Elsevier

The Lancet Oncology

Volume 11, Issue 6, June 2010, Pages 579-588
The Lancet Oncology

Review
Common misdiagnoses in lymphomas and avoidance strategies

https://doi.org/10.1016/S1470-2045(09)70351-1Get rights and content

Summary

Lymphoma diagnosis integrates clinical, morphological, immunophenotypical, and molecular genetic features, as shown in WHO classifications of lymphoid malignancies. Diagnosis of lymphoma is challenging. Reactive lesions such as Kikuchi lymphadenitis, infectious mononucleosis, autoimmune lymphoproliferative syndrome, and immunoglobulin G4-related sclerosing disease can be misdiagnosed as lymphomas. Anaplastic large-cell lymphoma variants that are positive for anaplastic lymphoma kinase, classical Hodgkin's lymphoma variants, and infarcted lymphomas might be misdiagnosed as reactive disorders. Difficulties with classification of lymphomas are also encountered, such as the distinction of classical Hodgkin's lymphoma from anaplastic large-cell lymphoma that is negative for anaplastic lymphoma kinase. Interpretation of immunophenotyping results is complicated in some cases by aberrant or cross-lineage expression of lymphoid antigens on lymphomas, and the occasional lymphoid antigen expression on non-lymphoid malignancies. Molecular analysis can help to define clonality and lineage, but can be affected by the sensitivity and specificity of tests and cross-lineage gene rearrangement and pseudoclonality. To resolve these issues, a close collaboration between the clinician, histopathologist, and molecular biologist is needed. The aim of this review is to provide pathologists and clinicians with a concise account of these pitfalls and avoidance strategies.

Introduction

Diagnosis of lymphoma is an evolving science. Initially based on morphology alone, classification of lymphomas has progressed to include lymphoid lineages, cell types, and clinical features. In WHO classifications, lymphomas are categorised on the basis of morphological, immunophenotypical, genetic, and clinical characteristics. An accurate diagnosis, apart from being pathologically important, provides useful guidance to clinicians for effective treatment.

Lymphoma diagnosis, however, is one of the most complicated tasks in histopathology. Importantly, reactive lymphoid disorders need to be distinguished from truly neoplastic lesions, because the exact classification greatly affects patient treatment. Lymphoma classification is not always concordant between histopathologists. For common B-cell lymphomas, the concordance rate between community and specialised lymphoma pathologists is about 95%.1 However, for more difficult subtypes of lymphomas, such as Burkitt's lymphoma and peripheral T-cell lymphoma, concordance based on morphology could be lower than 50%, although with immunophenotyping this rate might increase to 60–80%.2 Thus, 5% of patients with common B-cell lymphomas and up to 20–40% of patients with less common lymphoma types might be inaccurately diagnosed. Lymphoma diagnosis is based on morphological examination complemented by immunophenotyping and molecular genetic investigations. However, even pathologists with much experience can encounter difficulties in each of these steps.

Section snippets

Kikuchi lymphadenitis

Some reactive lymphoid proliferations exhibit a striking increase in large lymphoid cells, and when accompanied by distortion of tissue architecture, can strongly mimic lymphoma (panel 1). Kikuchi lymphadenitis is a self-limiting disorder, often affecting young women. It is of unknown cause and more prevalent in Asians than in white people.3 Patients usually present with enlarged lymph nodes in the neck, but are otherwise well. Typical laboratory findings are an increased ESR, lymphocytosis,

Malignant lymphoma often misdiagnosed as reactive disorders

Reasons that some lymphomas can mimic reactive lesions include: subtle cytological atypia and absence of cellular monotony, as in a small-cell variant of anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) and extranodal marginal zone lymphoma; paucity of neoplastic cells or abundance of inflammatory cells, as in lymphohistiocytic and paucicellular variants of ALK-positive ALCL, lymphomatoid granulomatosis, certain variants of classical Hodgkin's lymphoma, and

Complexities of classification

Errors in classification of lymphomas are inevitable in view of the complexities of WHO classifications (webappendix). In some instances, misclassifications might be inconsequential in relation to treatment. However, if aggressive lymphomas are misclassified as low-grade lymphomas, patient outcomes are jeopardised because of undertreatment. In poorly fixed tissues, thickly-cut sections, or core needle-biopsy materials, neoplastic cells of high-grade lymphomas, such as lymphoblastic lymphoma,

Difficulties in lymphoma diagnosis

Immunophenotyping is important in lymphoma diagnosis, and is crucial for making treatment decisions. Although lineage assignment is often possible with flow cytometry, or immunohistochemistry with an extensive panel of antibodies; in the routine laboratory, usually a panel of fewer antibodies that identify T cells, B cells, and NK-cell lineages are applied. However, cross-lineage expression of antigens can occasionally arise, creating diagnostic challenges. This outcome has been attributed

Cases needing clonality analysis

During lymphocyte development, antigen receptor genes undergo rearrangement. This stepwise rearrangement of the IG or TCR gene joins V, D, and J gene segments, with nucleotides deleted or randomly inserted at the joining sites, leading to a large diversity of antigen receptors. Reactive lymphoid proliferations have polyclonally rearranged IG or TCR genes, whereas malignant lymphoid lesions show clonal rearrangement.

In clinical practice, standard histopathological assessment supplemented by

Conclusion

With careful assessment of the clinical history and methodical morphological examination complemented by appropriate immunophenotyping, most cases of lymphomas can be correctly diagnosed and classified. Molecular analysis will be helpful if doubts exist, especially when the size or quality of the biopsy limits a comprehensive morphological and immunophenotypical examination. However, some cases will remain challenging, necessitating teamwork from the clinician, pathologist, and molecular

Search strategy and selection criteria

We searched PubMed from January, 1989, until October, 2009, for reports in English with the keywords “lymphoma”, “T-cell”, “B-cell”, “natural killer cell”, “Hodgkin”, “immunophenotyping”, and “molecular analysis”. We also searched the reference lists of selected reports so that all relevant articles could be reviewed. Some articles before 1989 were included if they were pertinent.

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