RESUMEN
BACKGROUND: Molecular testing improves the diagnostic accuracy of thyroid cancer. Whether specific molecular testing results are associated with tumor phenotype or provide prognostic information needs further delineation. METHODS: Consecutive thyroid cancer patients after index thyroidectomy with ThyroSeq version 3 (Rye Brook, NY) molecular testing obtained on preoperative fine-needle aspiration or thyroidectomy specimens from patients with thyroid cancer were categorized into 3 molecular risk groups based on detected mutations, fusions, copy number alterations, and/or gene expression alterations and correlated with histopathology and recurrence, defined as biochemical or structural. RESULTS: Of 578 patients, 49.9%, 37.5%, and 12.6% had molecular risk group-low, molecular risk group-intermediate, and molecular risk group-high cancers, respectively. With a median 19-month follow-up, 9.1% patients recurred. Compared with molecular risk group-low, molecular risk group-intermediate cancers were diagnosed in younger patients and more often had microscopic extrathyroidal extension, involved margins, and nodal disease. Compared with molecular risk group-intermediate, molecular risk group-high cancers were diagnosed in older patients and more often had gross extrathyroidal extension and vascular invasion. In multivariable analysis, recurrence was more likely in molecular risk group-high cancers than in molecular risk group-intermediate (hazard ratio = 4.0; 95% confidence interval, 1.9-8.6; P < .001) and more likely in molecular risk group-intermediate than in molecular risk group-low (hazard ratio = 5.0; 95% confidence interval, 2.0-12.5; P < .001). CONCLUSION: Using modern comprehensive genotyping, the genetic profile of thyroid cancers can be categorized into 3 novel molecular risk groups that were associated with histopathologic phenotype and recurrence in short-term follow-up.
Asunto(s)
Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/diagnóstico , Tiroidectomía/métodos , Biopsia con Aguja Fina , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
Asunto(s)
Adenoma Pleomórfico/patología , Biomarcadores de Tumor/genética , Mutación , Mioepitelioma/patología , Neoplasias Glandulares y Epiteliales/patología , Neoplasias de las Glándulas Salivales/patología , Adenoma Pleomórfico/diagnóstico , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Estudios de Seguimiento , Proteína HMGA2/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mioepitelioma/diagnóstico , Mioepitelioma/genética , Mioepitelioma/cirugía , Clasificación del Tumor , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/cirugía , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína SMARCB1/genética , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/cirugía , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. METHODS: Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. RESULTS: In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy). In total, 76% of RAS-positive nodules were malignant and follicular variant papillary thyroid cancer was the most common cancer type (83%). HRAS mutations had the greatest risk of cancer (92%) followed by NRAS (74%) and KRAS (64%; P = .05). No preoperative variables were associated with malignancy including age (P = .07), sex (P = .49), RAS isoform (P = .05), mutational allelic frequency (P = .49), nodule size (P = .14), cytology category (P = .63), or ultrasound bilaterality (P = .24), multifocality (P = .23), or presence of ≥1 suspicious feature (P = .86). Only 60% of patients with a unifocal nodule on ultrasound had single focus low-risk encapsulated follicular variant papillary thyroid cancer or benign disease. CONCLUSION: Preoperative RAS mutation detection in thyroid nodules carries a substantial risk of cancer with a greater risk associated with HRAS and NRAS. Most RAS malignancies are follicular variant papillary thyroid cancer, which may inform the extent of operation.
Asunto(s)
Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Adulto , Anciano , Biopsia con Aguja Fina , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios/métodos , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Análisis de Supervivencia , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/genética , Nódulo Tiroideo/patología , Nódulo Tiroideo/cirugía , Tiroidectomía/mortalidad , Resultado del TratamientoRESUMEN
p40 is selective for ΔNp63 isoforms and appears to be more specific for squamous differentiation than p63. Its performance as a basal/myoepithelial marker in salivary gland tumors has only rarely been addressed in the literature. We thus compared the performance of p63 and p40 (ΔNp63) immunohistochemical stain as markers of basal, squamoid, and myoepithelial differentiation in 105 salivary gland tumors selected from our archives. The neoplasms were categorized according to their presumed phenotype as ductoacinar (n=45), biphasic (dual ductal and myoepithelial/basal differentiation, n=44), purely myoepithelial (n=5), and excretory duct phenotype (n=11). Only nuclear staining for p63 and p40 was considered positive. Distribution of staining was scored as: 0 (no staining), 1+ (1% to 25%), 2+ (26% to 50%), 3+ (51% to 75%), and 4+ (76% to 100%). Intensity was scored as weak, moderate, or strong. p63 and p40 highlighted the basal and myoepithelial cells in normal salivary gland tissue as well as basal/myoepithelial/squamoid elements in biphasic tumors, purely myoepithelial tumors, and excretory duct type tumors (4+ with strong staining for p63, and moderate staining for p40). All ductal tumors were negative for p40. However, 13/13 polymorphous low-grade adenocarcinoma/cribriform adenocarcinomas of salivary gland, 7/9 canalicular adenomas, and 3/5 mammary analog secretory carcinomas showed some degree of p63 staining. Thus, we confirm that p40 is a more specific basal/myoepithelial/squamoid marker than p63 in salivary gland tumors. A subset of ductal tumors show a discordant p63+/p40- immunoprofile that can be a pitfall if not recognized, but may also help distinguish these tumors from truly biphasic tumors and myoepithelial tumors.