lymphoma s ~ b t y p e s . ~ ’ .They ~ ’ . ~ ~correspond
most closely to the lymphoplasmacytic immunocytoma of
the KieI ~ I a s s i f i c a t i o nWe
. ~ ~ propose
~~ restricting the terms
lymphoplasmacytoid lymphoma or immunocytoma to these
cases.
Immunophenotype. The cells have surface and cyto-
plasmic (some cells) Ig, usually of IgM type, usually lack
IgD, and are B-cell-associated antigens+ (CD19, 20, 22,
79a), CD5-, CD10-, CD43+”; CD25 or C D l l c maybe
faintly positive in some case^.^"'^ Lack of CD5 and the
1368 HARRIS ET AL

Table 4. Low-Grade B-Cell Lymphomas: Immunohistologic and Genetic Features in Differential Diagnosis
Lymphoma Type SIG CIG CD5 CD10 CD23 CD43’ Chromosome Abnormality

B-CLUSLL + -l+ + + + Trisomy 12 (30%)

Lyrnphoplasrnacytoid + + - - -l+ NA
Mantle cell + - + -It -
+ t(11;14)
Follicle center + - - +l- -l+ - t(14;18)
Marginal zone + 40% + - - -/+ -l+ Trisomy 3 (extranodal)
Abbreviations: f, 90% positive; +/-, >50% positive; -I+, <50% positive; -, 1 1 0 % positive.
* Positivity may vary depending on antibody used.

presence of strong cytoplasmic Ig are useful in distinction
from B-CLL (Table 4).
Genetic features. Ig heavy and light chain genes are re-
arranged. No specific abnormality is known.
Clinical features. Lymphoplasmacytoid lymphomdim-
munocytoma occurs in the same general age group as B-
CLL. Sites involved include BM, lymph nodes, and spleen;
less frequently peripheral blood or extranodal sites. The ma-
jority of patients have a monoclonal serum paraprotein of
IgM type; hyperviscosity symptoms may occur (Walden-
strom’s macroglobulinemia).”3’~34 (Note: other lymphomas
may also be associated with serum paraproteins.) The course
is indolent and the disease isnot generally curable with
available treatment. Transformation to large cell lymphoma
may occur.
Postulated normal counterpart. C D S peripheral B lym-
phocyte stimulated to differentiate to a plasma cell.
Mantle Cell Lymphoma
Synonyms. Rappaport: intermediately or poorly differen-
tiated lymphocytic, diffuse or nodular (ILLDDLPDL); Kiel:
centrocytic (mantle cell) lymphoma; Lukes-Collins: small
cleaved follicular center cell (FCC); Working Formulation:
small cleaved cell, diffuse or nodular; rarely diffuse mixed
or large cleaved cell; Other: mantle zone lymphoma.
Morphology. This tumor is defined according to the Kiel
classification criteria for centrocytic I y m p h ~ m a ’ ~(Table
~ ~ ~ ~ ~ *work of follicular dendritic cells (FDC) is present. Absence
3). In most cases the tumor is composed exclusively of small
to medium-sized lymphoid cells, usually slightly larger than
normal lymphocytes, with more dispersed chromatin, scant
pale cytoplasm, and inconspicuous nucleoli (Fig 3). In most
cases, the nuclei are irregular or “cleaved”; however, in
some cases the cells are nearly round and in others they may
be very small and resemble small lymphocytes. Transformed
cells with basophilic cytoplasm (centroblast- or immu-
noblast-like cells) are by definition extremely rare or absent.
A small proportion of the cases have larger nuclei with more
dispersed chromatin, and a high proliferation fraction.”.“
Because some of these resemble lymphoblastic lymphoma,
the term “blastic” variant has been applied. We propose the
terms “lymphoblastoid” or “blastoid” variant for this type,
to emphasize the cytologic resemblance to lymphoblasts,
rather than tolarge transformed blasts (centroblasts or immu-
noblasts). The relationship between this variant and the “an-
aplastic” or “large cell” centrocytic lymphoma of the origi-
nal Kiel Classification and the ‘‘centrocytoid centroblastic”
lymphoma of the updated Kiel Classification remains to be
determined.44Additional studies are necessary to define the
ends of the morphologic spectrum of mantle cell lymphoma.
The pattern of mantle cell lymphoma is usually diffuse
or vaguely nodular; well-defined follicles as in follicular
lymphomas are rarely but occasionally seen. In many cases
the tumor involves the mantle zones of at least some reactive
follicles; less commonly, a pure mantle zone pattern occurs.
Many cases contain individually scattered epithelioid histio-
cytes, creating a “starry-sky’’ appearance at low magnifica-
tion.
We recentlyproposedtheterm mantle cell lymphoma
to replace centrocytic lymphoma, intermediate lymphocytic
lymphoma (ILL), lymphocytic lymphoma of intermediate
differentiation (IDL), and mantle zone lymphoma.’ It corre-
sponds to centrocytic lymphoma of the Kiel Classification,
which is now believed not to arise from true follicle center
centrocytes, but rather possibly from a subset of follicle
mantle B cells. In the original Working Formulation study,
centrocytic lymphoma was included within the category of
diffuse small cleaved cell lymphoma, and comprised the
majority of the cases of this subtype. The blastoid variant
and some other cases with larger cells may fall within the
diffuse mixed orlarge cleaved cell categories of the Working
Formulation8; however, the tumor cells do not have baso-
philic cytoplasm and are distinct from the other lymphomas
in these heterogeneous Working Formulation categories.
Immunophenorype. The tumor cells are SIg”, usually
IgD+, h > K, B-cell-associated antigenf, C D S , CDIO”’,
CD23-, CD43+, CD1 IC-. A prominent, disorganized mesh-
of CD23 is useful in distinguishing mantle cell lymphoma
from B-CLL; Absence of CD23 is useful in distinguishing
mantle cell lymphoma from B-CLL; CD5 is useful in distinc-
tion from follicle center and marginal zone lymphomas (Ta-
ble 4),3l.33.42.45.46
Genetic features. A chromosomal translocation t(l1; 14)
involves the Ig heavy chain locus and the bcl-l locus on the
long arm of chromosome 1 1 in the majority of the cases.
This translocation results in overexpression of a gene known
as PRAD 1, which encodes for cyclin Dl, a cell-cycle protein
that is not normally expressed in lymphoid ce11s.36~44~47~s’
Clinical features. The tumor occurs in older adults, with
a high male-to-female ratio; it is usually widespread at diag-
nosis. Sites involved include lymph nodes, spleen, Walde-
yer’s ring, BM, blood, and extranodal sites, especially the
gastrointestinal tract (lymphomatous polyposis).s3 The
course is moderately aggressive, and it appears to be incur-
able with available treatment.54The median survival ranges
from 3 to 5 years; the blastoid variant is more aggressive
(median survival 3 years).” Transformation to a large cell
lymphoma composed of centroblast and/or immunoblast-like
cells does not appear to occur.
CONSENSUS LYMPHOMA CLASSIFICATION
Postulated n o m 1 counterpart. CD5+ CD23- periph-
eral B cell of inner follicle mantle.55
Follicle Center Lymphoma, Follicular. Provisional
Cytologic Grades: I (Predominantly Small Cell), II (Mixed
Small and Large Cell), III (Predominantly Large Cell)
Synonyms. Rappaport: nodular PDL, mixed lympho-
cytic-histiocytic, or histiocytic; Kiel: centroblasticlcen-
trocytic follicular, follicular centroblastic; Lukes-Collins:
small cleaved, large cleaved or large noncleaved FCC, follic-
ular; Working Formulation: follicular, small cleaved, mixed,
or large cell.
Morphology. This lymphoma is defined as a tumor com-
posed of follicle center cells, usually a mixture of centrocytes
(cleaved follicle center cells) and centroblasts (large non-
cleaved follicle center cells) (Table 3). The pattern is at least
partially follicular, but diffuse areas may be present3 (Fig 4).
Sclerosis is common in diffuse areas. Centrocytes typically
predominate; centroblasts are usually in the minority, but
by definition are always present. Rare lymphomas witha
follicular growth pattern consist almost entirely of
centroblasts; because the follicular pattern implies a germinal
center origin, we include these in the category of follicle
center lymphoma.
Examples of the tumor that we define in this manner have
been included in different categories in different classifica-
tions. By pattern, they would be included in the categories
of nodular or follicular lymphomas in the Rappaport Classi-
fication and Working Formulation. By cytology they would
be included in the categories of follicular center cell
lymphoma in the Lukes-Collins Classification and centro-
blasticlcentrocytic lymphoma in the Kiel Classification.
However, some of these categories may include lesions other
than follicle center lymphoma that may have a nodular pat-
tern (such as mantle cell or MALT-type lymphomas in the
Working Formulation), or consist of a monomorphous popu-
lation of cells believed to be of germinal center origin (Bur-
kitt’s lymphoma and some cases of diffuse large FCC
lymphoma in the Lukes-Collins classification). The category
of centroblastidcentrocytic lymphoma in the Kiel Classifi-
cation excludes cases of follicle center lymphoma that are
follicular but contain a predominance of large cells. There-
fore, we propose the term “follicle center lymphoma” to
encompass most tumors classified as follicular lymphomas
in the Working Formulation, most tumors with a follicular
pattern classified as follicular center cell lymphoma in the
Lukes-Collins classification, all cases in the Kiel Classifica-
tion category of centroblastic/centrocytic lymphoma with
any follicular pattern, and follicular centroblastic lymphoma.
Both the proportion of centroblasts and the size of the
centrocytes vary among cases. Follicle center lymphoma
cannot be sharply divided into distinct subtypes, but rather
shows a continuous gradation in the number of large cells.56
Although this has been called “subclassification” in the
past, it should be recognized as grading. Although it has
been repeatedly shown that an individual pathologist can
effectively predict outcome in follicular lymphoma by grad-
ing according to proportion of large cells, studies have shown
that this is difficult to reproduce among groups of patholo-
gist~.’~.~’By convention in the United States, follicular
1369
lymphomas are separated into predominantly small, mixed
small and large, and predominantly large cell categories. To
avoid this rather unsatisfactory terminology, which implies
distinct tumor types, the terms follicular lymphoma, grade
I, grade 11, and grade In, which are more analogous to terms
used for other tumor types, are suggested. We are not able
to recommend specific criteria for grading, but suggest that,
as with other tumors, each pathologist or institution should
adopt a grading scheme and use it consistently, until data
from prospective clinical trials are available to suggest a
uniform method.
In addition to cellular composition, the proportions of fol-
licular and diffuse areas vary from case to case, and these
are also associated with prognosis. The pattern in a given
case is usually reported as follicular or follicular and diffuse.
Provisional Subtype: Follicle Center Lymphoma, DifSuse
(Predominantly Small Cell)
Synonyms. Rappaport: diffuse poorly differentiated
lymphocytic; Kiel: centroblastidcentrocytic,diffuse; Lukes-
Collins: diffuse small cleaved FCC; Working Formulation:
diffuse small cleaved cell.
Rare lymphomas composed of cells that resemble
centrocytes, witha minor component of centroblasts, are
entirely diffuse; if both the small and large cells have the
phenotype of follicle center cells (see below), it may be
assumed that they represent the diffuse counterpart of a folli-
cle center lymphoma. These examples may represent a sam-
pling problem in some cases in which larger biopsies show
follicular areas. Most have been called diffuse small cleaved
cell lymphoma in the Working Formulation, but some may
have sufficient large cells to be called diffuse mixed small
and large cell.
Immunophenotype. The tumor cells are usually SIg+
(IgM +/- IgD > IgG > IgA), B-cell-associated antigen+,
CDlO+”, CDF, CD23”+, CD43-, CDllc- (Table 4).
Tightly organized meshworks of FDC are present in follicu-
lar areas~31.33.46.59.mBCL-2 protein expression is usefulin
distinguishing reactive from neoplastic follicles, because it
is absent from reactive follicles and present in most follicular
lymphomas61*62; however this is not useful in distinguishing
follicle center from other types of low-grade B-cell
lymphoma, most of which also express BCL-2 protein. Lack
of CD5 and CD43 is useful in distinguishing follicle center
lymphoma from mantle cell lymphoma, and the presence of
CD10 can be useful in distinguishing it from marginal zone
cell lymphomas (see below).
Genetic features. t(14; M), involving rearrangement of
the bcl-2 gene, is present in 70% to 95% of the cases, re-
sulting in expression of this “anti-apoptosis” gene, which
is switched off at the translational level in normal germinal
center cells; expression of the BCL-2 protein permits accu-
mulation of long-lived c e n t r ~ c y t e s . ~
This
~ ” ~translocation oc-
curs at an early stage of B-cell development, during Ig gene
and occasional cells with rearranged bcl-2
genes can be detected in normal lymphoid tissues in some
normal individuals.@These observations suggest that when
a resting B cell that carries the bcl-2 translocation undergoes
blast transformation in response to antigen, failure to switch
1370
off the bcl-2 gene may contribute to development of a
lymphoma.
Clinical features. Follicle center lymphoma affects pre-
dominantly adults, with an equal ma1e:female incidence.' It
constitutes asmuchas 40% of adult NHLsintheUnited
States; the incidence is apparently lower elsewhere.6 Most
patients have widespread disease at diagnosis. Sites involved
include predominantly lymph nodes, but also spleen, BM,
occasionally PB, or extranodal sites. The clinical course is
generally indolent, and it is not usuallycurable with available
treatment. Both the number of centroblasts and the size of
the centrocytes appear to correlate with p r o g n o ~ i s . ' , ' ~ , ~ ~with
Controversy exists over whether cases classified as follicular
mixed cell type may be curable with aggressive the rap^.'^.^"
Like the proportion of centroblasts, the proportion of the
tumor that has a follicular pattern is also related to progno-
s ~ s . ~ The
' . ~ *rare purely diffuse cases appear to have a worse
prognosis.73Progression to diffuse large B-cell lymphoma
may occur.
Postulated normal counterpart. Germinal center B cells,
both centrocytes (small cleaved follicular center cells) and
centroblasts (large noncleaved follicular center ce11s).59,74,75 neoplastic (monoclonal) in up to 40% of the cases.
Marginal Zone B-Cell Lymphoma
(1) Extranodal: Low-grade B-cell lymphoma of MALT
type (+/- monocytoid B cells); and ( 2 ) Nodal: (+/- mono-
cytoid B cells) (provisional).
Synonyms. Rappaport: (not specifically listed) well-dif-
ferentiated lymphocytic (WDL) or WDL-plasmacytoid, IDL,
ILL, PDL, mixed lymphocytic-histiocytic (nodular or dif-
fuse); Kiel: monocytoid B-cell, immunocytoma (some cases
previously classified as centroblastic/centrocytic or centro-
cytic); Lukes-Collins: small lymphocyte B, lymphocytic-
plasmacytic, small lymphocyte B, monocytoid; Working
Formulation: (not specifically listed) SLL (some c/w CLL,
some plasmacytoid), small cleaved or mixed small and large
cell (follicular or diffuse).
Two tumors have been described in recent years, which
have sufficient morphologic, immunophenotypic, and clini-
cal similarity to suggest that theymay be related. These
are the low-grade B-cell lymphoma of MALT type76,77 and
monocytoid B-cell l y r n p h ~ m a . ' The ~ ~ ~ nomenclature
~ for
these tumors has been confusing: some authorities have used
the term monocytoid B-cell lymphoma for both nodal and
extranodal d i s e a ~ e ~ others
~ ~ ' ~ have
~ ~ *restricted monocytoid
B-cell lymphoma to nodal disease,81and it has not been clear
whatto call extranodal non-mucosa-associated tumors or
nodal tumors with cells that are smaller than typical mono-
cytoid B cells. The tumors show morphologic evidence of
differentiation atleast in part into cells of marginal zone
type,83which appear to have the capacity to mature into both
monocytoid B cellsE4and plasma cells, and appear to display
tissue-specific homing pattern^.'^^^^ It seems reasonable to
postulate that the different clinical syndromes associated
with tumors of this morphologic type may be a result of
the homing pattern of the specific neoplastic clone.E9-95 In lymphoma) may result in regression of early lesions."" When
addition, proliferation of these cells at certain sites may de-
pend on the presence of activated, antigen-driven T cells.96 Transformation to large cell lymphoma may occur.
We propose the term "marginal zone B-cell lymphoma" to
encompass tumorswith these morphologic features, with
HARRIS ET AL
modifiersto indicate the clinical subtype: extranodal or
nodal.
Morphology. Marginal zone B-cell lymphoma is charac-
terized by cellular heterogeneity, including marginal zone
(centrocyte-like) cells (small, atypical cells resembling small
cleaved follicular center cells or centrocytes, but with more
abundant cytoplasm, similar to Peyer's patch, mesenteric
nodal, or splenic marginal zone cells), monocytoid B cells,
small lymphocytes, and plasma cells (Table 3, Fig SA). Oc-
casional large cells (centroblast- or immunoblast-like) are
present in most cases. Reactive follicles are usually present,
~ ~ ~neoplastic marginal zone or monocytoid B cells
, ~ ~ the
occupying the marginal zone andor the interfollicular region
(Fig 5B); occasional follicles may contain an excess of mar-
ginal zoneor monocytoid cells, giving them a neoplastic
appearance (follicular colonization). In epithelial tissues, the
marginal zone cells typically infiltrate the epithelium, form-
ing so-called lymphoepithelial lesions. In lymph nodes they
may have a perisinusoidal, parafollicular or marginal zone
pattern of distribution (Fig 6). Plasma cells are often distrib-
uted in distinct subepithelial or interfollicular zones, and are
Imrnunophenotype. Tumor cells express SIg (M > G or
A), lack IgD, and about 40% are CIg+; B-cell-associated
antigens (CD19, 20, 22, 79a) are expressed, and the tumors
are CD5-, CD10-, CD23-, CD43"' CDllc'" (Table 4).
Immunophenotyping studies are a useful adjunct to diagno-
sis, in excluding B-CLL (CDS'), mantle cell (CDS'), and
follicle center (CD10' CD43-, CDllc.., usually CIg-),
lymphomas.1',97~99
Genetic features. No rearrangement of bcl-2 or bcl-l is
seen'"'; trisomy 3 and or t( 11;18) havebeen reported in
extranodal cases.'"
Clinical features. There are two major clinical presenta-
tions of lymphoma with the above-described morphologic
and immunologic features.
(1) Extranodal marginal zone lymphoma (low-grade B-
cell lymphoma of MALT type). These are tumors of adults,
with a slight female predominance. Many patients have a
history of autoimmune disease, such as Sjogren's syndrome
or Hashimoto's thyroiditis, or of helicobacter gastritis. It
has been suggested that "acquired MALT"secondary to
autoimmune disease or infection in these sites may form the
substrate for lymphoma development. The majority present
with localized stage I or I1 extranodal disease, involving
glandular epithelial tissues of various sites, most frequently
the stomach; however, skin and soft tissues may be the pres-
enting site as well.l""w The term "extranodal marginal zone
lymphoma" can be used for cases not involving epithelial
tissues. Dissemination occurs in upto 30% of the cases, often
in other extranodal sites, with long disease-free intervals.'""
Localized tumors may be cured with local treatment.'04.'"5.'07
Recent studies suggest that proliferation in some early
MALT-type tumors may be antigen-dri~en,~~ and that ther-
apy directed atthe antigen (helicobacter pylori in gastric
disseminated, they appear to be indolent andnot curable.
(2) Nodalmarginal zone lymphoma (provisional sub-
type). The majority of nodal monocytoid B-cell lymphomas
CONSENSUSLYMPHOMA CLASSIFICATION
occur in patients with Sjogren’s syndrome or other extra-
nodal MALT-type lymphomas80~82 and, therefore, likely rep-
resent nodal spread of MALT-type lymphoma. However,
tumors with morphologic features identical to those de-
scribed for extranodal MALT-type or monocytoid B-cell
lymphomas have occasionally been reported with isolated
or disseminated nodal involvement, in the absence of extra-
nodal d i s e a ~ e ? ~ ~Other
~ * ~ ’sites
’ ~ involved include BM and,
rarely, PB.’l2 The clinical course is indolent, and when dis-
seminated, it is not usually curable with available therapy.
Transformation to large cell lymphoma may occur.
Postulated normal counterpart. Marginal zone B cell of
extranodal or nodal type with capacity to differentiate into
plasma cell and home to certain tissue compartments.
Splenic Marginal Zone Lymphoma, With or Without
Villous Lymphocytes (Provisional Entity)
Synonyms. Rappaport: (not specifically listed) WDL or
WDL-plasmacytoid; Kiel: not specifically listed; Lukes-Col-
lins: small lymphocyte B, Lymphocytic-plasmacytic, small
lymphocyte B, monocytoid; Working Formulation: (not spe-
cifically listed) SLL.
Several cases of splenic lymphoma have been reported,
involving both red and white pulp, with a mantle and/or
marginal zone pattern in the white p ~ l p ~ ~ . ”the ~ . ”term
~;
“splenic marginal zone lymphoma” has been proposed for
this entity. However, it appears to be both morphologically
and clinically distinct from extranodal (MALT type) and
nodal marginal zone B-cell lymphomas. There is overlap
between this entity and an uncommon type of adult chronic
B-lymphocytic leukemia, often mistaken for hairy cell leuke-
mia, called splenic lymphoma with villous lymphocytes
(SLVL).~Preliminary investigation suggests that the spleens
of patients with SLVL are identical to those previously re-
ported as splenic marginal zone lymphoma.
Morphology. The characteristic pattern is involvement
of both the mantle and marginal zone of the splenic white
pulp, usually with a central residual germinal center, which
may be either atrophic or hyperplastic. Red pulp involvement
maybe prominent. The neoplastic cells range from small
lymphocytes in the mantle zone to larger cells with irregular
nuclei and pale cytoplasm (marginal zone B cells) in the
marginal zone.
Zmmunophenotype. Similar to that of extranodal and
nodal marginal zone B-cell lymphomas.
Genetic features. Not well studied; however, trisomy 3
has not been detected.”’
Clinical features. Patients typically have BM and PB
involvement, usually without peripheral lymphadenopathy,
and may have a small M-c~mponent?~ The course is reported
to be indolent, and splenectomy may be followed by pro-
longed remission.
Postulated n o m 1 counterpart. Peripheral B cell with
differentiation in part to splenic marginal zone cell.
Hairy Cell Leukemia (HCL)
Morphology. Hairy cells are small lymphoid cells with
an oval or bean-shaped nucleus, chromatin slightly less
clumped than that of a normal lymphocyte, and abundant,
1371
pale cytoplasm with “hairy” projections on smear prepara-
tions. The BM is always involved; the infiltrate is interstitial,
diffuse, and characterized by widely spaced, small nuclei,
in contrast to the closely packed nuclei of most other low-
grade lymphoid neoplasms involving the marrow. Reticulin
is increased, often resulting in a “dry tap.” The diagnosis is
best made on BM biopsy; in cases of minimal involvement,
immunostaining with anti-B-cell antibodies such as DBA44
or L26 may be ~ s e f u l . ” ~In~the
” ~ spleen the tumor involves
the red pulp; the white pulp is usually atrophic. Lymph node
involvement is uncommon; when present, the infiltrate is
diffuse, and may leave spared follicles, resembling marginal
zone lymphoma.
Zmmunophenotype. The tumor cells are SIg+(M+/-D,
G, or A), B-cell-associated cell antigens+ (CD19, 20, 22,
79a), CDS, CD10-,CD23-, CDllc’ (strong), CD25’
(strong),I6FMC7+, CD103’ (MLA: mucosal lymphocyte
antigen, recognized by HML-1, B-ly7, Ber-ACT&
LF61)117”20; tartrate-resistant acid phosphatase is present in
most cases, but is not specific for the diagnosis. CD103 is
the most useful marker for distinguishing HCL from other
B-cell leukemias, because CD22, CD1 IC,CD25, FMC7, and
even TRAP can be present in disorders other than HCL.
Strong expression of these markers in association with
CD103, together with the characteristic morphologic fea-
tures, are most useful.
Genetic features. Ig heavy and light chain genes are re-
arranged.’” No specific abnormality is described.
Clinical features. Patients are adults with splenomegaly
and pancytopenia and may have few circulating neoplastic
cells. The course is indolent; spontaneous remissions are
reported. There is increased susceptibility to infections. The
tumor does not respond to conventional lymphoma chemo-
therapy, but interferon, deoxycoformycin, or 2-chlorodeoxy-
adenosine can induce long-term remissions.’z2,’z3
Postulated normal counterpart. Peripheral B cell of un-
known differentiation stage.
PlasmacytomdPlasma Cell Myeloma
Morphology. Plasmacytomdmyeloma is composed of
cells that resemble mature or immature plasma cells (plas-
mablasts), with no admixture of cells recognizable as
lymphoid. Some cases may have “cleaved” nuclei or cells
that resemble immunoblasts.’2aIncreased cellular immaturity
may be associated with a poor prognosis. An “anaplastic”
extramedullary stage resembling large cell lymphoma may
be a preteminal event in some cases.Iz5
Zmmunophenotype. Tumor cells are SIg-, CIg’ (G, A,
rare D or E; or light chainonly); most B-cell-associated
antigens negative (CD19, 20, 22), but CD79a+”; CD45”’,
HLA-DR”+, CD38+, EMA“+, CD43+/-, CD56+/-. (CD30
may be detected in paraffin sections using the BerH2 anti-
body.)34.126,127
Genetics. IgH and L genes are rearranged or deleted.
Clinical features. Plasma cell neoplasms are most often
disseminated BM tumors of adults (multiple myeloma).
Some cases present as solitary bone or extramedullary tu-
mors. The majority of solitary bone plasmacytomas progress
to multiple myeloma, whereas only 10% to 20% of solitary
extramedullary plasmacytomas show such progression.
 Fig l .

Fig 5.

Fig 6. Rg 10,
CONSENSUS LYMPHOMA CLASSIFICATION 1373

Postulated n o m 1 counterpart. Plasma cell. Table 5. ReproducibilityStudy: Subclassification

of Large B-Cell Lymphoma
DtfSuse Large B-Cell Lymphoma Consensus Diagnosis
No. of No. of Cases
Synonyms. Rappaport: diffuse histiocytic, occasionally Pathologists in Agreed on Large Cell
diffuse mixed lymphocytic-histiocytic; Kiel: centroblastic, Agreement (96) 1%) Centroblastic lmmunoblastic NOS
B-immunoblastic, large cell anaplastic (B-cell); Lukes-Col- 12
(100) 1 (4) 1
lins: large cleaved or large noncleaved FCC, B-immunoblas- 1 1 (92) 5 (17) 4 1
tic; Working Formulation: diffuse large cell cleaved, non- (75)
9 1 1 (48) 9 1 1
cleaved or immunoblastic; occasionally diffuse 2 mixed 14 small
(74) 17 a (67) 1
and large cell. 176 (50)(91) 21 3 1
Morphology. Diffuse large B-cell lymphomas are com- 23 cases, 4 categories, 12 pathologists. The fourth category (other)
posed of large cells (nuclei at least twice the size of a small was never selected by six or more pathologists; numbers in parenthe-
lymphocyte; usually larger than tissue macrophage nuclei) ses are percents.
with vesicular nuclei, prominent nucleoli, basophilic cyto-
plasm and a moderate to high proliferation fraction. In most
cases the predominant cell resembles either acentroblast all but one participant agreed on subclassification.Fifty per-
(large noncleaved cell) or an immunoblast; the most common cent or more agreed on 21 of the 23 cases (91%). The most
appearance is that of amixture of centroblast-like and immu- common subtype was centroblastic (80% of the 21 cases on
noblast-like cells6 (Fig 7). Other cell types include large which 50% agreed), which may be expected, because in the
cleaved or multilobated cells’**and anaplastic large cells updated KielClassification, this is defined as any tumor with
identical to those of T- or null-cell anaplastic large cell 10% or more centroblasts (large noncleaved cells). One case
lyrnph~ma.’~~ Some cases of large B-cell lymphoma may was considered unclassifiable by most of the group, because
be richin small T lymphocytes or histiocytes, creating a of poor technicalquality; at leastone observer considered 13
resemblance to either T-cell lymphoma or HD of the lympho- of the other 22 cases unclassifiable. Other than centroblastic,
cyte predominance type.”0”33Some of these cases have been immunoblastic, and large cell not classifiable, the mostcom-
placed in the diffuse mixed small and large cell category of mon “other” category proposedwas Burkitt’s lymphoma
the Working F~rmulation,’~~”~’ but we believe they should or small noncleaved, non-Burkitt type, proposed by one to
be considered to be large B-cell lymphomas for clinical pur- three participants in eight cases.
poses. Basedon this studyand our daily experience withthe
No correlation has been reported between immunopheno- difficulty of subclassifying large cell lymphomas on routine
type and histologic subtype of B-large cell lymphoma,” al- histologic sections, and the fact that treatment is currently
though cases with anaplastic morphology typically express similar for all types, we believe that with the current knowl-
the CD30 antigen, similarly to T-cell and null-cellanaplastic edge and methods it is impractical to subclassify these tu-
large cell lymph~ma.’*~*’~~*’’~ mors, and that they should all be designated, large B-cell
Reproducibilitystudy. Although onlyasmall,informal lymphoma. Further study should be directed at identifying
study, this exercise yielded interesting results (Table 5). morphologic, immunologic and/or genetic parameters that
Twelve participants received the slide sets and were able to might define clinically relevant subgroups. This study also
score the cases in time for the meeting. Among the23 cases suggested important overlap between the definitionsof large
and four possible categories, there was complete agreement B-cell
lymphoma and
so-called
small
noncleaved cell
on only one case (4%), and only four cases (17%)on which lymphoma, particularly of the non-Burkitt type.

4
Fig 5. Extrsnodal marginal zone B-cell lymphoma. (AI Gastric lymphoma, showing infiltration of the lamina propria by small lymphocytes,
marginal zone cellswith epithelial infiltration, and plasma cells (Giemsa, original magnification x 55). (B) Gastric lymphoma, showing marginal
zonelmonocytoid B cells surrounding a reactivefollicle deep in the lamina propria (H&€, original magnification x 218). (C) High magnification
of merginal zone type cells, showing round to irregular nuclei, abundant pale cytoplasm snd scattered plasmacytoidcells (Giemsa, original
magnification x 872).
Fig 6. Nodal monocytoid B a l l lymphoma in a patient with Sjogren‘s syndrome and extranodal MALT-type lymphoma of the salivary gland.
(A) The neoplastic monocytoid B cells occupythe parafollicularlparisinusoidel region, similarly to normal monocytoid B cells (HaE. original
magniticetion x 22). (B) Hlghar magnification, showing cells with similar nuclear featuresto those in Fig 5C. but with more abundant cytoplasm
IH&E, original magnification x 872).
flg 7. Large B-cell lymphomas. (A) The most common type shows a mixture of cells resembling centroblasts (one to three peripheral
nucleoli) and cells resembling immunoblasts (single central nucleolus) (Giemsa, original magnification x 872). (B) Mukilobated large B-cell
lymphoma (H=, original magnification x 872).
Fig 8. Burkitt‘s lymphoma (left); comparison with high-grade B-cell lymphoma, Burkii-like (right). Typical Burki‘s lymphoma has small-
to medium-sized monomorphous cells; cases such as that on the right have slightly larger, more pleomorphic cells, which are nonetheless
smaller than the cells of typical large B-cell lymphomas(Giemsa, original magnification x 872).
Fig 9. T-cell chronic lymphocytic leukemia, CD4+ type. Circulating cells have slight nuclear irregularity and some have nucleoli (left). The
lymph node (right) shows a monotonous infiltrate of small cells with irregular nuclei, resembling tho- of mantle cell lymphoma (Wright-
Giemse, original magnifidon x 872 [left]; Giemsa, original magnification x 872 [right]).
Fig 10. Largo granularlymphocyte leukemia, showing circulating cells with abundant, granular cytoplasm(WrightCiemsa, original magnifi-
cation x 872).
1374
Zmmunophenotype. Tumor cells are SIg+/-, CIg-", B-
cell-associated antigens+ (CD19, CD20, CD22, CD79a),
CD45+/-, CDs-/+, CD10-/+ 13.140
Genetic features. The bcl-2 gene is rearranged in about
30%'41,142; c-myc is reported to be rearranged in some
cases.143
Clinical features. Large B-cell lymphomas constitute
30% to 40% of adult NHLs; the median age is in the sixth
decade, but the range is broad, and these tumors maybe
seen in children.' Patients typically present with a rapidly
enlarging, often symptomatic mass at a single nodal or extra-
nodal site; up to 40% are extranodal. Large cell lymphomas
are aggressive but potentially curable with aggressive ther-
apy.8Although several studies have reported a slightly worse
prognosis for immunoblastic than large follicular center cell
type^,^.^^ other studies have failed to confirm t h i ~ . ' ~Cases ~ . ' ~ ~ loci on 2 [t(2; 8)] or 22 [t(8;22)].In African (endemic) cases,
of multilobated B-cell type are often extranodal.
Postulated normal counterpart. Proliferating peripheral
B cells (rearrangement of the bcl-2 gene has been interpreted
as evidence for a germinal center origin of some cases).
Large B-Cell Lymphoma Subtype: Primary Mediastinal
(Thymic) Large B-Cell Lymphoma
Morphology. The tumor is composed of large cells with
variablenuclear features, resembling centroblasts, large
centrocytes, or multilobated cells, often with palecytoplasm.
Less often, the tumor cells resemble immunoblasts. Reed-
Sternberg like cells may be present. Many cases have fine,
compartmentalizing sclerosis. Both clinically and pathologi-
cally (when appropriate tissue canbe studied), the tumor
usually involves the thymus at p r e ~ e n t a t i o n . ' ~ ~ . ' ~ ~
Immunophenotype. The tumor cells are often Ig-, but
express B-cell-associated antigens (CD19, CD20, CD22,
CD79a) andare CD45"- CD30"+ (weak CD30 expression
with Ber-H2 on frozen sections or microwave treated paraf-
fin sections), CD15-.146"49
Genetic features. Ig heavy and light chain genes are re-
a ~ ~ a n g e d ' ~ no
~ . ' specific
~'; abnormality is described.
Clinical features. Large B-cell lymphoma of the medi-
astinum appears to be a distinct clinicopathologic entity,
with a median age in the fourth decade, a higher incidence
in females than males, and a locally invasive anterior medi-
astinal mass originating in the thymus, with frequent airway
compromise and superior vena cava s y n d r ~ m e . ~Re-
lapses tend to be extranodal, including liver, gastrointesti-
nal tract, kidneys, ovaries, and central nervous system. Al-
though early studies suggested an unusually aggressive,
incurable tumor, others have reported cure rates similar to
that for other large cell lymphomas with aggressive ther-
apy.15'
Postulated normal counterpart. Putative thymic (medul-
lary) B ce11.146~153
Burkitt's Lymphoma
Synonyms. Rappaport: undifferentiated lymphoma, Bur-
kitt's type; Kiel: Burkitt's lymphoma; Lukes-Collins: small
noncleaved FCC; Working Formulation: small noncleaved
cell, Burkitt's type.
Morphology. Burkitt's tumor cells are monomorphic,
HARRIS ET AL
medium-sized cells withround nuclei, multiple (2 to 5 )
nucleoli, and relatively abundant basophilic cytoplasm,
which may give the cells a "cohesive" appearance (Fig 8).
Cytoplasmic lipid vacuoles are usually evident on imprints
or smears. This tumor has an extremely high rate of prolifera-
tion as well as a high rate of spontaneous cell death. A
"starry-sky'' pattern is usually present, imparted by numer-
ous benign macrophages that have ingested apoptotic tumor
cells.
Immunophenotype. Tumor cells are SIgM+,B-cell-as-
sociated antigens+(CD19, CD20, CD22, CD79a),CD10+,
CD5-, CD23"."4
Genetic features. Most cases have a translocation of c-
myc from chromosome 8 to the Ig heavy chain region on
chromosome 14 [t(8; 14)] or, less commonly, to light chain
the breakpoint on chromosome 14 involves the heavy chain
joining region, suggesting that the translocation occurs in
an early B cell, before complete Ig gene rearrangement. In
contrast, in nonendemic cases, the translocation involves the
Ig heavy chain switch region, suggesting that the transloca-
tion occurs at a later stage of B-cell development.'ss~lsh Ep-
stein-Barr virus (EBV) genomes can be demonstrated in the
tumor cells in most African cases and in 25% to 40% of the
cases associated with acquired immune deficiency syn-
drome,157-fsY but less frequently in non-African, nonimmune
deficient cases.
Clinical features. Burkitt's lymphoma is most common
in children (approximately one third of non-African pediatric
lymphomas); adult cases are often associated with immuno-
deficiency. The male-to-female ratio is 2 or 3 to 1. In African
(endemic) cases, the jaws and other facial bones are often
involved. In non-African (nonendemic) cases, jaw tumors
are less common; the majority of the cases present in the
abdomen, most often involving distal ileum, cecum andor
mesentery; ovaries, kidneys or breasts maybe involved.""
Rare cases present as acute leukemia with Burkitt's tumor
cells (W-ALL). The tumor is highly aggressive but poten-
tially curable; prognosis in children correlates with bulk of
disease at the time of diagnosis."'
Postulated normal Counterpart. B cell of unknown dif-
ferentiation stage.
Provsional Entity: High-Grade B-Cell Lymphoma, Burkitt-
~ ' ~ ' ~Like
~
Synonyms. Rappaport: undifferentiated, non-Burkitt;
Kiel:not listed; Lukes-Collins: small noncleaved FCC;
Working Formulation: small noncleaved cell, non-Burkitt.
Morphology. The participants in the meeting noted that
several of the cases in the large cell lymphoma reproducibil-
ity study set appeared to have morphologic features interme-
diate between large cell lymphoma with centroblastic or im-
munoblastic features and typical Burkitt's lymphoma (Fig
8). All recalled many cases in their own practices in which
distinction between large cell and Burkitt's lymphoma
seemed impossible. We believe that these difficult cases
comprise many of the cases designated undifferentiated, non-
Burkitt's in the Rappaport classification,16*small noncleaved
cell, non-Burkitt type in the Working F ~ r r n u l a t i o n ,for
~~~
which there is no clear counterpart in the Kiel Classification.
CONSENSUS LYMPHOMA CLASSIFICATION
(A category of Burkitt’s lymphoma with CIg may correspond
to some cases of this entity.6) A recent studyL63showed that
cases classified as “small noncleaved, non-Burkitt type”
lacked c-myc rearrangement and had frequent bcl-2 re-
arrangement, suggesting that these tumors are probably not
related to true Burkitt’s lymphoma. Therefore, we propose
a provisional category of “high-grade B-cell lymphoma,
Burkitt-like” (in preference to “non-Burkitt’s”’62) for cases
in which the cell size and nuclear morphology are intermedi-
ate between typical Burkitt’s lymphoma and typical large
cell lymphoma, in which there is a high proliferation rate,
with or without a starry-sky pattern. We believe that this is
not a reproducible category, and probably not a single dis-
ease entity, but it appears to be necessary for cases that
are borderline between large B-cell lymphoma and Burkitt’s
lymphoma.
Zmmunophenotype. Tumor cells are SIg+/- (may have
CIg), B-cell-associated antigens+, CDY, and usually
c~10-.154
Genetic features.c-myc rearrangement is uncommon;
the bcl-2 gene is rearranged in 30%.‘63
Clinical features. Tumors of this description are rela-
tively uncommon and appear to occur mostly in adults, with
or without a history of immunosuppression; they involve
lymph nodes more often than extranodal sites. Cases classi-
fied as small noncleaved, non-Burkitt type in children appear
to behave similarly to classic Burkitt’s turnor,l6’whereas in
adults they appear to be highly aggressive and often fatal.
Postulated normal counterpart. Proliferating peripheral
B cells.
T-cell and Putative Natural Killer Cell (NK)
Neoplasms
Precursor T-cell Neoplasm: Precursor T-Lymphoblastic
LymphomdLeukemia (T-LBL)
Synonyms. Rappaport: poorly differentiated lympho-
cytic, diffuse (modified to lymphoblastic); Kiel: T lympho-
blastic; Lukes-Collins: convoluted T lymphocytic; Working
Formulation: lymphoblastic, convoluted or nonconvoluted.
Morphology. The tumor cells are morphologically iden-
tical to those of precursor B-LBL: lymphoblasts, with round
or convoluted nuclei, finely dispersed chromatin, inconspicu-
ous nucleoli, and scant cytoplasm (Fig 1B). Immunopheno-
typing studies are necessary to distinguish this tumor from
precursor B-lymphoblastic neoplasms, and occasionally,
from peripheral B- or T-cell neoplasms or granulocytic sar-
coma.
Immunophenotype. Most cases are CD7+, CD3+ (cyto-
plasmic CD3 is usually present even when surface antigen
is absent); expression of other T-cell-associated antigens
(CD2,5) is variable. They express either a@, yS, or no T-
cell receptor molecule^."^'^^ Tumors are typically TdT+,
CDla+”, often CD4,8 double positive or double negative,
Ig-, B-cell-associated antigens-, occasional cases express
NK antigens (CD16, 57).’“I7O
Genetic features. Rearrangement of TCR genes is vari-
able’65;IgH rearrangement may be seer^^^.'^'.'^'; variable cy-
togenetic abnormalities are reported.”
Clinical features. Patients are predominantly adolescent
1375
and young adult males, but older adults are occasionally
affe~ted.’~’ It constitutes 40% of childhood lymphomas and
15% of acute lymphoblastic leukemias (defined as >25%
BM lymphoblasts). Patients present with rapidly enlarging,
symptomatic mediastinal (thymic) masses andor peripheral
lymphadenopathy. Untreated, it is rapidly fatal, usually ter-
minating in acute leukemia; central nervous system involve-
ment is common. The tumor is highly aggressive but poten-
tially curable. Clinically important subtypes may be defined
by immunophenotypic profiles: leukemic cases tend to have
a more immature phenotype than lymphoma
CD2- or NK (CD16+57+) cases may be more aggres-
sive.168-L70.173
Postulated normal counterpart. Precursor T cells: pro-
thymocyte, early thymocyte, common thymocyte.
Peripheral T-cell Neoplasms
T-cell Chronic Lymphocytic Leukemia (T-CLL)/T-
Prolymphocytic Leukemia (T-PLL)
Synonyms. Rappaport: WDL, PDL; Kiel: T-cell CLW
PLL; Lukes-Collins: small lymphocyte T, prolymphocytic;
Working Formulation: small lymphocytic, c/w CLL, diffuse
small cleaved cell; French-American-British (FAB): T-PLL.
Morphology. Most chronic T-cell leukemias have cells
with prominent nucleoli, some nuclear irregularity, and more
abundant cytoplasm than typical B-CLL, so that they fall
into the category of prolymphocytic leukemia (T-PLL).
However, some cases have smaller cells that may resemble
B-CLL.30*’74.’75 The cells are usually nongranular, but have
focal granular paranuclear positivity on acid phosphatase
and acid nonspecific esterase stains (Fig 9). Lymph node
involvement is diffuse and paracortical, with sparing of folli-
cles; it differs from B-CLL in lack of pseudofollicles. Promi-
nent small vessels of the high endothelial venule type (HEV)
may be numerous, and often contain atypical small lymphoid
cells.176Splenic red pulp and hepatic sinusoids may be infil-
trated. BM involvement is usually diffuse, and the marrow
may show increased reticulin.
Zmmunophenotype. In contrast to other CD4+ T-cell leu-
kemias (ATL/L and MF/SS), the tumor cells are CD7+, as
well as other T-cell-associated antigens+(CD2,3,5), most
cases are CD4+ (65%), some are CD4+8+ (21%), rare cases
are CD4-8’, and they are CD25-.30,’75*’77
Genetic features. Clonal rearrangements of TCR genes:
inv 14 (qll;q32) in 75%; trisomy 8q.
Clinicalfeatures. T-CLLPLL comprises 1% of CLL but
up to 20% of PLL. Patients have a high white count
(>lOO,OOO), and a high frequency of cutaneous or mucosal
infiltrates. BM, spleen, liver, and lymph nodes may be in-
volved. It is more aggressive than B-CLL, and not usually
curable with available therapy.L75
Postulated normal counterpart. Circulating peripheral T
cell.
Large Granular Lymphocyte (LGL) Leukemia, T-cell and
NK-Cell Types
Synonyms. Rappaport: SLL, CLL; Kiel: T-CLL, Lukes-
Collins: small lymphocyte, T; Working Formulation: small
lymphocytic, consistent with (c/w) CLL; FAB: T-CLL, T-
LGL.
1376
Morphologic features. This disorder corresponds to
cases described as T8 lymphocytosis with neutropenia, CD8,
or Ty lymphoproliferative disease, and CD8+ T-CLL.'7s317y
Peripheral blood cells have round or oval nuclei withmoder-
ately condensed chromatin and rare nucleoli, eccentrically
placed in abundant pale blue cytoplasm with azurophilic
granules (Fig 10). The cells are acid phosphatase positive,
with a granular pattern, and are nonspecific esterase negative
or weakly po~itive.~' BM infiltration is usually sparse, with
mild to moderate lymphocytosis as well as focal aggregates,
sometimes resembling B-cell lymphoma. There may be a
myeloid maturation arrest or erythroid hypoplasia. Splenic
red pulp and hepatic sinuses may be infiltrated.I8'
Immunophenotype. Two types: T-cell and NK-cell have
been rep~rted.'~'
T cell. CD2+ CD3+ CD5- CD7- TCRnP' CD4- CD8+
CD16+ CD56- CD57+/- CD25-.
NK cell. CD2' CD3- TCRaP- CD4- CD8+" CD16+
CD56+" CD57+/-.
Genetic features. T-cell cases show clonal rearrange-
ments of TCR genes. NK-cell cases are germline, and clon-
Association with EBV
ality is not proven in most cases.181,182
is reported in aggressive Asian cases.
Clinical features. Patients with both types have mild to
moderate, stable lymphocytosis (5 to Z0,000/mm3), often
with neutropenia; anemia is seen in T-cell cases. T-cell cases
usually have mild to moderate splenomegaly, without sig-
nificant lymphadenopathy or hepatomegaly; most NK cell
cases lack all of these. The course is usually indolent, with
morbidity related to cytopenias rather than tumor burden.
Occasional patients with both types have a more aggressive
course. The EBV' Asian cases have a more acute presenta-
tion and a more aggressive course.
Postulated n o m 1 counterpart. T-cell type: peripheral
CD8' T lymphocyte with suppressor but no NK function.
NK-cell type: NK-cell.
Mycosis Fungoides/Sezary Syndrome (MF/SS)
Synonyms. Rappaport: mycosis fungoideslsezary syn-
drome; Kiel: small cell, cerebriform; Lukes-Collins: cerebri-
form T; Working Formulation: mycosis fungoides.
Morphology. Tumor cells are predominantly small cells
with cerebriform nuclei, with a minority of larger cells with
similar nuclei, which infiltrate the epidermis, circulate in the
blood, and involve the paracortex of lymph nodes."33184The
infiltrate is invariably accompanied by interdigitating and
Langerhans' cells. The BM is usually normal.
Immunophenotype. Tumor cells express T-cell-associ-
ated antigens (CD2+3+5+);approximately one third are
CD7+; most cases are CD4+, but rare CD8+ cases are re-
ported. CD25 is usually negative, but positive cases have
been reported. S-100' CDla+ interdigitating and Langer-
hans' cells are present.'85
G e n e t i c f e a t u r e s . TCR genes are clonally rear-
ranged.'86,187
Clinicalfeatures. Patients are usually adults who present
with multiple cutaneous plaques or nodules, or with general-
ized erythroderma; lymphadenopathy is usually a late occur-
rence. Peripheral blood involvement may be subtle in MF
or prominent in Sezary's syndrome. As a terminal event, a
HARRIS ET AL
large cell lymphoma may develop, which is morphologically
and immunophenotypically similar to anaplastic large cell
lymphoma (ALCL). An association with HD andlymphoma-
toid papulosis has also been reported.'"
Postulated normal counterpart. Peripheral epidermo-
tropic CD4' T cell.
Peripheral T-cell Lymphomas, UnspeciJed (Provisional
Cytologic Categories: Medium-Sized Cell, Mixed Medium
and Large Cell, Large Cell)
Synonyms. Rappaport: diffuse PDL, diffuse mixed
lymphocytic-histiocytic, histiocytic; Kiel: T-zone lympho-
ma, lymphoepitheliolid cell lymphoma, pleomorphic, small,
medium, and large cell, T-immunoblastic; Lukes-Collins:
T-immunoblastic lymphoma; Working Formulation: diffuse
small cleaved cell, diffuse mixed small and large cell, large
cell immunoblastic (polymorphous or clear cell).
Peripheral T-cell lymphomas typically contain a mixture
of small and large atypical cells. They make up as many as
halfof the cases usually classified as diffuse mixed small
and large cell type134"37 and an unknown proportion of cases
classified aslarge cell immunoblastic in the Working Formu-
lation. Wefind, as have others, that peripheral T-cell
lymphomas can be difficult to understand and subclassify.
Roblems include their rarity in Western material, their ap-
parent heterogeneity, and the difficulty of identifying the
neoplastic cell population without a reliable immunopheno-
typic marker of T-cell malignancy. A number of distinct
clinical syndromes have been defined, which correspond to
recognizable morphologic subtypes of T-cell neoplasia, and
we have described these as distinct entities. Once these have
been separated out, there remains a large group of non-
lymphoblastic, non-CLL T-cell lymphomas, which likely
constitute the majority of cases of peripheral T-cell
1ymph0ma.I~~"~' Althoughthe Kiel Classification defines
multiple subtypes within this broad ~ a t e g o r y , ~ .members
~.'~~
of the group find it difficult to subclassify these cases with
confidence, and suspect that other pathologists may share
this experience.lY2Further clinicopathologic studies are re-
quired to confirm the feasibility and clinical relevance of
subclassification of peripheral T-cell lymphomas. For the
time being, we found it most practical to lump these cases
as "peripheral T-cell lymphomas, unspecified.' '
Morphologic features. Peripheral T-cell lymphomas of
unspecified type show a diffuse or occasionally interfollicu-
lar proliferation that ranges from atypical small cells to me-
dium-sized or large cells; most contain a mixed population
of small and large atypical cells, and even those with a
predominance of medium-sized or large cells often contain
a broad spectrum of cell s i ~ e s ' ~ ~(Fig
, ' ' ~11). Admixedeosin-
ophils or epithelioid histiocytes may be n~rnerous.''~
(Lymphoepithelioid cell [Lennert's] lymphoma is considered
a cytologic category of peripheral T-cell lymph~rna~'~~''~).
The neoplastic cells often have irregular nuclei, and vary
considerably in size and shape, with occasional large, hyp-
erchromatic cells that may resemble Reed-Stemberg cells.
True RS cells are rare or absent. For lack of other criteria,
we propose stratifying these cases by the number of large
cells, as medium-sized cell, mixed medium and large cell,
CONSENSUS LYMPHOMA CLASSIFICATION
and large cell types, recognizing that this is imprecise and
not reproducible.
Two subtypes of peripheral T-cell lymphoma appear to
have sufficiently distinctive morphology, immunophenotype,
and clinical behavior to warrant recognition as provisional
entities: hepatosplenic gamma-delta (76)T-cell lympho-
ma,’% and subcutaneous panniculitic T-cell lymphoma.Iw
Zmmunophenotype. T-cell-associated antigens are
variable (CD3+” CD2+” CD5’”CD7-’+), CD4 > CD8,
may be CD4-CD8-; B-cell-associated antigens are lack-
ing (may express CD45RA and lack CD45RO; rare CD20’
T-cell lymphomas are reported).19’.’93.’98-zo1
Genetic features. TCR genes are usually but not always
rearranged; Ig genes are germline?0’~z03
Clinicalfeatures. These tumors comprise less than 15%
of lymphomas in most European and US studies, but are
more common in other parts of the world. Patients are usu-
ally adults with generalized disease, occasionally with eosin-
ophilia, pruritis or hemophagocytic syndromesm; lymph
nodes, skin or subcutis, liver, spleen and other viscera may
be i n v ~ l v e d . ’ ~The
~ , ~ ~clinical
’ course is usually rather ag-
gressive, although potentially curable; relapses are more
common than in B-cell lymphomas of similar histologic
This category includes heterogeneous dis-
eases that require further definition.
Postulated normal counterpart. Peripheral T cells in
various stages of transformation.
Peripheral T-cell Lymphoma, Specific Variants
Four subtypes of peripheral T-cell lymphoma were consid-
ered by the group to have sufficiently clear defining fea-
tures-morphologic, immunologic, genetic, and/or clini-
cal-to be reliably recognized as distinct entities by most
pathologists. These include angioimmunoblastic T-cell
lymphoma, angiocentric lymphoma, intestinal T-cell
lymphoma, and adult T-cell 1ymphomaAeukemia(HTLVl+).
Although relatively uncommon in the United States and Eu-
rope, they are occasionally encountered in routine practice,
and should be recognized.
Angioimmunoblastic T-cell Lymphoma
Synonyms. Rappaport: not listed (diffuse mixed lympho-
cytic-histiocytic, histiocytic); Kiel: T-cell, angioimmu-
noblastic (AILD); Lukes-Collins: IBL-like T-cell lym-
phoma; Working Formulation: not listed (diffuse mixed
small and large cell, diffuse large cell, large cell immu-
noblastic).
Morphology. Although initially proposed to be an abnor-
mal immune reaction (angioimmunoblastic lymphadenopa-
thy
with dysproteinemia [AILD],m or immunoblastic
lymphadenopathy [IBL]), this entity is now generally ac-
cepted as a T-cell lymphoma, because most cases show
clonal rearrangements of T-cell receptor genes.’” The mor-
phologic features are similar to those described for angioim-
munoblastic lymphadenopathy.m3z” The nodal architecture
is effaced; peripheral sinuses are typically open and even
dilated, but the abnormal infiltrate often extends beyond the
capsule into the perinodal fat. Reactive follicles with germi-
nal centers are usually absent. The node typically has a pale,
1377
or depleted appearance at low power. There is a proliferation
of small, arborizing HEV, many of which show thickened
or hyalinized PASf walls (Fig 12). Expanded aggregates
of FDC, visible on immunostained sections, surround the
proliferating blood vessels, and may have the appearance of
“burnt-out’’ germinal centers. The lymphoid infiltrate usu-
ally appears relatively sparse, compared with other lympho-
mas, probably because of the large number of FDC. The
lymphoid cells are a mixture of small lymphocytes, immu-
noblasts, and a characteristic type of atypical “clear” cell,
which usually has a round to slightly indented nucleus and
abundant, pale or clear ~ytoplasm”~ (Fig 12). These cells
occur singly or in small aggregates or sheets. Epithelioid
histiocytes, plasma cells, and eosinophils may be admixed.”’
Zmmunophenotype. Tumor cells express T-cell-associ-
ated antigens and usually CD4; expanded FDC clusters are
present around proliferated The latter feature
has been suggested to be useful in distinguishing this disor-
der from other T-cell lymphomas.6
Geneticfeatures. TCR genes are rearranged in 75%; IgH
in EBV genomes are detected in many ~ a s e s ~ ’ ~ . ’ ’ ~ ;
trisomy 3 andor 5 may occur.‘15
Clinical features. This is a relatively rare disorder, but
is clinically distinctive. Patients typically have a systemic
disease, with generalized lymphadenopathy, which is rarely
massive, fever, weight loss, skin rash, and polyclonal hyper-
gammaglobulinemia.2*z’1The course is moderately aggres-
sive, with occasional spontaneous remissions or protracted
responses to steroids, and infectious complications. Progres-
sion to high grade lymphoma of T- or occasionally B-cell
type occurs.
Postulated normal counterpart. Peripheral T cell of un-
known subset in various stages of transformation.
Angiocentric Lymphoma
Synonymsand related disorders. Rappaport: not listed
(diffuse PDL, mixed lymphocytichistiocytic or histiocytic);
Lukes-Collins: not listed (T-immunoblastic sarcoma); Kiel
Classification: not listed (T, pleomorphic small, medium and
large cell); Working Formulation: not listed (diffuse small
cleaved, mixed small and large cell, diffuse large cell, large
cell immunoblastic); other, angiocentric immunoprolifera-
tive lesion (grades 2 and 3), polymorphic reticulosis, lethal
midline granuloma, midline malignant reticulosis, nasal T
cell lymphoma, ? lymphomatoid granulomatosis (some
cases).
Morphologic features. This disorder is characterized by
an angiocentric and angioinvasive infiltrate, usually com-
posed of a mixture of normal-appearing small lymphocytes
and variable numbers of atypical lymphoid cells and immu-
noblasts, along with plasma cells and occasionally eosino-
phils and h i s t i o ~ y t e s . ~ ’A~characteristic
*~’~ feature is invasion
of vascular walls and, usually, occlusion of lumina by
lymphoid cells with varying degrees of cytologic atypia (Fig
13).The vascular occlusion is usually associated with promi-
nent ischemic necrosis of bothtumor cells and normal tissue.
Cases with features of pulmonary “lymphomatoid granulo-
matosis” have been considered to belong to this entity216;
however, recent studies suggest that at least some pulmonary
1378 HARRIS ET AL

I".r __....-, -
inal magnification x 53). (B)T-
cell lymphoma with a predomi-
nance of
medium-sized cells
with irregular nuclei (H&€, origi-
nal magnification x 349). [C) T-
cell lymphoma containing a mix-
ture of medium-sized and large
cells IHtkE, original magnifica-
tion x 349). [D)T-cell lymphoma
composed predominantly of
large cells with pleomorphic, ir-
regular nuclei (H=, original
magnification x 349).

cases may be EBV-associated B-cell proliferations,and
therefore a distinct disease category?'8
Zmmunophenotype. The atypical cells in most cases ex-
press pan-T antigens (CD2+ CD5+" CD7+") but are often
CD3-, may be CD4+ or CD8+, and are often CD56+?l9-"'
In some pulmonary cases with features of lymphomatoid
granulomatosis, the atypical cells expressB-lineageanti-
gens.218
Genetic features. TCR and Ig genes are usually germ-
line; EBV genomes are usually present.217*z20*222~2z3
In some

Fig 12. Angioimmunoblastic T-cell lymphoma. (A) Medium-power
view showing diffuse architectural effacement with vascular prolifer-
ation (H&E, original magnification x 87). (B) The infiltrate contains
medium-sized cellswith clear cytoplasm, admixedwith eosinophils,
plasma cells, and occasionalimmunoblasts(H&E, original magnifica-
tion x 3491.
Fig13. Angiocentriclymphomaofnose. (A) Low magnification,
showing medium-sized blood vessels surrounded andinfiltrated by
atypical lymphoid cells, with necrosis of adjacent tissue (H&E, origi-
nal magnification x 55).(B) Same case, higher magnification, show-
ing a mixture of small and large atypical cells infiltrating a blood
vessel (H&E, original magnification x 218).
CONSENSUS LYMPHOMA CLASSIFICATION
pulmonary cases, clonal Ig gene rearrangement has been
shown, and EBV genomes are present in B cells.’18
Clinical features. Angiocentric lymphoma is a rare dis-
order in the United States and Europe, but is more common
inAsia. It may affect children or adults. Extranodal sites
are invariably involved, including nose, palate, and
s~n.217,220321.223 cases with pulmonary and central nervous
system involvement may represent a different entity (see
above). The clinical course appears to depend on the propor-
tion of large cells, and may be indolent or aggre~sive.”~ Multinucleated giant cells resembling Reed-Stemberg cells
Hemophagocytic syndromes may occur. Some cases of the
aggressive variant of NK cell leukemidymphoma may be
related to this disorder.224
Postulated normal counterpart. NK cell, ? unknown pe-
ripheral T-cell subset.
Intestinal T-cell Lymphoma (With or Without
Enteropathy)
Synonyms. Rappaport: not listed (diffuse mixed lympho-
cytic-histiocytic, histiocytic); Lukes-Collins: not listed (T-
immunoblastic sarcoma); Kiel:not listed (T, pleomorphic
small, medium and large cell); Working Formulation: not
listed (diffuse small cleaved cell, diffuse mixed small and
large cell, diffuse large cell, large cell immunoblastic); other, variants have been described.235Most common is the
malignant histiocytosis of the intestine, ulcerative jejunitis.
Morphology. This disorder was originally termed “ma-
lignant histiocytosis of the intestine,” but has since been
conclusively shown to be a T-cell lymphoma.225On gross
examination, jejunal ulcers are present, often multiple, and
often with perforation. A mass may or may not be present.
The tumors contain a variable admixture of small, medium/
mixed, large or anaplastic tumor cells, often with a high
content of intraepithelial T cells in adjacent mucosa. Adja-
cent mucosa may or may not show villous atrophy.205Early
lesions may show mucosal ulceration withonly scattered
atypical cells and numerous reactive histiocytes, without for-
mation of large masses.
Immunophenotype. Tumorcells are CD3+CD7+CD8+”
CD4- CD103’ (MLA: HML-1, LFGl, Bly7, Ber-ACT8).226 Cell Types)
Genetic features. TCRP genes are clonally rear-
ranged.225
Clinical features. This disease occurs in adults, often
with a history of gluten-sensitive enteropathy, but occasion-
ally as the initial event in a patient found to have typical
histologic features of sprue in the resected intestine, or less
commonly, without evidence of enteropathy. It is uncom-
mon, in most areas of the United States and Europe, but
is seen with increased frequency in areas in which gluten-
sensitive enteropathy is more common. Patients present with
abdominal pain, often associated with jejunal perforation;
stomach or colon are affected less often. The course is ag-
gressive and death usually occurs from multifocal intestinal
perforation caused by refractory malignant ulcers.
Postulated n o m 1 counterpart. Intestinal intraepithelial
T cell in various stages of transformation.
Adult T-cell Lymphoma/Zeukemia (ATL.5)
Synonyms. Rappaport: diffuse PDL, mixed lymphocytic-
histiocytic, or histiocytic; Lukes-Collins: T-immunoblastic
1379
sarcoma; Kiel: pleomorphic small, medium and large cell
types (HTLVl’); Working Formulation: diffuse small
cleaved cell, mixed small and large cell, diffuse large cell,
large cell immunoblastic.
Morphology. This disease is defined as a T-cellneo-
plasm caused by HTLV1:27-231The histology is variable.
The pattern in lymph nodes is diffuse; usually there is a
mixture of small and large atypical cells with pronounced
polymorphism and nuclear p l e ~ m o r p h i s m ’ ~(Fig ~ ~14A).
~~~~~~’
in some cases may cause a resemblance to HD.233Cells with
hyperlobated nuclei (“clover leaf” or “flower” cells) are
common in the peripheral blood3’ (Fig 14B). Marrow infil-
tration is diffuse, and ranges from sparse to marked.
Immunophenotype. Tumor cells express T-cell-associ-
ated antigens (CD2,3,5+) but usually lack CD7; most are
CD4+ CD25+; rare CD8+ cases have been reported.
Genetic features. TCR genes are clonally rearranged;
clonally integrated HTLVl genomes are found in all
cases.228,234
Clinical features. The majority of patients are adults,
who have antibodies to HTLV1. Most cases occur in Japan,
but an endemic focus is found in the Caribbean, and sporadic
cases are found in the United States?29-232 Several clinical
“acute” form, which presents with a high white blood cell
count, hepatosplenomegaly, hypercalcemia, and lytic bone
lesions; median survival is less than 1 year. The rare lympho-
matous form is characterized by isolated lymphadenopathy
without leukemia. A chronic form with lower white blood
cell count, without hypercalcemia or hepatosplenomegaly,
has slightly longer survival, and rare smoldering cases have
mild lymphocytosis, which is demonstrably clonal, but a
very indolent course.236Both chronic and smoldering forms
often have skin rashes.
Postulated normal counterpart. Peripheral CD4+ T cell
in various stages of transformation.
Anaplastic Large Cell (CD30+)Lymphoma (T- and Null-
Synonyms. Rappaport:not listed (histiocytic, diffuse);
Kiel: large cell anaplastic (T and null types); Lukes-Collins:
T-immunoblastic sarcoma; Working Formulation: not listed
(diffuse large cell immunoblastic); possible other names:
malignant histiocytosis, sinusoidal large cell lymphoma, re-
gressing atypical histiocytosis.
This tumor was originally recognized by application of
the Ki-l (CD30) antibody; tumors strongly expressing the
antigen had a characteristic morphology, now known as ana-
plastic large cell lymphoma (ALCL).129,237 Although other
lymphomas of either T-cell or B-cell type may strongly ex-
press CD30,’29*138,’39 believe
we there is sufficient evidence
that the anaplastic type is a distinct clinicopathologic entity
to warrant its inclusion in any lymphoma categorization at-
tempt.
Morphologic features. The tumor is composed of large
blastic cells with pleomorphic, often horseshoe-shaped or
multiple nuclei with multiple (usually) or single prominent
nucleoli. Multinucleated forms may resemble Reed-Stern-
berg cells (Fig 15). The tumor cells are usually much larger
1380
Fig 14. Adult T-cell Iyrnphomalleukemia, HTLVl+. (A)Lymph
node, showing mixture of small and large lymphoid calls (H&E, origi- cell) with vesicular, lobated nucleus and several small nucleoli (H&
nal magnificationx 349).(B) Peripheral blood, showing lymphoid cell E, original magnification x 872). (B) Mixed cellularity HD, showing
with lobated nucleus: so-called flowercell (Wright-Giemsa, original
magnification x 872).
thanthecellsofusuallargecelllymphomas,withmore
abundant cytoplasm. The cells grow in a cohesive pattern
and often preferentially involve the lymph node sinuses,as
well as extranodal sites, suchas soft tissue, bone, and skin.
There is a variable admixture of granulocytes and macro-
phages. A lymphohistiocytic variant occurs, in which reac-
tive histiocytes predominate and the rare neoplastic cells
may be smaller than classic ALCL cells?3* and a small cell because of variations in case definition, there
variant has been described recently, whose relationship to
classic ALCL remains to be dete1mined.2~' Many cases of
ALCL were previously diagnosed as malignant histiocytic
tumors, regressing atypical histiocytosis,24o metastatic carci- category (see below).
noma, melanoma, sarcoma, or lymphocyte-depleted HD.
Fig 15. Anaplasticlargecelllymphoma, T-cell type,showing a
dfluse proliferationof large cellswith pleomorphic nuclei, prominent
nucleoli, and abundant cytoplasm (Giemsa, original magnificationx
349).
HARRIS ET AL
Fig 16. HD. (A) Nodular lymphocyte predominance HD, showing
characteristic Reed-Sternberg cell variant ("popcorn" or "L and H"
classic, diagnostic binucleate Reed-Stemberg cell, with two eosino-
philic nucleoli (H&E, original magnificationx 872).
The majority of tumorswiththemorphologicfeatures
described above express one or more T-cell-associated anti-
gens, many express neither T- nor B-cell-associated anti-
gens and some cases express B-cell antigens. The group has
included the B-cell cases among the morphologic variants of
B-large cell lymphoma, rather than considering it a distinct
disease. Although the literature on this topic is confusing,
is evidence that
the T and "null" cases likely represent different antigenic
expressions of the same disease; however, there may two be
distinct clinical and possibly biological entities within this
Z m m p h m v p e . The tumor cells are CDM+,CD45+/-,
CD25+", Em+/-, CD15"+ CD3"+ , other T-cell-associ-
ated antigens variable, CD43"+, CD45RO"+,CD68- (when
studiedusingPGM1"'; W1 may stain somecases),and
" ' - ~ 50% have been reported to ex-
l y s ~ z y m e - ? ~ ~ * About
press H and Y blood group antigens, detected with a mono-
clonal antibody, BNH9.245 Primary cutaneous cases are re-
ported to lack EMA and express the cutaneous lymphocyte
antigen (CLA, HECA-452).246
Geneticfeatures. Cytogenetic studies on a small number
of cases of the systemic form have shown a
t(2;5)"'; cytoge-
netic studies on primary cutaneous cases have not been re-
ported. Fifty percentto 60% of thecaseshaveTCRre-
arranged; 40% to 60% have no rearrangementof TCR or Ig
genes."8*"9
Clinical features. Anaplasticlarge cell lymphomais a
relatively rare tumor, but may be diagnosed with increasing
frequency as its features are more widely recognized. Cases
CONSENSUS LYMPHOMA CLASSIFICATION
havebeenreported in all agegroups; 15% to 30% of the
cases in unselected series are under age 20.250Mostcases
arise “de novo”; however, some patients have a history of
other lymphomas including mycosisfungoides or HD.251
There is growing evidence for two distinct forms of primary
&CL: a systemic form, which may involve lymph nodes or
extranodal sites, including the skin, but is not localized to the
skin, and a primary cutaneous form, without extracutaneous
spread at the time of the diagn~sis.~’ Tumors that present
with systemic extracutaneous disease (with or without skin
involvement) have a bimodal age distribution in children and
adults, are clinicallymoreaggressive,and are EMA+ and
cutaneous lymphocyte antigen (CLA, HECA-452) negative.
Primary cutaneous tumors occur predominantly in adults, may
spontaneously regress, lack EMA and express the CLA, and
may represent a continuous spectrum with lymphomatoidpa-
pulosis typeA. Although the primary cutaneousform appears
to be indolent and incurable, the systemic form appears to
behave similarly toother large cell lymphomas, being moder-
ately aggressive but potentially curable with aggressive ther-
apy.247.252
Late relapses may be seen.
Postulated normal countevart. Extrafollicular CD30+
blasts.253
Provisional Entity: ALCL Hodgkin’s-Like (Hodgkin’s-
related)
Morphologic features. This tumor is composed of con-
fluent sheets of tumor cells, and a cohesive, often sinusoidal
growth pattern, similar to classic ALCL; but with architec-
tural features that resemble HD of the nodular sclerosis type
(NSHD), such as capsular thickening, nodular growth of
tumor cells, and sclerotic bands.244*245*254325These cases are
apparently usually classified by the American pathologists
in the group as either NSHD (syncytial, lymphocyte de-
pleted, or NSII type) or lymphocyte depletion (LDHD), retic-
ular type (“Hodgkin’s sarcoma”) (see below).
Immunophenotype. Identical to classic ALCL; tumors
are usually EBV-.
Genetic features. Not known.
Clinical features. Patients are young adults with aggres-
sive nodal disease, and often with bulky mediastinal masses;
according to European studies they do not do well with con-
ventional therapy for HD, but may have a good response to
very aggressive therapy, such as third generation chemother-
apy regimens for high-grade NHLs.’~~ We believe that further
study is required to define thispossible entity and its relation-
ship to HD on the one hand and classic ALCL on the other.
Postulated normal counterpart. Not known (as for
ALCL or NSHD).
Hodgkin’s Disease
Lymphocyte Predominance (Paragranuloma)
Synonyms. Lukes et alZs7: lymphocytic and/or histio-
cytic, nodular, lymphocytic andor histiocytic, diffuse (some
cases); Lennert and M0h1-i‘~~:paragranuloma, nodular or dif-
fuse.
Sufficient evidence has emerged in recent years to warrant
recognition of this subtype of HD as a distinct entity.25g
Although it resembles other types of HD in having a minority
1381
Table 6. HD, Lymphocyte Predominance (LPHD)
Versus Nodular Sclerosis and MixedCellularity (Classic HD)
LPHD Classic HD
Atypical cells LP variants Diagnostic RS cells,
(“L&H” or mononuclear or
”popcorn” lacunar cells
cells)
Diagnostic RS cells Rare to absent Always present
CD15 Negative Usually positive
CD30 Often positive Usually positive
CD20 Usually positive Usually negative
CD45 Positive Usually negative
EMA Often positive Negative
EBV (in large cells) Usually Often positive (20%-70%)
neaative
of putative neoplastic cells in a background of benign in-
flammatory cells, it differs both morphologically, immuno-
phenotypically, and clinically from classic HD2@265(Table
6). Because the category of diffuse lymphocyte predomi-
nance in the Rye Classificationprobably includes cases more
closely related to classic HD (see lymphocyte-rich classic
HD, below), the older term, paragranuloma, has been sug-
gested as a way of denoting this distinctive
Lymphocyte predominance HD usually has a nodular
growth pattern with or without diffuse areas; it is rarely
purely diffuse; nodularity may be more easily recognized
using immunohistologic stains with anti-B cell or anti-FDC
antibodies. Progressively transformed germinal centers are
often seen in the same or other nodes. The atypical cells
have vesicular, polylobated nuclei and small nucleoli (Fig
16); these have been called L&H cells (lymphocytic and/or
histiocytic) or “popcorn” cells. Although these cells may
be very numerous, usually no diagnostic Reed-Sternberg
cells are found. The background is predominantly lympho-
cytes with or without epithelioid histiocyte clusters; plasma
cells are infrequent, and eosinophils and neutrophils are
rarely seen?& Occasional sclerosis may cause lesions to re-
semble nodular sclerosis.
Immunophenotype. The atypical cells are CD45+, B-
cell-associated antigens+ (CD19, 20, 22, 79a), CDw75+,
EMA+” C D W , CD30”+, and are usually Ig- by routine
techniques, although one study reported light chain restric-
tion.261J-chain has been shown in many cases.2673268 Small
lymphocytes in the nodules are predominantly B cells with
a mantle zone phenotype; numerous T cells are present, with
CD57+ T cells surrounding the L&H cells. A prominent
meshwork of FDC is present within the nodules.26s264
Genetic features. Igand TCR genes are germline;
large cells are EBV- in most
Clinical features. The tumor occurs at all ages, adults
more commonly than children, males more than females. It
usually involves peripheral lymph nodes, with sparing of the
mediastinum; it is usually localized at diagnosis, but may
rarelybe disseminated. Survival is long, with or without
treatment, for localized cases. Late relapses have been re-
ported to be more common than in other types of HD’”; it
may be associated with or progress to large B-cell
lymphoma.”z~”4Prospective clinical studies using different
1382
forms of treatment should be attempted to determine the
optimal approach to this disorder.
Postulated normal counterpart. Undefined peripheral B
cell.
Nodular Sclerosis
Morphologic features. The tumor has at least a partially
nodular pattern, with fibrous bands separating the nodules
in most cases; diffuse areas are common, as is necrosis. The
characteristic cell is the lacunar type RS cell, which may be
very numerous; diagnostic RS cells are usually also present
(Fig 16). Thebackground contains lymphocytes, histiocytes,
plasma cells, eosinophils, and neutrophils.257 Subclassifica-
tion according to the number of atypical cells may be clini-
cally relevant; several grading schemes exist (NSI/I17.276
syncytial variant,277lymphocyte depleted, cellular phase).
Immunophenotype. Tumor cells are C D W - , CD30+,
CD45- (may be positive in frozen sections); usually B-cell-
and T-cell-associated antigen negative, EMA-.’29.278 CD 15
and CD30 may be difficult to detect in paraffin sections in
some cases unless microwave antigen-retrieval techniques
are used. Expression of B-cell- and T-cell-associated anti-
gens has been reported in a variable number of cases, usually
in a minority of the cells.279~282 The diagnosis is made on
routine sections, and immnnophenotyping studies are at best
an adjunct tothe diagnosis. In a morphologically typical
case, immunophenotyping studies are not needed, and failure
to detect CD15 or CD30 or expression of a B- or T-cell-
associated antigen should not preclude a diagnosis of HD.
Genetic features. Ig and TCR genes are usually germ-
line, but rearrangements of Ig genes are reported in some
cases, usuallywith faint bands.249.2R3-287 Tumor cells are
EBV’in about 40% of the cases.270~28x-290 bcl-2 re-
arrangement has been detected with the polymerase chain
reaction in a variable proportion of the cases in some labora-
tories2” but not in others292;these rearrangements have not
been proven to be in the neoplastic cells.269~293
Clinical features. This variant is most common in ado-
lescents and young adults, but can occur at any age; females
equal or exceed males. The mediastinum is commonly in-
volved; stage and bulk of disease have prognostic impor-
tance. It is often curable.
Postulated normal counterpart. Unknown; ?activated
lymphoid cell of an as yet unidentified B-cell or T-cell sub-
set, or of a primitive lymphoid cell.
Mixed Cellularity
Morphologic features. The infiltrate is diffuse or
vaguely nodular, without band-forming sclerosis, although
fine interstitial fibrosis may be present. RS cells are of the
classic type, although some lacunar cells may be seen (Fig
16). The infiltrate contains lymphocytes, histiocytes, eosino-
phils, neutrophils and plasma cells.257
Immunophenotype. Tumor cells are CD30+, CD15+/-,
C D 4 5 (may be positive in frozen sections), usually B-cell-
and T-cell-associated antigen negative, EMA-. CD15 and
CD30 may be difficult to detect in paraffin sections in some
cases unless microwave antigen-retrieval techniques are
used. Expression of B-cell- or T-cell-associated antigens
HARRIS ET AL
has been reported in a variable number of cases, usually in
a minority of the ~ e l l s . ’ ~ The
~ - ~diagnosis
’~ is made on routine
sections, and immunophenotyping studies are at best an ad-
junct to the diagnosis. In a morphologically typical case.
immunophenotyping studies are not needed, and failure to
detect CD15 or CD30 or expression of a B- or T-cell-associ-
ated antigen should not preclude a diagnosis of HD.
Genetic features. IgandTCRgenes are usually germ-
line.?4Y.28?-287The tumor cells are EBV’ in the majority of
the cases (60% to 70%).’7”.28x~29”
Clinicul features. Patients are usually adults; males out-
number females, and the stage may be more advanced than
NS or LP types, involving lymphnodes, spleen, liver, or
marrow. The course is moderately aggressive, but often cur-
able.
Postulated normal counterpart. Unknown; ?activated
lymphoid cell of an as yet unidentified B-cell or T-cell sub-
set, or of a primitive lymphoid cell.
Lymphocyte Depletion
Morphologic features. The infiltrate is diffuse and often
appears hypocellular, because of the presence of diffuse fi-
brosis and necrosis; there are large numbers of Reed-Stem-
berg cells, and bizarre “sarcomatous” variants, with a
paucity of other inflammatory cells. Confluent sheets of
Reed-Sternberg cells and variants may occur and rarely pre-
dominate (“reticular” variant or “Hodgkin’s sarcoma”).2s7
The borderline between the reticular variant and ALCL is not
sharp, and may be a matter of definition.244.245,254.255
Further
studies are required to resolve this issue.
Immunophenotype. Tumor cells are CD30’, CD15+”,
CD45-, B-cell-associated antigens and T-cell-associated
antigens-, EMA-. Because the histologic differential diag-
nosis often includes B- or T-large cell lymphoma or ALCL,
absence of T- and B-cell markers are usually required for
the diagnosis.
Genetic features. Ig and TCR genes are germline. (If
rearrangements are found, the tumor is usually classified as
a B-cell or T-cell lymphoma.)
Clinical features. This is the leastcommonvariantof
HD and is most common inolder people, in human immuno-
deficiency virus-positive (HIV’) individuals294and in nonin-
dustrialized countries. It frequently presents with abdominal
lymphadenopathy, spleen, liver and BM involvement, with-
out peripheral adenopathy. The stage is usually advanced at
diagnosis; however, response to treatment is reported not to
differ from other
Postulated normal counterpart. Unknown; ?activated
lymphoid cell of an as yet unidentified B-cell or T-cell sub-
set, or of a primitive lymphoid cell.
Provisional Entity: Lymphocyte-Rich Classical HD
Synonyms. Lukes et a1257:subset of diffuse lymphocyte
predominance; Lennert and MohriZs8:lymphocyte predomi-
nant mixed cellularity.
Morphologic features. This is defined as a diffuse tumor
with relatively infrequent Reed-Stemberg cells, which are
of the classic type, rather than the variants seen in nodular
LPHD; some lacunar cells may be present, in a background
CONSENSUSLYMPHOMA CLASSIFICATION
of lymphocytes, with infrequent eosinophils or plasma cells.
There is morphologic overlap with diffuse lymphocyte pre-
dominance, the cellular phase of NS, and mixed cellularity.
In contrast to diffuse LPHD, the Reed-Stemberg cells have
the morphology and immunophenotype of classic RS cells,
and therefore we believe these lesions should not be classi-
fied as true lymphocyte predominance. The immunopheno-
type, genetic features, and clinical features are similar to NS
and MCHD.
Unclassifiable Cases
For the well-defined disease categories to be meaningful,
it is important not to “squeeze” into them cases that do not
fulfill diagnostic criteria. Therefore, unclassifiable cases are
defined as those that do not fit into either a definite or provi-
sional category: they may be T cell, B cell, or undefined,
they may be borderline between HD and NHL, and they may
be either high or low histologic grade, based on proliferation
fraction and proportion of transformed (blast) cells. At least
the following categories should be recognized: (1) B-cell
lymphoma, unclassifiable: low-grade (predominantly small
cells), or high-grade (mixed small and large or predomi-
nantly large cells); (2) T-cell lymphoma, unclassifiable: low-
grade (predominantly small cells), or high-grade (mixed
small and large or predominantly large cells); (3) HD, un-
classifiable; (4) malignant lymphoma, unclassifiable: low-
grade or high-grade.
A case may be unclassifiable because of poor histologic
preparation, inadequate immunophenotyping or molecular
genetic studies, or because despite complete analysis with
available techniques it does not fit clearly into any of the
well-defined disease categories. The latter group is clearly
the most important for future growth of knowledge. For each
case, the reason for inability to classify should be stated.
DISCUSSION
The current lack of consensus on lymphoma classification
causes problems for practicing pathologists and clinicians,
and creates difficulty in interpreting published studies. Sev-
eral alternatives could be considered: (1) update the lnterna-
tional Working Formulation8to incorporate newly described
entities; (2) adopt the Kiel Classification, which has recently
been ~ p d a t e d , * *as ~ . ~international standard; or (3) de-
~ *the
velop a new lymphoma classification.
It has been suggested that the Working Formulation, the
most widely used method for lymphoma diagnosis in the
United States, and the basis for most American lymphoma
clinical trials, be updated to include new entities. Arguments
in favor of this course include the relative simplicity of the
Working Formulation, which make it easy to understand and
apply, the belief that its prognostic groups make it uniquely
clinically relevant, and the fact that it has been used in many
clinical trials in the last decade. Nonetheless, there are sev-
eral arguments against revising the Working Formulation.
One major reason is that the Working Formulation was not
intended by its authors to be a free-standing classification
scheme, but rather a method of translating between existing
classifications. At the time it was developed, six schemes
were in use in various parts of the world; pathologists could
1383
not reach a consensus, and the NCI-sponsored study failed
to show a clear advantage in survival prediction or reproduc-
ibility of any one classification.8Thus, the Working Formula-
tion was proposed as an inclusive scheme, in which all cate-
gories in all existing classifications could finda place.
However, since publication of the Working Formulation in
1982, most of the six classifications have not continued in
use;only the Kiel and Lukes-Collins classifications are
widely used. Thus, it is not clear what remains for the Work-
ing Formulation to “translate” between.
A second problem is that the Working Formulation cate-
gories were defined by survival data based on a group of
patients treated on chemotherapy protocols usedin the
1970s. Because its categories were based on survival data
from a defined patient population, it is difficult to see how
it can be formally revised without reference to the original
slides and patient data. Furthermore, a classification based
solely on response to treatment available 10 to 20 years ago
may not have continued relevance as new therapies become
available.
Finally, the morphologic diagnoses in the Working For-
mulation were based solely on review of hematoxylin and
eosin-stained sections; no special stains or immunologic data
were available. Many of the advances in lymphomas in re-
cent years have involved immunologic and genetic studies,
which are not available on the Working Formulation mate-
rial. For all of the above reasons, we believe that updating
the Working Formulation is impractical.
The Kiel Classification, used in Europe and elsewhere,
has recently been ~pdated.’.~.~.~ It could be argued that this
classification, which is widely used outside of the United
States, should be adopted as the new international standard
classification. The Kiel Classification is based on the postu-
lated relationship of neoplastic lymphoid cells to their nor-
mal counterparts in the immune system, and uses both de-
tailed morphologic analysis and immunologic studies to
define specific disease entities. It contains many well-defined
entities that are now accepted throughout the world, and
thus could serve as a basis for an international consensus
classification. However, it excludes primary extranodal
lymphomas other than mycosis fungoides and does not ad-
dress some issues of concern to North Americans, such as
the morphologic and clinical heterogeneity of follicular
lymphomas, which appear to be more common in the United
States than in Europe. Finally, it requires morphologic sub-
classification of entities such as large B-cell lymphoma and
peripheral T-cell lymphomas, whichmaybe difficult and
poorly reproducible.
For these reasons, we took the approach of determining
what experienced hematopathologists-none of whom had
been involved in developing one of the existing classifica-
tions-were actually doing in their daily practice. We as-
sumed that entities that we could all agree on could be recog-
nized by others, and that entities that we could not define
or diagnose reliably would likely cause difficulty for other
pathologists. This approach to lymphoma categorization is
not intended to replace either the Kiel Classification or the
Working Formulation. We have built on existing classifica-
tions and many other published studies, and simply produced
a compilation of existing knowledge ina practical form.
1384
Most of the entities listed are already included in the updated
Kiel Classification. Our list can be used in conjunction with
the Working Formulation, because many of the diseases rec-
ognized fall within one or another of the Working Formula-
tion categories. Conversely, American hematologists and on-
cologists may conclude that the Working Formulation has
outlived its usefulness and thatmore specific disease entities,
such as those listed here, should be recognized in clinical
trials. Because our effort builds on current European and
American classifications, we have termed it the “Revised
European-American Lymphoma Classification.’’
We have described a large number of disease entities,
which may alarm those who believe that a lymphoma classi-
fication must besimple. Given the complexity of the immune
system, it should not be surprising that its tumors are numer-
ous and complex. It is necessary to “split” before meaning-
ful “lumping” can occur. If several morphologically, immu-
nologically, and genetically distinct neoplasms prove to
respond identically to currently available treatment, they can
be “lumped” for the purposes of clinical treatment selection.
However, if new forms of treatment become available, par-
ticularly if these are directed against antigenic or genetic
features, it will be important to recognize and study each
disease separately. For those who argue that oncologists can-
not possibly remember a large number of diseases or incor-
porate new ones into their thinking, we call to mind the large
and (to pathologists) bewildering array ofnew drugs and
combinations that oncologists seem to understand and re-
member without difficulty. If the entities that we describe
here are indeed real diseases, the relevance and utility of
this approach will be readily apparent, and no one will com-
plain about the large number of diseases to study and treat.
If appropriate studies are conducted, proposed entities that
are not real diseases will soon be eliminated.
This study should be regarded as a preliminary effort to
bring some order to the chaos of lymphoma categorization,
and constitutes merely a framework for further study. Spe-
cifically, we have made no attempt to determine the repro-
ducibility of diagnosis of these various categories, either
among different pathologists or by the same pathologist over
time. We note that no prior tumor classification has been
based on reproducibility, and that when such studies have
been done with existing classifications of lymphoma, they
have shown disappointing r e s ~ l t s . * , ~We
* * ~expect
~ * that rec-
ognition of clearly defined entities, which have characteristic
immunophenotypes and in some cases genetic features, as
well as characteristic morphology, will facilitate reproduc-
ibility among pathologists.296We believe that formal repro-
ducibility studies should be undertaken, and should in gen-
eral be a more frequent activity in the pathologic diagnosis
of tumors.
We have also not made a systematic attempt to determine
the utility of these histologically and immunologically de-
fined categories in predicting clinical outcome. Our clinical
data are taken from studies already published in the litera-
ture, many of them conducted by pathologists rather than
clinicians. We believe that systematic application of the cri-
teria presented here to defined groups of patients, in collabo-
ration with our clinical colleagues, is imperative. Several of
us are associated with cooperative clinical groups studying
HARRIS ET AL
lymphomas in both the United States and Europe, and we
plan to undertake this important next step in the near future.
Finally, we recognize that the list of entities presented
here is likely to contain errors both of omission and commis-
sion: we have included some provisional entities that may
not prove to be real diseases, and excluded some recently
defined or controversial entities that may prove to be real in
the future. Thus, a critical feature of any tumor classification
is that it be periodically reviewed and updated to incorporate
new information. A model for this activity has been the FAB
group in its approach toleukemias.” Either our informal
group or a larger group, composed of subcommittees of the
major Hematopathology associations or the World Health
Organization, should undertake this task.
ACKNOWLEDGMENl
The authors gratefully acknowledge the assistance of Steven Con-
ley and Michele Forrestall in preparing the photomicrographs.
REFERENCES
1. Lennert K, Mohri N, Stein H, Kaiserling E The histopathology
of malignant lymphoma. Br J Haematol 31:193, 1975 (suppl)
2. Gerard-Marchant R, Hamlin I, Lennert K, Rilke F, Stansfeld
A, van Unnik J: Classification of non-Hodgkin’s lymphomas. Lancet
2:406, 1974
3. Lennert K: Malignant Lymphomas Other Than Hodgkin’s Dis-
ease. New York, NY, Springer-Verlag, 1978
4. Lennert K: Histopathology of Non-Hodgkin’s Lymphomas:
Based on the Kiel classification. New York, NY, Springer-Verlag,
1981
5. Stansfeld A, Diebold J, Kapanci Y, Kelenyi G, Lennert K,
Mioduszewska 0, Noel H, Rilke F, Sundstrom C, van Unnik 3,
Wright D: Updated Kiel classification for lymphomas. Lancet 1:292,
1988
6. Lennert K, Feller A: Histopathology of Non-Hodgkin’s
Lymphomas (ed 2). New York, NY, Springer-Verlag, 1992
7. Lukes R, Collins R: Immunologic characterization of human
malignant lymphomas. Cancer 34:1488, 1974
8. Non-Hodgkin’s lymphoma pathologic classification project.
National Cancer Institute sponsored study of classifications of non-
Hodgkin’s lymphomas: Summary and description of a Working For-
mulation for clinical usage. Cancer 49:2112, 1982
9. Banks P, Chan J, Cleary M, Delson G, De Wolf-Peeters C,
Gatter K, Grogan T, Harris N, Isaacson P, Jaffe E, Mason D, Pileri
S , Ralfkiaer E, Stein H, Warnke R: Mantle cell lymphoma: A pro-
posal for unification of morphologic, immunologic, and molecular
data. Am J Surg Path01 16:637, 1992
10. Harris N: Lymphoma 1987: An interim approach to diagnosis
and classification, in Fechner R, Rosen P (eds): Pathology Annual,
2. East Nonvallc, CT, Appleton & Lange, 1987, p 1
11. Knapp W, Dorken B, Rieber P, Schmidt R, Stein H, von dem
Borne A: CD antigens 1989. Am J Path01 135:420, 1989
12. Nathwani B,Kim H, Rappaport H: Malignant lymphoma,
lymphoblastic. Cancer 38:964, 1976
13. Pesando J, Ritz J, Lazarus H, Costello S , Sallan S , Schlossman
S : Leukemia-associated antigens in ALL.Blood 54:1240, 1979
14. Janossy G, Bollum F, Bradstock K, Ashley J: Cellular pheno-
types of normal and leukemic hematopoietic cells determined by
selected antibody combinations. Blood 56:430, 1980
15. Drexler H, Thiel E, Ludwig W-D: Review of the incidence
and clinical relevance of myeloid antigen-positive acute lymphoblas-
tic leukemia. Leukemia 5:637, 1991
16. Mason D, Cordell J, Tse A, Van Dongen J, Van Noesel C m ,
Pulford K, Vlensi F, Comans-Bitter W, Borst J, Gatter €2The IgM-
CONSENSUS LYMPHOMA CLASSIFICATION
associated protein mb-l as a marker of normal and neoplastic B-
cells. J Immunol 147:2474, 1991
17. Korsmeyer S, Hieter P, Ravetch J, Poplack D, Waldman T,
Leder P: Developmental hierarchy of immunoglobulin gene re-
arrangements in leukemic pre-B cells. Proc Natl Acad Sci USA
78:7096, 1981
18. Korsmeyer S, Arnold A, Bakhshi A, Ravetch J, U S, Hieter
P, Sharrow S, Le Bien T, Kersey J, Poplack D, Leder P, Waldmann
T Immunoglobulin gene rearrangement and cell surface antigen
expression in acute lymphocytic leukemias of T-cell and B-cell pre-
cursor origins. J Clin Invest 71:301, 1983
19. Tawa A, Hozumi N, Minden M, Mak T, Gelfand E: Re-
arrangements of the T-cell receptor p chain gene in non-T-cell, non-
B-cell acute lymphoblastic leukemia in childhood. N Engl J Med
313:1033, 1985
20. Sixth international workshop on chromosomes in leukemia:
London, England, May 11-18, 1987: Selected papers. Cancer Genet
Cytogenet 40:171, 1989
21. Borowitz M, Croker B, Metzgar R: Lymphoblastic lymphoma
with the phenotype of common acute lymphoblastic leukemia. Am
J Clin Pathol 79:387, 1983
22. Sander C, Medeiros L, Abruzzo L, Horak I, Jaffe E: Lympho-
blastic lymphoma presenting in cutaneous sites: A clinicopathologic
analysis of six cases. J Am Acad Dermatol 25:1023, 1991
23. Pangalis G, Nathwani B, Rappaport H: Malignant lymphoma,
well differentiated lymphocytic: Its relationship with chronic
lymphocytic leukemia and macroglobulinemia of Waldenstrom.
Cancer 39:999, 1977
24. Dick F, Maca R: The lymph node in chronic lymphocytic
leukemia. Cancer 41:283, 1978
25. Ben-Ezra J, Burke J, Swartz W, Brownell M, Brynes R, Hill
L, Nathwani B, Oken M, Wolf B, Woodruff R, Rappaport H: Small
lymphocytic lymphoma: A clinicopathologic analysis of 268 cases.
Blood 73579, 1989
26. Pugh W, Manning J, Butler J: Paraimmunoblastic variant of
small lymphocytic lymphomdeukemia. Am J Surg Pathol 12:907,
1988
27. Perry D, Bast M, Armitage J, Weisenburger D: Diffuse inter-
mediate lymphocytic lymphoma: A clinicopathologic study and
comparison with small lymphocytic lymphoma and diffuse small
cleaved cell lymphoma. Cancer 66:1995, 1990
28. Galton D, Goldman J, Wiltshaw E, Catovsky D: Prolympho-
cytic leukaemia, Br J Haematol 27:7, 1974
29. Melo J, Catovsky D, Galton D: The relationship between
chronic lymphocytic leukaemia and prolymphocytic leukaemia. I.
Clinical and laboratory features of 300 patients and characterization
of an intermediate group. Br J Haematol 63:377, 1985
30. Bennett J, Catovsky D, Daniel M-T, Flandrin G, Galton D,
Gralnick H, Sultan C: Proposals for the classification of chronic
(mature) B and T lymphoid leukemias. J Clin Pathol 42567, 1989
31. Zukerberg L, Medeiros L, Ferry J, Harris N: Diffuse low-
grade B-cell lymphomas: Four clinically distinct subtypes defined
by a combination of morphologic and immunophenotypic features.
Am J Clin Pathol 100:373, 1993
32. Lennert K, Tamm I, Wacker H-H: Histopathology and immu-
nocytochemistry of lymph node biopsies in chronic lymphocytic
leukemia and immunocytoma. Leuk Lymphoma 157, 1991 (suppl)
33. Stein H, Lennert K, Feller A, Mason D: Immunohistological
analysis of human lymphoma: Correlation of histological and immu-
nological categories. Adv Cancer Res 42:67, 1984
34. Hams N,BhanA: B-cell neoplasms ofthe lymphocytic,.
lymphoplasmacytoid, and plasma cell types: Immunohistologic anal-
ysis and clinical correlation. Hum Pathol 16:829, 1985
35. Knuutila S, Elonen E, Teerenhovi L, Rossi L, Leskinen R:
Trisomy 12 in B cells of patients with B-cell chronic lymphocytic
leukemia. N Engl J Med 314:865, 1986
1385
36. Athan E, Foitl D, Knowles D: Bcl-l rearrangement: Fre-
quency and clinical significance among B cell chronic lymphocytic
leukemias and non-Hodgkin’s lymphomas. Am J Pathol 138591,
1991
37. Croce C, Tsujimoto Y, Erikson J, Nowell P Chromosome
translocations and B cell neoplasia. Lab Invest 51:258, 1984
38. Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell
P Croce, CM: Molecular cloning of the chromosomal breakpoint of
B-cell lymphomas and leukemias withthe t(l I ; 14) chromosome
translation. Science 224: 14, 1984
39. Richter M: Generalized reticular cell sarcoma of lymph nodes
associated with lymphocytic leukemia. Am J Pathol 4:285, 1928
40. Brecher M, Banks P Hodgkin’s disease variant of Richter’s
syndrome: Report of eight cases. Am J Clin Pathol 93:333, 1990
41. Kipps T: The CD5 B cell. Adv Immunol 47: 117, 1989
42. Tolksdorf G, Stein H, Lennert K: Morphological and immu-
nological definition of a malignant lymphoma derived from germinal
centre cells with cleaved nuclei (centrocytes). Br J Cancer 41: 168,
1980
43. Lardelli P, Bookman M, Sundeen J, Longo D, Jaffe E:
Lymphocytic lymphoma of intermediate differentiation. Morpho-
logic and immunophenotypic spectrum and clinical correlations. Am
J Surg Pathol 14:752, 1990
44. Ott M, Ott G, KuseR, Porowski P, Gunzes U, Feller A,
Muller-Hermelink H: The anaplastic variant of centrocytic
lymphoma is marked by frequent rearrangements of the Bcl-l gene
and high proliferation indices. Histopathology 1994 (in press)
45. Swerdlow S, Habeshaw J, Murray L, Dhaliwal H, Lister T,
Stansfeld A: Centrocytic lymphoma: A distinct clinicopathologic
and immunologic entity. Am J Pathol 113:181, 1983
46. Harris N, Nadler L, Bhan A: Immunohistologic characteriza-
tion
of two malignant lymphomas of germinal center type
(centroblastickentrocytic and centrocytic) with monoclonal antibod-
ies: Follicular and diffuse lymphomas of small cleaved cell types
are related but distinct entities. Am J Pathol 117:262, 1984
47. Medeiros L, van Krieken J, Jaffe E, Raffeld M: Association
of bcl-l rearrangements with lymphocytic lymphoma of intermediate
differentiation. Blood 76:2086, 1990
48. Rimokh R, Berger F, Cornillet P, Wahbi K, Rouault J, French
M, Bryon P, Gadoux M, Gentilhomme 0, Germain D, Magaud J:
Break in the BCLl locus is closely associated with intermediate
lymphocytic lymphoma subtype. Genes Chrom Cancer 2:223, 1990
49. Williams ME, Westermann CD, Swerdlow SH: Genotypic
characterization of centrocytic lymphoma: Frequent rearrangement
of the chromosome 11 bcl-l locus. Blood 76:1387, 1990
50. Vandenberghe E, De Wolf-Peeters C, Van den Oord J, Wlo-
darska I, Delabie J, Stul M, Thomas J, Michaux J, Mecucci C,
Cassiman J, Vandenberghe H: Translocation (1 1; 14): A cytogenetic
anomaly associated with B-cell lymphomas of non-follicle centre
cell lineage. J Pathol 163:13, 1991
51. Rosenberg C, Wong E, Petty E, Bale A, Tsujimoto Y, Harris
N, Arnold A: Overexpression of PRADI, a candidate BCLl
breakpoint region oncogene, in centrocytic lymphomas. Proc Natl
Acad Sci USA 88:9638, 1991
52. Williams M, Swerdlow S, Rosenberg C, Arnold A: Character-
ization of chromosome 1 1 translocation breakpoints at the bcl-l and
PRADl loci in centrocytic lymphoma. Cancer Res 52:5541, 1992
(SUPPI)
53. O’Briain D, Kennedy M, Daly P, O’Brian A, Tanner W,
Rogers P, Lawlor E: Multiple lymphomatous polyposis of the gastro-
intestinal tract: A clinicopathologically distinctive form of non-
Hodgkin’s lymphoma of centrocytic type. Am J Surg Pathol 13:691,
1989
54. Meusers P, Engelhard M, Bartels H, Binder T, Fulle H, Gorg
K,Gunzer U, Havemann K, Kayser W, Konig E: Multicentre ran-
domized therapeutic trial for advanced centrocytic lymphoma: An-
1386
thracycline does not improve the prognosis. Hematol Oncol 7:365,
1989
55. lnghirami G, Foitl D, Sabichi A, Zhu B, Knowles D: Autoan-
tibody-associated cross-reactive idiotype-bearing human B lympho-
cytes: Distribution and characterization, including IgVH gene and
CD5 antigen expression. Blood 78:1503, 1991
56. Mann R, Berard C: Criteria for the cytologic subclassification
of follicular lymphomas: A proposed alternative method. Hematol
Oncol 1:187, 1982
57. Metter G, Nathwani B, Burke J, Winberg C, Mann R, Barcos
M, Kjeldsberg C, Whitcomb C, Dixon D, Miller T, Jones S: Morpho-
logical subclassification of follicular lymphoma: Variability of diag-
nosis among hematopathologists, a collaborative study between the
Repository Center and Pathology Panel for Lymphoma Clinical
Studies. J Clin Oncol 3:25, 1985
58. Nathwani B, Metter G, Miller T, Burke J, Mann R, Barcos
M, Kjeldsberg C, Dixon D, Winberg C, Whitcomb C, Jones S: What
should be the morphologic criteria for the subdivision of follicular
lymphomas? Blood 68:837, 1986
59. Stein H, Gerdes J, Mason D: The normal and malignant ger-
minal centre. Clin Haematol 11:531, 1982
60. Stein H, Lennert K, Feller A, Mason D: Immunological analy-
sis of tissue sections in diagnosis of lymphoma, in Hoffbrand A (ed):
Recent Advances in Haematology, 11. New York, NY, Churchill
Livingstone, 1985, p 127
61. Ngan B, Chen-Levy Z, Weiss L, Warnke R, Cleary M: Ex-
pression in non-Hodgkin’s lymphoma of the bcl-2 protein associated
withthe t(14; 18) chromosomal translocation. N Engl J Med
318:1638, 1988
62. Pezzella F, Tse A, Cordell J, Pulford K, Gatter K, Mason D:
Expression of the Bcl-2 oncogene protein is not specific for the 14-
18 chromosomal translocation. Am J Pathol 137:225, 1990
63. Tsujimoto T, Cossman J, Jaffe E, Croce C: Involvement of
the bcl-2 gene in human follicular lymphoma. Science 288:1440,
1985
64. Hockenbery D, Zutter M, Hickey W, NahmM,Korsmeyer
S: BCL2 protein is topographically restricted in tissues characterized
by apoptotic cell death. Proc Natl Acad Sci USA 88:6961, 1991
65. McDonnell T, Deane N. Platt F, Nunez G, Jaeger U, McKeam
J, Korsmeyer S: Bcl-2-immunoglobulin transgenic mice demonstrate
extended B cell survival and follicular lymphoproliferation. Cell
57:79, 1989
66. Limpens J, de Jong D, van Kneken J, Price C, Young B, van
Ommen G, Kluin P: Bcl-2 in benign lymphoid tissue with follicular
hyperplasia. Oncogene 6:2271, 1991
67. Rappaport H: Tumors of the hematopoietic system. Atlas of
Tumor Pathology, Series I, Section 111, Fascicle 8. Washington, DC,
Armed Forces Institute of Pathology, 1966
68. Jones S, Fuks 2, Bull M, Kadin M, Dorfman R, Kaplan H,
Rosenberg S, Kim H: Non-Hodgkin’s lymphomas IV. Clinicopatho-
logic correlation in 405 cases. Cancer 31:806, 1973
69. Anderson T, Bender R, Fisher R, DeVita V, Chabner B, Be-
rard C, Norton L, Young R: Combination chemotherapy in non-
Hodgkin’s lymphoma: Results of long-term follow-up. Cancer Treat
Rep 61:1057, 1977
70. Glick JH BJ Ezdlinli EZ, Berard CW, Orlow EL, Bennett
JM: Nodular mixed lymphoma: Results of a randomized trial failing
to confirm prolonged disease-free survival with COPP chemother-
apy. Blood 58:920, 1981
7 1. Wamke R, Kim H, Fuks Z, Dorfman R: The co-existence of
nodular and diffuse patterns in nodular non-Hodgkin’s lymphomas.
Cancer 40: 1229, 1977
72. Ezdlinli E, Costello W, Kucuk 0, Berard C: Effect of the
degree of nodularity on the survival of patients with nodular lympho-
mas. J Clin Oncol 5:413, 1987
73. Brittinger G, Bartels H, Common H, Duhmke E, Fulle H,
HARRIS ET AL
Gunzer U, Gyenes T, Heinz R, Konig E, Meusers P: Clinical and
prognostic relevance of the Kiel classification of non-Hodgkin
lymphomas: Results of a prospective multicenter study by the Kiel
lymphoma study group. Hematol Oncol 2:269, 1984
74. Warnke R, Levy R: Follicular lymphoma: A model of B
lymphocyte homing. N Engl J Med 298:481, 1974
75. Jaffe E, Shevach E, Frank M,Berard C, Green l: Nodular
lymphoma: Evidence for originfrom follicular B lymphocytes. N
Engl J Med 290313, 1974
76. Isaacson P, Wright D: Malignant lymphoma of mucosa asso-
ciated lymphoid tissue. A distinctive B cell lymphoma. Cancer
52:1410, 1983
77. Isaacson P, Spencer J: Malignant lymphoma of mucosa-asso-
ciated lymphoid tissue. Histopathology 1 1 :445, 1987
78. Cousar J, McGinn D, Glick A, List A, Collins R: Report of
an unusual lymphoma arising from parafollicular B lymphocytes or
so-called “monocytoid” lymphocytes. Am J Clin Pathol87:121,
1987
79. Sheibani K, Burke J, Swartz W, Nademanee A, Winberg C:
Monocytoid B cell lymphoma. Clinicopathologic study of21 cases
of a unique type of low grade lymphoma. Cancer 62: 1531, 1988
80. Ngan B-Y, Warnke R, Wilson M, Takagi K, Cleary M, Dorf-
manR: Monocytoid B-cell lymphoma: A study of36 cases. Hum
Pathol 22:409, 1991
81. Nizze H, Cogliatti S, von Schilling C, Feller A, Lennert K:
Monocytoid B-cell lymphoma: Morphological variants and relation-
ship to low-grade B-cell lymphoma ofthe mucosa-associated
lymphoid tissue. Histopathology 18:403, I991
82. Shin S, Sheibani K, Fishleder A, Ben-Ezra J, Bailey A, Koo
C, Burke J, Tubbs R, Rappaport H: Monocytoid B-cell lymphoma
in patients with Sjogren’s syndrome: A clinicopathologic study of
13 patients. Hum Pathol 22:422, 1991
83. Lin Y-J, Oldfield S, MacLennan I: Memory B cells in T-cell
dependent antibody responses colonise the splenic marginal zones.
Eur J lmmunol 18:355, 1988
84. Cardoso de Almeida P, Harris N, Bhan A: Characterization
of immature sinus histiocytes (monocytoid cells) in reactive lymph
nodes by use of monoclonal antibodies. Hum Pathol 15:330, 1984
85. Spencer J. Diss T, Isaacson P: A study of the properties of a
low-grade mucosal B-cell lymphoma using a monoclonal antibody
specific for the tumour immunoglobulin. J Pathol 160:231, 1990
86. Smith-Ravin J, Spencer J, Beverley P, Isaacson P: Character-
ization of two monoclonal antibodies (UCL4D12 and UCL3D3) that
discriminate between human mantle zone and marginal zone B cells.
Clin Exp lmmunol 82: 18 I , 1990
87. Pelstring R, Essell J, Kurtin P, Banks P: Diversity of organ
site involvement among malignant lymphomas of mucosa-associated
tissues. Am J Clin Pathol 96:738, 1991
88. Davis G, York J, Glick A. McCurley T, Collins R, Cousar
J: Plasmacytic differentiation in parafollicular (monocytoid) B-cell
lymphoma. A study of12 cases. Am J Surg Pathol 16:1066, 1992
89. Gowans J, Knight E: The route of recirculation of lympho-
cytes in the rat. Proc R SOC(Lond) B 159:257, 1964
90. Gallatin W, Weissman I, Butcher E: A cell-surface molecule
involved in organ-specific homing of lymphocytes. Nature 304:30,
1983
91. Van den Oord J, De Wolf-Peeters C, De Vos R, Desmet
V: Immature sinus histiocytosis. Light- and electron-microscopic
features, immunologic phenotype, and relationship withmarginal
zone lymphocytes. Am J Pathol 1985:266, 1985
92. Spencer J , Finn T, Pulford K, Mason D, Isaacson P: The
humangut contains a novel population of B lymphocytes which
resemble marginal zone cells. Clin Exp Immunol 62:607, 1985
93. Van den Oord J, De Wolf-Peeters C, Desmet V: The marginal
zone in the human reactive lymph node. Am J Clin Pathol 86:475.
I986
CONSENSUSLYMPHOMA CLASSIFICATION
94. Van den Oord J, De Wolf-Peeters C, Desmet V: Marginal
zone lymphocytes in the lymph node. Hum Pathol 20:1225, 1989
95. Butcher E: Cellular and molecular mechanisms that direct
leukocyte traffic. Am J Path01 136:3, 1990
96. Hussell T, Isaacson P, Crabtree J, Spencer J: The response of
cells from low-grade B-cell gastric lymphomas of mucosa-associated
lymphoid tissue to Helicobacter pylori. Lancet 342:571, 1993
97. Pins M, Rivas C, Morente M, Cruz M, Rubio C, Oliva H:
Monocytoid B-cell lymphoma, a tumour related to the marginal
zone. Histopathology 12:383, 1988
98. Schmid C, Kirkham N, Diss T, Isaacson P Splenic marginal
zone cell lymphoma. Am J Surg Pathol 16:455, 1992
99. Melo J, Hegde U, Parreira A, Thompson I, Lampert I, Catov-
sky D: Splenic B cell lymphoma with circulating villous lympho-
cytes: Differential diagnosis of B cell leukaemias with large spleens.
J Clin Pathol40642, 1987
100. Pan L, Diss T, Cunningham D, Isaacson PG: The bcl-2 gene
in primary B-cell lymphomas of mucosa associated lymphoid tissue
(MALT). Am J Pathol 135:7, 1989
101. Finn T, Isaacson P, Wotherspoon A: Numerical abnormality
of chromosomes 3,7,12, and 18 in low grade lymphomas of MALT-
type and splenic marginal zone lymphomas detected by interphase
cytogenetics on paraffin embedded tissue. J Pathol 170:335, 1993
102. Hyjek E, Isaacson P: Primary B cell lymphoma of the thyroid
and its relationship to Hashimoto’s thyroiditis. Hum Pathol 19:1315,
1988
103. Hyjek E, Smith W, Isaacson P: Primary B cell lymphoma
of salivary gland and its relationship to myoepithelial sialadentiis
(MESA). Hum Pathol 19:766, 1988
104. Li G, Hansmann M, Zwingers T, Lennert K: Primary
lymphomas of the lung: Morphological, immunohistochemical and
clinical features. Histopathology 16:519, 1990
105. Medeiros L, Harmon D, Linggood R, Hams N: Immunohis-
tologic features predict clinical behavior of orbital and conjunctival
lymphoid infiltrates. Blood 74:2121, 1989
106. Zukerberg L, Ferry J, Southern J, Harris N: Lymphoid infil-
trates of the stomach: Evaluation of histologic criteria for the diagno-
sis of low-grade gastric lymphoma on endoscopic biopsy specimens.
Am J Surg Pathol 14:1087, 1990
107. Cogliatti S, Schmid U, Schumacher U, Eckert F, Hansmann
M-L, Heddrich J, Takahashi H, Lennert K: Primary B-cell gastric
lymphoma: A clinicopathological study of 145 patients. Gastroenter-
ology 101:1159, 1991
108. Sundeen J, Longo D, Jaffe E: CD5 expression in B-cell
small lymphocytic malignancies: Correlations with clinical presenta-
tion and sites of disease. Am J Surg Pathol 16:130, 1992
109. Mattia A, Ferry J, Harris N: Breast lymphoma: A B-cell
spectrum including the low grade B-cell lymphoma of mucosa asso-
ciated lymphoid tissue. Am J Surg Pathol 17:574, 1993
110. Wotherspoon A, Doglioni C, Diss T, Pan L, Moschini A,
de Boni M, Isaacson P: Regression of primary low-grade B-cell
gastric lymphoma of mucosa-associated lymphoid tissue type after
eradication of Helicobacter pylori. Lancet 342:575, 1993
11 1.Cogliatti S, Lennert K, Hansmann M, Zwingers T: Monocyt-
oid B cell lymphoma: Clinical and prognostic features of 21 patients.
J Clin Path01 43:619, 1990
112. Carbone A, Gloghini A, Pinto A, Attadia V, Zagonel V,
Volpe R: Monocytoid B-cell lymphoma with bone marrow and pe-
ripheral blood involvement at presentation. Am J Clin Pathol92:228,
1989
113. Neiman R, Sullivan A, Jaffe R: Malignant lymphoma simu-
lating leukaemic reticuloendotheliosis: A clinicopathologic study of
ten cases. Cancer 43:329, 1979
114. Hollema H, Visser L, Poppema S: Small lymphocytic
lymphomas with predominant splenomegaly: A comparison of im-
1387
munophenotypes with cases of predominant lymphadenopathy. Mod
Pathol 4:712, 1991
115. Falini B, Pileri S, Flenghi L, Liberati M, Stein H, Gerli R,
Minelli 0, Martelli M: Selection of a panel of monoclonal antibodies
for monitoring residual disease in peripheral blood and bone marrow
of interferon-treated hairy cell leukemia patients. Br J Haematol
76:460, 1990
116. Hounieu H, Shashikant C, Saati T, De Mascarel A, Sabattini
E, Pileri S, Falini B, Ralfkiaer E, Le Tourneau A, Selves J, Viogt
J, Laurent G, Diebold J, Delsol G: Hairy cell leukemia: Diagnosis
of bone marrow involvement in paraffin-embedded sections with
monoclonal antibody DBA.44. Am J Clin Pathol 28:26, 1992
117. Moller P, Mielke B, Moldenhauer G: Monoclonal antibody
HML- 1, a marker for intraepithelial T cells and lymphomas derived
thereof, also recognizes hairy cell leukemia and some B-cell lympho-
mas. Am J Pathol 136:509, 1990
118. Visser L, Shaw A, Slupsky J, Vos H, Poppema S: Mono-
clonal antibodies reactive with hairy cell leukemia. Blood 74:320,
1989
119. Moldenhauer G, Mielke B, Dorken B, Schwartz-Albiez R,
Moller P: Identity of HML-1 antigen on intestinal intraepithelial T
cells and of B-ly7 antigen on hairy cell leukaemia. Scand J Immunol
32:77, 1990
120. Flenghi L, Spinozzi F, Stein H, Krushwitz M, Pileri S, Falini
B: LF61: A new monoclonal antibody directed against a trimeric
molecule (150 kD, 125 kD, 105 kD) associated with hairy cell leu-
kaemia. Br J Haematol 76:451, 1990
121. Korsmeyer S, Greene W, Cossman S: Rearrangement and
expression of immunoglobulin genes and expression of Tac antigen
in hairy cell leukemia. Proc Natl Acad Sci USA 80:4522, 1983
122. Spiers A, Moore D, Cassileth P, Hanington D, Cummings
F,Neiman R, Bennett J, O’Connell M: Remissions in hairy-cell
leukemia with Pentostatin (2’-deoxycofomycin). N Engl J Med
316:825, 1987
123. Piro L, Carrera C, Carson D, Beutler E: Lasting remissions
in hairy cell leukemia induced by a single infusion of 2’-chlorodeox-
yadenosine. Cancer 332: 1117, 1990
124. Zukerberg L, Ferry J, Conlon M, Harris N: Plasma cell
myeloma with cleaved, multilobated, and monocytoid nuclei. Am J
Clin Pathol 93:657, 1990
125. Falini B, De Solas I, Levine A, Parker J, Lukes R, Taylor
C: Emergence of B-immunoblastic sarcoma in patient with multiple
myeloma: A clinicopathologic study of 10 cases. Blood 59:923, 1982
126. Moller P, Matthaei-Maurer D, Moldenhauer G: CD30(Ki-I)
antigen expression in a subset of gastric mucosal plasma cells and
in a primary gastric plasmacytoma. Am J Clin Pathol 91:18, 1989
127. Van Camp B, Dune B, Spier C, De Waele M, Van Riet I,
Vela E, Frutiger Y, Richter L, Grogan T: Plasma cells in multiple
myeloma express a natural killer cell-associated antigen: CD56
(NHK-I; Leu-19). Blood 76:377, 1990
128. O’Hara C, Said J, Pinkus G: Non-Hodgkin’s lymphoma,
multilobated B cell type. Hum Pathol 17:593, 1986
129. Stein H, Mason D, Gerdes J, O’Connor N, Wainscoat J,
Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R,
Lennert K: The expression of the Hodgkin’s disease associated anti-
gen Ki-l in reactive and neoplastic lymphoid tissue: Evidence that
Reed-Stemberg cells and histiocytic malignancies are derived from
activated lymphoid cells. Blood 66:848, 1985
130. Ramsay A, Smith W, Isaacson P: T-cell-rich B-cell
lymphoma. Am J Surg Pathol 12:433, 1988
131. Ng C, Chan J, Hui P, Lau W: Large B-cell lymphomas with
a high content of reactive T-cells. Hum Pathol 20:1145, 1989
132. Chittal S, Brousset P, Voigt J, Delsol G: Large B-cell
lymphoma rich in T-cells and simulating Hodgkin’s disease. Histo-
pathology 19:211, 1991
133. Delabie J, Vandenberghe E, Kennes C, Verhoef G , Foschini
1388
M, Stul M, Cassiman J, De Wolf-Peeters C: Histiocyte-rich B-cell
lymphoma. A distinct clinicopathologic entity possibly related to
lymphocyte predominant Hodgkin’s disease, paragranuloma sub-
type. Am J Surg Pathol 16:37, 1992
134. Foucar K, Armitage J, Dick F: Malignant lymphomas, dif-
fuse mixed small and large cell. A clinicopathologic study of 47
cases. Cancer 51:2090, 1983
135. Katzin W, Linden M, Fishleder Aea: Immunophenotypic
and genotypic characterization of diffuse mixed non-Hodgkin’s
lymphomas. Am J Pathol 135:615, 1989
136. Medeiros L, Lardelli P, Stetler-Stevenson M, Longo DL,
Jaffe ES: Genotypic analysis of diffuse, mixed cell lymphomas:
Comparison with morphologic and immunophenotypic findings. Am
J Clin Pathol 95:547, 1991
137. Nathwani B, Metter G, Gams R, Bartolucci A, Hartsock R,
Neiman R, Byrne G, Barcos M,KimH, Rappaport H: Malignant
lymphoma, mixed cell type, diffuse. Blood 62:200, 1983
138. Pins M, Brown D, Gatter K, Mason D: CD30 expression in
non-Hodgkin’s lymphoma. Histopathology 17:211, 1990
139. Pins M, Gatter K, Mason D: CD30 expression in follicular
lymphoma. Histopathology 18:25, 1991
140. Doggett R, Wood G, Homing S, Levy R, Dorfman R, Bindl
J, Warnke R: The immunologic characterization of 95 nodal and
extranodal diffuse large cell lymphomas in 89 patients. Am J Pathol
115:245, 1984
141. Weiss L, Warnke R, Sklar J, Cleary M: Molecular analysis
of the t( 14;18) chromosomal translocation in malignant lymphomas.
N Engl J Med 317:1185, 1987
142. Lipford E, Wright J, Urba W, Whang-Peng J, Kirsch I,
Raffeld M, Cossman J, Logno D, Bakhshi A, Korsmeyer S: Refine-
ment of lymphoma cytogenetics by the chromosome 18q21 major
breakpoint region. Blood 70:1816, 1987
143. Yunis J, Mayer M, Amesen M: bcl-2 and other genomic
alterations in the prognosis of large-cell lymphoma. N Engl J Med
320:1047, 1989
144. Nathwani B, Dixon D, Jones S , Hartsock R, Rebuck J, Byrne
G, Sheehan W, Kim H, Coltman C, Rappaport H: The clinical sig-
nificance of the morphological subdivision of diffuse “histiocytic”
lymphoma: A study of 162 patients treated by the Southwest Oncol-
ogy Group. Blood 60:1068, 1982
145. Kwak L, Wilson M, Weiss L, Homing S, Warnke R, Dorf-
man R: Clinical significance of morphologic subdivision in diffuse
large cell lymphoma. Cancer 68:1988, 1991
146. Addis B, Isaacson P: Large cell lymphoma of the mediasti-
num: A B-cell tumor of probable thymic origin. Histopathology
10:379, I986
147. Lamarre L, Jacobson J, Aisenberg A, Harris N: Primary
large cell lymphoma of the mediastinum. Am J Surg Pathol 13:730,
1989
148. Yousem S, Weiss L, Warnke R: Primary mediastinal non-
Hodgkin’s lymphomas: A morphologic and immunologic study of
19 cases. Am J Clin Pathol 83:676, 1985
149. Moller P, Moldenhauer G, Momburg F, Lammler B, Eber-
lein-Gonska M, Kiesel S , Dorken B: Mediastinal lymphoma of clear
cell type is a tumor corresponding too terminal steps of B cell
differentiation. Blood 69:1087, 1987
150. Scarpa A, Bonetti F, Menestrina F: Mediastinal large cell
lymphoma with sclerosis. Genotypic analysis establishes its B nature.
Virchows Arch [A] 412:17, 1987
151. Levitt L, Aisenberg A, Hams N, Linggood R, Poppema
S : Primary non-Hodgkin’s lymphoma of the mediastinum. Cancer
50:2486, 1982
152. Jacobson J, Aisenberg A, Lamarre L, Willett C, Linggood
R, Miketic L, Harris N: Mediastinal large cell lymphoma: An uncom-
mon subset of adult lymphoma curable with combined modality
therapy. Cancer 62:1893, 1988
HARRIS ET AL
153. Hofmann W, Momburg F, Moller P, Otto H: Intra- and
extrathymic B cells in physiologic and pathologic conditions. Immu-
nohistochemical study on normal thymus and lymphofollicular hy-
perplasia of the thymus. Virchows Arch [A] 412:431, 1988
154. Garcia C, Weiss L, Warnke R: Small noncleaved cell
lymphoma: An immunophenotypic study of 18cases and comparison
with large cell lymphoma. Hum Pathol 17:454, 1986
155. Pelicci P, Knowles D, Magrath I, Dalla-Favera R. Chromo-
somal breakpoints and structural alterations of the c-myc locus differ
in endemic and sporadic forms of Burkitt lymphoma. Proc Natl Acad
Sci USA 83:2984, 1986
156. NeriA, Barriga F, Knowles D, Magrath I, Dalla-Favera
R: Different regions of the immunoglobulin heavy-chain locus are
involved in chromosomal translocations in distinct pathogenetic
forms of Burkitt lymphoma. Proc Natl Acad Sci USA 85:2748, 1988
157. Hamilton-Dutoit S, Pallesen G, Franzmann M, Karkov J ,
Black F, Skinhoj P, Pedersen C: AIDS-related lymphoma. Histopa-
thology, immunophenotype, and association with Epstein-Barr virus
as demonstrated by in situ nucleic acid hybridization. Am J Pathol
138:149, 1991
158. Meeker T, Shiramizu B, Kaplan L, Hemdier B, Sanchez H,
Grimaldi J, Baumgartner J, Rachlin J, Feigal E, Rosenblum M,
McGrath M: Evidence for molecular subtypes of HIV-associated
lymphoma: Division into peripheral monoclonal, polyclonal and cen-
tral nervous system lymphoma. AIDS 5669, 1991
159. Ballerini P, Gaidano G, Gong J, Tassi V, Saglio G, Knowles
D, Dalla-Favera R: Multiple genetic lesions in AIDS-related non-
Hodgkin lymphoma. Blood 81:166, 1993
160.Magrath 1, Shiramizu B: Biology and treatment of small
non-cleaved cell lymphoma. Oncology 3:41, 1989
161. Hutchison R, Murphy S, Fairclough D, Shuster J , Sullivan
M, Link M, Donaldson S, Berard C: Diffuse small noncleaved cell
lymphoma in children, Burkitt’s versus non-Burkitt’s types. Cancer
64:23, 1989
162. Grogan T, Warnke R,Kaplan H: A comparative study of
Burkitt’s and non-Burkitt’s “undifferentiated” malignant lym-
phoma: Immunologic, cytochemical, ultrastructural, cytologic, histo-
pathologic, clinical and cell culture features. Cancer 49:1817, 1982
163. Yano T, van Krieken J, Magrath I, Longo D, Jaffe E, Raffeld
M: Histogenetic correlations between subcategories of small non-
cleaved cell lymphomas. Blood 79:1282, 1992
164. Gouttefangeas C, Bensussan A, Boumsell L Study of the
CD3-associated T-cell receptors reveals further differences between
T-cell acute lymphoblastic lymphoma and leukemia. Blood 74:93 I ,
1990
165. Falini B, Flenghi L, Fagioli M, Martelli M, Pileri S, Grignani
F, Beltrami A, Novero D, Pelicci P: T-lymphoblastic lymphomas
expressing the non-disulfide-linked form of the T-cell receptor.
Blood 74:2501, 1989
166. Bernard A, Boumsell L, Reinherz L, Nadler L, Ritz J , Cop-
pinH, Richard Y,Valensi F, Dausset J, Flandrin G, Lemerle J,
Schlossman S: Cell surface characterization of malignant T cells
from lymphoblastic lymphoma using monoclonal antibodies: Evi-
dence for phenotypic differences between malignant T cells from
patients with acute lymphoblastic leukemia and lymphoblastic
lymphoma. Blood 57:1105, 1981
167. Weiss L, Bindl J, Picozzi V, Link M, Wamke R: Lympho-
blastic lymphoma: An immunophenotype study of 26 cases with
comparison to T cell acute lymphoblastic leukemia. Blood 67:474,
1986
168. Swerdlow S , Habeshaw J, Richards M, Rainey M, Murray
L, Stansfeld A: T lymphoblastic lymphoma withLeu-7 positive
phenotype and unusual clinical course: A multiparameter study.
Leuk Res 9:167, 1985
169. Sheibani K, Winberg C, Burke J: Lymphoblastic lymphoma
CONSENSUSLYMPHOMACLASSIFICATION
expressing natural killer cell-associated antigens: A clinicopatho-
logic study of six cases. Leuk Res 11:371, 1987
170. Sheibani K,Nathwani B, Winberg C: Antigenically defined
subgroups of lymphoblastic lymphoma: Relationship to clinical pre-
sentation and biological behavior. Cancer 60:183, 1987
171. Kitchingman G, Robigatti U, Mauer A, Melvin S, Murphy
S, Stass S: Rearrangement of immunoglobulin heavy chain genes in
T cell acute lymphoblastic leukemia. Blood 65:725, 1985
172. Nathwani B, Diamond L, Winberg C, Kim H, Bearman R,
Click J, Jones S, Gams R, Nissen N, Rappaport H: Lymphoblastic
lymphoma: A clinicopathologic study of 95 patients. Cancer
48:2347, 1981
173. Borowitz M, Dowell B, Boyett J: Clinicopathologic aspects
of E rosette negative T cell acute lymphocytic leukemia: A Pediatric
Oncology Group Study. J Clin Oncol 1986:170, 1986
174. Brouet J, Sasportes M, mandrin G, Preud’homme J, Selig-
mannM: Chronic lymphocytic leukemia of T cell origin. Lancet
25390, 1975
175. Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla
R, Dearden C, Sempere A, Catovsky D: Clinical and laboratory
features of 78 cases of T-prolymphocytic leukemia. Blood 78:3269,
1991
176. Suchi T, Lennert K, Tu L-Y: Histopathology and immuno-
histochemistry of peripheral T-cell lymphomas: A proposal for their
classification. J Clin Pathol 40:995, 1987
177. Knowles D: The human T-cell leukemias: Clinical, cytomor-
phologic, immunophenotypic, and genotypic characteristics. Hum
Pathol 17:14, 1986
178. Aisenberg A, Wilkes B, Harris N, Ault K, Carey R: Chronic
T-cell lymphocytosis with neutropenia: Report of a case studied with
monoclonal antibody. Blood 585318, 1981
179. Loughran T: Clonal diseases of large granular lymphocytes.
Blood 82:1, 1993
180. Agnarsson B, Loughran T, Starkebaum G,Kadin M: The
pathology of large granular lymphocyte leukemia. Hum Pathol
20543, 1989
181. Rambaldi A, Pelicci P, Allavena P, Knowles D, Rossini S,
Bassman R, Barbvi T, Dalla-Favera R, Mantovani A: T-cell receptor
B chain gene rearrangements in lymphoproliferative disorders of
large granular lymphocyteslnatural killer cells. J Exp Med 162:2156,
1985
182. Pelicci P, Allavena P, Alessandro R, Pirelli A, Di Bello M,
Subar M, Knowles D, Dalla-Favera R, Mantovani A: T-cell receptor
(a,P,y) gene rearrangements and expression distinguish large granu-
lar lymphocytelnatural killer cells and T-cells. Blood 70:1500, 1987
183. Colby T, Burke J, Hoppe R: Lymph node biopsy in mycosis
fungoides. Cancer 47:351, 1981
184. Burke J, Khalil S, Rappaport H: Dermatopathic lymphade-
nopathy. An immunophenotypic comparison of cases associated and
unassociated with mycosis fungoides. Am J Pathol 123:256, 1986
185. Ralfkiaer E, Wantzin G, Mason D, Hou-Jensen K, Stein H,
Thomsen K: Phenotypic characterization of lymphocyte subsets in
mycosis fungoides. Am J Clin Pathol 84:610, 1985
186. Aisenberg A, Krontiris T, Mak T, Wilkes B: The gene for
the beta chain of the T-cell receptor is rearranged in mycosis fun-
goides and dermatopathic lymphadenopathy. N Engl J Med 313:529,
1985
187. Weiss L, Hu E, Wood G, Moulds C , Cleary M, Warnke R,
Sklar J: Clonal rearrangements of T cell receptor genes in mycosis
fungoides and dermatopathic lymphadenopathy. N Engl J Med
313539, 1985
188. Davis T, Morton C, Miller-Cassman R, Balk S, KadinM:
Hodgkin’s disease, lymphomatoid papulosis, and cutaneous T-cell
lymphoma derived from a common T-cell clone. N Engl J Med
326:1115, 1992
189. Chott A, Augustin I, Wra F, Hanak H, Ohlinger W, Radasz-
1389
kiewicz T: Peripheral T-cell lymphomas-A clinicopathologic study
of 75 cases. Hum Pathol 21: 11 17, 1990
190. Weisenburger D, Linder J, Armitage J: Peripheral T cell
lymphoma. A clinicopathologic study of 42 cases. Hematol Oncol
5:175, 1987
191. Borowitz M, Reichert T, Brynes R, Cousar J, Whitcomb C,
Collins R, Crissman J, Byrne G: The phenotypic diversity of periph-
eral T-cell lymphomas. The Southeastern Cancer Study Group expe-
rience. Hum Pathol 17567, 1986
192. Hastrup N, Hamilton-Dutoit S, Ralfkiaer E, Pallesen G: Pe-
ripheral T-cell lymphomas: An evaluation of reproducibility of the
updated Kiel classification. Histopathology 18:99, 1991
193. Weiss L, Crabtree G, Rouse R, Warnke R: Morphologic and
immunologic characterization of 50 peripheral T-cell lymphomas.
Am J Pathol 118:316, 1985
194. Patsouris E, Noel H, Lennert K: Histological and immuno-
histological findings in lymphoepithelioid cell lymphoma (Lennert’s
lymphoma). Am J Surg Pathol 12:341, 1988
195. KimH, Jacobs C, Warnke R, Dorfman R: Malignant
lymphoma with a high content of epithelioid histiocytes: A distinct
clinicopathologic entity and a form of so-called “Lennert’s
lymphoma.” Cancer 41:620, 1978
196. Farcet J, Gaulard P, Marolleau J, Le Couedic J, Henni T,
Gourdin M, Divine M, Haioun C, Zafrani S, Goossens M, Hercend
T, Reyes F Hepatosplenic T-cell lymphoma: Sinusahinusoidal lo-
calization of malignant cells expressing the T-cell receptor 76.Blood
752213, 1990
197. Gonzalez C, Medeiros L, Braziel R, Jaffe E: T-cell
lymphoma involving subcutaneous tissue: A clinicopathologic entity
commonly associated with hemophagocytic syndrome. Am J Surg
Pathol 15:17, 1991
198. Strickler J, Weiss L, Copenhaver C, Bindl J, McDaidR,
Buck D, Warnke R: Monoclonal antibodies reactive in routinely
processed tissue sections of malignant lymphoma, with emphasis on
T-cell lymphomas. Hum Pathol 18:808, 1987
199. Hastrup N, Ralfkiaer E, Pallesen G: Aberrant phenotypes in
peripheral T cell lymphomas. J Clin Pathol 42:398, 1989
200. Said J, Shintaku P, Parekh K, Pinkus G: Specific phenotyp-
ing of T-cell proliferations in formalin-fixed paraffin-embedded tis-
sues. Use of antibodies to the T-cell receptor PFI . Am J Clin Pathol
93:382, 1990
201. Cabacadas J, Isaacson P: Phenotyping of T-cell lymphomas
inparaffin sections-Which antibodies? Histopathology 19:419,
1991
202. Weiss L, Trela M, Cleary M, Turner R, Warnke R, Sklar J:
Frequent immunoglobulin and T cell receptor gene rearrangement
in “histiocytic” neoplasms. Am J Pathol 121:369, 1985
203. Weiss L, Picker L, Grogan T, Warnke R, Sklar J: Absence
of clonal beta and gamma T-cell receptor gene rearrangements in a
subset of peripheral T-cell lymphomas. Am J Pathol 130:436, 1988
204. Falini B, Pileri S, De Solas I, Martelli M, Mason D, Delsol
G, Gatter K, Fagioli M: Peripheral T-cell lymphoma associated with
hemophagocytic syndrome. Blood 75:434, 1990
205. Chott A, Dragosics B, Radaszkiewicz T: Peripheral T-cell
lymphomas of the intestine. Am J Patbol 141:1361, 1992
206. Armitage J, Greer J, Levine A, Weisenburger D, Formenti
S, Bast M, Conky S, Pierson J, Linder J: Peripheral T-cell
lymphoma. Cancer 63:158, 1989
207. Lippman S, Miller T, Spier C, Slymen D, Grogan T: The
prognostic significance ofthe immunotype in diffuse large-cell
lymphoma: A comparative study of the T-cell and B-cell phenotype.
Blood 72:436, 1988
208. Coiffier B, Brousse N, Peuchmaur M, Berger F, Gisselbrecht
C, Bryon P, Diebold J: Peripheral T-cell lymphomas have a worse
prognosis than B-cell lymphomas: A prospective study of 361 immu-
1390
nophenotyped patients treated with the LNH-84 regimen. Ann Oncol
1:45, 1990
209. Frizzera G, MoranE, Rappaport H: Angio-immunoblastic
lymphadenopathy with dysproteinemia. Lancet 1: 1070, 1974
210. Feller A, Griesser H, Schilling C, Wacker H, Dallenbach F.
Bartels H, Kuse R, Mak T, Lennert K: Clonal gene rearrangement
patterns correlate with immunophenotype and clinical parameters in
patients with angioimmunoblastic lymphadenopathy. Am J Pathol
I33:549, I988
21 I . Patsouris D,Noel H, Lennert K: AILD type of T-cell
lymphoma with a high content of epithelioid cells. Histopathology
and comparison with lymphoepithelioid cell lymphoma. Am J Surg
Pathol 13:161, 1989
212. Weiss L, Strickler J, Dorfman R, Horning S, Warnke R,
Sklar J: Clonal T-cell populations in angioimmunoblastic lymphade-
nopathy and angioimmunoblastic lymphadenopathy-like lymphoma.
Am J Pathol 122:392, 1986
2 13. Anagnostopoulos 1, Hummel M, Finn T, Tiemann M, Korb-
juhn P, Dimmler C, Gatter K, Dallenbach F, Parwaresch M, Stein
H: Heterogeneous Epstein-Barr virus infection patterns in peripheral
T-cell lymphoma of angioimmunoblastic lymphadenopathy type.
Blood 80:1804, 1992
214. Weiss L, Jaffe E, Liu X, Chen Y, Shibata D, Medeiros L:
Detection and localization of Epstein-Barr viral genomes in angioim-
munoblastic lymphadenopathy and antioimmunoblastic lymphade-
nopathy-like lymphomas. Blood 79: 1789, 1992
215. Schlegelberger B, Feller A, Godde W, Lennert K: Stepwise
development of chromosomal abnormalities in angioimmunoblastic
lymphadenopathy. Cancer Genet Cytogenet SO: 15, 1990
216. Jaffe E: Post-thymic lymphoid neoplasia, in Jaffe E (ed):
Surgical Pathology of the Lymph Nodes and Related Organs, Major
Problems in Pathology, 16. Philadelphia, PA, Saunders, 1985, p 218
217. Lipford E, Margolich J, Longo D, Fauci A, Jaffe E: Angio-
centric immunoproliferative lesions: A clinicopathologic spectrum
of post-thymic T cell proliferations. Blood 5:1674, 1988
218. Guinee D, Kingma D, Fishback N,Krishnan J, Moran C,
Frizzera G, Travis W, Jaffe E, KossM: Pulmonary lesions with
features of lymphomatoid granulomatosis/angiocentric immunoprol-
iferative lesion (LYG/AIL); evidence for Epstein-Barr virus within
B lymphocytes (abstract). Mod Pathol 7:151, 1994
219. Ho F, Choy D, Loke S, Kung 1, Fu K, Liang R, Todd D,
Khoo R: Polymorphic reticulosis and conventional lymphomas of
the nose and upper aerodigestive tract-A clinicopathologic study
of 70 cases, and immunophenotypic studies of 16 cases. Hum Pathol
21:1041, 1990
220. Ferry J, Sklar J, Zukerberg L, Harris N: Nasal lymphoma:
A clinicopathologic studywith immunophenotypic and genotypic
analysis. Am J Surg Pathol 15:268, 1991
221. Chan J, Ng C, Lau W, Ho S: Most nasahasopharyngeal
lymphomas are peripheral T cell neoplasms. Am J Surg Pathol
1 l:418, 1987
222. Medeiros L, Peiper S, Elwood L, Yano T, Rafeld M, Jaffe
E: Angiocentric immunoproliferative lesions: A molecular analysis
of eight cases. Hum Pathol 22:l 150, 1991
223. Ho F, Srivastava G, Loke S, Fu K, Leung B, Liang R, Choy
D: Presence of Epstein-Barr virus DNA in nasal lymphomas of B
and T cell type. Hematol Oncol 8:271, 1990
224. Soler J, Bordes R, Ortuni F, Montagud M, Martorell J, Pons
C, Nomededeu J, Lopez-Lopez J, Prat J, Rutllant M: Aggressive
natural killer cell leukaemidlymphoma in two patients with lethal
midline granuloma. Br J Haematol 86:659, 1994
225. lsaacson P, Spencer J, Connolly C, Pollock D, Stein H,
O’Connor N, Bevan D, Kirkham N. Wainscoat J, Mason D: Malig-
nant histiocytosis of the intestine: A T-cell lymphoma. Lancet 2:688,
1985
226. Spencer J, Cerf-Bensussan N, Jarry A, Guy-Grand D,
HARRIS ET AL
Brousse N, Krajewski M, lsaacson P: Enteropathy-associated T-cell
lymphoma is recognized by a monoclonal antibody (HML-l) that
defines a membrane molecule on human mucosal lymphocytes. Am
J Pathol 132:1, 1988
227. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H:
Adult T-cell leukemia: Clinical and hematologic features of 16 cases.
Blood 50:481, 1977
228. Poiesz B, Ruscetti F, Gazdar A: Detection and isolation of
type C retrovirus particles from fresh and cultured lymphocytes of
a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA
77:7415, 1980
229. Tokunaga M, Sato E: Non-Hodgkin’s lymphomas in a south-
em prefecture in Japan: An analysis of 715 cases. Cancer 46: 1231,
I980
230. Yamada Y: Phenotypic and functional analysis of leukemic
cells from 16 patients with adult T cell leukemia/lymphoma. Blood
61:192, 1983
23 l . Jaffe E, Blattner W, Blayney D, Bunn P, Cossman J, Robert-
Guroff M, Gallo R: The pathologic spectrum of adult T-cell leuke-
midlymphoma in the United States. Am J Surg Pathol 8:263, 1984
232. Swerdlow S, Habeshaw J, Rohatiner A, Lister T, Stansfeld
A: Caribbean T-cell lymphomdleukemia. Cancer 54:687, 1984
233. Duggan D, Ehrlich G, Davey F, Kwok S, Sninsky 1, Gold-
berg J, Baltrucki L, Poiesz B: HTLV-I induced lymphoma mimick-
ing Hodgkin’s disease. Diagnosis by polymerase chain reaction am-
plification of specific HTLV-I sequences in tumor DNA. Blood
71:1027, 1988
234. Chadburn A, Athan E, Wieczorek R, Knowles D: Detection
and characterization of HTLV-I associated T neoplasms inan
HTLV-I non-endemic region by polymerase chain reaction. Blood
70: 1500, I99 1
235. Kikuchi M, Mitsui T, Takeshta M, Okamura H, Naitoh H,
Eimoto T: Virus associated adult T-cell leukemia (ATL) in Japan:
Clinical, histological and immunological studies. Hematol Oncol
4:67, 1987
236. Abrams M, Sidawy M, Novich M: Smoldering HTLV-asso-
ciated T-cell leukemia. Arch Intern Med 145:2257, 1985
237. Delsol G, AI Saati T, Gatter K, Gerdes J, Schwarting R,
Caveriviere P, Rigal-Huguet F, Robert A, Stein H, Mason D: Coex-
pression of epithelial membrane antigen (EMA), Ki-l, and interleu-
kin-2 receptor by anaplastic large cell lymphomas: diagnostic value
in so-called malignant histiocytosis. Am J Pathol 13059, 1988
238. Pileri S, Falini B, Delsol G, Stein H, Baglioni P, Poggi S,
Martelli M, Rivano M, Mason D, Stansfeld A: Lymphohistiocytic
T-cell lymphoma (anaplastic large cell lymphoma CD30+/Kil+)
with a high content of reactive histiocytes. Histopathology 16:383,
l990
239. Kinney M, Collins R, Greer J, Whitlock J, Sioutos N, Kadin
M: A small-cell-predominant variant of primary Ki-l (CD30)+ T-
cell lymphoma. Am J Surg Pathol 17:859, 1993
240. Headington J, Roth M, Schnitzer B: Regressing atypical
histiocytosis: A review and critical appraisal. Semin Diagn Pathol
4:29, 1987
241. Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B,
Durkop H, Eitelbach F, Thiele J, Pacini R, Cavaliere N, Sabattni M,
Poggi S, Stein H: PG-MI:A new monoclonal antibody directed
against a fixative-resistantepitope on the macrophage-restricted form
of the CD68 molecule. Am J Pathol 142:1359, 1993
242. Falini B, Pileri S, Stein H, Dienemann D, Dallenbach F,
Delsol G, Minelli 0, Poggi S, Martelli M, Pallesen G, Palestro G:
Variable expression of leucocyte-common (CD45)antigen in CD30
(Ki l)-positive anaplastic large-cell lymphoma: Implications for the
differential diagnosis between lymphoid andnonlymphoid malig-
nancies. Hum Pathol 21:624, 1990
243. Leoncini L, Del Vecchio M, Kraft R, Megha T, Barbini P,
Cevenini G, Poggi S, Pileri S, Tosi P, Cottier H: Hodgkin’s disease
CONSENSUS LYMPHOMA CLASSIFICATION
and CD30-positive anaplastic large cell lymphomas-A continuous
spectrum of malignant disorders. Am J Pathol 137:1047, 1990
244. Rosso R, Paulli M, Magrini U, Kind1 S, Boveri E, Volpato
G, Poggi S, Baglioni P: Anaplastic large cell lymphoma, CD30lK-
1 positive, expressing the CDISLeu-Ml antigen. Immunohisto-
chemical and morphological relationships to Hodgkin’s disease. Vir-
chow’s Arch [A] 416:229, 1990
245. Delsol G, Blancher A, A1 Saati T, Ralfkiaer F, Lauritzen A,
Bruigeres L, Brousset P, Rigal-Huguet F, Mazerolles C, Robert A,
Chittal S: Antibody BNH9 detects redblood cell-related antigens
on anaplastic large cell (CD30+) lymphomas. Br J Cancer 64:321,
1991
246.deBruinP, Beljaards R, van Heerde P, van der Valk P,
Noorduyn L, van Krieken J, Kluin-Nelemans J, Willemze R, Meijer
C: Differences in clinical behaviour and immunophenotype between
primary cutaneous and primary nodal anaplastic large cell lymphoma
of T-cell or null cell phenotype. Histopathology 23: 127, 1993
247. Mason D, Bastard C, Rimokh R, Dastugue N, Huret J, Kris-
toffersson U, Magaud J, NezelofC. Tilly H, Vannier J: CD30-
positive large cell lymphomas (“Ki-l lymphoma”) are associated
with a chromosomal translocation involving 5q35. Br J Haematol
74:161, 1990
248. O’Connor N, Stein H, Falini B, Gatter K, Mason D: Geno-
typic analysis of large cell lymphomas which express the Ki-l anti-
gen. Histopathology I1:733, 1987
249. Herbst H, Tippelmann G, Anagnostopoulos I, Gerdes J,
Schwarting R, Boehm T, Pileri S, Jones D, Stein H: Immunoglobulin
and T cell receptor gene rearrangements in Hodgkin’s disease and
Ki- 1 -positive anaplastic large cell lymphoma: Dissociation between
phenotype and genotype. Leuk Res 13:103, 1989
250. Agnarsson B, Kadin M: Ki-l positive large cell lymphoma:
A morphologic and immunologic study of 19 cases. Am J Surg
Pathol 12:264, 1988
25 I. Kaudewitz P, Stein H, Dallenbach F: Primary and secondary
Ki-l + (CD30+) anaplastic large cell lymphomas. Am J Pathol
135:359, 1989
252. Greer J, Kinney M, Collins R, Salhany K, Wolff S, Hains-
worth J, Flexner J, Stein R: Clinical features of 31 patients with Ki-
1 anaplastic large-cell lymphoma. J Clin Oncol 9539, 1991
253. Andreesen R, Osterholz J, Lohr G, Bross K: A Hodgkin cell-
specific antigen is expressed on a subset of auto- and alloactivated T
(helper) lymphoblasts. Blood 63: 1299, 1984
254. Pileri S, Mazza P, Zinzani P, Poggi L, Poletti G, Tuta S,
Falini B: Ki-l lymphoma and Hodgkin’s disease (letter). Haemato-
logica (Pavia) 74:333, 1989
255. Stein H, Herbst H, Anagnostopoulos I, Niedobitek G , Dal-
lenbach F, Kratzsch H-C: The nature of Hodgkin and Reed-Sternberg
cells, their association with EBV, and their relationship to anaplastic
large-cell lymphoma. Ann Oncol 233, 1991 (suppl 2)
256. Pileri S, Bocchia M, Baroni C, Martelli M, Falini B, Sabat-
tini E, Gherlinzoni F, Amadori S, Poggi S, Mazza P, Burgio V,
Zinzani P, Melilli G, Binni M, Saragoni L, Martelli M, Stein H,
Mandelli F, Tura S: Anaplastic large cell lymphoma (CD30+/Ki-
I +): Results o f a prospective clinicopathologic study of 69 cases.
Br J Haematol 86:s 13, 1994
257. Lukes R, Butler J, Hicks E: Natural history of Hodgkin’s
disease as related to its pathological picture. Cancer 19:317, 1966
258. Lennert K, Mohri N: Histologische Klassifizierung and Vor-
kommen des M. Hodgkin. Internist 1557, 1974
259. Mason D, Banks P, Chan J, Cleary M, Delsol G, De Wolf-
Peeters C, Falini B, Gatter K, Grogan T, Hams N, Isaacson P, Jaffe
E, Knowles D, Muller-Hermelink H-K, Pileri S, Piris M, Stein H,
Ralfkaier E, Warnke R: Hodgkin’s disease, lymphocyte predomi-
nance type, nodular (nodular paragranuloma). Am J Surg Pathol
1994 (in press)
260. Pinkus G, Said J: Hodgkin’s disease, lymphocyte predomi-
1391
nance type, nodular-Further evidence for a B cell derivation: L&
H variants of Reed-Sternberg cells express L26, a pan B cell marker.
Am J Pathol 133211, 1988
261. Schmid C, Sargent C, Isaacson P: L and H cells of nodular
lymphocyte predominant Hodgkin’s disease show immunoglobulin
light-chain restriction. Am J Pathol 139:1281, 1991
262. Coles F, Cartun R, Pastuszak W: Hodgkin’s disease, lym-
phocyte-predominant type: Immunoreactivity with B-cell antibodies.
Mod Pathol 1:274, 1988
263. Pinkus G, Said J: Hodgkin’s disease, lymphocyte predomi-
nance type, nodular-A distinct entity? Unique staining profile of
L&H variants of Reed-Sternberg cells defined by monoclonal anti-
bodies to leukocyte common antigen, granulocyte specific antigen,
and B-cell specific antigen. Am J Pathol 116:1, 1985
264. Timmens W, Visser L, Poppema S: Nodular lymphocyte
predominance type of Hodgkin’s disease is a germinal center
lymphoma. Lab Invest 54:457, 1986
265. Chittal S, Caveriviere P, Schwarting R, Gerdes J, AI Saati
T, Rigal-Huguet F, Stein H, Delsol G: Monoclonal antibodies in the
diagnosis of Hodgkin’s disease. The search for a rational panel. Am
J Surg Pathol 12:9, 1988
266. Burns B, Colby T, Dorfman R: Differential diagnostic fea-
tures of nodular L&H Hodgkin’s disease, including progressive
transformation of germinal centers. Am J Surg Pathol 8:253, 1984
267. Poppema S: The diversity of the immunohistological stain-
ing pattern of Sternberg-Reed cells. J Histochem Cytochem 28:788,
1980
268. Stein H, Hansmann M, Lennert K, Brandtzaeg P, Gatter
K, Mason D: Reed-Sternberg and Hodgkin cells in lymphocyte-
predominant Hodgkin’s disease of nodular subtype contain J chain.
Am J Clin Pathol 86:292, 1986
269. Said H, Sassoon A, Shintaku I, Kurtin P, Pinkus G : Absence
of bcl-2 major breakpoint region and Jh gene rearrangement in lym-
phocyte predominance Hodgkin’s disease: Results of Southern blot
analysis and polymerase chain reaction. Am J Pathol 138261, 1991
270. Weiss L, Chen Y, Liu X, Shibata D: Epstein-Barr virus and
Hodgkin’s disease: A correlative in situ hybridization and polymer-
ase chain reaction study. Am J Pathol 139:1259, 1991
27 I . Regula D, Hoppe R, Weiss L: Nodular and diffuse types of
lymphocyte predominance Hodgkin’s disease. N Engl J Med
318:214, 1988
272. Bennett M, MacLennan K, Hudson G, Hudson B:Non-
Hodgkin’s lymphoma arising in patients treated for Hodgkin’s dis-
ease in the BNLI: A 20-year experience. AnnOncol 233, 1991
(SUPPI 2)
273. Sundeen J, Cossman J, Jaffe E: Lymphocyte predominant
Hodgkin’s disease, nodular subtype with coexistent “large cell
lymphoma.” Histological progression or composite malignancy?
Am J Surg Pathol 12599, 1988
274. Hansmann M, Stein H, Fellbaum C, Hui P, Panvaresch M,
Lennert K: Nodular paragranuloma can transform into high-grade
malignant lymphoma of B type. Hum Pathol 20:1169, 1989
275. MacLennan K, Bennett M,TuA, Hudson B, Easterling J,
Hudson G, Jelliffe A: Relationship of histopathologic features to
survival and relapse in nodular sclerosing Hodgkin’s disease. Cancer
64:1686, 1989
276. Ferry J, Linggood R, Convery K, Efird J, Eliseo R, Harris N:
Hodgkin’s disease, nodular sclerosis type: Implications of histologic
subclassification. Cancer 71 :457, 1993
277. Strickler J, Michie S, Warnke R, Dorfman R: The “syncytial
variant” of nodular sclerosing Hodgkin’s disease. Am J Surg Pathol
I0:470, I986
278. Dorfman R, Gatter K, Pulford K, Mason D: An evaluation
of the utility of anti-granulocyte and anti-leukocyte monoclonal anti-
bodies in the diagnosis of Hodgkin’s disease. Am J Pathol 123508,
1986
1392
279. Falini B, Stein H, Pileri S, Ribacchi R, Canino S , Martelli
M, Grignani F, Ciani C, Minelli0 , Fagioli M, MoriA: Expression of
T-cell antigens on Hodgkin’s and Sternberg-Reed cells of Hodgkin’s
disease. A combined immunocytochemical and immunohistological
study using monoclonal antibodies. Histopathology 12: 129, 1987
280. Kadin M, Muramoto L, Said J: Expression of T cell antigens
on Reed-Stemberg cells in a subset of patients with nodular sclerosis
and mixed cellularity Hodgkin’s disease. Am J Pathol 130:345, 1988
28 I . Zukerberg L, Collins A, Ferry J , Harris N: Coexpression of
CD15 and CD20 by Reed-Sternberg cells in Hodgkin’s disease. Am
JPathol139:475,1991
282.SchmidC, Pan L, Diss T, Isaacson P: Expression of B-
cell antigens by Hodgkin’s and Reed-Stemberg cells. Am J Pathol
139:701, 1991
283. Weiss L, Strickler J, Hu E, Warnke R, SklarJ: Immunoglob-
ulin gene rearrangements in tissues involved by Hodgkin’s disease.
Hum Pathol 17:1006,1986
284.GriesserH,Feller A, Mak T, Lennert K: Clonal re-
arrangement of T-cell receptor and immunoglobulin genes and im-
mune phenotypic antigen expressionin different subclasses of Hodg-
kin’s disease. Int J Cancer 40:157, 1988
285. Knowles D, Neri A, Pelicci P, Burke J, Wu A, Winberg C,
Sheibani K, Dalla-FaveraR:ImmunoglobulinandT-cellreceptor
beta-chain gene rearrangement analysis of Hodgkin’s disease: Impli-
cationsforlineagedeterminationanddifferentialdiagnosis.Proc
Natl Acad Sci USA 83:7942, 1986
286. Sundeen J, Lipford E, Uppenkamp J, Sussman W. Wall L,
Raffeld M, Cossman J: Rearranged antigen receptor genes in Hodg-
kin’s disease. Blood 70:96, 1987
287. Jacobson J, Wilkes B, Harris N: T cell receptor genes are
polyclonally rearranged in Hodgkin’s disease: Implications for diag-
nosis. Mod Pathol 4:172, 1991
288. Anagnostopoulos I, Herbst H, Niedobitek G, Stein H: Dem-
onstration of monoclonal EBV genomes in Hodgkin’s disease and
HARRIS ET AL
Ki-l-positive anaplastic large cell lymphoma by combined Southern
blot and in situ hybridization. Blood 74:810, 1989
289. Brousset P, Chittal S, Schlaifer D, kart J, Payen C, Rigan-
Huguet F, Voigt J, Delsol G: Detection of Epstein-Barr virus messen-
ger RNA in Reed-Sternberg cells of Hodgkin’s disease byin h i t u
hybridization with biotinylated probes on specially processed modi-
fied acetone methyl benzoate xylene (ModAmeX) sectionb. Blood
77:1781,1991
290. Herbst H, Dallenbach F, Hummel M, Niedobotek G, Pileri
S , Muller-Lantzsch N, Stein H: Epstein-Barr virus latent membrane
protein expression in Hodgkin and Reed-Stemberg cells. Proc Natl
Acad Sci USA 88:4766, 199 1
291. Stetler-Stevenson M, Crush-Stanton S, Cossman J: Involve-
ment of thebcl-2gene in Hodgkin’sdisease. J Natl Cancerlnst
82:855,1990
292. Athan E, Chadburn A, Knowles D: The bcl-2 gene transloca-
tion is undetectable in Hodgkin’s disease by Southem blot hybridiza-
tion and polymerase chain reaction. Am J Pathol 141:193, 1992
293. Poppema S , Kaleta J, Hepperle B: Chromosomal abnormalit-
ies in PatientswithHodgkin’sdisease:Evidenceforfrequent
involvement of the 14q chromosomalregion but infrequentbcl-2
generearrangements in Reed-Stembergcells. J Natl Cancer Inst
84: 1789, 1992
294. Pelstring R, Zellmer R, Sulak L, Banks P, Clare N: Hodg-
kin‘sdisease in association with humanimmunodeficiencyvirus
infection. Cancer 67:1865, 1991
295. Kant J, Hubbard S, Longo D, Simon R, DeVita V, Jaffe E:
The pathologic and clinical heterogeneity of lymphocyte-depleted
Hodgkin’s disease. J Clin Oncol 4:284, 1986
296. Sheibani K, Nathwani B, Swartz W, Ben-Ezra J, Brownell
M, Burke J , Kennedy J, KooC, WinbergC: Variability in interpreta-
tion of immunohistologic findings in lymphoproliferative disorders
by hematopathologists. A comprehensive statistical analysisof inter-
observer performance. Cancer 62:657, 1988