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Absence of BRAF, NRAS, KRAS, HRAS Mutations, and RET/PTC Gene Rearrangements Distinguishes Dominant Nodules in Hashimoto Thyroiditis from Papillary Thyroid Carcinomas

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Abstract

Dominant nodules within Hashimoto thyroiditis (HT) may present with unique morphological features that overlap with but are not diagnostic of papillary thyroid carcinoma (PTC). Activating BRAF point mutations, RAS aberrations, and RET rearrangements are mutually exclusive events in the oncogenesis of papillary thyroid carcinoma, and RET rearrangements have been previously described in dominant nodules of HT. We identified 28 cases of Hashimoto thyroiditis with a dominant nodule, from 345 consecutive HT thyroidectomies. Screening for BRAF, RET, KRAS, NRAS, and HRAS mutations, as well as RET-PTC1 and RET-PTC3 rearrangements, was performed on paraffin-embedded material from 17 of these dominant nodules. Patients ranged in age from 29 to 76 years and were predominantly female, and the nodules ranged from 1.5 to 6.2 cm. No BRAF or RAS mutations or RET-PTC rearrangements were identified in a dominant nodule, including those with atypical, worrisome histopathologic features. Of ten cases with diagnostic concomitant or incidental papillary carcinoma, three had a V600E point mutation in BRAF, and one case had a BRAF exon 15 deletion (600–604E), while the dominant nodules were negative for mutation, supporting the notion that dominant nodules are neither malignant nor precursor lesions, and strict histological, clinical, and molecular criteria must be met for the diagnosis of papillary thyroid carcinoma.

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Acknowledgments

The BRAF data were presented, in part, at the United States and Canadian Academy of Pathology Annual Meeting in Atlanta, GA, February 11–16, 2006. The authors wish to acknowledge prior input from Dr. Kimberly Springer and Victoria Derr in the original presentation, as well as technical assistance from Amy Harlow and Andrea Warrick. This study is supported in part from funding from a VA Merit Review Grant (MCH). Dr. Heinrich has an equity interest in MolecularMD and serves as a consultant for MolecularMD.

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Authors and Affiliations

  1. Pathology Service, WRN219, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Peter M. Sadow

  2. Department of Medicine, Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR, 97239, USA

    Michael C. Heinrich

  3. Department of Pathology, Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR, 97239, USA

    Christopher L. Corless

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Jonathan A. Fletcher & Vânia Nosé

  5. Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA

    Peter M. Sadow, Jonathan A. Fletcher & Vânia Nosé

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  1. Peter M. Sadow
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  2. Michael C. Heinrich
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Correspondence to Peter M. Sadow.

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Sadow, P.M., Heinrich, M.C., Corless, C.L. et al. Absence of BRAF, NRAS, KRAS, HRAS Mutations, and RET/PTC Gene Rearrangements Distinguishes Dominant Nodules in Hashimoto Thyroiditis from Papillary Thyroid Carcinomas. Endocr Pathol 21, 73–79 (2010). https://doi.org/10.1007/s12022-009-9101-3

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