J Pathol Transl Med.  2022 Mar;56(2):92-96. 10.4132/jptm.2021.10.15.

An unusual case of microsatellite instability–high/deficient mismatch repair (MSI-H/dMMR) diffuse large B-cell lymphoma revealed by targeted gene sequencing

Affiliations
  • 1Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
  • 2Center for Precision Medicine, Seoul National University Hospital, Seoul, Korea
  • 3Cancer Research Institute, Seoul National University, Seoul, Korea

Abstract

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved as a tissue-agnostic biomarker for immune checkpoint inhibitor therapy in patients with solid tumors. We report the case of an MSI-H/dMMR diffuse large B-cell lymphoma (DLBCL) identified by targeted gene sequencing (TGS). A 90-year-old female who presented with vaginal bleeding and a large mass in the upper vagina was diagnosed with germinal center-B-cell-like DLBCL, which recurred at the uterine cervix at 9 months after chemotherapy. Based on TGS of 121 lymphoma-related genes and the LymphGen algorithm, the tumor was classified genetically as DLBCL of EZB subtype. Mutations in multiple genes, including frequent frameshift mutations, were detected by TGS and further suggested MSI. The MSI-H/dMMR and loss of MLH1 and PMS2 expression were determined in MSI-fragment analysis, MSI real-time polymerase chain reaction, and immunohistochemical tests. This case demonstrates the potential diagnostic and therapeutic utility of lymphoma panel sequencing for DLBCL with MSI-H/dMMR.

Keyword

Diffuse large B-cell lymphoma; Microsatellite instability; Deficient mismatch repair; Targeted gene sequencing

Figure

  • Fig. 1 Microscopy and immunohistochemical findings. (A) Atypical lymphoid cells show a centroblastic morphology and diffuse growth pattern. Atypical lymphoid cells are positive for CD20 (B), CD10 (C), and BCL6 (D) and are negative for MUM1 (E), BCL2 (F), and C-MYC (G). The Ki-67 labeling index was 80% (H). Scattered small CD3+ cells (I) and CD8+ cells (J) are observed. Programmed death-ligand 1 is expressed mainly in tumor-associated macrophages and occasionally in tumor cells (insert, about 5% of tumor cells in the whole slide) (K). Immunohistochemistry reveals mismatch repair proteins and loss of expression of MLH1 (L) and PMS2 (M) but intact expression of MSH6 (N) and MSH2 (O).

  • Fig. 2 Microsatellite instability (MSI) test results. MSI was detected in all five quasi-monomorphic markers using the U-TOP MSI detection test, revealing the MSI-high (MSI-H) status of the tumor. Genomic DNA from HeLa cells was used as a negative control.


Reference

References

1. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96:261–8.
2. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357:409–13.
3. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019; 25:3753–8.
Article
4. Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017; 2017:PO.17.00073.
Article
5. Middha S, Zhang L, Nafa K, et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis Oncol. 2017; 2017:PO.17.00084.
Article
6. Albayrak A, Garrido-Castro AC, Giannakis M, et al. Clinical pan-cancer assessment of mismatch repair deficiency using tumor-only, targeted next-generation sequencing. JCO Precis Oncol. 2020; 4:1084–97.
Article
7. Trabucco SE, Gowen K, Maund SL, et al. A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67,000 patient samples. J Mol Diagn. 2019; 21:1053–66.
Article
8. Duval A, Raphael M, Brennetot C, et al. The mutator pathway is a feature of immunodeficiency-related lymphomas. Proc Natl Acad Sci U S A. 2004; 101:5002–7.
Article
9. Tian T, Li J, Xue T, Yu B, Li X, Zhou X. Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B-cell lymphoma. Cancer Med. 2020; 9:2330–42.
Article
10. Wright GW, Huang DW, Phelan JD, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020; 37:551–68.
Article
11. Suraweera N, Duval A, Reperant M, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002; 123:1804–11.
Article
12. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016; 22:1342–50.
Article
13. Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol. 2019; 37:3291–9.
Article
14. Kuruvilla J, Ramchandren R, Santoro A, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2021; 22:512–24.
Article
15. Smith SD, Till BG, Shadman MS, et al. Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy. Br J Haematol. 2020; 189:1119–26.
Article
16. de Miranda NF, Peng R, Georgiou K, et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med. 2013; 210:1729–42.
Article
17. Dubois S, Viailly PJ, Mareschal S, et al. Next-generation sequencing in diffuse large B-cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study. Clin Cancer Res. 2016; 22:2919–28.
Article
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