David S Klimstra

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

Are you David S Klimstra?

Claim your profile

Publications (389)2089.49 Total impact

  • [Show abstract] [Hide abstract]
    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.
  • [Show abstract] [Hide abstract]
    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.
    AJR. American journal of roentgenology. 11/2014; 203(5):973-9.
  • [Show abstract] [Hide abstract]
    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.
    The American journal of surgical pathology. 10/2014;
  • Laura D. Wood, David S. Klimstra
    [Show abstract] [Hide abstract]
    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; · 1.62 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
  • Chanjuan Shi, David S. Klimstra
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic neuroendocrine neoplasms include mainly well-differentiated neuroendocrine tumors, but also rare poorly-differentiated neuroendocrine carcinomas. Molecular mechanisms underlying pancreatic neuroendocrine tumorigenesis have recently been elucidated. While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly-differentiated neuroendocrine carcinomas. With these discoveries, new molecular targeted therapies have become available and show promise in some patients with pancreatic well-differentiated neuroendocrine tumor.
    Seminars in Diagnostic Pathology 09/2014; · 1.62 Impact Factor
  • Ralph H Hruban, David S Klimstra
    Seminars in Diagnostic Pathology 09/2014; · 1.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic acinar cell carcinomas (PACCs) account for ~1% (~500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiation have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in ~23% of tumors. The most prevalent fusion, SND1-BRAF, results in activation of the mitogen activated protein kinase (MAPK) pathway which can be abrogated with MEK inhibition. SND1-BRAF transformed cells were sensitive to treatment with the MEK inhibitor, trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations (GAs) causing inactivation of DNA repair genes (45%); these GAs have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable GAs in the majority of PACCs, and provide a rationale for using personalized therapies in this disease.
    Cancer Discovery 09/2014; · 15.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ARID1A, a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch-syndrome screening; 59 (23%) were MMR-deficient by immunohistochemistry (44 MLH1/PMS2-deficient, 9 MSH2/MSH6-deficient, 4 MSH6-deficient, and 2 PMS2-deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2-deficient) and 4% of MMR-normal tumors (8/198) (p < 0.05). MLH1 promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (p = 0.04), poor tumor differentiation (p < 0.01), medullary histology (p < 0.01), and an increased rate of nodal and distant metastasis (p = 0.03); these patients also trended towards a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathologic features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but are likely to present with metastatic disease, warranting further investigation.
    Human pathology 09/2014; · 3.03 Impact Factor
  • Ralph H. Hruban, David S. Klimstra
    [Show abstract] [Hide abstract]
    ABSTRACT: Infiltrating ductal adenocarcinoma of the pancreas is a real enigma. On one hand it is one of the most deadly of all of the solid malignancies. On the other, the neoplastic glands can be remarkably well-differentiated and it can be difficult to distinguish between a reactive non-neoplastic gland and a gland of invasive adenocarcinoma. In this review we will present diagnostic criteria that one can “hang your hat on” when establishing the diagnosis of infiltrating ductal adenocarcinoma of the pancreas. We will also review clinically important features of the disease, and, with the impending incorporation of molecular genetics into everyday practice, we will emphasize clinical applications of cancer genetics.
    Seminars in Diagnostic Pathology 09/2014; · 1.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mono-allelic germline mutations in DNA mismatch repair (MMR) genes lead to Lynch syndrome (LS). Questions remain as to the timing of the inactivation of the wild-type allele in LS-associated tumorigenesis. Speculation exists that it happens after the neoplasia has been initiated. However, a recent study reported the presence of MMR-deficiency in non-neoplastic colonic crypts in LS; thus the possibility can be raised that these crypts may be tumor precursors, and as such, biallelic loss of MMR may occur prior to neoplasia. Here we report a unique case that showed findings supporting both of the two seemingly conflicting notions. The patient was a 40-year-old female with LS, MSH2 type, who underwent a segmental colectomy for an adenocarcinoma. By immunohistochemistry, the carcinoma lost MSH2/MSH6. Interestingly, there was also complete loss of MSH2/MSH6 in a distinct focus of 20 colonic crypts that were morphologically non-neoplastic, thus supporting the possibility of biallelic loss of MMR before initiation of neoplasia. However, in a separate adenoma, MMR was preserved in neoplastic glands with low grade dysplasia and lost only in glands with high grade dysplasia, i.e., MMR loss after tumor initiation. These are relevant findings with regard to the timing of MMR deficiency in LS tumorigenesis, and bring forth the possibility that varied tumorigenic pathways may exist. Additionally, we observed that the MMR-deficient non-neoplastic crypts harbored increased intraepithelial CD8-positive T-lymphocytes similar to the patient's carcinoma, providing a potential new venue for the study of the natural antitumor immune responses in LS individuals.
    Familial Cancer 08/2014; · 1.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acinar cell carcinoma (ACC), including its mixed variants, is a rare pancreatic malignancy. Recent reports have documented its occurrence in Lynch syndrome. Our aim was to evaluate the frequency and clinicopathologic significance of DNA mismatch repair (MMR) deficiency in ACCs in general.
    Pancreas 07/2014; · 2.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined.
    Annals of surgery. 07/2014; 260(1):142-148.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Histologic classification of ampullary carcinomas into intestinal, pancreatobiliary, or other subtypes is easily achievable in some cases but difficult in others. Immunohistochemical (IHC) stains may allow distinction between the subtypes; however, their added value to routine hematoxylin and eosin (H&E) evaluation has not been systematically evaluated. Inconsistent histologic subtyping has hampered current clinical research and therapeutic trials. In this study, a consecutive series of 105 ampullary carcinomas was subtyped first by H&E evaluation and then by the evaluation of an IHC panel composed of CK7, CK20, CDX2, MUC1, and MUC2, and the added value of IHC was analyzed. By H&E, a consensus diagnosis, defined as concordant subtyping among at least 3 of the 4 independent study pathologists, was achieved in 81 of the 105 (77%) cases. There was excellent agreement for poorly differentiated and mucinous subtypes (κ=0.72 and 0.89, respectively) but only good agreement for intestinal and pancreatobiliary subtypes (κ=0.57 and 0.48, respectively) and poor agreement for mixed subtype (κ=0.09). By IHC, CK7 showed no informative value (being positive in ≥70% of the cases in both intestinal and pancreatobiliary subtypes), whereas a subtyping schema incorporating the combination staining patterns of CK20, CDX2, MUC1, and MUC2 did. By this schema, "intestinal subtype" was defined as having (1) positive staining for CK20 or CDX2 or MUC2 and negative staining for MUC1, or (2) positive staining for CK20, CDX2, and MUC2, irrespective of the MUC1 result; and "pancreatobiliary subtype" was defined as having positive staining for MUC1 and negative staining for CDX2 and MUC2, irrespective of CK20 results. Cases not fitting one of these 3 categories were regarded as "ambiguous" immunohistochemically. By combining this schema with H&E evaluation, 97 of the 105 cases (92%) could be classified into either intestinal or pancreatobiliary subtype. In particular, immunophenotyping allowed categorization of 75% of poorly differentiated adenocarcinomas and 69% of cases with mixed histologic features as either intestinal or pancreatobiliary subtype. Most mucinous adenocarcinomas (88%) were clearly intestinal subtype by IHC. Thus, our IHC schema enhanced the subtyping of ampullary carcinoma and, in combination with H&E evaluation, allowed a dichotomous classification in 92% of the cases. Should further independent studies reaffirm our findings, this schema may serve as a valuable tool in both diagnostic and research settings.
    The American journal of surgical pathology 05/2014; · 4.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The minor duodenal papilla drains the accessory pancreatic duct of Santorini and lies proximal to the ampulla of Vater. Adenocarcinoma and its precursor lesions arising in the minor papilla are rare. Literature data thus far are limited to a few individual case reports, and the condition is consequently poorly defined. Our study cases were composed of carcinomas fulfilling all of the following criteria: location at 1.5 to 2.5 cm proximal to the major papilla; presence of associated submucosal pancreatobiliary-type ducts with periductal glands or acinar tissue; a predominant submucosal location of the tumor; and lack of an intestinal-type adenoma in the adjacent duodenal mucosa. Tumors were studied morphologically, immunohistochemically, and clinically. Nine cases fulfilling the inclusion criteria were identified. There were 5 men and 4 women with an age range of 50 to 76 years (median, 72 y). The tumor size ranged from 1.2 to 4.4 cm (median, 3 cm). The carcinomas were of colloid type (3 tumors), pancreatobiliary type (4), or nonmucinous intestinal type (2). Five cases were associated with an intraductal papillary mucinous neoplasm (IPMN)-like precursor lesion within the residual structures of the minor papilla in the duodenal submucosa. Immunohistochemically, the intestinal-type and mucinous-type tumors tended to be positive for CK20, CDX2, MUC2, and B72.3, and pancreatobiliary-type tumors tended to be positive for CK7, MUC1, B72.3, and CA125. Loss of DPC4 (Smad4) expression was found in the pancreatobiliary-type carcinomas only. Two tumors showed loss of DNA mismatch-repair protein expression, one losing MLH1 and PMS2 and the other losing MSH6. Both patients were older than 60 years, and neither had germline mutation testing. Follow-up information was available for 6 patients (median follow-up time, 67.5 mo): 3 of the 6 patients died of disease at 60, 75, and 85 months after surgery, respectively, and all 3 patients had an intestinal-type carcinoma (1 colloid and 2 nonmucinous). The patient whose tumor was MSH6 deficient was alive without evidence of disease 51 months after surgery. In conclusion, adenocarcinomas of the minor papilla are rare tumors occurring predominantly in the sixth to seventh decade. Some of them arise from IPMN-like precursors in the residual submucosal minor papilla tissue. Morphologically, immunohistochemically, and clinically they are similar to ampullary or IPMN-associated pancreatic carcinomas and can exhibit either an intestinal, colloid, or pancreaticobiliary phenotype. DNA mismatch-repair deficiency may occur. A careful gross and histologic examination is essential to accurately recognize the site of origin of minor papilla carcinomas.
    The American journal of surgical pathology 04/2014; 38(4):526-33. · 4.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastroenteropancreatic (GEP) neuroendocrine neoplasms are classified as low-grade, intermediate-grade, and high-grade tumors based on morphologic criteria and the proliferation rate. Most studies have been conducted in patients with well differentiated (low-grade to intermediate-grade) neuroendocrine tumors. Data are substantially scarcer on poorly differentiated, high-grade neuroendocrine carcinoma (NEC), which includes the entities of small cell carcinoma and large cell NEC. A literature search of GEP-NEC was performed. Long-term survival was poor even among patients who presented with localized disease. Several studies highlighted heterogeneity within the high-grade NEC category and a need for the further identification of discreet prognostic and predictive groups. Tumors with a Ki-67 proliferation index <55% were less responsive to platinum-based chemotherapy, and patients with such tumors or with well differentiated morphology had better survival than patients who had tumors with poorly differentiated morphology or a higher Ki-67 index. Treatment options beyond platinum-based chemotherapy are emerging. A revision of the World Health Organization high-grade NEC classification seems to be necessary based on recent data. Platinum-based chemotherapy may not be the optimal treatment for patients who have GEP-NEC with a moderately high proliferation rate. Adequate diagnostic and prognostic stratifications constitute the basis for future progress. Cancer 2014. © 2014 American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: For patients with unresectable intrahepatic cholangiocarcinoma (ICC), treatment options are limited and survival is poor. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine and dexamethasone (with or without bevacizumab) in advanced ICC. Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST). Pre-HAI dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) images were reviewed, and tumor perfusion data correlated with outcome. Forty-four patients were analyzed (floxuridine, 26; floxuridine/bevacizumab, 18). At a median follow-up of 29.3 months, 41 patients had died of disease. Partial response by RECIST was observed in 48 %, and 50 % had stable disease. Three patients underwent resection after response, and 82 % received additional HAI after removal from the trials. Median survival was similar in both trials (floxuridine 29.3 months vs. floxuridine/bevacizumab 28.5 months; p = 0.96). Ten (23 %) patients survived ≥3 years, including 5 (11 %) who survived ≥5 years. Tumor perfusion measured on pre-treatment DCE-MRI [area under the gadolinium concentration curve at 90 and 180 s (AUC90 and AUC180, respectively)] was significantly higher in ≥3-year survivors and was the only factor that distinguished this group from <3-year survivors (mean AUC90 22.6 vs. 15.9 mM s, p = 0.025, and mean AUC180 48.9 vs. 32.3 mM s, p = 0.003, respectively). Median hepatic progression-free survival was longer in ≥3-year survivors (12.9 vs. 9.3 months, respectively; p = 0.008). HAI chemotherapy can result in prolonged survival in unresectable ICC. Pre-HAI DCE-MRI may predict treatment outcome.
    Annals of Surgical Oncology 03/2014; · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    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 02/2014; · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.
    The American journal of surgical pathology 02/2014; · 4.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Duodenal neuroendocrine tumors are rare and few studies exist to guide surgical management. This study identifies factors associated with recurrence after resection. A retrospective, single institution review was performed between 1983 and 2011 on patients with a pathologic diagnosis of duodenal neuroendocrine tumor. Tumor grade was assigned based on WHO 2010 criteria (Ki-67 and mitotic rate). Seventy-five patients were identified that underwent curative resection. This included 12 patients with endoscopic mucosal resection, 34 that had local resection, and 29 that underwent pancreaticoduodenectomy. Two-year and 5-year recurrence-free survival was 84 and 81 %, respectively. There were 11 tumor recurrences (either local or distant), and four patients died of their disease (3/4 had high-grade lesions) with an overall median follow-up of 27 months. On univariate analysis, tumor size and tumor grade were identified as being associated with recurrence, but not intervention type, lymph node metastases, ampullary location, or margin status. Tumor grade and size are associated with recurrence-free survival in duodenal neuroendocrine tumors. When feasible, a less aggressive surgical approach to treat low-grade and low-stage duodenal NETs should be considered.
    Journal of Gastrointestinal Surgery 01/2014; · 2.36 Impact Factor

Publication Stats

17k Citations
2,089.49 Total Impact Points


  • 1995–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Surgery
      • • Department of Pathology
      • • Hepatopancreatobiliary Service
      New York City, New York, United States
  • 2013
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • Department of Pathology
      Hershey, Pennsylvania, United States
  • 2005–2013
    • University of Massachusetts Medical School
      • Program in Gene Function and Expression
      Worcester, Massachusetts, United States
    • Christian-Albrechts-Universität zu Kiel
      • Institute for General Microbiology
      Kiel, Schleswig-Holstein, Germany
  • 2012
    • University of Pennsylvania
      • Division of Gastroenterology
      Philadelphia, PA, United States
    • Weill Cornell Medical College
      • Department of Pathology and Laboratory Medicine
      New York City, NY, United States
  • 2011
    • San Antonio Military Medical Center
      Texas City, Texas, United States
    • University of Illinois at Chicago
      • Department of Surgery (Chicago)
      Chicago, IL, United States
    • Mount Sinai Medical Center
      New York City, New York, United States
    • University of Texas Southwestern Medical Center
      • Department of Pathology
      Dallas, TX, United States
  • 2010
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Surgery
      Baton Rouge, LA, United States
    • Technische Universität München
      München, Bavaria, Germany
    • Roger Williams University
      Bristol, Rhode Island, United States
    • Rutgers New Jersey Medical School
      • Cancer Institute of New Jersey
      Newark, NJ, United States
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2004–2010
    • Cornell University
      • • Department of Pathology and Laboratory Medicine
      • • Department of Medicine
      Ithaca, NY, United States
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 2008
    • University of Wisconsin–Madison
      • Department of Surgery
      Madison, Wisconsin, United States
  • 2007
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2000–2007
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 2000–2006
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States
  • 1998–2006
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
  • 1992–2005
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2002
    • University of Verona
      • Department of Pathology
      Verona, Veneto, Italy
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 1999
    • City of Hope National Medical Center
      Duarte, California, United States
  • 1997
    • University of Iowa
      • Department of Surgery
      Iowa City, IA, United States
  • 1994
    • CUNY Graduate Center
      New York City, New York, United States