terminal steps of B cell differentiation Mediastinal ...

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1987 69: 1087-1095

Mediastinal lymphoma of clear cell type is a tumor corresponding to terminal steps of B cell differentiation P Moller, G Moldenhauer, F Momburg, B Lammler, M Eberlein-Gonska, S Kiesel and B Dorken

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Mediastinal

Lymphoma Terminal By Peter

M#{246}Iler,Gerhard Maria

This

article

ring

in young

reports

predominantly badly

noted

and

in one

The

growth ever,

be

In

highly

tion

and

clear

carry stages

immunoglobulin of

the

HLA-D,

and surface such

expressed,

neoplastic

the

frequently

than

so-called

Ig

Ig constituents Ig deficiency,

from

deviant

that

they

kin’s (“T

cell,

convoluted”

Hodgkin’s thymic

is reported

and

carcinoma,

and

T cell

to

colleagues,23

(Mohri,24

rarely

50 cases)

148

cases)

tumors

of proven

B cell

reports

on primary

extranodal

to

origin.

non-Hodgkin’s

such

presenting

obstruction

as

originating

organs

cough,

in

and

antineoplastic

and

treatment.

as

rosis was

described

Concerning were able

to prove

dyspnea,

The

mediastinum

structures

described differentiated,

pain,

symptoms.

initial the

chest

tended

in most cases As to morphology,

are

of the

three

medias-

and

venous

tumors apparently to invade adjacent responded badly to the tumors were

being of diffuse large cell type or as poorly lymphocytic. In one series,27 pronounced sclethe

as an

additional

immunophenotype,

the “lymphoreticular

Blood, Vol 69. No 4 (April), 1987:

pp

characteristic

feature.

Perrone and colleagues27 origin” of 53 of their

1087-1095

type

of

B cell

of

B cell

terminal

steps

lym-

a mixture

of monoclonal

surface

that

these

of B cell origin although characterized late

stage

of B cell

29.4 years)

METHODS

B symptoms

female

of thoracic were

noted

lympho-

maturation. AND

predominantly

consisted

avail-

formalin-fixed

“null”-cell

the last 2 years, eight were observed. They occurred

symptoms

techniques using

present an immunophenotype by various defects, is indicative

During

tumors

pnea;

marker or by

mediastinal

and

MATERIALS

tinal

described by the three groups however, neither as B nor

of publication

we report

ic

primary

in young

thoracic I case.

medias-

( I 9 to 43 years,

(6 of 8) adults.

pain, in only

unusual

First

clinical

venectasia, Tumor

and dys-

localization

was

as mediastinal in 6 and as (para-)thymic in 2 cases. Initial diagnosis revealed involvement of the lungs in 3, of the pericardium in 2, and of cervical lymph nodes in I case; venous compression or invasion was observed in 3 patients. None was initially leukemic or developed leukemia. Serum electrophoreses were normal. The clinical course was characterized by therapeutic failure. Even though aggressive protocols against high-grade malignant lymphomas were

lymphomas

and poor prognohave a number of mostly young female

with pronounced aggressiveness Conspicuously, these lymphomas features in common: The patients were

tinum2527

adults

as by

however, Tubbs and (Bernard

there

sis.

undescribed

applying

by

using

time

Patients.

mediastinal

lymphoma

cell

described

Collins’8),

(reviewed

Nevertheless,

clini-

clear

Inc.

are

mas

mean

Hodg-

lymphomas

material. Here

detect-

primary

and

mediastinal

the

& Stratton,

tumors

at the

to lack

B cell

contain

able

that,

sarcoma

to

and

antibodies to leukocyte common (LC) antigen on paraffin sections. Furthermore, immunoreactivity with antisera to and A light chains suggested a B cell origin of five of these

of a very

and

the

is a previously

by Grune

even

malignomas of

and

fail

of

mediastinum is T cell tumors

Lukes

epithelial

a 1987

acute

lymphomas,’2’5

of immunophenotypical that

corresponding

orjgiflSO;

Otto20). Even large series of malignant lymphomas, (eg, Brittinger and colleagues,2’ 1,127 cases; colleagues,22 564 cases), of mediastinal lymphomas and

most

percentage of cases.” Apart of B cell tumors may be in physiologic development

according

disease,’9

In may

common

carcinoma.’7 The site of lymphoblastic

primary

to be the

known

and of B cell

mimic

and even

amounts. since

variable

HLA-DR

differentiation.

as T cell

antigen4

expression

actually

a small

occasionally

disease,’6

large Ig

and

B cell-restricted/associated

tumors. The remaining tumors of authors could be characterized,

cell-associated

lymphomas

cytomorphology that of B cells

from

differentiaby Nadler’) and

assumed

leukemia in

in

exhibited

HLA-A,B,C

of other

combination

60 mediastinal

histo-

I (1-ILA-

and the TlO

initially

are

lym-

lymphoma

(surface/cytoplasm). cells

LC,

major

class

plasma

deficient

“null”-cell

B lymphocytic

able

of

is secreted

leukemias

B cell was

express

PCA-l,2’3

however,

lymphoblastic chronic

as

surface. At the terminal differentiation antigens,

Ig disappear;

PC-l,

as the

and B cells,

more

occur

on their B cell

size.

of

suggests

(MCCL)

Ig

,

neoplastic

expression

This

features

phoma

how-

CD21 the

expression

antigens.

L#{227}mmler,

CD2O,

in the

to

D#{246}rken

In addition,

inconstant cal

a diffuse

immunophenotype

B cells

leuke-

could,

PC-i

defects

is pres-

of variable but

antigens

(Ig)

differentiation,

antigens are

cells

histologically.

the

patients

had

class II (HLA-D), lineage-restricted CDI9, CD2O, CD22 (reviewed

antigens

.

developed

characterized

cases.

CD19,

and

Corresponding

Birgit

Bernd

cALLa.

proliferative,

comprised

and

occur-

1 0, 1 1 , 1 3. 18,

died

Momburg,

years),

Progression

patients

Frank Kiesel,

29.4 Most

No patient

ORMAL PERIPHERAL compatibility (MHC)

A,B,C)

so

five

be classified

all

adults.

Sophie

tumors

mean

therapy.

immunohistologically

phomas.

N

and

not

years.

eight)

diagnosis.

Moldenhauer,

Eberlein-Gonska,

mediastinal

43

of

patient; were

pattern, could

(six

after

tumors

They

to

to aggressive

22 months

mia.

primary

(19

female

responded ently

eight

adults

of Clear Cell Type is a Tumor Steps of B Cell Differentiation

From

the

Medicine, ogy

Institute

and

July

Supported

by the

Baden-

and

ofHeidelberg:

Genetics,

FRG. Submitted Land

ofPathology

University

German

Cancer

14, /986;

accepted

Tumorzentrum

Wurttemberg

the

and

Department

of Internal

the

Instituzefor

Immunol-

Research

Center,

Heidelberg,

November

1, 1986.

Heidelberg/Mannheim (Forsch

and

the

ungsschwerpunkiprogramm

17.9).

Address gisches 220,

reprint

Inslitut D-6900

requests

der

to PD Dr med

Heidelberg,

The

publication

costs

ofthis

article

payment.

This

article

must

“advertisement”

Mbller,

Im

Neuenheimer

in

PatholoFeld

FRG.

charge indicate

Peter

Universit#{228}t Heidelberg,

accordance

with

were

defrayed

therefore 18

U.S.C.

in part

be hereby §1 734

by page

marked solely

to

this fact.

© /987 by Grune & Stratton, 0006-4971/87/6904-0019$3.OO/O

Inc.

1087


MOLLER

1088

Table Age

Case Patient

1

B.M.

Data

at

Clinical

Diagnosis

No.

1 . Clinical

Sex

lyears)

F

19

First Clinical Symptoms

Left breast facial

Primary Localization

venectasies;

Preliminary

Cell Morphology Tumor

(Para-)

edema

Large,

Diagnosis

polymorphic

Hodgkin’s

thymic

disease

Radiation

F

2 1

B-symptoms: night weight

3

WI.

F

3 1

Mediastinum

fever,

Large,

polymorphic

Malignant

sweats,

lym-

liver infiltrations

abdominal

loss

Thoracic

phoma

pain (left);

Mediastinum

Large

dry cough

and medium-

sized,

Malignant

poly-

lymphoma

morphic

4

LI.

F

35

Painful

right

thorax; G.S.

F

35

Mediastinum

Relatively

moderate

dyspnea 5

shoulder/

Thoracic

monomorphic

lym-

5.5.

F

43

Thoracic with

Mediastinum

Medium-sized relatively

on exertion

to

Thymoma

small,

piratory after

M

monomorphic

venectasies

Mediastinum

found

effusion

death

insufficiency

due to rae1 1 months

diagnosis

Local progression;

abdominal

lymph

involvement

node

Local proession;

Malignant

monomorphic

lymphoma

enlargement

Mediastinum

Medium-sized,

in a routine

lung involvement; lymphomas;

due to respiratory

Medium-sized,

cervical

Mediastinal

22

10 months lung involve-

and pericardic

retroperitoneal

intumescence KM.

7

death with

progression;

12 months

6

after diagnosis

progression;

ment

tracheo-

pneumonia;

fistula;

22 months

after diagnosis Local

and

lymphomas;

phoma

dry

moderate

dyspnea

Malignant

on exertion pain,

cough,

small,

Local

Intervention,

and Chemotherapy

Progression;

death

F.M.

Course

After Surgical

esophageal

2

ET AL

Hodgkin’s

polymorphic

disease

piratory after

diagnosis

after

Local pro’ession;

death

insufficiency death

insufficiency

due to res18 months

diagnosis

Presently

in complete

after combination

remission chemotherapy

X-ray 8

5G.

M

29

Cervical

swelling;

facial

and brachial

Do ne on th e basi s of routine applied

in 7 cases,

remission

hematoxylin was

achieved

(Pare-)

edema

and eosin in only

Medium-sized,

thymic

sect ions for rapid 1 case

(patient

7,

who received combination chemotherapy comprising endoxan, holoxan, vincristine, and prednisone [CHOP]). Five patients died I 0, 1 1 , I 3, 18 and 22 months after initial diagnosis of extensive disease and large thoracic tumor masses causing respiratory insufficiency (Table I). Tumor tissue. Fresh tissue was transferred to our laboratory immediately after surgical removal. Representative samples were quick-frozen

in liquid

nitrogen.

Frozen

sections

(4

to 6 Mm)

were

fixed in acetone for 10 minutes at room temperature, and immunostained immediately or stored at - 20#{176}C for I to 3 weeks. Another sample was fixed in Bouin’s fixative for routine processing purposes; histochemical stains from the paraffin-embedded material were achieved by using hematoxylin and eosin (H & E), periodic-acid Schiff’s (PAS), Giemsa, and the Gom#{246}rireticulin method; immunostaining of paraffin sections was preceded by bleaching and destruction of endogenous peroxidase by methanol/ H2O2. Reagents. Monoclonal antibodies (MAbs) to 1gM (R1/69) and IgD (IgD26), to the leukocyte common antigen (2Bl I and PD7/26), and anti-Ki-I were obtained from Dakopatts, Copenhagen. MAbs against the T4 antigen (anti-Leu-3a (5K2)), the T8 antigen (antiLeu-2b (SK3)), (163-42) and A (1-155-2) light chains, to the interleukin-2 (1L2) receptor (2A3) and the CD22 antibody antiLeu- I 4 were purchased from Becton Dickinson, Mountain View, CA. MAbs to the TI I , T6, and T3 antigens were obtained from New England Nuclear, Seattle (Lyt3) and Ortho Diagnostics, Raritan, Ni (OKT6, OKT3), respectively. MAbs to common-ALL antigen (cALLa) (J5), to the B cell antigens CD2O (BI), CD2I (B2), CDI9 (B4), and mAbs PC-I and PCA-l, both directed against plasma air-dried

overnight,

cell-associated Hialeah,

FL.

antigens, MAbs

were

specific

furnished to framework

by

Coulter determinants

Immunology, of

HLA-

Malignant

monomorphic

Pro’ession;

liver,

lym-

adrenal

gland

phoma

lymphomas

kidney, infiltrations;

and cervical

notification.

(W6/32) B cell activation

HLA-DR (2.06), and Blast-2, reacting with a (CD23 antigen) were generous gifts from the producing laboratories (given in references in Table 2); the B cell reagents HD6, HD28, HD37, HD237, HD39, and HD5O are products of some of us (B.D., G.M., 5K.), as is the antibody HEA I 25 that reacts with a surface glycoprotein (Egp34) restricted to normal and neoplastic epithelial cells (G.M., F.M.). A polyclonal biotinylated sheep antibody to mouse Ig and a streptavidin-biotinylated peroxidase complex, both obtained from Amersham Buchler, Braunschweig, FRG, served as detection system for the monoclonal primary antibodies. Unconjugated rabbitderived antisera to human -, a-, -, ic-, and A-chains, swine anti-rabbit Ig serum and peroxidase-rabbit antiperoxidase complex were purchased from Dakopatts. Anti-human 6-chain and i-chain sera were obtained from Nordic Immunology, Tilburg, Netherlands. Pooled human lgG (Gamma-Venin) was supplied by Behringwerke, Frankfurt, FRG, 3-amino-9-ethyl carbazole (AEC) and N’Ndimethylformamide (DMF) were obtained from Sigma, St Louis. Staining procedures. MAbs in culture supernatants were used undiluted; ascites preparations were used as 1 :200 dilutions. The anti-mouse Ig antibody was diluted I :50, and the streptavidinperoxidase complex was diluted 1: I 00. Dilutions of primary antisera ranged from I :50 to I : I 500; the anti-rabbit Ig antiserum was diluted I :20, and the peroxidase-antiperoxidase complex was diluted 1:100. All dilutions and washing steps were carried out in phosphatebuffered saline (PBS); the secondary antibody solution contained 5% pooled human IgG to inhibit cross-reactions with human surface 1g. Incubation times of tissues were I hour at room temperature for the primary antibody (respective antiserum) and 30 minutes for the second-step and third-step reagents. Using AEC as the chromogen (0.4 mg/mL in 0.1 mol/L of acetate buffer pH 5.0 with 5% DMF and 0.01% H202 for 10 minutes), the peroxidase reaction resulted in A,B,C

and

antigen

rny-,


MCCL

OF B CELL

TYPE

1089

Table

2.

Antigens

Detected

Antigen

an d Primary

Antibodies

MW KD

Used

in This

Study

Clone

Source

(Reference)

MHC B. C

HLA-A, HLA-DR

B cell-associated

12;45

W6/32

Barnstable

29;34

2.06

Charron

and McDevitt

et al (28)

Warnke

et al (30)

Leukocyte

common

cALLa(CD1O) B cell-restricted

200

PD7/26,

100

J5

Ritzetal(31)

2B 1 1

HD37

Pezzutto

B4

Nadleretal(33)

antigens

CD 19

95

CD 20

et al (32)

35 140

B1

Stashenko

CD21

B2

Nadleretal(35)

CD 22

135

HD6

Moldenhauer

HD39

Darken

Leul4

Schwarting

Blast-2

Thorley-Lawson

HD5O

(author’s

laboratory) et al (2)

CD 23 Plasma

45

cell-associated

et al (34) et al (36)

et al (37) et al (38) et al (39)

antigens

Plasma-cell

antigen

28

PC- 1

Anderson

Plasma-cell

antigen

24

PCA-1

Anderson

antigen

45

OKT1O

Reinherz

antigen

1 16/126

Ki-1

Stein

lL2 receptor

60

2A3

Pali et al (unpublished

T10

(29)

antigens

et al (3) et al (4)

Varia Ki-1

et aI (40)

(Becton

observations)

Dickinson)

T cell antigens Til

55

9.6

Kamounetal(41)

T6

49

OKT6

Reinherz

et al (4)

T3

19

OKT3

Reinherz

et al (42)

T4

55

SK2

Evansetal(43)

32;43

SK3

Evans

HEA125

Momberg

T8 Epithelial

Egp34 MHC.

major

34 histocompatibility

using

paraffin

negative method. MHC and

result Intrinsic antibodies

macrophages

on

and the

No staining

controls interstitial

that,

by their

reaction and thus controls were performed rum).

sections tissue

were

the

gled granulocytes was not destroyed.

frozen tumor

positive

was

from was

for

the

staining,

cells, indicated

except

sections

the

to ensure

and

not

that

due

primary for the

whose

antibody reaction

a

cells,

reliability

results.

endogenous

of

Negative (antiseof intermin-

(Fig

as

The

large

as the

further

lin fiber

characterized scaffold;

case

by an alveolar I showed

a diffuse abundant

even resembled Hodgkin’s immunophenotype.

Reed-

Sternberg cells. The nucleoli were predominantly small and mostly singular. In cases I and 2, the tumor cells are best described as large and pleomorphic; in case 3 as mixed, large

peripheral

histologic

picture

to microalveolar reticupronounced sclerosis. In

the

pleomorphic

resembling

monomorphic. twice

with any of the morphologically defined B cell listed in the current classifications. The histoof these lymphomas resembles either pleomor-

cells

nuclei

but

were

compatible lymphomas morphology

but varied considerably in size. The to very irregular; one tumor contained nuclei, and a second revealed giant

extremely

small

however,

conclusion,

cytoplasm in common nuclei were roundish cells with multilobated with

relatively

cells,

diffusely infiltrating normal lymphocytes that were a regular constituent of the lesion. Tumor necroses, mostly ill-defined and small but never confluent, were observed in six cases. Mitoses were numerous and always typical. Even more frequent were single-cell degenerations. The tumors were

phic

Most of the tumors showed 1). The cells had clear and

to tumor

6 and 8 as 1) as mixed,

peroxidase

RESULTS

Histomorphology. growth pattern

medium-sized smallest

of the

endothelial the

and medium-sized and pleomorphic; in cases medium-sized monomorphic; and in case 5 (Fig

to the

immunoreactivity

false-negative

by omitting observed,

tonsils

reliable

dendritic

excluded

in frozen

et al (44)

complex.

an intense red precipitate. The sections were counterstained with Harris’ hematoxylin and mounted with glycerol gelatin. Controls. To obtain reliable results, the detection of Ig components was performed twice, using antisera on paraffin sections and mAbs on frozen sections. Positive controls were made at the same time,

et al (43)

antigen

T cell lymphoma

of these

tumors

or thymoma;

disease. (Table 3)

The

was

not

in two cases,

tumors

were

it

LC

and HEA125 and thus clearly defined as nonepithelial in nature. They all expressed the B cell-restricted antigens CDI9 and CD2O, as could be shown by the binding of mAbs HD37, mAbs cases; expressed

HD237,

B4,

and

BI,

showed minor differences B4 failed to react with on the tumor

cells

respectively.

The

first

three

in binding intensity in five tumors 3 and 7. CD22 was

of six cases

but was

undetectable


MOLLER

1090

ET AL

in cases 3 and 8. CD23, a putative B cell activation antigen, was present on tumor cells ofcases I and 4 (Fig 2) and on a minor part of the neoplastic cells of cases 7 and 8. Two other activation antigens, Ki-l and the IL 2 receptor, could not be detected. chains,

Immunoglobulin constituents (heavy and J chain) were not detectable in the whole tumor

in either

the cytoplasm

or on the surface

of various light and heavy chain mature, morphologically typical ever, were very scarce. minute islands of small, surface

1gM

(Fig

3).

In

addition, one round lymphoid

The

Ig

neoplastic

case contained cells carrying

cells

of

every

case

bound

population and in a varying number 2, and 4. MAb OKTIO, also known reacted

population detected cies

cells.

was present only in cells, which, how-

PC- I , a mAb recognizing a plasma cellantigen (Fig 4). PCA-l, another mAb of this reacted in cases 5 and 6 with the entire neoplastic

strongly associated category,

cells,

of the tumor

classes plasma

light series

with

tumor

2 and

of tumor cells of cases I, to bind to normal plasma

with

parts

of the

neoplastic

of case 4 CALLA and CD2I could not be in either case. The tumors showed variable deficienMHC antigen expression: at least two cases com-

in

pletely lacked class I and class II antigens (Fig 5); a third case (case 6) contained only a very small number of scattered HLA-ABC

Fig 1 . Primary mediastinal clear cell lymphoma of B cell type: Case 5. Predominantly medium-sized tumor cells with very pale cytoplasm and roundish nuclei, diffuse growth pattern. Arrow: vessel surrounded by normal peripheral (T) lymphocytes. Hematoxylin and eosin; original magnification x 140.

origin,

3.

Antigen-Expre

ssion

of Tumor

Cell s in Eight

HLA-DR

cells

large

cells

(Fig 6); although be completely ruled

it cannot

among

probably out that

the of those

unreachistiocytic cells were

part of the neoplastic population. Four other tumors tamed varying proportions of MI-IC antigen-deficient plastic

Table

and

tumor

tive

Cases

cells.

The

coordinate

of lg-Mediastinal

Clear

expression

Cell Lympho

ofclass

I and

conneoclass

II

ma of B Ce II Type

Patient

Clone

Antigen

1, B.M.

2, F.M.

3, WI.

4, LI.

W6/32

-

+

-

HLA-DR

2.06

±

+

-

LC

PD7/26and

+

+

+

+

+

2B1

CALLA(CD

10)

CD19

± +>-

6, S.S.

5, G.S.

HLA-ABC

-

>

-

+

8, S.G.

-

±

-

+

+

+

+

->>+

+>-

7, KM.

1

J5

-

-

-

-

-

-

-

-

HD37

+

+

(+)

+

+

+

+

(+)

HD237

+

+

+

(+)

+

-

(+)

(+)

+

±

+

84

+

+

-

+

CD2O

Bi

+

+

+

+

+

+

+

CD21

B2

-

-

-

-

-

-

-

-

CD22

HD6

+

+

-

+

(+)

+

+

-

+

-

CD23

Plasma

cell-associated

antigen

antigen

lL2receptor T cell antigens

T6. Ti 1, T3, T4, T8

+

HD39

+

+

-

+

+

+

Leul4

+

+

-

+

+

+

Blast-2

+

-

-

+

-

-

±

±

HD5O

+

-

-

+

-

-

-

-

PC- 1

+

+

+

+

+

+

+

+

PCA-1

+

-

-

->>+

-

-

-

-

OKT1O

-

+

-

->+

-

-

-

-

-

-

-

-

-

-

-

-

Ki-1

-

-

-

-

-

-

-

-

2A3

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Ig (cytoplasmic/surface) Ki-1

(+)

OKT6,

Lyt3,

OKT3.

(+)

-

Leu3a,

Leu2b Egp34

.

-

,

HEA125 Negative;

+

,

positive

negative tumor cells clearly

reaction outnumber

on the entire positive

ones;

-

tumor -

-

cell population; >>

+ , very

(+

-

),

few scattered

weakly

positive

-

-

positive; cells,

±

, positive

putative

and negative tumor

cells.

-

tumor

-

cells in equal

-

parts,

+,


MCCL

OF B CELL

TYPE

1091

Fig 2. Case 4. Monoclonal the activation-associated CD23 to the

tumor

of the x122.

cell

population

lymphoma.

but

antibody antigen not

Immunoperoxidase;

(MAb) HD5O recognizing bound in varying intensity

to the

stromal

original

cell

component

magnification

Fig 4. Case 8. Monclonal plasma cell-associated antigen cell

population.

Negative

Immunoperoxidase;

antibody (MAb) bound strongly

connective

original

tissue

magnification

PC-i recognizing a to the entire tumor fibers

are

Fig 3. Case 2. Demonstration of 1gM by monoclonal antibody (MAb) Ri /69. The large tumor cells were devoid of detectable 1gM whereas scattered reactive small lymphocytes stained strongly. thus excluding a false-negative result. Immunoperoxidase; original

Fig 5. Case 5. Monoclonel antibody (MAb) W6/32 stained dendritic interstitial cells and small infiltrating cytes but did not bind to the tumor cell population. thus

magnification

original

x 305.

its

abnormal

loss

magnification

of

HLA-A.B,C

x 122.

molecules.

apparent.

x 133.

strongly Iymphoindicating

Immunoperoxidase;


1092

MOLLER

involvement

of pericardium

the patients Trump and involvement

aggressive

involvement

in Perrone’s

antineoplastic and

sion,

but

in three

of

and Mann’s group, and 3 times in our The chest wall was the most frequent site

of extrathoracic

of our patient

examination

of Levitt and colleagues, I of the patients of Mann, and in 2 of the patients of our series; lung was noted twice in Levitt and colleagues’ group,

3 times in Trump group of patients.

Levitt

at initial

ET AL

colleagues

neither

series.

treatment, reached

of Trump

a transient

and

patients was regarded developed leukemia.

When

10 of the

Mann’s

given

patients

complete

patients

of remis-

and

only

one

as disease-free afterwards. Progressive disease, relapse,

No and

chemotherapeutic failure was commonly noted. Four of the patients of Levitt and colleagues, 8 of Trump and Mann’s, 20 of the patients of Perrone and colleagues, and 5 of our patients were dead at time of publication, with a survival time

ranging

Trump we are

from

clinical

cells

but

stained

interstitial

antibody failed

dendritic

(MAb) 2.06 recognizing a to react with the tumor

cells

and

a small

of large scattered cells. most probably of histiocytic noperoxidase; original magnification x 195.

antigens cell

was

small

T6,

lymphoid

the

tumor

vessels

only in case

noticed

antigens

TI I, T3, cells

cells (Fig

I).

series

is characterized expression, by the

, CD2

CD20 ing

that

various

of

case. eight

and

represent

tumors

with

around blood mAb HEAI25

polymorphic

complete

against T stained

amounts

by variable defects constant phenotype

I , PC- I

they

in

Immu-

mediastinal

in MHC CDIO,

CD19,

differentiation.

aspects,

the clinical

non-Hodgkin’s

resemble

those

colleagues,25 leagues.27

As

of

Brittinger

and

there

seems

nal

“null”-cell

and

colleagues,

the

patients

has

to be a clear

ratio female

Levitt

and

male

predominance

to females

predominance

(eg, 9:1),

for mediasti-

lymphoma: 6 of 12 of the patients of Levitt 7 of I I of the patients of Trump and Mann,

mediastinal

mass,

,

cell phenotype never plasmocytic. neoplastic hairy cell

(Ku

T cell

,

antigens),

and Nine

colleagues and 6 of 8 of those of Levitt and and 85%

7 of our

patients of Perrone and

there

was

chest initial

additional

by

common

to all the

a terminal B cell differentiaby the presence of the plasma in 8 of 8, PCA-1 in 5 of 8, and that at least a partial plasma

is expressed although On the basis of the

cells, Anderson leukemia as a

and tumor

Plasmacytoma, plasma cell reported to express PCA-I

cytomorphology PCA-1 reactivity

is of

co-workers45 characterize of the pre-plasma cell.

leukemia, and myeloma PC-I ,2 and (OK)Tl0.’47

are On

other hand, the diffuse large cell lymphomas of B cell analyzed by Freedmann and co-workers48 failed to express PCA- I and PC-I , a finding that caused them to argue that these tumors are the neoplastic counterparts of normal B cells at the midstage of differentiation. Based on type

of cell

Perrone and colT lymphoblastic

group were aged s35 years. Cough, and venous obstruction were common from

with

mediastinum by

of males

colleagues, 8 of Trump and Mann’s, were younger adults ( 1 9 to 37 years);

Apart

patients

the

described

pronounced

colleagues,2’

43 of 60 of the patients of Perrone of those in our series were female.

colleagues’ dyspnea,

ofour of

Trump and Mann,26 and compared with mediastinal

which

lymphoma,

features

lymphoma

given

are B cell lymphoscheme given by CDIO, CD19,

observations

the

immunophenotype

of the

lymphomas described herein indicates that novel B lymphoma type. It might be placed

DISCUSSION

In several

CD2I

these tumors differentiation LC,

tumors of our series, suggests tion. This view is supported

these

primary

survival

the

antigen

Ig deficiency, suggestterminal B lymphocyte

of

CD20,

finding is that to the B cell immunophenotype

cell-associated antigens PC-I TI0 in 2 of 8 tumors, indicating

directed exclusively

T8

occasionally crowded epithelium-specific

in neither

tumors

2. MAbs

and

interspersed

and The

showed reactivity In sum, this

T4,

proportion

origin.

median

To conclude, we feel that type with a rather distinct

picture.

Our central mas. Referring Nadler,’ the Fig 6. Case 6. Monoclonal HLA-DR framework determinant

4 to 22 months;

and Mann was 16 months. dealing with a lymphoma

midstage

differentation

tumors.

regarded

This

cell

as the malignant

alternative cell,

and

tumor

pathway

also

known

counterpart

which

morphology

and

observations). Nevertheless,

plete

pain, signs.

(discussed unknown

tumor

express

loss

of

of Ig

CD22

alternatively

that

PCA-l

(P.

with

the

has

been

observed

to occur origin. antigen,

of an B

“immature cannot

differentiation that monocytoid are

be

stage

the monocytoid

so-called

sinus

be located

M#{246}ller,unpublished normal

mature

by

several

B cell,

lacks in This comauthors

in large cell B lymphomas Two of our tumors failed

as could

in

scheme. In this B cells have clear

MCCL exhibit considerable There are no Ig constituents.

previously) or follicular the

of the

as compared

the tumor cells antigen expression.

leukemia/plasma

of the final

is a B cell

current physiological context, it is noteworthy the

cell

cell might

of B cell development: as the cell

histiocytosis,”4952

hairy

variant

aleukemic

it is probably a between tumors

be verified

by staining

of to


MCCL

OF B CELL

with

three

ways.

1093

different

CD22

defect

TYPE

mAbs.

expression

in gene

This

may

expression

may

either or

differentiation.

Furthermore,

ularities

in the

of

defect

or

affinity CD23

of the

of eight defects,

is

epitope

expression

of the CD23

of MHC class tumors but one. describing lack

in malignant

lymphoma:

observed this lack in three lymphomas, and the Daudi fl2-microglobulin,54 molecule. Because

to

within

DR

to a lesser the the

antigen

of functional be suspected because

must

several

irreg-

in six

nature. Severe of the partial or I molecule (HLATo our knowledge, of class I antigen

Woda

and

is part

of the

I antigens

ments of T cell-mediated cytotoxicity,55 HLA-A,B,C-deficient tumor cells possibly escape immune attack by cytotoxic T cells.56 This may account for the clinical aggressiveness of the

primary mediastinal Six of eight of the defects in expression

B cell lymphomas. tumors had either of the HLA-DR

probably

negative

2.06.

Our

were

evaluation

neoplastic

cells

partial or complete framework deter-

Defects

lymphomas

underestimates

the

the real population

were

as

by parallel

antigens. neoplastic

For multiple myeloma, plasma cells lost their

entering the terminal we discuss this stage down-regulation more unlikely

reactive

small

T cells,

with

it was class

as

mAbs

Although group,

neoplastic

of clear

a

seems loss, ie,

since all tumors I antigen-deficient.

for B cell activation63’65 expression

contribute B cells

might

of the

was

to T cell

assumed that the II antigens while

expression also class

transducers

by

of nonreactivity

intermingled

stained

a defective

molecules

lymphoma

noted for HLA-

stage of differentiation.4542 of development for our tumor

are Thus,

trigger

II antigen

of MHC class II antigen expression to us than assumption ofa pathological

II antigens

entiation

extent

since

regarded sections

in class

sporadically

of the staining

suggested

maturation.

class I ele-

as restriction

authors.57

Class

co-workers53

heterodimeric

serve

by mAb

in B cell

a further defect in antigen lacking class II molecules were

cases of large “histiocytic” B cell cell line is known to be devoid of

which class

recognized

expression

of

failed

or just

probably

complete nonexpression A,B,C) observed in all very few reports exist

minor

be answered. Because related to activation,39

nonexpression

tumors however,

a

course

HD237

minant

two by

cells of case 3; B4 did not this is due to inaccessibil-

corresponding

or complete

are

mAbs:

of these antibodies cannot antigen seems to be closely

partial

in

impaired

in the there

CDI9

react with a subset of neoplastic recognize tumors 3 and 7. Whether ity

interpreted

been

abrogated

terminal

binding

be

have

of these

and

important

to the incomplete differin the primary mediastinal

cell type. ACKNOWLEDGMENT

We are indebted to Dr H. Schmitteckert from the LVA-Klinik f#{252}r Thoraxkrankheiten (Heidelberg/Rohrbach) for supplying clinical data, to Ingeborg Brandt and iohn Moyers for technical assistance, and to Christine Raulfs and Hans-Ulrich Burkhardt for help in editing the manuscript.

REFERENCES I

.

Nadler

LM:

comments,

(eds):

B cell/leukemia

in Reinherz

Leukocyte

Typing

2. Anderson Nadler

KC,

LM:

normal

EL,

II. New

Bates

neoplastic

Nadler

Springer,

and

Bernstein

ID

reactivity

i Immunol

4.

Reinherz

EL, Kung

Discrete

of normal Proc

NatI

stages

PC, Goldstein

of human

restricted

132:3172,

G, Leven

intrathymic

to

RH,

Schlossman

differentiation:

thymocytes and leukemic lymphoblasts Acad Sci USA 77:158, 1980

7. Pelicci

cell”) their 8.

50:735,

Knowles PG.

L, Burke

F, Dalla-Favera

TM,

Identification

of two

ma. Lab Invest

A,

characterization panel

Mi,

major

51:504,

9. Al-Katib by a new

Hicks

R,

iS, Wang Wang

CY:

iolley

B cell

CS,

forms

Rangel

of nodular

JYM, S1g,

Bonetti E,

ML, Trela

(CLL)

leukaemia

3:261,

H, of the

Lab

Invest

Bj#{246}rkholm M,

HoIm

leukaemic

cell

in relation

to disease

G:

population

Surface in chronic

activity.

1-lema-

1985 BN,

Sheibani

K, Winberg

CD,

Burke

nuclei

iS, Rappain follicular

CR, Colby TV, Marty J: Multilobated of 7 cases. Hematol Oncol 3:79, 1985

Kjeldsberg

A study

I, Palutke M, Tabaczka P, Goldfarb S, EisenMSY: B-cell lymphomas morphologically resembling lymphomas. Cancer 56: 1578, I 985 Mirchandani

I 5. Parfrey NA, Mann nant large cell lymphoma Cancer55:19l3, 1985

determination 1985 CS,

Jones

mixed

origin.

of

tance

17.

RB, Selonick SE, Beschorner WE: of B-cell type with multilobated

Malignuclei.

Linch

DC, Jones HM, Berliner N, MacLennan K, O’Flynn ER, Kay LA, Goff K: Hodgkin-cell leukaemia of B-cell Lancet 1:78, 1985

antibodies.

Weiss

LM,

Warnke

Gatter

KC,

of analysing

immunohistological SE:

lympho-

Hematol

Oncol

R, Sklar

i: Most

HS:

Johnson Hodgkin’s

Alcock

C, Heryet

malignant techniques.

18. Lukes Ri, human malignant 19.

monoclonal

Mi,

T-cell

F,

(“null-

3:271, 1985

10. Cleary

neoplasms.

L, Pak

16.

1984

of

B lineage

port H: Neoplastic B cells with cerebriform lymphomas. Hum Pathol 16:173, 1985

14.

Wang CY, Bardales R, Koziner B: Phenotypic of “non-T, non-B” acute lymphoblastic leukemia (BL)

Mellstedt pattern

Nathwani

12.

are

K, Huehns

non-Hodgkin’s lymphomas. Multiparametric B- or T-cell lineage. Am J Pathol l 20:356, Grogan

lymphocytic

berg

1984

DM II, Dodson Flug

E,

immunoglobulin

lineage.

6. Gregg EO, Al-Saffar N, iones DB, Wright DH, Stevenson FK, Smith iL: Immunoglobulin negative follicle centre cell lymphoBr i Cancer

lymphomas

I 3. Weiss RL, B cell lymphomas.

Analysis

of T-cell

cell 1985

tol Oncol

1984

5. Horning Si, Doggett RS, Warnke RA, Dorfman RF, Cox RS, Levy R: Clinical relevance of immunologic phenotype in diffuse large cell lymphoma. Blood 63: 1 209, 1984

ma.

large

53:521,

I I . Kimby SF,

3. Anderson KC, Prak EK, Bates MP, Leonhard RCF, Schlossman SF, Nadler LM: Antigens on human plasma cells identified by monoclonal antibodies. J Immunol 130:1 132, 1983 SF:

null

1986, p 3 B, Schlossman

with

cells.

Summary LM,

Slaughenhoupt

antibody

plasma

workshop:

BF,

York,

MP,

A monoclonal

and

panel

Haynes

A, Mason DY: Clinical importumours of uncertain origin with Lancet I :1 302, 1985

Collins RD: Immunological lymphomas. Cancer 34:1488,

characterization

of

1974

DW, Hoppe RT, Cox RS, Rosenberg disease limited to intrathoracic sites.

SA, Kaplan Cancer 52:8,

I983 ,. 20. Otto HF: Pathologic Uhlinger E (eds): Spezielle Springer, 1984, p 227

des Thymus, pathologische

in Doerr Anatomic

W, Seifert G, Bd I 7. Berlin,


MOLLER

1094

21.

Brittinger

prognostic

G,

the

relevance

lymphomas.

Results

lymphoma

the

Kid

study

group:

classification

of

non-Hodgkin

study

by the

of a prospective

multicenter

Clinical

and

22. Weick

disorders.

ative

Comprehensive

non-Hodgkin’s

ing formulation. 23.

Am

Bernard

Lemerle

Boumsell

and

24.

Mohri

Oncol

N:

13:591,

25.

Melvin

L: Non-T, with

B-cell

Li,

non-B

lymphomas

Trump

Aisenberg

DL,

lymphomas

with

subset

AC,

Perrone

RB:

lymphomas tumor.

Harris

are

Blood

J,

rare

in

59:549,

1982

Jpn

J Clin

origin.

NL,

Diffuse

with

patients

Linggood

lymphoma

RM,

of the

large

mediastinal

T, Frizzera

with

Pathol

cell and

undifferentiated

involvement.

non-Hodgkin’s

Pop-

mediastinum.

prog-

A poor

lymphoma.

Cancer

G, Rosai

diffuse

large-cell

sclerosis.

10:176,

Barnstable

J: Mediastinal

A clinicopathologic

study

of 60 cases.

Ci,

Bodmer

MP,

Brown

G, Galfre

G, Milstein

C,

antibodies

to

by two-dimensional

surface

anti-

of HLA-D-

gel electrophoresis.

J Exp

Med

l52:18s, 1980 30.

Warnke

Pulford

RA,

Gatter

K, Cordell

Diagnosis bodies.

of human N

31.

Falini

KC,

B, de WoIf-Peeters

lymphoma

with

Engl J Med 309:1275,

Ritz

J,

Modulation induced by

B, Hildreth

JL, Cohen

Pesando

JM,

of human monoclonal

P. Woolston

C, Mason

monoclonal

antileukocyte

Notis-McConarty

SF:

125:1506,

Pezzutto

A,

D#{246}rkenB, Feller

A, Moldenhauer

R, Wernet P, Thiel E, Hunstein W: HD37 useful reagent for further characterization phoid

malignancies,

1986,

p 590

33.

Nadler

LM,

iF, Schlossman expressed

J Immunol

34.

Stashenko

Proc Nail 35. horst antigen

36.

Anderson

on normal,

of cell

Acad

KC,

Marti

distinct

from

II. G,

BF,

Nadler LM, Bhan AK, Schooley RT: cell surface marker of human B cell by Epstein Barr virus. J Immunol

Lennert

of

K:

Bates

and

LM,

Hardy

after

human

Characterization BI.

J Immunol

that

and

neoplastic

disease

lymphoid

associated

tissue:

Reed-Sternberg

1979

43. Evans RL, Wall Testa CM, Good RA: Inhibition

ofcell

DW,

Platsoucas

CD, Siegal

Thymus-dependent mediated

FP, Fikrig

membrane

lympholysis

SM,

antigens

by monoclonal

in

antibod-

Acad Sci USA 78:544, 1981 G, H#{228}mmerling GJ, M#{246}ller P: Immunohistochemical study of the expression of epithelium-specific antigen Egp34 in normal and malignant tissues using monoclonal antibody HEA125. Cancer Res (in press) 45. Anderson KC, Boyd AW, Fisher DC, Leslie D, Schlossman SF, Nadler LM: Hairy cell leukemia: a tumor of pre-plasma cells. ies to the TH2 44.

antigen.

Momburg

Proc

F,

NatI

Moldenhauer

1985

1:761, 1986

Freedman Schlossman

AS, Boyd AW, Anderson KC, SF, Nadler LM: Immunologic

Fisher DC, Pinkus heterogeneity of

large

cell H,

Nadler

Immature sinus population. Am J Pathol I 17:44, 1984 50. Dc Almeida PC, Harris NL, Bhan AK: Characterization of immature sinus histiocytes (monocytoid cells) in reactive lymph nodes by use of monoclonal antibodies. Hum Pathol 15:330, 1984 5 1 . Sohn CC, Sheibani K, Winberg CD, Rappaport H: Monocytoid B lymphocytes: Their relation to the patterns of the acquired immunodeficiency syndrome (AIDS) and AIDS-related lymphadenopathy. Hum Pathol 16:979, 1985

LM,

Springer, E, Daley

antigen B lymphoSF:

Expres-

activation.

52.

R, van Agthoven 128:1941,

Hodgkin’s

Evidence cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66:848, 1985 41 . Kamoun M, Martin Pi, Hansen JA, Brown MA, Siadak AN, Nowenski R: Identification of human T lymphocyte surface protein associated with the E-rosette receptor. i Exp Med I 53:207, 1981 42. Reinherz EL, Kung PC, Goldstein G, Schlossman SF: A monoclonal antibody with selective reactivity with functional mature human thymocytes and all peripheral human T cells. J Immunol

antigen

Stein

malignant

human

the

J, R,

49.

B lymphocyte

ofa

expression

Ki- 1 in reactive

N, Wainscoat H, Schwarting

diffuse

M, Park

R, Schlossman

The

Gerdes J, O’Connor B, Delsol G, Lemke

antibody: A non-B” lym-

York,

New

leukemia.

GS,

1983

markers

SF:

Haynes

3 (alpha Blood 65:974,

G, Schwartz

B-lymphocyte-associated

Sci USA 78:3848, 1981 LM, Stashenko P. Hardy

C, Schlossman (B2)

EL,

Typing

mitogen-activated,

131:244, P. Nadler

surface

Nadler

Reinherz

Leukocyte

SF: B4, a human

cytes. sion

in

ID (eds):

Bernstein

monoclonal of “non-T,

cell

antibod-

S-HCL

Thorley-Lawson DA, (EBVCS), an early activation, is superinduced 134:3007, 1985 40. Stein H, Mason DY, Pallesen G, Gatter K, Falini 39.

Blast-2

48.

1980 32.

of hairy

monoclonal

46. San Miguel iF, Caballero MD, Gonzales M, Zola H, Borrasca AL: Immunological phenotype of neoplasms involving the B cell in the last step of differentiation. Br i Haematol 62:75, 1986 47. Erber WN, Mynheer LC, Mason DY: APAAP labelling of blood and bone-marrow samples for phenotyping leukaemia. Lancet

antigen

J Immunol

alpha

Blood6S:620,

anti-

leukemia

The

and

RE,

J, Schlossman

lymphoblastic in vitro.

CY:

Leu-l4)

DY:

1983

acute antibody

H, Wang

1985

man:

AF, Ziegler A: Production of monoclonal group A erythrocytes, HLA and other human cell gens-New tools for genetic analysis. Cell 14:9, 1974 29. Charron Di, McDevitt HO: Characterization antigens

Am

1986

Williams

region

Caillaud

R, Stein

S-HCLI (alpha allow the diagnosis

123:1312,

1982

27.

28.

Mann prominent

of

50:277,

J Surg

work-

WP,

ofextranodal

S: Primary non-Hodgkin’s Cancer 50:2486, 1982

lymphoma

S. Bowman

cutaneous

pema

nostic

including

international

1983

Levitt

26.

cases

564

by the

I 13:207, 1983

SB,

associated

of

classified

J Pathol

A, Murphy

J,

childhood

evaluation

lymphomas

Schwarting

alpha

Leu-M5)

Kid

group.

study

38. ies

Hematol Oncol 2:269, 1984 Tubbs RR, Fishleder A, Weiss RA, Savage RA, Sebek BA, JK: lmmunohistologic cellular phenotypes of lymphoprolifer-

lymphoma

257

Kid

of

ET AL

A, Ter-

B cell-specific 1981

Moldenhauer G, D#{246}rkenB, Schwartz R, Pezzutto A, H#{228}mmerling Gi: Characterization of a human B lymphocytespecific antigen defined by monoclonal antibodies HD6 and HD39, in Reinherz EL, Haynes BF, Nadler LM, Bernstein ID (eds): Leukocyte Typing II. New York, Springer, 1986, p97 37. D#{246}rkenB, Moldenhauer G, Pezzutto A, Schwartz R, Feller A, Kiesel 5, Nadler LM: HD39 (B3), a B lineage-restricted antigen whose cell surface expression is limited to resting and activated human B lymphocytes. J Immunol 136:1, 1986

sinus

Pins

148:159, 53.

MA,

histiocytosis:

54.

Woda

65:630,

1985

Rivas

C, Morente

M, Oliva

A

monocytoid

B-lymphoid

H, Rubio

BA,

Racklin antigens

B, Rappaport

“B”

on

F, Fellous

M, Dron beta 2-microglobulin

by interferon.

H:

large

Altered

cell

i Pathol

expression

lymphomas.

Zinkernagel

Immunogenetics RM,

M, Tovey mRNA

of

Blood

M, Revel M: Presence of in Daudi cells: Induction

17:125, 1983 Doherty

PC:

MHC

cytotoxic

on the biological role of polymorphic major antigens determining T cell restriction-specificity, responsiveness. Adv Immunol 27:51, 1979 Studies

C: Immature

reaction.

1981 Rosa

an abnormal 55.

Blood

Lennert K, Mason DY, Liangru 5, Ziegler A: histiocytes. Their identification as a novel B-cell

1986

histocompatibility 57:802,

lymphoma.

T

cells:

transplantation function and


MCCL

56. and

OF B CELL

TYPE

Sanderson

AR,

1095

Beverley

immunoselection

Today4:2ll, 57.

in

the

PCL:

Interferon,

pathway

to

M,

K, Pollard

C, Cancino

Han T, Henderson E, Ozer H: Non-Hodgkin’s lymphoma Problems in the use of heterologous and monoclonal Leuk Res 7:523, 1983

ing:

Stein cal

Pallesen

G, Beverley

PCL,

of non-B,

non-T

H: Nature on

study

frozen

tissues

Lane

EB,

Madsen

monoclonal

59.

Anderson

antigens

SF,

terminal 63.

60. chemical

Bates LM:

Blood

Krajewski

and 63:1424,

AS, Guy

analysis

non-Hodgkin’s

61.

KC, Nadler

of

M, Mason

DY,

antibodies.

anti-class

II

Guy K, Krajewski

Slaughenhoupt

BL,

Immunol

J Clin

Pinkus

GS,

of human

B cell-associated

lymphomas:

A model

of human

64.

96:442,

MHC

J Pathol AS, Dewar

B-cell

excitation.

B cell

with

Clement class

complex class

Cossar II

D: Immunohistoantigens

145:185, 1985 AE: Expression

in

B-cell

class

ofhuman

Crow

1 20: 1 480,

MK,

Pernis

B lymphocytes complex

HG: the

1978 B:

Anti-

is inhibited antibodies.

by Cell

LoCascio

NJ,

Ovnic

M,

Haughton

G:

Two

II (Ia) molecules: T-cell stimulation and Proc Natl Acad Sci USA 82:516, 1985 LT, Tedder TF, Gartland GL: Antibodies reactive ofclass

human

encoded B cell

for

by the

activation.

major i

histocompatibility Immunol

136:2375,

I986

R, Martinez-Maza 0, Guy K: Monclonal antibodies HLA-DR antigens replace T helper cells in activation of B lymphocytes. Proc Natl Acad Sci USA 80:3456, 1983 66.

against of MHC

lympho-

1985

II antigens inhibit

N,

histocompatibility

RB,

functions

J Immunol

Agostino

stimulation

Corley

65.

1984 AE,

VR, major

and non-Hodgkin’s

Wang CY, Winchester R, Kunkel of human “Ia-like” antigens during

of B cell development.

immunoglobulin

Expression

K, Dewar

human

lymphomas.

MP,

J, Fu SM,

stages

leukaemia

1986

expression

Bonagura

separate

on leukemias

differentiation.

of

phenotyp-

Pathol 37:91 1, 1984 Schlossman

Patterns

antibodies.

An immunohistologi-

lymphomas:

using

M,

53:161,

Halper

62.

J, Minato

Minowada

B-cell

human

ma.

Immunol

1983

Barcos

58.

II antigens in Br J Cancer

f32-microglobulin

malignancy.

Palacios