Experimental Oncology 23, 101-103, 2001 (June)
101
WORLD HEALTH ORGANIZATION CLASSIFICATION
OF MALIGNANT LYMPHOMAS
J. Diebold
Service d’Anatomie et de Cytologie Pathologiques, Hôtel Dieu, 75181 Paris Cedex 04, France
ÊËÀÑÑÈÔÈÊÀÖÈß ÇËÎÊÀ×ÅÑÒÂÅÍÍÛÕ ËÈÌÔÎÌ
ÂÑÅÌÈÐÍÎÉ ÎÐÃÀÍÈÇÀÖÈÈ ÇÄÐÀÂÎÎÕÐÀÍÅÍÈß
Æ. Äèáîëü
Îòäåë ïàòîëîãè÷åñêîé àíàòîìèè è öèòîëîãèè, ãîñïèòàëü Îòåëü Äüå, Ïàðèæ, Ôðàíöèÿ
The historical background of classification of the neoplasms of lymphoid tissue has been presented beginning from
the pioneer works of T. Hodgkin and R. Virchow till the up-to-date classification schemes developed by G. Rappaport
and K. Lennert. The basic principles of the new WHO classification elaborated by the international group of
pathologists have been analyzed in details with the emphasis on the criteria of delineating each nosologic entity
taking into account the patterns of the growth (nodular or diffuse) as well as the origin of malignant cells defined
upon the analysis of cytomorphological, immunophenotypic and molecular genetic features.
Key Words: lymphoma, classification.
Ïðåäñòàâëåí èñòîðè÷åñêèé îáçîð êëàññèôèêàöèé îïóõîëåé ëèìôîèäíîé òêàíè, íà÷èíàÿ ñ ïåðâûõ ðàáîò Ò. Õîäæêèíà, Ð. Âèðõîâà è äî ñîâðåìåííûõ ñõåì, ðàçðàáîòàííûõ Ã. Ðàïïîïîðòîì è Ê. Ëåííåðòîì. Äåòàëüíî àíàëèçèðóþòñÿ ïðèíöèïû íîâîé êëàññèôèêàöèè ÂÎÇ, ðàçðàáîòàííîé ìåæäóíàðîäíîé ãðóïïîé ïàòîëîãîâ, êðèòåðèè âûäåëåíèÿ îòäåëüíûõ íîçîëîãè÷åñêèõ ôîðì ñ ó÷åòîì õàðàêòåðà ðîñòà (íîäóëÿðíûé èëè äèôôóçíûé) è
ïðèðîäû îïóõîëåâûõ êëåòîê, îïðåäåëÿåìîé íà îñíîâå àíàëèçà öèòîìîðôîëîãè÷åñêèõ, èììóíîôåíîòèïè÷åñêèõ è ìîëåêóëÿðíî-ãåíåòè÷åñêèõ ïðèçíàêîâ.
Êëþ÷åâûå ñëîâà: ëèìôîìû, êëàññèôèêàöèÿ.
Malignant lymphomas are neoplasias due to
proliferation of lymphoid cells. The first type has been
published in 1832 by Thomas Hodgkin. It is now well
demonstrated that the malignant giant cells (Sternberg—Reed cells) are of B lymphocyte origin.
Virchow in 1845 described other types of what is
now called lymphomas under the term “lymphosarcoma”. During the second part of the nineteenth
century and the first half of the twentieth century, many
other types of lymphomas have been described.
Lymphomas represented by large cells were called
“reticulosarcoma”, those represented by small cells —
“lymphosarcoma”, and mixed variants were called
“lymphoreticulosarcoma”. Most of them have a diffuse
pattern, but peculiar lymphoma with a nodular pattern
has been described in 1927 by Symmers on the one
hand, and Bryll—Baehr and Rosenthal on the other.
Gall and Mallory proposed a first attempt of classification. But it’s Henry Rappaport who organized the
first classification which was clinically relevant. He
distinguished diffuse and nodular lymphoma, well
differentiated and undifferentiated, lymphocytic and
histiocytic lymphomas as well as blastic lymphoma.
In 1973, at a congress in London, two new classifications, very similar, based on new information
concerning the biology of the lymphoid tissue and
immunobiology have been presented by Karl Lennert
Received: March 23, 2001.
*Correspondence.
Fax: (33-01) 42348641
E-mail: [email protected]
and his group from Kiel (Germany) [1] and by Robert
Lukes and Collins from the USA [2].
Since that time, other classifications were used
in different countries, and clinicians became confused. In 1980, the National Health Institute in the
USA collected more than 1000 patients and proposed
to a group of expert pathologists from Europe and
USA to try to achieve a common classification. For
different reasons, this project failed. Clinicians then
propose a working formulation for clinical usage [3],
which allowed the comparison of the different classifications and gave information on the evolution of
each type of lymphoma.
But this was not a classification based on scientific
criteria. So the first Kiel classification proposed by
K. Lennert and the European Lymphoma Club in 1978
was up-dated in 1988 [4] and additional modification
was proposed in the book published by K. Lennert
and A. Feller in 1992 [5].
The most important points of the Kiel and the updated Kiel classification were the following:
1. To define lymphomas as anatomo-clinical entities.
2. To show that the so-called “histiocytic” lymphomas are in fact large cells of lymphocyte origin
(transformed cells).
3. To show that lymphomas should be distinguished
according to their origin from B or T lymphocytes.
The American Society for Hematopathology in the
USA and European Association for Hematopathology
in the 1980s allowed greater contact during congresses
between the hematopathologists of both side of the
Atlantic. Then, after the retirement of Karl Lennert and
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Ýêñïåðèìåíòàëüíàÿ îíêîëîãèÿ 23, 101-103, 2001 (èþíü)
the end of the European Lymphoma Club, a new group
has been created, the International Lymphoma Study
Group (ILSG), comprising hematopathologists from
different parts of the world. In 1991, they proposed a
new classification, the so-called REAL classification
(an acronym for Revised European American Lymphoma) [6].
This classification was based also on the definition of entities, and on the distinction of lymphoma
of B and T cell origin, resembling either precursor cells
or peripheral more mature cells. In addition to the
entities of the up-dated Kiel classification, new entities
have been added particularly extranodal lymphomas
of B or T cell origin.
The WHO project: an international classification
of neoplasias arising from hematopoietic cells. After
the publication of the so-called REAL classification, in
1995 the WHO executives propose to the presidents
and ex-presidents of both American Society for Hematopathology and European Association for Hematopathology to prepare an international classification of
neoplasias due to the proliferation of hematopoietic cells.
An executive committee was organized, who invited ten
hematopathologists to chair ten committees constituted
by two to six hematopathologists from all over the world.
Each committee had to propose a definition and a
description for lymphomas belonging to a given group,
for example: small B-cell or large B-cell or T-cell
lymphoma. The final proposal was discussed with
oncologists and hematologists for consensus [7].
Principles of the WHO classification [8–10]. The
main principle was as in the up-dated Kiel and in the
REAL classification to define distinct entities with
variants that can be recognized by pathologists and
that have clinical relevance.
Each disease entity is defined on the basis of a combination of morphologic, immunophenotypic, genetic, and
clinical features.
Then, to the possible extent, classification should
be based on the normal counterpart of the neoplastic
cell.
Criteria defining each entity [8–10]. The site of
the lymphoma, nodal or extranodal should first be defined
precisely. Then the size of the cells should be evaluated.
They can be small, medium or large. Large cells are
defined as having a nucleus with a size equal or greater
than 2 to 3 lymphocyte nuclei. Medium-sized cells have
a nucleus of the same size as nuclei of macrophages.
The morphology of the cell has to be described. Size
and shape of the nucleus, organization of the chromatin
(dark blocks or dispersed clear chromatin), size and
number of nucleoli, size, shape, and color of the cytoplasm.
The pattern of the proliferation: nodular or diffuse
is also important to define. The immunophenotype is
very important to define, first to distinguish B-cell from
T-cell lymphomas, a distinction of prognostic value,
T-cell lymphomas having always worse prognosis than
B-cell lymphomas. Then a complete immunophenotype
is sometimes useful to define precisely some entities,
for example small B-cell lymphoma or different variants
of T/NK lymphomas.
In addition, the presence or absence of typical
cytogenetic abnormalities can be useful, but their
analysis is not really required for a precise diagnosis
and for the choice of the best therapeutic strategy in
malignant lymphomas.
The expression of one or more peculiar oncogene
can be useful mainly for the evolution. For example,
hyperexpression of Bcl-2 and survivin stratifies large
B-cell lymphomas in more aggressive group.
Morphology of the cells, pattern of proliferation,
the precise immunophenotype are necessary often to
evaluate the cell of origin.
Then it has also been decided not to use any more
terms as low or high grade but to define each entity
according to the type of survival curves in treated
patients. Four types of curves have been described
by Armitage et al. [11, 12], each entity presenting
one of the four types of curves recognized.
Tables 1, 2 and 3 present the different entities of
B and T-non-Hodgkin’s lymphomas and the different
types of Hodgkin’s lymphoma [8–10].
Table 1. WHO classification of neoplastic diseases of hematopoietic and
lymphoid tissues. B-cell neoplasms
Precursor B-cell neoplasms
Precursor B-lymphoblastic leukemia / lymphoma
Mature (peripheral) B-cell neoplasms
B-CLL / small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Mantle-cell lymphoma
Follicular lymphoma (grade 1, 2 or 3)
Nodal marginal zone B-cell lymphoma (+/– monocytoid B cells)
Extranodal marginal zone B-cell lymphoma of MALT type
Splenic marginal zone B-cell lymphoma (+/– villous lymphocytes)
Hairy cell leukemia
Plasma cell myeloma / plasmacytoma
Diffuse large B-cell lymphoma
morphologic variants
- centroblastic
- immunoblastic
- T-cell / histiocyte-rich
- anaplastic large B-cell
- plasmablastic
clinical variants
- mediastinal (thymic) large B-cell lymphoma
- primary effusion lymphoma
- intravascular large B-cell lymphoma
- lymphomatoid granulomatosis type
Burkitt’s lymphoma / Burkitt cell leukemia
morphological variants
- Burkitt-like / or typical Burkitt
- with plasmacytoid differentiation (AIDS-associated)
clinical and genetic variants
- endemic
- sporadic
- immunodeficiency-associated
Experimental Oncology 23, 101-103, 2001 (June)
Table 2. WHO classification of neoplastic diseases of hematopoietic and lymphoid
tissues. T-cell and NK-cell neoplasms
Precursor T-cell neoplams
Precursor T-lymphoblastic leukemia / lymphoma
Mature (peripheral) T-cell neoplasms
Predominantly leukemic / disseminated
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell lymphoma / leukemia (HTLV1+)
Predominantly nodal
Angio-immunoblastic T-cell lymphoma
Peripheral T-cell lymphoma, not otherwise characterized
Anaplastic large-cell lymphoma, T / null cell, primary
systemic disease
Predominantly extranodal
Mycosis fungoides / Sézary syndrome
Anaplastic large-cell lymphoma, T / null cell, primary
cutaneous type
Subcutaneous panniculitis-like T-cell lymphoma
Extra-nodal NK / T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic gamma-delta T-cell lymphoma
Table 3. WHO classification of neoplastic diseases of hematopoietic and lymphoid
tissues. Hodgkin’s lymphoma (Hodgkin’s disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classical Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classical Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
CONCLUSION
The WHO classification represents the first classification with an international consensus. This classification
is now in press and will be published in 2001 [13]. We all
hope that this classification will allow comparison of the
series of patients all over the world. In the future new
entities will probably be described. But they will be easy
integrated into the scheme.
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