Uroepithelial and kidney carcinoma in Lynch syndrome.

Increased risk for urological tumors has been observed in mutation carriers with Lynch syndrome (LS). In this study, we evaluated the clinical features of uroepithelial (bladder and ureter) and kidney cancers in 974 Finnish mutation carriers. Altogether 30 patients had a total of 34 urological tumors: 12 ureter, 12 bladder, and 10 kidney cancers. Urological tumor was the only tumor in 9 (30 %) patients, and metachronous other tumor occurred in 21 (70 %). The occurrence of uroepithelial cancers was significantly higher in MSH2 mutation carriers (6 %; 95 % CI, 2.7-11.0) than in MLH1 carriers (2 %; 95 % CI, 1.1-3.2) and MSH6 mutation carriers (0 %) (p = 0.014). The mean ages of patients at the time of diagnosis were: bladder cancer, 57 years; ureter cancer, 58 years; and kidney cancer, 64 years. Overall 5-year survival rates were 70 % (95 % CI, 0.32-0.89) in bladder cancer, 81 % (95 % CI, 0.45-0.95) in ureter cancer, and 75 % (95 % CI, 0.31-0.93) in kidney cancer. Cancer-specific 5-year survival rates were 70 % (95 % CI, 0.32-0.89) in bladder cancer, 91 % (95 % CI, 0.51-0.98) in ureter cancer, and 100 % in kidney cancer. In conclusion, early age of onset was observed in patients with uroepithelial tumors, but not in patients with kidney cancer. The frequency of uroepithelial tumors was significantly higher in MSH2 mutation carriers than in MLH1 carriers. Further studies with larger numbers of patients, however, are needed to evaluate the potential benefit of surveillance of urological tumors in LS.

Quantification of angiogenesis by the Chalkley method and its prognostic significance in epithelial ovarian cancer.

AIM: The aim of the present study was to clarify prognostic role of angiogenesis in epithelial ovarian cancer. METHODS: Quantification of angiogenesis was performed by the Chalkley method after immunostaining of 175 epithelial ovarian cancer specimens with an antibody against CD34. RESULTS: The Chalkley count was categorised into two groups according to the median value: low <8 or high > or =8. The low Chalkley count correlated significantly with serous and clear cell histological subtype of the tumour (p<0.0005), whereas there existed no association with FIGO (International Federation of Gynecology and Obstetrics) stage, histological grade, presence of primary residual tumour, age at diagnosis, or chemotherapy response. In univariate analysis, the high Chalkley count predicted poor overall survival in the subgroup of patients with FIGO stages III-IV tumours (p=0.007) but not in the entire study cohort. However, in multivariate analysis, the Chalkley count was found to be an independent predictor of death from ovarian cancer in the entire study cohort (p=0.044, RR=1.50, 95% CI 1.01-2.21) as well as in the subgroup of FIGO stages III-IV tumours (p=0.046, RR=1.58, 95% CI 1.01-2.46) together with the presence of primary residual tumour (p<0.0005, RR=5.10, 95% CI 3.02-8.62, and p=0.002, RR=4.28, 95% CI 1.34-13.73, respectively). CONCLUSIONS: The Chalkley count seems to be suitable for evaluation of angiogenesis and to have prognostic significance in ovarian cancer.

Frequent gene dosage alterations in stromal cells of epithelial ovarian carcinomas.

Stromal cells are an active and integral part of epithelial neoplasms. We have previously observed allelic imbalance on chromosome 3p21 in both stromal and epithelial cells of ovarian tumors. This study was designed to explore gene dosage alterations throughout human chromosomes from stromal and epithelial cells of epithelial ovarian carcinomas. Thirteen stromal and 24 epithelial samples, microdissected from epithelial ovarian carcinomas, were analyzed using multiplex ligation-dependent probe amplification technique. Analysis covered 110 cancer related genes. Frequent genetic alterations were detected both in the stroma and epithelium of ovarian carcinomas. The mean number of altered genes per tumor was 10.8 in stroma and 23.6 in epithelium. In the stroma, the mean number of gains was 6.6 and of losses 4.2 and in the epithelium 13.7 and 9.9. The high number of changes associated with advanced tumor stage (p = 0.035) and death due to ovarian cancer (p = 0.032). The most frequent alteration was the deletion of the deleted in colorectal carcinoma (DCC) on chromosome 18q21.3 in 62% of samples. Loss of DCC was related to endometrioid subtype (p = 0.033). Large chromosomal aberrations were detected on the basis of alterations in adjacent genes. Most importantly, 38 genes showed similar genetic alterations (gain-gain or loss-loss) in stromal and epithelial compartments of 11 tumor pairs. Thus, frequent genetic alterations in stromal cells of epithelial ovarian carcinomas resembled those of malignant epithelial cells and may indicate a common precursor cell type. Epithelial-mesenchymal transition may generate transformed cancer cells and modify the tumor microenvironment with distinct properties.

Evaluation of the diagnostic accuracy of gastroscopy to detect gastric tumours: clinicopathological features and prognosis of patients with gastric cancer missed on endoscopy.

OBJECTIVES: Some gastric cancers are missed during diagnostic gastroscopy, but data are sparse on the clinical characteristics of patients with missed gastric cancers and on the accuracy of gastroscopy for detecting these tumours. We evaluated the number, clinicopathological characteristics, and survival of patients with missed gastric cancers, and the sensitivity and specificity of gastroscopy to detect these tumours. METHODS: Data on gastric cancers detected in 1996-2001 in a single hospital referral area were obtained from the National Cancer Registry. Patient files were examined to identify those who underwent gastroscopy less than 3.5 years before a cancer diagnosis. RESULTS: Of the 284 gastric cancer patients, 13 (4.6%) had undergone gastroscopy in the previous 3.5 years; their mean age was 72.4 years at the time of the first gastroscopy. The median delay in cancer diagnosis was 11.5 months. Histologically, all patients had gastric carcinoma. The sensitivity and specificity of gastroscopy for diagnosing gastric cancer were 0.93 and 1.00, respectively. Among the deceased patients, no difference was observed in the survival of cases with non-missed (n = 191) and missed (n = 10) carcinoma: 9.4 versus 7.3 months (P = 0.15). CONCLUSION: A small proportion of gastric carcinomas are missed on gastroscopy, causing a significant delay in diagnosis. However, the prognoses of patients with missed and non-missed gastric carcinoma were equally poor.

NOD2 3020insC alone is not sufficient for colorectal cancer predisposition.

Mutations in NOD2 have been shown to associate with increased susceptibility to Crohn's disease. A recent Polish study linked the truncating NOD2 3020insC variant with an increased risk of colorectal cancer (CRC) at an older age (>50 years) of disease onset, with an odds ratio of 2.23. We studied the possible contribution of the 3020insC variant to CRC risk in a series of 1,042 Finnish population-based patients from which 926 samples were successfully analyzed and in 348 anonymous cancer-free controls. The frequency of the 3020insC mutation was 3.7% in both CRC patients (34 of 926, including 1 homozygote) and cancer-free controls (13 of 348; odds ratio, 0.98; confidence interval, 0.51-1.88). Contrary to the Polish study, there was no significant difference in the mutation rates between CRC patients > 50 years of age (25 of 576; 4.3%) and controls in the present series. We studied respective tumor tissue DNAs of all patients displaying heterozygous 3020insC changes for loss of heterozygosity. Loss of heterozygosity at NOD2 was observed in only 1 of the 33 CRC samples. Our results suggest that NOD2 3020insC alone does not contribute to CRC risk. If this variant predisposes to CRC, additional factors not present in the Finnish population need to be involved.

Marked allelic imbalance on chromosome 5q31 does not explain alpha-catenin expression in epithelial ovarian cancer.

OBJECTIVE: Human alpha-catenin gene (CTNNA1) on chromosome 5q31 is aberrantly expressed in various types of cancer including epithelial ovarian tumors. Allelic imbalance on this region has also been described in several malignant diseases. In the present work, the role of CTNNA1 as a candidate tumor suppressor gene was studied by comparing protein expression with allelic imbalance in human epithelial ovarian tumors. METHODS: Alpha-catenin protein expression was determined from two areas of 41 tumors, and tissues from these areas were microdissected. After DNA extraction, AI analysis was carried out with eight microsatellite markers. RESULTS: Altogether, 93% of the tumors (38 of 41) showed allelic imbalance at one or more loci. Two distinct common regions of allelic imbalance were identified, one comprising markers D5S2002 and D5S1995 and the other markers D5S393 and D5S476. Loss of the CTNNA1 gene did not appear to be involved in down-regulation of alpha-catenin in ovarian tumors, since allelic imbalance with a variety of markers, including CTNNA1 associated marker D5S476, was found in tumor samples independently of alpha-catenin expression. Furthermore, allelic imbalance analyses of two different samples from the same tumor revealed genetic heterogeneity. CONCLUSIONS: High allelic imbalance frequency indicates that chromosomal region 5q31 is functionally important in epithelial ovarian cancer. Allelic imbalance occurs at two distinct regions of which one includes the CTNNA1 gene. However, this gene is likely to be inactivated by mechanisms other than allelic imbalance. In addition, genetic heterogeneity observed in these tumors demonstrates the multiclonal nature of epithelial ovarian tumors.

Genetic alterations in the peritumoral stromal cells of malignant and borderline epithelial ovarian tumors as indicated by allelic imbalance on chromosome 3p.

Stromal accumulation of hyaluronan in epithelial ovarian cancers is an independent predictor of tumor spreading and unfavorable outcome of the disease. We started to screen for chromosomal causes of this accumulation by studying deletions in 3p21.3, a region harboring 3 hyaluronidase genes (HYAL1-3) among other potentially important tumor suppressors. Using 6 microsatellite markers from this region, allelic imbalance was found in 60-87% of the informative tumor cells microdissected from histologic sections of 58 patients with epithelial ovarian cancer. However, adjacent stromal cells originally intended as controls showed allelic imbalance at a frequency almost as high as the tumor cells (52-80%). A further laser capture microdissection on 10 borderline tumors also showed a high rate of allelic imbalance, both in the epithelial and stromal cells, but with a pattern slightly different from cancers. Allelic imbalance in the tumor epithelium or stroma was not correlated with the accumulation of hyaluronan or clinicopathologic parameters, including tumor stage and grade. The results suggest that factors other than inactivation of the HYAL1-3 genes are responsible for hyaluronan accumulation in epithelial ovarian tumors. Moreover, the results indicate that the stromal cells of the epithelial ovarian cancers not only respond to the signals from malignant epithelium but also have themselves undergone genetic alterations in markers partly identical to those in the cancer epithelial cells and may actively contribute to the development of the tumor from its early stages to the late determinants of patient mortality.

Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Her-2/neu oncogene amplification and protein over-expression in interval and screen-detected breast cancers.

BACKGROUND: Studies of Her-2/neu protein expression in interval and screen-detected breast cancers have been conflicting. Therefore we assessed the Her-2/neu amplification status in these groups by using in situ hybridization. PATIENTS AND METHODS: The Her-2/neu oncogene amplification and protein over-expression were compared in 79 screen-detected and 39 interval breast carcinomas, using a novel and well-documented chromogenic in situ hybridization (CISH) method and immuhistochemistry. RESULTS: There were 33% CISH-positive cases in the interval cancer group and only 4% CISH-positive cases in the screen-detected group. The odds ratio for interval cancer was 14.1 (95% CI 2.2 to 91.0) in the CISH-positive tumours compared with CISH-negative tumours after adjustment for nodal status, tumour size and histological grade. CONCLUSION: Our results indicate, for the first time, that there is a clear-cut difference in Her-2/neu amplification between screen-detected and interval breast carcinomas. The amplification appears to be a rare event in screen-detected cancers but distinctly frequent in interval cancers when compared to cancers described in earlier studies.

Elevated hyaluronan concentration without hyaluronidase activation in malignant epithelial ovarian tumors.

The concentration and histological distribution of hyaluronan, a tumor promoting extracellular matrix polysaccharide, and the activity of hyaluronidase, a potential source of angiogenic hyaluronan oligosaccharides, were analyzed in malignant epithelial (n = 24), borderline (n = 8), benign epithelial (n = 20), functional cyst (n = 21), and normal (n = 5) tissue samples of human ovary. Hyaluronan concentration increased specifically in cancers (P = 0.001), particularly in grade 3 tumors (>49-fold) and in metastases (>89-fold). Hyaluronan staining in the tissues correlated with hyaluronan concentration (P = 0.002). Hyaluronidase activity slightly decreased from semimalignant through low grade to high grade tumors (P = 0.041). Therefore, hyaluronan accumulation, but not hyaluronidase activation, is associated with the aggressiveness of ovarian epithelial cancer.

The impact of upper GI endoscopy referral volume on the diagnosis of gastroesophageal reflux disease and its complications: a 1-year cross-sectional study in a referral area with 260,000 inhabitants.

OBJECTIVES: Less than half of patients with gastroesophageal reflux disease (GERD) have endoscopic erosive esophagitis (endoscopy positive GERD). Symptomatic GERD and Barrett's esophagus (BE), however, are risk factors for esophageal and gastric cardia adenocarcinomas. The aim of the present study was to examine the prevalence of GERD-related findings on endoscopy according to the volume of referrals to upper GI endoscopy. METHODS: The following data were gathered on all GERD patients who were sent for upper GI endoscopy by general practitioners (GPs) during 1 yr in our hospital referral area of 260,000 inhabitants: the number of referrals to endoscopy in health care units, and the numbers of endoscopy positive GERD, BE, and esophageal neoplasms. Patients with symptoms or signs suggesting acute upper GI bleeding and those attending follow-up endoscopy (e.g., for BE, peptic ulcer, or dysplasia) were excluded, as were patients with previous esophagogastric surgery or Helicobacter pylori eradication therapy. RESULTS: The study population consisted of 3378 patients, with a mean age of 58.1 yr (95% CI = 57.5-58.6) and a male:female ratio of 1:1.3. Of the 760 patients who underwent endoscopy because of heartburn or regurgitation, 254 (33.4%) had endoscopy positive (erosive) GERD, 11 (1.4%) BE (one with esophageal adenocarcinoma), six (0.8%) esophageal ulcer, and one peptic esophageal stricture (0.1%). Between health care units, the referrals to endoscopy (number of endoscopies/population/yr) varied from 0.6 to 9.2/1000 inhabitants/yr (median 3.3/1000/yr). In health care units with "high" referral volumes (> or = 3.3 referrals/1000/yr, N = 15, 1297 patients) and "low" referral volumes (< 3.3/1000/yr, N = 15, 2081 patients), the numbers of endoscopy positive GERD were 281 (21.7%) versus 308 (14.9%, p < 0.001), esophageal ulcer 13 (1.0%) versus 14 (0.7%, p = 0.3), esophageal stricture five (0.4%) versus seven (0.3%, p = 0.4), Barrett's esophagus eight (0.6%) versus 16 (0.8%, p = 0.6), and esophageal neoplasm two (0.2%) versus six (0.3%, p = 0.2). Five of the neoplasms were squamous cell carcinomas, two were adenocarcinomas, and one was lymphoma. Multivariate analyses showed that independent risk factors for endoscopy positive GERD were male sex (OR = 1.4, 95% CI = 1.2-1.7), GERD symptoms (OR = 3.3, 95% CI = 2.7-4.0), dysphagia (OR = 1.4,95% CI = 1.0-2.1), and living in a high referral area (OR = 1.4, 95% CI = 1.2-1.7). Independent risk factors for BE were male sex (OR = 2.6, 95% CI = 1.1-6.1) and GERD symptoms (OR = 2.9, 95% CI = 1.3-6.6), whereas the only independent risk factor for esophageal neoplasm was dysphagia (OR = 40.0 (95% CI = 7.7-207.5). CONCLUSIONS: There is a wide variation in GPs' referrals for endoscopy. Increasing the referral volume significantly increases the proportion of endoscopy positive GERD cases, but not that of GERD complications such as BE, esophageal ulcer, peptic stricture, or esophageal neoplasms.