. 2015 Aug 7:13:184.

doi: 10.1186/s12916-015-0419-z.

The variable phenotype and low-risk nature of RAS-positive thyroid nodules

Marco Medici¹, Norra Kwong², Trevor E Angell³, Ellen Marqusee⁴, Matthew I Kim⁵, Mary C Frates⁶, Carol B Benson⁷, Edmund S Cibas⁸, Justine A Barletta⁹, Jeffrey F Krane¹⁰, Daniel T Ruan¹¹, Nancy L Cho¹², Atul A Gawande¹³, Francis D Moore Jr¹⁴, Erik K Alexander¹⁵

Affiliations

¹ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. m.medici@erasmusmc.nl.
² Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. n.kwong@partners.org.
³ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. tangell@partners.org.
⁴ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. emarqusee@partners.org.
⁵ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. mikim@partners.org.
⁶ Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. mfrates@partners.org.
⁷ Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. cbenson@partners.org.
⁸ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ecibas@partners.org.
⁹ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jbarletta@partners.org.
¹⁰ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jkrane@partners.org.
¹¹ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. druan@partners.org.
¹² Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. nlcho@partners.org.
¹³ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. agawande@partners.org.
¹⁴ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. fmoore@partners.org.
¹⁵ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. ekalexander@partners.org.

PMID: 26253102
PMCID: PMC4528713
DOI: 10.1186/s12916-015-0419-z

The variable phenotype and low-risk nature of RAS-positive thyroid nodules

Marco Medici et al. BMC Med. 2015.

. 2015 Aug 7:13:184.

doi: 10.1186/s12916-015-0419-z.

Authors

Affiliations

¹ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. m.medici@erasmusmc.nl.
² Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. n.kwong@partners.org.
³ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. tangell@partners.org.
⁴ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. emarqusee@partners.org.
⁵ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. mikim@partners.org.
⁶ Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. mfrates@partners.org.
⁷ Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. cbenson@partners.org.
⁸ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ecibas@partners.org.
⁹ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jbarletta@partners.org.
¹⁰ Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jkrane@partners.org.
¹¹ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. druan@partners.org.
¹² Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. nlcho@partners.org.
¹³ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. agawande@partners.org.
¹⁴ Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. fmoore@partners.org.
¹⁵ Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. ekalexander@partners.org.

PMID: 26253102
PMCID: PMC4528713
DOI: 10.1186/s12916-015-0419-z

Abstract

Background: Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed.

Methods: We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations.

Results: Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100%). Out of the 17 RAS-positive nodules, ten underwent surgery, of which eight proved malignant (47%). All RAS-positive malignancies were low risk - all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results.

Conclusions: While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS-positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions.

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Comment in

Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer.
Xing M. Xing M. BMC Med. 2016 Jan 27;14:12. doi: 10.1186/s12916-016-0559-9. BMC Med. 2016. PMID: 26817707 Free PMC article.

References

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The variable phenotype and low-risk nature of RAS-positive thyroid nodules

Affiliations

The variable phenotype and low-risk nature of RAS-positive thyroid nodules

Authors

Affiliations

Abstract

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

Miscellaneous