—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 3 - Borrelia Burgdorferi-associated Marginal Zone B-cell Lymphoma

Lorenzo Cerroni
Medical University of Graz
Graz, Austria


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Clinical History
86-year-old woman with a large erythematous tumor on her left lower leg. The tumor was slowly growing for the last few months. The surrounding skin was normal. Complete staging investigations, including bone marrow biopsy, were negative. The patient had neither paraproteinemia nor Bence-Jones proteins in the urine. A biopsy was performed under local anesthesia. Histology revealed a dense lymphoid infiltrate throughout the entire dermis. The epidermis was spared. Cytomorphology showed a relatively monomorphous population of lymphoplasmacytoid cells admixed with marginal zone cells and some plasma cells. Intranuclear PAS+ inclusions (Dutcher bodies) could be detected in some of the cells. The cells expressed B-cell markers (CD20, CD79a) and monoclonal immunoglobulin light chains (kappa). Molecular analyses of the IgH gene performed by PCR on formalin-fixed, paraffin-embedded tissue revealed the presence of a monoclonal band. At the time of first observation a diagnosis of cutaneous immunocytoma was made. The patient was treated by radiotherapy with complete resolution of the lesion. Molecular analyses performed retrospectively by PCR with primers specific for Borrelia burgdorferi DNA sequences revealed a positive signal, indicating the presence of Borrelia microorganisms within the lesion. The patient died of unrelated causes 6 years after onset of the cutaneous tumor.


Case 3 - Figure 1 - Violaceous skin nodule.
Case 3 - Figure 2 - A dense lymphoid infiltrate is present throughout the entire dermis. The epidermis is spared.
Case 3 - Figure 3 - Cytomorphology shows a monomorphous population of lymphoplasmacytoid cells admixed with marginal zone cells and some plasma cells. Intranuclear PAS+ inclusions (Dutcher bodies) could be detected in some of the cells.

Discussion:
Cutaneous B-cell lymphomas (CBCLs) represent a group of extranodal lymphomas with particular tropism for the skin. The most common subtypes include marginal zone B-cell lymphoma (MZL), follicle center lymphoma (FCL) and large B-cell lymphoma, leg-type (LBCLL). Cutaneous marginal zone lymphoma and immunocytoma are considered today to represent morphologic subtypes of a single entity of low-grade malignant cutaneous B-cell lymphoma, and the term "marginal zone lymphoma" is now used to refer to both. In this context, it should be reminded that MZL of the skin is different from extranodal marginal zone lymphoma (which in turn is different from nodal marginal zone lymphoma and from splenic marginal zone lymphoma).

Primary cutaneous marginal zone lymphoma is one of the major subtypes of the low-grade malignant cutaneous B cell lymphomas, and is included as such in the revised WHO/EORTC classification of cutaneous lymphomas. Cases reported in the past as "cutaneous follicular lymphoid hyperplasia with monotypic plasma cells" probably represent examples of marginal zone lymphoma of the skin.

Association with Borrelia burgdorferi has been detected in some cases in areas both with and without endemic infection.However, this association may be regional as two other studies on cutaneous marginal zone lymphoma did not show evidence of infection by Borrelia burgdorferi. The association of cutaneous marginal zone lymphoma with Borrelia burgdorferi is conceptually similar to the observation that MALT-lymphomas (extranodal marginal zone B-cell lymphomas) can be associated with several infectious microrganisms in different organs (e.g., Helicobacter pylori in the stomach, Campylobacter jejuni in the intestine, Chlamydia psittaci in the ocular adnexa). It seems that a distinct proportion of low-grade malignant lymphomas of MALT-type are triggered by chronic infections, thus providing a conceptually a common framework for MALT-lymphomas arising in different organs.

Patients with cutaneous MZL are adults or elderly with a male predominance, but onset in childhood has been observed. They present with red to reddish-brown papules, plaques and nodules localized particularly to the upper extremities or the trunk. Lesions are commonly solitary but may be multiple characterized either by localized clusters of papules and small nodules or by several lesions scattered on the trunk and upper extremities. Lesions classifed in the past as cutaneous immunocytoma were often located on the lower extremities, and sometimes could be seen in areas of skin affected by chronic Borrelia burgdorferi infection (acrodermatitis chronica atroficans). Cutaneous recurrences are frequent and may be distant from the primary site of involvement. The onset of anetoderma in some lesions of cutaneous marginal zone lymphoma has been reported.

Histology shows patchy, nodular or diffuse infiltrates involving the dermis and sometimes the superficial part of the subcutaneous fat. The epidermis is not involved. A characteristic pattern can be observed at scanning magnification: nodular infiltrates with follicles, sometimes containing reactive germinal centres, are surrounded by a pale staining peri- and interfollicular population of small to medium-sized cells with indented nuclei, inconspicuous nucleoli and abundant pale cytoplasm (marginal zone cells, centrocyte-like cells). In addition, plasma cells (at the margins of the infiltrate), lymphoplasmacytoid cells, small lymphocytes and occasional large blasts are observed. The number of neoplastic cells within the infiltrate is variable and can be very low.

In typical cases the neoplastic population is comprised by marginal zone cells, a few lymphoplasmacytoid lymphocytes and several plasma cells. Usually marginal zone cells represent only a proportion of the neoplastic population, but in rare cases they predominate forming sheets without plasma cell differentiation. In other lesions, neoplastic plasma cells predominate admixed with a few marginal zone cells, resembling the picture of cutaneous plasmacytoma. Cases that in the past were classified as immunocytoma are characterized by a more monotonous proliferation of lymphoplasmacytoid cells admixed with plasma cells. Cases with predominance of blasts are rare and should be distinguished from examples of follicle centre cell lymphoma by accurate immunophenotyping. Even in cases with predominance of blasts reactive cells are a prominent component of the infiltrate and neoplastic cells are usually a minority of it. Eosinophils, as well as a granulomatous reaction, can be observed in a proportion of cases.

It should be emphasised that reactive cells (T- and B-lymphocytes, histiocytes, eosinophils) represent often the majority of the infiltrating cells in lesions of cutaneous marginal zone lymphoma, thus creating diagnostic problems.

The marginal zone cells reveal a CD20+, CD79a+, CD5–, CD10–, Bcl-2+ and Bcl-6- phenotype. Bcl-6 and CD10 antibodies are particularly useful for differentiation of cutaneous marginal zone lymphoma with blastic differentiation from follicle centre cell lymphoma. In about 75-85% of cases intracytoplasmic monotypic expression of immunoglobulin light chains can be observed. Staining for Ki67 (MIB-1) shows that the proliferating monoclonal population of B lymphocytes is characteristically disposed at the periphery of the cellular aggregates.

A monoclonal rearrangement of the JH gene can be observed in about 50-60% of cases. The t(11;18) and the t(1;14) are not present in cutaneous cases. Recently, a specific interchromosomal 14;18 translocation involving IgH and MALT1 has been described in a subset of cutaneous marginal zone lymphomas as well as of marginal zone lymphomas of other organs including the liver, ocular adnexa and salivary glands, indicating the relationship of cutaneous cases to those arising at extracutaneous sites. Gene expression studies using cDNA microarrays revealed that cases of cutaneous marginal zone lymphoma have a plasma cell signature.

Solitary lesions may be excised. Complete responses have also been achieved after administration of systemic steroids. Many patients can be managed with a so-called "watchful waiting" strategy. Patients with multiple lesions can be treated with interferon a or with anti-CD20 antibodies (rituximab). Complete responses after systemic antibiotics have been reported, and this should probably be the primary treatment for patients with evidence of Borrelia burgdorferi infection. Systemic chemotherapy should be reserved for those rare cases with extracutaneous dissemination.

The prognosis is excellent, and the estimated 5-year survival is 98%. Recurrences can be observed in 40-50% of patients after successful treatment but retain the low-grade features of the primary tumour. At present, the prognostic significance of different histopathological subtypes (i.e., mixed cell, predominance of marginal zone cells, predominance of plasma cells), if any, is unclear. Blastic transformation in recurrent lesions has been associated with a worse prognosis.

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