BRAFV600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer

doi:10.1016/j.surg.2010.09.005

Surgery

Volume 148, Issue 6, December 2010, Pages 1139-1146

Presented at the 29th Annual Meeting of the American Association of Endocrine Surgeons, Pittsburgh, Pennsylvania, April 18-20, 2010.

https://doi.org/10.1016/j.surg.2010.09.005 Get rights and content

Background

The role of the B-isoform of the Raf kinase (BRAF) mutation BRAF^V600E as an independent prognostic factor in papillary thyroid cancer (PTC) remains controversial. Some studies suggest that tumors containing BRAF^V600E have decreased radioiodine avidity and present a greater risk of nodal recurrence and distant metastases.

Methods

Paraffin-embedded specimens from consecutive patients who underwent surgery for PTC before 2003 were independently reviewed by an endocrine pathologist. DNA was extracted, amplified by polymerase chain reaction, and the presence of the BRAF^V600E mutation was determined by restriction digest. Tumor characteristics and long-term disease outcomes were analyzed according to BRAF^V600E status.

Results

BRAF^V600E was identified in 60 (59%) of 101 patients. At a median follow-up of 106 months, the overall disease-free survival was 78%. Clinically evident nodal recurrence occurred in 11% of BRAF^V600E-positive patients, and all patients required lateral neck dissection (P = .02). In contrast, subclinical nodal recurrence occurred in 7% of BRAF^V600E-negative patients, and all recurrences were successfully ablated with radioactive iodine. There was a trend toward poorer disease-free survival among patients with stage III/IV PTC and BRAF^V600E mutation (P = .08). All 5 disease-related deaths occurred in patients with BRAF^V600E-positive primary tumors (P = .06).

Conclusion

The BRAF^V600E mutation in PTC is associated with an increased risk of palpable nodal recurrence and the need for reoperative surgery.

Section snippets

Patients

This study involved 137 consecutive patients with PTC who underwent surgery between the years 1990 and 2003. Patients were identified from a prospectively maintained endocrine surgical database after approval from the local institutional human research ethics committee. Paraffin-embedded tissue was available only from the Department of Anatomical Pathology at the Royal North Shore Hospital, and its acquisition is regulated by the New South Wales Human Tissue Act 1983. Hence, the number of

Results

Of the 104 specimens tested, the tumor BRAF^V600E genotype was determined in 101, and the BRAF^V600E mutation was identified in 60 (59%) specimens. Of these 101 patients, 99 (98%) underwent total thyroidectomy or hemithyroidectomy followed by completion thyroidectomy; the remaining 2 patients refused completion thyroidectomy after initial hemithyroidectomy. At least 1 ablative dose of radioactive iodine was administered to 90 (89%) of the 101 patients. Radioiodine therapy was not performed in 11

Discussion

This study documents the influence of the BRAF^V600E mutation on long-term disease outcomes within an Australian cohort of patients. The data suggest that patients with tumors containing BRAF^V600E are at a greater risk of requiring reoperative surgery and that these tumors may have less iodine avidity than those associated with BRAF^V600E-negative PTC. The incidence of BRAF^V600E in our study (59%) is relatively high in comparison with other studies.8, 9 In contrast with several other large

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This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39–59 years) and a median follow-up time of 53 months (IQR, 25–93 months).
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BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.
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Fourth, no gene mutation data was considered in our models. Although some mutations may be associated with lymph node metastasis in PTC [42,43], further verification is needed to assess whether these mutations can be integrated with these nomograms. Fifth, although our nomograms may aid decision making regarding LND, whether undergoing LND is beneficial in terms of survival benefit for those who do not present with clinically involved nodes is still controversial.
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Unifocal PTC patients who underwent LND between April 2012 and August 2014 were identified. Clinical and pathological variables were retrospectively evaluated using univariate and stepwise multivariate logistic regression analysis. Variables that had statistical significance in final multivariate logistic models were chosen to build nomograms, which were further corrected using the bootstrap resampling method.
In all, 505 PTC patients were eligible for analysis. Among these, 178 patients (35.2%) had lateral neck metastasis. Two nomograms were generated: nomogram (c) and nomogram (c + p). Nomogram (c) incorporated four clinical variables: age, tumor size, tumor site, and extrathyroidal extension (ETE). It had a good discriminative ability, with a C-index of 0.79 (bootstrap-corrected, 0.78). Nomogram (c + p) incorporated two clinical variables and two pathological variables: tumor size, tumor site, extranodal extension (ENE), and number of positive nodes in the central compartment. Nomogram (c + p) showed an excellent discriminative ability, with a C-index of 0.86 (bootstrap-corrected, 0.85).
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La mutación BRAF V600E en el cáncer papilar de tiroides (CPT) parece asociarse a una resistencia al ¹³¹I. Nuestro principal objetivo fue cuantificar la respuesta al ¹³¹I tras la cirugía tanto en pacientes que presentaban la mutación (BRAF+) como en los que no presentaban el gen mutado (BRAF−).
Estudio prospectivo de los CPT intervenidos y tratados con ¹³¹I desde septiembre de 2015 hasta enero de 2017. Variables: edad, género, estadio tumoral, histológicas, tiroglobulina antes de ¹³¹I, a las 48 h y a los 6 meses; dosis absorbida y % de actividad a los 2 y a los 7 días y tiempo de eliminación.
Cuarenta y un pacientes y 67 restos tiroideos. El 61% eran BRAF+. En los estadios iii y iv, el 80% eran BRAF+. En el vaciamiento ganglionar terapéutico, el 100% eran BRAF+. El número de ganglios fue superior en BRAF+: 3,4 vs 1,2 (p = 0,01). La variante clásica fue predominante en BRAF+ (91,7% vs 8,3%; p = 0,03). El 85,7% vs 14,3% de los BRAF+ tuvieron reacción desmoplásica (p = 0,02). Los BRAF+ presentaban menor dosis absorbida respecto a la actividad administrada (5,4 vs 20 Gy/MBq; p = 0,02); menor % de actividad respecto a la unidad de masa a los 2 (0,046 vs 0,103%/g; p = 0,02) y a los 7 días (0,006 vs 0,034%/g, p = 0,04).
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BRAF is a serine/threonine kinase that promotes proliferation by constitutively activating the mitogen-activated protein kinase pathway [7-9]. Mutation of the BRAF gene occurs in many human cancers, including hairy cell leukemia (~100%) [8], pleomorphic xanthoastrocytoma (66%) [10], cutaneous melanoma (50%) [7,8,10], papillary thyroid cancer (46%) [8,9,11], borderline ovarian tumor (34%), biliary tract tumor (11%), colorectal cancer (10%) [12], and non–small cell lung cancer (2%) [8]. The most common BRAF mutation is a single amino acid substitution of valine for glutamic acid at residue 600 (V600E), which has been associated with a poor survival rate in metastatic melanoma, colorectal cancer, and papillary thyroid cancer patients.
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: Supported by in part from research grants from the New South Wales Cancer Institute (to C.J.O. and S.B.S.) and the Cancer Council of New South Wales (to M.B. and R.C-B.).

: The first two authors contributed equally to this publication.

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American Association of Endocrine SurgeonBRAFV600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer

Background

Methods

Results

Conclusion

Section snippets

Patients

Results

Discussion

Am J Med

Surgery

Increasing incidence of thyroid cancer in the United States, 1973-2002

JAMA

Thyroid Cancer in New South Wales

Papillary thyroid cancer: surgical management of lymph node metastases

Curr Treat Options Oncol

Prognostic factors associated with the survival of patients developing loco-regional recurrences of differentiated thyroid carcinomas

J Clin Endocrinol Metab

Staging systems for papillary thyroid carcinoma: a study of 2 tertiary referral centers

Ann Surg

BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications

Endocr Rev

Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis

Cancer

Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers

J Clin Endocrinol Metab

Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas

Am J Surg Pathol

BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas

J Clin Endocrinol Metab

American Association of Endocrine Surgeon
BRAF^V600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer