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The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2

Background Primary adenocarcinomas removed by pancreatoduodenectomy originate from the duodenum (DC), ampulla (AC), distal bile duct (DBC), or pancreas (PC). Pathobiology, staging, survival, and adjuvant chemotherapy vary among these cancers. The proximity of the structures of possible origin renders it difficult to obtain a correct diagnosis, which might lead to inconsistencies in reported data and inappropriate adjuvant treatment. Methods Records of 207 patients undergoing pancreatoduodenectomy (1998–2009) for periampullary adenocarcinoma were reviewed. Routine histopathology reports of tumour origin performed by multiple pathologists were independently re-evaluated based on predetermined criteria by two experienced pancreatic pathologists. Results Slide review changed the diagnosis in 55 (27%) patients. After reclassification, final distribution was 29 (14%) DC, 52 (25%) AC, 57 (28%) DBC, and 69 (33%) PC. The diagnosis was revised in 4 (14%) DC, 7 (17%) AC, 30 (53%) DBC and 14 (19%) PC. The underestimation of DBC during routine histopathology was caused by misinterpretation of DBC either PC or AC. Misclassification of PC was mainly due to erroneous diagnosis of AC. Reassignment of tumour origin caused no significant changes in survival within cancer type, but resulted in a significant difference in survival between DBC and PC (p = 0.004). Conclusion Specialist slide review resulted in reassignment of tumour origin in 27% of periampullary adenocarcinomas. Distal bile duct cancer was found to be most frequently misdiagnosed (53%). Correct diagnosis of tumour origin is crucial for data quality, appropriate adjuvant therapy, and patient inclusion in clinical trials.

Lymph node ratio (LNR) may be more useful than nodal (N) status in prognostic subclassification of adenocarcinomas after pancreatoduodenectomy. Ampullary (AC), biliary (DBC), and pancreatic (PC) adenocarcinomas are biologically distinct, and nodal involvement may have different prognostic importance among these separate cancers. We included 179 consecutive pancreatoduodenectomies for PC, AC, or DBC, and performed standardized histopathologic evaluation, including prospective registration and retrospective reevaluation of the cancer origin. Associations between histopathologic variables and LNR, N status, and number of metastatic nodes were evaluated. Unadjusted and adjusted survival analysis was performed. Overall 5 year survival was 6 % for PC (n = 72), 26 % for DBC (n = 46), and 46 % for AC (n = 61). Lymph node involvement was more frequent in PC (75 %) than in AC (48 %) and DBC (57 %). In PC, N status did not discriminate between prognostic groups (N1 vs. N0; p = 0.31). However, increasing LNR was associated with poorer survival in unadjusted analysis, as well as when adjusting for margin involvement, degree of differentiation, and tumor diameter (p = 0.032; hazard ratio 1.87, 95 % confidence interval 1.06–3.31). In AC and DBC, N status clearly discriminated between subgroups of patients with different long-term survival in unadjusted and adjusted survival analysis (N1 vs. N0; p

Westgaard A, Clausen OPF, Gladhaug IP. Survival estimates after pancreatoduodenectomy skewed by non-standardized histopathology reports. APMIS 2011; 119: 689–700. Survival estimates may be biased if quality control on histopathology is insufficient. We evaluated the effects of standardizing histopathology for pancreatoduodenectomy specimens and compared survival estimates based on standardized vs non-standardized histopathological evaluation. Microscopic slides and histopathological reports from 311 consecutive pancreatoduodenectomies (1980–2004) were reviewed, including 104 adenocarcinomas (1980–1997) resected before and 123 adenocarcinomas (1998–2004) resected after standardizing histopathology. Histopathological factors were re-evaluated for all primary adenocarcinomas (n = 227). The most frequent histological types were pancreatobiliary-type (n = 145) and intestinal-type (n = 73). Standardized histopathology was associated with sampling more blocks and nodes (p

Pancreatic cancer is the second most frequent gastrointestinal cancer in the Western world. Few reports on concomitant trends in pancreatic cancer incidence, diagnosis, mortality and survival exist at the national level. This study provides a baseline overview of the temporal patterns in these four indicators over the past four decades in Norway.We analysed trends in incidence, basis of diagnosis, relative survival and mortality from the Cancer Registry of Norway for the period 1965-2007.Included were 21,663 patients with pancreatic cancers. Incidence and mortality rates remained at around 6-8 per 100,000 over the study period. Diagnoses based on clinical examination alone dropped from 12.5% (in the 1950s) to1% (in the 2000s), while use of imaging techniques, such as CT and MRI, increased from 3.6% to30%. Previously high rates of autopsy-verified diagnosis and non-therapeutic surgery decreased accordingly. Consistently more primary tumours (from 12.9% to 19.4%) and metastases (from 12.5% to 22.4%) had histological examination, and use of endoscopy increased to approximately 10%. Relative survival after diagnosis of pancreatic cancer remains very low. However, in recent years, a modest improvement in short-term survival has been noted, with 1-year survival rates of 18% and 16% for males and females, respectively.The incidence and mortality for pancreatic cancer remain largely unchanged, with few 5-year survivors. Improved short-term survival may reflect more aggressive use of surgery and chemotherapy. Further elucidation of risk factors in pancreatic cancer is needed to enable effective prevention, early detection and improved treatment strategies.

Aims: To examine how accurately immunohistochemical markers discriminate between pancreatobiliary and intestinal-type adenocarcinomas in the pancreatic head and to explore the prognostic importance of these markers among each of these histological types. Methods and results: Histopathological features of 114 consecutively resected adenocarcinomas of pancreatobiliary (n = 67) and intestinal (n = 47) type of differentiation were recorded according to a standardized protocol. Immunohistochemistry for cytokeratin (CK) 7, CK20, MUC1, MUC2, MUC4 and CDX2 was performed on tissue microarrays. Classification of the adenocarcinomas based on immunohistochemistry was compared with the morphological evaluation of histological type. Presence of CK7 and MUC4, and absence of CDX2, were independent predictors of pancreatobiliary versus intestinal type. Using these markers to optimize immunohistochemical classification, agreement between immunohistochemical and morphological classification was only moderate (κ = 0.53). In pancreatobiliary differentiated tumours, MUC1 and/or MUC4 expression was an independent prognostic factor (hazard ratio 2.02, 95% confidence interval 1.02, 3.98) when adjusting for nodal involvement, vessel involvement and tumour size. In intestinally differentiated tumours, none of the markers was significantly associated with prognosis. Conclusions: Agreement between immunohistochemical and morphological classification of pancreatic head adenocarcinomas is moderate. In pancreatobiliary adenocarcinomas, MUC1 and/or MUC4 expression indicates a particularly poor prognosis.

Ampullary carcinomas typically have either intestinal or pancreatobiliary type of differentiation, histopathologically resembling carcinomas of its adjacent tissues (duodenum, bile duct, or pancreas). We evaluated whether the histologic type itself is more important for long-term survival than the fact that the tumor originated in the ampulla.Microscopic slides from 207 consecutive pancreatoduodenectomies were reviewed (72 pancreatic, 46 biliary, 61 ampullary, and 28 duodenal adenocarcinomas; 76 intestinal type, 131 pancreatobiliary type). Tumor size, nodal involvement, margin involvement, degree of differentiation, vascular involvement, and perineural growth, as well as overall survival, were compared between different origins of the same histologic type.Intestinal-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to duodenal adenocarcinomas, and pancreatobiliary-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to pancreatobiliary-type biliary and pancreatic adenocarcinomas. Adjusting for tumor size and nodal involvement, there was no difference in long-term survival between patients with intestinal-type ampullary, duodenal, or biliary and pancreatic tumors (p = 0.79), and there was no difference in long-term survival between patients with pancreatobiliary-type ampullary, biliary, or pancreatic tumors (p = 0.41).Long-term survival for patients with ampullary carcinomas equals pancreatic, biliary, and duodenal carcinomas when the same histologic type is compared. It can be questioned whether ampullary carcinomas should be regarded as a separate entity in classification of solid tumors. Clinical trials on adjuvant treatments for periampullary carcinomas should stratify by pancreatobiliary type versus intestinal type of histologic differentiation.

Gladhaug I P, Westgaard A, Schjolberg A R, Burum-Auensen E, Pomianowska E & Clausen O P F (2010) Histopathology56, 345–355 Spindle proteins in resected pancreatic head adenocarcinomas: BubR1 is an independent prognostic factor in pancreatobiliary-type tumours Aims: Spindle proteins such as Aurora A, Mad2 and BubR1 are important for chromosome segregation during mitosis. Dysfunction of these proteins is implicated in the development of many cancers. The aim was to examine their possible prognostic impact in resected adenocarcinomas in the pancreatic head. Methods and results: Two hundred and eighteen consecutively resected pancreatobiliary-type (n = 145) and intestinal-type (n = 73) adenocarcinomas involving the pancreatic head were examined for expression of Aurora A, Mad2 and BubR1 by immunohistochemistry on tissue microarrays. Aurora A (P

Histopathologic reporting after pancreatoduodenectomy is often non-standardised. Inappropriate reporting may bias survival estimates and make comparison between institutions difficult. Using population-based nationwide data from the Cancer Registry of Norway, we examined the influence on survival estimates of standardised histopathologic reporting versus non-standardised histopathologic reporting after pancreatoduodenectomy for adenocarcinomas in the pancreas, distal bile duct, ampulla and duodenum (n = 506). Standardised histopathologic reports from a study hospital (n = 113) were compared with reports from all other institutions (24 hospitals; n = 393) discriminating between high/medium-volume and low-volume institutions. In the study hospital, more tissue blocks were sampled, more nodes were evaluated, and more details about resection margins, size, origin and vascular and perineural infiltration were reported (p < 0.001). Multivariable survival analysis identified lymph node involvement as the factor that is most dependent on standardised reporting to discriminate between favourable and poor prognostic subgroups (p = 0.018). Standardised evaluation was more important than hospital volume for completeness of histopathologic reporting and for accuracy of survival estimates.

The composition and properties of glacigenic sediments in the southwestern Barents Sea are described based on data from 33 shallow boreholes (< 143 m below seabed) and 11 seabed cores (

Background The retroperitoneal margin is frequently microscopically tumour positive in non-curative periampullary adenocarcinoma resections. This margin should be evaluated by serial perpendicular sectioning. The aim of the study was to determine whether retroperitoneal margin involvement independently predicts survival after pancreaticoduodenectomy within a framework of standardized assessment of the resected specimens. Methods 114 consecutive macroscopically margin-free periampullary adenocarcinomas were examined according to a prospective standardized protocol for histopathologic evaluation. The retroperitoneal margin was assessed by serial perpendicular sectioning. The periampullary cancer origin (pancreas, ampulla, distal bile duct or duodenum) was registered prospectively and reevaluated retrospectively. Associations between histopathologic factors were evaluated by Chi-square test, Fisher's exact test, Kruskal-Wallis test, and Mann-Whitney test, as appropriate. Survival curves were calculated by the Kaplan-Meier method and compared using the log-rank test. Associations between histopathologic factors and survival were also evaluated by unadjusted and adjusted Cox regression analysis, including stepwise variable selection, in order to identify factors that independently predict a poor prognosis after periampullary adenocarcinoma resections. Results Microscopic resection margin involvement (R1 resection) was present in 40 tumours, of which 32 involved the retroperitoneal margin. Involvement of the retroperitoneal margin independently predicted a poor prognosis (p = 0.010; HR 1.89; CI 1.16–3.08) after presumed curative (R0 and R1) resection. In microscopically curative (R0) resections (n = 74), pancreatic tumour origin was the only factor that independently predicted a poor prognosis (p < 0.001; HR 4.71 for pancreatic versus ampullary; CI 2.13–10.4). Conclusion Serial perpendicular sectioning of the retroperitoneal resection margin demonstrates that tumour involvement of this margin independently predicts survival after pancreaticoduodenectomy for adenocarcinoma. Periampullary tumour origin is the only histopathologic factor that independently predicts survival in microscopically curative (R0) resections.

Background Resectable adenocarcinomas in the pancreatic head, by definition "periampullary", originate from ampullary, duodenal, biliary, or ductal pancreatic epithelium. Typically, periampullary adenocarcinomas have either intestinal or pancreatobiliary type of differentiation, and the type of differentiation might be prognostically more important than the anatomic site of origin. The aim of the study was to determine whether the histologic type of differentiation is an independent prognostic factor in periampullary adenocarcinoma, and whether tumour origin predicts the prognosis in pancreatobiliary type carcinomas independently of resection margin involvement, tumour size, nodal involvement, perineural and vascular infiltration, and degree of differentiation. Methods Histopathologic variables in 114 consecutively resected periampullary adenocarcinomas of pancreatobiliary (n = 67) and intestinal (n = 47) type differentiation were evaluated using a standardized, systematic protocol for evaluation of the resected specimen (study group). Histologic type of differentiation and tumour origin were compared as predictors of survival, and the results were validated by comparison with a historical control group consisting of 99 consecutive pancreaticoduodenectomies performed before standardization of histopathologic evaluation. Associations between histopathologic variables were evaluated by Chi-square and Mann-Whitney tests. Survival was estimated by the Kaplan-Meier method, comparing curves using log-rank test, and by univariate and multivariable Cox regression analysis. Results Both in the study group (n = 114) and in the historical control group (n = 99), the histologic type of differentiation independently predicted survival, while tumour origin predicted survival only in univariate analysis. Independent adverse predictors of survival in the study group were pancreatobiliary type differentiation (p < 0.001; HR 3.1; CI 1.8–5.1), regional lymph node involvement (p < 0.001; HR 2.5; CI 1.5–4.4), vessel involvement (p = 0.012; HR 1.9; CI 1.2–3.1), and increasing tumour diameter (measured in cm, p = 0.011; HR 1.3; CI 1.1–1.5). For pancreatobiliary differentiated adenocarcinomas (n = 67), lymph node status, vessel involvement, and tumour diameter remained independent prognostic factors, while tumour origin did not independently predict the prognosis due to significant association with tumour size (p < 0.001) and lymph node involvement (p = 0.004). Conclusion Pancreatobiliary versus intestinal type of differentiation independently predicts poor prognosis after pancreaticoduodenectomy for periampullary adenocarcinoma. Lymph node involvement, vessel infiltration, and increasing tumour diameter are adverse predictors of survival in tumours with pancreatobiliary differentiation.