Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity

Abstract

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.

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Fig. 1: Schematic representation of the cases included and analyses conducted in this study.
Fig. 2: Tall cell carcinomas with reversed polarity harbor recurrent IDH2 R172 hotspot mutations which are detectable by immunohistochemistry, frequently co-occurring with PIK3CA hotspot mutations.
Fig. 3: Detection of IDH2 R172 hotspot mutations by immunohistochemistry is feasible in excision and core needle biopsy specimens.
Fig. 4: Immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations in tall cell carcinomas with reversed polarity.

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Acknowledgements

This study was partially funded by the Breast Cancer Research Foundation. Research reported in this publication was partly funded by a Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute (grant No. P30CA008748). FP is partially funded by a K12 CA184746 grant and BW by a Cycle of Survival grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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JSR-F and EB conceived the study. EZ, FD, TMD, HYW, DG, MMH, GK, RB, JPP, EAR, SH, MS, LC, SS, Y-YC, and EB contributed with cases. FP and EB reviewed the cases. FP, EdS, and DF conducted the experiments. FP, EdS, DF, FCG, JRL, TB, ADCP, BW, and AAJ analyzed and interpreted the data. FP wrote the first manuscript that was reviewed by all co-authors.

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Correspondence to Jorge S. Reis-Filho or Edi Brogi.

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JSR-F reports receiving personal/consultancy fees from Goldman Sachs and REPARE Therapeutics, membership of the scientific advisory boards of VolitionRx and Page.AI, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech, and InVicro, outside the scope of this study. All other authors declare that they have no conflict of interest.

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Pareja, F., da Silva, E.M., Frosina, D. et al. Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity. Mod Pathol 33, 1056–1064 (2020). https://doi.org/10.1038/s41379-019-0442-2

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