Person:

Lauwers, Gregory Y.

Background: Lymph node metastases are prognostically significant in pancreatic ductal adenocarcinoma. Little is known about the significance of direct lymph node invasion. Aim: The aim of this study is to find out whether direct lymph node invasion has the same prognostic significance as regional nodal metastases. Methods: Retrospective review of patients resected between 1/1/1993 and 7/31/2008. “Direct” was defined as tumor extension into adjacent nodes, and “regional” was defined as metastases to peripancreatic nodes. Results: Overall, 517 patients underwent pancreatic resection for adenocarcinoma, of whom 89 had one positive node (direct 26, regional 63), and 79 had two positive nodes (direct 6, regional 68, both 5). Overall, survival of node-negative patients was improved compared to patients with positive nodes (N0 30.8 months vs. N1 16.4 months; p < 0.001). There was no survival difference for patients with direct vs. regional lymph node invasion (p = 0.67). Patients with one positive node had a better overall survival compared to patients with ≥2 positive nodes (22.3 and 15 months, respectively; p < 0.001). The lymph node ratio (+LN/total LN) was prognostically significant after Cox regression (p < 0.001). Conclusions: Isolated direct invasion occurs in 20% of patients with one to two positive nodes. Node involvement by metastasis or by direct invasion are equally significant predictors of reduced survival. Both the number of positive nodes and the lymph node ratio are significant prognostic factors.

Microsatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas.

Introduction: A histologic diagnosis of chronic colitis raises a relatively limited differential diagnosis that includes inflammatory bowel disease, long-standing infections, and chronic ischemia. In routine clinical practice, inflammatory bowel disease accounts for the majority of cases of chronic colitis. Although a variety of drug-induced injury patterns in the colon have been recognized, there are few well-documented examples of drug-induced chronic colitis. In this study, we report the clinical, histologic, and follow-up data on 17 cases of histologically documented cases of chronic colitis in which a definitive etiologic factor could not be identified. Methods: Using our electronic databases we recorded all cases of chronic colitis in adults over an 8-year period. Patients with a history (prior or subsequent) of inflammatory bowel disease were excluded. Cases showing histologic features of ischemic, pseudomembranous, or granulomatous colitis were excluded. The biopsies were evaluated and semiquantitatively scored for established histologic features of activity and chronicity. The clinical, endoscopic, and follow-up data, including drug usage, was recorded. Results: There were 10 males and 7 females and the mean age was 59 years. The majority of cases involved the cecum or ascending colon (16 of 17 cases). A majority of patients were asymptomatic (n=11), and in others, indications for colonoscopy were occult blood (n=3), hematochezia (n=2), and melena (n=1). The most common mucosal abnormality was erythema (n=10), ulcers (n=3), congestion (n=3), and edematous mucosa (n=1). All cases showed histologic features of chronicity and showed either basal plasmacytosis (94%) or crypt architectural distortion (94%). Eight (47%) patients reported nonsteroidal anti-inflammatory drugs (NSAID) use. Withdrawal of NSAIDs in 2 cases resulted in normalization of the colonic mucosa. On follow-up, all 17 patients were asymptomatic (median follow-up 42.8 mo) and did not progress to inflammatory bowel disease. Conclusions: We report a series of 17 histologically documented cases of incidental chronic colitis without a conventional etiology. However, both the frequent usage of NSAIDs, and normalization of mucosal changes after withdrawal of this drug suggest that NSAIDs may account for this cecal-based chronic colitis. The awareness of this histologically dramatic but clinically innocuous form of chronic colitis may avoid errors in mucosal biopsy diagnosis.

Spectrally encoded confocal microscopy and optical frequency domain imaging are two non-contact optical imaging technologies that provide images of tissue cellular and architectural morphology, which are both used for histopathological diagnosis. Although spectrally encoded confocal microscopy has better transverse resolution than optical frequency domain imaging, optical frequency domain imaging can penetrate deeper into tissues, which potentially enables the visualization of different morphologic features. We have developed a co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system and have obtained preliminary images from human oesophageal biopsy samples to compare the capabilities of these imaging techniques for diagnosing oesophageal pathology.

Micropapillary carcinoma (MPC) of the stomach is a rare, newly recognized entity, and only 2 patients with this histology have been reported. We investigated clinicopathologic features, expression of mucin (MUC2, MUC5AC, MUC6, CD10) and cytokeratin profiles (CK7 and CK20), epidermal growth factor receptors (EGFR and HER2), prognostic markers (p53 and Ki-67), and outcomes in 11 MPCs of the stomach. The proportion of MPC component ranged from 5% to 70%. Micropapillary features were often found at the deep advancing edge of the tumor. Endolymphatic tumor emboli were found in 10 cases (91%) and lymph node metastases were found in 4 cases (36%). In MPCs, positive expression was observed for Ki-67 (82%), CK7 (73%), EGFR (64%), p53 (64%), MUC5AC (45%), MUC6 (36%), and CK20 (27%). However, MUC2, CD10, and HER2 expression was negative in all cases. In 9 conventional adenocarcinomas and 11 papillary adenocarcinomas with multiple endolymphatic tumor emboli, used as control, positive expression was observed for Ki-67 (100%), CK7 (90%), EGFR (80%), CK20 (70%), p53 (70%), MUC5AC (70%), MUC6 (60%), MUC2 (40%), CD10 (25%), and HER2 (15%). Expression of MUC2, CK20, and the Ki-67 labeling index was significantly higher in control adenocarcinomas as compared with MPCs (P<0.05). However, there was no significant difference in other clinicopathologic features and overall patient survival. Subclassification of MPCs into 2 subgroups according to the proportion of micropapillary component (cut-off value was 20%) failed to find any significant clinicopathologic differences (P>0.05). Although MPCs in other organs show a poor prognosis, this does not seem to be true for gastric MPCs. Further larger studies are necessary to confirm our initial findings.

Recent morphologic and molecular evidence suggests that dysplasia in Barrett esophagus (BE) begins in the bases of the crypts [crypt dysplasia (CD)] and progresses with time to involve the upper portions of the crypts and surface epithelium. The aim of this study was to evaluate the criteria and reproducibility of diagnosing CD among 6 gastrointestinal pathologists, all with research interest in BE. Six gastrointestinal pathologists evaluated 2 clinical study sets, the first consisting of 40 BE cases [BE: 10, CD: 9, low-grade dysplasia (LGD): 10, high-grade dysplasia (HGD); 9, and intramucosal adenocarcinoma; 2] and the second consisting of 63 cases (BE: 16, CD: 15, LGD: 15, HGD: 15, and intramucosal adenocarcinoma: 2), at least 4 months apart. In between evaluations, all of the pathologists met at 1 hospital (consensus conference) to review the areas of disagreement and establish more objective criteria. Overall, the level of agreement for all cases was moderate ([kappa]=0.44), and the level of agreement did not change significantly after evaluation of the second study set. The highest levels of agreement were obtained for lesions at the low and high end of the spectrum (BE without dysplasia and HGD). Overall, the degree of agreement for CD was moderate after both the first and second study set review ([kappa]=0.44 and 0.46, respectively). However, the degree of agreement for CD was higher than that obtained for LGD in both study sets. In the first study set, 4 or more pathologists agreed with the original CD diagnosis in 78% of cases, and this value did not change significantly after review of the second study set. The observers agreed that characteristic features of CD include the presence of unequivocal dysplastic cells, similar in appearance to traditional LGD, involving any part, or all of the length, of the crypt in the absence of intercrypt surface epithelial involvement. Rare cases of CD may show high-grade cytologic features composed of markedly enlarged nuclei with increased nuclear/cytoplasmic ratio, eosinophilic cytoplasm, irregular nuclear membranes, and loss of polarity. The findings in this study suggest that CD can be diagnosed reliably with a moderate level of interobserver agreement. Long-term and multi-institutional studies should be carried out to further determine the biological and clinical significance and natural history of CD in patients with BE.

Gastric intestinal metaplasia can display cytoarchitectural atypia that falls short of qualifying for dysplasia but can be classified as indefinite for dysplasia. Yet few studies have evaluated the prevalence, the morphologic, and biologic characteristics of this variant. Out of a cohort of 554 biopsies with chronic atrophic gastritis and/or dysplasia, we categorized the cases as either (1) simple intestinal metaplasia; (2) intestinal metaplasia with hyperplasia; (3) intestinal metaplasia with basal gland atypia; and (4) gastric dysplasia. The relationship between the subtypes and various clinicopathologic features, mucin immunophenotypes, and biologic characteristics was evaluated. The final cohort consisted of 424 cases of simple intestinal metaplasia, 93 intestinal metaplasia with hyperplasia, 16 intestinal metaplasia with basal gland atypia, and 21 gastric dysplasia. Intestinal metaplasia with basal gland atypia had a prevalence of 2.8% and similar to gastric dysplasia, 3.7%. Both of these lesions were similar in body/fundus distribution (12.5%) and paucity of goblet cells (68.8%). Intestinal metaplasia with basal gland atypia and gastric dysplasia seem to share some biologic similarities but with a lower frequency of alpha-methylacyl-CoA racemase expression (25% versus 62%), p53 expression (6.3% versus 47.6%), and increased Ki-67 index on surface/pit and isthmus in intestinal metaplasia with basal gland atypia. Alternatively, simple intestinal metaplasia and intestinal metaplasia with hyperplasia did not differ statistically with regard to the various characteristics evaluated. We concluded that gastric intestinal metaplasia can be divided into 2 broad categories that are readily defined by cytoarchitectural and biologic characteristics. Based on the characteristics of intestinal metaplasia with basal gland atypia and in keeping with others, we confirm that this subtype could represent a preneoplastic lesion that needs further evaluation.

Sorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia—and its consequences on treatment resistance—remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen–positive (Gr-1+) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1+ myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis—despite persistently elevated hypoxia—in part by reducing Gr-1+ myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. Conclusion: Blocking SDF-1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment. (Hepatology 2014;59:1435-1447)

The distinction of Crohn's disease from ulcerative colitis is based on clinical, endoscopic, radiological, and histological findings, a paradigm that remains unchanged despite the advent of new understanding of the immunological and genetic basis of inflammatory bowel disease. There is a strong correlation between inflammatory bowel disease, predominantly ulcerative colitis, and autoimmune pancreatitis. We hypothesized that colonic biopsies from patients with inflammatory bowel disease would demonstrate increased numbers of IgG4-positive plasma cells and that this elevation might be restricted to ulcerative colitis. We examined a cohort of 78 cases of inflammatory bowel disease: 50 ulcerative colitis and 38 Crohn's disease. We identified treatment-naive biopsies. Additionally, four cases of inflammatory bowel disease associated with autoimmune pancreatitis and 15 cases of lymphocytic/collagenous colitis were also identified. Immunohistochemical stains for IgG4 were performed. Biopsies from patients with ulcerative colitis showed significantly higher numbers of IgG4-bearing plasma cells than those with Crohn's disease (mean IgG4 counts per high-power field (hpf) 9.8 vs 2.8, P=0.001). Samples from 19 (38%) ulcerative colitis patients had IgG4 counts >10/hpf, compared with only two (5%) patients with Crohn's disease; the sensitivity and specificity of a cutoff at 10 IgG4-positive plasma cells per hpf was 38 and 95%, respectively. Among individuals <18 years, there were no statistically differences in the IgG4 counts between the two subforms of inflammatory bowel disease. Among adult patients, a cutoff of 5 IgG4+ plasma cells distinguished ulcerative colitis from Crohn's disease with a sensitivity of 53% and specificity of 83%. In comparison to inflammatory bowel disease, patients with lymphocytic/collagenous colitis showed significantly lower numbers of IgG4-positive plasma cells (P=0.0001). Ulcerative colitis with pancolitis showed higher numbers of IgG4-bearing plasma cells (mean IgG4 12.8 vs 5.8 per hpf; P=0.09). An immunohistochemical stain for IgG4 may aid in making the distinction between ulcerative colitis and Crohn's disease (with exclusion of the pediatric cases), albeit with a relatively low sensitivity. This study also provides additional support to the hypothesis that a subset of ulcerative colitis cases is associated with a Th2 response.

Although the significance of focally enhanced gastritis (FEG) as a marker of Crohn disease (CD) in adults has been contested, several studies suggest that it may be more specific of CD in pediatric patients. This study describes the detailed histologic features of FEG in pediatric inflammatory bowel disease (IBD) and clarifies its association with CD. A series of 119 consecutive newly diagnosed IBD patients (62 CD cases, 57 ulcerative colitis [UC] cases) with upper and lower gastrointestinal biopsies were evaluated. The histology of the gastric biopsies was reviewed blinded to final diagnoses and compared with age-matched healthy controls (n=66). FEG was present in 43% of IBD patients (CD 55% vs. UC 30%, P=0.0092) and in 5% of controls. Among CD patients, FEG was more common in younger patients (73% in children aged 10 y and below, 43% in children above 10 y of age, P=0.0358), with the peak in the 5- to 10-year age group (80%). The total number of glands involved in each FEG focus was higher in UC (6.4±5.1 glands) than in CD (4.0±3.0 glands, P=0.0409). Amongst the CD cohort, patients with FEG were more likely than those without FEG to have active ileitis (79% vs. 40%, P=0.0128) and granulomas elsewhere in the gastrointestinal tract (82% vs. 43%, P=0.0016). There was no correlation between FEG and other gastrointestinal findings of UC. We demonstrate that differences in FEG seen in pediatric CD and UC relate to not only their frequencies but also the morphology and relationship with other gastrointestinal lesions. Further, FEG is associated with disease activity and the presence of granulomas in pediatric CD.