WHO-EORTC classification for cutaneous lymphomas

http://www.100md.com 《血液学杂志》

     the Department of Dermatology, Leiden University, Medical Center, the Netherlands

    Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

    Department of Dermatology, University Hospital Zürich, Switzerland

    Department of Dermatology, University of Graz, Austria

    Department of Dermatology, University of Milan-Biococca and Ospedale Magiore, Milan, Italy

    Department of Pathology, Division of Hematopathology, University of Pittsburgh School of Medicine, PA

    Department of Pathology, University of Copenhagen, Denmark

    Department of Dermatology, University of Rome, Italy

    Department of Dermatology, Cruces Hospital, Bilbao, Spain

    Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA

    Department of Dermatology, hospital Pasteur, Colmar, France

    Department of Pathology, University Hospital Zürich, Switzerland

    Department of Dermatology, University of Vienna, Austria

    Department of Dermatological Sciences, University of Florence, Italy

    Department of Dermatology, Allgemeines Krankenhaus St Georg, Hamburg, Germany

    Department of Human Pathology and Oncology, University of Florence, Italy

    Department of Dermatology, Charite, Humboldt University, Berlin, Germany

    Department of Pathology, hospital Henri Mondor, Creteil, France

    Skin Tumour Unit, St John's Institute of Dermatology, St Thomas' Hospital, London, England

    Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

    Abstract

    Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.

    Introduction

    A variety of T- and B-cell neoplasms can involve the skin, either primarily or secondarily. The term "primary cutaneous lymphoma" refers to cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas (CBCLs) that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After the gastrointestinal tract, the skin is the second most common site of extranodal non-Hodgkin lymphoma, with an estimated annual incidence of 1:100,000.1

    Primary cutaneous lymphomas often have a completely different clinical behavior and prognosis from histologically similar systemic lymphomas, which may involve the skin secondarily, and therefore require different types of treatment. For that reason, recent classification systems for non-Hodgkin lymphomas such as the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas and the World Health Organization (WHO) classification for tumors of hematopoietic and lymphoid tissues included primary cutaneous lymphomas as separate entities.2,3 In the EORTC classification, distinction was made between primary cutaneous lymphomas with an indolent, intermediate, or aggressive clinical behavior. The clinical validity of this classification has been validated by several large studies, including follow-up data of more than 1300 patients with a primary cutaneous lymphoma.2,4,5 Although there was consensus between the EORTC and WHO classifications on the classification of most types of CTCLs, remaining differences between the 2 classification systems, in particular the controversy on the definition and terminology of the different types of CBCLs, has resulted in considerable debate and confusion.6-9

    During consensus meetings in Lyon, France (September 2003) and Zurich, Switzerland (January 2004), these differences were resolved by representatives of both classification systems, and a consensus classification was developed (Table 1). In this report we present the new WHO-EORTC classification for cutaneous lymphomas. This review will focus on primary cutaneous lymphomas and a few other conditions that frequently first present in the skin, such as CD4+/CD56+ hematodermic neoplasm (formerly also known as blastic natural killer [NK] cell lymphoma) and adult T-cell leukemia/lymphoma. Other neoplasms that may also first present in the skin in a minority of cases, such as precursor B-lymphoblastic leukemia/lymphoma and acute myeloid leukemia, and secondary cutaneous manifestations of systemic lymphomas, are not discussed, but will be included in the monograph to be published in the WHO Blue Book series in 2005. After a discussion of the 2 most controversial groups of cutaneous lymphomas that were defined differently in the original EORTC and WHO classification schemes, the main features of the different types of primary cutaneous lymphoma are presented. In Table 2 the relative frequency and survival of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian cutaneous lymphoma registries are presented, to illustrate the clinical significance of the WHO-EORTC classification.

    Classification of CTCLs other than mycosis fungoides, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferations

    The classification of this remaining group of CTCLs is difficult and confusing, which is not surprising given the heterogeneity and rarity of these tumors. Together, they constitute less than 10% of all CTCLs.2,5 With few exceptions, these lymphomas are clinically aggressive and in most cases systemic chemotherapy is required. In the EORTC classification, most of these lymphomas were grouped as primary cutaneous CD30- large T-cell lymphoma or in the provisional group of primary cutaneous small/medium-sized pleomorphic CTCLs. Distinction between these 2 categories, which is based on the presence of more or less than 30% large neoplastic T cells, was considered useful because several studies demonstrated a significant difference in survival between these 2 groups.2,4,5,10 Recent studies suggest, however, that this favorable prognosis is restricted to small/medium-sized pleomorphic CTCLs with a CD4+ T-cell phenotype, in particular those that present with localized disease, in contrast to those with a CD8+ T-cell phenotype.11 Moreover, the EORTC category of CD30- large-cell CTCLs has become quite heterogeneous through the recognition of new diagnostic categories, such as subcutaneous panniculitis-like T-cell lymphoma (SPTL),12-17 extranodal NK/T-cell lymphoma, nasal type,18-20 CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma),21-24 aggressive epidermotropic CD8+ CTCL,16,25,26 and cutaneous gamma/delta T-cell lymphoma.27-31 In the WHO classification, SPTL, nasal-type NK/T-cell lymphoma, and blastic NK-cell lymphoma were included as separate entities, whereas the other entities were part of the broad category of peripheral T-cell lymphoma (PTL), unspecified.

    In the WHO-EORTC classification, extranodal NK/T-cell lymphoma, nasal type, and CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma), are defined as separate entities. Recent studies showed both clinical, histologic, and immunophenotypical differences between cases of SPTL with an / T-cell phenotype and those with a / T-cell phenotype, suggesting that these may represent different entities. Whereas SPTLs with an / T-cell phenotype are homogeneous with a rather indolent clinical behavior in many patients, SPTLs with a / T-cell phenotype overlap with other types of /+ T/NK-cell lymphoma and invariably run a very aggressive clinical course.14,16,17,31,32

    We therefore suggest that the term "SPTL" be restricted for SPTLs with an / T-cell phenotype.32 Recent studies have suggested that some disorders can be separated out as provisional entities from the broad group of "PTL, unspecified," in the WHO classification. These include aggressive epidermotropic CD8+ CTCL, cutaneous gamma-delta T-cell lymphoma (including cases formerly diagnosed as SPTL with a gamma/delta phenotype), and primary cutaneous small-medium CD4+ T-cell lymphoma. In the WHO-EORTC classification the term "PTL, unspecified," is maintained for remaining cases that do not fit into either of these provisional entities.

    Primary cutaneous follicle-center cell lymphoma and primary cutaneous diffuse large B-cell lymphoma

    In recent years, the EORTC categories of primary cutaneous follicle center cell lymphoma (PCFCCL) and primary cutaneous large B-cell lymphoma of the leg (PCLBCL-leg) have been the subject of much debate. The term PCFCCL was introduced in 1987 as a term encompassing cutaneous lymphomas that were composed of cells with the morphology of follicle center cells (ie, centroblasts and [large] centrocytes), and that were classified as either centroblastic/centrocytic or centroblastic lymphoma according to criteria of the Kiel classification.33 Whereas small and early lesions may show both small and large neoplastic B cells and many admixed T cells, and may have a partly follicular growth pattern, tumorous lesions generally show a predominance of large B cells, particularly large cleaved or multilobated cells, and less frequently a predominance of typical centroblasts and immunoblasts.33-35 In contrast to nodal follicular lymphomas, PCFCCLs do generally not express bcl-2 and are not typically associated with the t(14;18) translocation.36,37 Clinically, most patients present with localized skin lesions on the head or trunk and, regardless of the histologic subclassification on the basis of growth pattern or number of blast cells, are highly responsive to radiotherapy and have an excellent prognosis.2,4,5,33,34,35,38

    The WHO classification approached these lesions from a different perspective. PCFCCLs with a partly follicular growth pattern were included as a variant of follicular lymphoma and designated cutaneous follicle center lymphoma, while cases with a diffuse growth pattern and a predominance of large centrocytes or centroblasts were generally classified as diffuse large B-cell lymphoma. The designation of this latter group as diffuse large B-cell lymphoma was controversial, since it could lead to overtreatment with muliagent chemotherapy rather than radiotherapy.

    PCLBCL-leg was initially recognized as a subgroup of PCFCCL with a somewhat different histology and a more unfavorable prognosis.39 In the EORTC classification it was included as a separate subgroup. PCLBCL-leg particularly affects elderly people and has a higher relapse rate and a more unfavorable prognosis than PCFCCL with a diffuse large B-cell morphology.40 Histologically, they have a predominance of centroblasts and immunoblasts rather than large centrocytes, and consistently strongly express bcl-2 protein.41 Although delineation of this subgroup based on site has been criticized,6,8 recent clinicopathologic and genetic studies further support that PCFCCL and PCLBCL-leg are distinct groups of CBCL.42-46

    During the consensus meeting in Zurich, histologic slides of a large number of PCFCCLs and PCLBCL-leg's were reviewed, together with the immunophenotype and clinical data. It was recognized that PCFCCLs as defined in the EORTC classification indeed form a spectrum of disease that includes cases with a follicular, a follicular and diffuse, and a diffuse growth pattern, and a range of cellular composition from predominantly small centrocytes to a predominance of large centrocytes with variable numbers of admixed centroblasts and immunoblasts. This entity will further be referred to as "primary cutaneous follicle center lymphoma" (PCFCL). The group of PCLBCL-leg was also recognized as a separate entity. According to the results of a recent multicenter study, it is also clear that cases with a similar morphology (predominance or cohesive sheets of centroblasts and immunoblasts), immunophenotype (strong expression of bcl-2 and Mum-1/IRF4), and prognosis may arise at sites other than the leg.42 In the WHO-EORTC classification the term "PCLBCL, leg type" is proposed for both lesions on the legs and similar lesions at other skin sites. In addition, the term "PCLBCL, other" is introduced for rare cases of PCLBCL not belonging to the group of PCLBCL, leg type, or PCFCL with a diffuse infiltration of large centrocytes.

    Cutaneous T-cell lymphomas

    Mycosis fungoides

    Definition. Mycosis fungoides (MF) is a commonly epidermotropic CTCL characterized by a proliferation of small-to medium-sized T lymphocytes with cerebriform nuclei. The term MF should be used only for the classical "Alibert-Bazin" type characterized by the evolution of patches, plaques, and tumors, or for variants showing a similar clinical course. MF is the most common type of CTCL and accounts for almost 50% of all primary cutaneous lymphomas (Table 2).

    Clinical features. MF typically affects older adults (median age at diagnosis: 55-60 years; male-to-female ratio: 1.6-2.0:1), but may occur in children and adolescents.47-50 MF has an indolent clinical course with slow progression over years or sometimes decades, from patches to more infiltrated plaques and eventually to tumors (Figure 1A). In some patients, lymph nodes and visceral organs may become involved in the later stages of the disease. The initial skin lesions have a predilection for the buttocks and other sun-protected areas. Patients with tumor-stage MF characteristically show a combination of patches, plaques, and tumors, which often show ulceration. If only tumors are present, without preceding or concurrent patches or plaques, a diagnosis of MF is highly unlikely and another type of CTCL should be considered.

    Histopathology. Early patch lesions in MF show superficial bandlike or lichenoid infiltrates, mainly consisting of lymphocytes and histiocytes. Atypical cells with small-to medium-sized, highly indented (cerebriform), and sometimes hyperchromatic nuclei are few, and mostly confined to the epidermis (epidermotropism). They characteristically colonize the basal layer of the epidermis either as single, often haloed cells, or in a linear configuration.51 In typical plaques, epidermotropism is generally more pronounced than in the patches (Figure 1B). The presence of intraepidermal collections of atypical cells (Pautrier microabscesses) is a highly characteristic feature, but is observed in only a minority of cases.52 With progression to tumor stage, the dermal infiltrates become more diffuse and epidermotropism may be lost. The tumor cells increase in number and size, showing variable proportions of small, medium-sized, to large cerebriform cells, blast cells with prominent nuclei, and intermediate forms. Transformation to a diffuse large-cell lymphoma that may be either CD30- or CD30+ may occur and is often associated with a poor prognosis.53

    Immunophenotype. The neoplastic cells in MF have a mature CD3+, CD4+, CD45RO+, CD8- memory T-cell phenotype. In rare cases of otherwise classical, MF a CD4-, CD8+ mature T-cell phenotype may be seen.25,26,54,55 Such cases have the same clinical behavior and prognosis as CD4+ cases, and should not be considered separately. Demonstration of an aberrant phenotype (eg, loss of pan–T-cell antigens such as CD2, CD3, and CD5) is often seen and is an important adjunct in the diagnosis of MF.54 Expression of cytotoxic proteins (T-cell intracellular antigen-1 [TIA-1], granzyme B) by the neoplastic CD4+ T-cells has been detected in 10% of MF plaques, but is much more common in tumors showing blastic transformation.56

    Genetic features. Clonal T-cell receptor gene rearrangements are detected in most cases.51 Many structural and numerical chromosomal abnormalities have been described, in particular in the advanced stages of MF, but recurrent, MF-specific chromosomal translocations have not been identified.51,57 Chromosomal loss at 10q and abnormalities in p15, p16, and p53 tumor suppressor genes are commonly found in patients with MF.51

    Prognosis and predictive factors. The prognosis of patients with MF is dependent on stage, and in particular the type and extent of skin lesions and the presence of extracutaneous disease.47-49 Patients with limited patch/plaque-stage MF have a similar life expectancy to an age-, sex-, and race-matched control population. In recent studies, 10-year disease-specific survivals were 97%-98% for patients with limited patch/plaque disease (covering less than 10% of the skin surface), 83% for patients with generalized patch/plaque disease (covering more than 10% of the skin surface), 42% for patients with tumor stage disease, and about 20% for patients with histologically documented lymph node involvement.47-49 Patients with effaced lymph nodes, visceral involvement, and transformation into a large T-cell lymphoma have an aggressive clinical course. Patients usually die of systemic involvement or infections.

    Therapy. As long as the disease is confined to the skin, skin-targeted therapies as photo (chemo)–therapy (eg, psoralen plus ultraviolet A [PUVA]), topical application of nitrogen mustard or chlormustine (BCNU), or radiotherapy, including total skin electron beam irradiation, are preferred.58-60 In patients with limited patch-stage disease topical steroids or bexarotene gel can be used. Biologicals such as interferon alpha and other cytokines (eg, interleukin-12 [IL-12]), traditional and new retinoids such as bexarotene, and receptor-targeted cytotoxic fusion proteins (eg, DAB389IL-2; denileukin diftitox), are increasingly used in the treatment of MF.58,60-63 However, the exact place of these new treatments, either as single-agent therapy or in combination with other therapies (eg, PUVA) in the treatment of MF remains to be established. Multiagent chemotherapy is generally used in case of unequivocal lymph node or systemic involvement, or in cases with widespread tumor-stage MF refractory to skin-targeted therapies, but should not be considered in early patch/plaque stage disease.64

    Variants and subtypes of mycosis fungoides

    Apart from the classical Alibert-Bazin type of MF, many clinical and/or histologic variants have been reported. Clinical variants, such as bullous and hyper- or hypopigmented MF, have a clinical behavior similar to that of classical MF, and therefore are not considered separately. In contrast, folliculotropic MF (MF-associated follicular mucinosis), pagetoid reticulosis, and granulomatous slack skin have distinctive clinicopathologic features, and are therefore considered separately.

    Folliculotropic MF. Definition. Folliculotropic MF is a variant of MF characterized by the presence of folliculotropic infiltrates, often with sparing of the epidermis, and preferential involvement of the head and neck area. Most cases show mucinous degeneration of the hair follicles (follicular mucinosis) and are traditionally designated as MF-associated follicular mucinosis. Similar cases, but without follicular mucinosis, have been reported as folliculocentric or pilotropic MF.65 Recent studies showed no differences in clinical presentation and clinical behavior between cases of folliculotropic MF with or without associated follicular mucinosis, and suggested that cases with a preferential infiltration of hair follicles with or without the presence of mucin should be termed "follicular MF" or "folliculotropic MF."66-68 In the WHO-EORTC classification, folliculotropic MF is preferred as the most appropriate term. From a biologic point of view, the most relevant feature in both cases with and without associated follicular mucinosis is the deep, follicular, and perifollicular localization of the neoplastic infiltrates, which makes them less accessible to skin-targeted therapies.

    Clinical features. Folliculotropic MF occurs mostly in adults, but may occasionally affect children and adolescents. Males are more often affected than females. Patients may present with grouped follicular papules, acneiform lesions, indurated plaques, and sometimes tumors, which preferentially involve and are most pronounced in the head and neck area.68 The skin lesions are often associated with alopecia, and sometimes with mucinorrhea. Infiltrated plaques in the eyebrows with concurrent alopecia are a common and highly characteristic finding (Figure 2A). Unlike in classical MF, pruritus is often severe, and may represent a good parameter of disease progression. Secondary bacterial infections are frequently observed.

    Histopathology. Characteristic findings include the primarily perivascular and periadnexal localization of the dermal infiltrates with variable infiltration of the follicular epithelium by small, medium-sized, or sometimes large hyperchromatic cells with cerebriform nuclei, and sparing of the epidermis (folliculotropism instead of epidermotropism; Figure 2B). Most cases show mucinous degeneration of the follicular epithelium (follicular mucinosis), as assessed with Alcian blue staining. There is often a considerable admixture of eosinophils and sometimes plasma cells. In most cases the neoplastic T cells have a CD3+, CD4+, CD8- phenotype as in classical MF. An admixture of CD30+ blast cells is common.

    In some cases, prominent infiltration of both follicular epithelium and eccrine sweat glands may be observed.68 Similar cases with prominent infiltration of eccrine sweat glands, often associated with alopecia, have been designated as syringotropic MF.69,70

    Prognosis. Recent studies described a disease-specific 5-year survival of approximately 70%-80% in patients with folliculotropic MF (Table 2), which is similar to that of classical tumor-stage MF, but significantly worse than that of patients with classical plaque stage MF.68,71

    Treatment. Because of the perifollicular localization of the dermal infiltrates, folliculotropic MF is often less responsive to skin-targeted therapies, such as PUVA and topical nitrogen mustard, than classical plaque-stage MF. In such cases total skin electron beam irradiation is an effective treatment, but sustained complete remissions are rarely achieved.68 Alternatively, PUVA combined with retinoids or interferon alpha may be considered, whereas persistent tumors can be effectively treated with local radiotherapy.

    Pagetoid reticulosis. Definition. Pagetoid reticulosis is a variant of MF characterized by the presence of localized patches or plaques with an intraepidermal proliferation of neoplastic T cells. The term pagetoid reticulosis should only be used for the localized type (Woringer-Kolopp type) and not for the disseminated type (Ketron-Goodman type). Generalized cases would currently likely be classified as aggressive epidermotropic CD8+ CTCL, cutaneous gamma/delta-positive T-cell lymphoma, or tumor-stage MF.2,25,72

    Clinical features. Patients present with a solitary psoriasiform or hyperkeratotic patch or plaque, which is usually localized on the extremities, and is slowly progressive. In contrast to classical MF, extracutaneous dissemination or disease-related deaths have never been reported.

    Histopathology. The typical histologic picture shows a hyperplastic epidermis with marked infiltration by atypical pagetoid cells, singly or arranged in nests. The atypical cells have medium-sized or large, sometimes hyperchromatic and cerebriform nuclei, and abundant, vacuolated cytoplasm. The upper dermis may show a mixed infiltrate of lymphocytes or histiocytes, but does not contain neoplastic T cells.

    Immunophenotype. The neoplastic T cells may have either a CD3+, CD4+, CD8- or a CD3+, CD4-, CD8+ phenotype. CD30 is often expressed.73,74

    Treatment. The preferred mode of treatment is radiotherapy or surgical excision. In some instances topical nitrogen mustard or topical steroids may be an acceptable alternative.

    Granulomatous slack skin. Definition. Granulomatous slack skin (GSS) is an extremely rare subtype of CTCL characterized by the slow development of folds of lax skin in the major skin folds and histologically by a granulomatous infiltrate with clonal T cells.75

    Clinical features. This condition shows circumscribed areas of pendulous lax skin with a predilection for the axillae and groins. In approximately one-third of the reported patients, an association with Hodgkin lymphoma was observed, and association with classical MF has also been reported.75-77 Most patients have an indolent clinical course (Table 2).

    Histopathology. Fully developed lesions show dense granulomatous dermal infiltrates containing atypical T cells with slightly indented to cerebriform nuclei, macrophages and often many multinucleated giant cells, and destruction of elastic tissue. The epidermis may show focal infiltration by small atypical T cells. The atypical T cells have a CD3+, CD4+, CD8- phenotype.

    Therapy. Radiotherapy may be effective, but experience is limited. Rapid recurrences after surgical excision have been reported.

    Sezary syndrome

    Definition. Sezary syndrome (SS) is defined historically by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T cells (Sezary cells) in skin, lymph nodes, and peripheral blood.78 In a recent report of the International Society for Cutaneous Lymphomas (ISCL), criteria recommended for the diagnosis of SS include one or more of the following: an absolute Sezary cell count of least 1000 cells/mm3; demonstration of immunophenotypical abnormalities (an expanded CD4+ T-cell population resulting in a CD4/CD8 ratio more than 10, loss of any or all of the T-cell antigens CD2, CD3, CD4, and CD5, or both); or the demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods.79 It is acknowledged 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 these erythrodermic CTCLs have been proposed.79,80 However, until the results of an ISCL study investigating the clinical validity of these proposals are available, demonstration of a T-cell clone (preferably of the same T-cell clone in skin and peripheral blood) in combination with one of the above-mentioned cytomorphologic or immunophenotypic criteria are suggested as minimal criteria for the diagnosis of SS to exclude patients with benign inflammatory conditions simulating SS.

    Clinical features. SS is a rare disease and occurs exclusively in adults. It is characterized by erythroderma, which may be associated with marked exfoliation, edema, and lichenification, and which is intensely pruritic. Lymphadenopathy, alopecia, onychodystrophy, and palmoplantar hyperkeratosis are common findings.78

    Histopathology. The histological features in SS may be similar to those in MF. However, the cellular infiltrates in SS are more often monotonous, and epidermotropism may sometimes be absent. In up to one-third of biopsies from patients with otherwise classical SS the histologic picture may be nonspecific.81,82 Involved lymph nodes characteristically show a dense, monotonous infiltrate of Sezary cells with effacement of the normal lymph node architecture.83 Bone marrow may be involved, but the infiltrates are often sparse and mainly interstitial.84

    Immunophenotype. The neoplastic T cells have a CD3+, CD4+, CD8- phenotype. In cases with a predominant CD3+, CD4-, CD8+ T-cell population in the skin and peripheral blood, the diagnosis of actinic reticuloid should be considered.85 Circulating Sezary cells often show loss of CD7 and CD26.79

    Genetic features. T-cell receptor genes are clonally rearranged. Demonstration of clonal T cells in the peripheral blood is considered as an important diagnostic criterion allowing differentiation between SS and benign forms of erythroderma.2,79,80 Recurrent chromosomal translocations have not been detected in SS, but complex karyotypes are common.86,87 Several studies have identified a consistent pattern of identical chromosomal abnormalities in SS, which was almost identical to that in MF, suggesting that both conditions represent parts of the same spectrum of disease with a similar pathogenesis.88,89 Chromosomal amplification of the JUNB gene, a member of the activator protein-1 (AP-1) transcription factor complex involved in cell proliferation and T helper 2 (Th2) cytokine expression by T cells, has been identified in SS.90,91

    Prognosis and predictive factors. The prognosis is generally poor, with a median survival between 2 and 4 years, depending on the exact definition used.2,80 The disease-specific 5-year survival of 52 SS patients included in the Dutch and Austrian registries was 24% (Table 2). Most patients die of opportunistic infections that are due to immunosuppression.

    Therapy. Extracorporeal photopheresis (ECP), either alone or in combination with other treatment modalities (eg, interferon alpha), has been reported as an effective treatment in SS and erythrodermic MF, with overall response rates of 30%-80%, and complete response rates of 14%-25%.92,93 This great variation in response rates may reflect differences in patient selection and/or concurrent therapies. The suggested superiority of ECP over the traditional low-dose chemotherapy regimens has not yet been substantiated by controlled randomized trials.93 Beneficial results have also reported of interferon alpha, either alone or in combination with PUVA therapy, prolonged treatment with a combination of low-dose chlorambucil (2-4 mg/d) and prednisone (10-20 mg/d) or with methotrexate (5-25 mg/wk), but complete responses are uncommon. Skin-directed therapies like PUVA or potent topical steroids may be used as adjuvant therapy. Recent studies report beneficial effects of bexarotene and alemtuzumab (anti-CD52) but the long-term effects of these therapies remain to be established.58,62,94

    Adult T-cell leukemia/lymphoma

    Definition. Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm etiologically associated with the human T-cell leukemia virus 1 (HTLV-1). Skin lesions are generally a manifestation of widely disseminated disease. However, a slowly progressive form that may have only skin lesions has been described (smoldering variant).95

    Clinical features. ATLL is endemic in areas with a high prevalence of HTLV-1 in the population, such as southwest Japan, the Caribbean islands, South America, and parts of Central Africa. ATLL develops in 1% to 5% of seropositive individuals after more than 2 decades of viral persistence. Most patients present with acute ATLL characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia, and in about 50% skin lesions, most commonly nodules or tumors (33%), generalized papules (22%), or plaques (19%).96 Chronic and smoldering variants frequently present with skin lesions, which may closely resemble MF, whereas circulating neoplastic T cells are few or absent.

    Histopathology. Skin lesions show a superficial or more diffuse infiltration of medium-sized to large T cells with pleomorphic or polylobated nuclei, which often display marked epidermotropism. The histologic picture may be indistinguishable from MF. Skin lesions in the smoldering type may show sparse dermal infiltrates with only slightly atypical cells. The neoplastic T cells express a CD3+, CD4+, CD8- phenotype. CD25 is highly expressed.95,96

    Genetic features. T-cell receptor genes are clonally rearranged. Clonally integrated HTLV-1 genes are found in all cases, and are useful in differentiating between chronic or smoldering variants of ATLL and classical MF or SS.97

    Prognosis and predictive factors. Clinical subtype is the main prognostic factor. Survival in acute and lymphomatous variants ranges from 2 weeks to more than 1 year. Chronic and smoldering forms have a more protracted clinical course and a longer survival, but transformation into an acute phase with an aggressive course may occur.95,96

    Treatment. In most cases systemic chemotherapy is required.98,99 In chronic and smoldering cases mainly affecting the skin, skin-targeted therapies as in MF may be used.

    Primary cutaneous CD30+ lymphoproliferative disorders

    Primary cutaneous CD30+ lymphoproliferative disorders (LPDs) are the second most common group of CTCLs, accounting for approximately 30% of CTCLs (Table 2). This group includes primary cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases. It is now generally accepted that C-ALCL and LyP form a spectrum of disease, and that histologic criteria alone are often insufficient to differentiate between these 2 ends of this spectrum.100 The clinical appearance and course are used as decisive criteria for the definite diagnosis and choice of treatment. The term "borderline case" refers to cases in which, despite careful clinicopathologic correlation, a definite distinction between C-ALCL and LyP cannot be made. Clinical examination during further follow-up will generally disclose whether the patient has C-ALCL or LyP.101

    Primary cutaneous anaplastic large-cell lymphoma. Definition. Primary cutaneous anaplastic large cell lymphoma. (C-ALCL) is composed of large cells with an anaplastic, pleomorphic, or immunoblastic cytomorphology and expression of the CD30 antigen by the majority (more than 75%) of tumor cells.100 There is no clinical evidence or history of LyP, MF, or another type of CTCL.

    Clinical features. C-ALCL affects mainly adults with a male to female ratio of 2-3:1. Most patients present with solitary or localized nodules or tumors, and sometimes papules, and often show ulceration (Figure 3).101,102 Multifocal lesions are seen in about 20% of the patients. The skin lesions may show partial or complete spontaneous regression, as in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in approximately 10% of the patients, and mainly involves the regional lymph nodes.

    Histopathology. There is a diffuse, nonepidermotropic infiltrate with cohesive sheets of large CD30+ tumor cells. In most cases the tumor cells have the characteristic morphology of anaplastic cells, showing round, oval, or irregularly shaped nuclei, prominent eosinophilic nucleoli, and abundant cytoplasm (Figure 3). Less commonly (20%-25%), they have a nonanaplastic (pleomorphic or immunoblastic) appearance.101,103 Reactive lymphocytes are often present at the periphery of the lesions. Ulcerating lesions may show a LyP-like histology with an abundant inflammatory infiltrate of reactive T cells, histiocytes, eosinophils and/or neutrophils, and relatively few CD30+ cells. In such cases epidermal hyperplasia may be prominent.

    Immunophenotype. The neoplastic cells generally show an activated CD4+ T-cell phenotype with variable loss of CD2, CD5, and/or CD3, and frequent expression of cytotoxic proteins (granzyme B, TIA-1, perforin).104,105 Some cases (less than 5%) have a CD8+ T-cell phenotype. CD30 must be expressed by the majority (more than 75%) of the neoplastic T cells.106 Unlike systemic CD30+ lymphomas, most C-ALCLs express the cutaneous lymphocyte antigen (CLA), but do not express epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK), indicative of the 2;5 chromosomal translocation or its variants.2,107,108 Unlike Hodgkin and Reed-Sternberg cells in Hodgkin disease, staining for CD15 is generally negative. Coexpression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis.109

    Genetic features. Most cases show clonal rearrangement of T-cell receptor genes. The (2;5)(p23;q35) translocation and its variants, which is a characteristic feature of systemic ALCL, is not or rarely found in C-ALCL.108

    Prognosis and predictive factors. The prognosis is usually favorable with a 10-year disease-related survival exceeding 90%.101,102 Patients presenting with multifocal skin lesions and patients with involvement of only regional lymph nodes have a similar prognosis to patients with only skin lesions.101 No difference in clinical presentation, clinical behavior, or prognosis is found between cases with an anaplastic morphology and cases with a nonanaplastic (pleomorphic or immunoblastic) morphology.101,103

    Treatment. Radiotherapy or surgical excision is the first choice of treatment in patients presenting with a solitary or few localized nodules or tumors. Patients presenting with multifocal skin lesions can best be treated with radiotherapy in case of only a few lesions, or with low-dose methotrexate, as in LyP.101,110 Patients presenting with or developing extracutaneous disease or rare patients with rapidly progressive skin disease should be treated with doxorubicin-based multiagent chemotherapy.

    Lymphomatoid papulosis. Definition. Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a (CD30+) malignant lymphoma.

    Clinical features. LyP generally occurs in adults (median age, 45 years; male-to-female ratio, 1.5:1), but may occur in children as well.101,102,111,112 LyP is characterized by the presence of papular, papulonecrotic, and/or nodular skin lesions at different stages of development, predominantly on the trunk and limbs. Individual skin lesions disappear within 3 to 12 weeks, and may leave behind superficial scars (Figure 3). The duration of the disease may vary from several months to more than 40 years. In up to 20% of patients LyP may be preceded by, associated with, or followed by another type of malignant (cutaneous) lymphoma, generally MF, a (C-)ALCL, or Hodgkin lymphoma.101

    Histopathology. The histologic picture of LyP is extremely variable, and in part correlates with the age of the biopsied skin lesion. Three histologic subtypes of LyP (types A, B, and C) have been described, which represent a spectrum with overlapping features.100,101,112 In LyP type A lesions, scattered or small clusters of large, sometimes multinucleated or Reed-Sternberg–like, CD30+ cells are intermingled with numerous inflammatory cells, such as histiocytes, small lymphocytes, neutrophils, and/or eosinophils. LyP type C lesions demonstrate a monotonous population or large clusters of large CD30+ T cells with relatively few admixed inflammatory cells. LyP type B is uncommon (less than 10%) and is characterized by an epidermotropic infiltrate of small atypical cells with cerebriform nuclei similar to that observed in MF.

    Immunophenotype. The large atypical cells in the LyP type A and type C lesions have the same phenotype as the tumor cells in C-ALCL.113 The atypical cells with cerebriform nuclei in the LyP type B lesions have a CD3+, CD4+, CD8- phenotype and do not express CD30 antigen.

    Genetic features. Clonally rearranged T-cell receptor genes have been detected in approximately 60%-70% of LyP lesions.114 Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas.115 The (2;5)(p23;q35) translocation is not detected in LyP.108

    Prognosis and predictive factors. LyP has an excellent prognosis. In a recent study of 118 LyP patients only 5 (4%) patients developed a systemic lymphoma, and only 2 (2%) patients died of systemic disease over a median follow-up period of 77 months.101 Risk factors for the development of a systemic lymphoma are unknown.

    Treatment. Since a curative therapy is not available and none of the available treatment modalities affects the natural course of the disease, the short-term benefits of active treatment should be balanced carefully against the potential side effects.101 Low-dose oral methotrexate (5-20 mg/wk) is the most effective therapy to suppress the development of new skin lesions.110 Beneficial effects have been reported of PUVA and topical chemotherapy. However, after discontinuation of treatment the disease generally relapses within weeks or months. Therefore, in patients with relatively few and nonscarring lesions, long-term follow-up without active treatment should be considered.

    Subcutaneous panniculitis-like T-cell lymphoma

    Definition. Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of small, medium-sized, or large pleomorphic T cells and many macrophages, predominantly affecting the legs, and often complicated by a hemophagocytic syndrome.12 Recent studies suggest that at least 2 groups of SPTL with a different histology, phenotype, and prognosis can be distinguished. Cases with an /+ T-cell phenotype are usually CD8+, are restricted to the subcutaneous tissue (no dermal and/or epidermal involvement), and often run an indolent clinical course.14,16,17,32 In contrast, SPTL with a / T-cell phenotype, approximately 25% of all cases, are typically CD4-, CD8-, and often coexpress CD56, the neoplastic infiltrates are not confined to the subcutaneous tissue, but may involve the epidermis and/or dermis as well, and invariably have a very poor prognosis.13,14,16,17,116 In the WHO-EORTC classification the term "SPTL" is only used for cases with an /+ T-cell phenotype, whereas cases with a /+ T-cell phenotype are included in the category of cutaneous / T-cell lymphomas.32

    Clinical features. SPTL occurs in adults as well as in young children, and both sexes are equally affected. Patients generally present with solitary or multiple nodules and plaques, which mainly involve the legs, or may be more generalized (Figure 4A). Ulceration is uncommon. Systemic symptoms such as fever, fatigue, and weight loss may be present. The disease may be complicated by a hemophagocytic syndrome, which is generally associated with a rapidly progressive course.117 However, a hemophagocytic syndrome is probably less common than in cutaneous / T-cell lymphomas with panniculitis-like lesions. Dissemination to extracutaneous sites is rare. SPTL may be preceded for years or decades by an seemingly benign panniculitis.15,17,117

    Histopathology. Histopathology reveals subcutaneous infiltrates simulating a panniculitis showing small, medium-sized, or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrophages. The overlying epidermis and dermis are typically uninvolved.16,116 Rimming of individual fat cells by neoplastic T cells is a helpful, though not completely specific, diagnostic feature (Figure 4B,C).32 Necrosis, karyorrhexis, and cytophagocytosis are common findings. In the early stages the neoplastic infiltrates may lack significant atypia and a heavy inflammatory infiltrate may predominate.15,17,117

    Immunophenotype. These lymphomas show a /+, CD3+, CD4-, CD8+ T-cell phenotype, with expression of cytotoxic proteins (Figure 4D). 14,16,17,32 CD30 and CD56 are rarely, if ever, expressed.

    Genetic features. The neoplastic T cells show clonal T-cell receptor (TCR) gene rearrangements. Specific genetic abnormalities have not been identified. Epstein-Barr virus (EBV) is absent.

    Prognosis and predictive factors. In contrast to prior reports indicating that patients with a SPTL have a rapidly fatal course, recent studies suggest that many patients with a SPTL (with a CD8+, /+ T-cell phenotype) have a protracted clinical course with recurrent subcutaneous lesions but without extracutaneous dissemination or the development of a hemophagocytic syndrome.17,32 Based on the few published reports in which appropriate phenotyping was performed, the 5-year survival of such patients may be more than 80%,32 which is consistent with the data presented in Table 2.

    Treatment. Patients have generally been treated with doxorubicin-based chemotherapy and radiotherapy.12-17 However, recent studies suggest that many patients can be controlled for long periods of time with systemic corticosteroids.17,32

    Extranodal NK/T-cell lymphoma, nasal type

    Definition. Extranodal NK/T-cell lymphoma, nasal type, is a nearly always EBV+ lymphoma of small, medium, or large cells usually with an NK-cell, or more rarely a cytotoxic T-cell, phenotype. The skin is the second most common site of involvement after the nasal cavity/nasopharynx, and skin involvement may be a primary or secondary manifestation of the disease. Since both groups show an aggressive clinical behavior and require the same type of treatment, distinction between "primary" and "secondary" cutaneous involvement seems not useful for this category.16,19,32,118,119 Therefore, the WHO classification–derived term "extranodal NK/T-cell lymphoma, nasal type," rather than "(primary) cutaneous NK/T-cell lymphoma, nasal type," is preferred.

    Clinical features. Patients are adults with a predominance of males. This lymphoma is more common in Asia, Central America, and South America. Patients generally present with multiple plaques or tumors preferentially on the trunk and extremities, or in the case of nasal NK/T-cell lymphoma with a midfacial destructive tumor, previously also designated "lethal midline granuloma."18,19,32,119-122 Ulceration is common. Systemic symptoms such as fever, malaise, and weight loss may be present, and some cases are accompanied by a hemophagocytic syndrome. The disease is closely related to aggressive NK-cell leukemia, which also may have cutaneous manifestations, and is also EBV associated.

    Histopathology. These lymphomas show dense infiltrates involving the dermis and often the subcutis. Epidermotropism may be present. Prominent angiocentricity and angiodestruction are often accompanied by extensive necrosis.18,19 NK/T-cell lymphoma has a broad cytologic spectrum ranging from small to large cells, with most cases consisting of medium-sized cells. The cells may have irregular or oval nuclei, moderately dense chromatin, and pale cytoplasm. In some cases a heavy inflammatory infiltrate of small lymphocytes, histiocytes, plasma cells, and eosinophils can be seen.

    Immunophenotype. The neoplastic cells express CD2, CD56, cytoplasmic CD3, and cytotoxic proteins (TIA-1, granzyme B, perforin), but lack surface CD3.122 In rare CD56- cases detection of EBV by in situ hybridization and expression of cytotoxic proteins are required for diagnosis (Figure 5B).3 Latent membrane protein-1 (LMP-1) is inconsistently expressed.

    Genetic features. The T-cell receptor is usually in germline configuration, but can be rearranged in rare tumors with a cytotoxic T-cell phenotype. EBV is expressed almost in all cases, suggesting a pathogenetic role of this virus.18

    Prognosis and predictive factors. Nasal-type NK/T-cell lymphoma presenting in the skin is a highly aggressive tumor with a median survival of less than 12 months.18,19,120,121 The most important factor predicting poor outcome is the presence of extracutaneous involvement at presentation. In patients presenting with only skin lesions, a median survival of 27 months was reported, compared with 5 months for patients presenting with cutaneous and extracutaneous disease.121 CD30+, CD56+ cases reported to have a better prognosis may have been examples of C-ALCL with coexpression of CD56.20

    Therapy. Systemic chemotherapy is the first choice of treatment, but the results are disappointing.120,121

    Variant. Hydroa vacciniforme-like CTCL is a rare type of EBV-associated lymphoma of CD8+ cytotoxic T cells, which affects children almost exclusively in Latin America and Asia.123-125 Patients present with a papulovesicular eruption clinically resembling hydroa vacciniforme, particularly on the face and upper extremities (sunexposed areas). The prognosis is poor.

    Primary cutaneous peripheral T-cell lymphoma, unspecified

    PTL, unspecified, in the WHO classification represent a heterogeneous group which includes all T-cell neoplasms that do not fit into any of the better defined subtypes of T-cell lymphoma/leukemia. Recent studies have suggested that primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, and primary cutaneous small-medium CD4+ T-cell lymphoma can be separated out as provisional entities. For the remaining diseases that do not fit into either of these provisional entities the designation PTL, unspecified, is maintained. In all cases a diagnosis of MF must be ruled out by complete clinical examination and an accurate clinical history.

    Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (provisional entity). Definition. Primary cutaneous aggressive epidermotropic CD8+ CTCL is characterized by a proliferation of epidermotropic CD8+ cytotoxic T-cells and an aggressive clinical behavior.25,26 Differentiation from other types of CTCL expressing a CD8+ cytotoxic T-cell phenotype, as observed in more than 50% of patients with pagetoid reticulosis, and in rare cases of MF, LyP, and C-ALCL, is based on the clinical presentation and clinical behavior.25 In these latter conditions, no difference in clinical presentation or prognosis between CD4+ and CD8+ cases is found.

    Clinical features. Clinically, these lymphomas are characterized by the presence of localized or disseminated eruptive papules, nodules, and tumors showing central ulceration and necrosis or by superficial, hyperkeratotic patches and plaques (Figure 5A). 16,25 The clinical features are very similar to those observed in patients with a cutaneous / T-cell lymphoma and cases described as generalized pagetoid reticulosis (Ketron-Goodman type) in the past.32 These lymphomas may disseminate to other visceral sites (lung, testis, central nervous system, oral mucosa), but lymph nodes are often spared.25

    Histopathology. Histologically, these lymphomas show an acanthotic or atrophic epidermis, necrotic keratinocytes, ulceration, and variable spongiosis, sometimes with blister formation.16,25 Epidermotropism is often pronounced ranging from a linear distribution to a pagetoid pattern throughout the epidermis (Figure 5B). Invasion and destruction of adnexal skin structures are commonly seen. Angiocentricity and angioinvasion may be present. Tumor cells are small-medium or medium-large with pleomorphic or blastic nuclei.

    Immunophenotype. The tumor cells have a betaF1+, CD3+, CD8+, granzyme B+, perforin+, TIA-1+, CD45RA+, CD45RO-, CD2-, CD4-, CD5-, CD7-/+ phenotype (Figure 5C and 5D).11,16,25,26,32 EBV is generally negative.

    Genetic features. The neoplastic T cells show clonal TCR gene rearrangements. Specific genetic abnormalities have not been described.

    Prognosis and predictive factors. These lymphomas often have an aggressive clinical course with a median survival of 32 months.25 There is no difference in survival between cases with a small- or large-cell morphology.11

    Therapy. Patients are generally treated with doxorubicin-based multiagent chemotherapy.

    Cutaneous gamma/delta T-cell lymphoma (provisional entity). Definition. Cutaneous gamma/delta T-cell lymphoma (CGD-TCL) is a lymphoma composed of a clonal proliferation of mature, activated gamma/delta T cells with a cytotoxic phenotype. This group includes cases previously known as SPTL with a gamma/delta phenotype. A similar and possibly related condition may present primarily in mucosal sites.28 Whether cutaneous and mucosal gamma/delta TCL are all part of a single disease (ie, muco-cutaneous gamma/delta TCL) is not yet clear.29,122 Distinction between "primary" and "secondary" cutaneous cases is not useful in this group, since both groups have a very grim prognosis.

    Clinical features. Patients with CGD-TCL generally present with disseminated plaques and/or ulceronecrotic nodules or tumors, particularly on the extremities, but other sites may be affected as well.27-31 Involvement of mucosal and other extranodal sites is frequently observed,28 but involvement of lymph nodes, spleen, or bone marrow is uncommon. A hemophagocytic syndrome may occur in patients with panniculitis-like tumors.12,31

    Histopathology. Three major histologic patterns of involvement can be present in the skin: epidermotropic, dermal, and subcutaneous. Often more than one histologic pattern is present in the same patient in different biopsy specimens or within a single biopsy specimen.27,31 The neoplastic cells are generally medium to large in size with coarsely clumped chromatin. Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. Apoptosis and necrosis are common, often with angioinvasion. The subcutaneous cases may show rimming of fat cells, similar to SPTL of alpha/beta origin.

    Immunophenotype. The tumor cells characteristically have a betaF1-, CD3+, CD2+, CD5-, CD7+/-, CD56+ phenotype with strong expression of cytotoxic proteins. Most cases lack both CD4 and CD8, though CD8 may be expressed in some cases.29,31 In frozen sections the cells are strongly positive for TCR-delta. If only paraffin sections are available, the absence of betaF1 may be used to infer a gamma/delta origin under appropriate circumstances.14,30

    Genetic features. The cells show clonal rearrangement of the TCR gamma gene. TCR beta may be rearranged or deleted, but is not expressed. EBV is generally negative.28,31

    Prognosis and predictive factors. Most patients have aggressive disease resistant to multiagent chemotherapy and/or radiation.27-32 In a recent series of 33 patients, a median survival of 15 months was noted.31 This study showed a trend for decreased survival for patients who had subcutaneous fat involvement compared with patients who had epidermal or dermal disease only.

    Therapy. Patients should be treated with systemic chemotherapy, but the results are often disappointing.

    Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional entity). Definition. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma is a CTCL defined by a predominance of small-to medium-sized CD4+ pleomorphic T cells without (a history of) patches and plaques typical of MF, and in most cases, a favorable clinical course.2 In contrast to the EORTC classification, in the WHO-EORTC classification the term "small/medium-sized pleomorphic CTCL" is restricted to cases with a CD4+ T-cell phenotype. Cases with a CD3+, CD4-, CD8+ phenotype usually have a more aggressive clinical course are included in the group of aggressive epidermotropic CD8+ CTCLs.11

    Clinical features. Characteristically, these lymphomas present with a solitary plaque or tumor, generally on the face, the neck, or the upper trunk (Figure 6A). Less commonly, they present with one or several papules, nodules, or tumors.10,11,126-128

    Histologic features. These lymphomas show dense, diffuse, or nodular infiltrates within the dermis with a tendency to infiltrate the subcutis. Epidermotropism may be present focally. There is a predominance of small/medium-sized pleomorphic T cells (Figure 6B). A small proportion (less than 30%) of large pleomorphic cells may be present.10 In some cases a considerable admixture with small reactive lymphocytes and histiocytes may be observed.

    Immunophenotype. By definition these lymphomas have a CD3+, CD4+, CD8-, CD30- phenotype, sometimes with loss of pan–T-cell markers. Cytotoxic proteins are generally not expressed.11

    Genetic features. The TCR genes are clonally rearranged.126,128 No consistent cytogenetic abnormalities have yet been identified. Demonstration of an aberrant T-cell phenotype and clonality are useful criteria to differentiate these small/medium-sized pleomorphic CTCLs from pseudo–T-cell lymphomas, which may also present with a solitary plaque or nodule.129

    Prognosis and predictive factors. These lymphomas have a rather favorable prognosis, with an estimated 5-year survival of approximately 60% to 80% (Table 2).2,4,5,10,11,126-128 Particularly, cases presenting with a solitary or localized skin lesions seem to have an excellent prognosis.11

    Therapy. In patients with solitary localized skin lesions, surgical excision or radiotherapy is the preferred mode of treatment. Cyclophosphamide as single-agent therapy and interferon alpha have been reported effective in patients with more generalized skin disease.128 However, the optimal treatment for this group has still to be defined.

    Primary cutaneous peripheral T-cell lymphoma, unspecified. Definition. The designation PTL, unspecified, is maintained for cutaneous T-cell lymphomas that do not fit into any of the better defined subtypes of CTCL. Hence, other categories of T-cell lymphoma must be excluded. These include the 3 provisional entities described earlier.

    Clinical features. Patients are commonly adults, who present with solitary, localized, or more frequently generalized nodules or tumors.2,4,10,11 No sites of predilection have been recorded.

    Histopathology. Skin lesions show nodular or diffuse infiltrates with variable numbers of medium-to large-sized pleomorphic or immunoblast-like T cells. Epidermotropism is generally mild or absent. Large neoplastic cells represent at least 30% of the total tumor cell population.10

    Immunophenotype. Most cases show an aberrant CD4+ T-cell phenotype with variable loss of pan–T-cell antigens. CD30 staining is negative or restricted to a few scattered tumor cells. Rare cases may show coexpression of CD56. Expression of cytotoxic proteins is uncommon.11

    Prognosis and predictive factors. The prognosis is generally poor, with 5-year survival rates of less than 20% (Table 2).2,4,5,10,11 No statistical differences in survival were found between cases presenting with solitary/localized lesions and cases presenting with generalized skin lesions.11

    Treatment. Patients should be treated with multiagent chemotherapy.

    Precursor hematologic neoplasm

    CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)

    Definition. 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 leukemic dissemination. The blastic cytologic appearance and CD56 expression initially suggested an NK-precursor origin.3 More recent studies suggest derivation from a plasmacytoid dendritic cell precursor.23,24 "CD4+/CD56+ hematodermic neoplasm"22 and "early plasmacytoid dendritic cell leukemia/lymphoma"23 have been suggested as more appropriate terms for this condition.

    Clinical features. CD4+/CD56+ hematodermic neoplasm commonly presents in the skin with solitary or multiple nodules or tumors with or without concurrent extracutaneous localizations (Figure 7A). 21-24,32 About half of the patients have nodal or bone marrow involvement at presentation.23,121 Most patients presenting with only skin lesions rapidly develop involvement of bone marrow, peripheral blood, lymph nodes, and extranodal sites.23,121 CD4+/CD56+ hematodermic neoplasm should be differentiated above all from myelomonocytic leukemia cutis, and are conceptually similar to so-called "aleukemic leukemia cutis."32

    Histopathology. These lymphomas show nonepidermotropic, monotonous infiltrates of medium-sized cells with finely dispersed chromatin, and absent or indistinct nucleoli resembling lymphoblasts or myeloblasts (Figure 7B).3,21-24 The cells have sparse cytoplasm. Mitotic figures are frequent. Inflammatory cells are absent. There is generally no necrosis or angioinvasion.

    Immunophenotype. The tumor cells usually have a CD4+, CD56+, CD8-, CD7+/-, CD2-/+, CD45RA+ phenotype, but do not express surface and cytoplasmic CD3 or cytotoxic proteins (Figure 7C).3,23 TdT and CD68 may be positive. Since lymphoblastic and myeloblastic neoplasms can also be positive for CD56, stains for CD3 and myeloperoxidase should always be performed in order to exclude these entities.3 The cells express CD123 and TCL1, both of which support a relationship to plasmacytoid dendritic cells.23,24,130

    Genetic features. T-cell receptor genes are in germline configuration. Tumor cells are negative for EBV.

    Prognosis and predictive factors. CD4+/CD56+ hematodermic neoplasm is an aggressive disease with a poor prognosis (median survival, 14 months).21-24,121 Systemic chemotherapy usually results in a complete remission, but quick relapses unresponsive to further chemotherapy are the rule. No significant difference in survival is found between patients presenting with skin lesions with or without concurrent extracutaneous disease.121

    Recent studies suggest that patients can best be treated with regimens used in acute leukemias.121

    Cutaneous B-cell lymphomas

    Primary cutaneous marginal-zone B-cell lymphoma

    Definition. Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is an indolent lymphoma composed of small B cells, including marginal zone (centrocyte-like) cells, lymphoplasmacytoid cells, and plasma cells. It includes cases previously designated as primary cutaneous immunocytoma,131 and cases of cutaneous follicular lymphoid hyperplasia with monotypic plasma cells.132 Exceptional cases of primary cutaneous plasmacytoma without underlying multiple myeloma (extramedullary plasmacytoma of the skin) show considerable overlap with PCMZL and are therefore included in this category.133 PCMZL is considered part of the broad group of extranodal marginal zone B-cell lymphomas commonly involving mucosal sites, called MALT (mucosa-associated lymphoid tissue) lymphomas.

    Clinical features. In most instances patients with PCMZL present with red to violaceous papules, plaques, or nodules localized preferentially on the trunk or extremities, especially the arms. In contrast to PCFCL, presentation with multifocal skin lesions is frequent (Figure 8). Ulceration is uncommon. PCMZLs have a tendency to recur in the skin, but dissemination to extracutaneous sites is exceedingly rare.131,134-136 In some cases spontaneous resolution of the skin lesions may be observed. The development of anetoderma in spontaneously resolving lesions has been observed.137 An association with Borrelia burgdorferi infection has been reported in a significant minority of European cases of PCMZL, but not in Asian cases or cases from the United States.134,138-140 Associated autoimmune diseases are uncommon in PCMZL, but rather suggest secondary cutaneous involvement of a systemic lymphoma.131

    Histopathology. These lymphomas show nodular to diffuse infiltrates with sparing of the epidermis. The infiltrates are composed of small lymphocytes, marginal zone B cells (centrocyte-like cells), lymphoplasmacytoid cells, and plasma cells, admixed with small numbers of centroblast- or immunoblast-like cells and many reactive T cells. Reactive germinal centers are frequently observed. They may be surrounded by a population of small-to medium-sized cells with irregular nuclei, inconspicuous nucleoli, and abundant pale cytoplasm (marginal zone B cells). Monotypic plasma cells are often located at the periphery of the infiltrates and in the superficial dermis beneath the epidermis.131,132,135,136 periodic acid-schiff (PAS)+ intranuclear or intracytoplasmic inclusions may be present in cases with a predominance of lymphoplasmacytoid cells. PCMZLs rarely show transformation into a diffuse large B-cell lymphoma, but a relative increase in large transformed cells can be seen in some cases.

    Immunophenotype. The marginal zone B cells express CD20, CD79a, and bcl-2, but are negative for CD5, CD10, and bcl-6, which may be useful in distinction from PCFCL.141,142 Reactive germinal centers are typically bcl-6+, CD10+, and bcl-2-. Plasma cells express CD138 and CD79a, but generally not CD20, and show monotypic cytoplasmic immunoglobulin light chain expression on paraffin sections.

    Genetic features. Immunoglobulin heavy chain (IgH) genes are clonally rearranged. Recent studies suggest the presence of the t(14;18)(q32;q21) involving the IGH gene on chromosome 14 and the MLT gene on chromosome 18, and t(3;14)(p14.1;q32) involving IGH and FOXP1 genes, in a proportion of PCMZLs.143,144 However, other translocations observed in gastric MALT lymphomas, such as t(11;18)(q21;q21) and t(1;14)(p22;q32), have not been found in PCMZL.45,145

    Prognosis and predictive factors. The prognosis of PCMZL is excellent with a 5-year survival close to 100% (Table 2).131-136

    Therapy. Patients with a solitary or a few lesions can be treated with radiotherapy or surgical excision. In patients with associated B burgdorferi infection, systemic antibiotics should be tried first.146 For patients presenting with multifocal skin lesions, chlorambucil or intralesional or subcutaneous administration of interferon alpha may produce complete responses in approximately 50% of patients.146 Very good results have also been obtained with the use of systemic or intralesional anti-CD20 antibody (rituximab).147 In patients showing frequent skin relapses, topical or intralesional steroids may be considered; alternatively, an expectant strategy can be followed, similar to that used in other indolent B-cell lymphomas and leukemias.

    Primary cutaneous follicle-center lymphoma

    Definition. Primary cutaneous follicle center lymphoma (PCFCL) is defined as a tumor of neoplastic follicle center cells, usually a mixture of centrocytes (small and large cleaved follicle center cells) and variable numbers of centroblasts (large noncleaved follicle center cells with prominent nucleoli), with a follicular, a follicular and diffuse, or a diffuse growth pattern, which generally present on the head or trunk. Lymphomas with a diffuse growth pattern and a monotonous proliferation of centroblasts and immunoblasts are, irrespective of site, excluded and are classified as PCLBCL (Table 3).

    Clinical features. PCFCL has a characteristic clinical presentation with solitary or grouped plaques and tumors, preferentially located on the scalp or forehead or on the trunk, and rarely on the legs (Figure 9A-B).33-35 Particularly on the trunk, these tumors may be surrounded by erythematous papules and slightly indurated plaques, which may precede the development of tumorous lesions for months or even many years. In the past, PCFCLs with such a typical presentation on the back were referred to as "reticulohistiocytoma of the dorsum" or "Crosti lymphoma (Figure 9A)." 34,148 Presentation with multifocal skin lesions is observed in a small minority of patients, but is not associated with a more unfavorable prognosis.42,149 If left untreated, the skin lesions gradually increase in size over years, but dissemination to extracutaneous sites is uncommon.

    Histopathology. PCFCLs show nodular to diffuse infiltrates with almost constant sparing of the epidermis. The histologic picture is variable, which relates primarily to the age and the growth rate of the biopsied skin lesion as well as the location.35,39 A clear-cut follicular growth pattern is more commonly observed in lesions arising on the scalp than those presenting on the trunk.150 Small and early lesions contain a mixture of centrocytes, relatively few centroblasts, and many reactive T cells. Large centrocytes, often multilobated, are a common feature of PCFCL (Figure 9C). The large neoplastic B cells may have a fibroblast-like appearance. In small and/or early lesions a clear-cut follicular growth pattern or, more often, remnants of a follicular growth pattern may be observed. If present, the abnormal follicles are composed of malignant bcl-6+ follicle center cells enmeshed in a network of CD21+ or CD35+ follicular dendritic cells. The follicles are ill-defined, lack tingible body macrophages, and generally have a reduced or absent mantle zone.150,151 With progression to tumorous lesions the neoplastic B cells increase both in number and size, whereas the number of reactive T cells steadily decreases.35,39 Follicular structures, if present before, are no longer visible except for occasional scattered CD21+ or CD35+ follicular dendritic cells. Tumorous skin lesions generally show a monotonous population of large follicle center cells, generally large centrocytes and multilobated cells, and in rare cases spindle-shaped cells, with a variable admixture of centroblasts and immunoblasts.34,35,39,42,152 Usually, a prominent stromal component is present.

    Immunophenotype. The neoplastic cells express the B-cell–associated antigens CD20 and CD79a, and may show monotypic staining for surface immunoglobulins (sIgs). However, absence of detectable sIg is common in tumorous lesions showing a diffuse population of large follicle center cells. PCFCLs consistently express bcl-6.141,142,151 CD10 expression is particularly observed in cases with a follicular growth pattern, but is uncommon in PCFCLs with a diffuse growth pattern.142,153 Staining for CD5 and CD43 is negative. Unlike nodal and secondary cutaneous follicular lymphomas, PCFCLs do not express bcl-2 protein or show faint bcl-2 staining in a minority of neoplastic B-cells.36,41,150 (Figure 9D,E). Staining for MUM-1/IRF4 is negative.46

    Genetic features. Clonally rearranged immunoglobulin genes are present. Somatic hypermutation of variable heavy and light chain genes has been demonstrated, which further supports the follicle center cell origin of these lymphomas.154,155 In most studies PCFCLs, including cases with a follicular growth pattern, do not show the t(14;18), which is characteristically found in systemic follicular lymphomas and a proportion of systemic diffuse large B-cell lymphoma.37,41,151,153 (see "Comment" under "Primary cutaneous follicle-center lymphoma").

    Inactivation of p15 and p16 tumor suppressor genes by promotor hypermethylation has been reported in about 10% and 30% of PCFCLs, respectively.156 Chromosomal imbalances have been identified by comparative genomic hybridization (CGH) analysis in a minority of PCFCLs, but a consistent pattern has not yet emerged.44,157 In a recent study using interphase fluorescence in situ hybridization, no evidence for translocations involving IgH, myc, or bcl-6 loci were found.45 PCFCLs have the gene expression profile of germinal center–like large B-cell lymphomas.46

    Prognosis and predictive factors. Regardless of the growth pattern (follicular or diffuse), the number of blast cells, or the presence of either localized or multifocal skin disease, these PCFCLs have an excellent prognosis with a 5-year survival of more than 95% (Table 2).2,4,5,33-35,38,42,150,151 A recent study suggests that strong expression of bcl-2 in PCFCLs with a diffuse large-cell histology is associated with a more unfavorable prognosis.158

    Therapy. In patients with localized or few scattered skin lesions, radiotherapy is the preferred mode of treatment, even in cases with a predominance of large "cleaved" cells.38,42,149,159-161 Cutaneous relapses, observed in approximately 20% of patients, do not indicate progressive disease and can be treated with radiotherapy as well. Anthracycline-based chemotherapy is required only in patients with very extensive cutaneous disease and patients developing extracutaneous disease.42,150 Recent studies report beneficial effects of systemic or intralesional administration of anti-CD20 antibody (rituximab) therapy in small series of PCFCLs, but the long-term effects of this approach have yet to be determined.162-164

    Comment. Characteristically, PCFCLs do not express bcl-2 protein, or show faint bcl-2 staining in a minority of tumor cells, and do not show the t(14;18).36,37,41 However, recent studies report the presence of t(14;18) and/or bcl-2 expression in a significant minority of PCFCLs.43,153,165-167 Whether these discrepant results are the result of differences in patient selection (eg, incomplete staging) or different definitions for bcl-2 positivity, or represent regional differences is as yet unknown. Importantly, in PCFCLs with a follicular growth pattern there are no differences in clinical presentation and behavior between bcl-2 and/or t(14;18)-positive and -negative cases.36,152,165-167 In contrast, recent studies suggest that expression of bcl-2 protein by more than 50% of the neoplastic B cells in PCFCLs with a diffuse proliferation of large centrocytes, observed in approximately 15% of cases, is associated with a more unfavorable prognosis.158 Further studies are warranted to define the clinical and biological significance of bcl-2 expression and/or the presence of t(14;18) observed in some cases of PCFCL. Notwithstanding, demonstration of bcl-2 expression and/or t(14; 18) should always raise suspicion of a systemic lymphoma involving the skin secondarily.

    Primary cutaneous diffuse large B-cell lymphoma, leg type

    Definition. Primary cutaneous diffuse large B-cell lymphoma, leg type, is a PCLBCL with a predominance or confluent sheets of centroblasts and immunoblasts, characteristically presenting with skin lesions on the (lower) legs. Uncommonly, skin lesions with a similar morphology and phenotype can arise at sites other than the legs.

    Clinical features. PCLBCL, leg type, predominantly affects elderly patients, particularly females.40,42,43 Patients present with generally rapidly growing red or bluish-red tumors on one or both (lower) legs (Figure 10A). In contrast to the group of PCFCLs, these lymphomas more often disseminate to extracutaneous sites and have a more unfavorable prognosis.40,42 Reports on PCLBCL, leg type, arising at sites other than the leg are few. In a recent European multicenter study, 16 of 17 patients presented with solitary or localized skin lesions either on the trunk or head, and 7 of 17 patients developed extracutaneous disease.42

    Histopathology. These lymphomas show diffuse infiltrates, which often extend into the subcutaneous tissue. These infiltrates generally show a monotonous population or confluent sheets of centroblasts and immunoblasts (Figure 10B).40,42 Mitotic figures are frequently observed. Small B cells are lacking and reactive T cells are relatively few and often confined to perivascular areas. A prominent stromal reaction as in PCFCLs is not observed.

    Immunophenotype. The neoplastic B cells express monotypic sIg and/or cIg and B-cell–associated antigens CD20 and CD79a. In contrast to the group of PCFCLs, PCLBCL, leg type, shows strong bcl-2 expression, also in cases not located on the legs (Figure 10C).41,43,142,158 Bcl-6 is expressed by most cases, whereas CD10 staining is generally absent.142 Unlike PCFCL, most PCLBCL, leg types, express MUM-1/IRF4 protein (Figure 10D).46,168

    Genetic features. The t(14;18) is not found in PCLBCLs, although strong bcl-2 expression is common in this group.41,43 In some cases bcl-2 overexpression may result from chromosomal amplification of the bcl-2 gene.157 Inactivation of p15 and p16 tumor suppressor genes by promotor hypermethylation has been detected in 11% and 44% of PCLBCLs, respectively.156 Chromosomal imbalances have been identified in up to 85% of PCLBCLs, with gains in 18q and 7p and loss of 6q as most common findings.44,157 Recent studies demonstrated translocations involving myc, bcl-6, and IgH genes in 11 of 14 PCLBCL-leg cases, but not in patients with a PCFCL with a diffuse infiltration of large centrocytes.45 Recent studies suggest that patients with PCLBCL-leg have an activated B-cell gene expression profile.46

    Prognosis and predictive features. The 5-year survival of 78 cases included in the Dutch and Austrian registries was 55% (Table 2). PCLBCLs on the leg have an inferior prognosis compared to PCLBCLs presenting at other sites.42 The presence of multiple skin lesions at diagnosis is a significant adverse risk factor. In a recent study, patients presenting with a single skin tumor on one leg had a disease-related 5-year survival of 100%, whereas patients presenting with multiple skin lesions on one or both legs had a disease-related 5-year survival of 45% and 36%, respectively.42

    Therapy. These lymphomas should be treated as systemic diffuse large B-cell lymphomas with anthracycline-based chemotherapy.40,42 In patients presenting with a single small skin tumor, radiotherapy may sometimes be considered.42 Systemic administration of anti-CD20 antibody (rituximab) has proved effective in some patients, but long-term follow-up data are not available and the place of rituximab in the treatment of PCLBCL, either as single agent therapy or in combination with systemic chemotherapy remains to be established.162,169

    Primary cutaneous diffuse large B-cell lymphoma, other

    The term "PCLBCL, other," refers to rare cases of large B-cell lymphomas arising in the skin, which do not belong to the group of PCLBCL, leg type, or the group of PCFCLs. These cases include morphologic variants of diffuse large B-cell lymphoma, such as anaplastic or plasmablastic subtypes or T-cell/histiocyte rich large B-cell lymphomas. Such cases are generally a skin manifestation of a systemic lymphoma. Plasmablastic lymphomas are seen almost exclusively in the setting of HIV infection or other immune deficiencies.170-172 Some of these cases had only skin lesions at presentation. Rare cases of primary cutaneous T-cell/histiocyte-rich B-cell lymphoma, characterized by the presence of large scattered B cells in a background of numerous reactive T cells, have been reported.173,174 Clinically, they show similarities with the groups of PCFCL and PCMZL. These lymphomas commonly present with skin lesions on the head, the trunk or the extremities, and may in fact represent an exaggerated T-cell infiltrate in association with other forms of CBCL. Unlike their nodal counterparts, they appear to have an excellent prognosis.173,174 In addition, rare cases of primary cutaneous intravascular large B-cell lymphoma may be included in this category.

    Intravascular large B-cell lymphoma. Intravascular large B-cell lymphoma is a well-defined subtype of large B-cell lymphoma, defined by an accumulation of large neoplastic B cells within blood vessels. These lymphomas preferentially affect the central nervous system, lungs, and skin and are generally associated with a poor prognosis.175

    Patients often have widely disseminated disease, but cases with only skin involvement may occur. Clinically, intravascular large B-cell lymphoma may present with violaceous patches and plaques or teleangiectatic skin lesions usually on the (lower) legs or the trunk.175,176 Patients presenting with only skin lesions appear to have a significantly better survival than patients with other clinical presentations (3-year overall survival: 56% versus 22%).176 Interestingly, colonization of cutaneous cherry hemangiomas by neoplastic cells as the only presenting sign of intravascular large B-cell lymphoma has been reported.177-178 Histologically, dilated blood vessels in the dermis and subcutis are filled and often extended by a proliferation of large neoplastic B cells. These cells may cause vascular occlusion of venules, capillaries, and arterioles. In some cases small numbers of tumor cells can also be observed around blood vessels. Multiagent chemotherapy is the preferred mode of treatment, also in patients presenting with skin-limited disease.176

    Conclusions and future directions

    The WHO-EORTC classification for cutaneous lymphomas presented herein may be considered as an important step forward. First, the development of this consensus classification will put an end to the ongoing discussion whether the EORTC or the WHO scheme can best be used, and is expected to contribute to a more uniform diagnosis and hence a more uniform treatment of patients with a cutaneous lymphoma. Second, major progress has been made in a better definition of some controversial groups of cutaneous lymphoma, in particular the group of PCFCL/PCLBCL and the group of CTCL other than MF, SS, and the group of primary cutaneous CD30+ LPD.

    The new definitions of the groups of PCFCL, PCLBCL, leg type, and PCLBCL, other, will allow a more reliable distinction between indolent and more aggressive types of CBCL, and facilitate the decision whether radiotherapy or systemic chemotherapy should be selected as first choice of treatment. Large multicenter studies are now required to validate the current proposals, and in particular to investigate the diagnostic and prognostic value of bcl-2 and Mum-1/IRF4 protein expression.

    The classification of CTCL other than MF, SS, and the group of primary cutaneous CD30+ LPD is still difficult, as it requires accurate clinicopathologic correlation and a number of complementary techniques to arrive at a definite diagnosis. SPTL (with an alpha/beta phenotype), extranodal NK/T-cell lymphoma, nasal type, and CD4+/CD56+ hematodermic neoplasm are now fairly well-defined. However, considerable overlap is noted between cutaneous (and mucosal) GD-TCL and aggressive epidermotropic CD8+ CTCL. The similarities in clinical presentation and pattern of dissemination between these conditions may reflect similarities in homing profile and biologic function of normal gamma/delta-positive T-cells and activated CD8+ cytotoxic T cells, respectively. Apart from the group of SPTLs and the group of CD4+ small/medium-sized pleomorphic CTCLs, these rare types of CTCL have a very poor prognosis and are generally resistant to conventional chemotherapy. More aggressive regimens, including allogeneic bone marrow transplantation, for patients with aggressive types of CTCL including advanced stages of MF and SS are currently under investigation.179,180

    Recently, studies have started to investigate gene and protein expression profiles in different types of cutaneous lymphoma. It is expected that these studies will not only contribute to a better understanding of the molecular pathways involved in the development and progression of these lymphomas, but will also provide new molecular targets for diagnosis and therapeutic intervention, and ultimately to more refined classification schemes.

    Footnotes

    Prepublished online as Blood First Edition Paper, February 3, 2005; DOI 10.1182/blood-2004-09-3502.

    An Inside Blood analysis of this article appears at the front of the issue.

    References

    Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst. 2000;92: 1240-1251.

    Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC). Blood. 1997;90: 354-371.

    Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press;2001.

    Grange F, Hedelin G, Joly P, et al. Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides and the Sezary syndrome: the French study group on cutaneous lymphomas. Blood. 1999;93: 3637-3642.

    Fink-Puches R, Zenahlik P, Bck B, Smolle J, Kerl H, Cerroni L. Primary cutaneous lymphomas: applicability of current classification schemes (EORTC, WHO) based on clinicopathologic features observed in a large group of patients. Blood. 2002;99: 800-805.

    Norton AJ. Classification of cutaneous lymphoma: a critical appraisal of recent proposals. Am J Dermatopathol. 1999;21: 279-287.

    Sander CA, Flaig MJ, Jaffe ES. Cutaneous manifestations of lymphoma: a clinical guide based on the WHO classification. Clin Lymphoma. 2001;2: 86-100.

    Russell-Jones R. World Health Organization of hematopoietic and lymphoid tissues: implications for dermatology. J Am Acad Dermatol. 2003;48: 93-102.

    Willemze R, Meijer CJLM. EORTC classification for primary cutaneous lymphomas: the best guide to good clinical management. European Organization for Research and Treatment of Cancer. Am J Dermatopathol. 1999;21: 265-73.

    Beljaards RC, Meijer CJLM, van der Putte SCJ, et al. Primary cutaneous T-cell lymphomas: clinicopathologic features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma. J Pathol. 1994;172: 53-60.

    Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood. 2003;102: 2213-2219.

    Gonzalez CL, Medeiros LJ, Braziiel RM, Jaffe ES. T-cell lymphoma involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol. 1991;15: 17-27.

    Burg G, Dummer R, Wilhelm M, et al. A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma. N Engl J Med. 1991; 325: 1078-1081.

    Salhany KE, Macon WR, Choi JK, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol. 1998;22: 881-893.

    Weenig RH, Ng CS, Perniciaro C. Subcutaneous panniculitis-like T-cell lymphoma. Am J Dermatopathol. 2001;23: 206-215.

    Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas: report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. 2003;97: 610-627.

    Hoque SR, Child FJ, Whittaker SJ, et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol. 2003;148: 516-525.

    Chan JK, Sin VC, Wong KF, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997; 89: 4501-4513.

    Natkunam Y, Smoller BR, Zehnder JL, Dorfman RF, Warnke RA. Aggressive cutaneous NK and NK-like T-cell lymphomas: clinicopathologic, immunohistochemical, and molecular analyses of 12 cases. Am J Surg Pathol. 1999;23: 571-581.

    Mraz-Gernhard S, Natkunam Y, Hoppe RT, LeBoit P, Kohler S, Kim Y. Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course J Clin Oncol. 2001;19: 2179-2188.

    DiGiuseppe JA, Louie DC, Williams JE, et al. Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study. Am J Surg Pathol. 1997; 21: 1223-1230.

    Petrella T, Dalac S, Maynadie M, et al. CD4+ CD56+ cutaneous neoplasms: a distinct hematological entity Am J Surg Pathol. 1999;23: 137-146.

    Jacob MC, Chaperot C, Mossuz P, et al. CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells. Haematologica. 2003;88: 941-955.

    Petrella T, Comeau MR, Maynadie M,etal. "Agranular CD4+ CD56+ hematodermic neoplasm" (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes. Am J Surg Pathol. 2002;26: 852-862.

    Berti E, Tomasini D, Vermeer MH, Meijer CJLM, Alessi E, Willemze R. Primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphoma: a distinct clinicopathologic entity with an aggressive clinical behaviour. Am J Pathol. 1999; 155: 483-492.

    Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T-cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol. 1990;22: 569-577.

    Berti E, Cerri A, Cavicchini S, et al. Primary cutaneous gamma/delta lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol. 1991;96: 718-723.

    Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al. Nonhepatosplenic gamma-delta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. 1998;91: 1723-1731.

    de Wolf-Peeters C, Achten R. Gamma-delta T-cell lymphomas: a homogeneous entity Histopathology. 2000;36: 294-305.

    Jones D, Vega F, Sarris A, Medeiros LJ. CD4- CD8- "Double-negative" cutaneous T-cell lymphomas share common histologic features and an aggressive clinical course. Am J Surg Pathol. 2002;26: 225-231.

    Toro JR, Liewehr DJ, Pabby N, et al. Gamma-delta-T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood. 2003;101: 3407-3412.

    Massone C, Chott A, Metze D, et al. Subcutaneous, blastic natural killer (NK), NK/T-cell and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic and molecular study of 50 patients. Am J Surg Pathol. 2004;28: 719-735.

    Willemze R, Meijer CJLM, Sentis HJ, et al. Primary cutaneous large cell lymphomas of follicular center cell origin. J Am Acad Dermatol. 1987;16: 518-526.

    Berti E, Alessi E, Caputo R, Gianotti R, Delia D, Vezzoni P. Reticulohistiocytoma of the dorsum. J Am Acad Dermatol. 1988;19: 259-272.

    Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique type of low-grade lymphoma. Cancer. 1991;67: 2311-2326.

    Cerroni L, Volkenandt M, Rieger E, Soyer HP, Kerl H. Bcl-2 protein expression and correlation with the interchromosomal (14;18) translocation in cutaneous lymphomas and pseudolymphomas. J Invest Dermatol. 1994;102: 231-235.

    Child FJ, Russell-Jones R, Woolford AJ, et al. Absence of the t(14,18) chromosomal translocation in primary cutaneous B-cell lymphoma. Br J Dermatol. 2001;144: 735-744.

    Rijlaarsdam JU, Toonstra J, Meijer OW, Noordijk EM, Willemze R. Treatment of primary cutaneous B-cell lymphomas of follicular center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol. 1996;14: 549-555.

    Willemze R, Meijer CJLM, Scheffer E, et al. Diffuse large cell lymphomas of follicle center cell origin presenting in the skin: a clinicopathologic and immunologic study of 16 patients. Am J Pathol. 1987;126: 325-333.

    Vermeer MH, Geelen FAMJ, van Haselen CW, et al. Primary cutaneous large B-cell lymphomas of the legs: a distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Arch Dermatol. 1996;132: 1304-1308.

    Geelen FAMJ, Vermeer MH, Meijer CJLM, et al. Bcl-2 expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol. 1998; 16: 2080-2085.

    Grange F, Bekkenk MW, Wechsler J, et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol. 2001;19: 3602-3610.

    Goodlad JR, Krajewski AS, Batstone PJ, et al. Primary cutaneous diffuse large B-cell lymphoma: prognostic significance and clinicopathologic subtypes. Am J Surg Pathol. 2003;27: 1538-1545.

    Hallermann C, Kaune K, Siebert R, et al. Cytogenetic aberration patterns differ in subtypes of primary cutaneous B-cell lymphomas. J Invest Dermatol. 2004;122: 1495-1502.

    Hallermann C, Kaune KM, Gesk S, et al. Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6 and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol. 2004;123: 213-219.

    Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood. 2005;105: 3671-3678.

    van Doorn R, van Haselen CW, van Voorst PC, et al. Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients. Arch Dermatol. 2000;136: 504-510.

    Zackheim H, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 1999;40: 418-425.

    Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139: 857-866.

    Wain EM, Orchard GE, Whittaker SJ, Spittle M, Russell-Jones R. Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study. Cancer. 2003;98: 2282-2290.

    Smoller BR, Santucci M, Wood GS, Whittaker SJ. Histopathology and genetics of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 2003;17: 1277-1311.

    Nickoloff BJ. Light-microscopic assessment of 100 patients with patch/plaque-stage mycosis fungoides. Am J DermatoPathol. 1988;10: 469-477.

    Diamandidou E, Colome-Grimmer M, Fayad L, Duvic M, Kurzrock R. Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis. Blood. 1998;92: 1150-1159.

    Ralfkiaer E. Controversies and discussion on early diagnosis of cutaneous T-cell lymphoma: phenotyping. Dermatol Clin. 1994;12: 329-334.

    Whittam LR, Calonje E, Orchard G, Fraser-Andrews EA, Woolford A, Russell-Jones R. CD8-positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases. Br J Dermatol. 2000;143: 1199-1204.

    Vermeer MH, Geelen FAMJ, Kummer JA, et al. Expression of cytotoxic proteins by neoplastic T-cells in mycosis fungoides is associated with progression from plaque stage to tumor stage disease. Am J Pathol 1999;154: 1203-1210.

    Karenko L, Hyytinen E, Sarna S, Ranki A. Chromosomal abnormalities in cutaneous T-cell lymphoma and its premalignant conditions as detected by G-banding and interphase cytogenetic methods. J Invest Dermatol. 1997;108: 22-29.

    Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol. 2003; 149: 1095-1107.

    Jones GW, Kacinski BM, Wilson LD, et al. Total skin electron radiation in the management of mycosis fungoides: consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol. 2002;47: 364-370.

    Dummer R, Kempf W, Hess Schmid M, et al. Therapy of cutaneous lymphoma: current practice and future developments. Onkologie. 2003; 26: 366-372.

    Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9: 1089-1097.

    Duvic M, Cather JC. Emerging new therapies for cutaneous T-cell lymphoma. Dermatology Clinics. 2000;18: 147-156.

    Muche JM, Gellrich S, Sterry W. Treatment of cutaneous T-cell lymphoma. Seminars in Cutaneous Medicine and Surgery. 2000;19: 142-148.

    Kaye FJ, Bunn PA, Steinberg SM, et al. A randomized trial comparing combination electron beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Eng J Med. 1989;321: 784-790.

    Vergier B, Beylot-Barry M, Beylot C, et al. Pilotropic cutaneous T-cell lymphoma without mucinosis: a variant of mycosis fungoides Arch Dermatol. 1996;132: 683-687.

    Flaig MJ, Cerroni L, Schuhmann K, et al. Follicular mycosis fungoides: a histopathologic analysis of nine cases. J Cutan Pathol. 2001;28: 525-530.

    Ke MS, Kamath NV, Nihal M, et al. Folliculotropic mycosis fungoides with central nervous system involvement: demonstration of tumor clonality in intrafollicular T cells using laser capture microdissection. J Am Acad Dermatol. 2003;48: 238-243.

    Van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides: a distinct disease entity with or without associated follicular mucinosis. Arch Dermatol 2001;138: 191-198.

    Burg G, Schmockel C. Syringolymphoid hyperplasia with alopecia: a syringotropic cutaneous T-cell lymphoma Dermatology. 1992;184: 306-307.

    Zelger B, Sepp N, Weyrer K, Grunewald K, Zelger B. Syringotropic cutaneous T-cell lymphoma: a variant of mycosis fungoides Br J Dermatol. 1994;130: 765-769.

    Bonta MD, Tannous ZS, Demierre MF, Gonzales E, Harris NL, Duncan LM. Rapidly progressing mycosis fungoides presenting as follicular mucinosis. J Am Acad Dermatol. 2000;43: 635-640.

    Mielke V, Wolff HH, Winzer M, Sterry W. Localized and disseminated pagetoid reticulosis: diagnostic immunophenotypical findings. Arch Dermatol. 1989;125: 402-406.

    Burns MK, Chan LS, Cooper KD. Woringer-Kolopp disease (localized pagetoid reticulosis) or unlesional mycosis fungoides Arch Dermatol. 1995;131: 325-329.

    Haghighi B, Smoller BR, LeBoit PE, Warnke RA, Sander CA, Kohler S. Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular and clinicopathologic study. Mod Pathol. 2000;13: 502-510.

    LeBoit PE. Granulomatous slack skin. Dermatol Clin. 1994;12: 375-389.

    van Haselen CW, Toonstra J, van der Putte SJ, van Dongen JJ, van Hees CL, van Vloten WA. Granulomatous slack skin: report of three patients with an updated review of the literature. Dermatology. 1998;196: 382-391.

    Clarijs M, Poot F, Laka A, Pirard C, Bourlond A. Granulomatous slack skin: treatment with extensive surgery and review of the literature. Dermatology. 2003;206: 393-397.

    Wieselthier JS, Koh HK. Sezary syndrome: diagnosis, prognosis and critical review of treatment options. J Am Acad Dermatol. 1990;22: 381-401.

    Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. 2002; 46: 95-106.

    Scarisbrick JJ, Whittaker S, Evans AV, et al. Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Blood. 2001;97: 624-630.

    Sentis HJ, Willemze, Scheffer E. Histopathologic studies in Sezary syndrome and erythrodermic mycosis fungoides: a comparison with benign forms of erythroderma. J Am Acad Dermatol. 1986;15: 1217-1226.

    Trotter MJ, Whittaker SJ, Orchard GE, Smith NP. Cutaneous histopathology of Sezary syndrome: a study of 41 cases with a proven circulating T-cell clone. J Cutan Pathol. 1997;24: 286-291.

    Scheffer E, Meijer CJLM, van Vloten WA, Willemze R. A histologic study of lymph nodes from patients with the Sezary syndrome. Cancer. 1986;57: 2375-2380.

    Sibaud V, Beylot-Barry M, Thiebaut R, et al. Bone marrow histopathologic and molecular staging in epidermotropic T-cell lymphomas. Am J Clin Pathol. 2003;119: 414-423.

    Toonstra J, Henquet CJM, van Weelden H, van der Putte SCJ, van Vloten WA. Actinic reticuloid: a clinical, photobiologic, histopathologic and follow-up study of 16 cases. J Am Acad Dermatol. 1989;21: 205-214.

    Thangavelu M, Finn WG, Yelavarthi KK, et al. Recurring structural chromosome abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sezary syndrome. Blood. 1997; 89: 3371-3377.

    Mao X, Lillington DM, Czepulkowski B, Russell-Jones R, Young BD, Whittaker S. Molecular cytogenetic characterization of Sezary syndrome. Genes Chromosomes Cancer. 2003;36: 250-260.

    Karenko L, Kahkonen M, Hyytinen ER, Lindlof M, Ranki A. Notable losses at specific regions of chromosomes 10q and 13q in the Sezary syndrome detected by comparative genomic hybridization. J Invest Dermatol. 1999;112: 392-395.

    Mao X, Lillington D, Scarisbrick JJ, et al. Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides. Br J Dermatol. 2002;147: 464-475.

    Kari L, Loboda A, Nebozhyn M, et al. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med. 2003;197: 1477-1488.

    Mao X, Orchard G, Lillington DM, Russell-Jones R, Young BD, Whittaker SJ. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood. 2003; 101: 1513-1519.

    Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. N Eng J Med. 1987; 316: 297-303.

    Russell-Jones R. Extracorporeal photopheresis in cutaneous T-cell lymphoma: inconsistent data underline the need for randomized studies. Br J Dermatol. 2000;142: 16-21.

    Lundin J, Hagberg H, Repp R, et al. Phase II study of alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) in patients with advanced mycosis fungoides. Blood. 2003;101: 4267-4272.

    Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma: a report from the Lymphoma Study Group (1984-1987). Br J Haematol. 1991;79: 428-437.

    Setoyama M, Katahira Y, Kanzaki T. Clinicopathologic analysis of 124 cases of adult T-cell leukemia/lymphoma with cutaneous manifestations: the smouldering type with skin manifestations has a poorer prognosis than previously thought. J Dermatol. 1999;26: 785-790.

    Oshima K, Suzumiya J, Sato K, et al. Nodal T-cell lymphoma in an HTLV-I-endemic area: proviral HTLV-I DNA, histological classification and clinical evaluation. Br J Haematol. 1998;101: 703-711.

    Yamada Y, Tomonaga M. The current status of therapy for adult T-cell leukemia-lymphoma in Japan. Leuk & Lymphoma. 2003;44: 611-618.

    Hermine O, Allard I, Levy V, Arnulf B, Gessain A, Bazarbachi A. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J. 2002;3: 276-282.

    Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30+ lymphoproliferative disorders: a proposal for classification and guidelines for management and treatment. J Am Acad Dermatol. 1993; 28: 973-980.

    Bekkenk M, Geelen FAMJ, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30-positive lymphoproliferative disorders: long term follow-up data of 219 patients and guidelines for diagnosis and treatment: a report from the Dutch Cutaneous Lymphoma Group. Blood. 2000;95: 3653-3661.

    Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003; 49: 1049-1058.

    Paulli M, Berti E, Rosso R, et al. CD30/Ki-1 positive lymphoproliferative disorders of the skin: clinicopathologic correlation and and statistical analysis of 86 cases. J Clin Oncol. 1995;13: 1343-1354.

    Kaudewitz P, Stein H, Dallenbach F, et al. Primary and secondary cutaneous Ki-1+ (CD30+) anaplastic large cell lymphomas: morphologic, immunohistologic, and clinical-characteristics. Am J Pathol. 1989;135: 359-367.

    Kummer JA, Vermeer MH, Dukers DF, Meijer CJLM, Willemze R. Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype. J Invest Dermatol. 1997;109: 636-640.

    Beljaards RC, Meijer CJLM, Scheffer E, et al. Prognostic significance of CD30 (Ki-1/Ber-H2) expression in primary cutaneous large-cell lymphomas of T-cell origin: a clinicopathologic and immunohistochemical study in 20 patients. Am J Pathol. 1989;135: 1169-1178.

    de Bruin PC, Beljaards RC, van Heerde P, et al. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T- or null cell phenotype. HistoPathol. 1993;23: 127-135.

    DeCouteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large cell lymphoma of nodal origin. Blood. 1996;87: 3437-3441.

    Natkunam Y, Warnke RA, Haghighi B, et al. Coexpression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemichal and molecular analyses of seven cases. J Cut Pathol. 2000;27: 392-399.

    Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. 1996;34: 470-480.

    Nijsten T, Curiel-Lewandrowski C, Kadin ME. Lymphomatoid papulosis in children: a retrospective cohort study of 35 cases. Arch Dermatol. 2004;140: 306-312.

    El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol. 2004;140: 441-447.

    Kadin M, Nasu K, Sako D, Said J, Vonderheid E. Lymphomatoid papulosis: a cutaneous proliferation of activated helper T cells expressing Hodgkin's disease associated antigens. Am J Pathol. 1985;119: 315-325.

    Weiss L, Wood G, Trela M, Warnke RA, Sklar J. Clonal T-cell populations in lymphomatoid papulosis. N Engl J Med. 1986;315: 475-479.

    Davis TM, Morton CC, Miller-Cassman R, Balk SP, Kadin ME. Hodgkin's disease, lymphomatoid papulosis and cutaneous T-cell lymphoma derived from a common T-cell clone. N Engl J Med. 1992;326: 1115-1122.

    Takeshita M, Imayama S, Oshiro Y, et al. Clinicopathologic analysis of 22 cases of subcutaneous panniculitis-like CD56- and CD56+ lymphoma and review of 44 other reported cases. Am J Clin Pathol. 2004;121: 408-416.

    Marzano AV, Berti E, Paulli M, Caputo R. Cytophagocytic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma. Arch Dermatol. 2000;136: 889-896.

    El Shabrawi-Caelen L, Cerroni L, Kerl H. The clinicopathologic spectrum of cytotoxic lymphomas of the skin. Semin Cutan Med Surg 2000;19: 118-123.

    Miyamoto T, Yoshino T, Takehisa T, Hagari Y, Mihara M. Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases. Br J Dermatol. 1998;139: 481-487.

    Cheung MMC, Chan JKC, Lau WH, et al. Primary non-Hodgkin lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol. 1998;16: 70-77.

    Bekkenk MW, Jansen PM, Meijer CJLM, Willemze R. CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature. Ann Oncol. 2004;15: 1097-1108.

    Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol. 2003;40: 175-184.

    Barrionueva C, Anderson VM, Zevallos-Giampietri E, et al. Hydroa-like cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru. Appl Immunohistochem Molec Morphol. 2002;10: 7-14.

    Chen HH, Hsiao CH, Chiu HC. Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma. Br J Dermatol. 2002;147: 587-591.

    Magana M, Sangueza P, Gil-Beristain J, et al. Angiocentric cutaneous T-cell lymphoma of childhood (hydroa-like lymphoma): a distinctive type of cutaneous T-cell lymphoma. J Am Acad Dermatol. 1998;38: 574-579.

    von den Driesch P, Coors EA. Localized cutaneous small to medium-sized pleomorphic T-cell lymphoma: a report of 3 cases stable for years. J Am Acad Dermatol. 2002;46: 531-535.

    Sterry W, Siebel A, Mielke V. HTLV-1 negative pleomorphic T-cell lymphoma of the skin: the clinicopathologic correlations and natural history of 15 patients. Br J Dermatol. 1992;126: 456-462.

    Friedmann D, Wechsler J, Delfau MH, et al. Primary cutaneous pleomorphic small T-cell lymphoma. Arch Dermatol. 1995;131: 1009-1015.

    Bakels V, van Oostveen JW, van der Putte CJ, Meijer CJLM, Willemze R. Immunophenotyping and gene rearrangement analysis provide additional citeria to differentiate between cutaneous T-cell lymphomas and pseudo-T-cell lymphomas. Am J Pathol. 1997;150: 1941-1949.

    Herling M, Teittel MA, Shen RR, Medeiros LJ, Jones D. TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. Blood. 2003;101: 5007-5009.

    Rijlaarsdam JU, van der Putte SCJ, Berti E, et al. Cutaneous immunocytomas: a clinicopathologic study of 26 cases. Histopathology. 1993;23: 119-125.

    Schmid U, Eckert F, Griesser H, et al. Cutaneous follicular lymphoid hyperplasia with monotypic plasma cells. A clinicopathologic study of 18 patients. Am J Surg Pathol. 1995;19: 12-20.

    Torne R, Su WPD, Winkelmann RK, Smolle J, Kerl H. Clinicopathologic study of cutaneous plasmacytoma. Int J Dermatol. 1990;29: 562-566.

    Li C, Inagaki H, Kuo TT, Huo S, Okabe M, Eimoto T. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 Asian cases. Am J Surg Pathol. 2003;27: 1061-1069.

    Cerroni L, Signoretti S, Hfler G, et al. Primary cutaneous marginal zone B-cell lymphoma: a recently described entity of low-grade malignant cutaneous B-cell lymphoma. Am J Surg Pathol. 1997;21: 1307-1315.

    Bailey EM, Ferry JA, Harris NL, Mihm MC, Jacobson JO, Duncan LM. Marginal zone lymphoma (low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type) of skin and subcutaneous tissue: a study of 15 patients. Am J Surg Pathol. 1996;20: 1011-1023.

    Child FJ, Woollons A, Price ML, Calonje E, Russell-Jones R. Multiple cutaneous immunocytoma with secondary anetoderma: report of two cases. Br J Dermatol. 2000;143: 165-170.

    Cerroni L, Zchling N, Pütz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol. 1997;24: 457-461.

    Goodlad JR, Davidson MM, Hollowood K, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am J Surg Pathol. 2000;24: 1279-1285.

    Wood GS, Kamath NV, Guitart J, et al. Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States. J Cutan Pathol. 2001;28: 502-507.

    de Leval L, Harris NL, Longtine J, Ferry JA, Duncan LM. Cutaneous B-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification. Am J Surg Pathol. 2001;25: 732-741.

    Hoefnagel JJ, Vermeer MH, Janssen PM, Fleuren GJ, Meijer CJLM, Willemze R. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol. 2003;149: 1183-1191.

    Streubel B, Lamprecht A, Dierlamm J, et al. T(14; 18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood. 2003;101: 2335-2339.

    Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. t(3;14)(p14.1;932) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia. 2005 Feb 10; [Epub ahead of print].

    Gronbaek K, Ralfkiaer E, Kalla J, Skovgaard GL, Guldberg P. Infrequent somatic Fas mutations but no evidence of Bcl-10 mutations or t(11;18) in primary cutaneous MALT-type lymphoma. J Pathol. 2003;201: 134-140.

    Zenahlik P, Pink-Fuches R, Kapp KS, Kerl H, Cerroni L. Therapy of primary cutaneous B-cell lymphomas. Hautarzt. 2000;51: 19-24.

    Soda R, Constanzo A, Cantonetti M, Orlandi A, Bianchi L, Chimenti S. Systemic therapy of primary cutaneous B-cell lymphoma, marginal zone type, with rituximab, a chimeric anti-CD20 monoclonal antibody. Acta Derm Venereol. 2001;81: 207-208.

    Crosti A. Micosi fungoide e reticuloistiocitomi cutanei maligni. Minerva Dermat. 1951;26: 3-11.

    Bekkenk M, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary cutaneous B-cell lymphoma: guidelines of the Dutch Cutaneous Lymphoma Group. J Clin Oncol. 1999;17: 2471-2478.

    Cerroni L, Arzberger E, Pütz B, et al. Primary cutaneous follicular center cell lymphoma with follicular growth pattern. Blood. 2000;95: 3922-3928.

    Goodlad JR, Krajewski AS, Batstone PJ, et al. Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity. Am J Surg Pathol. 2002;26: 733-741.

    Cerroni L, El-Shabrawi-Caelen L, Pink-Fuches R, LeBoit PE, Kerl H. Cutaneous spindle-cell lymphoma: a morphologic variant of cutaneous large B-cell lymphoma. Am J DermatoPathol. 2000;22: 299-309.

    Kim BK, Surti U, Pandya AG, Swerdlow SH. Primary and secondary cutaneous diffuse large B-cell lymphomas. Am J Surg Pathol 2003;27: 356-364.

    Aarts WM, Willemze R, Bende RJ, Meijer CJLM, Pals ST, van Noessel CJ. VH gene analysis of primary cutaneous B-cell lymphomas: evidence for ongoing somatic hypermutation and isotype switching. Blood. 1998;92: 3857-3864.

    Gellrich S, Rutz S, Golembowski S, et al. Primary cutaneous follicle center cell lymphomas and large B-cell lymphomas of the leg descend from germinal center cells: a single cell polymerase chain reaction analysis. J Invest Dermatol. 2001; 117: 1512-1520.

    Child FJ, Scarisbrick JJ, Calonje E, Orchard G, Russell-Jones R, Whittaker SJ. Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma. J Invest Dermatol. 2002;118: 941-948.

    Mao X, Lillington D, Child FJ, Russell-Jones R, Young B, Whittaker S. Comparative genomic hybridization analysis of primary cutaneous B-cell lymphomas: identification of common genomic alterations in disease pathogenesis. Genes Chromosomes Cancer. 2002;35: 144-155.

    Grange F, Petrella T, Beylot-Barry M, et al. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood. 2004;103: 3662-3668.

    Pimpinelli N, Vallecchi C. Local orthovolt radiotherapy in primary cutaneous B-cell lymphomas: results in a series of 115 patients. Skin Cancer. 1999;14: 219-224.

    Piccinno R, Caccialanza M, Berti E. Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol. 2003;13: 49-52.

    Smith BD, Glusac EJ, McNiff JM, et al. Primary cutaneous B-cell lymphoma treated with radiotherapy: a comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems. J Clin Oncol. 2004;22: 634-639.

    Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer. 2000;89: 1835-1844.

    Gellrich S, Muche JM, Pelzer K, Audring H, Sterry W. Anti-CD20 antibodies in primary cutaneous B-cell lymphoma: initial results in dermatologic patients. Hautarzt. 2001;52: 205-210.

    Paul T, Radny P, Krober SM, Paul A, Blaheta HJ, Garbe C. Intralesional rituximab for cutaneous B-cell lymphoma. Br J Dermatol. 2001;144: 1239-1243.

    Aguilera NS, Tomaszewski MM, Moad JC, Bauer FA, Taubenberger JK, Abbondanzo SL. Cutaneous follicle center lymphoma: a clinicopathologic study of 19 cases. Mod Pathol. 2001;14: 828-835.

    Mirza I, Macpherson S, Paproski S, et al. Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol. 2002;20: 647-655.

    Bergman R, Kurtin PJ, Gibson LE, Hull PR, Kimlinger TK, Schroeter AL. Clinicopathologic, immunophenotypic, and molecular characterization of primary cutaneous follicular B-cell lymphoma. Arch Dermatol. 2001;137: 432-439.

    Paulli M, Viglio A, Vivenza D, et al. Primary cutaneous large B-cell lymphoma of the leg: histogenetic analysis of a controversial clinicopathologic entity. Hum Pathol. 2002;33: 937-943.

    Brogan BL, Zic JA, Kinney MC, Hu JY, Hamilton KS, Greer JP. Large B-cell lymphoma of the leg: clinical and pathologic characteristics in a North American series. J Am Acad Dermatol. 2003;49: 223-228.

    Nicol I, Boye T, Carsuzaa F, et al. Post-transplant plasmablastic lymphoma of the skin. Br J Dermatol. 2003;149: 889-891.

    Hausermann P, Khanna N, Buess M, et al. Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation. Dermatology. 2004;208: 287-290.

    Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol. 2004;28: 736-747.

    Sander CA, Kaudewitz P, Kutzner H, et al. T-cell rich B-cell lymphoma presenting in the skin. A clinicopathologic analysis of six cases. J Cutan Pathol. 1996;23: 101-108.

    Li S, Griffin CA, Mann RB, Borowitz MJ. Primary cutaneous T-cell rich B-cell lymphoma: clinically distinct from its nodal counterpart Mod Pathol. 2001;14: 10-13.

    Perniciaro C, Winkelmann RK, Daoud MS, Su WPD. Malignant angioendotheliomatosis is an angiotropic intravascular lymphoma: immunohistochemical, ultrastructural and molecular genetic studies. Am J DermatoPathol. 1995;17: 242-248.

    Ferreri AJM, Campo E, Seymour JF, et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases with special emphasis on the "cutaneous variant." Br J Haematol. 2004;127: 173-183.

    Rubin MA, Cossman J, Freter CE, Azumi N. Intravascular large cell lymphoma coexisting within hemangiomas of the skin. Am J Surg Pathol. 1997;21: 860-864.

    Kobayashi T, Munakata S, Sugiura H, et al. Angiotropic lymphoma: proliferation of B-cells in the capillaries of cutaneous angiomas. Br J Dermatol. 2000;143: 162-164.

    Guitart J, Wickless SC, Oyama Y, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in refractory cutaneous T-cell lymphoma. Arch Dermatol. 2002;138: 1359-1365.

    Soligo D, Ibatici A, Berti E, et al. Treatment of advanced mycosis fungoides by allogeneic stemcell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant. 2003;31: 663-666.(Rein Willemze, Elaine S. )

    http://www.100md.com/html/DirDu/2006/09/20/17/52/56.htm