Cytomorphological and molecular genetic findings in pediatric thyroid fine‐needle aspiration

Monaco, Sara E.; Pantanowitz, Liron; Khalbuss, Walid E.; Benkovich, Vanessa; Ozolek, John A.; Nikiforova, Marina N.; Simons, Jeffrey P.

doi:10.1002/cncy.21199

Cited by 142 publications

(198 citation statements)

References 35 publications

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“…This has been examined as a useful application in the fineneedle aspiration of pediatric thyroid nodules. 40 In summary, the experiences from our institution substantiate findings in similar studies and support a significantly lower rate of the BRAF V600E mutation in PTC in pediatric patients than in adults. Mutations in RAS genes do not contribute significantly to PTC tumorigenesis in this small group of pediatric patients.…”

Section: Commentsupporting

confidence: 85%

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Gertz

Nikiforov

Rehrauer

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population.Objective.-To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors.Design.-Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well.Results.-Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P ¼ .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3-base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%).Conclusions.-The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.(Arch Pathol Lab Med. 2016;140:134-139; doi: 10.5858/ arpa.2014-0612-OA) P apillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. Despite having an excellent prognosis with long-term mortality rates of less than 1%, 1,2 pediatric patients with PTC tend to present with advanced disease often with increased rates of extrathyroidal tumor extension, lymphovascular invasion, and distant metastases. 1,3-5The distinct clinical nature of papillary thyroid cancer in the pediatric population has prompted interest in the molecular tumorigenesis. The mitogen-activated protein kinase (MAPK) pathway includes components of particular interest, including BRAF, RAS, and RET. Between 37% and 52% of PTCs have been linked to the specific BRAF mutation V600E, and clinical correlations support that this foretells a more aggressive disease course in adults. [6][7][8][9] The incidence of this BRAF mutation in the pediatric population is thought to be lower than in adults with rates of 0% to 37%, 10-15 though 1 recent series 16 revealed a rate of 63%. The rearrangement mutations of RET are also considered a major contributor to PTC tumorigenesis, but rates of this mutation have fluctuated widely in reported series.17 RET/PTC rearrangements have been associated with young age 18 an...

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Section: Commentsupporting

confidence: 85%

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Gertz

Nikiforov

Rehrauer

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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“…FNA is a standard pre-operative diagnostic screening technique, for example, for the workup of patients with thyroid nodules. 4,5 In fact, the Bethesda standardized system of reporting thyroid lesions is specifically designed for FNA samples. [17][18][19] Cytological diagnostic procedures have been included in lung cancer staging guidelines based on the similar diagnostic efficacy compared with surgical excisional biopsies.…”

Section: Discussionmentioning

confidence: 99%

“…The median tumor percentages in the smears and cell blocks were 80% (range, 30-100) and 65% (range, 40-90), respectively. The median number of slides used to extract DNA was 1 for smears (range, 1-4) and 3.5 for cell blocks (range, [1][2][3][4][5][6][7][8]. The median DNA concentration for the smear and cell block samples were 0.276 ng/ml (range, 0.001-0.673) and 0.001 ng/ml (range, 0.00-0.613), respectively.…”

Section: Specimen Characteristicsmentioning

confidence: 99%

Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: promises and challenges for routine clinical diagnostics

et al. 2014

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Increasing use of fine needle aspiration for oncological diagnosis, while minimally invasive, poses a challenge for molecular testing by traditional sequencing platforms due to high sample requirements. The advent of affordable benchtop next-generation sequencing platforms such as the semiconductor-based Ion Personal Genome Machine (PGM) Sequencer has facilitated multi-gene mutational profiling using only nanograms of DNA. We describe successful next-generation sequencing-based testing of fine needle aspiration cytological specimens in a clinical laboratory setting. We selected 61 tumor specimens, obtained by fine needle aspiration, with known mutational status for clinically relevant genes; of these, 31 specimens yielded sufficient DNA for next-generation sequencing testing. Ten nanograms of DNA from each sample was tested for mutations in the hotspot regions of 46 cancer-related genes using a 318-chip on Ion PGM Sequencer. All tested samples underwent successful targeted sequencing of 46 genes. We showed 100% concordance of results between next-generation sequencing and conventional test platforms for all previously known point mutations that included BRAF, EGFR, KRAS, MET, NRAS, PIK3CA, RET and TP53, deletions of EGFR and wild-type calls. Furthermore, next-generation sequencing detected variants in 19 of the 31 (61%) patient samples that were not detected by traditional platforms, thus increasing the utility of mutation analysis; these variants involved the APC, ATM, CDKN2A, CTNNB1, FGFR2, FLT3, KDR, KIT, KRAS, MLH1, NRAS, PIK3CA, SMAD4, STK11 and TP53 genes. The results of this study show that next-generation sequencing-based mutational profiling can be performed on fine needle aspiration cytological smears and cell blocks. Next-generation sequencing can be performed with only nanograms of DNA and has better sensitivity than traditional sequencing platforms. Use of next-generation sequencing also enhances the power of fine needle aspiration by providing gene mutation results that can direct personalized cancer therapy.

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“…PTC accounts for 90% or more of all childhood cases (10,12,20,(26)(27)(28). Follicular thyroid cancer (FTC) is uncommon, while medullary thyroid cancer (MTC), poorly differentiated tumors, and frankly undifferentiated (anaplastic) thyroid carcinomas are rare in young patients.…”

Section: Introductionmentioning

confidence: 99%

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

Francis

Waguespack

Bauer

et al. 2015

Thyroid

922

1,316

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Background: Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population exhibit differences in pathophysiology, clinical presentation, and long-term outcomes. Furthermore, therapy that may be recommended for an adult may not be appropriate for a child who is at low risk for death but at higher risk for long-term harm from overly aggressive treatment. For these reasons, unique guidelines for children and adolescents with thyroid tumors are needed. Methods: A task force commissioned by the American Thyroid Association (ATA) developed a series of clinically relevant questions pertaining to the management of children with thyroid nodules and differentiated thyroid cancer (DTC). Using an extensive literature search, primarily focused on studies that included subjects £ 18 years of age, the task force identified and reviewed relevant articles through April 2014. Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force. Results: These inaugural guidelines provide recommendations for the evaluation and management of thyroid nodules in children and adolescents, including the role and interpretation of ultrasound, fine-needle aspiration cytology, and the management of benign nodules. Recommendations for the evaluation, treatment, and follow-up of children and adolescents with DTC are outlined and include preoperative staging, surgical management, postoperative staging, the role of radioactive iodine therapy, and goals for thyrotropin suppression. Management algorithms are proposed and separate recommendations for papillary and follicular thyroid cancers are provided.

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Cytomorphological and molecular genetic findings in pediatric thyroid fine‐needle aspiration

Cited by 142 publications

References 35 publications

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: promises and challenges for routine clinical diagnostics

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

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