Marina N Nikiforova

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (163)755.62 Total impact

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    ABSTRACT: Background: An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children. Methods: The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing. Results: Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V) (600E) ) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V) (600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V) (600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1). Conclusions: Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation. Cancer 2016. © 2016 American Cancer Society.
    No preview · Article · Jan 2016 · Cancer
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    ABSTRACT: Pendred syndrome is an autosomal recessive disorder characterized by hearing loss and goiter and is caused by bi-allelic mutations (homozygous or compound heterozygous) of the PDS (SLC26A4) gene. The incidence of Pendred syndrome is 7.5-10/100,000 in the general population, and it carries a 1 % risk of developing thyroid carcinoma. Herein, we report a case of a patient with Pendred syndrome who developed a follicular variant of papillary thyroid carcinoma (FVPTC)-that is approximately at an odd of 1/1,000,000. Targeted next-generation sequencing with ThyroSeq v2 was performed on the tumor, and only a TP53 mutation (TP53 p.R175H) was identified. The mutation was limited to the tumor nodule of FVPTC as shown by immunohistochemistry. This report represents the first extensive molecular study of a Pendred syndrome-associated thyroid carcinoma. The evidences support that thyroid carcinomas arising from dyshormonogenetic goiter require additional genetic alteration in addition to the purported thyroid-stimulating hormone (TSH) overstimulation. It is intrigue to note that the mutant p53 is involved in the development of a low-grade malignant thyroid tumor as FVPTC in this patient.
    No preview · Article · Jan 2016 · Endocrine Pathology
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    ABSTRACT: Background and aims: The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. Methods: The study population consisted of 225 patients that underwent EUS-guided fine-needle aspiration (EUS-FNA) for a pancreatic cyst between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen (CEA) analysis and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN. Results: Diagnostic pathology was available for 41 (18%) patients with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of IPMNs with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 (15%) patients with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue MRI surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasia with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value. Conclusions: The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Further, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue unnecessary MRI surveillance. The results of an alternative approach with integrative molecular testing are encouraging, but require further validation.
    No preview · Article · Dec 2015 · Gastrointestinal endoscopy
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    ABSTRACT: Background: Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies. Methods: We report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR. Results: GlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%-5% of mutant alleles for SNVs and 1%-5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas. Conclusions: GlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management.
    No preview · Article · Dec 2015 · Neuro-Oncology
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    ABSTRACT: Chromosomal rearrangements that result in oncogenic gene fusions are clinically important drivers of many cancer types. Rapid and sensitive methods are therefore needed to detect a broad range of gene fusions in clinical specimens that are often of limited quantity and quality. We describe a next-generation sequencing approach that uses a multiplex PCR-based amplicon panel to interrogate fusion transcripts that involve 19 driver genes and 94 partners implicated in solid tumors. The panel also includes control assays that evaluate the 3'/5' expression ratios of 12 oncogenic kinases, which might be used to infer gene fusion events when the partner is unknown or not included on the panel. There was good concordance between the solid tumor fusion gene panel and other methods, including fluorescence in situ hybridization, real-time PCR, Sanger sequencing, and other next-generation sequencing panels, because 40 specimens known to harbor gene fusions were correctly identified. No specific fusion reads were observed in 59 fusion-negative specimens. The 3'/5' expression ratio was informative for fusions that involved ALK, RET, and NTRK1 but not for BRAF or ROS1 fusions. However, among 37 ALK or RET fusion-negative specimens, four exhibited elevated 3'/5' expression ratios, indicating that fusions predicted solely by 3'/5' read ratios require confirmatory testing.
    No preview · Article · Dec 2015 · The Journal of molecular diagnostics: JMD
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    ABSTRACT: The molecular alterations in colorectal poorly differentiated neuroendocrine carcinoma remain incompletely characterized, particularly with respect to mutations in BRAF and KRAS. We analyzed 32 colorectal poorly differentiated neuroendocrine carcinomas and 40 colorectal poorly differentiated conventional adenocarcinomas for mutations in KRAS and BRAF and for DNA mismatch repair protein abnormalities to correlate histopathology with molecular alterations and survival. Compared with poorly differentiated conventional adenocarcinoma, poorly differentiated neuroendocrine carcinoma frequently harbored BRAF mutations (59% versus 5%; P < .001) and less frequently demonstrated KRAS codon 12 or 13 mutations (17% versus 43%; P = .03). BRAF mutations were identified in both pure poorly differentiated neuroendocrine carcinoma (60%) and poorly differentiated neuroendocrine carcinoma associated with a signet ring cell adenocarcinoma component (82%). Most (93%) poorly differentiated neuroendocrine carcinomas demonstrated proficient DNA mismatch repair by either microsatellite instability polymerase chain reaction or DNA mismatch repair immunohistochemistry. Patients with poorly differentiated neuroendocrine carcinoma had a significantly worse overall survival compared with patients with poorly differentiated conventional adenocarcinoma (P < .001). There was no significant difference in overall survival between patients with pure poorly differentiated neuroendocrine carcinoma and patients with both poorly differentiated neuroendocrine carcinoma and adenocarcinoma components (P = .5). In conclusion, colorectal poorly differentiated neuroendocrine carcinomas frequently harbor BRAF mutations and are associated with poor overall survival.
    No preview · Article · Nov 2015 · Human pathology

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  • No preview · Article · Nov 2015
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    ABSTRACT: Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell free DNA (cfDNA). Patients and methods: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n=43), bone (n=12) and brain metastases (n=38), and cfDNA (n=29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n=13), Y537S (n=3) and Y537C (n=1), and not for K303R, S463P or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3 to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n=5), mutations were detected in both (n=3) or in cfDNA only (n=2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases and cfDNA, suggesting that in some tumors rare ESR1 mutant clones are enriched by endocrine therapy.
    No preview · Article · Oct 2015 · Clinical Cancer Research
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    ABSTRACT: Conclusions: The BRAF K601E mutation is the second most common BRAF mutation after V600E found in thyroid nodules. Unlike BRAF V600E, this mutation is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC and may also be found in a follicular thyroid carcinoma. Overall, BRAF K601E mutant tumors show better clinical outcomes than BRAF V600E positive tumors, and preoperative BRAF K601E analysis can provide important prognostic information for use in clinical management.
    Preview · Article · Sep 2015 · Thyroid: official journal of the American Thyroid Association
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    ABSTRACT: The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. Fifteen cases were previously tested by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not previously tested. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could only identify molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules in order to aid future classification, treatment, and clinical management recommendations.
    No preview · Article · Sep 2015 · Pediatric and Developmental Pathology
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    ABSTRACT: Background: Fine-needle aspiration (FNA) cytology is a common approach to evaluate thyroid nodules. It offers definitive diagnosis of a benign or malignant nodule in the majority of cases. However, 10-25% of nodules yield one of three indeterminate cytologic diagnoses, leading to suboptimal management of these patients. Atypia of undetermined significance/follicular lesion of undermined significance (AUS/FLUS) is a common indeterminate diagnosis, with the cancer risk ranging from 6% to 48%. This study assessed whether a multi-gene next-generation sequencing (NGS) assay can offer significant improvement in diagnosis in AUS/FLUS nodules. Methods: From May 2014 to March 2015, 465 consecutive FNA samples with the cytologic diagnosis of AUS/FLUS underwent prospective molecular testing using the ThyroSeq v2.1 panel. The panel included 14 genes analyzed for point mutations and 42 types of gene fusions occurring in thyroid cancer. In addition, eight genes were assessed for expression in order to evaluate the cell composition of FNA samples. Ninety-eight (21%) of these nodules had definitive surgical (n = 96) or nonsurgical (n = 2) follow-up and were used to determine the assay performance. Results: Among 465 AUS/FLUS nodules, three were found to be composed of parathyroid cells and 462 of thyroid follicular cells. Of the latter, 31 (6.7%) were positive for mutations. The most frequently mutated genes were NRAS and HRAS, and overall point mutations in seven different genes and five types of gene fusions were identified in these nodules. Among 98 nodules with known outcome, histologic analysis revealed 22 (22.5%) cancers. ThyroSeq v2.1 was able to classify 20/22 cancers correctly, showing a sensitivity of 90.9% [confidence interval (CI) 78.8-100], specificity of 92.1% [CI 86.0-98.2], positive predictive value of 76.9% [CI 60.7-93.1], and negative predictive value of 97.2% [CI 78.8-100], with an overall accuracy of 91.8% [CI 86.4-97.3]. Conclusions: The results of the study demonstrate that the ThyroSeq v2.1 multi-gene NGS panel of molecular markers provides both high sensitivity and high specificity for cancer detection in thyroid nodules with AUS/FLUS cytology, which should allow improved management for these patients.
    Preview · Article · Sep 2015 · Thyroid: official journal of the American Thyroid Association
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    ABSTRACT: To correlate thyroid cancer genotype with histology and outcomes. The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.
    No preview · Article · Sep 2015 · Annals of surgery
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    ABSTRACT: Background: Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease. Methods: We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated. Cultured cell identity was confirmed by demonstration of the same NRAS mutation found in the original lesions and by immunophenotyping. Nevomelanocytic spheroids were treated with inhibitors of specific mediators of the NRAS signaling pathway (vemurafenib, MEK162, GDC0941, and GSK2126458). Drug sensitivity and cell viability were assessed. Results: Cultured cells were growth-factor dependent, grew as spheroids on Geltrex matrix, and maintained their clonogenicity in vitro over passages. Skin-derived cells formed more colonies than CNS-derived cells. Inhibitors of specific mediators of the NRAS signaling pathway reduced viability of NRAS mutated cells. The highest effect was obtained with GSK2126458, showing a viability reduction below 50%. Conclusions: NRAS mutated cells derived from clinical NCM samples are capable of continuous growth as spheroid colonies in vitro and retain their genetic identity. Drugs targeting the NRAS signaling pathway reduce in vitro viability of NCM cells. NCM lesional spheroids represent a new and reliable experimental model of NCM for use in drug testing and mechanistic studies.
    No preview · Article · Sep 2015 · Neuro-Oncology
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    ABSTRACT: Multiple endocrine neoplasias (MEN) are genetic syndromes consisting of neuroendocrine tumors in two or more organs and are further classified based upon specific genetic mutations and resulting neoplasms. MEN2 is associated with a germline mutation in the RET proto-oncogene. Though pulmonary carcinoid tumors have been described in MEN1 they have not been associated with MEN2. We report a nonsmoking male patient with known MEN2B who presented with advanced, primary pulmonary neuroendocrine carcinoma harboring only his germline RET mutation. He failed to respond to conventional chemotherapy, however responded dramatically to cabozantinib, a RET-targeted therapy approved for medullary thyroid carcinoma.
    No preview · Article · Aug 2015 · Endocrine Related Cancer
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    ABSTRACT: Clear cell follicular carcinoma is a rare type of thyroid cancer and some with aggressive biological behavior. The cytoplasmic clearing of the neoplastic cells has been attributed to the accumulation of various substances, such as glycogen, lipid, mucin, and thyroglobulin, or distension of mitochondria or endoplasmic reticulum. However, the molecular mechanisms responsible for the characteristic appearance of the cell cytoplasm and the biological behavior remain unknown. We report here a case of aggressive clear cell follicular carcinoma of the thyroid with molecular profile using targeted next generation sequencing (NGS) that presented as a metastatic tumor in a woman with a history of breast carcinoma. The NGS data revealed the coexisting of a well-characterized loss-of-function TP53 R248Q mutation and a putative gain-of-function mutation of TSHR L272V, which was suggested by the overexpression of thyroglobulin and SLC5A5 (NIS) genes in this tumor. TP53 mutations are usually related with dedifferentiation, progression, and metastasis of thyroid carcinomas. Identification of TP53 R248Q in this tumor correlated with its aggressive clinical behavior. Gain-of-function mutation of TSHR can overstimulate the thyroid follicular cells as the elevated level of TSH does and might have contributed to the development of clear cell morphology in this tumor. This report represents the first case of clear cell follicular carcinoma of the thyroid with NGS analysis and more molecular characterization is needed to elucidate the pathogenesis and provide more prognosis-relevant information for this uncommon variant of thyroid carcinomas.
    No preview · Article · Aug 2015 · Endocrine Pathology
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    ABSTRACT: The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutaneous melanocytosis. Detailed histological (biopsy and post-mortem) studies, tissue culture, and high-resolution cytogenetic analysis, including chromosome and array comparative genomic hybridization, Ion AmpliSeq Cancer Panel, and Sanger sequencing, were performed on tissues from a white male who succumbed at 17 months of age to congenital melanoma associated with a bathing-trunk nevus. We also used quantitative PCR to quantitatively assess the expression of NRAS among normal cells, including fibroblast and melanocytes, as well as melanoma cells from our patient. Full autopsy documented tumors in the brain, spinal cord, lung, liver, testis, bone marrow, and, retrospectively, in the placenta. Next-generation sequencing and chromosome microarray in our patient revealed novel findings, including duplication of a mutated NRAS gene, leading to an aggressive clinical course and disseminated disease. Quantitative PCR showed a five-fold increase in NRAS expression in the melanoma cell line when compared with normal melanocytes. Finally, three amino acid-changing germline variants were detected: homozygous TP53 p.P72R, heterozygous KIT p.M541L, and homozygous KDR (VEGFR2) p.Q472H. These genes are involved in malignancy and other potentially relevant pathways, such as mast cell and melanocytic signaling, as well as angiogenesis. These findings provide novel insights into the biology of congenital melanocytic proliferations, showing that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of neurocutaneous melanocytosis.
    No preview · Article · Aug 2015 · Melanoma research
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    ABSTRACT: BACKGROUND Although most unsuspected thyroid carcinomas qualify as microcarcinomas (≤1 cm), larger, nontargeted carcinomas may be found also. This study evaluated the significance of these nonmicrocarcinomas (>1 cm) in the setting of a large-volume thyroid practice.METHODS Thyroid resection specimens from May 2007 to December 2012 were reviewed. For these cases, the pathologic characteristics of nontargeted carcinomas larger than 1.0 cm were evaluated. Those interpreted as intrathyroidal metastases were not included in this study. Specifically, the histologic classification, size, and molecular features were documented.RESULTSFrom a total of 4815 thyroid resections and 9279 thyroid fine-needle aspiration procedures that were performed during the study period, 27 nontargeted nonmicrocarcinomas were identified (0.6% of resection cases) in 26 patients. The histologic classifications were as follows: follicular variant of papillary carcinoma (n = 19), classic papillary carcinoma (n = 3), papillary carcinoma with oncocytic features (n = 1), tall-cell variant of papillary carcinoma (n = 2), and follicular carcinoma (n = 2). The size parameters were as follows: mean, 1.9 cm; median, 1.4 cm; and range, 1.1 to 7.0 cm. RAS and BRAF mutations were identified in 8 and 7 cases, respectively (71% of the cases tested with a 7-gene panel), whereas 6 cases showed no mutation. Molecular information was not available for 6 cases.CONCLUSIONS In the authors' experience, nontargeted thyroid nonmicrocarcinomas (>1 cm) are rare (0.6%), and the majority are low-grade carcinomas. The likelihood of finding one of the common mutations (71%) is comparable to the likelihood for thyroid carcinomas in general (∼70%). Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society.
    Preview · Article · Aug 2015 · Cancer Cytopathology
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    ABSTRACT: The uncommon diagnosis of atypical parathyroid adenoma (APA) creates a clinical conundrum for surveillance. We evaluated a large series of APA to determine long-term outcomes. Prospectively collected data were retrieved for patients with a diagnosis of histologic APA defined by presence of ≥2 criteria: clinical/intraoperative adherence, fibrotic bands, trabecular growth, or mitotic rate of >1/10 per high-power field without indisputable signs of malignancy. Follow-up was at 2 weeks, 6 months, and yearly thereafter. From 1970 to 2014, 51 patients (1.2%) with primary hyperparathyroidism had a diagnosed APA. Mean age was 56 years (range, 19-83), and 61% were women. Intraoperatively, 11 of 51 glands (22%) were adherent, requiring concurrent thyroid lobectomy. Common microscopic findings were fibrosis (78%), trabecular growth (37%), and increased mitotic count (24%); the mean APA weight was 3.14 g (range, 167 mg-38 g). Loss of heterozygosity occurred in 25 of 38 tested patients (66%) at the p21 locus in 9 cases, at CDC73 and PTEN in 6, and at RB1 in 4 cases, with mean fractional allelic loss of 24% (range, 6-79). With mean follow-up of 5 years (range, 0.5-18), no patient has developed recurrence. Over a mean follow-up of 5 years, we observed no recurrences after APA resection. Molecular features had no discernable impact, indicating that long-term follow-up may be unnecessary. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Surgery
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    ABSTRACT: Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P < .002). All patients with colorectal carcinomas demonstrating isolated loss of MSH6 expression had Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Human pathology

Publication Stats

7k Citations
755.62 Total Impact Points

Institutions

  • 2007-2016
    • University of Pittsburgh
      • • Department of Pathology
      • • Division of Neuropathology
      Pittsburgh, Pennsylvania, United States
  • 2011
    • Magee-Womens Hospital
      • Department of Pathology
      Pittsburgh, Pennsylvania, United States
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 2005-2008
    • Cincinnati Children's Hospital Medical Center
      • Division of Pathology
      Cincinnati, Ohio, United States
  • 1998-2006
    • University of Cincinnati
      • • Department of Pathology and Laboratory Medicine
      • • Division of Endocrinology, Diabetes & Metabolism
      Cincinnati, OH, United States
  • 2003
    • University of Naples Federico II
      Napoli, Campania, Italy
    • Yale University
      New Haven, Connecticut, United States
  • 2002
    • Emory University
      Atlanta, Georgia, United States
  • 1996
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States