BRAF V600E and risk stratification of thyroid microcarcinoma: a multicenter pathological and clinical study.
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.
Department of Medicine (DIMES), Anatomic Pathology Unit, Bellaria Hospital, University of Bologna School of Medicine, Bologna, Italy.
Giovanni
G
Tallini
Department of Medicine (DIMES), Anatomic Pathology Unit, Bellaria Hospital, University of Bologna School of Medicine, Bologna, Italy.
Dario
D
de Biase
Department of Internal Medicine and Medical Specialties, University 'Sapienza', Rome, Italy.
Cosimo
C
Durante
Department of Medicine (DIMES), Anatomic Pathology Unit, Bellaria Hospital, University of Bologna School of Medicine, Bologna, Italy.
Giorgia
G
Acquaviva
Anatomic Pathology Unit, School of Biomedical Sciences, Etromapmacs Pole, Lesina, Italy.
Michele
M
Bisceglia
Endocrinology Unit, Tinchi-Pisticci Hospital, Matera, Italy.
Rocco
R
Bruno
Department of Medicine (DIMES), Cardiology Unit, University of Bologna, Bologna, Italy.
Maria Letizia
ML
Bacchi Reggiani
Anatomic Pathology Unit, AUSL Bologna-Maggiore Hospital, Bologna, Italy.
Gian Piero
GP
Casadei
Department of Health Science, University Magna Grecia di Catanzaro, Catanzaro, Italy.
Giuseppe
G
Costante
Endocrinology Unit, AUSL Bologna-Maggiore Hospital, Bologna, Italy.
Nadia
N
Cremonini
Department of Internal Medicine and Medical Specialties, University 'Sapienza', Rome, Italy.
Livia
L
Lamartina
Endocrinology Unit, AUSL Bologna-Bentivoglio Hospital, Bologna, Italy.
Domenico
D
Meringolo
Department of Experimental Medicine, Anatomic Pathology Unit, University 'Sapienza', Rome, Italy.
Francesco
F
Nardi
Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
Annalisa
A
Pession
Department of Medicine (DIMEC), Medical Genetics Unit, University of Bologna, Bologna, Italy.
Kerry J
KJ
Rhoden
Department of Internal Medicine and Medical Specialties, University 'Sapienza', Rome, Italy.
Giuseppe
G
Ronga
Department of Medical Science, Ospedale Casa Sollievo della Sofferenza-IRCCS, San Giovanni Rotondo, Italy.
Massimo
M
Torlontano
Department of Internal Medicine and Medical Specialties, University 'Sapienza', Rome, Italy.
Antonella
A
Verrienti
Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
Michela
M
Visani
Department of Internal Medicine and Medical Specialties, University 'Sapienza', Rome, Italy.
Sebastiano
S
Filetti
D000328:Adult; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf