Clinical, Sonographic, and Pathological Characteristics of RAS-Positive Versus BRAF-Positive Thyroid Carcinoma.
Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete.



We correlated clinical, radiographic, and pathological findings from patients with thyroid cancer harboring a BRAF or RAS mutation.



Prospective cohort study.



Academic, tertiary care hospital.



A total of 101 consecutive patients with well-differentiated thyroid cancer.



We compared the clinical, sonographic, and pathological characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer.



Of 101 patients harboring these mutations, 71 were BRAF-positive, whereas 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (P = .04), although BRAF-positive nodules were more likely to harbor concerning sonographic characteristics (hypoechogenicity [P < .001]; irregular margins [P = .04]). Cytologically, 70% of BRAF-positive nodules were classified positive for PTC, whereas 87% of RAS-positive nodules were indeterminate (P < .001). Histologically, 96% of RAS-positive PTC malignancies were follicular variants of PTC, whereas 70% of BRAF-positive malignancies were classical variants of PTC. BRAF-positive malignancies were more likely to demonstrate extrathyroidal extension (P = .003), lymphovascular invasion (P = .02), and lymph node metastasis (P < .001).



BRAF-positive malignant nodules most often demonstrate worrisome sonographic features and are frequently associated with positive or suspicious Bethesda cytology. In contrast, RAS-positive malignancy most often demonstrates indolent sonographic features and more commonly associates with lower risk, "indeterminate" cytology. Because BRAF and RAS mutations are the most common molecular perturbations associated with well-differentiated thyroid cancer, these findings may assist with improved preoperative risk assessment by suggesting the likely molecular profile of a thyroid cancer, even when postsurgical molecular analysis is unavailable.
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Sujay
S
Kakarmath
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Howard T
HT
Heller
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Caroline A
CA
Alexander
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Edmund S
ES
Cibas
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Jeffrey F
JF
Krane
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Justine A
JA
Barletta
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Neal I
NI
Lindeman
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Mary C
MC
Frates
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Carol B
CB
Benson
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Atul A
AA
Gawande
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Nancy L
NL
Cho
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Matthew
M
Nehs
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Francis D
FD
Moore
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Ellen
E
Marqusee
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Mathew I
MI
Kim
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
P Reed
PR
Larsen
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Norra
N
Kwong
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Trevor E
TE
Angell
Thyroid Section, Division of Endocrinology, Hypertension, and Diabetes (S.K., T.E.A., N.K., C.A.A., E.M., M.I.K., P.R.L., E.K.A.), and Departments of Radiology (H.T.H., M.C.F., C.B.B.), Pathology (E.S.C., J.F.K., J.A.B., N.I.L.), and Surgery (A.A.G., N.L.C., M.N., F.D.M.), The Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Erik K
EK
Alexander
D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D002291:Carcinoma, Papillary; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D016606:Thyroid Nodule / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D055815:Young Adult
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
Arch Pathol Lab Med. 2011 May;135(5):569-77
21526955
Cell. 2014 Oct 23;159(3):676-90
25417114
PLoS One. 2015 Jun 03;10(6):e0124711
26039708
PLoS One. 2014 Jun 17;9(6):e99451
24936796
Thyroid. 2009 Nov;19(11):1167-214
19860577
J Mol Diagn. 2014 Nov;16(6):660-72
25157968
J Clin Oncol. 2015 Jan 1;33(1):42-50
25332244
Thyroid. 2006 Feb;16(2):109-42
16420177
N Engl J Med. 2013 Feb 14;368(7):623-32
23406027
PLoS One. 2009 Nov 18;4(11):e7887
19924296
Thyroid. 2016 Jan;26(1):1-133
26462967
Am J Clin Pathol. 2009 Nov;132(5):658-65
19846805
PLoS One. 2014 Aug 01;9(8):e103325
25083769
Endocr Pract. 2016 May;22(5):622-39
27167915
Oncologist. 2013;18(8):926-32
23873720
Thyroid. 2015 Feb;25(2):221-8
25333496
Ann Surg Oncol. 2010 Jun;17(6):1471-4
20180029
Cancer. 2007 Dec 25;111(6):508-16
17999413
BMC Med. 2015 Aug 07;13:184
26253102
J Clin Endocrinol Metab. 2012 Dec;97(12):4390-8
23066120
PLoS One. 2011;6(9):e24433
21931712
JAMA. 2013 Apr 10;309(14):1493-501
23571588
Medicine (Baltimore). 2012 Sep;91(5):274-86
22932786
PLoS One. 2013 Sep 16;8(9):e74950
24066160
J Clin Endocrinol Metab. 2015 Dec;100(12 ):4434-40
26465395
Cancer Discov. 2012 Jan;2(1):82-93
22585170
Radiology. 2008 Jun;247(3):762-70
18403624