Hintergrund: Tumorprogression ist durch eine Störung des Gleichgewichts zwischen Zellproliferation und Apoptose gekennzeichnet. Das proapoptotische BAX-Protein scheint in diesem Kontext eine Schlüsselrolle zu spielen. Zielsetzung: Beim Rektumkarzinom sollte die Bedeutung der BAX-Proteinexpression in Korrelation zu klinisch-pathologischen Variablen, klinischen Resultaten und im Hinblick auf den p53/BAX-Signalweg überprüft werden.

This study examined whether the apoptosis-related protein, BAX, or the microsatellite-instability phenotype provide prognostic information in patients with resected colon cancer.

Thrombosis of the left subclavian vein occurred in a 44-year-old man. It was found to be caused by an atypical thymus carcinoid of the anterior mediastinum without carcinoid syndrome. Primary resection was not possible, but it was removed after three cycles of neoadjuvant chemotherapy with doxorubicin, cisplatin, vincristine and cyclophosphamide. Increased concentrations of alkaline phosphatase and parathormone were then noted. Subtotal parathyroidectomy revealed hyperplastic parathyroids. A gastrinoma was suspected from a history of peptic ulcer for many years which had persisted despite a Billroth II gastric resection 10 years ago. Serum gastrin, analysis of gastric secretion and a secretin-stimulating test confirmed the diagnosis. Recurrent episodes of weakness and syncope, in the presence of low blood sugar levels and a positive C-peptide suppression test, were interpreted as due to an insulinoma. There was no evidence of increased hypophyseal or adrenal function. Finally, in the absence of a family history, multiple endocrine neoplasia type 1 (MEN 1) was diagnosed with co-existing primary hyperparathyroidism, gastrinoma, insulinoma and thymus carcinoid. Somatostatin-receptor scintigraphy provided localization of the MEN 1 with enrichment in the thorax and abdomen.

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.

Different histogenetic pathways have been suggested between ulcerative colitis (UC)-associated neoplasia and sporadic colorectal neoplasia. Little is known about the cytokeratin (CK) and mucin expression in UC-associated neoplasms. To clarify the characteristics of UC-associated colorectal carcinogenesis, we examined the immunohistochemical expression of CK7, CK20, MUC2, MUC5AC and MUC6 in 90 colorectal neoplasms, including 22 UC-associated adenocarcinomas (colitic cancer; CC), ten high-grade dysplasias (HGD) in UC, nine low-grade dysplasias (LGD) in UC, 24 sporadic tubular adenomas (TA) and 25 adenocarcinomas (AC). CK7 was positive in most of UC-associated neoplasms: 59% of CC cases, 80% of HGD and 89% of LGD, respectively, whereas, in non-UC associated neoplasia, 21% of TA and 12% of AC. The frequency of MUC6 expression in UC-associated neoplasia was 32% in CC, 30% in HGD and 44% in LGD, respectively, whereas, in non-UC associated neoplasia, 4.2% in TA and 0% in AC. MUC5AC expression in UC-associated neoplasia was detectable in 73% of CC, 90% of HGD and 89% of LGD, respectively; in non-UC associated neoplasia 67% in AC and 20% in TA. There were obvious differences in the expression of CK7 and MUC6 between UC-associated neoplasms and sporadic tumors. The incidence of MUC5AC expression in UC-associated neoplasms was also higher than sporadic tumors. These results suggest that gastric-type mucins play an important role in the initial step of CC-tumorigenesis, and CK7 and gastric-type mucins may be useful in the differential diagnosis between UC-associated neoplasms and sporadic ones.

Functional inactivation of the />/r/%f"'' gene has been reported to be involved in the development of a variety of human malignancies. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of pI6'^K4a gene inactivation in sporadic colon cancer. This study sought to identify the significance of pI6INK4" methylation in the colonie epithelium of patients with long-standing ulcerative colitis. A total of 89 tissue samples was retrieved from three colectomy specimens. A methylation-specific PCR assay was applied. The methylation status was compared with his tolÃ3gica) findings and the flow cytometrically determined DNA index. Hypermethylation of the pl6INK4a promoter region was detected in 12.7% of samples that were negative for dysplasia. However, 70.0% of samples with dysplasia and all of the samples with carcinomatous lesions revealed hypermethylation. Hypermethylation of the pì6lfiK4agene promoter was detected already in 40% of specimens with lesions indefinite for dysplasia and in 13.7% of samples with exclusively diploid cell populations. These results suggest that hypermethylation of thep/o'**'*1 promoter region is a frequent and early occurring event during the process of neoplastic pro gression in ulcerative colitis.

Since 1985, when gastric-type well-differentiated adenocarcinomas were demonstrated in hyperplastic polyps of the stomach, we have studied phenotypic expression in gastrointestinal epithelial lesions. The recent discovery of MUC genes coding core proteins of mucin has improved research on the phenotypic expression of gastrointestinal neoplasms. The disease entity of gastric-type well-differentiated adenocarcinoma has recently been accepted, especially in Japan and Europe. This entity has often become a clinicopathological subject of discussion, because its biological behavior is possibly highly malignant, in spite of the difficulty in making endoscopic and histopathological diagnoses. Even under these circumstances, the term "gastric adenoma" usually means flat adenoma of the intestinal type. Gastric-type adenomas have been regarded as exceptional until recently. Although gastric-type adenomas could theoretically be classified into foveolar type and pyloric-gland type, foveolar-type adenoma is, in practice, difficult to distinguish from gastric-foveolar-type adenocarcinoma. In 2003, we first reported systematic clinicopathological analyses of pyloric gland adenoma, demonstrating its unstable and precancerous nature. In this article, we review and discuss the clinicopathological and molecular pathological aspects of gastric-type well-differentiated adenocarcinomas and pyloric gland adenomas, mainly based on our published and unpublished data.

The term "pyloric gland adenoma" reflects its etiogenesis from deep mucoid glands in the stomach. The diagnosis can be confirmed by immunohistochemistry. Typically, pyloric gland adenomas are strongly positive for Mucin 6 (deep mucoid gastric glands). These lesions express Mucin 6 over the whole lesion up to the surface often only with a small layer of columnar epithelium expressing Apomucin 5AC. The amount of mucin 5AC which is expressed on normal within the apical foveolar epithelium might vary from case to case. Combination or transdifferentiation with ordinary tubular (intestinal differentiation) adenoma can be observed. The gastric corpus mucosa of elderly female patients with autoimmune gastritis is highly affected. The frequency of pyloric gland adenoma is given in the literature being 2.7% of all gastric polyps. Therefore pyloric gland adenomas are not that rare that one might assume. Only a few publications are available which makes one think that these lesions are frequently misinterpreted. Pyloric gland adenomas can arise in gastric heterotopia and gastric metaplasia in the whole gastrointestinal tract. The clinical significance is given by a 30% rate of malignant transformation. These cases represent for the most well differentiated early adenocarcinomas which are known to have an excellent prognosis after complete polypectomy and limitation to the mucosal layer.

Pyloric gland adenoma is a recently described and very rare entity. The occurrence of adenoma is very unusual in Barrett’s epithelium of the esophagus. We report a case of esophageal polyp showing the features of pyloric gland adenoma, which was surrounded by so-called specialized columnar epithelium. Immunohistochemically, most tumor glands were strongly positive for MUC6, except in the superficial layer. MUC5AC was positive in almost all tumor cells, but MUC2 and CD10 were negative in the tumor. MIB-1-positive proliferating cells were distributed throughout the tumor. Microdissection and comparative genomic hybridization analyses revealed losses on 2p24–25.2, 2q14.1-ter, 5q31.3–32, 6q23–24, 8q23–24.2, 11q22.3–24 and 18q21.1–22. This is the first case of pyloric gland adenoma found to arise in Barrett’s epithelium of the esophagus, showing its unstable and precancerous nature.

For classification of perigastric lymph node metastases in gastric cancer, only topographical aspects are taken into consideration at present. As a numerical classification for lymph node metastases was proposed recently, the current problem is that of determining the number of dissectable perigastric lymph nodes and also assessing the quality of nodal dissection. The perigastric lymph nodes of 10 adults without gastric disease were therefore evaluated microscopically by a serial section technique. On average a total of 36.2 +/- 15.2 perigastric lymph nodes were found, e.g. 14.9 +/- 14.1 lymph nodes on the greater and 7.4 +/- 4.8 on the lesser curvature. These figures are similar to those in fetuses and newborn infants, but they exceed the numbers of perigastric lymph nodes reported in the literature for adults with or without gastric cancer. This difference could be attributable to our use of the serial section technique, because the so-called "micro-lymph nodes" with a diameter of less than 1.5 mm are consequently included in this study. Our results support the assumption, that pathologic processes do not result in any real increase of regional lymph nodes, but in an activation and enlargement of fetal lymph node reserve.

In a 46-year-old man, a pedunculated rectal polyp measuring 3.0x3.0x2.0 cm was diagnosed histologically as a pyloric gland-type adenoma arising in heterotopic gastric corpus mucosa. The luminal site was covered by glands of the gastric foveolar type, displaying focal marked proliferation interpreted as low-grade intraepithelial neoplasia. A bidirectional gastric differentiation was found: most lower glandular structures showed positivity for the deep gastric mucin core protein Muc 6 and superficial positivity for gastric foveolar epithelium mucin core protein Muc 5AC. Pyloric gland adenoma has so far been described in one larger series only and a few case reports of the stomach, gallbladder, pancreatic duct and within heterotopic gastric corpus mucosa of the duodenal bulb. The present case report is the first case of a pyloric gland-type adenoma within a gastric corpus heterotopia of the rectal mucosa.

9587 Background: To analyze the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in stage III colon cancer treated by adjuvant chemotherapy. Methods: 188 patients with UICC stage III colon carcinoma who had received a median of 12 cycles of 5-fluorouracil (FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. Protein expression patterns of BAX, Bcl-2, and p53 were analyzed by immunohistochemistry on sections of resected tumor samples. Results: BAX, Bcl-2 and p53 expression were high or positive in 59%, 70% and 50% of 188 cases, respectively. BAX was correlated with a higher degree of differentiation (p=0.01), whereas Bcl-2 was associated with left-sided tumors (p=0.03). In contrast to either p53 or Bcl-2, low BAX, advanced N-category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free (DFS) (p=0.0005, p=0.001, p=0.005, and p=0.01, respectively) and disease-specific overall survival (OS) (p=0.002, p=0.0001, p=0.003, and p=0.02, respectively). Besides N category and treatment arm, BAX was an independent variable related to both OS and DFS (p=0.003 and p=0.001, respectively). The p53 -/BAX high pattern in comparison with the p53 +/BAX high subgroup confered an significantly improved DFS (p=0.03), and an marginally improved OS (p = 0.07). Conclusions: BAX 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. No significant financial relationships to disclose.

Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.

Hintergrund: Eine Inaktivierung des auf Chromosom 9p21 lokalisierten Tumorsuppressorgens p16INK4a korreliert bei zahlreichen Tumoren mit einer ungünstigen Prognose. Ein wesentlicher Inaktivierungsmechanismus umfasst die Methylierung der Promoter-Region (PM) von p16. Ziel dieser Studie war es deshalb, beim Rektumkarzinom die prognostische Bedeutung von p16 PM zu überprüfen. Methoden: Wir untersuchten 91 Pat. mit präoperativ bestrahlten Rektumkarzinomen (UICC-Stadien I-III). Alle Pat. wurden im Anschluss an eine neoadjuvante Radiotherapie (kumulative Strahlendosis: 30 Gray) in derselben Einrichtung mit kurativer Intention operiert. Die Patienten wurden im Median 71.5 Monate nachbeobachtet. Der p16 PM-Status wurde mittels eines methylierungsspezifischen PCR-Assays analysiert. Ergebnisse: In 9/91 Proben (10%) war eine p16 PM detektierbar. Die univariate Analyse zeigte bis auf das Geschlecht keine Korrelation zwischen Methylierungsstatus und den klinisch-pathologischen Variablen wie Alter, Tumorlokalisation, TNM-Stadium, oder dem Differenzierungsgrad. In der univariaten Analyse ergab sich zwischen dem Vorliegen einer p16 PM und dem Auftreten eines Tumorrezidivs eine grenzwertig signifikante Korrelation (p=0.068). Überdies korrespondierte der Nachweis einer p16 PM statistisch signifikant negativ mit der Gesamtüberlebenszeit (p=0.02). In der Multivarianzanalyse erwies sich die Detektion einer p16 PM sowohl für die krankheitsfreie Zeit (p=0.02) als auch für die Gesamtüberlebenszeit (p=0.008) als ein unabhängiger negativer Faktor. Die Identifikation einer p16 PM war gegenüber dem Vorliegen eines fortgeschrittenen TNM-Stadiums der stärkere negative prädiktive Parameter (p=0.008 versus p=0.01; hazard ratio: 3.5 versus 2.5). Schlussfolgerungen: Unsere Daten suggerieren, dass beim präoperativ bestrahlten Rektumkarzinom das Vorhandensein einer p16 PM einen signifikanten negativen prädiktiven Faktor darstellt. Dies ist kohärent mit präklinischen Daten, die aufzeigen, dass intaktem p16 eine positive Bedeutung bei der Induktion von Apoptose zukommt. Studie gefördert durch die Deutsche Krebshilfe (70–2601). B.K. gefördert vom Interdiziplinären Zentrum für klinische Forschung der Universität Tübingen (IZKF IIIB2) u. dem Kompetenznetz CED(BMBF/DLR).

Einleitung: Der INK4a/ARF-Locus umfasst zwei verschiedene Tumorsuppressorgene, p16INK4a und p14ARF, die beide unabhängig voneinander in wesentliche Signalwege zur Zellzyklus-Kontrolle involviert sind, den RB-Signalweg (p16) oder den p53-Signalweg (p14). Eine funktionelle Inaktivierung des p53/p14ARF/MDM2- und/oder des RB/p16INK4a-Signalwegs findet sich häufig in Tumoren. Die Methylierung der Promoter-Region (PM) scheint hierbei ein bedeutender Mechanismus der Inaktivierung sowohl von p14 als auch p16 zu sein und wurde von uns deshalb beim Kolonkarzinom in Korrelation zu klinisch-pathologischen Variablen und im Hinblick auf klinische Resultate evaluiert. Material und Methoden: Wir untersuchten 291 Patienten (114 M, 177 F) mit Kolonkarzinomen (UICC Stadien I-III), die alle in derselben Klinik operiert worden waren. Kein Patient erhielt eine adjuvante Therapie. Die mediane Nachbeobachtungszeit betrug 48 Monate. Der PM Status von p14 und p16 wurde mittels eines methylierungs-spezifischen PCR-Protokolls analysiert. Ergebnisse: Eine p14 PM bzw. p16 PM konnte bei 34% bzw. 39% der Patienten detektiert werden. Im Gegensatz zu der p16 PM fand sich für die p14 PM eine positive Korrelation zum weiblichen Geschlecht (p=0.006) und einer rechtsseitigen Tumorlokalisation (proximal der linken Flexur) (p=0.003). Überdies korrelierten weder p14 PM noch p16 PM mit der krankheitsfreien- (p=0.39 bzw. p=0.59) oder der Gesamtüberlebenszeit (p=0.94 bzw. p=0.68)(univariate Analyse). Auch die Multivarianzanalyse zeigte diesbezüglich keine signifikanten Werte. Zusammenfassung: Unsere Daten zeigen, dass eine p14ARF PM oder eine p16INK4a PM häufige Ereignisse beim Kolonkarzinom der UICC Stadien I-III darstellen. Überdies scheint eine p14 PM analog zu anderen genetischen Alterationen, wie z.B. der Mikrosatelliteninstabilität, signifikant mit einer proximalen Tumorlokalisation zu korrelieren. Allerdings scheinen die p14 PM und die p16 PM gemäß unseren Resultaten keine prädiktive Bedeutung beim kurativ resezierten Kolonkarzinom im Stadium I-III zu besitzen. Studie gefördert durch die Deutsche Krebshilfe (70–2601). B.K. gefördert vom Interdiziplinären Zentrum für klinische Forschung der Universität Tübingen (IZKF IIIB2) u. dem Kompetenznetz CED (BMBF/DLR).

In the Dukes' B and C stages of colorectal carcinoma there are considerable variations in the observed courses of the disease. Since post-operative chemotherapy in patients with Dukes' C (node-positive) colon carcinoma has been demonstrated to be effective in improving overall-survival, a more exact prognosis assessment gains additional significance and therapeutic relevance.

BACKGROUND:Pyloric gland adenoma is a rarely described neoplasia of the gastric mucosa. Recent publications have shown that similar lesions are also found in the gallbladder, the main pancreatic duct, the duodenum and the cervix of the uterus. Apart from case reports, few clinical data are available on these patients. We therefore conducted a search of the archived material collected between 1990 and 2000 for more clinical data on patients with this rare lesion.PATIENTS AND METHODS:Between 1990 and 2000, 90 patients were diagnosed as having a pyloric gland adenoma in the stomach (77 patients), duodenal bulb (7 patients), duodenum (1 patient), bile duct (3 patients) or gallbladder (2 patients).RESULTS:Pyloric gland adenomas account for 2.7% of all gastric polyps and occur predominantly in old age (73+/-12.8 years), more frequently in women (75%) than in men. The predilection site in the stomach is the corpus mucosa (64%) and they are often found in patients suffering from autoimmune gastritis (36%). At the time of diagnosis, pyloric gland adenomas measure 16.1+/-9.1 mm in size. In 30% of gastric pyloric adenomas, transition to well-differentiated adenocarcinoma has been noted.DISCUSSION:In our material, pyloric gland adenoma is the third most common neoplastic polypoid lesion in the stomach. Since a search through the literature revealed only a few case reports on this lesion, it is possible that for some reason this lesion might be diagnosed more often than reported.CONCLUSION:Our study revealed that 30% of the gastric pyloric gland adenomas showed continuous transition to well-differentiated adenocarcinoma at the time of the initial diagnosis. This underscores the malignant potential of the lesion, and the need for polypectomy.