LYMPHOMAS WITH PRIMARY CUTANEOUS MANIFESTATIONS (so-called CUTANEOUS LYMPHOMAS)
(see also cutaneous lymphoid hyperplasia (CLH) and pseudolymphoma)

Table of contents :


  • cutaneous T-cell and NK-cell lymphomas (CTCL)
  • early plasmacytoid dendritic cell leukemia/lymphoma / CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
  • cutaneous B-cell lymphomas (CBCL)

  • 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 1:100,000ref. 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 entitiesref (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). 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 > 1300 patients with a primary cutaneous lymphomaref1, ref2, ref3. 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 confusionref1, ref2, ref3, ref4. 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. This focuses 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 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. Relative frequency and disease-specific 5-year survival of 1905 primary cutaneous lymphomas classified according to the WHO-EORTC classification :
    WHO-EORTC classification no. frequency, % (data are based on 1905 patients with a primary cutaneous lymphoma registered at the Dutch and Austrian Cutaneous Lymphoma Group between 1986 and 2002) disease-specific 5-year survival, %
      Cutaneous T-cell lymphoma      
         Indolent clinical behavior       
          mycosis fungoides (MF)   800    44%   88 
          folliculotropic MF   86    4%   80 
          pagetoid reticulosis   14    < 1%   100 
          granulomatous slack skin (GSS)   4   < 1%   100 
          primary cutaneous anaplastic large cell lymphoma (pcALCL)   146    8%   95 
          lymphomatoid papulosis   236    12%   100 
          subcutaneous panniculitis-like T-cell lymphoma (SPTCL)   18    1%   82 
          primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)*   39    2%   75 
         Aggressive clinical behavior       
          Sézary syndrome (SS)   52    3%   24 
          primary cutaneous extranodal NK/T-cell lymphoma, nasal type     < 1%   NR 
          primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)*   14    < 1%   18 
          primary cutaneous g/d T-cell lymphoma (provisional)*   13    < 1%   NR 
          primary cutaneous peripheral T-cell lymphoma, unspecified (excluding the 3 provisional entities indicated with a *)   47    2%   16 
      Cutaneous B-cell lymphoma      
         Indolent clinical behavior       
          primary cutaneous marginal zone B-cell lymphoma   127    7%    99 
          primary cutaneous follicle center lymphoma   207    11%    95 
         Intermediate clinical behavior       
          primary cutaneous diffuse large B-cell lymphoma, leg type   85    4%    55
          primary cutaneous diffuse large B-cell lymphoma, other     < 1%    50 
          primary cutaneous intravascular large B/cell lymphoma     < 1%    65 

    Cutaneous T-cell lymphomas (CTCL) (indolent) : a group of lymphomas including a spectrum of disorders, all of which exhibit (1) antigen-independent clonal expansion of malignant T lymphocytes arrested at varying stages of differentiation of cells committed to the series of Th2 lymphocytes, and (2) malignant infiltration of the skin, which may be the chief or only manifestation of diseaseref. Therapy : increase of CD25+ cells in CD3+ and CD4+ populations after treatment in a subset of patients possibly reflecting activation of reactive helper T cells, proliferation of neoplastic T cells, or proliferation of T-regulatory cells. In summary, at this dose and schedule recombinant IL-2 is largely ineffective as therapy in patients with advanced CTCL. Whether IL-2 has the potential to suppress antitumor activity by stimulation of regulatory T cells needs to be clarifiedref.

    Cutaneous B-cell lymphomas : the TCL1 oncogene product is uncommonly expressed in PCBCL (20% of cases, mainly of the follicle-centre subtype); in contrast, CD27 is often expressed in PCBCL (60% of cases), mainly of the marginal-zone subtype; the coexpression of TCL1 and CD27 may be seldom observed in PCBCL (8% of cases); PCBCL does not seem to show, in terms of either TCL1 or CD27 expression, significant differences compared with its systemic counterpartsref

  • primary cutaneous marginal-zone B-cell lymphoma (PCMZL)ref 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 immunocytomaref, and cases of cutaneous follicular lymphoid hyperplasia with monotypic plasma cellsref. 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 categoryref. 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.

  • Epidemiology : in Japan ages of the patients ranged from 26 to 75 years (mean 55.7 years) with a slight female predilectionref
    Pathogenesis : the chromosomal aberrations in MALT lymphoma such as t(11;18)(q21;q21), t(14;18)(q32;q21) and t(3;14)(p14.1;q32) were not reported in any of the Japanese casesref
    Symptoms & signs : 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. Ulceration is uncommon. PCMZLs have a tendency to recur in the skin, but dissemination to extracutaneous sites is exceedingly rareref1, ref2, ref3, ref4. In some cases spontaneous resolution of the skin lesions may be observed. The development of anetoderma in spontaneously resolving lesions has been observedref. An association with Borrelia burgdorferi infection has been reported in a significant minority of European cases of PCMZL (Italyref and Scottish Highlandsref), but not in Asian cases (Japanref1, ref2) or cases from the USAref. Associated autoimmune diseases are uncommon in PCMZL, but rather suggest secondary cutaneous involvement of a systemic lymphomaref. 2/16 Japanese patients had suffered from Sjogren's syndromeref.
    Laboratory examinations : Prognosis : excellent with a 5-year survival close to 100%ref1, ref2, ref3, ref4, ref5, ref6
    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 firstref. For patients presenting with multifocal skin lesions, chlorambucil or intralesional or subcutaneous administration of IFN-a may produce complete responses in approximately 50% of patientsref. Very good results have also been obtained with the use of systemic or intralesional rituximabref. In patients showing frequent skin relapses, topical or intralesional corticosteroids may be considered; alternatively, an expectant strategy can be followed, similar to that used in other indolent B-cell lymphomas and leukemias. Characteristic clinical presentation with multiple nodules and small tumors on the back and arms :
  • 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. Characteristic features of PCFCL and PCLBCL, leg type :

  •   PCFCL   PCLBCL, leg type
    morphology  predominance of centrocytes that are often large, especially in diffuse lesions.  predominance or confluent sheets of medium-sized to large B cells with round nuclei, prominent nucleoli, and coarse chromatin resembling centroblasts and/or immunoblasts. 
    centroblasts may be present, but not in confluent sheets.  diffuse growth pattern.
    growth pattern may be follicular, follicular and diffuse, or diffuse (a continuum without distinct categories or grades).   
    phenotype  Bcl-2: -/+ (Faint staining, when present; minority of cells (see comments in paragraph on PCFCL)) Bcl-2: ++ (strong staining; in most neoplastic cells)
    Bcl-6: +  Bcl-6: +/- 
    CD10: -/+ (Diffuse lesions, mostly CD10-) CD10: - 
    Mum-1: -  Mum-1: + 
    clinical features  middle-aged adults.  elderly, especially females, 
    localized lesions on head or trunk (90%).  lesions localized on leg(s), most often below the knee. 
    multifocal lesions in rare cases. rare cases with lesions at other sites than the leg (10%).
    Symptoms & signs : 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 legsref1, ref2, ref3. 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"ref (Crosti A. Micosi fungoide e reticuloistiocitomi cutanei maligni. Minerva Dermat. 1951;26: 3-11). Presentation with multifocal skin lesions is observed in a small minority of patients, but is not associated with a more unfavorable prognosisref1, ref2. If left untreated, the skin lesions gradually increase in size over years, but dissemination to extracutaneous sites is uncommon. Primary cutaneous follicle center lymphoma. (A) Typical presentation with tumors on the chest surrounded by less infiltrated erythematous skin lesions. (B) Presentation with multiple tumors confined to the scalp. (C) Diffuse dermal infiltrate mainly consisting of large centrocytes and multilobated cells (H&E staining; original magnification, x 480). (D-E) Serial sections stained for CD20 (D) and bcl-2 (E). Bcl-2 is expressed by perivascular T cells, but not by the neoplastic B cells. Image acquisition for panels A and C-E was performed as described for Figure 1B. An HC Plan APO objective was used (40x/0.85 for panel C; 10x/0.40 for panels D and E).

    Laboratory examinations : Prognosis : 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 > 95%ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10. A recent study suggests that strong expression of bcl-2 in PCFCLs with a diffuse large-cell histology is associated with a more unfavorable prognosisref.
    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" cellsref1, ref2, ref3, ref4, ref5 (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). 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 diseaseref1, ref2. Recent studies report beneficial effects of systemic or intralesional administration of rituximab therapy in small series of PCFCLs, but the long-term effects of this approach have yet to be determinedref1, ref2, ref3
    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)ref1, ref2, ref3. However, recent studies report the presence of t(14;18) and/or bcl-2 expression in a significant minority of PCFCLsref1, ref2, ref3, ref4, ref5. 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 casesref1, ref2, ref3, ref4, ref5. 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 prognosisref. 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 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.

  • Epidemiology : predominantly affects elderly patients, particularly femalesref1, ref2, ref3.
    Symptoms & signs : generally rapidly growing red or bluish-red tumors on one or both (lower) legs. In contrast to the group of PCFCLs, these lymphomas more often disseminate to extracutaneous sites and have a more unfavorable prognosisref1, ref2. 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 diseaseref
    Laboratory examinations : Prognosis : the 5-year survival of 78 cases included in the Dutch and Austrian registries was 55%. PCLBCLs on the leg have an inferior prognosis compared to PCLBCLs presenting at other sitesref. 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%, respectivelyref. Primary cutaneous diffuse large B-cell lymphoma, leg type. (A) Clinical presentation with multiple tumors on right lower leg. (B) Monotonous proliferation of centroblasts and immunoblasts (H&E staining; original magnification,x 480). (C-D) Characteristically, the neoplastic B cells strongly express bcl-2 (C) and Mum-1/IRF-4 (D). Image acquisition for panels B-D was performed as described for Figure 1B. An HC Plan APO objective was used (40x/0.85 for panel B; 20x/0.70 for panels C and D).

    Therapy : these lymphomas should be treated as systemic DLBCLs with anthracycline-based chemotherapyref1, ref2. In patients presenting with a single small skin tumor, radiotherapy may sometimes be consideredref. Systemic administration of 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 establishedref1, ref2.
  • primary cutaneous diffuse large B-cell lymphoma, 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 deficienciesref1, ref2, ref3. 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 reportedref1, ref2. 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 prognosisref1, ref2. In addition, rare cases of primary cutaneous intravascular large B-cell lymphoma may be included in this category.
  • Therapy : rituximab 375 mg/m2 once weekly for 4 or 6 consecutive weeksref
    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 a/b 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 investigationref1, ref2. 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 schemesref

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