Marina N Nikiforova

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (142)667.07 Total impact

  • [Show abstract] [Hide abstract]
    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.
    Annals of surgery 09/2015; 262(3):519-525. DOI:10.1097/SLA.0000000000001420 · 7.19 Impact Factor
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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.
    Endocrine Related Cancer 08/2015; DOI:10.1530/ERC-15-0307 · 4.91 Impact Factor
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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.
    Endocrine Pathology 08/2015; DOI:10.1007/s12022-015-9388-1 · 1.64 Impact Factor
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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.
    Cancer Cytopathology 08/2015; DOI:10.1002/cncy.21603 · 3.81 Impact Factor
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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.
    Surgery 07/2015; DOI:10.1016/j.surg.2015.06.022 · 3.11 Impact Factor
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    ABSTRACT: Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression without a germline PMS2 mutation must have MLH1 mutation analysis performed.
    The American journal of surgical pathology 04/2015; Publish Ahead of Print. DOI:10.1097/PAS.0000000000000425 · 4.59 Impact Factor
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    ABSTRACT: Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."
    American Journal of Surgical Pathology 02/2015; 39(6). DOI:10.1097/PAS.0000000000000410 · 4.59 Impact Factor
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    ABSTRACT: Context .- Genomic sequencing for cancer is offered by commercial for-profit laboratories, independent laboratory networks, and laboratories in academic medical centers and integrated health networks. The variability among the tests has created a complex, confusing environment. Objective .- To address the complexity, the Personalized Health Care (PHC) Committee of the College of American Pathologists proposed the development of a cancer genomics resource list (CGRL). The goal of this resource was to assist the laboratory pathology and clinical oncology communities. Design .- The PHC Committee established a working group in 2012 to address this goal. The group consisted of site-specific experts in cancer genetic sequencing. The group identified current next-generation sequencing (NGS)-based cancer tests and compiled them into a usable resource. The genes were annotated by the working group. The annotation process drew on published knowledge, including public databases and the medical literature. Results .- The compiled list includes NGS panels offered by 19 laboratories or vendors, accompanied by annotations. The list has 611 different genes for which NGS-based mutation testing is offered. Surprisingly, of these 611 genes, 0 genes were listed in every panel, 43 genes were listed in 4 panels, and 54 genes were listed in 3 panels. In addition, tests for 393 genes were offered by only 1 or 2 institutions. Table 1 provides an example of gene mutations offered for breast cancer genomic testing with the annotation as it appears in the CGRL 2014. Conclusions .- The final product, referred to as the Cancer Genomics Resource List 2014, is available as supplemental digital content.
    Archives of pathology & laboratory medicine 12/2014; DOI:10.5858/arpa.2014-0330-CP · 2.88 Impact Factor
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    ABSTRACT: BACKGROUND Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules.METHODS The evaluation of 143 consecutive FNA samples with a cytologic diagnosis of FN/SFN from patients with known surgical outcomes included 91 retrospective samples and 52 prospective samples. Analyses were performed on a proprietary sequencer using the targeted ThyroSeq v2 NGS panel, which simultaneously tests for point mutations in 13 genes and for 42 types of gene fusions that occur in thyroid cancer. The expression of 8 genes was used to assess the cellular composition of FNA samples.RESULTSIn the entire cohort, histologic analysis revealed 104 benign nodules and 39 malignant nodules. The most common point mutations involved the neuroblastoma RAS viral oncogene homolog (NRAS), followed by the Kirsten rat sarcoma viral oncogene homolog (KRAS), the telomerase reverse transcriptase (TERT) gene, and the thyroid-stimulating hormone receptor (TSHR) gene. The identified fusions involved the thyroid adenoma associated (THADA) gene; the peroxisome proliferator-activated receptor γ (PPARG) gene; and the neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) gene. Performance characteristics were similar in the retrospective and prospective groups. Among all FN/SFN nodules, preoperative ThyroSeq v2 performed with 90% sensitivity (95% confidence interval [CI], 80%-99%), 93% specificity (95% CI, 88%-98%), a positive predictive value of 83% (95% CI, 72%-95%), a negative predictive value of 96% (95% CI, 92%-100%), and 92% accuracy (95% CI, 88%-97%).CONCLUSIONS The current results indicate that comprehensive genotyping of thyroid nodules using a broad NGS panel provides a highly accurate diagnosis for nodules with FN/SFN cytology and should facilitate the optimal management of these patients. Cancer 2014. © 2014 American Cancer Society.
    Cancer 12/2014; 120(23). DOI:10.1002/cncr.29038 · 4.90 Impact Factor
  • M. A. Melan · A. I. Wald · S. Zhong · R. Hamilton · C. Horbinski · M. N. Nikiforova
    Annual Meeting of the Association-for-Molecular-Pathology (AMP); 11/2014
  • M. Durso · S. Zhong · S. Mercurio · A. I. Wald · G. Mantha · M. N. Nikiforova
    Annual Meeting of the Association-for-Molecular-Pathology (AMP); 11/2014
  • Annual Meeting of the Association-for-Molecular-Pathology (AMP); 11/2014
  • International journal of radiation oncology, biology, physics 11/2014; 90(5):S35-S36. DOI:10.1016/j.ijrobp.2014.08.212 · 4.18 Impact Factor
  • Annual Meeting of the Association-for-Molecular-Pathology (AMP); 11/2014
  • Source
    Sean McDermott · Liron Pantanowitz · Marina Nikiforova · Sara Monaco
    10/2014; 3(5):S6–S7. DOI:10.1016/j.jasc.2014.09.014
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    ABSTRACT: The underlying molecular alterations in chronic idiopathic inflammatory bowel disease-associated intestinal adenocarcinoma remain largely unknown. Somatic IDH mutations are often seen in gliomas and myeloid leukemia but have also been recently reported in a subset of other neoplasms. We analyzed a series of intestinal adenocarcinomas with (n=23) and without (n=39) associated chronic idiopathic inflammatory bowel disease treated at our institution for IDH1 and IDH2 mutations and correlated the clinicopathologic findings with mutation status. Compared with intestinal adenocarcinomas not associated with inflammatory bowel disease, adenocarcinomas associated with inflammatory bowel disease more frequently demonstrated IDH mutations (13% vs. 0%, P=0.047). All IDH mutations were identified in IDH1 and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1 mutations were frequently (66%) associated with concurrent KRAS mutations (p.G12D, c.35G>A). IDH1-mutated intestinal adenocarcinomas were seen in the setting of both Crohn disease and ulcerative colitis and were located in both the ileum and colon. Compared with IDH1-negative inflammatory bowel disease-associated adenocarcinoma, IDH1-positive adenocarcinomas more frequently demonstrated tubuloglandular histology (100% vs. 25%, P=0.032) and were more frequently associated with precursor lesions exhibiting serrated morphology (66% vs. 6%, P=0.034). IDH1 mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1 mutations are occasionally identified in inflammatory bowel disease-associated intestinal adenocarcinoma but not in intestinal adenocarcinoma not associated with inflammatory bowel disease. In addition, IDH1-mutated intestinal adenocarcinoma is associated with a characteristic low-grade tubuloglandular histology and often harbors concurrent KRAS mutations. Identification of patients with IDH1-mutated intestinal adenocarcinoma may become clinically important as new therapies emerge that target tumors that harbor IDH mutations.
    American Journal of Surgical Pathology 08/2014; 38(8):1147-1156. DOI:10.1097/PAS.0000000000000239 · 4.59 Impact Factor
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    ABSTRACT: We analyzed a series of 55 disseminated appendiceal mucinous neoplasms treated at our institution for GNAS and KRAS mutations in an attempt to correlate mutation status with clinicopathologic findings and patient survival. GNAS mutations (p.R201H, c.602G > A and p.R201C, c.602C > T) were identified in 17/55 (31%) of disseminated mucinous neoplasms and were found in 8/23 (35%) low-grade mucinous neoplasms, 7/19 (37%) high-grade mucinous adenocarcinomas lacking a signet ring cell component, and 2/13 (15%) high-grade mucinous adenocarcinomas with a signet ring cell component. All seven mucinous adenocarcinomas composed of pure (>95%) signet ring cells harbored wild-type GNAS. There was no significant association between GNAS mutations and gender and age (both with p > 0.05) or between GNAS mutations and individual adverse histologic features including cytologic grade, destructive invasion, tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells (all with p > 0.05). KRAS mutations were identified in 22/55 (40%) disseminated mucinous neoplasms. GNAS-mutated disseminated appendiceal mucinous neoplasms more frequently harbored concurrent KRAS mutations compared with GNAS-wild-type tumors (65% vs. 29%, p = 0.018). GNAS mutations were not significantly associated with overall survival (both with p > 0.05). Only overall tumor grade was an independent predictor of overall survival in the multivariable analysis (p = 0.01). Our results indicate that GNAS mutations are frequently identified in both low-grade and high-grade disseminated appendiceal mucinous neoplasms indicating that GNAS mutation status cannot be used to distinguish between low-grade from high-grade appendiceal mucinous neoplasms.
    Human pathology 08/2014; 45(8). DOI:10.1016/j.humpath.2014.04.018 · 2.81 Impact Factor
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    ABSTRACT: BACKGROUND Mutations in the RAS gene in the thyroid gland result in the activation of signaling pathways and are associated with a follicular growth pattern and the probability of a carcinoma outcome ranging from 74% to 87%. In the current study, the authors investigated the cytopathologic and histopathologic features of common RAS mutation subtypes.METHODS Malignant, indeterminate, and selected benign thyroid cytology cases were tested prospectively for the presence of NRAS61, HRAS61, and KRAS12/13 mutations. For each case, the Bethesda System for thyroid cytopathology diagnosis, additional cytologic descriptors, and surgical pathology outcomes were documented. The Fisher exact test and Wilcoxon 2-sample test were used for statistical comparison between the groups.RESULTSA total of 204 thyroid fine-needle aspiration cases with RAS mutations (93.6% of which were associated with indeterminate cytopathology diagnoses) and corresponding surgical pathology resection specimens were identified. The KRAS12/13 mutation was associated with a significantly lower carcinoma outcome (41.7%) when compared with HRAS61 (95.5%) and NRAS61 (86.8%) mutations (P<.0001). Furthermore, oncocytic change was observed in a significantly higher percentage of cytology and resection specimens with KRAS12/13 mutations (66.7% and 75.0%, respectively) in comparison with those with HRAS61 (4.5% and 4.5%, respectively) and NRAS61 (15.4% and 14.7%, respectively) mutations (P<.0001). RAS mutations also were identified in cases of poorly differentiated carcinoma (NRAS61), anaplastic carcinoma (HRAS61), and medullary thyroid carcinoma (HRAS61 and KRAS12/13).CONCLUSIONS Subclassification of RAS mutations in conjunction with cytopathologic evaluation improves presurgical risk stratification, provides better insight into lesional characteristics, and may influence patient management. In particular, KRAS12/13-mutated thyroid nodules were found to be different from HRAS61-mutated and NRAS61-mutated nodules with regard to cytopathologic and surgical outcome characteristics. Cancer (Cancer Cytopathol) 2014. © 2014 American Cancer Society.
    Cancer Cytopathology 08/2014; 122(12). DOI:10.1002/cncy.21474 · 3.81 Impact Factor
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    ABSTRACT: Objective: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. Background: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. Methods: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. Results: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). Conclusions: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPAR gamma, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.
    Annals of Surgery 07/2014; 260(1):163-168. DOI:10.1097/SLA.0000000000000215 · 8.33 Impact Factor
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    ABSTRACT: Purpose: Management guidelines for pancreatic IPMNs and MCNs are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA) remains unclear. Experimental Design: GNAS and KRAS testing was performed on EUS-FNA obtained fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNETs), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts and 1 lymphoepithelial cyst. Results: Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity (95% confidence interval [CI], 0.83-1.00), but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had a 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92). Conclusions: The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms.
    Clinical Cancer Research 06/2014; 20(16). DOI:10.1158/1078-0432.CCR-14-0513 · 8.19 Impact Factor

Publication Stats

6k Citations
667.07 Total Impact Points

Institutions

  • 2007–2015
    • University of Pittsburgh
      • • Department of Pathology
      • • Division of Neuropathology
      Pittsburgh, Pennsylvania, United States
  • 2002–2013
    • Stanford University
      • Department of Radiation Oncology
      Palo Alto, California, United States
  • 2012
    • University of Kentucky
      • Department of Plant Pathology
      Lexington, KY, United States
  • 2011
    • Magee-Womens Hospital
      • Department of Pathology
      Pittsburgh, Pennsylvania, United States
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 2009
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 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
    • Yale University
      New Haven, Connecticut, United States
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 1996
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States