Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period.

Periampullary adenocarcinoma, including pancreatic cancer, has a poor prognosis that has not improved in the last decades. Therefore, in order to find more effective treatment regimens, it is necessary to gain more insight into the biology and clinical behaviour of these tumours. This thesis entails a thorough histopathological characterization of retrospectively collected tumours from a consecutive cohort of patients with resected periampullary adenocarcinoma, followed by tissue microarray-based immunohistochemical studies of eight candidate protein biomarkers. Tumours were classified as being of pancreatobiliary type (PB-type) or intestinal type (I-type), using histological criteria, and all biomarker analyses were performed in strata according to morphological type. In Paper I, histopathological studies showed that a standardized and meticulous protocol for assessment of the surgical specimens, as well as blind revisions of slides, had impact on the decision on tumour origin, the number of involved lymph nodes and involved margins. The biomarker studies in Paper II revealed that expression of the global gene regulator special AT-rich sequencebinding protein 1 (SATB1) was an independent factor of poor prognosis in PB-type tumours. SATB1 expression, however, also indicated a better response to adjuvant chemotherapy, in particular in I-type tumours. A closely related protein, SATB2, was found to be expressed in a few tumours only, making it difficult to draw any firm conclusions on its prognostic value. In Paper III, biomarker studies on proteins related togemcitabine metabolism revealed that a high ratio between cytoplasmic and nuclear expression of human protein R (HuR) indicated resistance to chemotherapy in PB-type tumours. In I-type tumours, high expression of human equilibrative nucleoside transporter 1 (hENT1) was a favourable prognostic factor and high expression of deoxycytidine kinase (dCK) indicated sensitivity to chemotherapy. In Paper IV, biomarker studies on the human epidermal growth factor receptors 1-3 (HER1-3) revealed a potential negative predictive effect of high EGFR (HER1) expression in relation to adjuvant chemotherapy in PB-type tumours. Six percent of I-type tumours had high expression of HER2, and gene amplification was confirmed in assessable cases. In I-type tumours, high expression of HER3 was a favourable prognostic factor, but not independent of other prognostic factors. Several of the potentially treatment predictive associations described in this thesis are novel, and may be of clinical interest if the results can be repeated in other cohorts and if the mechanistic basis is understood. The results presented here must be however be interpreted with caution, since the cohort is retrospective and many tests have been made

Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas

The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n=175) and (Cohort 2, n=189). The effect of TGF-beta -induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.Peer reviewe

Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis

The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study

The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types

Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.</p

Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma.

Variability in reported histopathology parameters in operated periampullary adenocarcinomas may affect the prognostic weight of the parameters. Standardized axial sectioning produces a higher incidence of involved margins and also seems to produce a lower relative incidence of pancreatic compared with distal bile duct origin and a higher incidence of involved lymph nodes, compared with non-standardized procedure. The aims of this study were to 1) assess how a previously not described standardized pathology procedure, with longitudinal sectioning along the distal bile duct, affects reported tumour origin, margin status and involved lymph nodes, compared with non-standardized procedure, 2) assess if re-evaluation of microscopic slides affects the prognostic value of margin status and 3) compare the results of this standardized procedure with reported results of other standardized and non-standardized procedures

Gastric ectopic pancreas: not always an innocent bystander.

A 38-year-old male patient presented to the emergency room due to acute epigastric pain, nausea and vomiting. Physical examination revealed tenderness in the upper abdomen. Body temperature was 37.3°C. C-reactive protein was 113 mg/L (reference range: 0-3 mg/L) and his white blood cell count was raised (15.5 x109/L; reference range: 3.5-8.8 x109/L). Renal and liver function tests and serum pancreatic amylase were normal. He was otherwise healthy and was not taking any medications. Upper gastrointestinal endoscopy showed a subepithelial lesion in the gastric antrum (Figure 1). Abdominal computed tomography scan revealed a heterogeneous 4 cm malignant-looking lesion in the gastric antrum with suspected invasio

Endoscopic submucosal dissection of malignant non-pedunculated colorectal lesions

Background and study aimsEndoscopic submucosal dissection (ESD) is an established method for en bloc resection of large non-pedunculated colorectal lesions in Asia but dissemination of ESD in Western countries is limited. The aim of this study was to evaluate the role of ESD in the management of malignant non-pedunculated colorectal lesions in a European center.Patients and methods Among 255 patients undergoing colorectal ESD between 2014 and 2016, 29 cases were identified as submucosal invasive cancers and included in this study. The main outcomes were en bloc, R0 and curative resection as well as procedural time, complications and recurrence.Results Median tumor size was 40 mm (range 20 – 70 mm). Thirteen cancers were located in the colon and 16 were located in the rectum. Procedural time was 89 minutes (range 18 – 594 minutes). Complete resection was achieved in 28 cases, en bloc and R0 resection rates were 83 % and 69 %, respectively. Curative resection rate was 38 %. One case had a perforation in the sigmoid colon requiring emergency surgery. No significant bleeding occurred. Six patients underwent additional surgery after ESD, one of whom had residual tumor. One recurrence was detected in 20 patients that were followed-up endoscopically, median follow-up time was 13 months (range 2 – 30 months).Conclusion ESD seems to be a safe and effective method for treating non-pedunculated malignant colorectal lesions after careful patient selection and proper endoscopic training

Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma.

Adenocarcinoma of the periampullary region is associated with poor prognosis and new prognostic and treatment predictive biomarkers are needed for improved treatment. Membranous expression of podocalyxin-like 1(PODXL), which is a cell-adhesion glycoprotein and stem cell marker, has been found to correlate with an aggressive tumour phenotype and adverse outcome in several cancer types. The aim of the present study was to examine the clinicopathological correlates, prognostic and predictive significance of tumour-specific PODXL expression in a retrospective cohort of pancreatic and periampullary carcinoma, morphologically divided into intestinal type (I-type) and pancreatobiliary type (PB-type) tumours

Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma

Abstract Background Periampullary adenocarcinomas, including pancreatic cancer, are a heterogeneous group of tumors with poor prognosis, where classification into intestinal type (I-type) or pancreatobiliary type (PB-type) is a relevant prognostic factor. The clinical significance of deficient mismatch repair (dMMR) in periampullary adenocarcinoma is comparatively unexplored. Herein, we examined the associations of MMR immunophenotype with long-term survival in patients with resected periampullary adenocarcinoma, with particular reference to morphology and adjuvant treatment response. Methods MMR protein expression was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective cohort of 175 patients with periampullary adenocarcinoma treated with pancreaticoduodenectomy during 2001–2011 in Malmö and Lund University Hospitals, Sweden. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results After a mean follow-up of 46.5 (1.9–185.1) months, 35 patients (20.3%) were alive, 24 with I-type and 11 with PB-type tumors. MMR protein expression could be evaluated in 172 cases, in which dMMR was denoted in 20 (11.6%) cases, 13/63 (20.6%) in I-type and 7/109 (6.4%) in PB-type tumors. dMMR was associated with a significantly prolonged overall survival in the entire cohort (HR = 0.28, 95% CI 0.13–0.57), and in I-type tumors (HR = 0.20, 95% CI 0.06–0.68), however not independent of conventional prognostic factors. In PB-type tumors, dMMR was not prognostic, but there was a significant negative interaction between dMMR and adjuvant treatment (pinteraction = 0.015). Conclusions dMMR is more frequent in I-type compared to PB-type periampullary adenocarcinoma, and is a prognostic factor for long-term survival only in the former. The finding of the small number of PB-type tumors with dMMR potentially lacking benefit from adjuvant chemotherapy is however noteworthy and merits further validation