Does a RAS gene mutation mean a thyroid lump is cancer?
Thyroid nodules carrying a RAS mutation turned out to be cancer in fewer than half of cases, and the cancers that were found were all low-risk.
Source
The variable phenotype and low-risk nature of RAS-positive thyroid nodules
Study at a glance
- Design
- Cohort — Prospective blinded cohort at one Boston thyroid clinic: every nodule over 1 cm had FNA cytology plus a 17-alteration mutation panel, interpreted independently of surgical histology; RAS-positive benign nodules were traced back through prior ultrasound records and compared with matched mutation-negative controls.
- N
- N=362 · 362 nodules from 318 patients after exclusions; 17 nodules were RAS-positive, of which 5 benign nodules had long-term ultrasound follow-up compared with 15 matched mutation-negative controls.
- Population
- Euthyroid adults referred for ultrasound-guided biopsy of thyroid nodules larger than 1 cm at Brigham and Women's Hospital, 2010-2012.
- Outcome
- Histological malignancy and cancer features in RAS-positive nodules; nodule growth and cytology over time in RAS-positive benign nodules.
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What they did
Every adult who came for a biopsy of a thyroid nodule larger than 1 cm between 2010 and 2012 had the usual cell (cytology) test plus a separate gene-mutation panel, with pathologists and lab staff blinded to each other's results. Nodules with suspicious cytology generally went to surgery, while benign ones were watched. For RAS-positive nodules the team recorded surgical pathology and, for benign ones, looked back through years of earlier ultrasound scans and compared growth with age- and sex-matched mutation-negative nodules.
What they found
Of 362 nodules, 17 carried a RAS mutation and 8 of these (47%) proved malignant; all 8 were encapsulated follicular-variant papillary cancers with no invasion, spread to lymph nodes or distant metastasis. The other nine RAS-positive nodules were benign, and five followed by ultrasound for a mean of 8.3 years showed no significant growth, whereas matched mutation-negative benign nodules grew by 4.6 mm on average. Patients with benign RAS-positive nodules were about 13 years older than those whose RAS-positive nodules were cancerous. Every cancer was also flagged by abnormal cytology, so the cell test outperformed RAS testing alone.
The limits
What it doesn't show
Only 17 RAS-positive nodules were found, and just five benign ones had long-term follow-up, so the low-risk conclusion rests on very small numbers and cannot rule out later malignant change. Benign nodules that were not operated on were classed by cytology rather than histology, and the study took place at one institution. It was not designed to test whether mutation testing improves outcomes or is cost-effective, and the authors do not recommend routine RAS testing of all nodules.
Key terms
- RAS mutation
- An activating change in one of the HRAS, KRAS or NRAS genes, which drive cell growth signalling and are found in both benign and malignant thyroid nodules.
- Fine needle aspiration (FNA)
- Sampling cells from a nodule with a thin needle, usually under ultrasound guidance, for cytology or molecular testing.
- Cytology versus histology
- Cytology examines loose cells from a needle sample; histology examines tissue architecture from a surgically removed specimen and is the reference standard for cancer.
- Follicular variant of papillary thyroid carcinoma
- A subtype of papillary thyroid cancer with follicular growth pattern, often encapsulated and low risk.
- Blinding
- Keeping assessors unaware of other test results so that one result cannot bias interpretation of another.
- Overdiagnosis
- Labelling a lesion as dangerous or treating it when it would never have caused harm.
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Quiz yourself
About what share of RAS-positive nodules proved malignant?
Common questions
If RAS-positive nodules were cancer 47% of the time, isn't that high?
It is higher than the 9.1% malignancy rate across all nodules, but it also means more than half were benign, so surgery based on the mutation alone would remove many harmless nodules.
Why did the authors look at old ultrasound scans?
Several RAS-positive benign nodules had been scanned or biopsied years before, which let the team see whether they had grown or changed; none had.
Should everyone with a thyroid nodule get a RAS test?
The authors argue not: cytology caught every cancer, and routine mutation testing has not been shown to be cost-effective or improve outcomes.
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