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Gregory Y Lauwers

Publications and source records attributed to Gregory Y Lauwers.

At least 19 recordsLinked to original sources
PubMed2007

Cystic pancreatic endocrine tumor: a variant commonly confused with cystic adenocarcinoma.

BACKGROUND: Most cystic pancreatic neoplasms are currently evaluated by an endoscopic ultrasound-guided fine-needle aspiration biopsy (FNAB). In the authors' experience, FNAB of cystic pancreatic endocrine tumors (PETs) frequently causes diagnostic difficulties, partly because of unexpected overlapping features with cystic ductal adenocarcinomas. METHODS: The authors identified 5 histologically confirmed cystic PETs that were evaluated by FNAB and compared their cytomorphologic features to cystic ductal adenocarcinomas (n = 5) and solid PETs (n = 39) of the pancreas. RESULTS: Cytologically, 2 of the aspirates of cystic PETs were devoid of tumor cells whereas the other 3 were variably cellular and composed of cohesive aggregates of monomorphic cellular elements with variably coarse chromatin. Tumor necrosis and nuclear membrane irregularities were not identified in cystic PETs. Alternatively, in contrast to PETs, cystic ductal adenocarcinomas were characterized by nuclear pleomorphism, nuclear membrane irregularities, and tumor necrosis. CONCLUSIONS: Given the clinical implications, awareness of cystic PETs and their deceptive cytologic features would assist in distinguishing these lesions from cystic ductal adenocarcinomas.

Adenocarcinoma↗
PubMed2007

Mucin expression in reactive gastropathy: an immunohistochemical analysis.

CONTEXT: Reactive gastropathy is the second most common diagnosis made on gastric biopsies. Increased epithelial proliferation and modifications of epithelial cytokeratin profile, distinct from those of Helicobacter pylori gastritis, have been previously reported. However, the evaluation of mucins, important components of the protective mucosal mucous layer, has not been reported. OBJECTIVE: To investigate alterations of membrane and secreted mucins in reactive gastropathy of various etiologies using antibodies against mucin glycoproteins. DESIGN: Thirty-eight gastric biopsies diagnosed as reactive gastropathy, related to nonsteroidal anti-inflammatory drugs (n = 18) or bile reflux (n = 6) or of indeterminate etiology (n = 14), were evaluated using antibodies to MUC1, MUC5AC, MUC6, and MUC2. All cases were confirmed to be negative for H. pylori. The biopsies were classified in 3 groups based on the severity of cytoarchitectural changes (mild, moderate, and severe). Mucin expression and its distribution were recorded and the results correlated with the cytoarchitectural alterations and etiologies. RESULTS: Loss of MUC1, either patchy or complete, was noted in 67% of the cases. Aberrant expression of MUC5AC in pyloric glands was observed in 81% of the cases, and aberrant expression of MUC6 in the upper foveolar epithelium was diffusely seen in 14% of the cases. Aberrant expression of MUC2 in non-goblet cells was observed in a single case. Aberrant expression of MUC6 was less extensive in the nonsteroidal anti-inflammatory drugs group than in other 2 groups (P = .03). Concurrently, the diffuse distribution of aberrant MUC6 expression was seen only in the cases of severe gastropathy (P = .09). There was no correlation between modifications in expression of other mucins and either the etiologies or the severity of cytoarchitectural changes. CONCLUSIONS: Expressions of membrane (MUC1) and secreted (MUC5AC, MUC6) mucins are frequently modified in reactive gastropathy. The alteration of MUC1, which is involved in cell adhesion and polarity, may play a role in the development of the serrated profile of reactive gastropathy. Milder modifications of the secreted mucins may be explained by the reactive/regenerative nature of the process. Importantly, theses changes are different from the increase in MUC6 and reduction of MUC5AC expression reported in H. pylori gastritis, underlying their mechanistic differences. It is worth noting that similar alterations of mucin expression are shared by various etiologies, that is, nonsteroidal anti-inflammatory drugs and bile reflux, consistent with the nonspecific nature of reactive gastropathy.

Adult↗
PubMed2006

Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.

SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC-alone or in combination with PDAC--relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS(G12D) allele, SMAD4 deficiency enabled rapid progression of KRAS(G12D)-initiated neoplasms. While KRAS(G12D) alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS(G12D) and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS(G12D) INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-beta (TGF-beta) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-beta-induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS(G12D)-initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF-beta-dependent growth.

Alleles↗
PubMed2006

Identifying intestinal metaplasia at the squamocolumnar junction by using optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) is an optical imaging method that produces high-resolution cross-sectional images of the esophagus. The accuracy of OCT for differentiating tissue types at the squamocolumnar junction (SCJ) has not been established. OBJECTIVE: The purpose of this study was to identify and validate OCT image criteria for distinguishing metaplastic from nonmetaplastic tissue at the SCJ. DESIGN: A total of 196 biopsy-correlated OCT images of the SCJ were acquired from 113 patients undergoing upper endoscopy. A pathologist blinded to the OCT results reviewed each pathology specimen and determined the presence of the following histopathology: gastric cardia, squamous mucosa, pancreatic metaplasia, and intestinal metaplasia. An algorithm for diagnosing specialized intestinal metaplasia (SIM) was created by reviewing a training set of 40 biopsy-correlated OCT images. Two blinded investigators prospectively tested the algorithm on a validation set of 123 images. RESULTS: OCT images of squamous mucosa were characterized by a layered appearance without epithelial glands; gastric cardia, by vertical pit and gland structure, a well-defined epithelial surface reflectivity, and relatively poor image penetration; and SIM by an irregular architecture and good image penetration. The OCT criteria were 85% sensitive and 95% specific for SIM when applied retrospectively to the training set. When applied to the validation set, the algorithm was 81% sensitive for both OCT readers and 66% and 57% specific for diagnosing SIM. The interobserver agreement was good (kappa = 0.53). CONCLUSIONS: OCT imaging can identify SIM at the SCJ with an accuracy similar to that of endoscopy.

Algorithms↗
PubMed2006

Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.

PURPOSE: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. RESULTS: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. CONCLUSION: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.

Adenocarcinoma↗
PubMed2006

Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases.

PURPOSE: Chemotherapy before resection of hepatic colorectal metastases (CRM) may cause hepatic injury and affect postoperative outcome. PATIENTS AND METHODS: Four hundred six patients underwent hepatic resection of CRM between 1992 and 2005. Pathologic review of the nontumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal injury. The effect of chemotherapy and liver injury on perioperative outcome was analyzed. RESULTS: One hundred fifty-eight patients (38.9%) received no preoperative chemotherapy, whereas 248 patients (61.1%) did. The median duration of chemotherapy was 16 weeks (range, 2 to 70 weeks). Chemotherapy consisted of fluoropyrimidine-based regimens (fluorouracil [FU] alone, 15.5%; irinotecan plus FU, 23.1%; and oxaliplatin plus FU, 19.5%) and other therapy (3.0%). On pathologic analysis, 36 patients (8.9%) had steatosis, 34 (8.4%) had steatohepatitis, and 22 (5.4%) had sinusoidal dilation. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy (18.9% v 1.9%, respectively; P < .001; odds ratio [OR] = 8.3; 95% CI, 2.9 to 23.6). In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy (20.2% v 4.4%, respectively; P < .001; OR = 5.4; 95% CI, 2.2 to 13.5). Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4). CONCLUSION: Steatohepatitis is associated with an increased 90-day mortality after hepatic surgery. In patients with hepatic CRM, the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant.

Adolescent↗
PubMed2006

Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations.

Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia.

Animals↗
PubMed2006

Endoscopic mucosal resection using a cap-fitted endoscope improves tissue resection and pathology interpretation: an animal study.

BACKGROUND: Endoscopic mucosal resection using a cap-fitted endoscope (EMRC) has been proposed to be significantly better and safer for tissue resection compared with standard snare EMR. However, there are no valid animal or clinical data to support this. We aimed to compare EMRC with standard snare EMR in a porcine model with respect to tissue resected, ease of procedure, and degree of diathermic injury to the resected specimen. METHODS: Gastric EMRs were randomly performed in pigs using a variety of techniques, including EMRC (1mm and 17-mm cap) and the standard snare technique, using a single-channel method without a grasping forceps. Geometric and histological assessment of the resection specimen for size, histological depth, and diathermic injury were performed by a single pathologist, blinded to the endoscopic techniques used. RESULTS: Thirty-six gastric mucosal resections were randomly performed in three pigs. Use of EMRC resulted in a statistically significant greater resection specimen by weight, size, and histological depth compared with standard EMR (P < 0.04). Large-cap EMRC resulted in a statistically significant greater resection weight and size compared to small-cap EMRC (P < 0.05). There was a statistically significant greater degree of diathermic injury in the specimens resected using the standard snare EMR technique compared with EMRC (P < 0.006). There were no acute complications with either technique. CONCLUSION: Gastric EMRC is more technically effective than and as safe and easy as standard snare EMR. Use of the cap, especially the larger cap, is associated with larger and deeper mucosal resection and less diathermic injury compared with the standard snare technique, making the pathologic assessment of depth and margin involvement more reliable. When possible, EMRC should be the EMR method of choice.

Animals↗
PubMed2006

Novel virtual biopsy of the kidney with near infrared, reflectance confocal microscopy: a pilot study in vivo and ex vivo.

PURPOSE: Current diagnostic strategies for the kidney combine noninvasive imaging techniques with invasive procedures such as needle biopsy. However, renal needle biopsy is not devoid of risks, such as bleeding or infection. Additionally, histology studies are limited to ex vivo morphology and processing induces tissue artifacts, is time-consuming and limits the performance of further studies. Near infrared, reflectance CM is a novel technique that allows high resolution optical sectioning through intact tissues without using any exogenous fluorescent stains. Contrast between structures is based on the natural differences in refractivity. In this pilot study we assessed the usefulness of CM in the study of the kidney in vivo and ex vivo. MATERIALS AND METHODS: Kidneys of live rats were imaged with CM. Contrast in images is based on native properties of the tissue upon being shone with a near infrared laser. By convention hyperrefractile structures are seen as white and hyporefractile structures are seen as black. CM imaging planes varied along the x, y and z axes of space. Images of live kidney were compared with those from ex vivo CM imaging and standard histology procedures. RESULTS: The tubules, glomeruli, vessels and interstitium were readily identified, revealing intracellular detail. Differences between the kidney in vivo and ex vivo were also observed. Experimental contrast agents further highlighted the nuclei. CONCLUSIONS: CM is a useful noninvasive imaging technique that is an adjunct to current techniques for 3-dimensional study of the kidney in vivo and ex vivo. Future technical developments will provide key applications during surgical intervention, transplantation and rapid tissue assessment.

Animals↗
PubMed2006

Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms.

Endoscopic mucosal resection (EMR), which is advocated for the treatment of early (superficial) gastroesophageal neoplasms, has also been alluded to represent a superior diagnostic and staging modality. We compared the diagnostic concordance of preceding biopsies with EMR specimens in 31 gastric and 10 esophageal EMRs consisting of 6 low-grade and 12 high-grade dysplasias, 21 intramucosal adenocarcinomas, and 2 submucosal invasive adenocarcinomas. Discrepancies were considered as either major or minor if the histologic grades differed by 2 or more, or by only 1, respectively. Discrepant and concordant cases were compared with regard to the size of lesion (maximum dimension and surface area), number of biopsy fragments, and extent of biopsy sampling (ratio between lesion size and number of biopsy fragments). These same variables were used to evaluate the differences seen between gastric and esophageal cases. Of the 41 cases, 16 (39%) had discrepant diagnoses, including 14 gastric and 2 esophageal neoplasms. A major discrepancy was seen in 2% of the cases (n = 1, gastric) and a minor discrepancy, in 15 cases. All but 2 of the discrepant cases were found to have a higher grade on EMR. The average number of biopsy fragments was 4.4 in both concordant and discrepant groups. The maximal dimension, surface area, and biopsy sampling ratios of the lesion were significantly greater in the discrepant cases than in the concordant cases. The esophageal cases trended toward having smaller size and a significantly extensive biopsy sampling. We conclude that EMR is superior to biopsy for diagnosing superficial gastroesophageal tumors. Discrepancies between the specimens occur in larger lesions (>10 mm) with less extensive biopsy sampling. EMR can substantially modify the diagnostic grade of a lesion and therefore facilitate optimal therapeutic decisions by avoiding undertreatment and overtreatment based on inaccurate grading and staging.

Adenocarcinoma↗
PubMed2006

Post-gastric endoscopic mucosal resection surveillance biopsies: evaluation of mucosal changes and recognition of potential mimics of residual adenocarcinoma.

Endoscopic mucosal resection (EMR) offers curative treatment for patients with node-negative early gastric carcinoma of less than 2 cm without ulceration or ulceration scar. Follow-up biopsies are frequently performed to ensure the absence of residual neoplasia. We performed a retrospective analysis of post-EMR biopsies from 33 patients who underwent gastric EMR. Histologic changes included inflammation (100%), stromal edema (97.0%), foveolar hyperplasia (78.8%), ectatic vessels (66.7%), epithelial atypia (60.6%), increased glandular mitoses (57.6%), epithelial anisonucleosis (54.5%), fibrinopurulent materials (51.5%), ischemia (48.5%), stromal hemorrhage (33.3%), mucin depletion (12.1%), clear cell degeneration (15.2%), and signet-ring cell-like change (6.1%). Especially, clear cell degeneration and signet-ring cell-like change were conspicuous in the area of ischemia. Residual adenocarcinomas were noted in 4 of 33 cases, and consistently showed high nuclear-to-cytoplasmic ratio with high glandular density. Glandular clear cell degeneration and/or signet-ring cell-like change were worrisome and sometimes difficult to be distinguished from residual neoplastic glands. However, these degenerative glands were usually embedded in a nondesmoplastic stroma and showed anisonucleosis of glandular epithelia. Mimics of residual adenocarcinoma, namely clear cell degeneration and signet-ring cell-like change should be judiciously assessed to avoid unnecessary surgery.

Adenocarcinoma↗
PubMed2006

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.

Intraductal papillary mucinous neoplasm (IPMN) is a unique pancreatic neoplasm developing in the ductal system. Two major histologic subtypes have been reported, that is the gastric type and the intestinal type. However, their histopathologic features, especially those of the gastric type, have not been fully described. To evaluate the features of these two types and refine their differences, we analyzed 80 IPMNs including 50 cases of the gastric type and 30 cases of the intestinal type with mucin immunohistochemistry. By defining a main duct-type lesion as predominantly involving the main pancreatic duct with or without branch ducts, and a branch duct-type lesion as exclusively centered on branch ducts or consisting of a collection of small cystic lesions, gastric-type IPMNs were mostly branch duct-type lesions (98%), whereas the intestinal-type IPMNs were usually main duct type (73%). The histologic grade of the intestinal type was generally higher than that of the gastric type. The intestinal type was also characterized by frequent intraluminal nodular growth, and severe atrophy and fibrosis of the surrounding parenchyma with mucous lake formation. In contrast, pyloric glandlike structures at the base of the papillae and pancreatic intraepithelial neoplasia (PanIN)-like complexes were more frequently observed in the gastric type. A significant difference was observed between the gastric type and the intestinal type with regard to all the above features (P<0.05). Seven cases (23%) of the intestinal type were associated with an invasive adenocarcinoma (6 mucinous and 1 ductal), versus only 1 case (2%) of the gastric type (invasive ductal carcinoma). All cases of both gastric and intestinal types expressed MUC5AC; however, high immunolabeling scores for MUC2 were mostly observed in the intestinal type (P<0.05). In conclusion, gastric and intestinal types of IPMNs have distinct histopathologic features and mucin profiles, suggesting that they may follow different biologic pathways.

Adenocarcinoma, Mucinous↗
PubMed2006

Autoimmune pancreatitis: a systemic immune complex mediated disease.

Autoimmune pancreatitis (AIP) is a mass forming inflammatory pancreatobiliary-centric disease. Recent reports of multiorgan inflammatory mass forming lesions with increased numbers of IgG4 positive plasma cells suggest that AIP may have a systemic component. In this study, we explore the systemic nature of AIP, investigate the relevance of subtyping AIP, perform a systematic study of tissue IgG4 immunoperoxidase, and ultrastructurally evaluate the presence of immune complexes. Our study group consisted of 36 patients with AIP, 21 of whom underwent a Whipple procedure. On the basis of the pattern of inflammation, pancreatic involvement was subtyped as ductocentric (AIP-D) or lobulocentric (AIP-L). Extrapancreatic lesions included bile duct (n=3), salivary glands (n=3), lung (n=2), gallbladder (n=11), and kidney (n=4). Clinical and radiologic data was recorded. Immunohistochemistry for IgG4 was performed on both pancreatic and extrapancreatic tissues and the numbers of IgG4 positive plasma cells were semiquantitatively scored. A control cohort composed of pancreatic adenocarcinoma (n=19) and chronic pancreatitis-not otherwise specified (NOS) (n=14) was also evaluated. Eleven pancreatic specimens, including 2 cases of chronic pancreatitis-NOS and 4 kidneys were evaluated ultrastructurally. The pancreas, bile duct, gall bladder, salivary gland, kidney, and lung lesions were characterized by dense lymphoplasmacytic infiltrates with reactive fibroblasts and venulitis. IgG4 positive plasma cells were identified in all pancreatic and extrapancreatic lesions. The AIP cases showed significantly more pancreatic IgG4 positive plasma cells than chronic pancreatitis-NOS or adenocarcinoma (P=0.001). However, IgG4 positive cells were identified in 57.1% of chronic pancreatitis-NOS and 47.4% of ductal adenocarcinoma. Fifteen of 21 resected cases were classified as AIP-D, and 6 as AIP-L, the latter notably showing significantly more IgG4 positive plasma cells than the former (P=0.02). Additionally, clinical and radiologic differences emerged between the 2 groups. Ultrastructurally, electron dense deposits of immune complexes were identified in the basement membranes of 7 of the 9 AIP cases and in 3 of the 4 renal biopsies evaluated. AIP represents the pancreatic manifestation of a systemic autoimmune disease. Clinical and immunologic findings justify the recognition of pancreatic lobulocentric and ductocentric subtypes. Documentation of increased numbers of tissue IgG4 positive plasma cells, although not an entirely specific marker for AIP, may provide ancillary evidence for the diagnosis of a IgG4-related systemic disease.

Adolescent↗