Transcript Lennert et al

History of Malignant Lymphoma
---- What ’s kind of road we have traced?
By Jie Wei
Three stages of lymphoma cognition

Morphology before 70’, 21st century

Cell protein expression level during
70’~80’, 21st century

DNA/mRNA molecular level after 80’
21st century
Description of Hodgkin lymphoma

Thomas Hodgkin published his
paper,On some Morbid appearance
of the Absorbent gland and the
spleen, in 1832.

7 cases were mentioned, of which 3 / 7
were proved to be Hodgkin lymphoma
later.
Fig 2: A 7-yearold boy
(W.D.M.,) in
Dorothy Reed's
classic paper,
showing
similar
presentation to
Ellenborough
King. Johns
Hopkins
Hospital
Reports with
permission
Fig 1. Thomas
Hodgkin (17981866), 'a man
distinguished
alike for
scientific
attainments,
medical skill,
and selfsacrificing
philanthropy.'
Epitaph
inscribed on
his tomb in
Jaffa.

Sir Samuel Wilks (1865), provided a
more detailed and critical clinical
and pathological description of the
some disorder and acknowledged
Hodgkin's earlier contribution. The
term “Hodgkin’s disease” was
estabished.

Greenfield (1878), among others,
described characteristic giant cells
in patients with HD primarily.
 A full description of the diagnostic cells
was published by Sternberg (1898) and
Dorothy Reed (1902) (Fig 3). This
diagnostic cell was termed “R-S cell”
later.
Fig 3. ReedSternberg cells
drawn by Dorothy
Reed's own hand.
The mirror-image
cell at the lower
left is diagnostic.
(From Reed
(1902) .John
Hopkins Hosipltal
Reports With
permission.

Jackson & Parker (1947) introduced The
first histological classification of
Hodgkin's lymphoma (paragranuloma,
granuloma and sarcoma).

Lukes & Butler (1966) added the nodular
sclerosis category and further refined the
Jackson & Parker’s earlier system.

Conference held in Rye, New York in
1966 simplified the Lukes and Butler
scheme into a four-part classification
and expanded into its present version at
conferences held in Ann Arbor, Michigan
(1971), which further remodified by
Costwolds in 1989.

After further modified the Ann Arbor
classification in the REAL (Revised
European-American Lymphoma)
classification (Harris et al, 1994), WHO,
In 1997, estabished a new Hodgkin’s
lymphoma classification scheme.
View of main classification of Hodgkin’s lymphoma
Rye
Jackson &
Lukes & Butter
Parker
Lymphocyte
predominant
Lymphocyte/lymph
tissue predominant
Nodular
sclerosis
Nodular sclerosis
Mixed cellularity
type
Mixed type
Granuloma
Lymphocyte
depletion
Diffuse fibrosis
type
Sarcoma
Reticulum cell
type
Paragranuloma
WHO classification of Hodgkin’s lymphoma
Nodular lymphocyte predominance
Classic Hodgkin’s lymphoma
Mixed cellularity type
Nodular sclerosis type
Lymphocyte predominance type
Anaplasia larger cell type*
* Remain Altercation for adding anaplasia larger cell type HD and
omiting Lymphocyte depletion type HD
The delineation of the Non-Hodgkin's
lymphomas

Virchow (1845) and Bennett (1845)
described the first cases of leukaemia.

Virchow (1864-1865) divided leukaemia
into the leukaemic and 'aleukaemic' types,
employing the designation
'lymphosarcoma' for a subdivision of the
latter.
 A probable case of acute leukaemia was
published by Cohnheim (1865) under the
descriptive term ‘pseudoleukaemia’.
 Kundrat (1893) and colleagues again
employed the term lymphosarcoma in the
modern sense used by Virchow a
generation earlier .
 The follicular or nodular lymphomas were
first clearly described by Brill et al (1925).
 The term reticulum cell sarcoma was
applied to lymph node neoplasms by
Roulet (1930), another designation
which generated considerable confusion
in lymphoma classification.
 Gall and Mallory (1942) introduced a
lymphoma classification based on
clinicopathologic criteria, which, for all
its shortcomings, was the first
systematic attempt to make order out of
the chaotic NHL situation.
 Rappaport et al (1956) presented
medicine with a lymphoma classification
that could be applied easily and was
prognostically useful. Two criteria were
employed to differentiate lymphoma
subtypes: the presence or absence of
nodularity, and cell size (small,
intermediate and large lymphoid cells).

Burkitt (1958) described a new type of
lymphoma in African children restricted
to regions of high temperature and high
rainfall.
 In 1972, it became possible to
immunophenotype B and T lymphocytes,
initially by the presence of clonal
immunoglobulin and/or sheep cell
receptor on the cell surface, and later
with a host of B- and T-subset-specific
monoclonal antibodies.

Lukes & Collins (1974) established a new
immnuological classification based on
their knowledge about B-cell
transformation after antigen stimulation.

The follicle centre cell was recognized
by Lennert et al (1978) and became
the basis of alternate classifications:
Lennert's Kiel system (Lennert et al,
1978; Lennert & Feller, 1992).
Ag
T免母细胞
T2细胞
前T细胞 T1细胞
B免母细胞
淋浆
Ag
干细胞
浆细胞
前B细胞
B2细胞
中心母细胞 /中心细胞

The recent National Cancer Institute
sponsored Working Formulation for
Clinical Usage (Rosenberg et al,
1985) provided an unsatisfactory
solution to the vexing search for a
clinically-relevant system that could
be reproducibly applied by working
pathologists.

The REAL classification (Harris et al, 1994)
represents a radical, if tentative, consensus
redo of lymphoma classification, based on
prior classifications and, for the first time,
defining lymphoma subtypes by
immunophenotype and molecular genotype, as
well as by morphology and clinical
characteristics.

WHO classification of ML

First edition (1976)

1997 edition based on REAL classification

Remain alternation

Published in 2000 Finally
 In 1981 B-cell lineage could be confirmed
by the presence of clonally rearranged
immunoglobulin heavy and light chain
genes (Korsmeyer et al).
Identify clonal T-cell proliferations by the
presence of clonally rearranged T-cell
receptor genes (Aisenberg; Minden;
Waldmann et al, 1985)
 Lymphoblastic lymphoma (Barcos & Lukes,
Lennert) was a separate clinicopathologic
entity.

Adult T-cell leukaemia/lymphoma reported
in 1977 from Japan, concentrated in the
South-western islands.

MALT (mucosa-associated lymphoid
tissue) lymphomas (Isaacson & Wright,
1978),
 Mantle cell lymphoma (Banks, 1992).
 large cell lymphomas of the mediastinum
derived from B cells of the thymic
medulla (Aisenberg, 1999).
Aetiology and pathogenesis
 The nature of Hodgkin's lymphoma
The malignant nature of Hodgkin's
lymphoma was disputed. The majority
of investigators, Virchow, Wilks, and
most modern students of the disorder,
considered it a neoplasm of the
lymphoid system.
 but some distinguished observers,
including both Reed and Sternberg, held
a contrary opinion. Indeed, until recently,
the R-S cell resisted attempts to define its
lineage because of its sparsity. Its
immunophenotypic characteristics were
not those of garden-variety B
lymphocytes, T lymphocytes,
macrophage/monocytes, or dendritic
cells.
 Recent evidence of clonally rearranged
Ig genes obtained from PCR study of
single R-S cell, and from
immunophenotype study, strongly
supports their neoplastic and aberrant
('crippled') B-cell lineage in nodular
sclerosis, mixed cellularity and
lymphocyte-depletion HD (Kuppers &
Rajewsky, 1998; Kuppers et al, 1999).
Viruses and the aetiology of lymphoma
 The regular isolation of Epstein-Barr
virus (EBV) from African Burkitt's
lymphoma in 1964 and since that time
(Epstein et al, 1964), together with
extensive epidemiologic (serologic)
evidence, established an aetiologic role
of this DNA herpes-type virus in the
endemic disorder.

EBV has been identified in
lymphomas which complicate a
variety of acquired and inherited
immune deficiency states.

Gallo and Wong-Staal (1982) isolated a novel
retrovirus (HTLV-I) from a patient with an atypical
cutaneous T-cell lymphoma. Subsequently, the
same virus was regularly recovered from the
tumour cells of Japanese and Caribbean patients
with adult T-cell leukaemia/lymphoma (ATL), and
antibody to the virus was demonstrated in almost
all individuals with that disorder.

Recently, the relation between H. pylori
and MALToma of Gastrointestinal tract,
HCV and regional B-cell lymphomas was
elevation.
Molecular genetics and oncogenes.
 The chromosomal localization of the
human immunoglobulin genes between
1979 and 1981 provided the basis for
breathtaking insight into the
pathogenesis of Burkitt's lymphoma
 In 1982, both the Leder and the
Croce laboratories cloned the
translocation breakpoint, and
identified the c-myc oncogene on
the chromosome 8 fragment (8q24).
 Tsujimoto et al (1984) cloned the
breakpoint of the 14;18 translocation of
follicular lymphoma. This breakpoint
involved the junction of a joining region
segment of the IgM gene at chromosome
14q32, and the bcl-2 oncogene (at 18q21),
whose protein product suspends
apoptosis or programmed cell death.
 The 11;14 translocation of mantle cell
lymphoma juxtaposed the bcl-1 gene
(cyclinD) on chromosome 11q13 to
the same IgM gene (Rosenberg et al,
1991) .
 Bcl-3, an oncogene at 19q13 whose
product regulates gene transcription,
is similarly joined in a small fraction
of cases of CLL (Wulczyn et al, 1992).
 Putative oncogene Bcl-6 involved in
chromosome 3q27 translocated to a
variety of chromosomal sites in a
fraction of large cell lymphomas
(Offit, 1994).
 BCL-8 involved in DLBC with t(14;15)
(q32; q11-13).
 BCL-9 gene cloned in precusror B
lymphoblastic leukemia with t(1;14)
(q21;q32).
 BCL-10 gene cloned in MALToma, which
may contribute to the occurrence of
such kind of low grade lymphoma.
 ALK-NPM (p80) involved in anaplasia
large cell lymphoma.
 In T-cell lymphomas, one breakpoint
site is at chromosome 14;q11, the
site where the gene for the delta
chain of the T-cell receptor is
embedded in the T-cell receptor
alpha chain gene (Reis, 1989).
 Thus, the generation of antigen receptor
genes, immunogloblin genes and T-cell
receptor genes is a major cause of human
lymphoma. Available evidence suggests
that more than a single genetic
misadventure is required for tumour
induction. The remarkable progress in
understanding the molecular events in
lymphomagenesis achieved in the past
several years suggests that comprehensive
understanding of the process is not far off.
Year
Reference
Advance in cognition of lymphoma
1832 Hodgkin
The primary malignant tumor of lymph nodes
subsequently termed Hodgkin’s disease described
1845 Virchow
The nature of leukemia defined
1856
1965
Hodgkin’s cases rediscovered
Wilks
1864 Viechow
The concept of lymphoma is defined and placed
under the rubric ‘aleukemic leukemia’
1865 Cohnheim
The term ‘pesudoleukaemia’ prpposed for
Virchow’s ‘aleukaemic leukaemia’
1892 Dreschfeld
Lymphosarcoma separated from
pseudoleukaemia and Hodgkin’s disease
1893 Kundrat
Lymphosarcoma separated from
pseudoleukaemia and Hodgkin’s disease
Year Reference
Advance in cognition of lymphoma
1898 Sternberg
The histological picture of Hodgkin’s disease
characterized including the diagnostic giant cell
1902 Reed
The histological picture of Hodgkin’s disease
characterized including the diagnostic giant cell
1925 Brill et al
Follicular (nodular ) lymphoma descrbed
1927 Symmers
Follicular (nodular ) lymphoma descrbed
1930 Roulet
Reticulum- cell sarcoma distinguished from
lymphosarcoma
1947 Jachson &
Hodgkin’s disease divided into paragranuloma,
granuloma and sarcoma
Packer
1956 Rappaport
The first modern classification of non-Hodgkin’s
lymphoma based on cytology and the presence
orabsebce of follicular structure introduced
Year Reference
Advance in cognition of lymphoma
1958 Burkitt
Endemic (African) Burkitt’s lymphoma described
Lukes &
1966
Butler
Nodular sclerosis Hodgkin’s disease described
1966 Lukes et al
The modern four-part classification of Hodgkin’s
disease developed
1972
Surface markers employed to establish B- and TAisenberg
Preud’homme cell lineage of lymphoid neoplasms
1973
Barcos &
Lukes
Lymphoblastic lymphoma defined
Lennert et
1973 al
The concept of the follicle centre cell developed
and employed to the Kiel classification of nonHodgkin’s lymphoma
Lukes &
1974
Collins
An immunological classification of non-Hodgkin’s
lymphoma based on perceived B- and T-cell
lineage proposed
Year Reference Advance in cognition of lymphoma
1977
Uchiyama et
al
Adult T-cell leukaemia/lymphoma described in
Japan
1978
Isaacson &
Wright
Delineation of MALT-lymphoma
1981
Korsmeyer
et al
Lineage and clonality of B-cell lymphomas defined
by immunoglobulin gene rearrangement
1982
Taub et al
Cloning of the c-myc oncogene from the t(11;14) of
Dalla-Favera Burkitt lymphoma
et al
1984
Tsujimoto et
al
Cloning of the bcl-2 oncogene from the t(14;18) of
follicular lymphomas
1985
Aisenberg,
et al
Lineage and clonality of T-cell lymphoma defined
by T-cell receptor gene rearrangement
Rosenberg
Cloning of the bcl-1 oncogene from the t(11;14) of
mantle cell lymphoma
1991
et al
Year Reference
Advance in cognition of lymphoma
1993 Ye et al
Cloning of the bcl-6 oncogene from diffuse large
cell lymphoma
1994 Harris et al
Revised European-American Classification of
Lymphoid Neoplasms (REAL classification)
1997
WHO classification first edition
1998
Cloning of the bcl-10 oncogene from MALTlymphomas
1999 Aisenberg
large cell lymphomas of the mediastinum derived
from B cells of the thymic medulla
2000
Later WHO classification edition
细胞性淋巴瘤
淋
巴
母
细
胞
淋
巴
瘤
浆
细
胞
瘤
免
疫
母
细
胞
淋
巴
瘤
滤
泡
性
淋
巴
瘤
Burkitt
淋巴瘤
HL之LP、MC
Thank you !