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Consensus WHO/EORTC Classification of Cutaneous Lymphomas


Steven H. Swerdlow
University of Pittsburgh Medical Center
Pittsburgh, PA


The issue of cutaneous lymphomas frequently causes consternation among pathologists because cutaneous lymphoid infiltrates are difficult to deal with, classification of cutaneous lymphomas has been contentious and now, the concept that our trusted 2001 WHO monograph might be out of date just reinforces the instability of life in the 21st century!

Currently, there are two major ways in which cutaneous lymphomas are being classified. The EORTC (European Organisation for Research and Treatment of Cancer) classification of cutaneous lymphomas, published in 1997, emphasized the need for a classification specifically for primary cutaneous lymphomas. [1] The WHO classification of tumours of hematopoietic and lymphoid tissues published in 2001 covers all lymphomas and does include some skin-specific categories/variants such as "cutaneous follicle centre lymphoma." [2] Soon, there will be a new WHO-EORTC consensus classification of cutaneous lymphomas. This consensus classification, to be used for primary cutaneous lymphomas, resulted from the planning for the new upcoming WHO classification of skin tumors. Discussions that led to the final classification were held at the editorial consensus conference for the WHO skin tumor blue book in September, 2003 in Lyon, France and additional discussions to resolve remaining issues with some of the B-cell lymphomas were held in Zurich, Switzerland in January, 2004 hosted by G. Burg, the editor responsible for the section on cutaneous lymphomas. These discussions included individuals who were intimately involved in the WHO classification of lymphoid tumors (led by E. Jaffe) as well as others who were intimately involved in the EORTC classification.

The presentation today will review the basic structure of the new WHO-EORTC classification of cutaneous lymphomas and then explore some of the major differences from current 2001 WHO classification, first looking at the T-cell lymphomas and then the more contentious B-cell lymphomas. The new classification will be published, hopefully this year, in the WHO Classification of Skin Tumors. Much of it, including the agreed upon criteria for many of the entities, will also be published in a manuscript that is scheduled to appear in Blood in mid-2005 (WHO-EORTC Classification for Cutaneous Lymphomas, R. Willemze, E.S. Jaffe, G. Burg, L. Cerroni, E. Berti, S.H. Swerdlow, E. Ralfkiaer, S. Chimenti, J.L. Diaz-Perez, L.M. Duncan, F. Grange, N.L. Harris, W. Kempf, H. Kerl, M. Kurrer, R. Knobler, N. Pimpinelli, C. Sander, M. Santucci, W. Sterry, M.H. Vermeer, J. Wechsler, S. Whittaker, C.J.L.M. Meijer). This presentation in essence relies on work done by all of these listed individuals as well as the additional participants in the two consensus conferences.

The classification, as it exists in late, 2004 and provided by Burg, et al, is below. Some of the finer details remain subject to change. Although the listing does include some extracutaneous lymphomas that "frequently" involve the skin as a secondary site (printed in italics), the thrust of the classification and of this discussion is to cover primary cutaneous lymphomas, meaning those without any extracutaneous disease at diagnosis. The prior criterion that no extracutaneous disease could be present for six months following diagnosis has been dropped.

WHO-EORTC Classification of Cutaneous Lymphomas

Mature T-cell & NK-cell neoplasms
 Mycosis fungoides
 Variants of MF
 Pagetoid reticulosis (localized disease)
 Follicular, syringotropic, granulomatous variants
 Subtype of MF
 Granulomatous slack skin
 Sezary Syndrome
 CD30+ T-cell lymphoproliferative disorders of the skin
 Lymphomatoid papulosis
 Primary cutaneous anaplastic large cell lymphoma
 Subcutaneous panniculitis-like T-cell lymphoma (αβ -type)
 Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified
 Subtypes of PTL
 Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma (provisional)
 Cutaneous γ/δ -positive T-cell lymphoma (provisional)
 Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma (provisional)
 Extranodal NK/T-cell lymphoma, nasal type
 Hydroa vacciniformia-like lymphoma (variant)
 Adult T-cell leukemia/lymphoma
 Angioimmunoblastic T-cell lymphoma
Mature B-cell neoplasms
 Cutaneous marginal zone B-cell lymphoma (MALT-type)
 Primary cutaneous follicle centre lymphoma
 Cutaneous diffuse large B-cell lymphoma, leg type
 Cutaneous diffuse large B-cell lymphoma, others
 Intravascular large B-cell lymphoma
 Lymphomatoid granulomatosis
 Chronic lymphocytic leukemia
 Mantle cell lymphoma
 Burkitt lymphoma
Immature Hematopoietic Malignancies
 Blastic NK-cell lymphoma (CD4+/CD56+ hematodermic neoplasm)
 Precursor lymphoblastic leukemia/lymphoma
 T-lymphoblastic lymphoma
 B-lymphoblastic lymphoma
 Myeloid and monocytic leukemias
Hodgkin lymphoma

The relative incidence of primary cutaneous lymphomas based on 1905 patients from the Dutch & Austrian Lymphoma Group is below (from Blood, 2005).



Mature T-cell & NK-cell neoplasms

There are no radical changes in the new classification for the following T-cell disorders: mycosis fungoides and its variants/subtype, Sezary Syndrome or the CD30+ T-cell lymphoproliferative disorders of the skin which include lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (as well as some borderline cases). Pagetoid reticulosis is now a term only to be applied to localized cases.

Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL), however, is defined differently with resultant clinical implications. SCPTCL has been considered an aggressive lymphoma although many relatively indolent cases were included in past series. [3] However, this diagnosis is now to be restricted cases that are of α/β type. With that exception, however, the criteria are similar to those in past. [3, 4, 5] Phenotypically, as now defined, SCPTLCL are expected to be CD3+, CD8+, cytotoxic protein + and CD56 "rarely if ever +" (but CD56+ α/β cases are certainly reported). [4] SCPTCL is now to be considered to have a rather indolent course with a reported disease specific 5 year survival of 82% (Blood, 2005) in spite of patients sometimes having recurrent subcutaneous lesions. [6] Cases that previously would have been called SCPTCL of γδ type are to be classified with the other cutaneous γδ lymphomas (see below). These aggressive lymphomas have always been recognized as being somewhat different pathologically with frequent extension of the lymphoma into the dermis and a phenotype like other γδ lymphomas including CD56 expression.

Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified is a heterogeneous category of T-cell lymphomas that do not fit into another cutaneous T-cell lymphoma category. [7] It is always important to rule out the possibility of mycosis fungoides and other specific types of mature T-cell lymphoma before making this diagnosis. There are also now three provisional subtypes of PTL:

Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma
Cutaneous γ/δ-positive T-cell lymphoma
Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma is an epidermotropic CD8+ cytotoxic T-cell lymphoma with an aggressive clinical behavior (just as the name says). [5, 8] Histologic distinction from other CD8+ CTCL can be "difficult or even impossible." [8] Differentiation from other rare CD8+ T-cell neoplasms that can be epidermotropic "is based on the clinical presentation and clinical behavior." (Blood, 2005) Other features, such as a high Ki-67 and a typical phenotypic "profile" (CD3+, βF1+, CD7+, CD8+, CD45RA+, TIA-1+, granzyme B variable) can help as well. [8] These patients usually present with generalized skin lesions that can include a spectrum from patches to tumors, often with hemorrhage and central ulceration. It is said to mimic disseminated pagetoid reticulosis. There is frequent spread to "unusual" sites (testis, lungs, CNS, oral cavity, not lymph nodes) and the course is reported to be very aggressive (median survival 32 mo., 18% 5 yr. survival). [8] (Blood, 2005)

Cutaneous γ/δ-positive T-cell lymphoma is a very aggressive neoplasm composed of γ/δ cytotoxic T-cells that may be epidermotropic, involve the dermis and/or grow in the subcutaneous tissue. [6, 9, 10] Thus, some cases resemble SCPTCL and others mycosis fungoides or PTL, unspecified. [11] The question has been raised as to whether these cases are a part of a single disease entity, namely mucocutaneous γ/δ T-cell lymphoma. [9, 10] Patients with cutaneous γ/δ-positive T-cell lymphoma do not respond well to chemotherapy and have a median survival of only 15 months. [11] These cases account for at least many of the aggressive cases of SCPTCL and, those who have subcutaneous involvement show a trend for having a worse survival. [11]

Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma is defined as a primary cutaneous lymphoma composed of CD4+ T-cells that form a mass lesion in the dermis ± subcutaneous involvement. [7] The neoplastic cells are small/medium-sized pleomorphic lymphocytes with less than 30% large pleomorphic cells. There can be admixed small reactive lymphocytes and histiocytes. The T-cells usually do not have cytotoxic markers and only some cases show pan-T antigen loss. Proof of T-cell clonality is useful to help distinguish these cases from a benign infiltrate (especially if the phenotype is not aberrant). The lesions are usually but not always solitary. At least the localized lesions have a good prognosis (local treatments have been used). Overall, a 75% 5 year survival is reported. (Blood, 2005)

The classification then lists some extracutaneous T and NK lymphomas that "frequently" involve the skin as a secondary site (in italics). They include: extranodal NK/T-cell lymphoma, nasal type (with hydroa vacciniformia-like lymphoma [5, 6, 12] considered a variant at this time), adult T-cell leukemia/lymphoma and angioimmunoblastic T-cell lymphoma. [2]

Mature B-cell neoplasms

The primary mature B-cell neoplasms listed in the new classification include:

Cutaneous marginal zone B-cell lymphoma (MALT-type)
Primary cutaneous follicle centre lymphoma
Cutaneous diffuse large B-cell lymphoma, leg type
Cutaneous diffuse large B-cell lymphoma, others

Cutaneous marginal zone B-cell lymphoma (MALT-type) is not a controversial entity at the moment and there are no major changes to deal with. This category does include cases previously diagnosed as "immunocytoma" as well as non-myelomatous "plasmacytomas" of skin.

The more contentious B-cell lymphomas
There were lengthy discussions about the remaining mature primary cutaneous B-cell lymphomas that engendered the second consensus conference held in Zurich. WHO and EORTC oriented individuals reviewed slides of follicular/follicle center cell and diffuse large B-cell lymphomas together with all available clinical data, follow-up, and a variety of ancillary studies. The major question was how to slice the pie that includes the B-cell lymphomas which in the WHO classification would fall into the categories of follicular lymphoma (including cutaneous follicle centre lymphoma) and the diffuse large B-cell lymphomas. The ultimate conclusion and resultant classification rested upon the clinical aspects of these neoplasms being critical in what would be grouped and what segregated, with biologic features also important. Specifically, the questions that had to be answered included:

What defines a cutaneous lymphoma of follicular or follicle center (cell) type? Some definitions are very broad and others much more restricted. It had to be determined whether to follow guidelines similar to those for lymph nodes or something different. In the former instance, growth pattern and the number of centroblasts are very important.
When should a lymphoma, that might even be of follicular center origin, be called a diffuse large B-cell lymphoma (DLBCL)? Discussion of this topic included concern that many primary cutaneous "DBLCL" do well with local therapies [13] and, use of the term DLBCL puts these patients at risk for being overtreated. [1]
Are DLBCL of the leg something unique that should be segregated from other DLBCL?

The following three categories were agreed upon, together with the criteria for each.

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

In brief, one can think of these categories as being recognized because the first defines an indolent lymphoma believed to be composed of neoplastic follicular center cells. In contrast, the leg type DLBLC are aggressive and also a relatively homogeneous group of cases from a cytologic/phenotypic perspective. The third category is there because it was felt that there were lymphomas that needed to be diagnosed as a DLBCL that did not fall into either of the other two categories.

Primary cutaneous follicle centre lymphoma usually presents with solitary or grouped plaques or tumors, mostly on the head and neck or trunk regions (rare on legs). The prognosis is excellent, without evidence that the category should be further subdivided in any way (5 year survival >95%).(Blood, 2005) Most cases are treated with radiotherapy including cutaneous relapses. Rituximab might also have a role to play.

The complexity of this area is emphasized by the fact that this is the only entity in the Blood, 2005 paper to have a "comment" section because there is so much variation between what has been found in different studies. Possible reasons for the variation have included geographic differences (European studies are often different than American ones), the possible inclusion of secondary cases due to incomplete staging and possibly technical or interpretive differences with the ancillary studies.

Primary cutaneous follicle centre lymphoma (PCFCL) is defined as a lymphoma composed of neoplastic follicular center cells -- centrocytes with variable numbers of centroblasts. They can have a follicular, follicular and diffuse or diffuse growth pattern. The growth pattern is not considered to be of any clinical significance. The only difference the cytologic composition would make is if there were pure sheets of centroblasts growing diffusely in which case one of the types of DLBCL would have to be diagnosed. In other words, these lymphomas are not graded, in contrast to follicular lymphomas occurring at any other site. The cases that are totally diffuse often do have many large centrocytes and, in part because of this, and in part because there can be a moderate number of centroblasts present, an important subset of these cases would fulfill the criteria for a DLBCL at other sites. It is important, however, to also remember that PCFCL is not just a default diagnosis to make when one has a B-cell lymphoma that is not on the leg and not a marginal zone B-cell lymphoma! It remains critical to exclude other primary or secondary cutaneous lymphomas. One does not want to end up diagnosing a secondary DLBCL as a PCFCL and having the patient undertreated.

The description of PCFCL will include the following phenotypic/genotypic characteristics:

Monoclonal B-cells although they may lack surface immunoglobulin
CD10 variable, less often found in diffuse lesions
Bcl-6 positive
MUM-1 negative
Bcl-2 protein negative or faint staining in a minority of cells (see below)
BCL2 translocation absent (see below)

However, the comment section in the Blood paper acknowledges a significant body of literature that describes definite bcl-2 staining and even some BCL2 translocations in primary cutaneous follicular lymphomas (FL) (generally diagnosed using the criteria for FL at any site). Bcl-2 protein expression is reported in up to 86% of primary cutaneous FL, with its presence more common in cases with fewer centroblasts.(reviewed in Kim, et al, AJSP, 29:69,2005) BCL2/IGH translocations are reported in 10 - 41% of primary cutaneous FL, with its presence more common in cases with fewer centroblasts.(reviewed in Kim, et al, AJSP, 29:69,2005) One must remember that FCL is a broader category than FL so that these studies do not reflect the proportions of cases one would find using the WHO-EORTC criteria for the former type of lymphoma .

These observations and comparisons to secondary and nodal FL do mean that because bcl-2 abnormalities are found more often in the former types of FL compared to the primary cutaneous cases, their presence might at least raise more suspicion that the lesion is not primary or, if diffuse, that lymphoma is not a FCL at all. Their presence in a primary cutaneous FL is not supposed to be of clinical significance. One must be cautious, however, because once you are dealing with a primary cutaneous large B-cell lymphoma (including diffuse FCCL), bcl-2 protein expression (>50% of cells) is an adverse prognostic indicator. [14]

Primary cutaneous diffuse large B-cell lymphomas – Two categories

Primary cutaneous DLBCL, leg type is defined as an aggressive B-cell lymphoma that usually but not always presents on the (lower) leg and is composed of a generally monotonous proliferation of immunoblasts or, perhaps less often, centroblast-like transformed cells with few admixed reactive cells. [15, 16] The leg type DLBCL reportedly make up most non-FCL diffuse B-cell lymphomas composed of large cells. They occur mostly in elderly females who present with rapidly growing tumors on one or both legs; however, as noted, some are located at other sites. In contrast to PCFCL, they are more likely to disseminate to extracutaneous sites (50%). [16] They are aggressive with a 5 year survival of 55% (Blood, 2005) and usually require treatment with combination chemotherapy (perhaps with the exception of single small lesions where radiation therapy might be sufficient). The presence of multiple lesions is an adverse prognostic indicator. [16]

Recognition of the leg type DLBCL is based on a number of different parameters. Site is an important clue but not pathognomonic and one must be able to diagnose these at non-leg sites. Histologically, one should see sheets of transformed B-cells with few admixed reactive elements. Immunophenotypic studies show the following:

Strong bcl-2 expression (versus little in diffuse FCL)
Bcl-6+ but CD10- in most cases (some exceptions especially re bcl-6)
MUM-1/IRF4+ (versus absent in FCL)

Based on the above, not surprisingly the leg-type DLBCL have an activated B-cell gene expression profile. [17] One cytogenetic FISH study demonstrated MYC translocation [6] or BCL6 [5] translocation in 11/14 large B-cell lymphomas of the leg. [18] BCL2/IGH translocations are not present.

There are rare other diffuse large B-cell lymphomas not of PCFCL or DLBCL, leg type that are to be classified as primary cutaneous DLBCL, other. Some of these cases fall into subcategories that are already well known and well defined, including the following entities:

T-cell/histiocyte rich large B-cell lymphoma (believed to be more indolent than its nodal "counterpart") [19]
Cutaneous plasmablastic lymphoma [20]
"Cutaneous" intravascular large B-cell lymphoma (reported to have a better prognosis than the more frequent cases that are not restricted to the skin) [21]

Other cases, however, just do not fit in any of the other categories.

Extracutaneous lymphomas that can involve skin (listed in the classification)

Intravascular large B-cell lymphoma
Lymphomatoid granulomatosis
Chronic lymphocytic leukemia
Mantle cell lymphoma
Burkitt lymphoma

Immature Hematopoietic Malignancies
The main contribution in this realm relates to the neoplasm termed blastic NK-cell lymphoma but which is known by many today as CD4+/CD56+ hematodermic neoplasm. [5, 6, 22] Based on its putative cell of origin the term "early plasmacytoid dendritic cell leukemia/lymphoma" has also been suggested. [23] This entity will not be discussed further. The other immature hematopoietic malignancies listed include:

Precursor lymphoblastic leukemia/lymphoma
 T-lymphoblastic lymphoma
 B-lymphoblastic lymphoma
Myeloid and monocytic leukemias

Hodgkin Lymphoma
Hodgkin lymphoma can rarely involve the skin and is listed in the classification but will not be discussed.

Summary
We will have a new classification of the primary cutaneous lymphomas this year that reflects a consensus/compromise between those used to a skin-only classification and those used to the classic 2001 WHO classification of lymphoid tumors. The new classification, however, does not mean that everything is now settled in this problematic field. In fact, much remains to be learned.

References

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  2. Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds.): Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

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  23. Jacob MC, Chaperot L, Mossuz P, Feuillard J, Valensi F, Leroux D, Bene MC, Bensa JC, Briere F, Plumas J: CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells. Haematologica 2003, 88:941-955.