Annals of Oncology 11 (Suppl 1): S17-S21, 2000.
© 2000 Khmer Academic Publishers. Printed in the Netherlands
Symposium article
Cutaneous lymphomas: A proposal for a unified approach to classification
using the R.E.A.L./WHO Classification*
E. S. Jaffe,1 C. A. Sander2 & M. J. Flaig2
1
Hemalopathology Section, Laboratory of Pathology, National Cancer Institute. Bethesda, MD, USA; 2 Department of Dermatology,
Ludwig-Maximilians- Universitaet, Munich, Germany
anatomic sites. While the EORTC Classification for cutaneous
lymphomas attempts to emphasize certain aspects of these
Background: The classification of cutaneous lymphomas has neoplasms of importance to dermatologists, the use of multibeen controversial. The EORTC has proposed that conven- ple classification systems is a step backward, and may lead to
tional classification schemes are not suitable for cutaneous confusion among hematologists/oncologists, and dermatologists. Nevertheless, cutaneous lymphomas often have a more
lymphomas, and that a unique classification system is required.
Design: The authors review the suitability of the R.E.A.L. indolent natural history than nodal lymphomas, and may
Classification for cutaneous lymphomas, and compare it with require different therapeutic approaches. Clinical features are
the newly proposed EORTC system. The priniciples of the an important prognostic factor and should be utilized in guiding
R.E.A.L. Classification have been adopted by the WHO com- therapy. For cutaneous lymphomas the presence or absence of
mittees for the classification of hematopoietic and lymphoid systemic spread is particularly important. Additionally, the site
neoplasms. Each disease is defined as a distinct entity based on of origin is often important in the definition of disease entities.
Conclusions: Organ-specific classification schemes, such as
an integration of morphology, immunophenotypic and genetic
features, clinical presentation and course, and normal cellular the EORTC Classification for cutaneous lymphomas, are not
counterpart. If either primary or secondary involvement of the required, and indeed may impede the recognition of common
skin is a constant factor, this aspect is considered integral to features of diseases involving multiple anatomic sites. A common classification system, such as the R.E.A.L./WHO Classidisease definition.
Results: Organ-specific classification schemes may impede fication, should be utilized for all lymphomas, regardless of the
the recognition of common features of diseases involving site of origin.
multiple anatomic sites. For example, cutaneous marginal zone
B-cell lymphomas (formerly designated cutaneous immuno- Key words: cutaneous lymphoma, lymphoma, R.E.A.L. Classicytomas) mirror the features of MALT lymphomas in other fication, skin
Summary
Introduction
The classification of malignant lymphomas has been
controversial for many years. In the 1970s, several
schemes were proposed in an attempt to incorporate the
new information that was being derived about the immune system. While the Working Formulation was proposed as an interim compromise approach, it became
the de facto classification system in use in the US [1].
The Kiel Classification remained in widespread use in
Europe and Asia [2]. The absence of a standardized
internationally accepted classification system impeded
both biological and clinical studies of the malignant
lymphomas, since neither clinical data nor basic laboratory studies could be readily compared among institutions.
In the past 15-20 years, much has been learned about
the immunophenotypic features and genetics of the
malignant lymphomas. Through international cooperation and study, a consensus gradually emerged regarding
most lymphoma entities. The International Lymphoma
Study Group (I.L.S.G.) acted upon this emerging consensus to propose a new classification system, termed
the Revised European-American Classification of Lymphoid Neoplasms or R.E.A.L. Classification [3]. It proposed that lymphomas should be viewed as a group of
individual diseases, and that each disease can be defined
by a constellation of morphological, biological and
clinical features.
Importantly, in relation to the subject of cutaneous
lymphomas, it was appreciated that the site of presentation was often a signpost for underlying biological
distinctions, and that extranodal lymphomas were not
equivalent to their nodal counterparts. For example,
many extranodal lymphomas, including many cutaneous
B-cell lymphomas, have common features identifying
* The US Government's right to retain a non-exclusive, royalty-free licence in and to any copyright is acknowledged.
18
them as part of the spectrum of marginal zone B-cell
lymphomas of mucosal-associated lymphoid tissues, socalled MALT-lymphomas [4-8]. Similarly, for some
lymphomas cutaneous involvement is an essential part
of the definition of the disease, such as mycosis fungoides.
The R.E.A.L. Classification was based on the building
of consensus through the input of 19 expert hematopathologists with a primary interest in lymphoma.
Moreover, it relied on previously published biological,
pathological and clinical studies, rather than on theoretical and untested proposals. Following its publication,
an international study directed by Dr J. Armitage
sought to determine if the R.E.A.L. Classification could
be readily applied by a group of independent expert
pathologists. Other goals of the international lymphoma
classification project were: 1) to determine the role of
immunophenotyping and clinical data in the diagnosis
of disease entities; 2) to determine both intraobserver
and interobserver reproducibility in the diagnosis of
the various entities; 3) to further investigate the clinical
features and/or epidemiology of the various entities; and
4) to determine if clinical groupings would be practical
or useful for clinical trials or practice. The conclusions
of that study affirmed the principles of the R.E.A.L.
Classification [9].
We propose that the principles of the R.E.A.L. Classification are applicable to cutaneous lymphomas. Moreover, organ-specific classification schemes are not required, and indeed may impede the recognition of
common features of diseases involving multiple anatomic sites. While we recognize that the EORTC Classification for cutaneous lymphomas attempts to emphasize
certain aspects of these neoplasms of importance to
dermatologists, the use of multiple classification systems
is a step backward, and may lead to confusion among
hematologists/oncologists, and dermatologists [10].
Nevertheless, cutaneous lymphomas in many instances are distinct. Their natural history is often more
indolent than nodal lymphomas, and for that reason
they often require different therapeutic approaches. We
agree with the efforts of the EORTC Classification to
emphasize the unique clinical aspects of many cutaneous
lymphomas, as this recognition is essential for appropriate clinical management.
Application of the R.E.A.L./WHO Classification to
cutaneous lymphomas
The R.E.A.L. Classification agreed with the Kiel Classification and other immunologically based schemes that
lineage must be the starting point for any classification
of lymphoid malignancies [2, 3]. While B-cell and T-cell
lymphomas represent the vast majority of tumors, NICcell lymphomas and leukemias also exist [11]. For any cell
lineage, the R.E.A.L. Classification distinguishes between precursor and mature lymphoid cells. Each disease
is defined utilizing the following features: morphology,
Table 1 B-cell lymphomas with frequent cutaneous involvement.
Follicular lymphoma (primary or secondary)
Cutaneous marginal zone B-cell (MALT-type) lymphoma (primary or
secondary)
Large B-cell lymphoma (primary or secondary)
Variants
Centroblastic
Immunoblastic
T-cell rich B-cell lymphoma
B-large cell anaplastic lymphoma
Intravascular large B-cell lymphoma
Precursor B-cell lymphoblastic lymphoma/leukemia
immunophenotype including stage of differentiation,
genotype, etiology, epidemiology and clinical behavior.
In contrast to the Kiel Classification and the Working
Formulation, lymphomas and leukemias are not stratified according to cytologic grade or expected clinical
behavior. Alternatively, it is recognized that many
entities exhibit a range of both cytologic grade and
clinical behavior. Moreover, cytologic grade is not always
predicative of clinical outcome. For example, angioimmunoblastic T-cell lymphoma was considered of low
cytologic grade in the Kiel Classification, but it generally has an aggressive course with a median survival of
under three years [12, 13]. Departing from prior classification schemes for only non-Hodgkin's lymphomas,
Hodgkin's disease is included in the classification as a
lymphoid malignancy.
The R.E.A.L. Classification was not regarded as a
final document, but recognized that a classification
system must undergo continuous revision as knowledge
advances. The proposed WHO Classification of hematopoietic and lymphoid malignancies is based on the
R.E.A.L. Classification, and incorporates revisions or
clarifications based on new information [14]. Entities
listed as provisional in the original R.E.A.L. Classification have been either retained or eliminated, based on
recent studies.
In addition, the development of the WHO Classification permitted a broadening of the consensus that led to
the R.E.A.L. Classification. More than 50 expert hematopathologists and hematologists have served on the
committees that developed the WHO Classification. In
addition, a Clinical Advisory Committee was formed,
chaired by Drs Clara Bloomfield and T. Andrew Lister,
to ensure that the classification met the needs of the
clinicians and would be suitable for daily clinical practice and clinical trials.
Some of the changes from the R.E.A.L. Classification incorporated into the WHO Classification affect
cutaneous lymphomas. Tables 1 and 2 illustrate B- and
T-cell lymphomas with frequent cutaneous involvement.
For example, subclassification of anaplastic large-cell
lymphomas into systemic and primary cutaneous types
is more precisely defined. Primary cutaneous anaplastic
large-cell lymphoma is viewed as part of the spectrum
of CD30+ T-cell lymphoproliferative disease of the skin
19
and is distinguished from systemic anaplastic large-cell
lymphoma of T/null-cell type [15]. The former cases are
never associated with the t(2;5) [16]. Minor changes in
terminology of some cutaneous disorders have been
adopted such as: T/NK-cell lymphoma, nasal and nasaltype, in lieu of angiocentric lymphoma [17]; subcutaneous
panniculitis-like T-cell lymphoma in lieu of subcutaneous
panniculitic T-cell lymphoma; follicular lymphoma in
lieu of follicle-center lymphoma.
Peripheral or mature B-cell neoplasms
Approximately 25% of all cutaneous lymphomas are of
B-cell lineage [18]. A high proportion of B-cell lymphomas involving the skin (Table 1) are primary in this site,
and have a low risk of systemic dissemination. Moreover, although many morphologically resemble their
nodal counterparts, primary cutaneous B-cell lymphomas often exhibit biologically and clinically distinctive
features. The most common entities presenting in skin
are follicular lymphomas, marginal zone B-cell lymphomas, and diffuse large B-cell lymphomas. Many, but not
all, cases of primary cutaneous follicular lymphoma
appear biologically distinct from their nodal counterparts, and may represent a different entity. They are
frequently negative for BCL-2 gene rearrangements,
and are often surface immunoglobulin negative [19, 20].
Peripheral or mature T-cell and NK-cell neoplasms
A number of distinct entities derived from T cells and
NK cells frequently involve the skin and subcutaneous
tissue, either as a primary site of involvement or a
secondary site of spread (Table 2). These include mycosis fungoides and Sezary syndrome, as well as nasal-type
T/NK-cell lymphomas, subcutaneous panniculitis-like
T-cell lymphomas, angioimmunoblastic T-cell lymphomas, adult T-cell leukemia/lymphomas, and both primary and systemic anaplastic large-cell lymphomas.
Most other peripheral T-cell neoplasms involving the
skin are classified as PTL unspecified.
R.E.A.L./WHO vs. EORTC approaches for cutaneous
lymphomas
Since the skin is the second most common extranodal
site involved by lymphoma, any modern classification
scheme for lymphoma should highlight those aspects of
cutaneous lymphoid malignancies that are unique to the
skin and those that are comparable to other organ
systems. The R.E.A.L./WHO Classification does not
deal separately with cutaneous lymphomas. Rather, it
proposes that if cutaneous involvement is a unique
aspect of a disease entity, this fact is considered integral
to disease recognition.
Cutaneous lymphomas can be primary or secondary.
In some instances, it may be difficult to make this
distinction, especially prior to complete clinical evalua-
Table 2. T-cell and NK-cell lymphomas with frequent or constant
cutaneous involvement.
Primary cutaneous T-cell lymphomas
Mycosis fungoides
Sezary syndrome
Primary cutaneous anaplastic large-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
OtherT- or NK-cell lymphomas with cutaneous involvement
Precursor T-lymphoblastic lymphoma/leukemia
T-cell prolymphocytic leukemia
Blastic NK-cell lymphoma
Aggressive NK-cell leukemia
NK/T-cell lymphoma, nasal and nasal-type
Angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphoma. unspecified
Adult T-cell leukemia/lymphoma
Systemic anaplastic large-cell lymphoma
tion and staging. However, the EORTC Classification
includes only primary cutaneous lymphomas. This approach results in certain inconsistencies for the EORTC
scheme. For example, Sezary's syndrome (SS), which is
included, is in actuality a generalized disease from presentation. Patients manifest not only erythroderma, but
ubiquitous leukemic involvement. However, adult T-cell
leukemia/lymphoma (ATLL), a disease with a very high
incidence of cutaneous involvement (> 60%) is excluded
from the classification because it is considered a generalized disease [21].
Both dermatologists and hemato/oncologists should
be familiar with both primary and secondary lymphomas, and the expected clinical behaviors of both types.
A classification system restricted to only primary lymphomas does not promote an encompassing view of
these diseases. For example, lymphoblastic lymphoma
usually presents with generalized disease. However, it
can present only in the skin, with no clinically detectable
disease at other sites [22]. Other lymphomas which may
have their initial manifestations in the skin include
systemic anaplastic large-cell lymphomas, nasal and
nasal-type NK/T-cell lymphomas [23], and blastic NKcell lymphomas [24]. These diseases are not regarded as
primary cutaneous lymphomas, and are therefore omitted
from the EORTC Classification. However, appropriate
clinical management dictates that such cases be accurately diagnosed and treated. Therefore, a lymphoma
classification restricted to only those neoplasms usually
primary in the skin may compromise the ability of
dermatologists to manage all cutaneous lymphomas
appropriately.
The evolution of the definition of cutaneous immunocytoma is further illustrative of why organ-specific classification schemes are not desirable, and may impede the
recognition of single diseases common to multiple anatomic sites. The term cutaneous immunocytoma was
derived from the lymphoplasmacytic appearance of the
neoplastic cells, and the presence of relatively abundant
cytoplasmic immunoglobulin, in at least a subpopulation
of neoplastic cells. However, cutaneous immunocytomas remain confined to the skin with a low risk of
20
systemic spread [25, 26]. Utilizing the concepts of the
R.E.A.L. Classification, this process may be recognized
as a cutaneous form of marginal zone B-cell lymphoma,
which mirrors of the features of other MALT-type lymphomas both morphologically and clinically [6, 7]. The
use of the term immunocytoma might falsely imply a high
risk of systemic disease with expected lymph node and
bone marrow involvement, leading to inappropriate and
overlying aggressive therapy. We propose that the term
immunocytoma be applied only to secondary cutaneous
involvement by a lymphoplasmacytoid/cytic lymphoma.
In the R.E.A.L./WHO Classification, diffuse large
B-cell lymphomas subsume T-cell rich B-cell lymphoma,
monomorphic centroblastic lymphoma (Kiel Classification), most large-cell lymphomas (Working Formulation), immunoblastic lymphoma, and the large-cell
anaplastic lymphomas of B-cell type. Single skin lesions
usually have an excellent prognosis, present commonly
on the head and scalp, and may be treated locally.
However, the presence of multiple cutaneous lesions,
and/or nodal or other extranodal sites of disease are
associated with more aggressive clinical behavior [27].
We question the creation of the entity known as large
B-cell lymphoma of the leg [24]. We believe that the poor
prognosis associated with these cases in the literature is
due to multiple sites of disease at presentation, a fact
which implies dissemination. In the study reported by
Kurtin et al. cases of large-cell lymphoma presenting on
the scalp and exhibiting multiple skin lesions at presentation have an equally aggressive clinical course [27].
The data suggest that clinial outcome correlates with
recognized clinical prognostic factors, not the primary
site of presentation [28].
In conclusion, many cutaneous lymphomas require
specialized diagnostic and therapeutic approaches. The
site of presentation must be taken into consideration by
both the pathologist and the clinician. However, an
organ-specific classification scheme for cutaneous lymphomas could lead to confusion and potential misdiagnosis, and would create an unfortunate precedent. We
believe that pathologists, dermatologists, and hemato/
oncologists would be best served through the use of a
common classification system for all lymphomas.
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Correspondence to:
Dr E. S. Jaffe
Building 10/2N202
10 Center Drive MSC-1500
Bethesda, MD 20892
USA
E-mail: elainejaffe(a nih.gov