Case 1 -

Atypical Marginal Zone Hyperplasia Of Mucosa Associated Lymphoid Tissue: A Reactive Condition Of Childhood Showing Immunoglobulin Lambda Light Chain Restriction Ahmet Dogan MD PhD Professor of Pathology Mayo Clinic, Rochester, MN, USA

Case history: 4 year-old female Enlarged tonsils, difficulty in breathing Normal laboratory findings Tonsillectomy Case 1 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Histological features: Asymmetrically enlarged tonsil Overall preserved lymphoid architecture Marked follicular hyperplasia Marked marginal zone hyperplasia; marginal zone cells infiltrate the crypt epithelium and colonize some of the hyperplastic follicles Cytologically the marginal zone cells are a mixture of so-called centrocyte-like cells and transformed immunoblasts. Immunophetypic features: Marginal zone cells: CD20+, CD79a+, IgD+, IgM+, λ+, Bcl-2+, CD43+, IRTA1+, CD3-, κ-, CD10-, Bcl-6-, CD27-, MIB-1 high Follicles: CD20+, CD79a, CD10+, Bcl-6+, CD3- Bcl-2-, CD43-, polytypic for κ and λ, MIB-1 high. Molecular genetic features: Clonality analysis with polymerase chain reaction for IGH, IGK, IGL was polyclonal Clinical outcome: The patient is well without evidence of disease after 1 year of follow-up Discussion: Initially, the histological and immunophenotypic features of the case described here strongly supported a diagnosis of an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The cells comprising the expanded marginal zones included numbers of transformed blasts, infiltrated the tonsillar crypt epithelium and colonized reactive B-cell follicles, all features that have been documented as characteristic of MALT lymphoma. Immunophenotyping further supported a diagnosis of MALT lymphoma with aberrant expression of CD43 by B-cells and, most importantly, Igλ light chain restriction. However, the high proliferation fraction, expression of both μ and δ heavy chains and absence of molecular evidence of monoclonal Ig gene rearrangement argued against this diagnosis. This case falls within the spectrum of 6 similar cases described recently as atypical marginal zone hyperplasia of mucosa associated lymphoid tissue. [1]. These cases were characterised by young age (in children aged 3-11 years), extranodal mucosal presentation (4 tonsils, 2 appendices) and histological and immunophenotypic features indicative of lymphoma but polyclonality at the molecular level. No lymphoma directed therapy was given and patients remain alive and well (5 cases, median follow up 35.3 months). The involved tonsil and appendix showed florid marginal zone hyperplasia with prominent intra-epithelial B-cells. Both components showed a high proliferation fraction and a CD20+, CD21+, CD27-, IRTA-1+, CD43+, MUM-1, IgM+D+ phenotype. PCR, cloning and sequencing of rearranged IGH and IGL genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the marginal zone B-cells were polyclonal and the IgH genes non-mutated. A second study documenting marginal zone lymphoma in children and young adults, Tadesse-Heath, et al reported its occurrence in the tonsil / adenoid in 3 children. [2] In these 3 cases, all presenting with stage 1 disease, a histological diagnosis of lymphoma was made on the basis of "aberrant" CD43 expression and/or Igλ light chain restriction. In the 2 cases in which PCR for IgH gene rearrangement was performed, the polyclonal result was interpreted as false negative. These three cases are also likely to represent examples of this unusual CD43 positive, Igλ light chain restricted, reactive proliferation, rather than lymphoma. The aberrant expression of the T-cell marker CD43 by B-cells is frequently interpreted as a marker of B-cell malignancy. CD43 is a T-cell lineage-associated antigen, reported to be negative in the majority of non-neoplastic B-cells, except plasma cells and rare lympho-plasmacytoid cells. It is expressed by most mantle cell lymphomas, small lymphocytic lymphomas and Burkitt lymphomas. Ten to 20% of diffuse large B-cell lymphomas and 10% of follicular lymphomas have been reported to express CD43. Thus, when present in B-cell proliferations, CD43 expression is considered a fairly reliable marker of malignancy. Its wide usage in this capacity is in part due to the technical difficulties and problems of interpretation commonly encountered in immunoglobulin light chain immunohistochemistry, and the cost and lack of availability of molecular genetic studies for clonality analysis, in routine diagnostic work. Clearly, a degree of caution is warranted in interpreting CD43 expression. In an attempt to ascertain which population of cells is expanded in this peculiar reactive process, Attygalle et al compared the immunophenotypic and molecular genetic characteristics with those of tonsillar intraepithelial B-cells. These cells together with a component in the sub-epithelial region are thought to comprise the marginal zone B-cells of the tonsil. Like the atypical marginal zone hyperplasia, the tonsillar marginal zone B-cells express IgM, IgD, CD21 (weakly), CD43 and IRTA-1 and have a high proliferation fraction. However, a major immunophenotypic discrepancy between the expanded marginal zone cells and the intraepithelial B-cells of normal tonsils is CD27 expression by the latter. CD27 expression is usually found on B-cells with somatically mutated Ig genes. In the normal tonsil, the marginal zone B-cells, like their counterparts in the dome region of the Peyer's patches and the splenic marginal zone, are heterogeneous with regard to somatic mutations, and comprise both mutated and unmutated cells. In atypical marginal zone hyperplasia, the lesional cells were consistently CD27 negative. Moreover, genetic analysis showed that by contrast with the CD27 positive intraepithelial B-cells of the normal tonsil in which the Ig genes were mutated, the Ig genes of the expanded "marginal zone" B-cell population were in germline configuration. Therefore it is likely that CD27 negative marginal zone B-cell that is the likely cell of origin in this peculiar hyperplastic condition. This would also explain the expression of CD43, as normal rather than "aberrant" and entirely consistent with a hyperplastic process. There remains the question of Igλ light chain restriction in all case reported so far. This might be explained by superantigen activation of the marginal zone B-cells but the absence of biased usage of any IgVH family member or IgH D segment is against the likelihood of this. The reason behind the preferential expansion of Igλ expressing B-cells remains unclear. The only previous documentation of such a phenomenon, is in HHV-8-related Castleman's disease and associated lymphoproliferative disorders, where polyclonal expansion of Igλ light chain expressing HHV-8 infected naïve B-cells have been demonstrated. More recently, predominantly follicular proliferation showing light chain restriction but polyclonality at the genetic level has been described. [3] This suggest that such an usual light chain restricted but polyclonal lymphoid proliferations are more frequent then we realize and questions definitive role of light chain restriction in diagnosis of lymphoid neoplasms in young patients. References: Attygalle AD, Liu H, Shirali S, Diss TC, Loddenkemper C, Stein H, Dogan A, Du MQ, Isaacson PG. Atypical marginal zone hyperplasia of mucosa-associated lymphoid tissue: a reactive condition of childhood showing immunoglobulin lambda light-chain restriction. Blood. 2004;104:3343-8 Taddesse-Heath L, Pittaluga S, Sorbara L, et al. Marginal zone B-cell lymphoma in children and young adults. Am J Surg Pathol. 2003;27:522–531. Müller-Hermelink HK; Haralambieva E; Rüdiger, T. Follicular and Marginal Zone Lesions of the Lymph Node: Benign or Malignant? Pathology Case reviews 2004; 9:185-191.