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.

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.

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.

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.

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.

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.

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.

Characterization of disseminated tumor cells.

The most prominent secondary organs screened for the presence of occult disseminated tumor cells are regional lymph nodes and bone marrow. The current data suggest that micrometastatic cells represent a selected population of dormant cancer cells, which still express a considerable degree of heterogeneity. The analysis of micrometastatic cells will open a new avenue to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones may help in understanding the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge on the biological characteristics of micrometastatic cancer cells in bone marrow and lymph nodes of cancer patients.

Minimal residual disease in non-small-cell lung cancer.

Early metastatic relapse after complete resection (R0) of apparently localized primary tumors is frequent in patients with non-small-cell lung cancer (NSCLC). This observation indicates an occult tumor cell dissemination already present at the time of primary surgery but undetectable by current tumor staging methods. During the past 10 years ultrasensitive immunohisto-/-cytochemical and molecular assays have been developed that are able to detect single tumor cells and small tumor cell clusters present in lymph nodes classified as tumor-free by conventional histopathologic analysis, bone marrow, or peripheral blood. Here we present an overview of the incidence and prognostic impact of such early disseminated tumor cells in patients with NSCLC.

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.

Molecular profiling of micrometastatic cancer cells.

Malignant tumors of epithelial tissue are the most common form of cancer and are responsible for the majority of cancer-related deaths in Western industrialized countries. As a result of progress in surgical treatment of these tumors, lethality is linked increasingly to early metastasis, which is generally occult at the time of primary diagnosis. For this reason, the direct identification of minimal residual cancer is of particular importance. The studies described below demonstrate the utility of immunocytochemical and molecular analysis in the diagnosis and characterization of minimal residual cancer. These methods not only can identify this critical stage of tumor progression but also may facilitate the development of therapies to prevent manifest metastasis.

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.

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.

[Molecular markers in colorectal carcinoma]. / Molekulare Marker beim kolorektalen Karzinom.

Due to introduction of immunohistochemical, cytochemical, molecular and cytogenetic methods in oncologic research, understanding of genetic basis in tumor genesis is improving. Furthermore, different studies gave evidence for prognostic relevance of some (cyto)genetic alterations or residual tumor cells in lymph nodes or bone marrow, respectively. More prospective, large studies are needed, before applying these findings in clinical routine, and the methods have to be standardized.

[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).

The initial approach to anorectal abscesses: fistulotomy is safe and reduces the chance of recurrences.

BACKGROUND/AIMS: Anorectal abscesses are most frequently based on a coexistent fistula in ano. Whether these should be searched for and excised initially or not remains controversial. Our aim was to determine which approach has less recurrences and carries a lower risk of continence disorders. METHODS: 158 patients with an anorectal abscess or anal fistula were identified in our institution over a period of 75 consecutive months. The records and follow-up questionnaires of 131 patients were evaluable. The mean follow-up period was 40 (range 3-78) months. RESULTS: When fistulotomy was performed at the time of draining the abscess, the recurrence rate could be reduced, in comparison to incision and drainage alone, from 34 to 4% (p = 0.007). In the group of patients undergoing surgery for a recurrence, the recurrence rate could even be reduced from 67 to 0% (p = 0.03) by simultaneous fistulotomy. A total of 4 of the 131 patients (3%) developed incontinence of liquid stool and flatus, but no incontinence of solid stool occurred. Incontinence did only occur after recurrent disease. CONCLUSIONS: The number of recurrences requiring surgery can be significantly reduced by initial fistulotomy. The risk to develop incontinence increases with recurrent anorectal disease, not with careful fistulotomy.