Primary cutaneous Bcell lymphomas - Wiley Online Library

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DOI: 10.1111/j.1610-0387.2011.07852.x

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Primary cutaneous B-cell lymphomas Werner Kempf1, 2, Natalja Denisjuk2, Katrin Kerl1, Antonio Cozzio1, Christian Sander3 (1) Department of Dermatology, University Hospital Zurich, Switzerland (2) Kempf and Pfaltz, Histological Diagnostics, Zurich, Switzerland (3) Eduard Arning Clinic for Dermatology and Allergolgoy, Asklepios Clinic St. Georg, Hamburg, Germany

JDDG; 2012 • 10:12–23

Submitted: 29. 7. 2011 | Accepted: 11. 10. 2011

Section Editor Prof. Dr. Jan C. Simon, Leipzig

Keywords

Summary

• • • • • • •

Cutaneous B-cell lymphomas (CBCL) are the second most common form of primary cutaneous lymphomas. The cutaneous follicle center lymphoma and the cutaneous marginal zone lymphoma (extranodal MALT type lymphoma) account for the vast majority of CBCL and manifest with nodules. These two lymphoma entities have an indolent, slowly progressive course and an excellent prognosis despite a high rate of recurrences. In contrast, cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of CBCL display an impaired prognosis and therefore require to be treated with multiagent chemotherapy and anti-CD20 monoclonal antibodies in most cases. Clinicopathologic correlation, histology with immunohistochemical profile and genotyping as well as staging examinations are crucial diagnostic elements in the work-up of CBCL.

B-cell lymphoma follicle center lymphoma marginal zone lymphoma MALT leg type diagnosis therapy

Introduction Primary cutaneous B-cell lymphomas (CBCL) represent 25–30 % of primary cutaneous lymphomas and are the second largest group of primary cutaneous lymphomas [1]. Their incidence is about 3 new cases per year per million. The group of CBCL includes malignant proliferations of B cells of varying degree of malignancy with different clinical, histological as well as immunophenotypic characteristics. Their prognosis and treatment differ considerably from comparable primary nodal B-cell non-Hodgkin lymphomas (NHL). By definition CBCL develop in the skin and remain limited to the skin organ for a long time or for the entire disease course. CBCL are classified according to the WHO classification (4th edition, 2008) which largely takes over the WHO-EORTC classification of primary cutaneous lymphomas [1] (Table 1). The WHO-EORTC classification and the WHO classification define the lymphoma entities on the basis of distinct clinical, morphological, immunophenotypic, molecular and prognostic features [2]. These broadly based classifications have particularly in the field of CBCL allowed for comparison of study results. The three most common forms of CBCL are primary cutaneous marginal zone lymphoma (MZL; extranodal MALT lymphoma), primary cutaneous follicle center lymphoma (FCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (DLBL), which constitute over 90 % of CBCL. MZL and FCL represent forms of CBCL of low malignancy and a 5-year survival rate of over 90 % to 95 %, while the DLBL as a highly malignant form takes an aggressive course with a 5-year survival rate of only 20–60 %.

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© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2012/1001

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Table 1: Cutaneous B-cell lymphomas according to the WHO classification for hematopoietic and lymphoproliferative disorders (4th edition, 2008) and the WHO-EORTC classification. WHO-EORTC Classification (2005) Primary cutaneous marginal zone B-cell lymphoma

WHO Classification (4th edition, 2008) Extranodal marginalzone lymphoma (MALT type)

Primary cutaneous follicle center lymphoma Growth patterns: follicular, follicular and diffuse, diffuse

Primary cutaneous follicle centre lymphoma

Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Diffuse large B-cell lymphoma, NOS EBV-associated diffuse large B-cell lymphoma of the elderly Primary cutaneous intravascular large B-cell lymphoma Intravascular large B-cell lymphoma

Diagnostics When CBCL is clinically suspected, biopsy is the first step in diagnostics. The biopsy should be of a representative size (at least 5 mm in diameter) and include subcutaneous tissue. In smaller tumors accessible to total excision, this should be attempted. The growth pattern (follicular, diffuse), the cytomorphology of the tumor cells and the immunophenotype are of key significance for classification within the group of CBCL. The detection of a monoclonal rearrangement of the gene for the immunoglobulin heavy chain (IgH) is a further diagnostic clue for a CBCL. Identification is performed using the polymerase chain reaction (PCR) ideally employing a BIOMED-2 protocol, which represents a standardized procedure with worldwide acceptance [3]. In the differentiation of MZL from cutaneous B-cell pseudolymphoma (B-PSL) (synonym: cutaneous lymphoid hyperplasia), the detection of a monoclonal expression of immunoglobulin light chains (Ig kappa and lambda) is helpful, where the distribution in monoclonal infiltrates should demonstrate a ratio of at least 5 : 1. Clonality, however, cannot per se be equated with a malignant lymphoma, as B-cell pseudolymphomas can occasionally have clonal B-cell populations. In addition, as in maximally 80 % of CBCL a clonal rearrangement of IgH genes can be detected by PCR-based techniques, a negative result of molecular biological tests does not exclude a CBCL. The finding of molecular biological studies should always be interpreted together with the clinical, histological and immunophenotypic findings. In B-cell infiltrates with plasma cellular, plasmablastic and immunoblastic differentiation in situ hybridization to detect RNA of the Epstein-Barr virus (EBV-RNA: EBER) is recommended. In FCL, MZL and B-PSL Borrelia serology (antibody search test with ELISA and confirmatory test with Western blot) and detection of Borrelia DNA in tumor tissue using PCR should be attempted, as antibiotic therapy is indicated in the presence of a Borrelia infection. In light of overlapping histological or immunophenotypic findings, accurate differentiation of CBCL from infiltrates of nodal or other extranodal B-cell lymphomas is only possible by means of staging examinations (Table 2). These are summarized in Table 2 and encompass history with regard to B symptoms (fever, night sweats, weight loss), examination of the entire skin, blood tests to exclude a leukemic component, blood chemistry especially of an elevated lactate dehydrogenase (LDH) level, Borrelia serology and serum electrophoresis to exclude a monoclonal gammopathy. Radiologic studies include CT enhanced by contrast media of thorax, abdomen and head-and-neck region (the latter only in the event of onset of lesions on the head and neck) or total body PET-CT. The role of bone marrow biopsy is discussed controversially. According to the ISCL-EORTC guidelines (ISCL: International Society for Cutaneous Lymphomas; EORTC: European Organization for Research and Treatment of Cancer) this is indicated for diffuse large B-cell lymphoma, while it is optional in patients with MZL and FCL [4]. We partially disagree and also recommend bone marrow examination in FCL and MZL with multifocal lesions. Ideally diagnostics are performed in centers specializing in CL and is usually interdisciplinary by (dermato-)oncologists, hematologists and (dermato-)pathologists.


The growth pattern (follicular, diffuse), the cytomorphology of the tumor cells and the immunophenotype are of key significance for classification within the group of CBCL.

In light of overlapping histological or immunophenotypic findings, accurate differentiation of CBCL from infiltrates of nodal or other extranodal Bcell lymphomas is only possible by means of staging examinations.

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Table 2: Staging in cutaneous B-cell lymphomas. (1) History and clinical findings: B symptoms (fever, night sweats, weight loss), extension of lesions, lymph node involvement, enlargement of tonsils, liver and spleen (2) Laboratory tests: blood count, hepatic and renal function, lactate dehydrogenase, uric acid. Serum electrophoresis or immunoelectrophoresis. FACS analysis if leukemic variants are suspected (B-cell subsets) (3) Radiologic examinations: contrast medium-enhanced CT (thorax, abdomen including pelvis and head-and-neck region in case of lesions in the head-and-neck area) or total body PET-CT (4) Lymph node biopsy in case of pathologically enlarged lymph nodes (5) Bone marrow biopsy in FCL, MZL with multifocal lesions and in all other B-cell lymphomas Staging is performed according to the new TNM system (Table 3) which was published in 2008 and evaluates cutaneous spread more adequately than other classifications [10]. The T1 stage corresponds to a solitary lesion, while multiple lesions with involvement of one or two neighboring regions (T2) or more body regions (T3) denote a higher T stage (details in Table 3).

The diagnostic measures and therapies mentioned in this article are based on national and international recommendations [4, 5].

MZL manifests primarily in the 3rd to 5th decade of life (average age 39 years) and presents in the majority of patients with multifocal red nodules.

The tumor cells in most cases display a lymphoplasmacytoid differentiation.

Primary cutaneous B-cell lymphomas – entities Primary cutaneous marginal zone lymphoma (MZL) According to the WHO classification (4th edition, 2008), MZL is assigned to the group of extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT lymphoma) [6]. This form of CBCL with low malignancy is defined as a proliferation of small B cells resembling marginal zone cells, lymphoplasmacytoid cells and plasma cells. The neoplasias termed cutaneous immunocytoma and primary cutaneous plasmocytoma in past classifications are assigned to MZL. MZL is the second most common form of CBCL, accounting for about 35–40 % of all CBCL. MZL manifests primarily in the 3rd to 5th decade of life (average age 39 years) and presents in the majority of patients (70 %) with multifocal red nodules [1, 7] (Figure 1). The tumors display slow growth and usually do not ulcerate. The arms and trunk are sites of predilection [7]. Spontaneous regression leaving anetoderma-like lesions can be observed. Histologically nodular infiltrates of small lymphocytes are seen with the infiltrate being separated from the overlying epidermis by an infiltrate-free Grenz zone as in other CBCL. Within the infiltrates consisting primarily of small lymphocytes reactive follicles (Figure 2a) containing tingible body macrophages and regularly structured networks of CD21-positive follicular dendritic cells (FDC) are found in the majority of cases. The tumor cells in most cases display a lymphoplasmacytoid differentiation (Figure 2b). In some cases a monocytoid cytomorphology with reni-

Table 3: TNM staging in cutaneous B-cell lymphoma (according to [10]). T1 T2 T3

Solitary skin lesion Regional skin involvement with multiple lesions limited to one or two neighboring body regions Generalized skin involvement with multiple lesions in two non-neighboring or more than 3 body regions

N0 N1 N2

No clinical or pathological lymph node involvement Involvement of one locoregional lymph node region Involvement of one or two locoregional lymph node regions or involvement of far-removed lymph node regions

M0 M1

No extracutaneous involvement beyond lymph nodes Extracutaneous involvement beyond lymph nodes

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form nuclei and a pale cytoplasm predominates. The infiltrates may also include eosinophilic granulocytes. Characteristically, plasma cells can be observed particularly in the periphery of the tumor infiltrates. The lymphoma cells express B-cell markers (CD20, CD79a) and bcl-2, but are negative for bcl-6 and CD10. The plasma cells typically display monoclonal expression of immunoglobulin light chains (kappa, lambda), with a ratio of 5 : 1 or 10 : 1 being viewed as monoclonality. With molecular biological methods (PCR, BIOMED-2 protocol), a monoclonal rearrangement of the genes for the heavy chain (IgH) can be detected in up to 80 % of MZL. The translocations t(11;18) and t(14;18)(q32;q21) found in other extranodal MALT lymphomas can be detected in only a small proportion of cutaneous MZL. With regard to the expression of immunoglobulins cutaneous MZL (IgG, IgA, IgE) also differ from other extranodal MALT lymphomas (IgM). These findings suggest that cutaneous MZL is an unique form of extranodal MZL. Interestingly, in cutaneous MZL in addition to the B cells numerous CD3+ T cells and CD123+ plasmacytoid dendritic cells are found. The latter are arranged in small clusters in close vicinity the T cells and monoclonal plasma cells and may play an important role in the pathogenesis of MZL.

The plasma cells typically display monoclonal expression of immunoglobulin light chains (kappa, lambda).

Figure 1: Cutaneous marginal zone lymphoma (extranodal MALT lymphoma): several reddish nodes on the left arm.

Figure 2: Cutaneous marginal zone lymphoma: (a) dermal nodular lymphocytic infiltrate with (b) tumor cells of predominantly lymphoplasmacytoid differentiation.


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Table 4: Therapy of cutaneous B-cell lymphoma. B-cell lymphoma form

Therapy of first choice

Other therapeutic options

Marginal zone lymphoma (extranodal MALT)

Excision, radiotherapy, antibiotics* In multifocal involvement: rituximab i.v.

Interferon-␣ i.l. Rituximab i.l. Steroids i.l.

Follicle center lymphoma

Excision, radiotherapy In multifocal involvement: rituximab i.v.

Interferon-␣ i.l. Rituximab i.l.

Diffuse large B-cell lymphoma, leg type

R-CHOP

Radiotherapy Rituximab i.v.

*in the event of proven association with Borrelia infection; i.l.: intralesional

An association with Borrelia burgdorferi infections has been reported in European cases of MZL.

The prognosis of MZL is on the whole very good with a 5-year survival rate of over 95 %. Recurrences do appear in nearly one-half of the patients, but are not associated with a poor prognosis. Excision and radiotherapy are therapy of first choice.

FCL is defined as a neoplasia of follicle center cells with predominantly centrocytic differentiation. Sites of predilection are the head and neck region as well as the trunk, where FCL presents as red or livid nodes of firm consistency. Three histological growth patterns are differentiated in FCL, with the diffuse growth pattern being most common.

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In the plasmacellular variant of MZL, which was formerly termed immunocytoma or cutaneous plasmocytoma, the entire infiltrate consists of plasma cells. Immunoglobulins are often seen either in the nucleus itself (Dutcher bodies) or in the cytoplasm (Russell bodies) as PAS-positive inclusions. The tumor cells express CD79a or CD138 and display monotypic expression of immunoglobulin light chains. The tumors manifest as large nodules with a smooth surface and can occur on acrodermatitis chronica atrophicans. An association with Borrelia burgdorferi infections has been reported in European cases paralleling Helicobacter pylori-associated MALT lymphomas of the gastrointestinal tract. Large geographic differences appear to exist, as an association with a Borrelia infection has not been observed in all European countries and up to now also not in the USA or Asia. Differential diagnosis includes in the first place B-PSL, which also can occur as a consequence of borreliosis. The detection of an immunoglobulin light chain restriction and clinico-pathologic correlation are of great significance in diagnostic differentiation of MZL from B-PSL. In contrast to mantle cell lymphoma and small lymphocytic lymphomas MZL does not express cyclin D1 or CD5. In plasma cell-rich variants of MZL the differential diagnosis includes skin infiltrates by a plasma cell myeloma, with the latter entities being recognized by adequate staging. The prognosis of MZL is on the whole very good with a 5-year survival rate over 95 % [1, 7]. Recurrences do appear in nearly one-half of the patients, but are not associated with a poor prognosis. In less than 10 % of patients is extracutaneous spread of MZL observed. Excision or radiotherapy are therapy of first choice [4] (Table 4). In case of association with a Borrelia infection antibiotic therapy (doxycycline 2 ⫻ 100 mg daily for 3–6 weeks) is recommended [4]. For lesions on exposed body sites or in the event of multifocal involvement intralesional administration of interferon-␣ or intralesional or intravenous therapy with anti-CD20 antibodies (rituximab; Mabthera®) can be considered. Chemotherapy (CHOP) is only indicated for extracutaneous spread. Cutaneous follicle center lymphoma (FCL) FCL is the most common form of CBCL and is also termed cutaneous follicular lymphoma (primary cutaneous follicle center lymphoma). FCL is defined as a neoplasia of follicle center cells with predominantly centrocytic differentiation [6]. The disease manifests predominantly in older patients of both genders in the 6th and 7th decade (average age: 59 years). Sites of predilection are the head and neck region as well as the trunk, where FCL presents with red or livid nodules of firm consistency (Figure 3) [1, 7]. In the surroundings tumor infiltrates can be seen as erythema or red plaques. Three histological growth patterns (follicular, follicular-diffuse, diffuse) are differentiated in FCL, with the diffuse growth pattern being most common [1]. Nodular infiltrates in all levels of the dermis and in part extending into the subcutis


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Figure 3: Cutaneous follicle center lymphoma: nodes on the forehead with surrounding plaque-like infiltrates.

with separation from the epidermis by an infiltrate-free Grenz zone are seen (Figure 4a). Tumor cells with centrocytic differentiation of variable size and cleaved nuclei predominate. Centroblastic differentiated tumor cells (large cells with round nuclei and peripheral nucleoli) or immunoblastic differentiated cells, which are characterized by large nuclei with a prominent central nucleolus are dispersed in the infiltrate. In the diffuse growth form structures resembling follicle centers are missing, while in the follicular form large neoplastic follicular structures with only a small mantle zone and without polarization are found. In contrast to the reactive follicle centers in MZL and B-PSL, which contain tingible body macrophages, these are lacking in the majority (80 %) of FCL [8]. The tumor cells express the B-cell markers CD19, CD20 and CD79a as well as bcl-6 and CD10. Irregular networks of CD21-positive follicular dendritic cells are typically observed and differentiate FCL from reactive germinal centers in cutaneous B-cell pseudolymphomas and in MZL. In contrast to nodal follicular lymphoma, the tumor cells in FCL in 90 % of the cases do not express bcl-2. The translocation t(14;18), which results in the expression of bcl-2 and is a feature of nodal follicular lymphomas is lacking in FCL. A light-chain restriction of immunoglobulin kappa and lambda can occasionally be detected. A monoclonal rearrangement of IgH genes can be found in 80 % of FCL using the BIOMED-2 protocol [3]. FCL with a follicular growth pattern must be differentiated from B-PSL and MZL. In the event of expression of bcl-2 by the tumor cells a secondary cutaneous involvement by a nodal follicle center lymphoma should be taken into consideration and excluded by staging. The clinico-pathologic correlation can be misleading here, as both primary cutaneous FCL as well as secondary cutaneous involvement by a nodal FCL can manifest with tumoral lesions in the head and neck region. In the diffuse growth form of FCL differential diagnostically primary cutaneous diffuse large B-cell lymphoma, leg type, stands in the forefront with significant prognostic and therapeutic implications. Cytomorphology with the predominance of tumor cells with centroblastic and immunoblastic differentiation and with strong expression of bcl-2 and MUM-1 in DLBL, leg type, are helpful diagnostic markers in addition to the clinico-pathologic correlation. In contrast to nodal follicular lymphomas (5-year survival rate 60–80 %), the prognosis of FCL is very good with a 5-year survival rate of over 90 % [1]. The prognosis is not affected by the number of tumors, recurrences or the histological growth type. Only location on the legs is associated with a poorer prognosis. Recurrences appear in 20–53 % of those affected. Extracutaneous spread is rare.


The tumor cells express the B-cell markers CD19, CD20 and CD79a as well as bcl-6 and CD10. In contrast to nodal follicular lymphoma, the tumor cells in FCL in 90 % of the cases do not express bcl-2.

The prognosis of FCL is very good with a 5-year survival rate of over 90 %.

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Figure 4: Cutaneous follicle center lymphoma – follicular growth type: (a) nodular infiltrate with extensive neoplastic follicle centers consisting of (b) predominantly cells of centrocytic differentiation.

Figure 5: Cutaneous diffuse large B-cell lymphoma, leg type: multiple nodes on the left lower leg.

As in MZL, excision and/or radiotherapy are therapy of first choice [4]. In locally very extensive or multifocal involvement intralesional or systemic therapy with antiCD20 antibodies (rituximab Mabthera®) is effective. Polychemotherapy is employed in extracutaneous involvement.

DLBL is a neoplasm of activated B cells with predominantly centroblastic and immunoblastic morphology. Usually older patients are affected, with a peak in the 7th decade of life (average age: 78 years) women being affected predominantly.

The tumor cells have a characteristic phenotype with expression of B-cell markers (CD19, CD20, CD22 and CD79a) and strong expression of bcl-2, MUM-1 and IgM, while bcl-6 and CD10 are not or only weakly expressed.

The prognosis of DLBL is poor with a 5-year survival rate of on the average 55 % (20–60 %).

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Cutaneous diffuse large B-cell lymphoma, leg type DLBL, leg type, is a relatively rare form of CBCL, which should, however, be recognized as early as possible in view of the poor prognosis. DLBL is a neoplasia of activated B cells with predominantly centroblastic and immunoblastic morphology [1]. Usually older patients are affected, with a peak in the 7th decade of life (average age: 78 years) women being affected predominantly. DLBL manifests with rapidly growing nodular tumors which can ulcerate (Figure 5). The disease appears on one or both legs, but rarely other locations have also been reported for the initial manifestation. Histologically, DLBL is characterized by nodular (or in case of a biopsy diffuse) non-epidermotropic monomorphic dense infiltrates with a Grenz zone but filling the entire dermis with extension into the subcutis (Figure 6a). The infiltrates consist almost exclusively of large blasts that either resemble centroblasts (round nuclei, marginalized nucleoli) or immunoblasts (large, round nuclei with a central prominent nucleolus) or occasionally anaplastic cells (bizarre, irregularly configured, usually with a broad cytoplasm) (Figure 6b). Apoptotic tumor cells are frequently observed. Only sparse small lymphocytes are found. Follicular structures are lacking. The tumor cells have a characteristic phenotype with expression of Bcell markers (CD19, CD20, CD22 and CD79a) and strong expression of bcl-2, MUM-1 and IgM, while bcl-6 and CD10 are not or only weakly expressed. A high proliferation rate (MIB-1; Ki67) is seen. CD21-positive or CD35-positive FDC are lacking. A clonal rearrangement of IgH genes can be detected in most cases. In some cases a loss of expression and function of p16 by chromosomal aberration of 9p21.3 or promoter-hypermethylation, which represents a prognostically unfavorable factor, have been found. In contrast to both CBCL forms with low malignancy, MZL and FCL, the prognosis of DLBL is poor with a 5-year survival rate of on the average 55 % (20– 60 %). Progression with cutaneous and extracutaneous dissemination can occur


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Figure 6: Cutaneous diffuse large B-cell lymphoma, leg type: (a) dermal diffuse infiltrate consisting of (b) cells of predominantly centroblastic and immunoblastic differentiation.

during the course. The appearance of multiple tumors, the location on both legs (involvement of one leg vs. both legs: 5-year survival rate 45 % vs. 36 %; [9]), the loss of expression of p16 (p16 negative vs. positive: 5-year survival rate 43 % vs. 70 %) and an activated apoptosis cascade are prognostically unfavorable markers. For solitary tumor nodes excision and radiotherapy are therapy of first choice, while in multiple lesions and involvement of both legs polychemotherapy in combination with anti-CD20 antibodies (rituximab; Mabthera®) or radioimmunotherapy are indicated [4].

For solitary tumor nodes excision and radiotherapy are therapy of first choice, while in multiple lesions and involvement of both legs polychemotherapy in combination with anti-CD20 antibodies (rituximab; Mabthera®) or radioimmunotherapy are indicated.

Rare cutaneous B-cell lymphomas Cutaneous diffuse large B-cell lymphoma, other, is a very rare form of CBCL, for which only limited data exist in the literature. The disease presents with usually solid nodules with the tumor being located on the leg in one-half of the patients. Tumors have also been reported on the head, trunk and arms. Histologically, infiltrates of blasts are found that in addition to B-cell markers demonstrate expression of bcl-6 (100 %), MUM-1 (67 %), FOX-P1 (72 %) with lack of expression of bcl2. Small CD3+ T cells are dispersed in the infiltrates. The 5-year survival rate is 50


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Figure 7: Classification of body regions (from: [10]).

The cutaneous form of IVBL has a better prognosis as opposed to the systemic form.

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%. In view of poor prognosis similar therapeutic approaches as in DLBL, leg type, are employed. The intravascular large B-cell lymphoma (IVBL) is an intravascular proliferation of neoplastic B cells, which probably can be attributed to a defect of homing receptors of the tumor cells (CD29 = beta 1 integrin; CD54 = ICAM1). A systemic form is differentiated from a cutaneous form of IVBL. The cutaneous form of IVBL has a better prognosis as opposed to the systemic form (5-year survival rate 56 % vs. 33 %). On the skin IVBL manifests with livedo racemosaor panniculitis-like lesions, painful telangiectases or nodular lesions. The systemic form of IVBL is a multi-organ disease that manifests predominantly in small and mid-size vessels of the central nervous system and the skin but also in the lungs and other visceral organs. Clinical symptoms are fever and focal neurological defects. Histology is characteristic with mid-size to large atypical lymphocytes with expression of B-cell markers intraluminally in capillaries, venules, arterioles and small arteries. A T-cell variant of intravascular lymphoma has been described. Differential diagnoses include reactive angioendotheliomatosis, e. g. within the context of subacute bacterial endocarditis, as a reactive concomitant disease and intralymphatic or intravascular histiocytosis in rheumatoid arthritis or following joint replacement with metal implants. In view of the aggressive course of IVBL, polychemotherapy in combination with anti-CD20 antibodies is employed. EBV-associated diffuse large B-cell lymphoma of the elderly has only recently been described and is listed as a subtype of DLBL, NOS in the WHO classification (4th edition, 2008) [6]. This rare lymphoma is characterized by rapidly growing ulcerated nodes in patients above 50 years of age. Tumorogenesis is brought


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into connection with EBV-elicited transformation of B cells in age-related reduction of immune defense. Histologically, a dense infiltrate of large tumor cells of centroblastic, immunoblastic or plasmablastic differentiation is found with expression of B-cell markers (especially CD79a) and bcl-2 as well as MUM-1. The characteristic feature is the detection of EBV transcripts (EBV-RNA; EBER) in tumor cells. The disease is highly malignant with treatment corresponding to that of DLBL, leg type. The very rare forms of CBCL in immunosuppressed patients after organ transplantation or within the context of HIV infection and B-cell lymphoproliferative processes during treatment with methotrexate will not be reviewed in this article [6]. B-cell lymphomas with secondary cutaneous involvement The skin can be affected by infiltrates of a nodal or systemic B-cell lymphoma. Secondary cutaneous involvement usually manifests as multiple nodules and indicates an advanced disease stage. Diagnostic classification is based in addition to the histology of the cutaneous infiltrate primarily on the findings in the lymph nodes and/or bone marrow biopsy and radiological staging. Mantle cell lymphoma constitutes about 10 % of nodal B-cell non-Hodgkin lymphomas. Skin involvement occurs in about 2–6 % of patients, usually as the initial manifestation of dissemination. Macules, papules, plaques and nodular lesions often on the thorax or limbs are seen. Histology usually reveals infiltrates of blastic or centrocytic tumor cells. The expression of cyclinD1 as a result of translocation t(11;14) CCND1-IgH is a diagnostic clue. Secondary skin involvement occurs in about 20 % of patients with precursor B lymphoblastic lymphoma within the context of a leukemic course. The disease preferentially affects children and manifests with purpuric plaques and red-blue nodules. Histologically, a monomorphic infiltration by usually mid-size B lymphoblasts in part with a cobblestone-like growth pattern of tumor cells is observed. The blast-like tumor cells express CD10, CD79a and TdT, but are negative for the B-cell marker CD20. Polychemotherapy in cooperation with hemato-oncologists and pediatricians is indicated. Lymphomatoid granulomatosis is a rare EBV-associated systemic B-cell lymphoproliferative disorder with preferentially extranodal involvement particularly of the lungs, the skin, the central nervous system and the kidneys. Cutaneous involvement is observed in one-half of those affected with multiple papules and subcutaneous, in part ulcerated nodules, folliculitis-like lesions and facial edema being reported. Histologically, angiocentric and angiodestructive infiltrates with necroses are observed in lymphomatoid granulomatosis. The tumor cells express B-cell markers, are EBER (EBV-RNA)-positive and are embedded in an infiltrate of numerous reactive T cells. Treatment consists of polychemotherapy and interferon-␣. Prognosis is variable, with two-thirds of patients dying after several months.

Tumorogenesis is brought into connection with EBV-elicited transformation of B cells in age-related reduction of immune defense.

Mantle cell lymphoma constitutes about 10 % of nodal B-cell nonHodgkin lymphomas. Skin involvement occurs in about 2–6 % of patients, usually as the initial manifestation of dissemination. Secondary skin involvement occurs in about 20 % of patients with precursor B lymphoblastic lymphoma within the context of a leukemic course.

Histologically, angiocentric and angiodestructive infiltrates with necroses are observed in lymphomatoid granulomatosis. The tumor cells express B-cell markers, are EBER (EBV-RNA)positive and are embedded in an infiltrate of numerous reactive T cells.

Conclusions Cutaneous B-cell lymphomas are the second most common form of primary cutaneous lymphomas. Cutaneous follicle center lymphoma and marginal zone lymphoma (of the MALT type) are the two most common forms of CBCL. Both lymphoma entities manifest with nodular lesions and possess an indolent, slowly progressive course with an excellent prognosis despite a high recurrence rate. In contrast, cutaneous diffuse large B-cell lymphoma, leg type, as well as other, rare forms of CBCL have a poorer prognosis, so that early diagnosis should be strived for and in most cases polychemotherapy in combination with anti-CD20 antibodies is indicated. Clinico-pathologic correlation, histology and detailed immunophenotypic and molecular characterization of the tumor cells as well as staging are the central, indispensable measures in the evaluation of CBCL.