Ralph H Hruban

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (842)4944.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Intraductal papillary mucinous neoplasms (IPMNs) have malignant potential, and can progress from low- to high-grade dysplasia to invasive adenocarcinoma. The management of patients with IPMNs is dependent on their risk of malignant progression, with surgical resection recommended for patients with branch duct-IPMN (BD-IPMN) who develop high-risk features.There is increasing evidence that liver transplant patients are at increased risk of extra-hepatic malignancy. However there are few data regarding the risk of progression of BD-IPMNs in liver transplant recipients. The aim of this study was to determine if liver transplant recipients with BD-IPMNs are at higher risk of developing high-risk features than patients with BD-IPMNs who did not receive a transplant.Methods: Consecutive patients who underwent a liver transplant with BD-IPMNs were included. Patients with BD-IPMNs with no history of immunosuppression were used as controls. Progression of the BD-IPMNs was defined as development of a high-risk feature (jaundice, dilated main pancreatic duct, mural nodule, cytology suspicious or diagnostic for malignancy, cyst diameter ≥3cm).Results: Twenty three liver transplant patients with BD-IPMN were compared with 274 control patients. The median length of follow-up was 53.7 and 24 months in liver transplant and control groups respectively. Four (17.4%) liver transplant patients and 45 (16.4%) controls developed high-risk features (p=0.99). In multivariate analysis, progression of BD-IPMNs was associated with age at diagnosis but not with liver transplantation.Conclusion: There was no statistically significant difference in the risk of developing high-risk features between the liver transplant and control groups. Liver Transpl , 2014. © 2014 AASLD.
    Liver Transplantation 08/2014; · 3.94 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the ability of computed tomography (CT) in differentiating between intrapancreatic accessory spleen (IPAS) from pancreatic neuroendocrine tumor (PanNET).
    Journal of computer assisted tomography. 06/2014;
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    ABSTRACT: Background: Evidence suggests the incidence of oral tongue squamous cell carcinoma is increasing in young patients, many who have no history of tobacco use. Methods We clinically reviewed 89 oral tongue cancer patients. Exomic sequencing of tumor DNA from 6 non-smokers was performed and compared to previously sequenced cases. RNA from 20 tumors was evaluated by massively parallel sequencing to search for potentially oncogenic viruses. Results Non-smokers (53 of 89) were younger than smokers (36 of 89) (mean 50.4 vs. 61.9 years, P<0.001), and appeared more likely to be female, (58.5% vs. 38.9%, P=0.069). Non-smokers had fewer TP53 mutations (P=0.02) than smokers. No tumor-associated viruses were detected. Conclusions The young age of non-smoker oral tongue cancer patients, and fewer TP53 mutations suggest a viral role in this disease. Our efforts to identify such a virus were unsuccessful. Further studies are warranted to elucidate the drivers of carcinogenesis in these patients. Head Neck, 2014.
    Head & neck. 06/2014;
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    ABSTRACT: Background: Solid-pseudopapillary neoplasm (SPN) is a rare pancreatic malignancy with an excellent prognosis. It is most commonly diagnosed in young women. This article comprehensively reviews the clinical, pathological and radiological features of this neoplasm, as well as its clinical management. Methods: A literature review of SPN was performed of all articles published in the English language in PubMed prior to November 1, 2013. Cytomorphological features, histopathology, immunohistochemistry, patient general demographics, molecular studies, radiologic imaging and clinical management were reviewed. Results: SPN displays distinct cytomorphological features on fine-needle aspiration - thin, delicate, branching vessels in a 'Chinese character' pattern lined by one to several layers of loosely cohesive neoplastic cells. Nuclear features include indented or grooved nuclei with an evenly distributed chromatin pattern and small inconspicuous nucleoli. SPN is characteristically immunoreactive for CD10, β-catenin (in an abnormal nuclear pattern), CD99 in a perinuclear dot-like pattern, α1-antitrypsin, and progesterone receptor. Almost all SPNs harbor an activating point mutation in exon 3 of the β-catenin gene (CTNNB1). Clinicopathological features generally do not correlate with prognosis, and most patients experience excellent long-term survival. Conclusions: SPN can mimic other neoplasms of the pancreas, which can lead to diagnostic challenges in a limited cytologic specimen. Distinct cytomorphological features can help distinguish SPNs from other pancreatic neoplasms. Complete surgical resection as well as resection of metastatic disease is preferred given a low rate of tumor recurrence and long periods of disease-free intervals. © 2014 S. Karger AG, Basel.
    Acta cytologica 06/2014; · 0.69 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies. Cancer Immunol Res; 2(7); 1-16. ©2014 AACR.
    Cancer immunology research. 06/2014;
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    ABSTRACT: Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts. Cancer Res; 74(13); 1-9. ©2014 AACR.
    Cancer research. 06/2014;
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    ABSTRACT: Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with a high resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data reveal distinct patterns of both overall proteome expression as well as tyrosine kinase activities across the three different metastatic lesions. This heterogeneity is significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver and lung metastasis-derived cell lines as compared to tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve administration of a combination of agents with each agent targeted to the features of different subclones.
    Molecular & cellular proteomics : MCP. 06/2014;
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    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death in the world. The etiology of pancreatic cancer is heterogeneous with a wide range of alterations that have already been reported at the level of the genome, transcriptome, and proteome. The past decade has witnessed a large number of experimental studies using high-throughput technology platforms to identify genes whose expression at the transcript or protein levels is altered in pancreatic cancer. Based on expression studies, a number of molecules have also been proposed as potential biomarkers for diagnosis and prognosis of this deadly cancer. Currently, there are no repositories which provide an integrative view of multiple Omics data sets from published research on pancreatic cancer. Here, we describe the development of a web-based resource, Pancreatic Cancer Database (http://www.pancreaticcancerdatabase.org), as a unified platform for pancreatic cancer research. PCD contains manually curated information pertaining to quantitative alterations in miRNA, mRNA, and proteins obtained from small-scale as well as high-throughput studies of pancreatic cancer tissues and cell lines. We believe that PCD will serve as an integrative platform for scientific community involved in pancreatic cancer research.
    Cancer biology & therapy 05/2014; 15(8). · 3.29 Impact Factor
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    ABSTRACT: One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.
    Oncotarget 05/2014; 5(9):2839-52. · 6.64 Impact Factor
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    ABSTRACT: Incidental pancreatic cysts are common, a small number of which are premalignant or malignant. Multidisciplinary care has been shown to alter management and improve outcomes in many types of cancers, but its role has not been examined in patients with pancreatic cysts. We assessed the effect of a multidisciplinary pancreatic cyst clinic (MPCC) on the diagnosis and management of patients with pancreatic cysts. The referring institution and MPCC diagnosis and management plan were recorded. Patient were placed into one of five categories-no, low, intermediate, or high risk of malignancy within the cyst, and malignant cyst-on the basis of their diagnosis. Patients were assigned one of four management options: surveillance, surgical resection, further evaluation, or discharge with no further follow-up required. The MPCC was deemed to have altered patient care if the patient was assigned a different risk or management category after the MPCC review. Referring institution records were available for 262 patients (198 women; mean age 62.7 years), with data on risk category available in 138 patients and management category in 225. The most common diagnosis was branch duct intraductal papillary mucinous neoplasm. MPCC review altered the risk category in 11 (8.0%) of 138 patients. The management category was altered in 68 (30.2%) of 225 patients. Management was increased in 52 patients, including 22 patients who were recommended surgical resection. Management was decreased in 16 patients, including 10 who had their recommendation changed from surgery to surveillance. MPCC is helpful and alters the management over 30% of patients.
    Annals of Surgical Oncology 05/2014; · 4.12 Impact Factor
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    ABSTRACT: The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy (PD) for adenocarcinoma is still unclear. A retrospective review of all patients undergoing PD at our institution between 1995 and 2011 was performed. Clinicopathological data, including Clavien-Dindo complication grade, time to adjuvant therapy (TTA), and survival, were analyzed. A total of 1,144 patients underwent PD for adenocarcinoma between 1995 and 2011. The overall complication rate was 49.1 % and clinically severe complications (≥IIIb) occurred in 4.2 %. Overall, 621 patients (54.3 %) were known to have received adjuvant therapy. The median TTA was 60 days. Although the presence of a complication was associated with a delay in TTA (p = 0.002), the grade of complication was not (p = 0.112). On multivariate analysis, only age > 68 years (p < 0.001) and length of stay >9 days (p = 0.002) correlated with no adjuvant therapy. Patients with postoperative complications were more likely to receive single adjuvant chemotherapy or radiation therapy (31.4 %) than were patients without complications (17.1 %; p < 0.001). Patients without a complication had a longer median survival compared with patients who experienced complications (19.5 vs. 16.1 months; p = 0.001). Patients without complications who received adjuvant therapy had longer median survival than patients with complications who received no adjuvant therapy (22.5 vs. 10.7 months; p < 0.001). Multivariate analysis demonstrated that complications [hazard ratio (HR) 1.16; p = 0.023] and adjuvant therapy (HR 0.67; p < 0.001) were related to survival. Complications and no adjuvant therapy are common following PD for adenocarcinoma. Postoperative complications delay TTA and reduce the likelihood of multimodality adjuvant therapy. Identifying patients at increased risk for complications and those unlikely to receive adjuvant therapy warrants further investigation as they may benefit from a neoadjuvant approach.
    Annals of Surgical Oncology 04/2014; · 4.12 Impact Factor
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    ABSTRACT: The aim of the study was to determine if there had been any change in the number of solid-pseudopapillary neoplasm (SPN) cases detected and their evaluation or management over time. A systematic review of SPN was performed of all articles published in English in PubMed and Scopus. A total of 2744 patients with SPN were identified in 484 studies published between 1961 and 2012; 87.8% of the cases were reported between 2000 and 2012. A total of 2408 (87.8%) were females, and the mean age was 28.5 (SD, 13.7) years. The most common symptom was abdominal pain in 63.6% of the cases and incidentally detected in 38.1% of the cases. There were 2285 patients who underwent pancreatic resection. The mean tumor size was 8.6 (SD, 4.3) cm. Follow-up was reported for 1952 (90.5%) patients, with a mean follow-up of 36.1 (SD, 32.8) months. Disease-free survival was documented in 1866 (95.6%) patients with recurrence in 86 (4.4%) patients; the median time to recurrence was 50.5 months. The number of SPNs reported in the literature has seen a 7-fold increase in the number of cases reported since 2000 compared with before. Solid-pseudopapillary neoplasms continue to be primarily found in young women and present with nonspecific symptoms. Surgery remains the mainstay of treatment with an excellent long-term prognosis.
    Pancreas 04/2014; 43(3):331-7. · 2.95 Impact Factor
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    ABSTRACT: The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound-guided fine-needle aspiration, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and post-biopsy management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings, and synthesis of selected online comments of the draft document. This document presents the results of these discussions regarding the use of ancillary testing in the cytologic diagnosis of biliary and pancreatic lesions. Currently, fluorescence in situ hybridization (FISH) appears to be the most clinically relevant ancillary technique for cytology of bile duct strictures. The addition of FISH analysis to routine cytologic evaluation appears to yield the highest sensitivity without loss in specificity. Loss of immunohistochemical staining for the protein product of the SMAD4 gene and positive staining for mesothelin support a diagnosis of ductal adenocarcinoma. Immunohistochemical markers for endocrine and exocrine differentiation are sufficient for a diagnosis of endocrine and acinar tumors. Nuclear staining for beta-catenin supports a diagnosis of solid-pseudopapilary neoplasm. Cyst fluid analysis for amylase and carcinoembryonic antigen aids in the preoperative classification of pancreatic cysts. Many gene mutations (KRAS, GNAS, VHL, RNF43, and CTNNB1) may be of aid in the diagnosis of cystic neoplasms. Other ancillary techniques do not appear to improve diagnostic sensitivity sufficiently to justify their increased costs. Diagn. Cytopathol. 2014;42:351–362. © 2014 Wiley Periodicals, Inc.
    Diagnostic Cytopathology 04/2014; 42(4). · 1.49 Impact Factor
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    ABSTRACT: Solid-pseudopapillary neoplasms are rare, but are distinctive pancreatic tumors of low-malignant potential. While the histogenesis of these tumors is unclear, they are often associated with gain-of-function mutations in the catenin (cadherin-associated protein), beta 1 (88 kDa), or CTNNB1 gene, resulting in nuclear accumulation of CTNNB1. CTNNB1 is a central component of the Wnt signaling pathway and mediates gene expression through the lymphoid enhancer-binding factor 1 (LEF1) /T-cell factor transcription complex. Although LEF1 has a pivotal role in the transactivation of Wnt/CTNNB1 responsive genes, the status of LEF1 in solid-pseudopapillary neoplasms and other pancreatic tumors has not been examined. We analyzed both LEF1 and CTNNB1 in a large cohort of pancreatic tumors (n=155). In all cases of solid-pseudopapillary neoplasms including surgical resections (n=27) and cytologic samples (n=8) had strong and diffuse nuclear labeling for both LEF1 and CTNNB1. The surrounding uninvolved pancreatic parenchyma was devoid of any LEF1 staining. All resection and cytologic specimens from well-differentiated pancreatic neuroendocrine tumors (n=44; n=29, respectively), high-grade pancreatic neuroendocrine carcinomas (n=2; n=1), pancreatic ductal adenocarcinomas (n=25; n=12), and acinar cell carcinomas (n=9; n=2) studied were negative for both nuclear LEF1 and CTNNB1. However, nuclear LEF1 and CTNNB1 were detected in all four resected pancreatoblastomas (no cytologic specimens were available for immunolabeling), but primarily centered around and within squamoid corpuscles. In summary, abnormal CTNNB1 accumulation was accompanied by nuclear LEF1 overexpression in both solid-pseudopapillary neoplasms and pancreatoblastomas. But, in contrast to pancreatoblastomas, a diffuse, nuclear labeling was observed in solid-pseudopapillary neoplasms and further implicates the CTNNB1/LEF1 transcriptional complex in the development of solid-pseudopapillary neoplasms. In addition, as part of an immunohistochemical panel, LEF1 can be a useful ancillary stain in the diagnosis of solid-pseudopapillary neoplasms.Modern Pathology advance online publication, 21 March 2014; doi:10.1038/modpathol.2014.40.
    Modern Pathology 03/2014; · 5.25 Impact Factor
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    ABSTRACT: The objective of the study was to characterize pancreatic serous cystadenomas on dual-phase multidetector computed tomography in a surgical series. This is a retrospective review of preoperative dual-phase multidetector computed tomographic scans from 68 patients with surgically resected and pathologically confirmed pancreatic serous cystadenomas. Pancreatic serous cystadenomas were most commonly found in the tail (39%). The mean (SD) axial dimension was 4.5 (2.7) cm. A total of 36% contained internal calcifications. Dilatation of the main pancreatic duct (14%) and pancreatic parenchymal atrophy (11%) were uncommon. The mean (SD) attenuation of components with the highest attenuation was 49.1 (35.0) Hounsfield units on the arterial phase and 48.5 (33.4) Hounsfield units on the portal venous phase. Only 20% of neoplasms demonstrated "classic" morphology, as defined by multiple thin nonenhancing septations, calcifications, as well as the absence of main pancreatic duct dilatation and vascular involvement. Only 20% of surgically resected serous cystadenomas fulfilled classic morphology. Attenuation was helpful in differentiating serous cystadenomas from insulinomas and other cystic pancreatic masses, but it was not helpful in differentiation from pancreatic adenocarcinomas. Morphologic features were more helpful in differentiating serous cystadenomas from malignant masses.
    Journal of computer assisted tomography 03/2014; 38(2):258-63. · 1.38 Impact Factor
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    ABSTRACT: Gallbladder cancer carries an extremely high mortality rate, with a 5-year survival rate as low as 12%. Survival is dependent on the diagnosis of these tumors in their earliest stages. This study sought to describe the clinical and imaging features of stages T1, T2, and T3 gallbladder tumors and to illustrate features that may allow radiologists to make an early diagnosis. After approval from the institutional review board, a search of the pathology department database yielded 18 patients with surgically proven T1, T2, and T3 gallbladder cancers with available preoperative computed tomography (CT) or magnetic resonance imaging. The imaging was reviewed for lesional morphology (focal polyploid mass, focal wall thickening, circumferential wall thickening), enhancement characteristics, liver invasion, locoregional lymphadenopathy, and distant metastatic disease. The electronic medical record was also searched for demographic information and clinical presentation. There were 10 women and 8 men with a mean age of 69 years. Virtually all patients were symptomatic, with most patients demonstrating symptoms suggestive of underlying malignancy (including jaundice, weight loss, and chronic abdominal pain). Tumors on CT and MRI included 6 polyploid masses, 9 tumors with focal wall thickening, and 3 with circumferential wall thickening. The mean attenuation of those tumors imaged with CT was 59.4 Hounsfield units (HUs) on the arterial phase and 86.5 HUs on the venous phase, with a mean increase in Hounsfield attenuation between the arterial and venous phases of 28.2 HUs. Twelve of the 18 patients were correctly diagnosed prospectively on CT. The imaging findings of gallbladder cancer can be subtle, regardless of whether the tumor presents as a discrete mass, focal wall thickening, or circumferential diffuse wall thickening, and radiologists should be aware of the wide range of different possible appearances. Moreover, the vast majority of these patients had clinical symptoms suggestive of an underlying malignancy, and this should precipitate a careful evaluation of the gallbladder in all such cases.
    Journal of computer assisted tomography 03/2014; · 1.38 Impact Factor
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    ABSTRACT: Cancers comprise a heterogeneous group of human diseases. Unifying characteristics include unchecked abilities of tumor cells to proliferate and spread anatomically, and the presence of clonal advantageous genetic changes. However, universal and highly specific tumor markers are unknown. Herein, we report widespread long interspersed element-1 (LINE-1) repeat expression in human cancers. We show that nearly half of all human cancers are immunoreactive for a LINE-1-encoded protein. LINE-1 protein expression is a common feature of many types of high-grade malignant cancers, is rarely detected in early stages of tumorigenesis, and is absent from normal somatic tissues. Studies have shown that LINE-1 contributes to genetic changes in cancers, with somatic LINE-1 insertions seen in selected types of human cancers, particularly colon cancer. We sought to correlate this observation with expression of the LINE-1-encoded protein, open reading frame 1 protein, and found that LINE-1 open reading frame 1 protein is a surprisingly broad, yet highly tumor-specific, antigen.
    American Journal Of Pathology 03/2014; · 4.60 Impact Factor
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    ABSTRACT: Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N=8) or ampullary adenocarcinoma (N=3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N=11) or intestinal (N=5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.
    The American journal of surgical pathology 03/2014; 38(3):360-3. · 4.06 Impact Factor
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    ABSTRACT: Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110α) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens. Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and the E17K mutation in the AKT1 gene. A hot-spot mutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRAS mutation. No mutations were identified in the AKT1 gene. Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy.
    Pancreas 03/2014; 43(2):245-9. · 2.95 Impact Factor
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    ABSTRACT: Intraductal neoplasms are important precursors to invasive pancreatic cancer and an opportunity to detect and treat pancreatic neoplasia before an invasive carcinoma develops. The diagnostic evaluation of these lesions is challenging as diagnostic imaging and cytological sampling do not provide accurate information on lesion classification, the grade of dysplasia or the presence of invasion. Moreover, the molecular driver gene mutations of these precursor lesions have yet to be fully characterized. Fifty-two intraductal papillary neoplasms, including 48 intraductal papillary mucinous neoplasms (IPMNs) and 4 intraductal tubulopapillary neoplasms (ITPNs), were subjected to the mutation assessment in 51 cancer-associated genes, using Ion Torrent semiconductor-based next-generation sequencing. P16 and Smad4 immunohistochemistry was performed on 34 IPMNs, and 17 IPMN-associated carcinomas. At least one somatic mutation was observed in 46/48 (96%) IPMNs; 29 (60%) had multiple gene alterations. GNAS and/or KRAS mutations were found in 44/48 (92%) of IPMNs. GNAS was mutated in 38/48 (79%) IPMNs, KRAS in 24/48 (50%), and these mutations coexisted in 18/48 (37.5%) of IPMNs. RNF43 was the third most commonly mutated gene and was always associated with GNAS and/or KRAS mutations, as were virtually all the low frequency mutations found in other genes. Mutations in TP53 and BRAF genes (10% and 6%) were only observed in high-grade IPMNs. P16 was lost in 7/34 IPMNs and 9/17 IPMN-associated carcinomas; Smad4 was lost in 1/34 IPMN and 5/17 IPMN-associated carcinomas. In contrast to IPMNs, only one of four ITPN had detectable driver gene (GNAS and NRAS) mutations. Deep sequencing DNA from 7 cyst fluid aspirates identified 10 of the 13 mutations detected in their associated IPMN. Using next-generation sequencing to detect cyst fluid mutations has the potential to improve the diagnostic and prognostic stratification of pancreatic cystic neoplasms.
    The Journal of Pathology 03/2014; · 7.59 Impact Factor

Publication Stats

42k Citations
4,944.96 Total Impact Points


  • 1992–2014
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Surgery
      • • Department of Medicine
      • • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1984–2014
    • Johns Hopkins Medicine
      • • Department of Surgery
      • • Department of Pathology
      • • Department of Radiology and Radiological Science
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2013
    • University of Colorado
      • Division of GI, Tumor and Endocrine Surgery
      Denver, CO, United States
  • 2009–2013
    • Howard Hughes Medical Institute
      Maryland, United States
    • Johns Hopkins Bloomberg School of Public Health
      Baltimore, Maryland, United States
  • 2012
    • Weill Cornell Medical College
      • Department of Pathology and Laboratory Medicine
      New York City, NY, United States
  • 2011–2012
    • Vanderbilt University
      Nashville, Michigan, United States
    • University Medical Center Utrecht
      • Department of Pathology
      Utrecht, Provincie Utrecht, Netherlands
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
    • Cancer Research UK Cambridge Institute
      Cambridge, England, United Kingdom
    • Centro Nacional de Investigaciones Oncológicas
      Madrid, Madrid, Spain
  • 2009–2012
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 1995–2012
    • University of Chicago
      • Department of Radiation & Cellular Oncology
      Chicago, IL, United States
    • The Ohio State University
      • Pathology
      Columbus, OH, United States
  • 2008–2011
    • Shizuoka Cancer Center
      Sizuoka, Shizuoka, Japan
    • University College Dublin
      • School of Medicine & Medical Science
      Dublin, L, Ireland
    • Thomas Jefferson University
      • Department of Surgery
      Philadelphia, PA, United States
  • 2000–2011
    • University of Texas Southwestern Medical Center
      • Department of Pathology
      Dallas, TX, United States
  • 2010
    • University of Texas MD Anderson Cancer Center
      • Department of Pathology
      Houston, TX, United States
  • 2007–2009
    • Purdue University
      West Lafayette, Indiana, United States
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
    • Southern Illinois Healthcare
      Illinois, United States
  • 1990–2009
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Pathology
      • • Department of Surgery
      New York City, NY, United States
  • 2005–2007
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Pathology
      Baton Rouge, LA, United States
    • Eastern Virginia Medical School
      • Department of Surgery
      Norfolk, VA, United States
    • University of Michigan
      • Department of Pathology
      Ann Arbor, MI, United States
    • Sapienza University of Rome
      Roma, Latium, Italy
    • Roswell Park Cancer Institute
      • Department of Cancer Genetics
      Buffalo, NY, United States
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 2003–2007
    • Mayo Clinic - Rochester
      • • Department of Laboratory Medicine & Pathology
      • • Department of Health Science Research
      Rochester, MN, United States
    • National and Kapodistrian University of Athens
      • Department of Surgery
      Athens, Attiki, Greece
    • University of Münster
      Muenster, North Rhine-Westphalia, Germany
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States
    • Mayo Foundation for Medical Education and Research
      • Department of Pathology
      Scottsdale, AZ, United States
  • 2006
    • Indiana University-Purdue University Indianapolis
      • Department of Surgery
      Indianapolis, IN, United States
  • 1999–2006
    • University of Pennsylvania
      • • Department of Medicine
      • • Department of Surgery
      Philadelphia, Pennsylvania, United States
  • 2004
    • National Human Genome Research Institute
      Maryland, United States
  • 2002–2004
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 1997–2002
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 1995–1999
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 1998
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
  • 1993
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
    • Medical University of Ohio at Toledo
      • Department of Surgery
      Toledo, Ohio, United States