Matti Juhola

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.

Gastroesophageal Reflux Disease: Prevalence, Clinical, Endoscopic and Histopathological Findings in 1,128 Consecutive Patients Referred for Endoscopy due to Dyspeptic and Reflux Symptoms

Background and Aims: Gastroesophageal reflux disease (GERD) reportedly has increased in prevalence while Helicobacter pylori infection and peptic ulcer disease have been on the decrease. The aim of the present study was to examine the prevalence of GERD as well as the clinical, endoscopic and histologic variables that associate with GERD in patients referred for endoscopy. Patients and Methods: The study population was drawn from 1,562 consecutive patients referred for endoscopy. The exclusion criteria were previous H. pylori eradication, gastric surgery, anemia and weight loss. Thus 1,128 patients were enrolled in the present study. Results: Of the 1,128 patients, 199 (18%) were referred for endoscopy due to heartburn and/or regurgitation. GERD, defined as chronic (>6 months) heartburn and/or regurgitation with or without erosive esophagitis, Barrett’s esophagus, esophageal ulcer or stricture, was detected in 248 (22%) patients. Of the 248 GERD patients, 81 (33%) had endoscopy-negative GERD, but of those aged <50 years (n = 67), 57 (85%) were endoscopy-negative. The overall incidence of GERD was 307 per 100,000 population/year and that of endoscopy-positive GERD 207/100,000/year. The positive and negative predictive values of heartburn and regurgitation for endoscopy-positive GERD were 0.37 (95% CI 0.31–0.44) and 0.90 (95% CI 0.88–0.92), respectively. Independent risk factors for GERD were male sex (OR 1.9, 95% CI 1.3–2.7), previous medication for upper gastrointestinal symptoms (OR 2.7, 95% CI 1.7–4.1), the use of nonsteroidal anti-inflammatory drugs (NSAIDs; OR 2.0, 95% CI 1.3–3.0), histologic esophagitis (OR 2.2, 95% CI 1.5–3.2) and incomplete intestinal metaplasia at the gastroesophageal junction (OR 1.7, 95% CI 1.0–3.1). Chronic gastritis was protective against GERD (OR 0.7, 95% CI 0.5–0.9). No association was observed between GERD and H. pylori infection. The risk of patients aged <50 years (n = 407) of having major lesion (Barrett’s esophagus, esophageal stricture, peptic ulcer, esophageal/gastric carcinoma) was significantly lower than that of patients aged >50 years (n = 721; OR 0.5, 95% CI 0.3–0.9, p = 0.01). Conclusions: The correlation between reflux symptoms and endoscopy-positive GERD is poor and most GERD patients aged <50 years have endoscopy-negative GERD. The use of NSAIDs is a risk factor for GERD, whereas chronic gastritis, but not H. pylori infection, may protect against GERD. Incomplete intestinal metaplasia at the gastroesophageal junction is associated with GERD.

Is gastric cancer part of the tumour spectrum of hereditary non‐polyposis colorectal cancer? A molecular genetic study

Background: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy. Aim: To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. Subjects and methods: The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status. Results: This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI. Conclusion: The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.

Specialized columnar epithelium of the esophagogastric junction : Prevalence and associations

Specialized columnar epithelium of the esophagogastric junction: prevalence and associations

Prognostic significance of E-cadherin–catenin complex in epithelial ovarian cancer

Objective: To clarify the prognostic role of E-cadherin and β- and γ-catenins, and their relation to CD44 in epithelial ovarian carcinoma. Methods: The expression of E-cadherin and β- and γ-catenins was analysed immunohistochemically in 305 primary epithelial ovarian cancers and 44 metastases, and related to CD44 expression, clinicopathological factors, and the patients’ survival. Results: Reduced cell surface expression of E-cadherin, β-catenin, and γ-catenin was particularly frequent in serous and endometrioid histological types. Reduced cell surface expression of E-cadherin and β-catenin was also associated with poor differentiation. Nuclear positivity of β-catenin was associated with high CD44 expression, endometrioid histology, and local stage of the tumour, whereas nuclear γ-catenin expression was associated with serous histology and poor differentiation. In the univariate analysis, preserved cell surface β-catenin expression in the whole study material and nuclear expression of β- and γ-catenins in the subgroup of endometrioid ovarian cancers were predictors of better 10 year disease related survival. Preserved cell surface expression of E-cadherin and β-catenin predicted favourable recurrence-free survival. These statistical significances were not retained in multivariate analysis. Conclusions: The correlation between nuclear β-catenin and CD44 indicates that β-catenin may regulate the transcription of CD44 in epithelial ovarian cancer. E-cadherin–catenin complex members are associated with the prognosis of patients with epithelial ovarian cancer, but these univariate associations were not strong enough to compete for significance with the traditional clinicopathological factors.

Complete and incomplete intestinal metaplasia at the oesophagogastric junction: prevalences and associations with endoscopic erosive oesophagitis and gastritis

BACKGROUND/AIMS Intestinal metaplasia (IM) is a common finding at the oesophagogastric junction, but the aetiopathogenesis of the different IM subtypes—that is, incomplete IM (specialised columnar epithelium, SCE) and complete IM— and their associations with gastro-oesophageal reflux disease and Helicobacter pylori gastritis are unclear. METHODS 1058 consecutive dyspeptic patients undergoing gastroscopy were enrolled. The gastric, oesophagogastric junctional, and oesophageal biopsy specimens obtained were stained with haematoxylin and eosin, alcian blue (pH 2.5)-periodic acid Schiff, and modified Giemsa. RESULTS Complete junctional IM was detected in 196 (19%) of the 1058 subjects, and in 134 (13%) was the sole IM subtype. Incomplete junctional IM (SCE) was detected in 101 (10%) subjects, of whom 62 (61%) also had the complete IM subtype. Of patients with normal gastric histology (n = 426), 6% had complete IM and 7% junctional SCE. The prevalence of both types of IM increased with age in patients with either normal gastric histology or chronic gastritis (n = 611). Epithelial dysplasia was not detected in any patients with junctional IM. In multivariate analysis, independent risk factors for incomplete junctional IM were age (odds ratio (OR) 1.3 per decade, 95% confidence interval (CI) 1.2 to 1.6), endoscopic erosive oesophagitis (OR 1.9, 95% CI 1.1 to 3.2), and chronic cardia inflammation (OR 2.9, 95% CI 1.3 to 6.2), but not gastric H pylori infection (OR 1.0, 95% CI 0.6 to 1.7). In univariate analysis, junctional incomplete IM was not associated with cardia H pylori infection. Independent risk factors for “pure” complete junctional IM (n = 134) were age (OR 1.2 per decade, 95% CI 1.0 to 1.4), antral predominant non-atrophic gastritis (OR 2.6, 95% CI 1.3 to 5.2), antral predominant atrophic gastritis (OR 2.1, 95% CI 1.1 to 5.2), and multifocal atrophic gastritis (OR 7.1, 95% CI 2.5 to 19.8). In univariate analysis, junctional complete IM was strongly associated with chronic cardia inflammation and cardia H pylori infection (p<0.001). CONCLUSIONS Both complete and incomplete junctional IM are independent acquired lesions that increase in prevalence with age. Although IM subtypes often occur simultaneously, they show remarkable differences in their associations with gastritis and erosive oesophagitis: junctional complete IM is a manifestation of multifocal atrophic gastritis, while the incomplete form (SCE) may result from carditis and gastro-oesophageal reflux disease. The frequency of dysplasia in intestinal metaplasia at the oesophagogastric junction appears to be low.

Specialized columnar epithelium of the esophagogastric junction: prevalence and associations. The Central Finland Endoscopy Study Group.

OBJECTIVES:In Barretts esophagus (BE) normal squamous esophageal epithelium is replaced by specialized columnar epithelium (SCE). BE is related to gastroesophageal reflux disease (GERD) and is a risk factor for esophageal adenocarcinoma. SCE is detected also at normal-appearing esophagogastric junction without BE (junctional SCE). The relationships between junctional SCE, GERD, and cardia adenocarcinoma are obscure and controversial. The aims of the present study were to investigate the prevalence and demographics of junctional SCE and to compare these figures with those reported for BE, and esophageal and cardia adenocarcinoma. A further aim was to examine the association between junctional SCE and GERD, Helicobacter pylori infection, and gastritis.METHODS:One thousand one hundred-nineteen consecutive dyspeptic patients underwent gastroscopy and were enrolled into the study.RESULTS:Junctional SCE was detected in 110 patients (10%). The age-specific prevalence of junctional SCE increased with age. The male:female ratio was 1:1.1. In multivariate analysis, junctional SCE was independently and positively related to endoscopic erosive esophagitis (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1–3.1), cardia inflammation (carditis) (OR, 3.1; 95% CI, 1.4–6.8), and age (OR, 1.4 per decade; 95% CI, 1.2–1.6), but not to corpus H. pylori infection (OR, 1.4; 95% CI, 0.7–2.8), antral (OR, 1.0; 95% CI, 0.5–2.1) or corpus (OR, 0.8; 95% CI, 0.4–1.8) gastritis, or intestinal metaplasia of the antral mucosa in stomach (OR, 1.2; 95% CI, 0.7–2.1). In univariate analysis, junctional SCE was, however, significantly more common in patients with antral-predominant atrophic gastritis (20%), compared with those with normal gastric histology (8%, p < 0.001).CONCLUSIONS:Junctional SCE is age related and may therefore be an acquired lesion. It is associated with cardia inflammation and endoscopic erosive esophagitis, but not with H. pylori infection or gastric intestinal metaplasia. Unlike BE and cardia cancer, junctional SCE occurs with similar frequency in men and women.

Chronic inflammation at the gastroesophageal junction (carditis) appears to be a specific finding related to Helicobacter pylori infection and gastroesophageal reflux disease

Chronic inflammation at the gastroesophageal junction (carditis) appears to be a specific finding related to Helicobacter pylori infection and gastroesophageal reflux disease

Chronic inflammation at the gastroesophageal junction (carditis) appears to be a specific finding related to Helicobacter pylori infection and gastroesophageal reflux disease. The Central Finland Endoscopy Study Group.

Objective:The clinical significance of chronic inflammation at the gastroesophageal junction (carditis) is unknown: it may be associated with Helicobacter pylori (H. pylori) gastritis or with gastroesophageal reflux disease (GERD). We aimed to examine the association between carditis and H. pylori gastritis and endoscopic erosive esophagitis.Methods:One thousand and fifty-three patients undergoing gastroscopy were enrolled in the study. Biopsy specimens were obtained from gastric antrum and corpus, immediately distal to normal-appearing squamocolumnar junction and distal esophagus.Results:Chronic inflammation at the gastroesophageal junctional mucosa (carditis) was detected in 790 (75%) of 1053 patients. The male:female ratio of the carditis group was 1:1.5 and of the noncarditis group 1:1.6 (p= 0.6). The mean age of the carditis group was 58.7 yr (95% confidence interval [CI], 57.6–59.9) and of the noncarditis group, 52.6 yr (95% CI, 50.7–54.6, p < 0.001). Of the carditis group (N = 790), 549 (69%) had chronic gastritis (70% H. pylori positive) and 241 (31%) had normal gastric histology. In multivariate analyses, the only risk factor for carditis in subjects with chronic gastritis was H. pylori infection (odds ratio [OR], 2.9; 95% CI, 1.6–5.0), whereas the independent risk factor for carditis in subjects with histologically normal stomach was endoscopic erosive esophagitis (OR, 1.8; 95% CI, 1.1–3.1). The prevalence of complete intestinal metaplasia (IM) in the gastric cardia mucosa was 7% in the noncarditis group, 19% (p < 0.001) in the carditis group with chronic gastritis, and 10% (p= 0.3) in the carditis group with normal stomach. The respective prevalences of incomplete IM were 3%, 12% (p < 0.001), and 12% (p < 0.001). Among carditis patients with normal stomach histologically (N = 241), those with complete and/or incomplete IM (N = 49) were older than those with carditis only (63.6 yr [95% CI, 59.9–67.2] vs 51.4 yr [95% CI, 48.9–53.9]; p < 0.001).Conclusions:Two dissimilar types of chronic inflammation of the gastric cardia mucosa seem to occur, one existing in conjunction with chronic H. pylori gastritis and the other with normal stomach and erosive GERD. Most cases of chronic gastric cardia inflammation and intestinal metaplasia are detected in patients with chronic H. pylori gastritis.

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 Barretts 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 (≥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), Barretts 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.