Cutaneous B cell pseudolymphoma

INTRODUCTION — The term "cutaneous pseudolymphoma" refers to a heterogeneous group of benign skin disorders that simulate cutaneous lymphomas histologically and sometimes clinically. Cutaneous pseudolymphomas can be separated into two major subtypes: pseudolymphoma mimicking a cutaneous B cell lymphoma (B cell pseudolymphoma) and pseudolymphoma mimicking a cutaneous T cell lymphoma (T cell pseudolymphoma) (table 1) [1-3].

Cutaneous B cell pseudolymphoma (previously called lymphadenosis benigna cutis, lymphocytoma cutis, pseudolymphoma of Spiegler-Fendt, or cutaneous lymphoid hyperplasia) represents a reactive B cell proliferation response to a variety of antigenic stimuli, including arthropod bites, piercings, tattoo dyes, and drugs. It usually presents as an erythematous nodule or plaque that simulates indolent primary cutaneous B cell lymphomas, in particular primary cutaneous marginal zone lymphoma (PCMZL) or primary cutaneous follicle center lymphoma (PCFCL).

This topic will discuss the pathogenesis, clinical presentation, and differential diagnosis of B cell pseudolymphoma. Primary cutaneous B cell lymphomas, cutaneous T cell pseudolymphoma, and lymphomatoid papulosis are discussed separately.

●(See "Primary cutaneous marginal zone lymphoma".)

●(See "Primary cutaneous follicle center lymphoma".)

●(See "Primary cutaneous large B cell lymphoma, leg type".)

●(See "Cutaneous T cell pseudolymphomas".)

●(See "Lymphomatoid papulosis".)

EPIDEMIOLOGY — The overall incidence and prevalence of cutaneous B cell pseudolymphomas are unknown. They may occur at any age but are more frequently seen in young adults. B cell pseudolymphomas caused by Borrelia burgdorferi infection often occur in children [4].

ETIOLOGY AND PATHOGENESIS — Cutaneous B cell pseudolymphoma is a localized reactive B cell proliferation induced by various antigenic stimuli, including arthropod bites, vaccinations, acupuncture, piercings, tattoo dyes (particularly red pigments), and drugs [1,5-13]. In most cases, however, the cause of cutaneous B cell pseudolymphoma is unknown (idiopathic B cell pseudolymphoma).

B cell pseudolymphoma has been frequently associated with B. burgdorferi infection (borrelial lymphocytoma cutis) in Europe, in areas endemic for the Ixodes ricinus tick [14-16]. (See "Clinical manifestations of Lyme disease in adults", section on 'Cutaneous findings'.)

CLINICAL PRESENTATION — Most patients present with an asymptomatic, solitary, skin-colored or red nodule or plaque, preferentially located on the face or chest (picture 1). Scaling and ulceration are generally absent. Less frequently, patients present with multiple lesions within a circumscribed area (picture 2) or with generalized skin lesions [17].

B. burgdorferi-associated pseudolymphoma typically presents as a soft, bluish-red nodule or plaque at sites of Borrelia infection, such as the earlobes (picture 3), nipples, and scrotum [5,16]. It develops weeks to months after the infection and is relatively frequent in children [4,18]. In a review of 144 adult patients, borrelial lymphocytoma was located on the breast in 106 patients (74 percent), on the ear lobe in 27 (19 percent), and at other sites in 11 (7 percent). Concomitant erythema migrans was found in 104 of 144 patients (72 percent) [16]. (See "Clinical manifestations of Lyme disease in adults".)

Clinical course — The clinical course of B cell pseudolymphomas is variable. Some lesions may resolve spontaneously in several months or years. Drug-induced B cell pseudolymphoma may resolve after cessation of the offending drug [12,13]. Resolution of borrelial lymphocytoma occurs after a median time of two to eight weeks after starting antibiotic treatment [4,16,18].

Progression of B cell pseudolymphoma to a malignant lymphoma is unlikely; reported cases may represent misdiagnosed cases of early cutaneous B cell lymphoma. A proportion of cases classified as cutaneous B cell pseudolymphoma in the past are now considered to be low-grade malignant cutaneous B cell lymphoma, in particular primary cutaneous marginal zone lymphoma [19,20].

PATHOLOGY

Morphology — On histologic examination, most cases of cutaneous B cell pseudolymphoma show nodular to diffuse mixed-cellular infiltrates throughout the entire dermis, often with formation of lymphoid follicles (picture 4) [21,22]. Reactive germinal centers are generally surrounded by well-formed mantle zones, but in rare cases they may become confluent, simulating a primary cutaneous follicle center lymphoma (PCFCL) [5]. A mixed infiltrate of small lymphocytes, histiocytes, eosinophils, and plasma cells can be observed between the lymphoid follicles. The epidermis is not involved and is separated from the dermal infiltrate by a distinct grenz zone.

Immunophenotyping — Immunohistochemical analysis of B cell pseudolymphoma usually shows distinct B and T cell compartments. Stainings for CD35 or CD21 properly visualize networks of follicular dendritic cells within reactive germinal centers (picture 4). The germinal center cells (centrocytes and centroblasts) have a normal CD20⁺, CD10⁺, BCL6⁺, BCL2^- phenotype, show a polytypic staining pattern for immunoglobulin (Ig) light chains, and a high proliferation rate as assessed by MIB-1 staining [22]. Reported cases of B cell pseudolymphoma with monotypic plasma cells are now considered primary cutaneous marginal zone lymphoma (PCMZL) [23].

Clonality analysis — Ig gene rearrangement analysis is usually performed to differentiate between benign and malignant lymphoproliferations. Clonal Ig gene rearrangements have been found in a small subset of B cell pseudolymphomas, as defined by immunohistochemical criteria, but are detected in 60 to 80 percent of PCMZL and PCFCL [24-26]. The demonstration of B cell clonality therefore supports the diagnosis of cutaneous B cell lymphoma but is by itself insufficient to make a definite diagnosis. (See 'Differential diagnosis' below.)

DIAGNOSIS — The diagnosis of B cell pseudolymphoma requires a representative biopsy. Excisional biopsies are preferred to punch biopsies, but if a punch biopsy is taken, the diameter should be at least 4 mm.

The biopsy specimen is evaluated for morphology, growth pattern, and immunophenotype. These lesions characteristically show mixed B cell and T cell infiltrates, with or without reactive germinal centers, and do not show clonal immunoglobulin H (IgH) gene rearrangements or monotypic Ig light chain expression.

Clinical evaluation should focus on potential triggers for B cell pseudolymphomas (vaccinations, tattoos, arthropod bites, drugs). In patients traveling or living in areas endemic for Lyme disease, serologic tests for B. burgdorferi infection should be performed [5]. (See "Diagnosis of Lyme disease".)

Demonstration of Borrelia deoxyribonucleic acid (DNA) can also be performed on tissue sections by polymerase chain reaction (PCR), but this is not used routinely in daily practice.

DIFFERENTIAL DIAGNOSIS — B cell pseudolymphomas should be differentiated from indolent types of cutaneous B cell lymphomas, including primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL), and from secondary skin localizations of systemic nodular lymphomas. (See "Primary cutaneous marginal zone lymphoma" and "Primary cutaneous follicle center lymphoma" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Primary cutaneous marginal zone lymphoma

●Clinical features – Both primary cutaneous marginal zone lymphoma (PCMZL) and B cell pseudolymphoma can present as a solitary nodule or tumor (picture 5). Presentation with multiple scattered nodules on the trunk and/or upper arms is rarely seen in B cell pseudolymphoma and strongly suggests a diagnosis of PCMZL (picture 6) [27]. (See "Primary cutaneous marginal zone lymphoma", section on 'Clinical features'.)

●Histology and immunophenotyping – Both PCMZL and B cell pseudolymphoma show nodular to diffuse infiltrates that may contain reactive germinal centers. PCMZL characteristically shows collections of plasma cells at the periphery of these infiltrates or in the subepidermal area (picture 7). Demonstration of monotypic plasma cells expressing either kappa or lambda light chains by immunohistochemistry or in situ hybridization on paraffin sections is generally used as a decisive criterion for PCMZL (picture 8) [19,28]. However, monotypic plasma cells may be scant and undetectable in recurrent lesions. (See "Primary cutaneous marginal zone lymphoma", section on 'Pathologic features'.)

●Clonality analysis – (See 'Clonality analysis' above.)

Are cutaneous B cell pseudolymphoma and primary cutaneous marginal zone lymphoma a disease spectrum? — Based upon the overlapping clinical and histologic features and the observation that both PCMZL and B cell pseudolymphoma may develop from chronic stimulation by intradermally applied antigens, it has been suggested that they may represent a continuous spectrum of cutaneous B cell proliferations progressing from a reactive to a neoplastic state [1]. There is an ongoing discussion on whether PCMZL, or at least a major subset of PCMZL with extremely indolent behavior, should or should not be considered an overt malignant lymphoma [29]. Consequently, in the published International Consensus Classification for mature lymphoid neoplasms, PCMZL is renamed "primary cutaneous marginal zone lymphoproliferative disorder" [30]. (See "Primary cutaneous marginal zone lymphoma".)

Primary cutaneous follicle center lymphoma — Histologically, primary cutaneous follicle center lymphoma (PCFCL) can show a follicular, follicular and diffuse, or diffuse growth pattern [23]. Distinguishing B cell pseudolymphomas from PCFCL with a diffuse and partly follicular growth pattern (most cases) is generally not difficult, but differentiation from cases with a follicular growth pattern (minority of cases) can be a challenge:

●Clinical features – Most patients with a PCFCL present with multiple, sometimes confluent plaques and nodules in a circumscribed area of the trunk (picture 9) or head, particularly the scalp (picture 10) [27,31]. This clinical presentation is an important clue to the correct diagnosis. (See "Primary cutaneous follicle center lymphoma", section on 'Clinical features'.)

●Histologic criteria – Histologic criteria used in the past, including the presence of a mixed cellular infiltrate preferentially located in the upper dermis ("top-heavy" as opposed to "bottom-heavy" in malignant lymphomas) and the presence of lymphoid follicles with formation of germinal centers, cannot reliably differentiate between B cell pseudolymphoma and cutaneous B cell lymphoma [21]. In contrast to the reactive follicles seen in B cell pseudolymphomas and PCMZL, the neoplastic follicles in PCFCL with a (partly) follicular growth pattern are ill defined and show a reduced or absent mantle zone, loss of polarization, no or few tangible body macrophages, and a monotonous population of medium-sized to large centrocytes with variable numbers of admixed centroblasts [22] (see "Primary cutaneous follicle center lymphoma", section on 'Morphology'). However, the distinction between reactive and neoplastic follicles can sometimes be difficult. The presence of many admixed eosinophils is rarely observed in cutaneous B cell lymphoma and favors a diagnosis of B cell pseudolymphoma [5,21].

●Immunophenotype – The germinal center cells in both reactive germinal centers in B cell pseudolymphoma and PCMZL and neoplastic germinal centers in PCFCL with a follicular growth pattern have the same CD20⁺, CD10⁺, BCL6⁺, BCL2^- phenotype. Strong expression of BCL6, CD10, and BCL2 should raise suspicion of systemic follicular lymphoma with secondary cutaneous involvement [32,33]. However, this pattern may also be observed in a minority of PCFCL, but rarely in B cell pseudolymphomas. The presence of clusters of CD10 and/or BCL6-positive cells outside the neoplastic follicles strongly suggests a diagnosis of PCFCL.

In frozen sections, PCFCL may express monotypic surface immunoglobulin (sIg) or the cells may lack sIg, whereas B cell pseudolymphomas show a polytypic sIg light chain expression [24]. Examination of paraffin sections for sIg is generally not useful because of the low sIg expression by germinal center cells and the high background staining.

Clonality analysis – (See 'Clonality analysis' above.)

Secondary cutaneous follicular lymphoma — Systemic follicular lymphoma, the second most common type of non-Hodgkin lymphoma, can secondarily involve the skin. Secondary skin involvement may present as generalized nodules and tumors or as a solitary tumor, most commonly located on the head.

Histologically, these lesions show a diffuse infiltrate containing many neoplastic lymphoid follicles. The neoplastic germinal center cells show strong expression of BCL6, CD10, and BCL2 [33,34]. In most cases, the translocation t(14;18) can be demonstrated by fluorescence in situ hybridization (FISH). (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

TREATMENT — B cell pseudolymphoma is an uncommon disorder. Evidence regarding treatment is mainly derived from small series of cases or single-case reports [35]. The approach to treatment depends on the number of lesions, their location, the presence of symptoms (eg, pruritus), the identification of an inciting cause, and patient preference.

●Patients with negative tests for B. burgdorferi – Because B cell pseudolymphomas may resolve spontaneously over time, observation may be an option for patients with asymptomatic lesions who have negative tests for B. burgdorferi. In clinical practice, however, lesions are often initially treated with topical superpotent corticosteroids or intralesional corticosteroids. There are isolated reports of refractory lesions successfully treated with radiotherapy [36,37], thalidomide [38,39], and intralesional rituximab [40]. Solitary lesions may be excised surgically. Drug-induced B cell pseudolymphomas may resolve after cessation of the offending drug [12,13].

●Patients with B. burgdorferi-associated B cell pseudolymphoma – Patients with B. burgdorferi-associated B cell pseudolymphoma (borrelial lymphocytoma) should be treated for Lyme disease. (See "Treatment of Lyme disease", section on 'Cutaneous manifestations of Eurasian Lyme disease'.)

In a review of 33 children with borrelial lymphocytoma, antibiotic treatment resulted in the resolution of the skin lesions in a median time of 16 days [18]. In another study including 56 children with borrelial lymphocytoma, treatment with amoxicillin or phenoxymethyl penicillin cleared the skin lesions in a median time of two months after initiating antibiotic treatment [4]. In a study of 144 adult patients with borrelial lymphocytoma, the skin lesions disappeared within a median time of 21 days after the start of treatment; treatment failures occurred in 14 of 144 patients (9.7 percent) [16].

SUMMARY AND RECOMMENDATIONS

●Definition, etiology, and pathogenesis – Cutaneous B cell pseudolymphoma (previously called lymphadenosis benigna cutis, lymphocytoma cutis, pseudolymphoma of Spiegler-Fendt, or cutaneous lymphoid hyperplasia) represents a reactive B cell proliferation response to a variety of antigenic stimuli, including arthropod bites, Borrelia infection, piercings, tattoo dyes, and drugs. (See 'Introduction' above and 'Etiology and pathogenesis' above.)

●Clinical presentation – Most patients present with an asymptomatic, solitary, skin-colored or red nodule or plaque, preferentially located on the face or chest (picture 1). Less frequently, patients present with multiple lesions within a circumscribed area (picture 2). Borrelia burgdorferi-associated pseudolymphoma typically presents as a soft, bluish-red nodule or plaque at sites of Borrelia infection, such as the earlobes (picture 3), nipples, and scrotum. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of B cell pseudolymphoma requires a skin biopsy for histopathologic evaluation and immunophenotyping. Patients with cutaneous B cell pseudolymphomas traveling or living in areas endemic for Lyme disease should undergo serologic testing for B. burgdorferi infection. (See 'Diagnosis' above and 'Pathology' above and "Diagnosis of Lyme disease".)

●Treatment – B cell pseudolymphomas may resolve spontaneously over time. In clinical practice, lesions are often initially treated with topical or intralesional corticosteroids. Refractory lesions may be treated with surgical excision or radiotherapy. Patients with B. burgdorferi-associated B cell pseudolymphoma (borrelial lymphocytoma) should be treated for Lyme disease. (See 'Clinical course' above and 'Treatment' above and "Treatment of Lyme disease", section on 'Cutaneous manifestations of Eurasian Lyme disease'.)