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Diagnostic Impact of Molecular Lineage Analysis on Paraffin-Embedded Tissue in Hematolymphoid Neoplasia Reclassified by Current WHO Criteria

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Abstract

Background and Objective: By current WHO criteria, most — though not all — cases of hematolymphoid neoplasm can be diagnosed immunomorphologically, diminishing the role of molecular tests for lymphoid antigen receptor clonality in lymphoma diagnosis. Hence, our objective was to glean immunomorphological and molecular correlates from hematolymphoid neoplasms that had remained unresolvable without diagnostic molecular input.

Methods: Thirty-five such cases were reviewed histologically and with standard immunoperoxidases. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNAs (EBER) was performed on selected cases. PCR amplification of genes encoding T-cell receptors (TcR) and immunoglobulin heavy chains (IgH) [TR and IGH genes, respectively] was performed on whole tissue in all cases, and on microdissected cells in two cases.

Results: Twenty-five cases (71%) requiring diagnostic molecular genotyping had some form of peripheral T-cell lymphoma (PTCL). Twenty (80%) of these were complicated by a proliferation of B-lineage cells, either within the same tissue (‘syntopic’) as large B cells (LBC) or Reed-Sternberg (RS)-like cells (17 cases), florid lymphoid hyperplasia (two cases, one also with syntopic LBC) or monotypic plasma cells (one case), or at a separate (‘metatopic’) site as a B-cell lymphoma (two cases, one of which also had syntopic LBC) or Hodgkin lymphoma (HL; one case, also showing syntopic LBC). Fifteen (75%) of these 20 PTCLs with B-lineage proliferation yielded monoclonal TR gene rearrangements, and only two (10%) showed IGH monoclonality, which was transient in one case. Three (18%) of the PTCLs with LBC had originally been misinterpreted as some form of HL. Conversely, of the remaining cases, three of four (75%) that had been diagnosed initially as some form of large cell non-HL (NHL), including two of three that were called ‘anaplastic’, had to be revised to grade II/syncytial nodular sclerosing (NS) HL, yielding polyclonal TcRγ gene (TRG) rearrangements, with one case, in addition, disclosing a biallelic clonal IGH gene rearrangement that excluded anaplastic large cell lymphoma.

Discussion/Conclusion: Paradoxically, monoclonality of TR rather than IGH gene rearrangement may more often be detectable in a predominantly dispersed (‘hodgkinoid’), large B-lineage cell proliferation, consistent with release from immune regulation in the milieu of impaired immunosurveillance within a PTCL. This is compounded by the difficulty in ascertaining clonal IGH gene rearrangements resulting from (1) poor consensus primer hybridization due to somatic hypermutations, and (2) ‘dilution’ in a T-cell-rich milieu. These same difficulties also account for the long-elusive identification of the RS cell lineage. Conversely, anaplastic lymphoma, which is of non-B lineage, may be mimicked by NSHL, which is of B lineage.

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Notes

  1. Please refer to the table in the supplementary material to this article, which is listed as ‘ArticlePlus’ and can be found with the electronic version of this article on AdisOnline (http://moleculardiagnosistherapy.adisonline.com).

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Acknowledgments

We thank Dr Puay-Hoon Tan (Singapore General Hospital [SGH]) for her contributions of Cases 5 and 6 as consultations; Dr Danilo Giron (Tan Tock Seng Hospital, Singapore) for contributing Case 10; Dr Amy Chadburn and Dr Elizabeth Hyjek (Weill-Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA) for sharing Case 14; Dr Norman Chan (Tawam Hospital, Al Ain, Abu Dhabi, UAE) for contributing Case 23; Hui-Qin Lim and Shoa-Nian Choo (National University of Singapore [NUS]), as well as Jane Tan, Maryam Hazly Hilmy and Mei-Jiuan Chng (SGH) for performing the immunohistochemical stains; Adrian Lee (SGH) for performing the molecular work on cases in SGH; Tee-Chok Tan (NUS) for assistance in photomicrography; Jean Chen (National University Hospital [NUH]) for the karyotyping of Case 25; and Wendy Ang (NUH) for configuring the tables in this article.

This work was partly funded by a grant from the Health Services Development Program of the Ministry of Health, Singapore, and partly funded by a grant (no. DCR/P30/06) from the Department of Clinical Research, SGH. The authors have no conflicts of interest that are directly relevant to the content of this study.

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  1. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Leonard Hwan Cheong Tan & Evelyn Siew Chuan Koay

  2. Department of Pathology, Singapore General Hospital, Outram Road, 169608, Singapore

    Leonard Hwan Cheong Tan

  3. Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore

    Lily-Lily Chiu & Evelyn Siew Chuan Koay

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  1. Leonard Hwan Cheong Tan
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Correspondence to Leonard Hwan Cheong Tan.

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Tan, L.H.C., Chiu, LL. & Koay, E.S.C. Diagnostic Impact of Molecular Lineage Analysis on Paraffin-Embedded Tissue in Hematolymphoid Neoplasia Reclassified by Current WHO Criteria. Mol Diag Ther 11, 29–53 (2007). https://doi.org/10.1007/BF03256221

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