Primary cutaneous B-cell lymphomas – Clinicopathological, prognostic and therapeutic...

ORIGINAL ARTICLE: CLINICAL

Primary cutaneous B-cell lymphomas – Clinicopathological, prognosticand therapeutic characterisation of 54 cases according to theWHO-EORTC classification and the ISCL/EORTC TNM classificationsystem for primary cutaneous lymphomas other than mycosisfungoides and Sezary syndrome

PHILIPPA GOLLING, ANTONIO COZZIO, REINHARD DUMMER, LARS FRENCH, &

WERNER KEMPF

Department of Dermatology, Cutaneous Lymphoma Study Group, University Hospital, CH-8091 Zurich, Switzerland

(Received 5 December 2007; revised 6 March 2008; accepted 18 March 2008)

AbstractClinical, prognostic and therapeutic features of 54 primary cutaneous marginal zone B-cell lymphoma (pcMZL), folliclecentre lymphoma (pcFCL) and diffuse large B-cell lymphoma, leg type (pcDLBL) were analysed applying the WHO-EORTC classification for cutaneous lymphomas and the new TNM staging scheme of the International Society ofCutaneous Lymphomas. Solitary (T1) or regionally clustered (T2) tumors were observed in pcMZL and pcFCL.Disseminated tumors (T3 stage) were found in 26% of patients with pcMZL and in one patient with pcDLBL. A completeremission was achieved in 41% of the patients. Three of 7 patients (43%) with pcDLBL died due to lymphoma. The newTNM staging system is easily applicable for disease documentation, but our relatively small number of patients in each Tstage does not allow the assessment of its prognostic value. Surgical excision or radiotherapy is highly effective in pcMZL andpcFCL.

Keywords: Cutaneous, lymphoma, B cell, staging, therapy

Introduction

In recent years, the terminology and classification

of primary cutaneous B-cell lymphomas (CBCL)

has undergone crucial changes. Major differences

in previous classifications such as WHO classifica-

tion [1] and EORTC classification for primary

cutaneous lymphomas [2] resulted in divergent

data on clinicopathological presentation as well as

prognostic and therapeutic aspects of CBCL. In

the new WHO-EORTC classification for cutaneous

lymphomas introduced in 2005 [3,4], classifi-

cation of CBCL was redefined and includes three

main entities: primary cutaneous marginal zone

B-cell lymphoma (pcMZL), primary cutaneous

follicle centre lymphoma (pcFCL) and primary

cutaneous diffuse large B-cell lymphoma, leg type

(pcDLBL).

Previous TNM staging systems did not sufficiently

reflect the biology and tumor burden of CBCL. Thus

a new TNM staging system has recently been

proposed for cutaneous lymphomas other than

mycosis fungoides (MF) and Sezary syndrome (SS)

[5]. This scheme has been elaborated by the ISCL

and EORTC Task Force Group for cutaneous

lymphomas and creates a T system accepted by

experts for cutaneous lymphomas world-wide. It

remains to be determined whether this T classi-

fication has any prognostic or therapeutic

implications [6].

Although the clinical, histological and immuno-

phenotypic features of CBCL have become more

Correspondence: Werner Kempf, Department of Dermatology, University Hospital Zurich, CH-8091 Zurich, Switzerland. Tel: þ41-44-255-25-50.

Fax: þ41-44-255-44-03. E-mail: [email protected].

Leukemia & Lymphoma, June 2008; 49(6): 1094 – 1103

ISSN 1042-8194 print/ISSN 1029-2403 online � 2008 Informa UK Ltd.

DOI: 10.1080/10428190802064925

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clearly characterised [7–11], staging and therapy of

CBCL are not yet standardised. This is in part due to

a lack of a widely accepted staging system for

CBCL and definition criteria for CBCL entities.

Furthermore, various new treatment modalities such

as monoclonal antibodies against CD20 (e.g. ritux-

imab) or intralesional gene transfer using adenovirus

[11,12] have been introduced. Data on the disease

extent and prognosis based on ISCL-EORTC TNM

staging system in CBCL are very limited [6].

Thus the aims of our study on 54 CBCL cases

were: (i) to characterise the clinical features of the

three main CBCL forms according to the recent

WHO-EORTC classification, (ii) to assess the value

of the new TNM staging system for staging, (iii) to

assess prognosis of the three subtypes of CBCL

with respect to the tumor stage and (iv) the response

to the various treatment modalities employed in

CBCL.

A description of the new TNM classification [5] is

given in Table I.

Materials and methods

In the files of our institute 212 patients with B-cell

lymphoproliferative diseases were identified between

1991 and 2006. A total of 136 cases were excluded

from further analysis, due to a lack of data on clinical

presentation or results of the staging examinations or

follow-up or lack of immunohistochemical or geno-

typic data, which did not allow appropriate classifica-

tion. Five CBCL cases belonged to CBCL entities

other than the three main forms (pcMZL, pcFCL,

pcDLBL) and 17 cases represented secondary

cutaneous involvement of primary nodal or extra-

nodal and extracutaneous B-cell lymphomas. The

remaining 54 cases were classified according to the

WHO-EORTC classification for cutaneous lympho-

mas (Table II). All patients had undergone complete

staging including chest X-ray, ultrasound examina-

tion of lymph nodes and abdomen as well as bone

marrow biopsy as suggested by the ISCL-EORTC

Cutaneous Lymphoma Task Force [5]. In none of

the 54 CBCL patients included in the study could

extracutaneous lymphoma infiltrate be identified at

the time of diagnosis or completion of staging

procedures. Histological review was performed on

HE stained sections and immunohistochemical

stainings including B-cell markers (CD20, CD79a),

bcl-2, bcl-6, MUM-1 (in DLBCL), immunoglobulin

light chains kappa and lambda and CD21 (to identify

networks of follicular dendritic cells indicating

germinal centre formation). Positivity for bcl-2, bcl-

6 and MUM-1 was defined by expression of those

markers by at least 50% of the tumor cells.

The following parameters were evaluated: Age at

diagnosis, sex, localisation, number and extent of

lesions at time of diagnosis according to the new

TNM staging scheme [5], diagnosis according to

WHO-EORTC classification for cutaneous lympho-

mas [3,4], length of follow-up (in months), interval

to first relapse, treatment modality (e.g. surgical

excision, radiotherapy, excision and radiotherapy,

antibiotics, chemotherapy) and response to treatment

of primary lesions (complete remission [CR], partial

remission [PR], stable disease, progressive disease),

response to as well as treatment modalities for

relapses, and outcome (alive with no disease, alive

with disease lymphoma, death due to disease

lymphoma, death due to other causes).

Statistical analysis was performed using SPSS

version 15.0. (SPSS Chicago II).

Results

A total of 54 CBCL patients were identified and

classified according to the WHO-EORTC classifica-

tion for cutaneous lymphomas as pcMZL (n¼ 31;

Table I. ISCL/EORTC proposal on T classification of cutaneous

lymphoma other than mycosis fungoides and Sezary syndrome.

Solitary T1 Small T1a 1 solitary lesion

�5 cm diameter

Large T1b 1 solitary lesion

45 cm diameter

Multiple T2 Small T2a All encompassing in

�15 cm diameter

Medium T2b All enc. in 415 cm

and �30 cm diameter

Large T2c All encompassing in

430 cm diameter

Generalized T3 T3a 2 non-contiguous

body regions

T3b �3 body regions

Table II. Epidemiological data of our series of CBCL patients.

No. of

patients (%)

Median age at

diagnosis

a) CBCL subgroup

pcMZL 31 (57%) 39 years

pcFCL 16 (30%) 59 years

pcDLBL 7 (13%) 78 years

Total 54 (100%) –

b) Sex distribution

Male 31 (57%)

Female 23 (43%)

Total 54 (100%)

CBCL staging and therapy 1095

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57%), pcFCL (n¼ 16; 30%) and pcDLBL (n¼ 7;

13%) (Table II). There were slightly more males

(57%) than females (Table II).

Clinical features and staging

pcMZL

The median age of patients at diagnosis was 39

years (range from 18 to 77 years) (Table II). In 12

of 31 patients (39%), the disease at onset featured

a solitary lesion (corresponding to T1) and in 11 of

31 patients (35%) multiple, but regional tumors

(corresponding to T2). In the remaining 8 patients

(26%), multiple disseminated lesions (correspond-

ing to T3) were present at diagnosis (Table III).

The predilection sites for pcMZL at diagnosis were

the upper back and upper arms, whereas head and

neck were the second most common site of tumor

localisation [Figure 1(b)]. In only a few cases were

tumors located on the lower legs and buttocks and

this was observed only in patients with dissemi-

nated tumors. Clinically MZL started with skin-

coloured or erythematous nodules [Figure 1(a)].

Ulceration was not observed.

pcFCL

The median age at diagnosis was 59 years (range

from 44 to 80 years). In 7 of 16 patients (44%), the

disease started with a solitary lesion (T1) and in 9 of

16 patients (56%) with multiple, but regional tumors

(T2). None of the patients showed multiple dis-

seminated lesions at diagnosis (Table III). The

predilection sites were the head and neck region

and the upper back [Figure 2(b)]. Tumors were not

found on the extremities in any of the patients.

Clinically FCL began with and stayed as erythema-

tous nodules and surrounding plaques [Figure 2(a)].

Ulceration was not observed.

pcDLBL

The median age at diagnosis was 78 years (range

from 52 to 98 years). The disease became apparent

due to a solitary lesion (T1) in 3 of 7 patients (43%)

and with multiple, but regional tumors (T2) in the

remaining 4 patients (57%). One patient showed

multiple disseminated lesions at diagnosis (Table

III). The predilection sites were the legs, but tumors

were also found on the head and neck and on the

upper arm in 1 of the 7 patients [Figure 3(b)].

Clinically DLBL started with erythematous to

violaceous nodules [Figure 3(a)]. Ulceration was

not uncommon in this CBCL subset.

Borrelia status and CBCL

Thirty-nine of the 54 patients (72%) were examined

for Borrelia infection. In 6 of 39 cases serological tests

were performed and were negative. In the remaining

33 cases DNA extracted from archival tissue was

examined by nested PCR. Borrelia DNA could be

detected in 4 of the 33 cases (12%).

Course and prognosis

pcMZL

CR was achieved in 14 of 31 patients (45%).

Recurrences were observed in 10 of these 14 patients

with CR (71%). In 9 of 10 patients (90%) relapses

occurred in the same body area where the primary

tumor was localised. Extracutaneous spread was not

observed in any of the patients. The average time

until recurrences occurred in pcMZL was 20

months. The detailed timecurve is shown in Figure 4.

None of the patients died due to lymphoma after a

mean follow up time of 5.4 years.

pcFCL

CR was achieved in 7 of 16 patients (44%).

Recurrences were observed in 3 of these 7 patients

with CR (43%) after an average period of 7 months.

All recurrences were observed in the same body area

as the primary tumor. Extracutaneous spread was not

observed in any of the patients during a mean follow

up time of 5.3 years. One patient died due to an

unrelated cause.

pcDLBL

CR was achieved in 1 of 7 patients (14%). The time

to this one relapse was 12 months, and it occurred in

a non-contiguous field. Progressive disease was

Table III. T stage of our CBCL patients at the time of diagnosis.

T stage

All CBCL

No. of

patients

pcMZL

No. of

patients

pcFCL

No. of

patients

pcDLBL

No. of

patients

T1 a 21 (39%) 12 6 3

b 1 (2%) – 1 –

T2 a 13 (24%) 7 6 –

b 9 (17%) 4 3 2

c 1 (2%) – – 1

T3 a 3 (6%) 2 – 1

b 6 (11%) 6 – –

Total 54 (100%) 31 16 7

1096 P. Golling et al.

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observed in 4 of 7 patients (57%) and 3 of these

patients died due to extracutaneous spread of

lymphoma after a mean follow up time of 1.4 years.

One patient died from a cause not related to the

cutaneous lymphoma.

Treatment modalities and response to

treatment

Surgical excison is an important therapy in pcMZL

and pcFCL. In these two subgroups of CBCL it

was performed not only in 10 of our patients with

solitary tumors (T1 stage), but also in 5 patients

with T2a, one patient with T2b and one with T3b

(Detailed description of categories is given in

Table I).

The treatment standard for radiotherapy of CBCL

at our clinic is a single dose of 2–4 Gy and 16–20 Gy

in total per field.

Our systemic antibiotic treatment of pcMZL and

pcFCL consists of doxycyclin 200 mg per day for 3

weeks.

Figure 1. (a) pcMZL – characteristic clinical presentation with non-ulcerated slightly reddish nodules on the trunk. (b) Distribution of

tumors in the group of pcMZL at the time of diagnosis. Body regions as defined by the TNM classification system for primary cutaneous

lymphomas other than mycosis fungoides and SS.


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pcMZL

First-line therapy included surgical excision in 11

patients (35%), radiotherapy in 2 (6%), and anti-

biotic treatment in 11 of 31 patients (35%)

(Table IV). For the remaining 7 patients (23%)

various therapies such as radiotherapy in combina-

tion with chemotherapy (CHOP) (n¼ 1), intra-

lesional injection of interferon alpha (n¼ 2) [13],

topical corticosteroids (n¼ 3) or topical chemother-

apy with BCNU (n¼ 1) were employed.

After surgical excision CR was found in 10 of

11 patients (91%) (Table IV). Even one patient

with T stage 3b with tumors on both upper arms

and on the upper back achieved CR after surgery.

After 10 months he had a relapse on the right and

left upper arm. In 8 of the 10 patients (80%)

with CR, the mean period until recurrence of the

tumor occurred was 17 months. CR was achieved

in both patients treated with radiotherapy. In 1 of

the 2 latter patients, the tumor relapsed in the

same body area 29 months later. Systemic

Figure 2. (a) pcFCL – characteristic clinical presentation with red nodules on the scalp. (b) Distribution of tumors in the group of pcFCL at

the time of diagnosis. Body regions as defined by the TNM classification system for primary cutaneous lymphomas other than mycosis

fungoides and SS.


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antibiotic treatment resulted in PR in 3 of the

11 patients (27%), but in no case did it result

in CR.

pcFCL

Initial therapy included surgical excision in 6 of 16

patients (38%), radiotherapy in 4 (25%), systemic

Figure 3. (a) pcDLBL – typical clinical presentation with multiple red to violaceous nodules on the lower leg. (b) Distribution of tumors in

the group of pcDLBL at the time of diagnosis. Body regions as defined by the TNM classification system for primary cutaneous lymphomas

other than mycosis fungoides and SS.


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antibiotic therapy in 4 (25%) and surgical excision

followed by PUVA in 1 patient (6%). One patient

refused treatment.

After surgical excision CR was observed in 4 of 6

patients (67%) and PR in one patient (17%). This one

patient had T stage 2b with multiple small tumors in an

area of 10620 cm2. After having reduced the tumor

load (PR), we then applied radiotherapy successfully

(CR). Recurrences were observed after a mean period

of 7 months in 3 of the 4 patients (75%) who had

achieved CR and occurred in the same area as the

primary tumor. Radiotherapy resulted in CR in 3 of 4

patients (75%), with no recurrences occurred during

the follow-up time. Systemic antibiotic therapy re-

sulted in PR in only 1 of 4 patients (25%), the

remaining 3 patients did not respond.

pcDLBL

In 5 of 7 patients (71%) tumors were initially treated

with radiotherapy alone. Since the majority of lesions

in DLBL, leg type were solitary or regional, at that

time radiotherapy was applied as first-line treatment.

The one patient with disseminated lesions refused

chemotherapy. CR after radiotherapy was achieved in

only 1 of the 5 patients (20%) and recurrence was

observed after 12 months in this patient. The

remaining 4 patients (80%) experienced disease

progression. Three of the 4 patients (75%) died

from their lymphoma after a median period of 8.6

months. Two patients refused treatment, one of them

was 98 years old.

Discussion

This is the second study of the clinico-pathological,

prognostic and therapeutic characteristics of CBCL

staged according to the new TNM staging system

introduced in 2007 [6,11].

Among the 54 CBCL cases in our study the vast

majority (87%) of CBCL were pcMZL and pcFCL,

i.e. low-grade malignant CBCL with pcMZL

Table IV. Treatment modalities, number of complete remissions and relapses.

Therapy

pcMZL pcFCL pcDLBL

Patients No. of CR Relapses Patients No. of CR Relapses Patients No. of CR Relapse

SE 11 10 8 6 4 3 0 – –

RT 2 2 1 4 3 0 5 1 1

AB 11 0 – 4 0 – 0 – –

Misc. 7 2 1 1 0 – 0 – –

None 0 – – 1 0 – 2 0 –

SE, surgical excision; RT, radiotherapy; AB, antibiotic therapy (doxycyclin 200 mg per day for 3 weeks), Misc., miscellaneous (topical

steroids, topical chemotherapy, IFN-alpha, PUVA); None, no therapy; CR, complete response.

Figure 4. Time to relapse of the CBCL patients who achieved a CR.


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accounting for more than half of all the cases. This

percentage is slightly higher than that reported in

other series and may reflect geographical differences

[11,14]. In addition, the introduction of the new

WHO-EORTC classification for CL has led to

reclassification of many cases and subsequent

changes in epidemiologic aspects [11].

The average age at diagnosis in our groups of

pcFCL and pcDLBL was similar to that found in

other reports, being 59 years for pcFCL and 78 years

for pcDLBL [9,11,14]. But our 31 patients with

pcMZL were on average much younger at diagnosis

(39 years) than reported before, e.g. median age at

diagnosis for pcMZL 53 years [6] and 50 years [9].

All three CBCL entities showed differences in their

predilection sites [Figures 1(b), 2(b), 3(b)].

PcMZL – in contrast to pcFCL – often presented

on arms and legs. Clinically, all CBCL entities

manifested with skin-coloured to erythematous or

violaceous nodules. Additionally, in pcFCL sur-

rounding plaques and in pcDLBL ulceration were

often observed.

According to the new TNM classification system

for cutaneous lymphomas other than MF and SS [5],

in all three CBCL entities a comparable number of

cases became apparent as a solitary tumor (T1 stage)

or multiple lesions limited to one body region or two

contiguous body regions (i.e. regional skin involve-

ment; T2 stage). Generalised skin involvement

with multiple lesions involving two non-contiguous

or 4 3 body regions (T3) occurred in our series in 8

of 31 pcMZL cases, and in one of the 7 pcDLBL

cases (9 of 54 (17%)) but was not associated with

impaired prognosis.

Due to the relatively small number of cases in

each T stage the data do not allow us to draw

conclusions on the relevance of the T stages for

recurrence rate (Table V). Nevertheless, it is useful

for precise anatomic documentation of disease

extent [5].

In our study an association between CBCL and

Borrelia could be detected by PCR from archival

tissue specimens in 12% of our patients. The per-

centage is lower than reported in the literature which

may be due to geographical differences [9,15].

Various treatment modalities were employed in

our series of patients; surgical excision, radiotherapy

and systemic antibiotics being the most common

first-line therapies. In pcMZL and pcFCL, surgical

excision or radiotherapy resulted in CR in 11 of 13

(85%) and in 7 of 10 (70%) of our patients

respectively. The response rates after surgical exci-

sion and radiotherapy are comparable to the data in

the literature. In contrast to these therapeutic

modalities, no response was achieved by antibiotic

treatment resulting in lower overall response rates

after initial therapy.

Recurrence of the tumor was observed after a

mean period of 14 months after initial treatment in

10 of 14 CR of pcMZL (71%) and 3 of 7 CR of

pcFCL (43%). The recurrence rates were similar to

previous studies reported in literature [7,9,10,16,17].

In our series of pcMZL and pcFCL, all recurrences

but one occurred in the same area as the primary

tumor. The number of patients is too small to assess

whether relapses were more common in T2 or T3

stages as compared to T1. In our series occurrence of

relapses did not affect prognosis in any of the CBCL

cases.

Radiotherapy resulted in CR in 3 of 4 pcFCL

with no recurrences during the follow-up. The

beneficial effect of radiotherapy in pcFCL is in

accordance with the results reported by Rijlaarsdam

et al. [18]. It can be speculated that the higher

recurrence rates observed after surgical excision

may in part be due to the fact that the excised area

is smaller than the therapy field in radiotherapy.

Wider and standardised excision margins could be

considered in CBCL in the aim of reducing

recurrence rates, but to date there is no evidence

in other types of lymphoma to strongly support such

a procedure.

Systemic antibiotic treatment did not induce CR

in any of our patients.

Extracutaneous spread and death due to lym-

phoma is very rare in pcMZL and pcFCL and has

been previously reported in 4% to 23% of pcMZL

[8,9,15,19] and in 5.3% of pcFCL [3,11]. In our

series none of our 47 patients with low-grade

malignant CBCL died due to lymphoma after a

Table V. T stages of our CBCL, number of complete remissions and relapse ratio.

pcMZL pcFCL pcDLBL

Patient CR Relapses Without relapse Patient CR Relapses Without relapse Patient CR Relapses Without relapse

T1 12 8 6 2 (25%)* 7 4 2 2 (50%) 3 1 1 0

T2 11 4 2 2 (50%) 9 3 1 2 (67%) 3 0 – –

T3 8 2 2 0 0 – – – 1 0 – –

*Percentage represents the number of patients without a relapse at the end of follow-up with respect to the number of CRs.


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median follow-up period of 5.2 years. In contrast,

3 of 7 patients (43%) with pcDLBL showed

extracutaneous spread and died due to lymphoma.

This finding is in accordance with the data in the

literature reporting 5-year overall survival rates of

37% to 67% in pcDLBL [11,20–23].

Conclusion

In the vast majority of patients, the CBCL showed up

with solitary or clustered nodules. PcMZL – in

contrast to pcFCL – often present on arms and legs.

Multiple disseminated lesions were found in

26% of patients with pcMZL, but in none of the

patients with pcFCL and only in one patient with

pcDLBL.

Surgical excision or radiotherapy are highly

effective in pcMZL and pcFCL, although after

surgery recurrences in the same body area are

common. Antibiotic treatment with doxycyclin

did not result in CR in any of the patients studied

herein.

On the basis of these results, and given the lack of

current therapies able to induce durable CR in all

three CBCL subgroups, new effective and well

tolerated therapies for CBCL are still needed. Future

studies employing new treatment modalities have to

clarify whether the recurrence rate can be decreased

and whether such new treatment would be beneficial

in CBCL.

Acknowledgements

The study was partially funded by the Bruno

Bloch Stiftung, Zurich, Switzerland. We are grateful

to Mrs. Petra Graf for the excellent technical

assistance.

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Primary cutaneous B-cell lymphomas – Clinicopathological, prognostic and therapeutic...

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