Losses at chromosome 4q are associated with poor survival in operable ductal pancreatic adenocarcinoma.

Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin-embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico-pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi-square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox-multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified.

Current status of radical systematic lymphadenectomy in pancreatic cancer--a review of the literature.

BACKGROUND: Pancreatic cancer is the fourth most common cause of death in malignancies with an incidence of 8-12 cases per 100000 in western world. In spite of numerous modifications in therapeutical approaches, prognosis has not improved. METHODS: In the last few years numerous studies have been performed to reduce tumor mortality with more radical surgical procedures. Several articles of the last 15 years have been investigated to objectivate the benefit of extended lymphadenectomy in pancreatic surgery. Staging of the cancers, prognostic factors, technique and interpretation of lymphadenectomy have been analysed RESULTS: All studies document a lowered perioperative mortality in pancreatic resections. The procedure is counted as a standardized and safe one. However, several controversies exist. The distinct staging systems in Japan and the western world aggravate the comparison in all studies. Japanese authors in mostly retrospective analyses seem to document a survival benefit by radical surgery. Similar results could not be achieved by western authors. CONCLUSION: Over all, a significant benefit in extreme radical surgery could not bee found. However, there are indications of subgroups of patients in whom extended lymphadenectomy might be beneficial. This subgroup should be defined only by large multicentric, prospective, randomized studies.

The detection of oesophageal adenocarcinoma by serum microsatellite analysis.

BACKGROUND AND AIMS: Organ-confined oesophageal cancer in an early stage can be cured in many patients, whereas more extensive lesions have a poor prognosis. We sought to develop a non-invasive test for cancer detection and evaluation of the prognosis of the patients by using a novel molecular approach. MATERIAL AND METHODS: Matched normal-, tumour- and serum-samples were obtained from 32 patients with adenocarcinoma of the oesophagus. DNA was extracted and the samples were subjected to microsatellite analysis using 12 markers. Serum and normal samples from 10 healthy individuals served as controls. RESULTS: Twenty-seven of the 32 patients (84.4%) with malignant tumours were found to have one or more microsatellite DNA alterations in their primary tumour. Twenty-six of the 32 patients (81.3%) had alterations in the serum by microsatellite analysis. Interestingly, all patients without lymphatic metastasis and three early carcinomas (pT1pN0) already displayed LOH alteration in the serum, while all serum DNA of samples from normal control subjects were negative. Survival was not significantly correlated with either LOH in the tumour or LOH in the serum. CONCLUSION: These data suggest that microsatellite DNA analysis in serum specimens might provide a potentially valuable tool for early detection of oesophageal cancer. The evidence of circulating tumour DNA reflects the propensity of these tumours to spread to distant sites. Up to now the follow-up is still too short to draw further conclusions on the prognostic impact of this finding.

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes.

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Esophageal cancer: the mode of lymphatic tumor cell spread and its prognostic significance.

PURPOSE: Data on skip metastases and their significance are lacking for esophageal cancer. This issue is important to determine the extent of lymphadenectomy for esophageal resection. In this study we examined the lymphatic spread in esophageal cancer by routine histopathology and by immunohistochemistry. PATIENTS AND METHODS: A total of 1,584 resected lymph nodes were obtained from 86 patients with resected esophageal carcinoma and evaluated by routine histopathology. Additionally, frozen tissue sections of 540 lymph nodes classified as tumor-free by routine histopathology were screened for micrometastases by immunohistochemistry with the monoclonal antibody Ber-EP4. The lymph nodes were mapped according to the mapping scheme of the American Thoracic Society modified by Casson et al. RESULTS: Forty-four patients (51%) had pN1 disease, and 61 patients (71%) harbored lymphatic micrometastases detected by immunohistochemistry. Skip metastases detected by routine histopathology were present in 34% of pN1 patients. Skipping of micrometastases detected by immunohistochemistry was found in 66%. The presence of micrometastases was associated with a significantly decreased relapse-free and overall survival (56.0 v 10.0 months and > 64 v 15 months, P <.0001 and P =.004, respectively). Cox regression analysis revealed the independent prognostic influence of micrometastases in lymph nodes. Lymph node skipping had no significant independent prognostic influence on survival. CONCLUSION: Histopathologically and immunohistochemically detectable skip metastases are a frequent event in esophageal cancer. Only extensive lymph node sampling, in conjunction with immunohistochemical evaluation, will lead to accurate staging. An improved staging system is essential for more individualized adjuvant therapy.

Three novel mutations in the RET proto-oncogene.

Medullary thyroid carcinoma (MTC) occurs as a sporadic tumor or in connection with inherited cancer syndromes of multiple endocrine neoplasia type 2 and familial MTC. Missense RET proto-oncogene mutations and small in-frame deletions are found in most of the cases. In a significant amount of sporadic MTC cases somatic mutation at codon 918 (exon 16), or at codons 609, 611, 618, 620 (exon 10), or codons 630, 634 (exon 11) appear. We report here on three new somatic cell missense mutations of the RET proto-oncogene associated with sporadic MTC. In one tumor mutation at codon 922 TCC(Ser)-->TTC(Phe) in exon 16 was found. In another tumor two mutations at codons 639 GCA(Ala)-->GGA(Gly) and 641 GCT(Ala)-->CGT(Arg) in the exon 11 were observed. Allele-specific PCR followed by sequencing demonstrated the presence of both mutations at the same allele.

Mode of spread in the early phase of lymphatic metastasis in non-small-cell lung cancer: significance of nodal micrometastasis.

The impact of lymphatic micrometastases on prognosis of non-small-cell lung cancer has not been clearly established. We therefore prospectively assessed the frequency, mode of mediastinal spread, and prognostic significance of lymphatic micrometastases in lymph nodes of 93 patients with completely resected non-small-cell lung cancer staged as pT1 to pT4 pN0 and pN1 by conventional histopathologic techniques. Frozen tissue sections from 471 lymph nodes that were staged as free of metastases by routine histopathologic examination were screened for micrometastases by the alkaline phosphatase-antialkaline phosphatase immunostaining technique with the monoclonal antibody Ber-Ep-4. Twenty of 73 patients (27.4%) with disease staged as pN0 and nine of 20 patients (45.0%) with disease staged as pN1 had nodal micrometastases. Eight of 17 patients with upper lobe primary tumors and five of 12 patients with lower lobe primary tumors exhibited skip micrometastases. Mean relapse-free survival was significantly increased in patients with pN0 disease without micrometastases (41.1 vs 29 months, p = 0.0081). In patients with pN1 disease, mean relapse-free and cancer-related survivals were also significantly increased if no micrometastases were found (34.8 and 38.2 months vs 18 and 23.5 months, p = 0.0157 and p = 0.0094). Patients with disease staged as pN0 and pN1 with micrometastases revealed no difference in cancer-related survival compared with a control population of patients with disease staged as pN2. The mode of spread was erratic. The prognosis of patients after upstaging of pN0 and pN1 disease according to results of immunohistochemical staining correlated strongly with the prognosis of patients whose disease was staged at the higher stages by conventional histopathologic examination. These findings could represent a new indication for adjuvant therapy, supporting extensive lymph node sampling for staging purposes.

Early lymphatic tumor cell dissemination in pancreatic cancer: frequency and prognostic significance.

Tumor relapse occurs frequently in patients with ductal pancreatic head cancer despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to detect minimal amounts of disseminated tumor cells present in secondary organs, which might be the seed for subsequent metastatic relapse. We evaluated lymph nodes from 18 patients without overt metastases who had undergone radical tumor resection (R0 resection). Lymph nodes judged as "tumor-free" by routine histopathology were further examined for the presence of single tumor cells using immunohistochemistry with the antiepithelial monoclonal antibody Ber-EP4. Sixteen of 37 "tumor-free" lymph nodes (43.2%), obtained from 13 of 18 patients (72.2%), displayed Ber-EP4+ tumor cells. Twelve of these 18 patients presented at pT2 stage. Nine of 12 patients (75%) staged as pN0 had these cells. Two of six pN1 patients had no Ber-EP4+ in histopathologically tumor-free lymph nodes. Using multivariate Cox's regression analysis, the presence of Ber-EP4+ cells in "tumor-free" lymph nodes was an independent factor for a significantly reduced relapse-free survival (p = 0.006) and overall survival (p = 0.01). Remarkably, all patients who were restaged as lymph node negative by both histopathology and immunohistochemistry survived the observation period without recurrence. The frequent occurrence of disseminated tumor cells in patients with pancreatic cancer and their prognostic impact support the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination. Thus patients with a minimal residual tumor load who might benefit from an adjuvant therapy could be selected.

Expression and prognostic significance of HLA class I, ICAM-1, and tumor-infiltrating lymphocytes in esophageal cancer.

Most solid malignancies show some degree of lymphoid infiltration suggesting a specific immunologic host vs. tumor reaction. Tumor-infiltrating lymphocytes (i.e., CD3 + T-lymphocyte subsets), the human leukocyte antigen (HLA) class I molecules, and the intercellular adhesion molecule-1 (ICAM-1) are key factors involved in T-cell-mediated immune surveillance. The present study was designed to assess the expression pattern of intratumoral lymphocyte infiltrates and their relationship to HLA class I and ICAM-1 expression with regard to primary esophageal carcinoma and to evaluate their prognostic influence. Representative samples of primary tumors were obtained from 55 patients who had undergone radical en bloc esophagectomy. Frozen sections of these tumors were stained with monoclonal antibodies directed against CD3 for the assessment of tumor-infiltrating lymphocytes, HLA class I, and ICAM-1. The mean postoperative observation period was 19.5 months (range 5 to 45 months). Lymphocyte infiltration was absent in four tumors (8%), whereas 31 tumors (64%) showed moderate and 13 (27%) showed strong infiltration. HLA class I expression was deficient in 24 tumors (45%). Coexpression of HLA class I and ICAM-1 was significantly associated with lymphocyte infiltration of the tumor. Kaplan-Meier analyses revealed a significant beneficial influence on relapse-free survival for patients with lymphocyte infiltration of primary tumors compared to those with no lymphocyte infiltration of tumors (median 4 months vs. 18 months; P <0.002) and for HLA class I+ tumors compared to HLA class I- tumors (median survival >18 months vs. 7 months; P = 0.0081). The present data support the hypothesis that T-cell-mediated immunity may influence the fate of patients with esophageal cancer.

Expression of 17-1A antigen and complement resistance factors CD55 and CD59 on liver metastasis in colorectal cancer.

Despite radical surgery, the prognosis for colorectal cancer patients with liver metastases has not changed markedly. Furthermore, no standard adjuvant therapeutic regimen has been developed. Adjuvant therapy with monoclonal antibodies (e.g., against 17-1A), which has been shown to be effective in preventing metastatic relapse in patients with Dukes' C colorectal cancer, might be a promising approach for these patients. However, the cytotoxic effects of monoclonal antibodies can be blocked by coexpression of complement resistance factors that inhibit antibody-dependent complement-mediated cytotoxicity. We therefore analyzed immunohistochemically the expression of 17-1A and the membrane-bound complement resistance factors CD55 and CD59 on metastatic tumor cells in the livers of 71 patients with colorectal carcinoma who had undergone resection of their metastases with curative intent. In 67 (94%) of 71 patients, liver metastases with homogeneous expression of 17-1A was seen. Heterogeneous expression of 17-1A was seen in four patients (6%). Heterogeneous expression of CD55 or CD59 was observed in 8 (11%) of 71 patients and 4 (6%) of 71 patients, respectively. None of the patients showed homogeneous expression of either CD55 or CD59. All patients with CD55 or CD59 expression showed homogeneous 17-1A expression, whereas none of the four patients with heterogeneous 17-1A expression was positive for CD55 or CD59. Our data indicate that 17-1A is widely expressed on liver metastases of patients with colorectal carcinoma. Therefore patients with completely resected liver metastases might be suitable candidates for adjuvant therapy with and-17-1A antibody since only a few of these lesions showed coexpression of complement resistance factors.

Klatskin tumors and Klatskin mimicking lesions of the biliary tree.

AIM: We report on the preoperative capability of imaging modalities and clinical assessment to differentiate between Klatskin tumors and Klatskin mimicking lesions of the biliary tree. Adenocarcinomas of the hepatic ducts (Klatskin tumors) mimic benign fibrosing cholangitis. Extensive resections carry a substantial risk but offer the only chance for cure in patients with a Klatskin tumor. METHODS: Thirty-three consecutive patients who underwent resection for suspicion of a malignant tumor of the hepatic hilum were reviewed. All patients underwent preoperative ultrasonography, computed tomography, ERCP and angiography. The patients were divided into a group of true Klatskin tumors and a group of benign Klatskin mimicking lesions. RESULTS: Twenty-seven of the resected specimens were malignant tumors, and six lesions showed only fibrosing cholangitis. Preoperative clinical presentation and imaging modalities were very similar between Klatskin tumors and fibrosing cholangitis. CONCLUSIONS: Management of obstruction of the liver hilum is dictated by the suspicion of malignancy. Complete removal of the tumor remains the therapeutic aim but clinical presentation and imaging modalities cannot help to differentiate between Klatskin tumors and Klatskin mimicking lesions prior to surgery.

Chronic pancreatitis--from losing heart to acting smart!

BACKGROUND: Chronic pancreatitis is a progressive disease which complications lead to increased morbidity and social and professional problems. MATERIAL AND METHODS: The authors analysed the current treatment options for chronic pancreatitis and compared it to the former treatment options. RESULTS: Historically surgical treatment options of chronic pancreatitis were associated with a high complication rate due to pancreatitic surgery. Furthermore, inadequate assessment of outcome lead to the treatment approach of watchful waiting and endoscopic interventions. Improving experiences with pancreatic surgery (high volume, combination of resection and drainage, e.g., duodenum-preserving pancreatic head resection) in some centers combined to modern evaluation methods revealed a low mortality (<5%), acceptable perioperative morbidity (15-20%), low reoperation rate (10%) and in 80% of the patients complete freedom of pain. CONCLUSION: A combination of drainage and resection tailored to the patient's need and performed early before developing endocrine insufficiency, seems to be the best medical care currently available to patients suffering from chronic pancreatitis.

Pancreas-sparing duodenectomy in duodenal pathology: indications and results.

BACKGROUND/AIMS: Pancreas sparing-duodenectomy is an organ-preserving surgical procedure suitable for patients with premalignant or early malignant lesions of the duodenum. The surgical technique is challenging due to the close anatomical relationship between the pancreas and the duodenum. METHODOLOGY: All patients undergoing pancreas-sparing duodenectomy for benign or premalignant condition of the duodenum operated on between 1998 and 2001 were analyzed prospectively. The surgical technique, the hospital course, and complications are described. RESULTS: A total of four patients underwent pancreas sparing-duodenectomy. Two patients experienced an uncomplicated postoperative course. In one patient, after completing the pancreas sparing-duodenectomy, the operation was converted to a Whipple procedure after the intraoperative diagnosis of malignant disease in the fresh frozen section. One patient had a complicated postoperative course with postoperative pancreatitis requiring several reoperations. At follow-up all patients are well, free of recurrence and alive. CONCLUSIONS: Pancreas-sparing duodenectomy is a challenging surgical technique and requires excellent knowledge of the anatomy. Intraoperative fresh-frozen section is mandatory to exclude malignant disease. If performed for appropriate indications, pancreas sparing-duodenectomy offers the potential to preserve the anatomical gastrointestinal passage and the integrity of the pancreas.

Heterotopic pancreas--clinical presentation and pathology with review of the literature.

BACKGROUND/AIMS: Heterotopic pancreas is usually a silent gastrointestinal malformation, but it may become clinically evident when complicated by chronic inflammation or by growth. METHODOLOGY: We report on eleven cases of heterotopic pancreatic tissue. The cases were selected from the records of our Surgical Department and Institute of Pathology. The literature about heterotopic pancreas is reviewed. RESULTS: Nausea and vomiting (27%), epigastric pain (27%), ulceration (27%) and weight loss (18%) were the three most frequent symptoms and signs. The lesions were diagnosed as gastrointestinal tumor or ulcer by gastroduodenoscopy (36%). The other patients were diagnosed during surgery (64%). Definitive diagnosis was only achievable by pathology. Heterotopic pancreas was the reason for surgery in 36% of the cases, in another 45% diagnosis was incidental during surgery and in 18% the diagnosis was established endoscopically and surgery was not necessary. CONCLUSIONS: The diagnosis of heterotopic pancreas is rarely established, most cases remain clinically silent. In symptomatic patients diagnosis should to be secured histologically to exclude malignant disease.

[Is the stapled suture in visceral surgery still justified? A prospective controlled, randomized study of cost effectiveness of manual and stapler suture]. / Ist die Klammernaht in der Visceralchirurgie noch gerechtfertigt? Eine prospektiv kontrollierte, randomisierte Studie zur Kosteneffektivität von Hand- und Klammernaht.

Hospitals are facing increasing economic pressure. It therefore seems necessary to evaluate the efficiency and effectiveness of medical or surgical interventions. In this study 324 anastomoses (167 stapled and 157 hand-sewn) were performed after randomization during 200 elective operations [20.5% gastrectomies, 14% gastric resections (Billroth II), 15% Whipple's procedures, 4% segmental colonic resections, 18% right-sided hemicolectomies, 4% left-sided hemicolectomies, 22% sigmoid- or anterior rectal resections, 2.5% total colectomies with pouch-anal anastomoses] in 200 patients. Postoperative motility (time to full oral diet, time with naso-gastric tube) and hospitalization were comparable in both groups. Anastomotic insufficiency was observed in 2.1% of all patients, five after stapled and two after hand-sewn anastomoses. Hospital mortality was 1.5%. All stapled anastomoses were performed significantly (P < 0.001) faster. However, the cost of material for these anastomoses was significantly (P < 0.001) higher, resulting in significantly higher total costs for reconstruction. The time saving for the reconstruction did not influence the total operative time (except for stapled gastrectomy). Therefore, all operations with stapled reconstruction were more expensive than those with sutured reconstruction. The difference was significant for the gastrectomy (P < 0.01), colonic resection (P < 0.01) and sigmoid and rectal resection (P < 0.001) groups. Stapled and sutured anastomoses are equally effective. Stapled anastomoses are not efficient, however, and should be reserved for individual indications.

Multi-visceral resection for locally advanced gastric cancer.

Fifty-three of sixty-four patients who underwent gastrectomy for gastric carcinoma presented with advanced gastric cancer. 8 patients underwent palliative gastrectomy. In 17 patients gastrectomy and lymphadenectomy was performed. In 28 patients with locally advanced gastric carcinoma, extended resection was performed. Patients who underwent splenectomy were only included if tumorous adherence to the spleen was present. Hospital mortality and morbidity were 3.6% and 25% in extended resection and 5.9% and 18% in gastrectomy and lymphadenectomy alone. R0 resection was performed in 26/28 and in 16/17 patients, respectively. In R0 (complete) resections the mean one and two-year-survival rates were 64% and 44% in extended resection, and 67% and 47% in gastrectomy and lymphadenectomy. In patients (11) with residual tumour (R1/R2) mean one and two-year-survival rates were 27% and 0%, respectively. If complete resection (R0) is achieved, extended resection for locally advanced gastric carcinoma provides survival time, which is comparable, stage for stage, with survival rates observed after R0 resection for cancer limited to the stomach.

Frequency and prognostic significance of occult tumor cells in lymph nodes in patients with adenocarcinoma of the papilla of Vater.

BACKGROUND: Occurrence of tumor relapse is frequent in patients with carcinoma of the papilla of Vater despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to identify minimal amounts of tumor cells disseminated to secondary organs, which might be precursors of subsequent metastatic relapse. The aim of the study was to assess the frequency and prognostic impact of minimal tumor cell spread in lymph nodes classified as 'tumor-free' in routine histopathologic evaluation. MATERIALS AND METHODS: A total of 41 'tumor-free' lymph nodes from 23 patients with adenocarcinoma of the papilla of Vater who underwent curative tumor resection (R0) were examined by immunohistochemistry with the monoclonal anti-EpCAM antibody Ber-EP4 for minimal disseminated tumor cells. RESULTS: Twelve (29.3%) of the 41 'tumor-free' lymph nodes obtained from 9 (39.1%) of the 23 patients displayed EpCAM-positive cells. Kaplan-Meier survival analysis revealed that patients with EpCAM-positive cells in lymph showed a clearly reduced relapse-free and overall survival compared with patients without such cells. However, these differences were not statistically significant (p = 0.13 for relapse-free survival, p = 0.11 for overall survival). DISCUSSION: Immunohistochemical assessment may refine the staging of resected lymph nodes in patients with carcinoma of the papilla of Vater. However, the presence of minimal disseminated tumor cells in lymph nodes had no significant impact on the prognosis in these patients.

[Significance of immunohistochemically detectable tumor cells in lymph nodes]. / Die Rolle von immunhistochemisch detektierbaren Tumorzellen in Lymphknoten.

Distant metastasis is mainly determined by the tumor biology, whereas local relapse after complete (R0) resection of solid tumors is largely determined by the effectiveness of the surgeon. The detection of a minimal tumor cell spread in lymph nodes became recently possible by the introduction of sensitive immunohistochemical and molecular methods and is increasingly considered as clinically relevant because of its independent prognostic significance. Furthermore, these tumor cells, compared to solid metastases, are appropriate targets for intravenously applied anti-cancer therapeutics because they are easily accessible for macromolecules and immunologic effector cells. Double staining analyses have demonstrated that the majority of these tumor cells stay in a non proliferating phase of the cell cycle. This phenomenon could be an explanation for the extended latency period ("dormancy") between their primary diagnosis and the occurrence of a subsequent metastatic relapse, and it may furthermore explain the failure of anti-proliferative chemotherapy. Consequently, adjuvant therapeutic strategies, which are directed also against these "dormant" tumor cells are of increasing importance after radical local tumor resection (R0).