Langenbecks Arch Surg (2014) 399:225–228 DOI 10.1007/s00423-013-1153-7
REVIEW ARTICLE
BRAF mutation status in papillary thyroid carcinoma: significance for surgical strategy P. Miccoli & F. Basolo
Received: 13 November 2013 / Accepted: 11 December 2013 / Published online: 30 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background BRAF mutation is probably the only molecular marker acting as a risk factor that is available before surgery: for this reason, soon after it became quite widespread, it seemed an important tool as a guide towards an individualized surgical therapy in papillary thyroid carcinoma. Purpose Capsule invasion, multifocality, and lymph node involvement are the most important parameters influencing the choice of surgical strategy in front of small papillary cancers and, in more detail, of micro papillary carcinomas. The relationship between these parameters and the BRAF mutation are closely examined through the more recent literature. Capsular invasion seems to show the strongest correlation with the mutation and this has important correlations, thus suggesting that a more aggressive local surgery might be advisable, whereas the correlation between the mutation and lymph node involvement would be weaker, at least according to the most recent studies. Conclusions The personalization of surgical therapy, today, seems easier to achieve thanks to molecular testing. In particular, an important result could be in the short term reduction in the number of completion thyroidectomies following simple lobectomies. Also, post operative radioactivated iodine therapies should be more carefully evaluated and tailored according to BRAF status. A possible flow chart for the decision of the therapeutic approach is proposed in accordance to the results of the literature. Keywords BRAF . Thyroid carcinoma . Thyroid surgery . Risk stratification . Tailored surgery P. Miccoli : F. Basolo Department of Surgical Pathology, University of Pisa, Pisa, Italy P. Miccoli (*) AOUP Pisa, Via Paradisa 2, 56124 Pisa, Italy e-mail: [email protected]
Introduction BRAF is a member of the RAF kinase family that promotes signaling through the RAS-MAP kinase signal-transduction cascade. An activating mutation located on exon 15 of the B isoform of the RAF kinase gene results in a valine-to-glutamic acid substitution at amino acid 600 (BRAF V600E), leading to destabilization of the kinase encoded by the gene and promoting tumorigenesis through the MAPK pathway [1]. Since its initial description in thyroid cancer [2, 3], BRAF V600E has been widely found in papillary thyroid carcinoma (PTC), with a prevalence of approximately 45 %. In recent years, BRAF V600E has emerged as a promising prognostic factor in the risk stratification of PTC [4]. Although some researchers have reported that the BRAF mutation has no relationship to poor prognosis [5], many studies have demonstrated significant associations between BRAF mutation and high-risk clinical-pathological characteristics of PTCs [6]. The possible importance of BRAF mutation in stratifying the patients for a tailored surgical strategy is due to the fact that this mutation is probably the only molecular marker acting as a risk factor that is available before surgery [4, 7]. A correct stratification of surgical strategy in patients presenting a PTC according to their BRAF status though should take into account that the real challenge for surgeons is constituted by those tumors that, in spite of their pre operative conventional staging, could benefit from a more aggressive surgical approach; in other words, for small papillary carcinomas that would be otherwise considered as being “low-risk” tumors. On the other hand, an absence of the mutation could allow simplifying the follow-up of these patients; for example, avoiding unnecessary radioactivated iodine therapy after surgery or even limiting to a unilateral thyroidectomy the operative procedure for these cases. Actually, using
226
laser dissection, the mutation can be found even in microcarcinomas which are as small as 1 mm or less [8]. Even though there is no certainty that these tumors might evolve in clinically relevant carcinomas, they probably should be regarded with higher caution. In a large study, on more than 1,000 cases operated for PTC published in 2010 [9], it was readily apparent that some parameters of tumor invasiveness, which would involve a worse prognosis, were all linked with the presence of BRAF mutation, but not all of them with an identical statistical significance. Moreover, only a few of them could influence the choice of the surgical procedure to adopt. In more details, the parameters that could imply to a larger extent a personalization of the surgical strategy seem to be the capsule invasion, the multifocality, and the lymph node involvement [9].
Langenbecks Arch Surg (2014) 399:225–228
Multifocality Recent papers [10] showed that there was no clear evidence that BRAF V600E mutation is associated with higher rate of tumor multicentricity or at least, the association proved to have a low-statistical significance: in other words, this parameter, though important, can hardly be predicted by the presence of the mutation. This assumption could lead the surgeon to propose a hemithyroidectomy to these patients harboring a small PTC even in presence of a BRAF mutation. The reduced extent of surgery at the gland level though should be balanced by a higher aggressiveness towards the lymph nodes in the central compartment. Therefore, would it be reasonable to propose a lobectomy plus a sixth-level node clearance in a patient with this profile? Even though this approach is
Fig. 1 Flow chart: BRAF analysis available before surgery (a) and after surgery (b). WT wild type
Langenbecks Arch Surg (2014) 399:225–228
currently often adopted in several surgical backgrounds, particularly in Eastern countries [11], this solution still raises many doubts. In fact, since it is well ascertained that BRAF mutation tends to be associated with a higher incidence of node metastases that, on the other hand, tend to show a reduced iodine avidity, it is presumable that a more aggressive radioiodine treatment is necessary but it implies the absence of any thyroid tissue in the neck to serve the purpose as it is expected. For this reason, in our opinion, a total thyroidectomy can still be considered the best option in all PTC patients presenting with a BRAF mutation, no matter what the size of the tumor is. Lymph node involvement Many papers seem to be concordant about the increased rate of lymph node metastases in patients with BRAF mutation [4, 7, 10, 12] so as to justify the necessity of performing a routine central compartment lymphadenectomy, in these cases, even in the presence of small tumors and no evidence of enlarged nodes at pre operative imaging. These led some authors to propose a flow chart where a total thyroidectomy plus a central compartment lymphadenectomy was the treatment of choice for these patients [7]. Very recently though, some studies appeared [13, 14] that seem to deny a sure correlation between BRAF mutation and node metastases. Even the general role of this mutation as a negative prognostic factor should be entirely re-evaluated according to some [13]. Also, authors that always supported the prognostic value of this mutation recently admitted that the “predictive power of BRAF for CLN metastases was high but less prominent than some of these pathological factors…” [4, 15]. For these reasons, it is difficult to totally share the above mentioned flow chart since a central compartment clearance, only on the basis of BRAF mutation, cannot be considered mandatory according to the most recent studies. In fact, further data are concordant about the necessity of matching the mutation with other tumor parameters since it is not an independent prognostic factor [4, 16]. In particular, aggressive histotypes and extrathyroidal extension should be taken into account. Capsular invasion This parameter showed the highest correlation with BRAF mutation [8, 9]: it was significantly more common in tumors invading the thyroid capsule, to such an extent that there was no statistically significant difference between pT1 tumors with capsule invasion and pT3 tumors in this series. For this reason, even at risk of emphasizing the obvious, the recommendation of an aggressive surgical approach to the thyroid should be widely accepted in all patients presenting this mutation. This means in most, if not all, cases, performing a total
227
thyroidectomy and paying particular attention to the perithyroidal tissue and the overlying thyro-iode muscles when the tumor is anterior. Basically, what has been said until now needs to be better specified in order to give to the above data the right value in indicating a possible surgical strategy and attempting a possible decisional flow chart (Fig. 1). First of all, is the presence of BRAF mutation known before the operation (Fig. 1a) on a cytological specimen or only after the operation on the histological specimen (Fig. 1b)? On one side, it might look advisable to obtain this datum on all the patients before surgery since BRAF is the only risk factor available in small PTC before surgery; on the other hand, searching for BRAF mutation on all cytological specimens in the entire population is probably unrealistic due to its well-recognized inability to improve significantly the diagnostic outcomes which makes this marker poorly cost effective in a pre operative phase. Much simpler would be to have the information, at least when needed, on the histological specimen. In fact, this might strongly influence the decision whether to perform a completion total thyroidectomy or not after a unilateral surgery. If the removed lobe is negative for BRAF mutation in a papillary microcarcinoma, the completion could be avoided, provided that we are not in the presence of an aggressive histotype and there is not a microscopic capsular invasion (not very probable when BRAF is negative) (Fig. 1). On the other hand, if the histological specimen shows the presence of a mutation, I131 therapy should be adopted even in the presence of a microcarcinoma, in particular, if a central compartment lymphadenectomy has not been performed; but if the mutation is absent, radioactivated iodine administration can be excluded with no risk for the patient. To summarize, we might conclude that in those cases where the presence of mutation is known before surgery, a total thyroidectomy is highly recommended also because it constitutes the necessary prerequisite for an aggressive 131I therapy. A central compartment lymphadenectomy can be recommended but its necessity is arguable because not all agree about BRAF's importance on decision making at this level. Finally, it is to be reminded that the exact role of minimally invasive or cosmetic thyroidectomies should also be determined since, as it was said, the main advantage of molecular testing is expressed in micro papillary carcinomas, which are ideal candidates for these approaches. The two techniques which seem to better guarantee a full total thyroidectomy together with a central compartment clearance, when necessary are, up to now, the minimally invasive video assisted thyroidectomy and the robotic axillary thyroidectomy [13, 17, 18].
228
Conclusion Certainly, a trend towards a personalization of surgical therapy according to molecular testing does exist and is probably highly advisable since it could lead to not only more individualized operations but also even more individualized post operative radioactivated iodine therapies. According also to Witt et al. [19], one of the most important downstream results of these testings could be a significant reduction of the completion thyroidectomies after unilateral surgery. In spite of these encouraging conclusions, we cannot elude the problem that some of these techniques might prove to be logistically very demanding and too expensive.
Conflicts of interest None.
References 1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954 2. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RASBRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457 3. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE (2003) BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 88:5399–5404 4. Xing M (2010) Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 321:86–93 5. Kim TY, Kim WB, Song JY, Rhee YS, Gong G, Cho YM, Kim SY, Kim SC, Hong SJ, Shong YK (2005) The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol 63:588–593 6. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW (2005) BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373–6379
Langenbecks Arch Surg (2014) 399:225–228 7. Yip I, Nikiforova MN, Carty SE, Yim JH, Stang ML, Tublin MJ, Lebeau SO, Hodak SP, Ogilvie JB, Nikiforov YE (2009) Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 146:1215–1233 8. Ugolini C, Giannini R, Lupi C, Salvatore G, Miccoli P, Proietti A, Elisei R, Santoro M, Basolo F (2007) Presence of BRAF V600 in very early stages of papillary thyroid carcinoma. Thyroid 17(5):381– 388 9. Basolo F, Torregrossa L, Giannini R, Miccoli M, Lupi C, Sensi E, Berti P, Elisei R, Vitti P, Baggiani A, Miccoli P (2010) Correlation between the BRAF V600 mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 mm: analysis of 1060 cases. J Clin Endocrinol Metab 95:4197–4205 10. Elisei R, Viola D, Torregrossa L, Giannini R, Romei C, Ugolini C, Molinaro E, Agate L, Biagini A, Lupi C, Valerio L, Materazzi G, Miccoli P, Piaggi P, Pinchera A, Vitti P, Basolo F (2012) The BRAF (V600E) mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: singleinstitution results from a large cohort study. J Clin Endocrinol Metab 97(12):4390–4398 11. Hyun SM, Song HY, Kim SY, Nam SY, Roh JL, Han MW, Choi SH (2012) Impact of combined unilateral central neck dissection and hemithyroidectomy in patients with papillary thyroid micro carcinomas. Ann Surg Oncol 19:591–596 12. Joo JY, Yoon YH, Choi B, Kim J, Jo YS, Shong M, Koo BS (2012) Prediction of occult central lymph node metastases in papillary thyroid cancer by pre operative BRAF analysis using fine needle aspiration biopsy: a prospective study. J Clin Endocrinol Metab 97: 3996–4003 13. Gandolfi G, Sancisi V, Torricelli F, Ragazzi M, Frasoldati A, Piana S, Ciarrocchi A (2013) Allele percentage of BRAF V600E mutation in papillary thyroid carcinomas and corresponding lymph node metastases: no evidence for a role in tumor progression. J Clin Endocrinol Metab 98:E934–E942 14. Dutenhefner SE, Marui S, Santos AB, de Lima EU, Inoue M, Neto JS, Shiang C, Fukushima JT, Cernea CR, Friguglietti CU (2013) BRAF: a tool in the decision to perform elective neck dissection? Thyroid. In press. 15. Alzahrani AS, Xing M (2013) Impact of lymph node metastases identified on central neck dissection (CND) on the recurrence of papillary thyroid cancer: potential role of BRAF V600E mutation in defining CND. Endocr Relat Cancer 20:13–22 16. Xing M, Alzahrani AS, Carson KA et al (2013) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493–1501 17. Miccoli P, Pinchera A, Materazzi G, Biagini A, Berti P, Faviana P, Molinaro E, Viola D, Elisei R (2009) Surgical treatment of low and intermediate risk papillary thyroid carcinomas with minimally invasive video assisted thyroidectomy. J Clin Endocrinol Metab 94:1618– 1622 18. Lee J, Chung WY (2012) Current status of robotic thyroidectomy and neck dissection using a gasless trans axillary approach. Curr Opin Oncol 24:7–15 19. Witt RL, Ferris RL, Pribitkin EA, Sherman SI, Steward DL, Nikiforow YE (2013) Diagnosis and management of differentiated thyroid cancer using molecular biology. Laryngoscope 123:1054–1064
REVIEW ARTICLE
BRAF mutation status in papillary thyroid carcinoma: significance for surgical strategy P. Miccoli & F. Basolo
Received: 13 November 2013 / Accepted: 11 December 2013 / Published online: 30 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background BRAF mutation is probably the only molecular marker acting as a risk factor that is available before surgery: for this reason, soon after it became quite widespread, it seemed an important tool as a guide towards an individualized surgical therapy in papillary thyroid carcinoma. Purpose Capsule invasion, multifocality, and lymph node involvement are the most important parameters influencing the choice of surgical strategy in front of small papillary cancers and, in more detail, of micro papillary carcinomas. The relationship between these parameters and the BRAF mutation are closely examined through the more recent literature. Capsular invasion seems to show the strongest correlation with the mutation and this has important correlations, thus suggesting that a more aggressive local surgery might be advisable, whereas the correlation between the mutation and lymph node involvement would be weaker, at least according to the most recent studies. Conclusions The personalization of surgical therapy, today, seems easier to achieve thanks to molecular testing. In particular, an important result could be in the short term reduction in the number of completion thyroidectomies following simple lobectomies. Also, post operative radioactivated iodine therapies should be more carefully evaluated and tailored according to BRAF status. A possible flow chart for the decision of the therapeutic approach is proposed in accordance to the results of the literature. Keywords BRAF . Thyroid carcinoma . Thyroid surgery . Risk stratification . Tailored surgery P. Miccoli : F. Basolo Department of Surgical Pathology, University of Pisa, Pisa, Italy P. Miccoli (*) AOUP Pisa, Via Paradisa 2, 56124 Pisa, Italy e-mail: [email protected]
Introduction BRAF is a member of the RAF kinase family that promotes signaling through the RAS-MAP kinase signal-transduction cascade. An activating mutation located on exon 15 of the B isoform of the RAF kinase gene results in a valine-to-glutamic acid substitution at amino acid 600 (BRAF V600E), leading to destabilization of the kinase encoded by the gene and promoting tumorigenesis through the MAPK pathway [1]. Since its initial description in thyroid cancer [2, 3], BRAF V600E has been widely found in papillary thyroid carcinoma (PTC), with a prevalence of approximately 45 %. In recent years, BRAF V600E has emerged as a promising prognostic factor in the risk stratification of PTC [4]. Although some researchers have reported that the BRAF mutation has no relationship to poor prognosis [5], many studies have demonstrated significant associations between BRAF mutation and high-risk clinical-pathological characteristics of PTCs [6]. The possible importance of BRAF mutation in stratifying the patients for a tailored surgical strategy is due to the fact that this mutation is probably the only molecular marker acting as a risk factor that is available before surgery [4, 7]. A correct stratification of surgical strategy in patients presenting a PTC according to their BRAF status though should take into account that the real challenge for surgeons is constituted by those tumors that, in spite of their pre operative conventional staging, could benefit from a more aggressive surgical approach; in other words, for small papillary carcinomas that would be otherwise considered as being “low-risk” tumors. On the other hand, an absence of the mutation could allow simplifying the follow-up of these patients; for example, avoiding unnecessary radioactivated iodine therapy after surgery or even limiting to a unilateral thyroidectomy the operative procedure for these cases. Actually, using
226
laser dissection, the mutation can be found even in microcarcinomas which are as small as 1 mm or less [8]. Even though there is no certainty that these tumors might evolve in clinically relevant carcinomas, they probably should be regarded with higher caution. In a large study, on more than 1,000 cases operated for PTC published in 2010 [9], it was readily apparent that some parameters of tumor invasiveness, which would involve a worse prognosis, were all linked with the presence of BRAF mutation, but not all of them with an identical statistical significance. Moreover, only a few of them could influence the choice of the surgical procedure to adopt. In more details, the parameters that could imply to a larger extent a personalization of the surgical strategy seem to be the capsule invasion, the multifocality, and the lymph node involvement [9].
Langenbecks Arch Surg (2014) 399:225–228
Multifocality Recent papers [10] showed that there was no clear evidence that BRAF V600E mutation is associated with higher rate of tumor multicentricity or at least, the association proved to have a low-statistical significance: in other words, this parameter, though important, can hardly be predicted by the presence of the mutation. This assumption could lead the surgeon to propose a hemithyroidectomy to these patients harboring a small PTC even in presence of a BRAF mutation. The reduced extent of surgery at the gland level though should be balanced by a higher aggressiveness towards the lymph nodes in the central compartment. Therefore, would it be reasonable to propose a lobectomy plus a sixth-level node clearance in a patient with this profile? Even though this approach is
Fig. 1 Flow chart: BRAF analysis available before surgery (a) and after surgery (b). WT wild type
Langenbecks Arch Surg (2014) 399:225–228
currently often adopted in several surgical backgrounds, particularly in Eastern countries [11], this solution still raises many doubts. In fact, since it is well ascertained that BRAF mutation tends to be associated with a higher incidence of node metastases that, on the other hand, tend to show a reduced iodine avidity, it is presumable that a more aggressive radioiodine treatment is necessary but it implies the absence of any thyroid tissue in the neck to serve the purpose as it is expected. For this reason, in our opinion, a total thyroidectomy can still be considered the best option in all PTC patients presenting with a BRAF mutation, no matter what the size of the tumor is. Lymph node involvement Many papers seem to be concordant about the increased rate of lymph node metastases in patients with BRAF mutation [4, 7, 10, 12] so as to justify the necessity of performing a routine central compartment lymphadenectomy, in these cases, even in the presence of small tumors and no evidence of enlarged nodes at pre operative imaging. These led some authors to propose a flow chart where a total thyroidectomy plus a central compartment lymphadenectomy was the treatment of choice for these patients [7]. Very recently though, some studies appeared [13, 14] that seem to deny a sure correlation between BRAF mutation and node metastases. Even the general role of this mutation as a negative prognostic factor should be entirely re-evaluated according to some [13]. Also, authors that always supported the prognostic value of this mutation recently admitted that the “predictive power of BRAF for CLN metastases was high but less prominent than some of these pathological factors…” [4, 15]. For these reasons, it is difficult to totally share the above mentioned flow chart since a central compartment clearance, only on the basis of BRAF mutation, cannot be considered mandatory according to the most recent studies. In fact, further data are concordant about the necessity of matching the mutation with other tumor parameters since it is not an independent prognostic factor [4, 16]. In particular, aggressive histotypes and extrathyroidal extension should be taken into account. Capsular invasion This parameter showed the highest correlation with BRAF mutation [8, 9]: it was significantly more common in tumors invading the thyroid capsule, to such an extent that there was no statistically significant difference between pT1 tumors with capsule invasion and pT3 tumors in this series. For this reason, even at risk of emphasizing the obvious, the recommendation of an aggressive surgical approach to the thyroid should be widely accepted in all patients presenting this mutation. This means in most, if not all, cases, performing a total
227
thyroidectomy and paying particular attention to the perithyroidal tissue and the overlying thyro-iode muscles when the tumor is anterior. Basically, what has been said until now needs to be better specified in order to give to the above data the right value in indicating a possible surgical strategy and attempting a possible decisional flow chart (Fig. 1). First of all, is the presence of BRAF mutation known before the operation (Fig. 1a) on a cytological specimen or only after the operation on the histological specimen (Fig. 1b)? On one side, it might look advisable to obtain this datum on all the patients before surgery since BRAF is the only risk factor available in small PTC before surgery; on the other hand, searching for BRAF mutation on all cytological specimens in the entire population is probably unrealistic due to its well-recognized inability to improve significantly the diagnostic outcomes which makes this marker poorly cost effective in a pre operative phase. Much simpler would be to have the information, at least when needed, on the histological specimen. In fact, this might strongly influence the decision whether to perform a completion total thyroidectomy or not after a unilateral surgery. If the removed lobe is negative for BRAF mutation in a papillary microcarcinoma, the completion could be avoided, provided that we are not in the presence of an aggressive histotype and there is not a microscopic capsular invasion (not very probable when BRAF is negative) (Fig. 1). On the other hand, if the histological specimen shows the presence of a mutation, I131 therapy should be adopted even in the presence of a microcarcinoma, in particular, if a central compartment lymphadenectomy has not been performed; but if the mutation is absent, radioactivated iodine administration can be excluded with no risk for the patient. To summarize, we might conclude that in those cases where the presence of mutation is known before surgery, a total thyroidectomy is highly recommended also because it constitutes the necessary prerequisite for an aggressive 131I therapy. A central compartment lymphadenectomy can be recommended but its necessity is arguable because not all agree about BRAF's importance on decision making at this level. Finally, it is to be reminded that the exact role of minimally invasive or cosmetic thyroidectomies should also be determined since, as it was said, the main advantage of molecular testing is expressed in micro papillary carcinomas, which are ideal candidates for these approaches. The two techniques which seem to better guarantee a full total thyroidectomy together with a central compartment clearance, when necessary are, up to now, the minimally invasive video assisted thyroidectomy and the robotic axillary thyroidectomy [13, 17, 18].
228
Conclusion Certainly, a trend towards a personalization of surgical therapy according to molecular testing does exist and is probably highly advisable since it could lead to not only more individualized operations but also even more individualized post operative radioactivated iodine therapies. According also to Witt et al. [19], one of the most important downstream results of these testings could be a significant reduction of the completion thyroidectomies after unilateral surgery. In spite of these encouraging conclusions, we cannot elude the problem that some of these techniques might prove to be logistically very demanding and too expensive.
Conflicts of interest None.
References 1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954 2. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RASBRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457 3. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE (2003) BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 88:5399–5404 4. Xing M (2010) Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 321:86–93 5. Kim TY, Kim WB, Song JY, Rhee YS, Gong G, Cho YM, Kim SY, Kim SC, Hong SJ, Shong YK (2005) The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol 63:588–593 6. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW (2005) BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373–6379
Langenbecks Arch Surg (2014) 399:225–228 7. Yip I, Nikiforova MN, Carty SE, Yim JH, Stang ML, Tublin MJ, Lebeau SO, Hodak SP, Ogilvie JB, Nikiforov YE (2009) Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 146:1215–1233 8. Ugolini C, Giannini R, Lupi C, Salvatore G, Miccoli P, Proietti A, Elisei R, Santoro M, Basolo F (2007) Presence of BRAF V600 in very early stages of papillary thyroid carcinoma. Thyroid 17(5):381– 388 9. Basolo F, Torregrossa L, Giannini R, Miccoli M, Lupi C, Sensi E, Berti P, Elisei R, Vitti P, Baggiani A, Miccoli P (2010) Correlation between the BRAF V600 mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 mm: analysis of 1060 cases. J Clin Endocrinol Metab 95:4197–4205 10. Elisei R, Viola D, Torregrossa L, Giannini R, Romei C, Ugolini C, Molinaro E, Agate L, Biagini A, Lupi C, Valerio L, Materazzi G, Miccoli P, Piaggi P, Pinchera A, Vitti P, Basolo F (2012) The BRAF (V600E) mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: singleinstitution results from a large cohort study. J Clin Endocrinol Metab 97(12):4390–4398 11. Hyun SM, Song HY, Kim SY, Nam SY, Roh JL, Han MW, Choi SH (2012) Impact of combined unilateral central neck dissection and hemithyroidectomy in patients with papillary thyroid micro carcinomas. Ann Surg Oncol 19:591–596 12. Joo JY, Yoon YH, Choi B, Kim J, Jo YS, Shong M, Koo BS (2012) Prediction of occult central lymph node metastases in papillary thyroid cancer by pre operative BRAF analysis using fine needle aspiration biopsy: a prospective study. J Clin Endocrinol Metab 97: 3996–4003 13. Gandolfi G, Sancisi V, Torricelli F, Ragazzi M, Frasoldati A, Piana S, Ciarrocchi A (2013) Allele percentage of BRAF V600E mutation in papillary thyroid carcinomas and corresponding lymph node metastases: no evidence for a role in tumor progression. J Clin Endocrinol Metab 98:E934–E942 14. Dutenhefner SE, Marui S, Santos AB, de Lima EU, Inoue M, Neto JS, Shiang C, Fukushima JT, Cernea CR, Friguglietti CU (2013) BRAF: a tool in the decision to perform elective neck dissection? Thyroid. In press. 15. Alzahrani AS, Xing M (2013) Impact of lymph node metastases identified on central neck dissection (CND) on the recurrence of papillary thyroid cancer: potential role of BRAF V600E mutation in defining CND. Endocr Relat Cancer 20:13–22 16. Xing M, Alzahrani AS, Carson KA et al (2013) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493–1501 17. Miccoli P, Pinchera A, Materazzi G, Biagini A, Berti P, Faviana P, Molinaro E, Viola D, Elisei R (2009) Surgical treatment of low and intermediate risk papillary thyroid carcinomas with minimally invasive video assisted thyroidectomy. J Clin Endocrinol Metab 94:1618– 1622 18. Lee J, Chung WY (2012) Current status of robotic thyroidectomy and neck dissection using a gasless trans axillary approach. Curr Opin Oncol 24:7–15 19. Witt RL, Ferris RL, Pribitkin EA, Sherman SI, Steward DL, Nikiforow YE (2013) Diagnosis and management of differentiated thyroid cancer using molecular biology. Laryngoscope 123:1054–1064
