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


Authors: Pareja, F.; da Silva, E. M.; Frosina, D.; Geyer, F. C.; Lozada, J. R.; Basili, T.; Da Cruz Paula, A.; Zhong, E.; Derakhshan, F.; D’Alfonso, T.; Wen, H. Y.; Giri, D. D.; Hayes, M. M.; Krings, G.; Bhargava, R.; Palazzo, J. P.; Rakha, E. A.; Hoda, S. A.; Sanders, M. E.; Collins, L. C.; Schnitt, S. J.; Chen, Y. Y.; Weigelt, B.; Jungbluth, A. A.; Reis-Filho, J. S.; Brogi, E.
Article Title: 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. © 2020, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Keywords: immunohistochemistry; adult; clinical article; human tissue; aged; excision; gene mutation; exon; gene locus; immunoreactivity; monoclonal antibody; breast carcinoma; needle biopsy; papillary carcinoma; breast papilloma; isocitrate dehydrogenase 2; sanger sequencing; human; priority journal; article; hotspot mutation; tall cell carcinoma
Journal Title: Modern Pathology
Volume: 33
Issue: 6
ISSN: 0893-3952
Publisher: Nature Publishing Group  
Date Published: 2020-06-01
Start Page: 1056
End Page: 1064
Language: English
DOI: 10.1038/s41379-019-0442-2
PUBMED: 31896809
PROVIDER: scopus
PMCID: PMC7286791
DOI/URL:
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
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MSK Authors
  1. Dilip D Giri
    146 Giri
  2. Yong Hannah Wen
    178 Wen
  3. Edi Brogi
    397 Brogi
  4. Achim Jungbluth
    387 Jungbluth
  5. Denise Frosina
    100 Frosina
  6. Britta Weigelt
    366 Weigelt
  7. Jorge Sergio Reis
    403 Reis
  8. John Roy Lozada
    20 Lozada