British Journal of Dermatology Volume 153 Issue 5 2005 [Doi 10.1111%2Fj.1365-2133.2005.06905.x] D.N....

REVIEW ARTICLE DOI 10.1111/j .1365-2133.2005.06905.x

The new World Health OrganizationEuropean Organizationfor Research and Treatment of Cancer classication forcutaneous lymphomas: a practical marriage of two giantsD.N. Slater

Department of Histopathology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K.

CorrespondenceDavid Slater.

E-mail: [email protected]

Accepted for publication3 June 2005

Key words:classification, cutaneous lymphoma, European

Organization for Research and Treatment of

Cancer, World Health Organization

Conicts of interest:None declared.

Summary

Following consensus meetings of the two parent organizations, a new WorldHealth OrganizationEuropean Organization for Research and Treatment of Can-cer (WHOEORTC) classification for primary cutaneous lymphomas has recentlybeen published. This important development will now end the ongoing debateas to which of these was the preferred classification. The new classification willfacilitate more uniformity in diagnosis, management and treatment of cutaneouslymphomas. In particular, it provides a useful distinction between indolent andmore aggressive types of primary cutaneous lymphoma and provides practicaladvice on preferred management and treatment regimens. This will thereby pre-vent patients receiving high-grade treatment for low-grade biological disease.This review focuses on those diseases which have found new consensus agree-ment compared with the original WHO and EORTC classifications. In cutaneousT-cell lymphomas, these include folliculotropic mycosis fungoides, defining fea-tures of Sezary syndrome, primary cutaneous CD30+ lymphoproliferative disor-ders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosisand borderline lesions) and subcutaneous panniculitis-like T-cell lymphoma. Pri-mary cutaneous CD4+ small medium-sized pleomorphic T-cell lymphoma, pri-mary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma andcutaneous c d T-cell lymphoma are allocated provisional entry status and therebyafford better definitions for some cases of currently unspecified primary cutane-ous peripheral T-cell lymphoma. In cutaneous B-cell lymphomas, diseases whichhave found new consensus agreement include primary cutaneous marginal zoneB-cell lymphoma, primary cutaneous follicular centre lymphoma, primary cuta-neous diffuse large B-cell lymphoma, leg type and primary cutaneous diffuselarge B-cell lymphoma, other. CD4+ CD56+ haematodermic neoplasm (earlyplasmacytoid dendritic cell leukaemia lymphoma) now appears as a precursorhaematological neoplasm and replaces the previous terminology of blastic NK-celllymphoma. Other haematopoietic and lymphoid tumours involving the skin, aspart of systemic disease, will appear in the forthcoming WHO publication Tumoursof the Skin. The new classification raises interesting new problems and questionsabout primary cutaneous lymphoma and some of these are discussed in this art-icle. It is, however, a splendid signpost indicating the direction in which researchin cutaneous lymphoma needs to go. In the interim, we have an internationalconsensus classification which is clinically meaningful.

The classification of cutaneous lymphoma continues to evolve

rapidly. Although designed primarily for general lymphoid

neoplasms, the Revised EuropeanAmerican Lymphoma

(REAL) classification was the first to be based on definable

clinicopathological entities.1 Proposals were made to apply the

REAL classification to the skin, but these received little promin-

ence owing to the emergence of the European Organization for

Research and Treatment of Cancer (EORTC) classification.2 The

874 2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880

EORTC classification for primary cutaneous lymphoma used a

similar approach to the REAL, basing diagnoses on a combina-

tion of clinical, histological, immunohistochemical and geno-

typic criteria. In addition, the EORTC classification enjoyed

substantial support because of its identification of distinct cuta-

neous disease entities, with well-defined clinical and histologi-

cal features, including a predictable clinical course, response to

therapy and prognosis. The World Health Organization

(WHO) classification of tumours of haematopoietic and lym-

phoid tissues was the first worldwide consensus classification

of these neoplasms.3 The WHO adopted the principles of the

REAL and recognized disease entities based on a combination

of morphology, immunophenotypic, genetic and clinical fea-

tures. The WHO classification undoubtedly received support

with reference to skin lymphoma, as the number of named pri-

mary cutaneous entities increased significantly from those in

the REAL classification. Although both the EORTC and WHO

classifications were significant improvements on the original

REAL classification, both classifications were recognized to have

significant shortcomings and this resulted in considerable con-

tinuing debate.4 In particular, this related to the classification

of cutaneous T-cell lymphomas (CTCLs) other than mycosis

fungoides (MF) and Sezary syndrome (SS), and cutaneous

B-cell lymphomas (CBCLs). During consensus meetings in

2003 and 2004, however, representatives of both organizations

reached agreement on a new classification which has been des-

ignated the WHOEORTC classification (Table 1).5

The basic premise of the new classification is that primary

cutaneous lymphomas often have a completely different clin-

ical behaviour and prognosis from histologically similar nodal

lymphomas and therefore require different types of manage-

ment and treatment.

This review will focus on those diseases that have achieved

consensus reclassification since their inclusion in the original

EORTC and or WHO publications. Sensibly, the term primarycutaneous lymphoma is now defined as cases that present in

the skin with no evidence of extracutaneous disease at the

time of presentation. For purists, however, this could cause

problems in the inclusion of entities such as precursor haema-

tological neoplasm in this grouping.

Mycosis fungoides

Surprisingly, the publication provides little guidance on the

early diagnosis of MF. The main issue addressed is the minor

redesignation of folliculotropic and granulomatous slack skin

variants subtypes of MF. Other clinical, histological and pheno-typic variants, such as the increasingly recognized papular

variant of MF, receive no consideration.

Folliculotropic mycosis fungoides

This was previously designated as MF-associated follicular

mucinosis in both EORTC and WHO classifications. Recent

studies, however, have shown no differences in clinical pres-

entation and behaviour between cases of folliculotropic MF

with or without associated follicular mucinosis. Accordingly,

it has been agreed that the preferred term is that of folliculo-

tropic MF. From the clinical point of view, the most relevant

feature is the deeper localization of the neoplastic infiltrates

and the reduced response to skin-targeted therapies such as

psoralen plus ultraviolet A treatment.

Granulomatous slack skin

Although originally regarded by the EORTC as a provisional

entry, the new classification formally recognizes it as a formal

variant of MF.

Sezary syndrome

The WHOEORTC appear supportive of the recent report from

the International Society for Cutaneous Lymphomas (ISCL) on

erythrodermic CTCL.6 In this, the criteria recommended for

the diagnosis of SS include one or more of the following: an

absolute Sezary cell count of at least 1000 cells mm)3, a

CD4 CD8 ratio of 10 or higher caused by an increase in circu-lating T cells and or an aberrant loss or expansion ofpan-T-cell markers evidenced by flow cytometry, increased

lymphocyte counts with evidence of a T-cell clone in the

Table 1 World Health OrganizationEuropean Organization for

Research and Treatment of Cancer classification of cutaneouslymphomas with primary cutaneous manifestations

Cutaneous T-cell and NK-cell lymphomasMycosis fungoides

Mycosis fungoides variants and subtypesFolliculotropic mycosis fungoides

Pagetoid reticulosisGranulomatous slack skin

Sezary syndromeAdult T-cell leukaemia lymphomaPrimary cutaneous CD30+ lymphoproliferative disorders

Primary cutaneous anaplastic large cell lymphoma

Lymphomatoid papulosisSubcutaneous panniculitis-like T-cell lymphoma

Extranodal NK T-cell lymphoma, nasal typePrimary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous aggressive epidermotropic CD8+ T-celllymphoma (provisional)

Cutaneous c d T-cell lymphoma (provisional)Primary cutaneous CD4+ small medium-sized pleomorphic

T-cell lymphoma (provisional)

Cutaneous B-cell lymphomasPrimary cutaneous marginal zone B-cell lymphoma

Primary cutaneous follicle centre lymphomaPrimary cutaneous diffuse large B-cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma, otherIntravascular large B-cell lymphoma

Precursor hematological neoplasm

CD4+ CD56+ hematodermic neoplasm (blastic NK-celllymphoma)

2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880

The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater 875

blood by Southern blot or polymerase chain reaction tech-

niques or a chromosomally abnormal T-cell clone. The WHO

EORTC acknowledge that SS is part of a broader spectrum of

erythrodermic CTCL, and that alternative staging systems for

assessment of the degree of peripheral blood involvement in

erythrodermic CTCL are necessary. However, until the results

of an ISCL study investigating the clinical validity of these pro-

posals are available, demonstration of a T-cell clone (prefer-

ably of the same T-cell clone in skin and peripheral blood) in

combination with one of the above-mentioned cytomorpho-

logical or immunophenotypical criteria are suggested as min-

imal criteria for the diagnosis of SS to exclude patients with

benign inflammatory conditions simulating SS. With regard to

the treatment of SS, they provide an observatory comment

that, although extracorporeal photopheresis is currently

favoured over traditional low-dose chemotherapy, this has not

yet been substantiated by randomized controlled trials.

Primary cutaneous CD30+ lymphoproliferativedisorders

Primary cutaneous anaplastic large cell lymphoma (C-ALCL)

and lymphomatoid papulosis (LYP) are presented as entities

on the same disease spectrum and it is emphasized that histo-

logical criteria alone are often insufficient to differentiate

them. The term borderline refers to those cases in which,

despite careful clinicopathological correlation, a definitive dis-

tinction between C-ALCL and LYP cannot be made. In general,

this approach is very much that originally recommended by

the EORTC. In particular, LYP no longer lies under the previ-

ous WHO title of T-cell proliferation of uncertain malignant

potential. The new classification also demonstrates a redefini-

tion of the 2001 WHO borderline group in this area. LYP type

C is now more appropriately placed with other types of LYP

and C-ALCL of LYP type receives no specific designation.

Primary cutaneous anaplastic large cell lymphoma

Although adopting the 2001 WHO definition of primary

C-ALCL, the entity now incorporates the EORTC concept of

including not only anaplastic but also pleomorphic and immu-

noblastic cells. Clinical features mentioned, which overlap con-

siderably with LYP, include multifocal lesions in about 20% of

patients, the ability of lesions to show partial or complete spon-

taneous regression, the tendency towards cutaneous relapse,

extracutaneous dissemination in approximately 10% of cases

and potential spread to regional lymph nodes. The prognosis is

stated to be favourable, with a 10-year disease-related survival

exceeding 90% and patients with multifocal skin lesions or

regional lymph node involvement having a similar prognosis.

As in the original EORTC classification, the different mor-

phological cell types are recognized to have no differences in

terms of clinical presentation, behaviour or prognosis. Radio-

therapy, surgical excision or low-dose methotrexate are

recommended as the primary treatments and doxorubicin-

based multiagent chemotherapy is advised to be restricted to

extracutaneous or rapidly progressive skin disease. In addition,

the histological diagnostic difficulty of ulcerated lesions is

highlighted. These may show a LYP-like histology with an

abundant infiltrate of reactive T cells, histiocytes, eosinophils

and or neutrophils, plus prominent epidermal hyperplasia butwith relatively few CD30+ cells.

Lymphomatoid papulosis

The new classification adopts the well-established EORTC clas-

sification of dividing LYP into types A, B and C. The latter

represents patients with clinical features of LYP but histologi-

cally demonstrating a monotonous population or substantial

clusters of large CD30+ T cells with relatively few admixed

inflammatory cells. Although LYP type B is understandably

included, the tendency towards an absence of CD30+ T cells

is paradoxical for a disease under a generic heading incorpor-

ating this CD number. The new publication emphasizes that,

as no curative therapy is available and none of the available

treatment modalities affects the natural course of the disease,

the short-term benefits of active treatment (such as low-dose

oral methotrexate) should be balanced carefully against the

potential side-effects. Accordingly, whenever possible, long-

term follow-up without active treatment should always be

considered.

Subcutaneous panniculitis-like T-celllymphoma

This cytotoxic T-cell lymphoma was previously defined as a

specific entity by the WHO but was regarded as a provisional

entity by the EORTC. The entity has, however, been signifi-

cantly redefined in the new WHOEORTC classification. Cases

with an a b T-cell receptor (TCR) phenotype are usuallyCD8+, are restricted to the subcutaneous tissue and often run

an indolent course. In contrast, cases with a c d TCR pheno-type are typically CD4 and CD8, often express CD56, may

involve the epidermis and have a poor prognosis. On that

basis, the category of subcutaneous panniculitis-like T-cell

lymphoma (SPTCL) in the WHOEORTC classification is now

restricted to cases with an a b TCR phenotype, whereas caseswith a c d TCR phenotype are placed in the new category ofcutaneous c d T-cell lymphoma (CGD-TCL).

Although patients have classically often been treated with

doxorubicin-based chemotherapy and radiotherapy, recent

studies suggest that many patients can be controlled for long

periods of time with systemic corticosteroids.

Extranodal NK T-cell lymphoma, nasal type

The new WHOEORTC classification has adopted the 2001

WHO entry, which was totally missing in the EORTC classifi-

cation. The skin is the most common site of involvement after

the nasal cavity nasopharynx, and skin involvement may be aprimary or secondary manifestation of the disease. The disease

is aggressive, with a median survival of 5 months for patients


876 The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater

with cutaneous and extracutaneous disease. In patients pre-

senting with only skin lesions, however, a median survival of

27 months is reported. Although systemic chemotherapy is

the first treatment of choice, the results are often disappoint-

ing. Most cases are positive for CD56 and EpsteinBarr virus

(EBV), although rare CD56 cases have been reported.

Hydroa vacciniforme-like CTCL is a rare type of EBV-associ-

ated lymphoma of CD8+ cytotoxic T cells, which affects chil-

dren almost exclusively in Latin America and Asia. This is

considered by the WHOEORTC to be a new variant of extra-

nodal NK T-cell lymphoma, nasal type, although this could bedebated given a significant number of CD56 cases.

Primary cutaneous peripheral T-celllymphoma, unspecied

Peripheral T-cell lymphoma (PTL), unspecified in the

WHO classification, represents a heterogeneous group which

includes all T-cell neoplasms that do not fit into any of the

better defined subtypes of T-cell lymphoma leukaemia. Recentstudies have, however, suggested that some cases may repre-

sent specific entities and accordingly have been given the sta-

tus of provisional entries in the WHOEORTC classification.

For remaining cases that do not fit into these provisional enti-

ties, the designation PTL, unspecified is still maintained. In all

cases a diagnosis of MF must be ruled out by clinical history

and examination.

Primary cutaneous aggressive epidermotropic CD8+

cytotoxic T-cell lymphoma (provisional entry)

Clinically, this lymphoma is characterized by the presence of

localized or disseminated eruptive papules, nodules and

tumours showing central ulceration and necrosis or by super-

ficial, hyperkeratotic patches and plaques.7 The clinical features

are very similar to those observed in patients with CGD-TCL.

The lymphoma may disseminate to other visceral sites (lung,

testis, central nervous system and oral mucosa) but lymph

nodes are often spared. Histologically, there is pronounced

epidermotropism and the cells are of CD8+ CD56 cytotoxic

T-cell type. The lymphoma has an aggressive clinical course,

with a median survival of 32 months. There is no difference

in survival between cases of small or large cell morphology.

Patients are generally treated with doxorubicin-based multi-

agent chemotherapy. Patients with so-called disseminated pag-

etoid reticulosis (KetronGoodman disease) are now generally

regarded as representing this type of lymphoma, CGD-TCL or

tumour-stage MF.

Cutaneous cc dd T-cell lymphoma (provisional entry)

CGD-TCL is a lymphoma composed of activated c d T cellswith a cytotoxic phenotype. This group includes cases previ-

ously known as SPTCL with a c d TCR phenotype. A similarand possibly related condition may be present primarily at

mucosal sites. Whether cutaneous and mucosal c d T-cell

lymphoma are all part of a single disease, i.e. mucocutaneous

c d T-cell lymphoma, is not yet clear. Distinction betweenprimary and secondary cutaneous cases is not useful as all

cases have a poor prognosis. CGD-TCL generally presents with

disseminated plaques and or ulceronecrotic nodules ortumours, particularly on the extremities. Involvement of mu-

cosal and other extranodal sites is frequently observed but

involvement of lymph nodes, spleen or bone marrow is

uncommon. A haemophagocytic syndrome may occur in

patients with panniculitis-like tumours. The histological pat-

tern may be epidermotropic, dermal or subcutaneous. The

neoplastic cells are usually of medium to large blast cell type

and angioinvasion and necrosis are common.

The tumour cells characteristically have a CD56 phenotype

with strong expression of cytotoxic proteins, and most cases

lack CD4 and CD8. Patients should be treated with systemic

chemotherapy but the results are often disappointing, with a

median survival of 15 months. There is a trend for decreased

survival in patients with subcutaneous fat involvement in com-

parison with those with only epidermal and dermal involve-

ment. Unfortunately, their immunohistological diagnosis

using c TCR antibodies still requires the use of frozen tissue.

Primary cutaneous CD4+ small medium-sizedpleomorphic T-cell lymphoma (provisional entity)

Characteristically, these tumours present with a solitary plaque

or tumour, generally on the upper half of the body, but

without a history of patches and plaques to suggest MF. In

contrast to the EORTC classification, the term small medium-sized pleomorphic CTCL is restricted to cases with a CD4

T-cell phenotype.8 By definition, the number of large cells

present must be less than 30%. These lymphomas have a

rather favourable prognosis, with an estimated 5-year survival

of approximately 6080%. Surgical excision or radiotherapy is

the preferred mode of treatment, although cyclophosphamide

may be effective in patients with more generalized skin dis-

ease. Optimal treatment for this group, however, has still to

be defined.

Primary cutaneous peripheral T-cell lymphoma,

unspecied

After the three provisional entries have been excluded, the

remaining cases in this category usually display large neoplas-

tic cells, which represent at least 30% of the cell population.

CD30 staining is negative or restricted to a few scattered cells

and rare cases may show coexpression of CD56. The prognosis

is generally poor, with a 5-year survival rate of less than 20%.

Patients should be treated with multiagent chemotherapy.

CD4+ CD56+ hematodermic neoplasm (blasticNK-cell lymphoma)

In the WHO classification, blastic NK-cell lymphoma

was included as a clinically aggressive neoplasm with a high



incidence of cutaneous involvement and risk of leukaemic dis-

semination. More recent studies, however, have suggested a

derivation from a plasmacytoid dendritic cell precursor.9

Accordingly, CD4+ CD56+ hematodermic neoplasm or earlyplasmacytoid dendritic cell leukaemia lymphoma have beensuggested as more appropriate terms. Approximately 50% of

patients have nodal or bone marrow involvement at presenta-

tion and the blast cells are of CD4+, CD56+ and CD123+

phenotype.

Recent studies suggest that patients are better treated with

acute leukaemia regimens and although complete remission

can be initially induced, quick relapse unresponsive to further

chemotherapy is frequent. Median survival is approximately

14 months.

Primary cutaneous marginal zone B-celllymphoma

After many years of resistance, the EORTC has now accepted

this as the favoured diagnostic term and has also accepted that

it incorporates their previous entries of immunocytoma and

plasmacytoma. The recommended term in the WHOEORTC

classification is certainly more user-friendly than the lengthy

2001 WHO term of extranodal marginal zone B-cell lym-

phoma of mucosa-associated lymphoma tissue (MALT lym-

phoma). The neoplastic cells are bcl-2+ but, in contrast to

primary cutaneous follicular centre lymphoma (PCFCL), are

CD10 and bcl-6. The prognosis of primary cutaneous mar-

ginal zone lymphoma (PCMZL) is stated to be excellent, with

a 5-year survival close to 100%. Emphasis is given with regard

to the propensity of lesions to involve the trunk or arms pref-

erentially, and a tendency to be multifocal and to recur. In

some cases, spontaneous resolution of skin lesions may be

observed. An association in some parts of the world with

Borrelia burgdorferi is also noted. Patients with solitary or few

lesions can be treated with radiotherapy or surgical excision,

and chlorambucil can be used in those presenting with multi-

focal skin lesions. Intralesional or systemic anti-CD20 antibody

(rituximab) is also mentioned as a potential treatment for this

and other types of CBCL. Cytogenetic analysis has continued to

provide variable findings with regard to t(14;18)(q32;q21),

t(11;18)(q21;q21) and t(1;14)(p22;q32) translocations.

Primary cutaneous follicular centre lymphoma

PCFCL characteristically presents with solitary or grouped

lesions, preferentially located on the scalp, forehead or trunk.

PCFCL has an excellent prognosis, with a 5-year survival of

over 95%. Multifocal skin lesions are observed in a small

minority of patients but are not associated with a more unfa-

vourable prognosis. Cutaneous relapses are observed in

approximately 10% of patients. Radiotherapy or surgery are

the preferred modes of treatment and anthracyclin-based che-

motherapy is advised in patients with extensive cutaneous dis-

ease or extracutaneous spread. The previous EORTC term of

primary cutaneous follicular centre cell lymphoma has been

replaced by the 2001 WHO term of primary cutaneous folli-

cular centre lymphoma, reflecting that the tumour can have

follicular, follicular and diffuse or purely diffuse growth pat-

terns.

The constituent cells are predominantly follicular centre

small or large centrocytes and although some centroblasts can

be present, a monotonous proliferation of the latter warrants

the term primary cutaneous diffuse large B-cell lymphoma,

leg type (PCLBCL, leg type).

This does, however, place a major onus on the histopathol-

ogist to recognize these cell types accurately and to make a

distinction from, for example, reactive dendritic cells. Despite

WHOEORTC optimism that reproducible ability exists to

achieve this aim, interobserver variation in this area is gener-

ally regarded as high. The neoplastic cells consistently express

bcl-6 and recent studies suggest that PCFCL has the same

B-cell differentiation gene expression profile as germinal cen-

tre B-cell-like diffuse large B-cell lymphoma (DLBCL).10 A

continuum of changes is observed between follicular and dif-

fuse lesions, with an increasing number of B-cell lymphocytes

but decreasing CD10, T- and CD21 dendritic cells.11 In com-

parison with PCLBCL, leg type, the neoplastic cells are negat-

ive for multiple myeloma 1 (MUM1) interferon regulatoryfactor (IRF4).12 Unlike nodal lymphoma, histological grading

of PCFCL is not advised by the WHOEORTC as the growth

pattern and number of blast cells do not appear to have a

prognostic contribution. Published cytogenetic findings with

regard to the presence of t(14;18) translocation and or bcl-2expression have been variable, but in general these are often

negative. Positivity for one or both of these, however, must

raise the possibility of nodal follicular lymphoma involving

the skin. In PCFCL with a follicular growth pattern, there

appears to be no difference in clinical presentation and beha-

viour between bcl-2 and or t(14;18) positive and negativecases. There is some evidence that expression of bcl-2 protein

by more than 50% of the neoplastic B cells in PCFCL with a

diffuse proliferation of large centrocytes may be associated

with a more unfavourable prognosis.13

The diagnosis, clinical implications, management and treat-

ment of PCFCL are emphasized to be dramatically different

from nodal follicular lymphoma, although continuing studies

in this area are clearly indicated.

Primary cutaneous diffuse large B-celllymphoma, leg type

Although previously identified in the EORTC classification as

an intermediate prognosis tumour on the leg, this entity was

not recognized by the WHO in 2001. In the latter classifica-

tion cases were incorporated into the general group of DLBCL.

PCLBCL, leg type characteristically involves the lower legs of

elderly women and shows a predominance of confluent sheets

of medium-sized to large cells with round nuclei and promin-

ent nucleoli resembling centroblasts and or immunoblasts.Interestingly, the European multicentre study required at

least 50% of the cells to be large and round to enter this



category.14 Small B cells and reactive stromal T cells are relat-

ively few in number. Although the disease characteristically

presents on the leg, lesions with a similar morphology and

phenotype can arise at cutaneous sites elsewhere. This possi-

bility is accordingly acknowledged by qualifying the original

EORTC term to leg type. The theoretical possibility of, for

example, PCLBCL, leg type occurring on the cheek seems para-

doxical and raises a query as to whether the most appropriate

term has been selected. Recent studies suggest that PCLBCL,

leg type has a B-cell differentiation gene expression profile of

postgerminal centre (activated) B-cell-like DLBCL.10 In keeping

with this, the cells consistently express MUM1 and bcl-2, and

CD10 is generally absent. Most cases are stated to express

bcl-6, although this is generally a marker of B-cell germinal

centre differentiation. Information on other immunohistologi-

cal markers of postgerminal centre plasmacellular differenti-

ation, such as CD138 (syndecan-1), are limited, but to date

the neoplastic cells have been reported as negative.15 t(14;18)

translocation is generally absent, but recent studies have dem-

onstrated frequent translocations, similar to those in systemic

DLBCL, involving IgH, myc and bcl-6 genes.16 Various chro-

mosomal imbalances have been described in PCLBCL, leg type

and these are present in greater number and with differences

compared with PCFCL.17 Inactivation of p15 and p16 tumour

suppressor genes by promotor hypermethylation has been

reported in both PCFCL and PCLBCL.18 The overall prognosis

in this group is poor, with a 5-year survival of 55% and a

tendency to disseminate to extracutaneous sites. Occurrence

on the leg and multiple lesions appear to be particular adverse

risk factors and, with the exception of single small lesions

which have a more favourable prognosis, it is recommended

that this type of lymphoma should be treated as systemic

DLBCL with anthracycline-based chemotherapy.

Primary cutaneous diffuse large B-celllymphoma, other

This group refers to cases of large B-cell lymphoma arising in

the skin which do not belong to the groups of PCFCL and

PCLBCL, leg type. These cases include morphological variants

of the 2001 WHO DLBCL such as anaplastic or plasmablastic

subtypes. These cases are generally a skin manifestation of

nodal lymphoma and may be seen in the setting of human

immunodeficiency virus infection. In addition, rare cases of

primary cutaneous intravascular large B-cell lymphoma are

included in this category. A recent study has investigated chro-

mosomal aberrations in PCLBCL, leg type and PCLBCL, other

and has found similar aberrations irrespective of anatomical

site, cell morphology and bcl-2 expression.19 This highlights

the similarities between these two groups of primary cutane-

ous large B-cell lymphoma designated by the WHOEORTC

and nodal DLBCL.

Some cases of primary cutaneous T-cell histiocyte-richB-cell lymphoma are, however, characterized by the presence

of large scattered B cells in a background of numerous

reactive T cells. Clinically, these cases appear to show greater

similarities with the groups of PCFCL and PCMZL and, unlike

their nodal counterparts, may have an excellent prognosis.20

Conclusion

The new WHOEORTC classification for primary cutaneous

lymphomas is a much welcomed practical marriage of two

professional giants. In this, however, the EORTC has undoubt-

edly emerged as the predominant partner. Although the

EORTC has accommodated many WHO concepts, traditional

EORTC ones present themselves with substantial strength. In

addition, although previous WHO cancer classifications have

been renowned for their proven evidence base, it could be

regarded as uncharacteristic for a WHO-linked classification to

admit to the requirement for new randomized multicentre tri-

als to validate some of their proposals. Somewhat perplex-

ingly, whereas EORTC concepts previously examined by the

WHO failed to gain entry into their 2001 classification, this

has now changed. Part of this new acceptance, however, has

to be acknowledged as resulting from clinical trial information

not available at the time.

The new WHOEORTC classification represents a major

improvement on the independent classifications published by

the two parent organizations. There can also be no doubt that

it will end the considerable time wasted in discussing whether

countries, organizations or individuals should use the previous

EORTC or WHO classifications for skin lymphoma. In addi-

tion, it will contribute significantly to more uniform diagno-

sis, management and treatment of cutaneous lymphoma. Its

more reliable distinction between indolent and aggressive

types of cutaneous lymphoma will certainly facilitate clinical

decisions, whether to use surgical, radiotherapy, chemothera-

peutic or indeed no treatment regimens. In particular, it is

likely that the classification will actively prevent patients

receiving inappropriate high-grade treatment for low-grade

biological disease.

As acknowledged by the authors, however, this new classifi-

cation is merely a new beginning and could be regarded as a

signpost indicating the direction in which research in cutane-

ous lymphoma needs to develop. New genetic findings and

the advent of methodologies such as gene and protein expres-

sion profiling will undoubtedly find new evidence relevant to

both diagnosis and treatment and will result in the necessity

for a further updated classification in the not too distant

future. Several areas of likely future development are easily

identified. In CTCL, there will hopefully be guidance on the

early diagnosis of MF, fine tuning of the current provisional

entries under PTL, unspecified and possible subdivision of

CTCL according to Th1 and Th2 status. Russell-Jones has

recently reviewed the current and potential future status of the

diagnosis and staging of erythrodermic CTCL.21 In CBCL,

greater emphasis will probably be given to B-cell differenti-

ation and in particular germinal centre and postgerminal

centre status. Indeed, application of this knowledge may see

the eventual disappearance of the nearly sacrosanct clinical link

between CBCL and the leg site. There is also the intriguing



possibility, as with nodal follicular lymphoma, that the micro-

environment of nonmalignant tumour-infiltrating immune

cells in CBCL may have prognostic relevance.22 Furthermore,

although contrary to the ethos of current WHOEORTC thera-

peutic guidance, it perhaps should be contemplated whether

early chemotherapeutic intervention in CBCL could reduce its

significant cutaneous relapse rate.23 In addition, it would

appear sensible for the WHOEORTC to consider formally col-

laborating with the ISCL in its research and peer consultation

programmes.

It must also be noted that the WHOEORTC classification of

cutaneous lymphomas will be contained in the forthcoming

WHO Blue Book Series publication Tumours of the Skin (in

press). This will provide the important opportunity to include

other haematopoietic and lymphoid tumours involving the

skin as part of systemic disease.

References

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British Journal of Dermatology Volume 153 Issue 5 2005 [Doi 10.1111%2Fj.1365-2133.2005.06905.x] D.N....

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