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

Thomas Hodgkin published his

paper,On some Morbid appearance

of the Absorbent gland and the

spleen, in 1832.

Description of Hodgkin lymphoma

7 cases were mentioned, of which 3 / 7

were proved to be Hodgkin lymphoma l

ater.

Fig 2: A 7-year-old 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 (1798-1866), 'a man distinguished alike for scientific attainments, medical skill, and self-sacrificing 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, de

scribed characteristic giant cells in p

atients with HD primarily.

A full description of the diagnostic cells

was published by Sternberg (1898) and

Dorothy Reed (1902) (Fig 3). This diagno

stic cell was termed “R-S cell” later.

Fig 3. Reed-Sternberg 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 19

66 simplified the Lukes and Butler sche

me into a four-part classification and exp

anded into its present version at confere

nces held in Ann Arbor, Michigan (1971),

which further remodified by Costwolds i

n 1989.

After further modified the Ann Arbor c

lassification in the REAL (Revised Eur

opean-American Lymphoma) classific

ation (Harris et al, 1994), WHO, In 1997,

estabished a new Hodgkin’s lympho

ma classification scheme.

View of main classification of Hodgkin’s lymphoma

Rye Lukes & ButterJackson & Parker

Lymphocyte predominant

Lymphocyte/lymph tissue predominant

Paragranuloma

Nodular sclerosis

Nodular sclerosis

Mixed cellularity type

Mixed type Granuloma

Lymphocyte depletion

Diffuse fibrosis type

Sarcoma

Reticulum cell type

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 ap

plied to lymph node neoplasms by Roul

et (1930), another designation which gen

erated considerable confusion in lymph

oma classification.

Gall and Mallory (1942) introduced a lym

phoma classification based on clinicopat

hologic criteria, which, for all its shortco

mings, was the first systematic attempt t

o make order out of the chaotic NHL situ

ation.

Rappaport et al (1956) presented medici

ne with a lymphoma classification that c

ould be applied easily and was prognosti

cally useful. Two criteria were employed

to differentiate lymphoma subtypes: the

presence or absence of nodularity, and c

ell size (small, intermediate and large ly

mphoid cells).

Burkitt (1958) described a new type of l

ymphoma in African children restricted

to regions of high temperature and high

rainfall.

In 1972, it became possible to immunoph

enotype B and T lymphocytes, initially by

the presence of clonal immunoglobulin a

nd/or sheep cell receptor on the cell surf

ace, and later with a host of B- and T-sub

set-specific monoclonal antibodies.

Lukes & Collins (1974) established a new

immnuological classification based on th

eir knowledge about B-cell transformatio

n after antigen stimulation.

The follicle centre cell was recognized

by Lennert et al (1978) and became th

e basis of alternate classifications: Le

nnert's Kiel system (Lennert et al, 197

8; Lennert & Feller, 1992).

Ag

Ag

/ 中心细胞

中心母细胞

干细胞

前 T 细胞 T1 细胞

T 免母细胞T2 细胞

前 B 细胞

B 免母细胞

B2 细胞

浆细胞

淋浆

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) repres

ents a radical, if tentative, consensus redo of ly

mphoma classification, based on prior classific

ations and, for the first time, defining lymphom

a subtypes by immunophenotype and molecula

r genotype, as well as by morphology and clini

cal 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 clinicopathologi

c entity.

Adult T-cell leukaemia/lymphoma reported

in 1977 from Japan, concentrated in the

South-western islands.

MALT (mucosa-associated lymphoid tiss

ue) lymphomas (Isaacson & Wright, 197

8),

Mantle cell lymphoma (Banks, 1992).

large cell lymphomas of the mediastinum

derived from B cells of the thymic medull

a (Aisenberg, 1999).

Aetiology and pathogenesis

The nature of Hodgkin's lymphoma

The malignant nature of Hodgkin's lym

phoma was disputed. The majority of i

nvestigators, Virchow, Wilks, and most

modern students of the disorder, consi

dered it a neoplasm of the lymphoid sy

stem.

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 I

g genes obtained from PCR study of sing

le R-S cell, and from immunophenotype s

tudy, strongly supports their neoplastic a

nd aberrant ('crippled') B-cell lineage in n

odular sclerosis, mixed cellularity and ly

mphocyte-depletion HD (Kuppers & Raje

wsky, 1998; Kuppers et al, 1999).

The regular isolation of Epstein-Barr vir

us (EBV) from African Burkitt's lympho

ma in 1964 and since that time (Epstein

et al, 1964), together with extensive epid

emiologic (serologic) evidence, establis

hed an aetiologic role of this DNA herpe

s-type virus in the endemic disorder.

Viruses and the aetiology of lymphoma

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 retr

ovirus (HTLV-I) from a patient with an atypical cut

aneous T-cell lymphoma. Subsequently, the sam

e virus was regularly recovered from the tumour

cells of Japanese and Caribbean patients with ad

ult T-cell leukaemia/lymphoma (ATL), and antibo

dy to the virus was demonstrated in almost all in

dividuals with that disorder.

Recently, the relation between H. pylori

and MALToma of Gastrointestinal tract, H

CV and regional B-cell lymphomas was el

evation.

Molecular genetics and oncogenes.

The chromosomal localization of the hum

an immunoglobulin genes between 1979

and 1981 provided the basis for breathta

king insight into the pathogenesis of Bur

kitt's lymphoma

In 1982, both the Leder and the Croc

e laboratories cloned the translocati

on breakpoint, and identified the c-m

yc oncogene on the chromosome 8 f

ragment (8q24).

Tsujimoto et al (1984) cloned the breakpo

int of the 14;18 translocation of follicular

lymphoma. This breakpoint involved the j

unction of a joining region segment of th

e IgM gene at chromosome 14q32, and th

e bcl-2 oncogene (at 18q21), whose prote

in product suspends apoptosis or progra

mmed cell death.

The 11;14 translocation of mantle cell

lymphoma juxtaposed the bcl-1 gene

(cyclinD) on chromosome 11q13 to th

e same IgM gene (Rosenberg et al, 19

91) .

Bcl-3, an oncogene at 19q13 whose p

roduct regulates gene transcription, i

s similarly joined in a small fraction o

f cases of CLL (Wulczyn et al, 1992).

Putative oncogene Bcl-6 involved in

chromosome 3q27 translocated to a

variety of chromosomal sites in a fra

ction 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, whic

h may contribute to the occurrence of su

ch 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

Wilks Hodgkin’s cases rediscovered

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 RouletReticulum- cell sarcoma distinguished from lymphosarcoma

1947 Jachson & Packer

Hodgkin’s disease divided into paragranuloma, granuloma and sarcoma

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

1966Lukes & Bu

tler

Nodular sclerosis Hodgkin’s disease described

1966 Lukes et alThe modern four-part classification of Hodgkin’s disease developed

1972 Aisenberg Preud’homme

Surface markers employed to establish B- and T- cell lineage of lymphoid neoplasms

1973 Barcos & Lukes

Lymphoblastic lymphoma defined

1973Lennert et al

The concept of the follicle centre cell developed and employed to the Kiel classification of non-Hodgkin’s lymphoma

1974Lukes & 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

1982Taub et al

Dalla-Favera et al

Cloning of the c-myc oncogene from the t(11;14) of Burkitt lymphoma

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

1991Rosenberg

et al Cloning of the bcl-1 oncogene from the t(11;14) of mantle cell lymphoma

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 MALT-lymphomas

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 !