BRAF V600E and risk stratification of thyroid microcarcinoma: a multicenter pathological and clinical study

Abstract

Studies from single institutions have analyzed BRAF in papillary microcarcinomas, sometimes with contradictory results. Most of them have provided limited integration of histological and clinical data. To obtain a comprehensive picture of BRAF V600E-mutated microcarcinomas and to evaluate the role of BRAF testing in risk stratification we performed a retrospective multicenter analysis integrating microscopical, pathological, and clinical information. Three hundred and sixty-five samples from 300 patients treated at six medical institutions covering different geographical regions of Italy were analyzed with central review of all cases. BRAF V600E statistical analysis was conducted on 298 microcarcinomas from 264 patients after exclusion of those that did not meet the required criteria. BRAF V600E was identified in 145/298 tumors (49%) including the following subtypes: 35/37 (95%, P<0.0001) tall cell and 72/114 (64%, P<0.0001) classic; conversely 94/129 follicular variant papillary microcarcinomas (73%, P<0.0001) were BRAF wild type. BRAF V600E-mutated microcarcinomas were characterized by markedly infiltrative contours (P<0.0001) with elongated strings of neoplastic cells departing from the tumor, and by intraglandular tumor spread (P<0.0001), typically within 5 mm of the tumor border. Multivariate analysis correlated BRAF V600E with specific microscopic features (nuclear grooves, optically clear nuclei, tall cells within the tumor, and tumor fibrosis), aggressive growth pattern (infiltrative tumor border, extension into extrathyroidal tissues, and intraglandular tumor spread), higher American Thyroid Association recurrence risk group, and non-incidental tumor discovery. The following showed the strongest link to BRAF V600E: tall cell subtype, many neoplastic cells with nuclear grooves or with optically clear nuclei, infiltrative growth, intraglandular tumor spread, and a tumor discovery that was non-incidental. BRAF V600E-mutated microcarcinomas represent a distinct biological subtype. The mutation is associated with conventional clinico-pathological features considered to be adverse prognostic factors for papillary microcarcinoma, for which it could be regarded as a surrogate marker. BRAF analysis may be useful to identify tumors (BRAF wild type) that have negligible clinical risk.

Incidental thyroid carcinomas. A retrospective study

“…However, the data resulting from postoperative scintigraphic controls (57.69% of lymph node metastasis detected) gives us the validation of our approach and some authors agree with us (23,(79)(80)(81)(82). On the contrary some Authors do not share this setting (83)(84)(85)(86)(87)(88)(89)(90)(91) and others suggest a stratification of the risk of recurrence based on the presence of BRAF mutation, extrathyroidal extension, lateral neck lymph node metastases, multifocality, TSH levels, molecular markers, high metabolic tumor volume and tumor stage (92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102).…”

The Genetics of Papillary Microcarcinomas of the Thyroid: Diagnostic and Prognostic Implications

“…It has been advanced by some authors that RET/PTC rearrangements are significantly more frequent in mPTC than in PTC [18, 20, 80], but these observations were not confirmed by others, who found similar rates of RET/PTC rearrangements in both types of tumors [24, 30]. The knowledge about the prevalence of the three more frequent RET/PTC rearrangements, RET/PTC-1, -2 and -3, in mPTC is still scarce and incomplete; data published in the literature indicate a higher prevalence of RET/PTC-1 [18].…”

“…The considerable difficulty of categorization results from their small size together with the fact that WHO classification does not specifically subtype mPTC neoplasias. Preliminary studies indicate that BRAF mutation is more prevalent in conventional [29-32] and tall cell types [30, 33] than in the follicular patterned mPTC [30, 33-35]. In these studies, BRAF mutation in conventional mPTC ranged between 43-81%, between 93%-100% in tall cell variant and between 0–67% in the follicular variant of mPTC.…”

“…Nevertheless, the majority of them (16/27) observed a significant association between BRAF and at least one of such characteristics (Table 3 ). LNM (either analyzing central lymph nodes, lateral lymph nodes or both) was the most frequently studied clinico-pathologic feature and 12 out of 25 studies observed a significant association between BRAF mutation and the presence of LNM [25, 30, 33, 41, 47, 49-51, 57, 59, 60, 64]. The second most commonly investigated association was the one between BRAF mutation and extrathyroidal extension, with 9 out of 17 papers describing a positive correlation with BRAF status [30, 33, 40, 42, 47, 49, 50, 57, 60].…”

Therapeutic Strategies and Clinical Outcome in Papillary Thyroid Microcarcinoma: A Multicenter Observational Study

“…In several studies [25,26], microcarcinomas with BRAF V600E mutation were associated with aggressive behavior. A recent multicenter study [27] suggested that BRAF V600E may represent a surrogate marker for an increased clinical risk. However, the rarity of MPTC recurrence and progression, which was also observed in our study, raises doubts about the usefulness of molecular biology screening aimed at identifying potentially aggressive forms of microcarcinoma.…”