[Langerhans cell histiocytosis of the stomach with BRAF-V600E-mutation: case report and review of the literature]. / Langerhans-Zellhistiozytose des Magens mit BRAF-V600E-Mutation: Fallbericht und Literaturübersicht.

Langerhans cell histiocytosis is a disease with different clinical presentations and a wide spectrum of organ involvements. Rarely Langerhans cell histiocytosis can involve the gastrointestinal tract of adult patients. A case of infiltration of gastric mucosa by Langerhans cell histiocytosis is presented. The neoplastic nature of this infiltrate is underlined by the detection of a BRAF-V600E-mutation. Additionally, an overview of the so far 5 cases published in the English literature is provided. The published clinical experience indicates a benign curse of the disease.

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade.

BACKGROUND: Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS: To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS: The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS: Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.

Foveolar gastric metaplasia of the duodenum: a frequent, so far neglected type of duodenal polyp.

Foveolar gastric metaplasia of the duodenum (FGM) is considered as imperfect mucosal healing in the context of H. pylori gastritis and intake of NSAIDs or ASS.  Typical endoscopic findings are redness of the mucosa, erosion/ulcer and loss of mucosal folds. During diagnostic histological examinations we observed a frequent so far not described association of FGM with endoscopically observed duodenal polyps. The archives of two institutes of pathology with high gastroenterological workload (approximately 100 000 patients per year) were investigated for an association between "duodenal polyp" and "foveolar gastric metaplasia". In Institute 1, of 481 duodenal polyps 41 % were classified as FGM, 9 % as adenoma and 2 % as heterotopic gastric mucosa. In 48 % no histological correlate was present. In Institute 2, 217 cases of FGM were diagnosed. Of these, in 69 cases the endoscopic finding was "polyp" (32 %). In the other cases, the endoscopic findings were mucosal defect (18 %), redness/inflammation (16 %), suspicion for gastric heterotopia (5 %) and scar (3 %). In 26 % of cases no pathologic endoscopic finding was reported. Both groups of patients with FGM showed a similar distribution of age ranges (24 - 83 years and 16 - 88 years), median age (62 years and 61 years, respectively) and a dominance of male sex (both 1.5:1). In conclusion, foveolar gastric metaplasia is a frequent, so far neglected correlate of endoscopically detected duodenal polyps.

[Serrated polyps of the duodenum. Three cases with immunohistological and molecular pathological findings]. / Serratierte Polypen des Duodenums. Drei Fälle mit immunhistologischen und molekularpathologischen Befunden.

We report on three cases of serrated polyps of the duodenum which were incidental endoscopic findings in three male patients with a median age of 70 years (range 63-84 years). Architecturally the histological findings in cases 1 and 2 were similar to hyperplastic polyps of the colon. In case 3 there was a low grade intraepithelial neoplasia which covered the whole polyp. This polyp relapsed after 2 years with similar histological findings. Immunohistochemically an increased proliferative activity was found in case 3 as well as associated overexpression of p16 (INK4a) and p53. No abnormal expression of MLH1 and ß-catenin was found in any of the polyps. Molecular pathological analysis showed a BRAF mutation (V600E) in case 3. A wild type sequence in the KRAS gene was found in all polyps. In conclusion, serrated polyps should be included in the diagnostic spectrum of benign duodenal polyps.

[Paraneoplastic acanthosis nigricans of the esophagus: a case report]. / Acanthosis nigricans als paraneoplastische Erkrankung des Ösophagus: ein Fallbericht.

A 69-year-old man presented for endoscopic examination of the upper gastrointestinal tract because of dysphagia for solid food and unintended weight loss. Several months before, he had noticed brownish-gray skin lesions in the neck, in the thorax and in both axillae. A dermatological consultant expressed the suspicion of a paraneoplastic disease. Endoscopic examination revealed an adenocarcinoma of the esophagogastric junction as well as multiple small polyps in the middle and the lower thirds of the esophagus. Histological examination showed papilloma-like proliferations without atypia, which were diagnosed as acanthosis nigricans of the esophagus. After completion of the staging investigation regarding the cardiac carcinoma, combination chemotherapy was started because of the presence of liver metastases. Subsequently, partial regression of the carcinoma as well as of the dermal and esophageal lesions was noted. Acanthosis nigricans is a rare paraneoplastic disease of the esophagus. As an indicator lesion, its detection should prompt a search for a malignant tumor in the gastrointestinal tract.

Synthesis of hyaluronan in oesophageal cancer cells is uncoupled from the prostaglandin-cAMP pathway.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX2) and hyaluronic acid (HA) are common in tumours and both independently promote tumour progression. Furthermore, COX2-dependent synthesis of prostaglandins (PGs) stimulates HA synthase-1 (HAS1) and HAS2 mRNA expression, together with HA synthesis via the cAMP/protein kinase A pathway in vascular smooth muscle cells. Therefore, the aim of the present study was to elucidate whether COX2-mediated PGs induce transcription of HAS isoforms in cancer cells as well. EXPERIMENTAL APPROACH: Human oesophageal squamous cell (OSC) carcinoma specimens were characterized with respect to HA, COX2 and CD44 expression by immunohistochemistry. OSC cell lines (OSC1, OSC2) and HeLa cell lines (D98, H21) were exposed to exogenous PG analoques (100 nmol.L(-1)), etoricoxib (10 micromol.L(-1)) and forskolin (10 micromol.L(-1)). Subsequently, cAMP levels, HA secretion and HAS isoform expression were determined by elisa and real-time RT-PCR (reverse transcriptase polymerase chain reaction) respectively. KEY RESULTS: COX2, HA and CD44 were detected immunohistochemically in >90% of human oesophageal tumour samples. Under basal conditions, OSC1 and OSC2 cells express HAS2 and HAS3, COX2 and Galpha(s)-coupled EP(2) and EP(4) PG receptors. Neither stimulation with the PGI(2) analogue, iloprost, addition of exogenous PGE(2) nor forskolin induced HAS1 or HAS2 mRNA expression in OSC1 and OSC2 cells. Furthermore, in HeLa cells after induction of COX2 by tumour necrosis factor alpha and subsequent PGE(2) release, inhibition of COX2 by etoricoxib did not affect HAS expression or HA secretion. CONCLUSIONS AND IMPLICATIONS: We conclude that in oesophageal and HeLa cancer cells, HAS1/2 expression was not responsive to the PG/cAMP pathway.

Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia.

Cell surface presence of the coxsackie and adenovirus receptor (CAR) is considered a crucial prerequisite for the uptake of attenuated adenovirus. In cancers, however, a frequent loss of CAR has been noted potentially hampering the success of adenovirus-based therapy. In esophageal Barrett's carcinomas and its precursor lesions CAR presence has not been systematically determined yet. Immunohistochemical assessment in tissue specimens of 111 patients revealed CAR-positivity in all cases of Barrett's esophagus, including various degrees of intraepithelial neoplasia. In contrast, no considerable CAR presence was seen in squamous esophageal epithelium. Among Barrett's carcinomas, 93% displayed CAR presence, whereas CAR-negativity was observed preferentially in advanced cancers. Aiming to evaluate whether this loss of CAR impacts tumor-biologic properties of esophageal adenocarcinomas we studied cell lines OE19 and OE33 and observed an increased proliferation, migration and invasion upon siRNA-mediated functional CAR knock down. In conclusion, our results indicate that CAR may provide a valuable target for adenovirus-based therapy of Barrett's carcinomas and its precursor lesions. These data do also suggest that CAR does not contribute substantially to carcinogenesis in Barrett's esophagus, however, it may be speculated that loss of CAR promotes tumor progression in advanced stages of Barrett's carcinomas.

Critical reappraisal of current surveillance strategies for Barrett's esophagus: analysis of a large German Barrett's database.

Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE). Based on a large database, gathered from predominantly community-based practices in Germany, we aimed to investigate the time-course of malignant progression and apply these findings to current clinical practice. Data of 1438 patients with BE from a large German BE database were analyzed. Patients with at least one follow-up endoscopy/biopsy were included. Detection of 'malignant Barrett' (either high-grade intra-epithelial neoplasia or invasive adenocarcinoma) was considered as study end-point. Of 1438 patients with BE, 57 patients had low-grade intra-epithelial neoplasia (LG-IN) on initial biopsy and 1381 exhibited non-neoplastic BE. 'Malignant Barrett' was detected in 28 cases (1.9%) during a median follow-up period of 24 months (1-255), accounting for an incidence of 0.95% per patient year of follow-up. The frequency of 'malignant Barrett' was significantly higher (P < 0.001, chi(2)-test) in the LG-IN group (n = 11, 19.3%) compared with the non-neoplastic BE group (n = 17, 1.2%). In the non-neoplastic BE group, 'malignant Barrett' was predominantly found during re-endoscopy within the first year of follow-up (12 of 17; 70.6%), in contrast to the LG-IN group, in which 'malignant Barrett' was observed predominantly after a time exceeding 12 months (8 of 11, 72.7%; P = 0.05, Fisher's exact test). Initial endoscopic evaluations seem to play the most crucial role in managing BE. After 1 year of follow-up, endoscopic surveillance should be focused on patients with LG-IN. In patients with repeatedly proven non-neoplastic BE, elongation of the follow-up intervals to the upper limit of current guidelines, that is, 5 years, might be justified.

[Endoscopic ultrasound-guided biopsy: diagnostic yield, pitfalls, quality management]. / Endosonografisch gestützte Biopsie: diagnostischer Ertrag, Fallstricke, Qualitätssicherung.

The differential diagnosis of tumorous lesions in the pancreas, liver, adrenal gland or lymph nodes is ambiguous. Specific tissue diagnoses are essential for treatment decisions. Endoscopic ultrasound-guided biopsy has proven to be a reliable and effective modality in obtaining samples for cytological or histological examinations either primarily or in cases in which other biopsy techniques have failed. The reproducibility of cytopathological diagnoses among pathologists with special experience in assessing material obtained by endoscopic ultrasound-guided biopsies is very high. False positive diagnoses of malignancy in endoscopic ultrasound-guided biopsy are rare; false negative diagnoses appear in a variable frequency depending on target tissue, technical factors, and expertise of the endosonographer and cytopathologist. There are numerous challenges and pitfalls in the differential diagnostic classification of benign and malignant lesions. These problems are related to the characteristics of samples obtained by endoscopic ultrasound-guided biopsy, as well as to the multiple diagnoses with similar or overlapping cytological or histological characteristics. This review discusses the performance of endoscopic ultrasound-guided biopsy in establishing specific tissue diagnoses, possible pitfalls as well as opportunities to minimise differential diagnostic errors.

[Endoscopic ultrasound-guided biopsy: diagnostic yield, pitfalls, quality management part 1: optimizing specimen collection and diagnostic efficiency]. / Endosonografisch gestützte Biopsie: diagnostischer Ertrag, Fallstricke, Qualitätssicherung Teil 1: Optimierung von Materialgewinnung und diagnostischer Effizienz.

Endoscopic ultrasound-guided biopsies have proven to be of significant value in the diagnostic evaluation of benign and malignant diseases, as well as in the staging of malignant tumours of the gastrointestinal tract and adjacent organs. The high prognostic and therapeutic relevance of the resulting cytopathological diagnoses necessitates a shared responsibility of endosonographer and cytopathologist. Quality control programs are required. The diagnostic yield of endoscopic ultrasound-guided biopsies depends on the location, size and characteristics of target tissues, and technical factors (i. e., type of needle used, biopsy technique, and material processing). Other weighing factors include training, expertise and interaction of the endosonographer with cytopathologists. On-site cytological evaluation, which has proven to be successful in optimising the diagnostic efficiency of endoscopic ultrasound-guided fine-needle aspiration biopsy, is notably practiced in Northern American and French academic institutions. It seems to be a sensible alternative to collect specimens for histological and immunohistochemical investigations in addition to the cytological smears in consideration of the economic and structural terms in the German health-care system. Endoscopic ultrasound-guided fine-needle aspiration succeeds in harvesting core biopsies in 3 out of 4 cases with 22-gauge needles. Therefore the use of 19-gauge needles for endoscopic ultrasound-guided aspiration or trucut biopsy may be necessary only in selected cases.

Expression of prostaglandin E synthase in Barrett's cancer.

Expression of prostaglandin E synthase (PGES) - an enzyme of the prostaglandin biosynthetic pathway with suspected impact on carcinogenesis--was studied in Barrett's cancer to determine its pathogenetic role and prognostic impact in this entity. Expression analysis of PGES was performed on mRNA level (quantitative reverse transcription polymerase chain rection [RT-PCR]) in a large surgical series of 123 primary resected adenocarcinomas of the distal esophagus (Barrett's cancer). Gene expression results were correlated with clinical parameters, overall survival and expression levels of previously analyzed target genes of the cyclooxygenase (COX) pathway (COX-1, COX-2) and mediators of angiogenesis (vascular endothelial growth factor [VEGF]-A) and lymphangiogenesis [VEGF-C]. Expression of PGES was demonstrated in all 123 tumors (100%) on mRNA level (quantitative RT-PCR). Relative mRNA expression levels were highly variable between different cases. Gene expression showed a strong positive correlation with both COX isoforms (COX-1: r = 0.502, P < 0.001; COX-2: r = 0.679, P < 0.001), with the angiogenetic VEGF-A (r = 0.583, P < 0.001) and with the lymphangiogentic VEGF-C (r = 0.465, P < 0.001). PGES mRNA expression showed no significant correlation with clinicopathologic parameters (i.e. pTNM categories, UICC stage, survival). Variable overexpression of PGES seems to be potentially implicated in Barrett's carcinogenesis. Gene expression of PGES is strongly correlated with other mediators of the prostaglandin biosynthetic pathway, that is both COX isoforms (COX-1 and COX-2). However, no impact on patients' outcome in relation to PGES expression was found.

Polymorphisms in methionine synthase (A2756G) and cystathionine beta-synthase (844ins68) and susceptibility to carcinomas of the upper gastrointestinal tract.

PURPOSE: Folate deficiency is considered to increase the risk for the development of malignant tumors such as prostate and colorectal cancer. Methionine synthase (MTR) and cystathionine ss-synthase (CBS) are enzymes that play a central role in folate metabolism, thereby affecting DNA methylation and synthesis. A single A-->G substitution at nucleotide 2756 of the MTR and a 68 bp CBS insertion polymorphism in exon 8 have been associated with decreased enzyme activity. The purpose of this study is to compare the association of the MTR A2756G polymorphism and CBS insertion polymorphism with susceptibility to carcinomas of the upper gastrointestinal tract. METHODS: Using the restriction fragment length polymorphism (RFLP)-PCR, the prevalence of MTR A2756G and CBS insertion polymorphism was determined in healthy controls (n = 257) and in patients with esophageal squamous cell carcinoma (ESCC) (n = 263), Barrett's esophagus-associated esophageal adenocarcinoma (BC) (n = 89), cardiac carcinoma (CC) (n = 144), or gastric carcinoma (GC) (n = 221) from German Caucasian subjects. RESULTS: No significant difference in MTR A2756G genotype distribution was observed between controls (A/A 66.9%, A/G 29.8%, G/G 3.3%) and patients with ESCC (A/A 61.7%, A/G 36.3%, G/G 2.1%), BC (A/A 69.2%, A/G 26.9%, G/G 3.9%), CC (A/A 51.8%, A/G 44.6%, G/G 3.6%), or GC (A/A 73.4%, A/G 20.9%, G/G 5.7%). Similarly, the CBS genotype (I: allele with 68 bp insertion; N: allele without insertion) distribution among German patients with ESCC (N/N 86.8%, I/N 13.2%), BC (N/N 90.2%, I/N 9.8%), CC (N/N 90.1%, I/N 9.9%) or GC (N/N 91.3%, I/N 8.7%) was not different from healthy controls (N/N 90.4%, I/N 9.6%). The gene allele constellation I/I was not present. CONCLUSIONS: The current study suggests that there is no association between MTR A2756G polymorphism and the CBS (844ins68) insertion polymorphism and cancer of the upper gastrointestinal tract.

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus.

Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P=0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P=0.0061) and p53-phospho (P=0.0064). Expression of p53 correlated with expression of p53-phospho (P<0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma.

Analysis of the E-cadherin repressor Snail in primary human cancers.

Epithelial-mesenchymal transition (EMT), a normal developmental process, is known to play a crucial role in tumor progression. Molecules involved in this process, such as the E-cadherin repressor Snail, facilitate migration and invasion of carcinoma cells. A growing number of studies addressing the expression of Snail in clinical samples have been reported and are discussed in this review. A total of 2,112 cases from 9 different tumor types were evaluated. So far, a clear picture has emerged only in some cancer types analyzed with regard to overexpression of Snail and clinical-pathological parameters. Currently, it seems that Snail may play a role in hormone-dependent carcinomas but may be of minor importance in gastrointestinal cancers for tumor dedifferentiation and the maintenance of the invasive phenotype. It should be kept in mind, however, that the threshold for Snail activity does not have to be the same in every tumor type analyzed. The recent introduction of well-characterized novel monoclonal antibodies reacting with the short-lived nuclear Snail protein may help to establish a potential clinical usefulness for this master molecule of EMT, at least for certain types of cancer.

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX.

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin.

Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin is known to play an important role in tumour progression. The aim of our study was to investigate the mRNA expression of two EMT regulators-Slug and E12/E47-in primary human gastric carcinomas and to compare this with the expression of E-cadherin and other EMT regulators (Snail, Twist, and SIP1). We studied a series of 59 gastric carcinomas by real-time quantitative RT-PCR in formalin-fixed and paraffin-embedded tissues. Thirty-four cases (58%) showed Slug up-regulation in the tumour; reduced or negative expression of E-cadherin was present in 24 of these (71%, p<0.0001). Twenty-one cases (36%) showed E12/E47 up-regulation that was not significantly associated with E-cadherin down-regulation (p=0.5734). Slug up-regulation accompanied by E-cadherin down-regulation correlated with the presence of distant metastases (p=0.0029) and with advanced pTNM stages (p=0.0424). A statistically significant association was found between Slug up-regulation and the expression of SIP1 in intestinal (p=0.0014) and Snail in diffuse (p=0.0067) carcinomas. We present the first study integrating the analysis of several EMT regulators in primary gastric carcinomas and conclude that Slug up-regulation is associated with E-cadherin down-regulation in diffuse and intestinal-type gastric carcinoma, and that this effect could be complemented by the presence of other EMT regulators.

Lack of EGFR gene mutations in exons 19 and 21 in esophageal (Barrett's) adenocarcinomas.

Epidermal growth factor receptor is over-expressed in several tumors and is the target for the tyrosine kinase inhibitor gefitinib. This receptor is also over-expressed in esophageal adenocarcinomas. In non-small cell lung cancer, specific somatic mutations residing in the epidermal growth factor receptor tyrosine kinase in the activation loop and the glycine-rich P-loop, are responsible for an enhanced sensitivity toward gefitinib. We analyzed exons 19 and 21 coding for the receptor tyrosine kinase of the epidermal growth factor gene in 105 samples of esophageal (Barrett's) adenocarcinoma by denaturing high-pressure liquid chromatography. We found only one silent mutation in exon 19 of adenine to guanine in codon 754 leading to a substitution of K to K, the rest of the sample being wild-type genotype. In conclusion, mutations within the tyrosine kinase domain of EGFR associated with sensitivity of non-small cell lung cancer patients to gefitinib are not present in esophageal (Barrett's) adenocarcinoma.

Squamous cell carcinoma and Zenker diverticulum.

Squamous cell carcinoma in a Zenker diverticulum is a very rare condition. We report a case of a patient with a Zenker carcinoma, who was primarily functionally inoperable and therefore received neoadjuvant radiochemotherapy before cardiac bypass surgery. After a complicated course with cardiogenic shock and myocardial infarction, a re-evaluation of functional risk analysis and the tumor situation revealed operability. Subsequently, partial hypopharyngectomy and partial cervical esophageal resection with lymphadenectomy was performed. Reconstruction of the gastrointestinal continuity was made by interposition of a free small bowel graft and microvascular anastomosis. The postoperative course showed a small anastomotic leakage of the hypopharyngeal-small bowel anastomosis, which was successfully treated conservatively.

Expression of cyclo-oxygenase 1 and 2, prostaglandin E synthase and transforming growth factor beta1, and their relationship with vascular endothelial growth factors A and C, in primary adenocarcinoma of the small intestine.

BACKGROUND: Primary adenocarcinomas of the small intestine are rare. The prostaglandin biosynthetic pathway plays a major role in carcinogenesis and is linked with angiogenesis in various tumours. Promotion of tumour growth by transforming growth factor (TGF) beta may be mediated through the prostaglandin pathway. METHODS: Expression of cyclo-oxygenase (COX) 1 and 2, prostaglandin E synthase (PGES), TGF-beta1 and vascular endothelial growth factor (VEGF) A and C genes was analysed in 54 primary adenocarcinomas of the small intestine and corresponding normal intestinal mucosa. All patients had undergone surgical resection without previous antineoplastic therapy. Target gene expression was analysed at the mRNA level by reverse transcriptase-polymerase chain reaction and correlated with clinicopathological parameters as well as survival. COX-2 protein expression was examined by immunohistochemistry. RESULTS: Expression of COX-2 protein was detected immunohistochemically in 98 per cent of the carcinomas. COX-1, COX-2, VEGF-A, VEGF-C, PGES and TGF-beta1 mRNA expression varied markedly in different tumours, but all were overexpressed compared with levels in normal intestinal mucosa. There were significant associations between levels of COX-1, COX-2, TGF-beta1 and PGES mRNAs and those of VEGF-A and VEGF-C. CONCLUSION: Correlations between levels of mRNA for COX-1, COX-2, TGF-beta1 and PGES and those for proangiogenic factors VEGF-A and VEGF-C suggest a role for these factors in the propagation of primary adenocarcinomas of the small intestine.

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.