David S Klimstra

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (422)2253.2 Total impact

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    ABSTRACT: The biological relevance of histological subtyping of ampullary carcinoma into intestinal vs pancreaticobiliary types remains to be determined. In an effort to molecularly profile these subtypes of ampullary carcinomas, we conducted a two-phase study. In the discovery phase, we identified 18 pancreatobiliary-type ampullary carcinomas and 14 intestinal-type ampullary carcinomas using stringent pathologic criteria and performed next-generation sequencing targeting 279 cancer-associated genes on these tumors. Although the results showed overlapping of genomic alterations between the two subtypes, trends including more frequent KRAS alterations in pancreatobiliary-type ampullary carcinoma (61 vs 29%) and more frequent mutations in APC in intestinal-type ampullary carcinoma (43 vs 17%) were observed. Of the entire cohort of 32 tumors, the most frequently mutated gene was TP53 (n=17); the most frequently amplified gene was ERBB2 (n=5); and the most frequently deleted gene was CDKN2A (n=6). In the second phase of the study, we aimed at validating our observation on ERBB2 and assessed ERBB2 amplification and protein overexpression in a series of 100 ampullary carcinomas. We found that (1) gene amplification and immunohistochemical overexpression of ERBB2 occurred in 13% of all ampullary carcinomas, therefore providing a potential target for anti-HER2 therapy in these tumors; (2) amplification and immunohistochemical expression correlated in all cases, thus indicating that immunohistochemistry could be used to screen tumors; and (3) none of the 14 ERBB2-amplified tumors harbored any downstream driver mutations in KRAS/NRAS, whereas 56% of the cases negative for ERBB2 amplification did, an observation clinically pertinent as downstream mutations may cause primary resistance to inhibition of EGFR family members.Modern Pathology advance online publication, 15 May 2015; doi:10.1038/modpathol.2015.57.
    Modern Pathology 05/2015; DOI:10.1038/modpathol.2015.57 · 6.36 Impact Factor
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    ABSTRACT: Background The prognostic and predictive abilities of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) have not been studied in patients with unresectable colorectal liver metastases (uCRLM) treated with combined hepatic arterial infusion (HAI) and systemic chemotherapy.Objectives The ability of PET-CT metabolic response parameters to predict conversion to resectability and oncologic outcome in this setting was evaluated.Methods Thirty-eight patients undergoing serial PET-CT as part of a Phase II trial of HAI and systemic chemotherapy for uCRLM were included. Metabolic response was determined as the percentage change in standard uptake value (SUV) and total lesion glycolysis (TLG). Conversion to resection, overall survival (OS), progression-free survival (PFS) and recurrence-free survival were evaluated using standard statistics.ResultsVolumetric response sufficient to facilitate resection was seen in 53% of patients after a median of 5 months of therapy. Median follow-up was 38 months (range: 32–52 months). Median OS was not reached [95% confidence interval (CI) 32 months–unknown] and 3-year OS was 54% (range: 33–71%). Median PFS was 13 months (95% CI 6–21 months) and 3 year PFS was 10% (range: 3–20%). Neither baseline values nor the percentage change in any of the metabolic parameters evaluated correlated with conversion to resection, survival variables or hepatic recurrence on Cox regression analysis.Conclusions Pre- and post-treatment PET-related metabolic parameters do not predict conversion to resection or oncologic outcome in patients with uCRLM treated with HAI and systemic chemotherapy. Metabolic parameters should not be used to monitor response or to determine prognosis in these patients.
    HPB 05/2015; 17(7). DOI:10.1111/hpb.12421 · 2.05 Impact Factor
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    ABSTRACT: Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Pancreas 04/2015; 44(5). DOI:10.1097/MPA.0000000000000368 · 3.01 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma is a highly deadly malignancy, accounting for approximately 800,000 deaths worldwide every year. Mutation of the p53 tumor suppressor gene is a common genetic change in HCC, present in 30% of cases. p53 R175H (corresponding to
    PLoS ONE 04/2015; 10(4). DOI:10.1371/journal.pone.0123816 · 3.53 Impact Factor
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    ABSTRACT: Myoepithelial carcinoma (MECA) is an underrecognized rare tumor with a diverse clinical behavior. The histologic features of this tumor are not well characterized, much less its grading, which is controversial. The objective of this study is to provide a better characterization of MECA and its prognostic factors. A total of 48 cases were retrieved from the pathology files. The cases were subjected to a detailed histopathologic, immunohistochemical, statistical, and clinical analysis. Tumors were classified as de novo MECA in 22 cases (46%) and carcinoma ex-pleomorphic adenoma (CA ex-PA) in 26 cases (54%). Tumor necrosis, high mitotic count (≥6/10 high-power fields), and severe pleomorphism were identified in 38%, 33%, and 21%, respectively. Perineural invasion, vascular invasion, and positive margins were noted in 10%, 12%, and 47%, respectively. Median follow-up was 38 months. Four patients had lymph node metastasis at presentation, 9 developed local recurrences, and 12 had distant metastases with the lung being the most common site (83%). The presence of CA ex-PA, necrosis, and vascular invasion correlated significantly with disease-free survival (P=0.02, 0.01, 0.03, respectively). No distant recurrence was noted in all 23 patients lacking necrosis in their neoplasms (median follow-up: 44 mo). MECA is a relatively aggressive tumor that is associated with a high rate of distant metastasis (27%). Compared with de novo MECA, CA ex-PA correlates with worse clinical outcome. A grading system based on the presence of tumor necrosis should be used to identify high-grade MECA and predict its clinical behavior.
    The American journal of surgical pathology 04/2015; 39(7). DOI:10.1097/PAS.0000000000000452 · 4.59 Impact Factor
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    ABSTRACT: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤0.5, >0.5-≤1, >1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic). These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.
    Annals of Surgery 03/2015; DOI:10.1097/SLA.0000000000001173 · 7.19 Impact Factor
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    ABSTRACT: The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.
    American Journal of Surgical Pathology 02/2015; 39(5). DOI:10.1097/PAS.0000000000000408 · 4.59 Impact Factor
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    ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations. Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43). Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis. Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Surgeons 02/2015; 220(5). DOI:10.1016/j.jamcollsurg.2014.11.029 · 4.45 Impact Factor
  • Journal of Vascular and Interventional Radiology 02/2015; 26(2):S124-S125. DOI:10.1016/j.jvir.2014.12.336 · 2.15 Impact Factor
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    ABSTRACT: Background/purpose: Fibrolamellar hepatocellular carcinoma (FL-HCC) arises in pediatric/adolescent patients without cirrhosis. We retrospectively evaluated the impact of resection, nodal status, metastasis, and PRETEXT stage on overall survival (OS). Methods: With IRB approval, we reviewed records of 25 consecutive pediatric patientswith FL-HCC treated at our institution from 1981 to 2011. We evaluated associations between OS and PRETEXT stage, nodal involvement, metastasis, and complete resection. Results: Median age at diagnosis was 17.1 years (range, 11.6-20.5). Median follow-up was 2.74 years (range, 5-9.5). Five (28%) patients had PRETEXT stage 1 disease, 10 (56%) had stage 2, 2 (11%) had stage 3, and 2 (11%) had stage 4 disease. On presentation, 17 (68%) patients had N1 disease, and 7 (28%) had parenchymal metastases. Complete resection was achieved in 17 (80.9%) of 21 patients who underwent resection. Five-year OS was 42.6%. Survival was positively associated with complete resection (P = 0.003), negative regional lymph nodes (P = 0.044), and lower PRETEXT stage (P < 0.001), with a trend for metastatic disease (P= 0.05). Conclusions: In young patients with FL-HCC, lower PRETEXT stage and complete resection correlated with prolonged survival, while metastatic disease and positive lymph node status were associated with poor prognosis. Thus, we recommend complete resection and regional lymphadenectomy whenever possible.
    Journal of Pediatric Surgery 01/2015; 50(1). DOI:10.1016/j.jpedsurg.2014.10.039 · 1.31 Impact Factor
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    ABSTRACT: OBJECTIVES:: To evaluate the association of tumor-associated neutrophils (TANs) with malignant progression in intraductal papillary mucinous neoplasms (IPMNs) and to study the cyst fluid from these lesions for biomarkers of the inflammation-carcinogenesis association. BACKGROUND:: There is a strong link between TANs and malignant progression. Inflammatory mediators released by these cells may be a measurable surrogate marker of this progression. METHODS:: We evaluated 78 resected IPMNs (2004-2013). Lesions were divided into the low-risk (low- and intermediate-grade dysplasia: n = 48) and high-risk (high-grade dysplasia and invasive carcinoma: n = 30) groups. TANs were assessed and categorized (negative, low, and high). A multiplexed assay was performed to evaluate 87 different cyst fluid proteins, including cyst fluid inflammatory markers (CFIMs), as possible surrogate markers for parenchymal inflammation. RESULTS:: Significant positive correlation between grade of dysplasia and TANs was found. High levels of TANs were identified in 2%, 33%, and 89% of the lesions when stratified by grade of dysplasia into low/intermediate-grade dysplasia, high-grade dysplasia, and invasive carcinoma, respectively (P < 0.001). Higher grades of dysplasia were also found to have positive correlation with 29 of the measured proteins, of which 23 (79%) were CFIMs. Higher levels of TANs correlated with higher levels of 18 CFIMs, of which 16 (89%) were also found to be associated with higher grades of dysplasia. CONCLUSIONS:: In this study, TANs were strongly associated with malignant progression in IPMNs. Measurement of CFIMs may be a surrogate marker for IPMN progression and allow for the identification of high-risk disease.
    Annals of Surgery 01/2015; DOI:10.1097/sla.0000000000001044 · 7.19 Impact Factor
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    ABSTRACT: Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.
    01/2015; 35:92-103. DOI:10.14694/EdBook_AM.2015.35.92
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    ABSTRACT: Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model of murine pancreatic system to discover characteristics of this deadly malignancy.
    Cell 12/2014; DOI:10.1016/j.cell.2014.12.021 · 33.12 Impact Factor
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    ABSTRACT: Reliable assessment of the BRAF mutation status is becoming increasingly important in the clinical management of colorectal carcinomas (CRC). The aim of this study was to investigate the use of a recently developed mutation-specific antibody (VE1; SpringBio, Pleasanton, CA) to detect the BRAF V600E protein in paraffin tissue. We analyzed by immunohistochemistry (IHC) 117 cases that had been evaluated for BRAF mutation using a MALDI-TOF mass spectrometry-based assay. Immunohistochemical staining was evaluated without the knowledge of the genetic data and was considered positive when there was distinct homogenous cytoplasmic staining in the tumor cells. The analyzed cases included 4 polyps, 63 primary CRC, and 50 metastatic CRC. Forty-five of the 46 (97.8%) cases that were positive by IHC had a BRAF V600E mutation by genetic analysis; the 1 discordant case was notably of signet ring cell type. Similarly, 66 of the 67 (98.5%) cases that were negative by IHC were also negative by genetic analysis. Four cases that showed weak cytoplasmic staining and/or nuclear staining in the tumor cells were considered to be IHC equivocal; by genetic analysis, 2 of the 4 were positive and 2 were negative. The overall sensitivity and specificity of IHC for the detection of a BRAF V600E mutant tumor was 93.7% and 95.6%, respectively. Our results support the use of VE1 IHC for identification of colorectal neoplasms harboring the BRAF V600E mutation. Difficulties in immunohistochemical interpretation may arise in a small number of cases and in those cases molecular testing is required.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 12/2014; DOI:10.1097/PAI.0000000000000116 · 2.06 Impact Factor
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    ABSTRACT: OBJECTIVE. The purpose of this retrospective study was to measure interobserver agreement in the assessment of malignant imaging features of intraductal papillary mucinous neoplasms (IPMNs) on MDCT. MATERIALS AND METHODS. Pancreatic protocol CT studies were reviewed for 84 patients with resected IPMNs. Maximal diameter of the dominant cyst, presence of a mural nodule, presence of a solid component, and diameters of the main pancreatic duct (MPD) and common bile duct (CBD) were measured by four radiologists independently. In each patient, the IPMN was classified into one of three types: main duct, branch duct, or mixed IPMN. Interobserver agreement of lesion features was examined using the intraclass correlation coefficient (ICC) for continuous features and Fleiss kappa for categorical features. RESULTS. The final dataset included 55 branch duct IPMNs, nine main duct IPMNs, and 20 mixed IPMNs. Moderate agreement (ĸ = 0.458; 95% CI, 0.345-0.564) was observed in assigning branch duct, main duct, or mixed IPMN subtypes. Measurement agreement was substantial to excellent for dominant cyst (ICC = 0.852; 95% CI, 0.777-0.907), MPD (0.753, 0.655-0.837), and CBD (0.608, 0.463-0.724) but only fair to moderate for the detection of the presence of mural nodule (ĸ = 0.284, 0.125-0.432) or solid component (ĸ = 0.405, 0211-0.577). CONCLUSION. Substantial to excellent interobserver agreement in the measurement of cyst diameter, MPD, and CBD support their use for characterizing malignant features of IPMN on MDCT. However, the subjective interpretation of the presence of solid components and mural nodules by individual radiologists was more variable.
    American Journal of Roentgenology 11/2014; 203(5):973-9. DOI:10.2214/AJR.13.11490 · 2.74 Impact Factor
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    ABSTRACT: Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.
    American Journal of Surgical Pathology 10/2014; 39(3). DOI:10.1097/PAS.0000000000000340 · 4.59 Impact Factor
  • Laura D. Wood, David S. Klimstra
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    ABSTRACT: Pancreatic neoplasms with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma, and carcinomas with mixed differentiation, are distinctive pancreatic neoplasms with a poor prognosis. These neoplasms are clinically, pathologically, and genetically unique when compared to other more common pancreatic neoplasms. Most occur in adults, although pancreatoblastomas usually affect children under 10 years old. All of these neoplasms exhibit characteristic histologic features including a solid or acinar growth pattern, dense neoplastic cellularity, uniform nuclei with prominent nucleoli, and granular eosinophilic cytoplasm. Exocrine enzymes are detectable by immunohistochemistry and, for carcinomas with mixed differentiation, neuroendocrine or ductal lineage markers are also expressed. The genetic alterations of this family of neoplasms largely differ from conventional ductal adenocarcinomas, with only rare mutations in TP53, KRAS, and p16, but no single gene or neoplastic pathway is consistently altered in acinar neoplasms. Instead there is striking genomic instability, and a subset of cases have mutations in the APC/β-catenin pathway, mutations in SMAD4, RAF gene family fusions, or microsatellite instability. Therapeutically targetable mutations are often present. This review summarizes the clinical and pathologic features of acinar neoplasms and reviews the current molecular data on these uncommon tumors.
    Seminars in Diagnostic Pathology 10/2014; 31(6). DOI:10.1053/j.semdp.2014.08.003 · 1.80 Impact Factor
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    ABSTRACT: Receptor tyrosine kinases (RTK) are in the focus of targeted therapy for epithelial tumors. This study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in context of therapeutic EGFR and HER2 inhibitors. In archival pre-treatment biopsies of esophageal carcinomas (n=110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p=0.088) and HER2 (34.4%; p<0.001) with HER3 (91.5%; p<0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to Erlotinib, Gefitinib as well as Lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33, SK-GT-4), Lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers, some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (Trastuzumab, Pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19, OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g. with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; 135(7). DOI:10.1002/ijc.28771 · 5.01 Impact Factor
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    ABSTRACT: Choledochal cysts (CDCs) are believed to represent a risk factor for the development of neoplasia. However, the frequency and morphology of neoplastic changes have not been systematically studied, especially in North America. Our aims were to study the frequency and morphology of preneoplastic/neoplastic changes of CDCs. 36 cysts were subjected to clinicopathological analyses. Metaplasia was found in 14/35, of which 9 had Biliary Intraepithelial Neoplasia (BilIN). Of the 14 with metaplasia, 13 showed pyloric gland (PG), 5 intestinal (IN), and 2 squamous. BilINs included 6 BilIN-1, 2 BilIN-2, and 2 BilIN-3. Carcinoma was identified in 5 cases of which 3 were associated with metaplasia and BilIN. Only 1/18 cases without metaplasia had BilIN and none had carcinoma (p=0.0008). There was a trend towards more BilIN and carcinoma with intestinal rather than with pyloric gland metaplasia. All cases with metaplasia or/and BilIN were negative for MUC1. All cases with intestinal metaplasia were positive for CK20, CDX2, and MUC2, whereas cases with pyloric gland were positive for MUC6. MUC1, CEA and B72.3 were positive only in carcinoma. There was a trend toward increasing p53 and ki-67 from metaplasia to BilIN to carcinoma. 4/5 patients with carcinoma died and one was alive with disease. All others were free of disease except for one who developed new cysts. CDCs are associated with a high rate of BilIN (28.5%) and carcinoma (14.3%). CDCs show a sequence of tumor progression from metaplasia to BilIN and carcinoma.
    Human pathology 10/2014; 45(10). DOI:10.1016/j.humpath.2014.06.016 · 2.81 Impact Factor
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    ABSTRACT: During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.
    Genes & Development 10/2014; 28(19):2134-50. DOI:10.1101/gad.249599.114 · 12.64 Impact Factor

Publication Stats

20k Citations
2,253.20 Total Impact Points

Institutions

  • 1993–2015
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Pathology
      • • Department of Surgery
      • • Hepatopancreatobiliary Service
      • • Department of Medicine
      New York, New York, United States
  • 2012
    • University of Pennsylvania
      • Division of Gastroenterology
      Philadelphia, PA, United States
  • 2010
    • Technische Universität München
      München, Bavaria, Germany
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2004–2007
    • Cornell University
      • Department of Medicine
      Ithaca, New York, United States
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 2000–2006
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States
  • 2005
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
    • Christian-Albrechts-Universität zu Kiel
      • Institute for General Microbiology
      Kiel, Schleswig-Holstein, Germany
  • 1992–2005
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2002
    • University of Verona
      • Department of Pathology
      Verona, Veneto, Italy
  • 1998–2002
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 2001
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
    • Karmanos Cancer Institute
      Detroit, Michigan, United States