Primary cutaneous B-cell lymphoma

Primary cutaneous B-cell lymphoma

Current Diagnostic Pathology (2001) 7, 33d44 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cdip.2000.0051, available online at

618KB Sizes 0 Downloads 15 Views

Current Diagnostic Pathology (2001) 7, 33d44 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cdip.2000.0051, available online at on

Primary cutaneous B-cell lymphoma J. R. Goodlad* and K. HollowoodR * Department of Pathology, Highland Acute Hospitals NHS Trust, Raigmore Hospital, Old Perth Road, Inverness, IV2 3UJ, and RDepartment of Cellular Pathology, Level 1, The John Radcliffe Hospital, Headley Way, Oxford, UK

KEYWORDS B-cell, lymphoma, hyperplasia, skin, classification, Borrelia burgdorferi

Summary Knowledge and understanding of primary cutaneous B-cell lymphoma is ever increasing, not least in the recognition that many have a much better prognosis and require less toxic treatment than morphologically similar lymphomas presenting in lymph nodes. Nevertheless, controversy persists regarding how best to classify primary cutaneous B-cell lymphoma and differentiating benign from malignant B-cell infiltrates in the skin is not always straightforward. This article addresses both these issues and provides a brief overview of recent advances made regarding the aetiology of B-cell lymphoma arising primarily in skin. ^ 2001 Harcourt Publishers Ltd

INTRODUCTION B-cell lymphoma may involve the skin as part of systemic disease or arise primarily within this organ. This article deals mainly with the latter situation. Primary cutaneous B-cell lymphoma (PCBCL) has been defined as B-cell lymphoma confined to the skin at presentation and without evidence of extracutaneous spread for at least 6 months thereafter,1 although for practical purposes localised disease following adequate staging is sufficient. PCBCL constitute approximately 40% of all cases of primary cutaneous lymphoma which, although rare with an estimated annual incidence of 0.5/100000, is the second most common lymphoma arising at extranodal sites.2, 3 Many studies of PCBCL were undertaken prior to widespread acceptance of the Revised EuropeanAmerican Lymphoma (REAL) classification,4 and before the introduction of reliable paraffin-section immunohistochemistry with antigen retrieval and polymerase chain reaction (PCR) techniques for detecting immunoglobulin heavy chain gene rearrangement and chromosomal translocations. Coupled with the relative rarity of PCBCL, these factors contribute to the confusion which often surrounds these lesions. This is compounded by the continued controversy over classification.5d8 Some authors adopt the REAL classification, whilst others advocate a separate classification system devoted solely to primary cutaneous

Correspondence to: JRG. Fax: #44 (0) 1463 705648; E-mail: John. [email protected]

lymphoma, and some remain unhappy with all current classifications.1, 9, 10 As an appropriate classification system is fundamental to the understanding of any disease process the bulk of this article will concentrate on outlining a practical and meaningful approach to classifying PCBCL. From this perspective the often challenging issue of differentiating neoplastic from benign cutaneous B-cell proliferations will be considered followed by a brief update on the aetiopathogenesis of this fascinating group of disorders.

CLASSIFICATION Although the updated Kiel classification recognised mycosis fungoides and Sezary syndrome as distinct forms of lymphoma characterised by cutaneous involvement, all other forms of lymphoma arising in the skin were held equivalent to morphologically similar lesions arising in lymph nodes, which was inaccurate in some cases.11 Considerable progress was made with the advent of the REAL classification, founded on the principle that lymphomas are a group of individual disease entities defined by a constellation of morphological, biological and clinical features.4 Significantly, site of presentation was recognised as a marker for underlying biological differences and it was appreciated that extranodal lymphomas were not always equivalent to their nodal counterparts. As the REAL classification was emerging the European Organisation for Research and Treatment of Cancer (EORTC) cutaneous lymphoma study group was also devising a classification system dedicated solely to primary cutaneous lymphoma. Using the same philosophy as



Table 1 EORTC classification of primary cutaneous lymphoma; B-cell lymphomas *Indolent

*Intermediate RProvisional

Follicle centre cell lymphoma Immunocytoma (marginal zone B-cell lymphoma) Large B-cell lymphoma of the leg Intravascular large B-cell lymphoma Plasmacytoma

* Lymphoma subtypes are grouped according to their expected behaviour. R Provisional entities display characteristic histological features but distinctive clinical presentation and/or outcome has yet to be defined due to the small numbers of cases studied.

employed in the REAL classification, but with greater emphasis on clinical aspects, they compiled a list of what they considered to be well-defined clinicopathological entities occurring in the skin.1 The main categories of PCBCL within the EORTC classification are listed in Table 1. In many respects, the EORTC classification represented a significant step forward in understanding cutaneous lymphoma, not least because it highlighted the relatively indolent nature of many disease entities with morphological features normally associated with aggressive behaviour when encountered at a nodal site. Nevertheless, although the EORTC classification has much to commend it and is a perfectly adequate system for diagnosing and treating primary cutaneous lymphoma, it seems likely that a single classification system based on REAL will prevail, not least because it is the first lymphoma classification to achieve general acceptance on a global scale. Indeed, the forthcoming World Health Organisation (WHO) classification of haematopoeitic and lymphoid neoplasms, which represents an evolution of the REAL classification, begins to accommodate the distinctive features of many primary cutaneous lymphomas.12 This article adopts a similar approach and will use terminology consistent with the REAL/WHO classification whilst incorporating the clinical findings of the EORTC group to highlight lymphoma subtypes which are biologically distinct when they occur primarily in the skin.

Follicular lymphoma The entity defined as primary cutaneous follicle centre cell lymphoma (PCFCCL) in the EORTC classification comprises a group of lymphomas with a variable histological appearance, but most with a diffuse large cell morphology and lack of CD10 expression.1 This entity does not equate with follicular lymphoma (FL) in the REAL/ WHO classification, the latter defined as a lesion

displaying CD10 positivity and possessing at least a partly follicular growth pattern.4, 12 Few, if any such lesions, are included in the EORTC category of primary cutaneous follicle centre cell lymphoma, the majority of which would be classified as diffuse large B-cell lymphoma and a minority as marginal zone lymphoma using REAL/ WHO criteria.1, 13d15 Follicular lymphoma as described in the REAL/ WHO classification undoubtedly does occur primarily in the skin, although there are only a few studies of such lesions.16d18 Although one of these studies suggested that FL is the most common subtype of PCBCL, many of the patients in that study did not undergo bone marrow biopsy, meaning secondary involvement of the skin by disseminated lymphoma was not excluded entirely.17 In our experience, primary cutaneous FL is rare. In an on-going study of PCBCL registered with the Scotland and Newcastle Lymphoma Group (SNLG), only four of the first 50 cases were of follicular type. Others also seem to encounter primary cutaneous FL infrequently.19 We confine the diagnosis of FL to those cases which have at least in part a follicular architecture.

Clinical features Most cases arise in the head and neck with scalp being a favoured site although other body sites may be affected.16d18 The clinical course is generally indolent with long-term survival the norm despite a relatively high recurrence rate.16d18 Radiotherapy is probably the treatment of choice for localised lesions.

Pathological features The lymphoid infiltrate often involves the deep dermis and subcutaneous fat. Unlike nodal FL, it is our experience that the neoplastic follicles may be widely spaced in some cases, separated by a prominent population of reactive interfollicular cells, many of which are of T-lineage (Fig. 1). In some cases they assume a large irregular configuration. The neoplastic follicles comprise an admixture of centroblasts and centrocytes. There is no zonation and mantles are generally poorly formed or absent (Fig. 1). All grades of follicular lymphoma as defined by the Working-Formulation16 or Mann and Berard grading17, 18 may be encountered. Tingible body macrophages and mitotic figures are few in number in low grade lesions but more frequent in high grade FL. In some cases a sizeable diffuse component comprising an admixture of centrocytes and centroblasts may be present but follicular structures are always identifiable.

Immunophenotype/genetics Antibodies to CD21 highlight follicular dendritic cells within the follicles; these must be present for a nodule of


35 follicle centre cells.18, 19 Another reported bcl-2 positivity in 7 out of 15 cases,17 although this was the study in which the possibility of secondary skin involvement was not completely excluded. Nevertheless, even this higher figure is significantly lower than that seen in nodal follicular lymphoma. This finding is mirrored in the fact that t(14;18) is undetectable in the majority of cases in some studies and all cases in others.17d19 Thus, primary cutaneous FL may well be pathogenetically and biologically distinct from its nodal counterpart.

Marginal zone B-cell lymphoma Figure 1 A case of primary cutaneous follicular lymphoma showing widely spaced follicles with a monotonous appearance and poorly formed mantles.

Figure 2 CD10 immunostaining of the same case as in Fig. 1 showing positivity of the follicle centre cells and some interfollicular lymphocytes.

lymphocytes to be considered a true follicle.18 In all cases the follicle centre cells express CD20.18 All cases should react with antibodies to either CD10 (Fig. 2) or bcl-6, and the majority stain positively with both.17, 18 Interfollicular CD10 positive lymphocytes are also commonly seen.18 Reports of a uniform lack of CD10 expression in an early study can be attributed to the use of frozen section immunohistochemistry, a technique with a low sensitivity and subject to difficulties in interpretation.16 Although occasional CD10 negative cases may still be encountered, if both CD10 and bcl-6 are lacking, the lymphoma is likely to be of some other type. The neoplastic lymphocytes do not react with antibodies to CD5, CD43 or cyclin-D1 but a proportion may express CD23. Staining with MIB-1 generally reveals a low proliferation fraction.18 The proportion of cases expressing bcl-2 is still a matter of debate. Some recent studies described an absence of detectable protein in all cases despite unequivocal evidence of monoclonality within the population of

Marginal zone B-cell lymphoma (MZL) is the term employed by the REAL classification for the group of lymphomas originally described as arising from mucosa associated lymphoid tissue.4 These lesions are held to be distinct from morphologically similar lymphomas arising in the spleen and lymph nodes and this is reflected in the forthcoming WHO classification where extranodal marginal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type is the preferred terminology.12 Extranodal MZL has been described in a variety of extranodal locations,20 although skin was one of the last sites at which primary occurrence was documented and only a few series have been published to date.21d26 This is probably attributable to the fact that identical lesions were already well recognised in the skin under the heading of primary cutaneous immunocytoma, so-called because of the lymphoplasmacytoid appearance of the constituent cells.27, 28 Although the authors of the EORTC classification acknowledged that many cases of primary cutaneous immunocytoma shared identical features with MZL, they preferred to retain the former terminology in their classification.29 They argued that primary cutaneous immunocytoma was a well defined and recognised clinicopathological entity, whereas the term MZL was employed differently by different authors to describe all small PCBCL, to encompass all CBCL, or to define an entity distinct from cutaneous immunocytoma.29 While these criticisms of the indiscriminate use of MZL may have an element of validity in some instances, they are easily resolved by adopting the forthcoming WHO criteria which restricts the use of extranodal MZL to infiltrates composed mostly of small lymphocytes.12 This includes all cases previously reported as primary cutaneous immunocytoma and some examples of PCFCCL where the neoplastic infiltrate is diffuse and predominantly of small cell type. The cases described by Schmid et al under the rubric of ‘cutaneous follicular lymphoid hyperplasia with monotypic plasma cells’ are also almost certainly examples of extranodal MZL.30 We agree with others that the term primary cutaneous immunocytoma should be dropped since there is potential for confusion



with what haematopathologists generally recognise as immunocytoma, namely a lymphoplasmacytic lymphoma which is usually disseminated at presentation and associated with Waldenstrom’s macroglobulinaemia.31

Clinical features Primary cutaneous MZL commonly presents as red or red/purple papules, nodules or tumours which may have an erythematous halo, or as infiltrated erythematous plaques.22, 23, 25d28 Despite early reports suggesting a preference for the upper extremities,27 later studies indicated that the trunk and head and neck are equally or more likely to be involved at presentation.21d23, 25, 26, 30 Lesions are often multiple and involvement of more than one skin area is not uncommon.22, 26, 27, 30 Spontaneous regression has been documented in rare cases,27 and surgical excision appears to be effective in some instances,22, 25 but radiotherapy is probably the treatment of choice. A high percentage of patients suffer relapses which are often multiple but almost always confined to (sub)cutaneous sites. Despite this, prognosis is excellent with long-term survival the norm, although dissemination to other extranodal and nodal sites does occur in rare cases.22, 23, 25, 26

Pathology Infiltrates are usually nodular with a perivascular and periadnexal distribution, although some lesions may be predominantly diffuse. Involvement of the subcutaneous fat is common. Reactive germinal centres are typically present,24 the neoplastic infiltrate surrounding these structures in a marginal zone pattern or forming diffuse sheets between residual follicles (Fig. 3). The malignant lymphocytes are of intermediate size with relatively abundant pale staining or clear cytoplasm and round

Figure 4 (a) Primary cutaneous marginal zone lymphoma showing a diffuse infiltrate of monocytoid cells with scattered blasts. (b) Primary cutaneous marginal zone lymphoma showing prominent plasmacellular differentiation.

(monocytoid cells) or cleaved (centrocyte-like cells) nuclei (Fig. 4A). Scattered blast cells are invariably present. Plasma cells are seen in the majority of cases, and are often arranged around the periphery of nodular lymphoid infiltrates or in a subepidermal location. Eosinophils may also frequently be present. Lymphoepithelial lesions are uncommon, unlike MZL at other sites. Cases described as immunocytoma represent a variation of this picture27, 28 in which there is prominent lymphoplasmacytoid differentiation (Fig. 4B).


Figure 3 A case of primary cutaneous marginal zone lymphoma showing a diffuse infiltrate with residual reactive germinal centres.

The neoplastic lymphocytes are CD20 positive except where they show significant plasmacellular differentiation, in which case they are better identified with antibodies to CD38 or CD79a. They do not express CD5, CD10, cyclin-D1 or bcl-6 but in a minority of cases may react with antibodies to CD23 and/or CD43.26 Almost all cases are bcl-2 positive. Little information is available regarding cytogenetic abnormalities in this group of lymphomas. Trisomy 3,

PRIMARY CUTANEOUS B-CELL LYMPHOMA a relatively common finding in extranodal MZL at other sites, has been described in a small number of cases but there are no studies currently published investigating the frequency of t(11;18) or t(1;14), the other consistently reported cytogenetic abnormalities.20, 32

Diffuse large B-cell lymphoma In the REAL classification most diffuse large B-cell lymphomas (DLBCL) are composed of variable proportions of centroblasts and centrocytes, although large cleaved, multilobated and anaplastic cells may form part or all of the lesion.4 All cases of diffuse large B-cell lymphoma of the leg, as defined by the EORTC classification would be subsumed under this heading, as would the majority of PCFCCL,5 most of which have a diffuse large cell morphology (Table 1).1, 13, 14 The small number of cases reported as T-cell rich large B-cell lymphoma are also best included in this group, as occurs at other sites.33, 34 Most cases of Crosti’s reticulohistiocytoma of the dorsum probably also fall within this category although some may represent primary cutaneous MZL or primary cutaneous FL.35 Although omitted from the REAL classification, intravascular large B-cell lymphoma is included as a provisional entity in the EORTC classification and is referred to as a subtype of DLBCL in summaries of the forthcoming WHO classification.1, 12 It will be considered separately at the end of this section. The proposal to amalgamate PCFCCL and DLBCL of the leg into one subtype of lymphoma, namely DLBCL, has been the subject of considerable discussion. The well-rehearsed arguments can be summarised as follows. Proponents of the EORTC classification maintain that PCFCCL and DLBCL of the leg are distinct clinicopathological entities.6, 29 PCFCCL, as defined in the EORTC classification, occur predominantly on the head and trunk and have an excellent prognosis despite their diffuse large cell morphology, with radiotherapy being the treatment of choice.1, 36 On the other hand, DLBCL of the leg occur in a more elderly population with a female predominance, have a much higher relapse rate and more unfavourable long term survival; chemotherapy is the optimum treatment.1, 37 They argue that if both entities are grouped together under the heading of DLBCL, the group of PCFCCL will be overtreated, since the standard therapy for even stage I DLBCL is multiagent chemotherapy with or without radiotherapy.6, 29, 38 They also point to an independent study by the French Cutaneous Lymphoma group which appears to corroborate their findings, and immunohistochemical studies that support the concept of DLBCL of the leg as a distinct clinicopathological entity.39, 40 Those who argue against adoption of the EORTC classification maintain that the behaviour of a lymphoma

37 is unlikely to be determined by whether it occurs above or below the waist. They suggest that the poor prognosis of DLBCL of the leg is most likely related to the frequent presence of multiple lesions at presentation, and cite cases of DLBCL presenting with multiple lesions on the scalp and which have an equally aggressive clinical course, in support of this argument.31, 41, 42 This is obviously an area meriting further study in order to resolve the main prognostic indicators for this group of tumours with a diffuse large-cell morphology. Nevertheless, nomenclature consistent with the REAL classification can still be applied provided the clinical findings of the EORTC group are taken into account to ensure patients are appropriately managed.

Clinical features Primary cutaneous DLBCL arises on the trunk, head and neck and lower legs.36, 37, 41d43 The upper extremities seem to be rarely involved. Most lesions present as tumours or papulonodules which may be surrounded by a slightly infiltrated erythematous halo, the latter often preceding the development of the former. Lesions on the upper body are frequently solitary or localised to a circumscribed area, whereas those on the leg more often affect multiple discrete sites.37 Despite a relatively high recurrence rate the prognosis is generally very favourable with 5-year survival rates up to and in excess of 95% quoted.1, 36 Radiotherapy is the treatment of choice for single/localised lesions on the head and trunk, whereas multi-agent chemotherapy is preferred for multiple lesions at separate sites, whether or not these include the leg.1, 36 Whether solitary lesions arising on the leg require aggressive multi-agent chemotherapy or can be adequately managed by radiotherapy remains to be determined. Cases described as T-cell rich large B-cell lymphoma share the characteristic indolent behaviour of other DLBCL when limited to a single site.33, 34 There is also a recent description of DLBCL occurring as a recurrence in three cases of MZL and in contrast to many previous reports all three patients died of lymphoma.42

Pathological features Most cases show a diffuse infiltrate extending from the upper dermis to subcutaneous fat, although early lesions may display a periadnexal and perivascular distribution superficially.13, 17, 41 A grenz zone is usually present. The infiltrate usually has a polymorphic appearance comprising an admixture of centroblasts, immunoblasts and large centrocyte-like (cleaved) cells, the former characteristically forming the majority (Fig. 5A). Cells with multilobated nuclei and anaplastic cells may also be present in varying numbers. Lesions occurring on the leg are said to often have a monotonous appearance,


CURRENT DIAGNOSTIC PATHOLOGY further studies are required to confirm or refute this hypothesis.40 Cases which can be reliably identified as possessing a diffuse large cell morphology in the literature uniformly lack t(14;18) when investigated by PCR, despite expression of CD10 or bcl-6.17, 44

Intravascular large B-cell lymphoma

Figure 5 (a) Primary cutaneous diffuse large B-cell lymphoma comprising a polymorphic population of lymphocytes including large cleaved cells. (b) Primary cutaneous diffuse large B-cell lymphoma from the leg composed predominantly of round cells, many with the appearance of immunoblasts.

Intravascular large B-cell lymphoma is the currently preferred term for a distinctive type of lymphoma previously described under a variety of names including malignant angioendotheliomatosis, angiotropic lymphoma and intravascular lymphomatosis. It almost invariably affects only extranodal sites and is characterised by an accumalation of large atypical lymphocytes within the lumens of small to intermediate-sized blood vessels of the affected tissue. Any organ or system may be involved but most commonly it is central nervous system and skin. Cutaneous manifestations usually take the form of erythematous or violaceous nodular subcutaneous masses which may ulcerate. Trunk and extremities are favoured sites.45 Cases initially confined to the skin, and fulfilling criteria for PCBCL, have rarely been reported and a more favourable clinical course has been suggested when this is the case.1, 46, 47 However, the numbers are too few to draw any meaningful conclusions, especially as some such cases progress relatively rapidly to disseminated disease and death.48

Plasmacytoma consisting almost entirely of large round cells, either centroblasts or immunoblasts (Fig. 5B).37 Macrophages are often present but eosinophils, neutrophils and plasma cells are not commonly seen. Small T-cells may be present in large numbers in some cases, accounting for reports of cutaneous T-cell rich large B-cell lymphoma.33, 34

Neoplastic proliferations of plasma cells occur in plasma cell leukaemia, multiple myeloma, solitary myeloma of bone and extramedullary plasmacytoma. Involvement of the skin is uncommon but most often occurs in disseminated myeloma.49, 50 Extramedullary plasmacytoma restricted to the skin, i.e. primary cutaneous plasmacytoma, is exceedingly rare, and many previously reported cases are more likely examples of MZL lying at the ‘immunocytoma’ end of the spectrum.

Immunophenotype/genetics Immunohistochemical studies using modern monoclonal antibodies suitable for paraffin sections and antigen retrieval are few in number. In all cases the neoplastic lymphocytes express CD20 and appear to lack CD5 and cyclin-D1, although a significant proportion co-express CD10 and/or bcl-6.17 In a minority of cases CD43 and/or CD30 expression may be seen.41 Bcl-2 positivity is seen in a variable number of cases.17, 40, 42, 44 It has been proposed that bcl-2 expression is largely restricted to lesions occurring on the leg and that presence of the protein is associated with a poor prognosis, although

Clinical features Most patients present with solitary or multiple violaceous or red nodules.1, 49d53 It is difficult to be certain of the prognosis in this group of neoplasms, due to the paucity of cases in the literature. Some authors suggest that even when restricted to the skin the outcome is likely to be worse than for extramedullary plasmacytoma at other sites with a disease related mortality of around 40%,54 whereas the EORTC experience seems to indicate an excellent prognosis.1 Progressive disease may be characterised by dissemination to bone marrow or

PRIMARY CUTANEOUS B-CELL LYMPHOMA may be restricted to the skin. Surgery or radiotherapy may be adequate treatment for localised disease but chemotherapy should be considered when multiple skin lesions are present.1, 54

Pathology The skin is involved by nodular or diffuse infiltrates consisting almost entirely of plasma cells. Multinucleate forms may be present as may nuclear atypia and mitotic figures. By definition there must be no admixture of neoplastic lymphocytes, a feature which discriminates these lesions from MZL with prominent plasmacytic differentiation.

39 disease.57, 58 Of the only two possible cases of primary cutaneous mantle cell lymphoma reported,57 one remained confined to the skin with cutaneous recurrences for 3 years whilst the other developed generalised lymphadenopathy and massive hepatosplenomegaly within 2 years of diagnosis. Although the neoplastic lymphocytes were CD5 positive in both cases, monoclonal plasma cells were also present, a rarely described phenomenon in mantle cell lymphoma. As the study was performed before antibodies to cyclin D1 became readily available, a definite diagnosis of mantle cell lymphoma cannot be confirmed in these cases. This is especially true given the presence of monoclonal plasma cells and the recent description of rare cases of CD5 positive MZL occurring at extranodal sites.59

Immunophenotype/genetics The neoplastic plasma cells typically do not express CD20 or CD45 but react with antibodies to CD38 and CD79a.

B-lymphoblastic lymphoma B-lymphoblastic lymphoma most commonly occurs in children and young adults and is characterised by an infiltrate of lymphoblasts which are slightly larger than small lymphocytes but smaller than the blast cells of large B-cell lymphoma. They possess round or convoluted nuclei with fine chromatin and inconspicuous nucleoli and small amounts of basophilic cytoplasm. They are more likely to express CD79a than CD20 and may coexpress CD10. Demonstration of TdT is useful in differentiating B-lymphoblastic lymphoma from neoplasms of peripheral B-cells.4 T-lymphoblastic lymphoma is far more common than B-lymphoblastic lymphoma but the majority of cases involving the skin are of B-lineage, suggesting a particular affinity of B-lymphoblastic lymphoma for this site.55, 56 Cutaneous involvement may be the presenting feature of B-lymphoblastic lymphoma but systemic disease is usually also present when staging is undertaken. The only reported examples possibly confined to the skin lacked follow-up and cannot be considered as true PCBCL.55, 56

Mantle cell lymphoma Mantle cell lymphoma is a lymphoma of small to medium sized lymphocytes with irregular or cleaved nuclei displaying a dispersed chromatin pattern and small nucleoli.4 The lymphocytes express CD20, CD5 and often CD43 but not CD10 or CD23. Positive nuclear staining with antibodies to cyclin D1 confirms the diagnosis. Mantle cell lymphoma has been described in the skin but most cases are manifestations of systemic

Lymphomas not yet recognised arising primarily in skin There are no convincing cases of B-cell small lymphocytic lymphoma or Burkitt’s lymphoma yet described arising primarily in the skin although both may involve this organ secondarily.

Unclassifiable cases Although there has been considerable progress in the recognition of specific subtypes of PCBCL there still remain a significant minority that do not fit into any of the categories detailed above. In our experience there are two common types that do not fulfil the criteria for FL, MZL or DLBCL. The first consists of a diffuse infiltrate of centrocytelike cells, small B-lymphocytes and scattered blasts admixed with a significant, diffuse infiltrate of small Tcells. Unlike MZL there is no monoclonal plasma cell infiltrate or residual FDC networks. The diagnosis of lymphoma relies upon demonstration of light chain restriction or immunoglobulin gene rearrangement in conjunction with the clinical picture. Although such tumours would be classified PCFCCL in the EORTC scheme we would not classify them as FL. There is currently insufficient immunophenotypic/genetic data (e.g. CD10 positivity) to ascertain whether these cases represent a diffuse variant of FL or perhaps MZL in which all the follicular networks have been destroyed. The second type of PCBCL that we find difficult to classify is that which consists of irregular, sometimes indistinct nodules of large B-cellseoften a combination of cells resembling centroblasts, large centrocytes and immunoblastseset in a background of small Band T-cells. As noted by Norton60 it shows some resemblance to the nodal condition of progressive transformation of germinal centres (PTGC). However, unlike PTGC or grade 3 FL, which they may also

40 resemble, these nodules do not possess FDC and the large cells do not express CD10.

DIFFERENTIATING BENIGN FROM NEOPLASTIC CUTANEOUS B-CELL INFILTRATES Background B-cell cutaneous lymphoid hyperplasia (B-CLH) is the preferred term for a group of reactive B-cell infiltrates previously described under a variety of synonyms, including lymphadenosis benigna cutis, lymphocytoma cutis, Spiegler-Fendt sarcoid and B-cell pseudolymphoma. This, together with the fact that many previously described cases of B-CLH would be reclassified as PCBCL if current criteria and techniques were applied, renders the literature on this subject potentially confusing. Original studies defining histological features for BCLH selected patients on the basis of clinical criteria. At this time all cutaneous lymphomas were thought to be manifestations of disseminated nodal disease with an attendant poor prognosis. A lack of systemic spread for 5 years after the initial skin biopsy was taken as the decisive factor in defining a benign lymphoproliferation. Based on this distinction a variety of criteria were defined which were held to discriminate B-CLH from cutaneous B-cell lymphoma.61, 62 Following the advent of immunohistochemistry for light chain restriction it became apparent that many cases of cutaneous B-cell lymphoma, as defined by immunohistochemical demonstration of monoclonality, had a very good prognosis and could remain confined to the skin for long periods of time.15, 16, 43 Thus, the criteria originally reported as specific for B-CLH also applied to a considerable proportion of PCBCL. As this subject has been revisited many of the histological features historically considered indicative of one process or another have been largely discredited.24, 63 For example ‘top-heavy’ and ‘bottom-heavy’ infiltrates can occur in either B-CLH or PCBCL, and in one recent study germinal centres were seen more frequently in primary cutaneous MZL than B-CLH.24, 63 The distinction of benign from malignant B-cell infiltrates in the skin has also been hindered by a lack of a consensus classification meaning that like has not always been compared with like. Nevertheless, with the use of modern immunohistochemical and molecular techniques and a better understanding of the lymphoma subtypes which occur primarily in the skin a spectrum of reactive cutaneous B-lymphoproliferations can be recognised in the skin and differentiated from the particular subtype of PCBCL with which they share similar features.


B-cell cutaneous lymphoid hyperplasia Clinical features In a minority of cases a precipitating stimulus can be found for cutaneous B-cell hyperplasia. Reported causes include Borrelia burgdorferi infection, cutaneous vaccination, antigen hyposensitisation injection, acupuncture, drugs, tatoo pigment and gold contact hypersensitivity. The vast majority of cases are idiopathic.64 Most patients present with red to violaceous papules or tumours, usually on the head and neck or trunk, although the limbs can also be involved.63 The lesions are often solitary or if multiple confined to one anatomical area, but occasionally multiple body sites are affected.63 They may persist for several months or even years but tend to resolve spontaneously. None of the clinical features allows reliable distinction from PCBCL.

Pathology The histological appearances are varied and overlap considerably with some cases of PCBCL. Infiltrates may be nodular or diffuse and may be present throughout the dermis or preferentially involve the upper (‘top-heavy’) or lower (‘bottom-heavy’) dermis, although a ‘top-heavy’ distribution is more commonly seen. In many cases germinal centres with well-formed mantles are present, separated by a mixed infiltrate rich in small Tlymphocytes with an admixture of scattered immunoblasts of T- or B-lineage. Small blood vessels may be prominent in the interfollicular area. In some cases eosinophils, histiocytes and polytypic plasma cells are present. In other instances no reactive follicles are identified although the infiltrate tends to retain a polymorphous appearance.24, 63

Differentiation from PCBCL Distinction of B-CLH from PCBCL displaying a diffuse large cell morphology is not usually difficult. The main problems lie in differentiating B-CLH from primary cutaneous MZL, follicular lymphoma and T-cell rich large B-cell lymphoma. These difficulties occur irrespective of whether the lymphoma is primarily or secondarily involving the skin.

Marginal zone B-cell lymphoma Many of the features described in MZL are also recognised in B-CLH. However, collections of marginal zone cells, sheets of plasma cells, Dutcher bodies and a B:T-cell ratio of greater than 3:1 (excluding germinal centre cells), all point towards a diagnosis of the former.24 Aberrant expression of CD43 by B-lymphocytes is another feature in favour of malignancy.65



Follicular lymphoma

Figure 6 A case of primary cutaneous marginal zone lymphoma with prominent plasmacellular differentiation. Immunohistochemistry demonstrates monoclonality with a vast excess of lambda positive plasma cells (a), over kappa positive ones (b). Many of the neoplastic plasma cells are distributed at the periphery of nodules of lymphocytes.

Demonstration of monoclonality by immunohistochemical methods is also indicative of lymphoma. When plasma cells are numerous and form part of the neoplastic infiltrate this is usually straightforward, as cytoplasmic staining is easily recognised (Fig. 6). Perinuclear light chain restriction is much harder to demonstrate when lymphocytes form the bulk of the neoplastic infiltrate but is worth attempting in all cases. Molecular techniques, either southern blotting (if fresh tissue is available) or PCR, can also be employed to detect clonal immunoglobulin gene rearrangement. However, the results of such studies, particularly when PCR is used, should be interpreted with caution since clonal immunoglobulin gene rearrangement has been demonstrated in a small percentage of cases of B-CLH which do not progress to overt lymphoma.66d69 In addition, clonal rearrangements of the immunoglobulin gene can only be identified in a significant number of PCBCL by using complex PCR techniques utilising primers to the framework 1 region of the immunoglobulin heavy chain gene or leader sequence primers.70

Morphological distinction of the neoplastic follicles in follicle centre lymphoma from reactive follicles present in some examples of B-CLH can be achieved by application of the same criteria as used in lymph nodes.71 Thus, neoplastic follicles tend to have a monotonous appearance, lack well-defined mantles, show no differentiation into light and dark zones, and have few tingible body macrophages or mitotic figures, although tingible body macrophages and mitotic figures may be numerous when the FL displays grade 3 morphology. No one single feature can be relied upon and often the distinction may not be clear cut, in which case ancillary studies may be helpful. Immunohistochemical detection of bcl-2 expression by follicle centre cells, or detection of t(14:18) by PCR or southern blot, is indicative of lymphoma44, 72 but is much less useful in skin than lymph nodes due to the high proportion of primary cutaneous FL which lack the translocation and are bcl-2 negative. When bcl-2 is not expressed demonstration of MT2 in a few cases may be useful.72 In addition, although both reactive and neoplastic follicle centre cells express CD10, the presence of clusters of CD10 positive B-cells in interfollicular areas is highly suggestive of lymphoma.18, 73 As with MZL, demonstration of light chain restriction or clonal immunoglobulin gene rearrangement is useful if achieved, given the caveats discussed above.

T-cell rich large B-cell lymphoma In T-cell rich large B-cell lymphoma the neoplastic population of B-lymphocytes may be difficult to identify against a background of numerous reactive T-cells. Even when recognised, distinction from blasts seen in some cases of B-CLH may be difficult and in many instances demonstration of light chain restriction or clonal immunoglobulin gene rearrangement must be relied upon.

Indeterminate cases Despite careful attention to detail and application of a range of ancillary studies the biological potential of a proportion of cutaneous B-cell infiltrates will remain unresolved following pathological examination. In such instances it is of prime importance to exclude the possibility that one is dealing with disseminated B-cell lymphoma involving the skin secondarily. Thus, if there is a suspicion of lymphoma it is reasonable to request staging studies are performed since the presence of nodal disease would have major therapeutic implications. If negative, then the indolent nature of PCBCL permits a wait-and-watch policy. Rebiopsy of the original lesion should it progress, or of any subsequent lesion which develops may then permit a more definitive diagnosis.



AETIOLOGY Evidence in support of a link between infection with Borrelia burgdorferi , the causative agent of Lyme disease, and PCBCL has slowly emerged over a number of years. Early studies described cases of PCBCL arising at sites of acrodermatitis chronica atrophicans, a cutaneous manifestation of Lyme disease, or in patients with raised antibody titres to the organism.74, 75 More recently B. burgdorferi has been identified within lesional skin of patients with PCBCL either by culture or PCR.76d78 In our study we identified DNA from the B. burgdorferi flagellin gene in seven out of 20 cases of PCBCL from the Highlands of Scotland, but only one of 40 controls, demonstrating a statistically significant relationship for the first time.78 An SNLG study is currently underway to see if this association is reproducible in other parts of the country. In two of these patients we were also able to demonstrate B. burgdorferi in biopsies of erythematous skin rashes which preceded the development of overt cutaneous B-cell lymphoma. Both were characterised histologically by a dense perivascular lymphoid infiltrate containing collections of transformed B-cells, and in one case this B-cell population appeared to be clonally related to the MZL which developed subsequently.79 These findings indicate that B. burgdorferi -associated PCBCL arises from chronically stimulated lymphoid tissue acquired in response to B. burgdorferi infection in a manner analogous to gastric MZL and Helicobacter pylori infection. This similarity extends to cases of PCBCL which have resolved following antibiotic therapy to eradicate B. burgdorferi. 76, 80 A second infective agent, human herpes virus-8, has also been implicated recently as a possible aetiological agent in a very small number of cases of PCBCL.81




Thorough staging, including bone marrow examination, is required in all cases of cutaneous B-cell lymphoma to exclude the possibility of systemic disease. Follicular lymphoma does occur primarily in the skin but is defined differently from the cases of primary cutaneous follicle centre cell lymphoma described in the European Organisation for Research and Treatment of Cancer classification. Bcl-2 staining cannot be relied upon to differentiate benign from neoplastic follicles in the skin. When a diagnosis of primary cutaneous diffuse large B-cell lymphoma is rendered on a pathology report the indolent nature of the disease and optimum therapy for localised lesions (radiotherapy) must be emphasised to avoid overtreatment with potentially harmful chemotherapy.




Further studies are required to determine the relative proportions of bcl-2 negative and positive follicular lymphoma (FL) in the skin and whether they represent separate clinicopathological entities. Studies are also required to investigate the underlying cytogenetic abnormalities in cutaneous FL without t(14;18) and to determine if a diffuse variant of FL exists. Studies of prognostic factors, such as currently in progress under the auspices of the European Organisation for Research and Treatment of Cancer, are required to determine what clinical (e.g. site), morphological (e.g. round cell vs cleaved cell) immunophenotypic (e.g. bcl-2 expression), or genetic [e.g. using microarray technology as recently applied to nodal diffuse large B-cell lymphoma (DLBCL)]82 features are related to prognosis in DLBCL.

REFERENCES 1. 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 Organisation for Research and Treament of Cancer. Blood 1997; 90: 354d371. 2. Isaacson P G, Norton A J. Cutaneous lymphoma. In: Extranodal Lymphomas. Edinburgh: Churchill Livingstone, 1994: 131d191. 3. Weinstock M A, Horn J W. Mycosis fungoides in the United States: increasing incidence and descriptive epidemiology. JAMA 1988; 260: 42d46. 4. Harris N L, Jaffe E J, Stein H et al. A revised European-American Classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361d1392. 5. Russell-Jones R. Primary cutaneous B-cell lymphoma: how useful is the new European Organization for Research and Treatment of Cancer (EORTC) classification? Br J Dermatol 1998; 139: 945d949. 6. Willemze R, Meijer C J L M. Classification of primary cutaneous B-cell lymphomas: EORTC classification or REAL classification. Br J Dermatol 1999; 141: 350d352. 7. Slater D N. Priamry cutaneous B-cell lymphoma: how useful is the new European Organization for Research and Treatment of Cancer classification? Br J Dermatol 1999; 141: 352d353. 8. Sterry W. Classification of primary cutaneous B-cell lymphomas. Br J Dermatol 1999; 141: 353d354. 9. Sander C A, Kind P, Kaudewitz P, Raffeld M, Jaffe E S. The Revised European-American Classification of Lymphoid Neoplasms (REAL): a new perspective for the classification of cutaneous lymphomas. J Cutan Pathol 1997; 24: 329d341. 10. Slater D N. Is the WHO classification suitable for skin lymphoma? Histopathology 2000: 37; 282d283. 11. Stansfeld A G, Diebold J, Noel H et al. Updated Kiel classification for lymphomas. Lancet 1988; i: 292d293. 12. Harris N L, Jaffe E S, Diebold J et al. The World Health Organization classification of neoplastic diseases of the haematopoeitic and lymphoid tissues; a report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Histopathology 2000; 36: 69d86.


13. Willemze R, Meijer C J L M, Scheffer E et al. Diffuse large cell lymphomas of follicular center cell origin presenting in the skin. A clinicopathologic and immunologic study of 16 patients. Am J Pathol 1987; 126: 325d333. 14. Pimpinelli N, Santucci M, Bosi A et al. Primary cutaneous follicular centre-cell lymphomaea lymphoproliferative disease with a favourable prognosis. Clin Exp Dermatol 1989; 14: 12d19. 15. Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases. Cancer 1991: 67; 2311d2326. 16. Garcia C F, Weiss L, Warnke R A, Wood G S. Cutaneous follicular lymphoma. Am J Surg Pathol 1986; 10: 454d463. 17. Yang B, Tubbs R R, Finn W, Carlson A, Pettay J, Hsi E D. Clinicopathologic reassessment of primary cutaneous B-cell lymphomas with immunophenotypic and molecular characterization. Am J Surg Pathol 2000; 24: 694d702. 18. Cerroni L, Arzberger E, Putz B et al. Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Blood 2000: 95; 3922d3928. 19. Child F J, Calonje E, Woolford A et al. Histopathological and molecular features of primary cutaneous B-cell lymphoma (PCBCL). Br J Dermatol 2000: 143 (Suppl. 57); 31d32. 20. Isaacson P G. Gastric MALT lymphoma: from concept to cure. Annals Oncol 1999; 10: 637d645. 21. Bailey E M, Ferry J A, Harris N L, Mihm M C, Jacobsen J O, Duncan L M. 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: 1011d1023. 22. Cerroni L, Signoretti S, Hofler 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: 1307d1315. 23. Fouchardiere A de la, Balme B, Chouvet B et al. Primary cutaneous marginal zone lymphoma: a report of 9 cases. J Am Acad Dermatol 1999; 41: 181d188. 24. Baldassano M F, Bailey E M, Ferry J A, Harris N L, Duncan L M. Cutaneous lymphoid hyperplasia and cutaneous marginal zone lymphoma. Comparison of morphologic and immunophenotypic features. Am J Surg Pathol 1999; 23: 88d96. 25. Tomaszewski M-M, Abbondanzo S L, Lupton G P. Extranodal marginal zone B-cell lymphoma of the skin: a morphologic and immunophenotypic study of 11 cases. Am J Dermatopathol 2000; 22: 205d211. 26. Goodlad J R, Dunn-Walters D, Davidson M M et al. Primary cutaneous marginal zone lymphoma of the skin and its relationship to Borrelia burgdorferi infection. J Pathol 1999; 189 (Suppl.); 20A. 27. Rijlaarsdam J U, Van der Putte S C J, Berti E et al. Cutaneous immunocytomas: a clinicopathologic study of 26 cases. Histopathology 1993; 23: 117d125. 28. LeBoit P E, McNutt S, Reed J A, Jacobson M, Weiss L M. Primary cutaneous immunocytoma. A B-cell lymphoma that can easily be mistaken for cutaneous lymphoid hyperplasia. Am J Surg Pathol 1994; 18: 969d978. 29. Willemze R, Meijer C J L M. Classification of cutaneous lymphomas: crosstalk between pathologist and clinician. Curr Diagn Pathol 1998; 5: 23d33. 30. 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: 12d20. 31. Sander C A, Flaig M J, Kaudewitz P, Jaffe E S. The Revised EuropeanAmerican Classification of Lymphoid Neoplasms (REAL): a preferred approach for the classification of cutaneous lymphomas. Am J Dermatopathol 1999; 21: 274d278. 32. Baldassano M F, Harris N L, Duncan L M. Trisomy 3 in cutaneous marginal zone lymphoma. J Cutan Pathol 1999; 26: 459.


33. Arai E, Sakurai M, Nakayama H, Morinaga S, Katayama I. Primary cutaneous T-cell-rich B-cell lymphoma. Br J Dermatol 1993; 129: 196d200. 34. Sander C A, 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: 101d108. 35. Berti E, Alessi E, Caputo R, Gianotti R, Delia D, Vezzoni P. Reticulohistiocytoma of the dorsum. J Am Acad Dermatol 1988; 19: 259d272. 36. Rijlaarsdam J U, Toonstra J, Meijer O W M, Noordijk E M, Willemze R. Treatment of primary cutaneous B-cell lymhpomas of follicle center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 1996; 14: 549d555. 37. Vermeer M H, Geelen F A M J, van Haselen C W 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: 1304d1308. 38. Miller T P, Dahlberg S, Cassady J R et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localizad intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998; 339: 21d26. 39. Grange F, Hedelin G, Joly P et al. Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides and the Sezary syndrome. Blood 1999; 93: 3637d3642. 40. Geelen A M J, Vermeer M H, Meijer C J L M et al. bcl-2 protein expression in primary cutaneous large B-cell lymphoma is siterelated. J Clin Oncol 1998; 16: 2080d2085. 41. Kurtin P J, DiCaudo D J, Habermann T M, Chen M G, Su W P D. Primary cutaneous large cell lyphomas. Morphologic, immunophenotypic and clinical features of 20 cases. Am J Surg Pathol 1994; 18: 1183d1191. 42. Gronbaek K, Moller P H, Nedergaard T et al. Primary cutaneous B-cell lymphoma: a clinical, histological, phenotypic and genotypic study of 21 cases. Br J Dermatol 2000; 142: 913d923. 43. Willemze R, Meijer C J L M, Sentis H J et al. Primary cutaneous large cell lymphomas of follicular center origin. A clinical follow-up study of nineteen patients. J Am Acad Dermatol 1987; 16: 518d526. 44. Cerroni L, Volkenandt M, Rieger E, Soyer P, Kerl H. Bcl-2 protein expression and correlation with the interchromosomal 14;18 translocation in cutaneous lymphomas and pseudolymphomas. J Invest Dermatol 1994; 102: 231d235. 45. Warnke R A, Weiss L M, Chan J K C, Cleary M L, Dorfman R F. Malignant lymphoma, diffuse, large cell and variants. In: Rosai J, Sobin L H (eds). Atlas of Tumor Pathology. Tumors of the Lymph Nodes and Spleen. Washington: Armed Forces Institute of Pathology, Fascicle 14, 1995: 153d220. 46. Willemze R, Kruyswijk M R J, De Bruin C D, Meijer C J L M, Van Berkel W. Angiotropic (intravascular) large cell lymphoma of the skin previously classified as malignant angioendotheliomatosis. Br J Dermatol 1987; 116: 393d399. 47. Chang A, Zic J A, Boyd A S. Intravascular large cell lymphoma: a patient with asymptomatic purpuric patches and a chronic clinical course. J Am Acad Dermatol 1998; 39: 318d321. 48. Rubin M A, Cossman J, Freter C E, Azumi N. Intravascular large cell lymphoma coexisting with hemangiomas of the skin. Am J Surg Pathol 1997; 21: 860d864. 49. Braun-Falco O, Plewing G, Wolff H H et al. Malignant cutaneous lymphomas. In: Dermatology. Berlin: Springer-Verlag, 1991: 1094d1095. 50. Chang Y-T, Wong C-K. Primary cutaneous plasmacytomas. Clin Exp Dermatol 1994; 19: 177d180. 51. Torne R, Su W P D, Winkelmann R K, Smolle J, Kerl H. Clinicopathologic study of cutaneous plasmacytoma. Int J Dermatol 1990; 29: 562d566. 52. Llamas-Martin R, Postigo-Llorente C, Vanaclocha-Sebastian F, Gil-Martin R, Iglesias-Diez L. Primary cutaneous extramedullary





56. 57.

58. 59.


61. 62.






CURRENT DIAGNOSTIC PATHOLOGY plasmacytoma secreting k IgG. Clin Exp Dermatol 1993; 18: 351d355. Walker E, Robertson A G, Boorman J G, McNicol A M. Primary cutaneous plasmacytoma: the use of in situ hybridization to detect monoclonal immunoglobulin light chain mRNA. Histopathology 1992; 20: 135d138. Wong K F, Chan J K C, Li L P K, Yau T K, Lee A W M. Primary cutaneous plasmacytoma e report of two cases and review of the literature. Am J Dermatopathol 1994; 16: 392d397. Sander C A, Medeiros L J, Abruzzo L V, Horak I D, Jaffe E S. Lymphoblastic lymphoma presenting in cutaneous sites: a clinicopathologic analysis of six cases. J Am Acad Dermatol 1991; 25: 1023d1031. Chimenti S, Fink-Puches R, Peris K et al. Cutaneous involvement in lymphoblastic lymphoma. J Cutan Pathol 1999; 26: 379d385. Bertero M, Novelli M, Fierro M T, Bernengo M G. Mantle zone lymphoma: an immunohistologic study of skin lesions. J Am Acad Dermatol 1994; 30: 23d30. Geerts M L, Busschots A M. Mantle-cell lymphomas of the skin. Dermatol Clin 1994; 12: 409d417. Ferry J A, Yang W I, Zukerberg L R, Wotherspoon A C, Arnold A, Harris N L. CD5#extranodal marginal B-cell (MALT) lymphoma. A low grade neoplasm with a propensity for bone marrow involvement and relapse. Am J Clin Pathol 1996; 105: 31d37. Norton A J. Classification of cutaneous lymphoma: a critical appraisal of recent proposals. Am J Dermatopath 1999; 21: 279d287. Caro W A, Helwig H B. Cutaneous lymphoid hyperplasia. Cancer 1969; 24: 487d502. Evans H L, Winkleman R K, Banks P M. Differential diagnosis of malignant and benign cutaneous infiltrates: a study of 57 cases in which malignant lymphoma had been diagnosed or suspected in the skin. Cancer 1979; 44: 699d717. Rijlaarsdam J U, Meijer C J L M, Willemze R. Differentiation between lymphadenosis benigna cutis and primary cutaneous follicle center cell lymphomas. A comparative clinicopathological study of 57 patients. Cancer 1990; 65: 2301d2306. Rijlaarsdam J U, Willemze R. Cutaneous pseudolymphomas: classification and differential diagnosis. Semin Dermatol 1994; 13: 187d196. Ritter J H, Adesokan P, Fitzgibbon J F, Wick M R. Paraffin-section immunohistochemistry as an adjunct to morphologic analysis in the diagnosis of cutaneous lymphoid infiltrates. J Cutan Pathol 1994; 21: 481d493. Wood G S, Ngan B Y, Tung R et al. Clonal rearrangements of immunoglobulin genes and progression to B cell lymphoma in cutaneous lymphoid hyperplasia. Am J Pathol 1989; 135: 13d19. Rijlaarsdam U, Bakels V, van Oostven J W et al. Demonstration of clonal immunoglobulin gene rearrangements in cutaneous B-cell lymphomas and pseudo-B-cell lymphomas: differential diagnostic and pathogenetic aspects. J Invest Dermatol 1992; 99: 749d754.

68. Hammer E, Sangueza O, Suwanjindar P, White C R, Braziel R M. Immunophenotypic and genotypic analysis in cutaneous lymphoid hyperplasias. J Am Acad Dermatol 1993; 28: 426d433. 69. Ritter J H, Wick M R, Adesokan P N, Fitzgibbon J F, Zhu X, Humphrey P A. Assessment of clonality in cutaneous lymphoid infiltrates by polymerase chain reaction analysis of immunoglobulin heavy chain gene rearrangement. Am J Clin Pathol 1997; 108: 60d68. 70. Child F J, Woolford A, Calonje E, Russell-Jones R, Whittaker S. Molecular analysis of the immunoglobulin heavy chain (IgH) gene in primary cutaneous B-cell lymphoma (PCBCL). Br J Dermatol 2000; 142: 610. 71. Goodlad J R, Levison D A. Lymphoreticular system. In: Al-Sam S Z, Lakhani S R, Davies J D (eds). Practical Atlas of Pseudomalignancy. Benign lesions mimicking malignancy. London: Arnold, 1998: 141d167. 72. Chimenti S, Cerroni L, Zenahlik P, Peris K, Kerl H. The role of MT2 and anti-bcl-2 protein antibodies in the differentiation of benign from malignant cutaneous infiltrates of B-lymphocytes with germinal center formation. J Cutan Pathol 1996; 23: 319d322. 73. Dogan A, Bagdie E, Munson P, Isaacson P G. CD10 and bcl-6 expression in paraffin sections of normal lymphoid tissues and B-cell lymphomas. Am J Surg Pathol 2000; 24: 846d852. 74. Goos M. Acrodermatitis chronica atrophicans and malignant lymphoma. Acta Derm Venereol (Stockh) 1971; 51: 457d459. 75. Garbe C, Stein H, Dienemann D, Orfanos C E. Borrelia burgdorferi -associated cutaneous B cell lymphoma: clinical and immunologic characterisation of four cases. J Am Acad Derm 1991; 24: 584d590. 76. Kutting B, Bonsmann G, Metze D, Luger T A, Cerroni L. Borrelia burgdorferi -associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a. J Am Acad Dermatol 1997; 36; 311d314. 77. Cerroni L, Zochling N, Putz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol 1997; 24: 457d461. 78. Goodlad J R, Davidson M M, 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: 1279d1285. 79. Goodlad J R, Davidson M M, Hollowood K, Batstone P, Ho-Yen D O. Borrelia burgdorferi -associated cutaneous marginal zone lymphoma. A clinicopathological study of 2 cases illustrating the temporal progression of B burgdorferi -associated B cell proliferation in the skin. Histopathology 2000; 37: 501}508. 80. Roggero E, Zucca E, Mainetti C et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol 2000; 31: 263d268. 81. Zochling N, Putz B, Wolf P, Kerl H, Cerroni L. Human Herpesvirus 8-specific DNA sequences in primary cutaneous B-cell lymphomas. Arch Dermatol 1998; 134: 246d247. 82. Alizadeh A A, Eisen M B, Davis R E et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503d511.