Oesophageal signet ring cell carcinoma as complication of gastro-oesophageal reflux disease

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1 Alimentary Pharmacology and Therapeutics Oesophageal ring cell carcinoma as complication of gastro-oesophageal reflux disease K. O. Turner*,, R. M. Genta*,, & A. Sonnenberg, *Miraca Life Sciences Research Institute, Irving, TX, USA. University of Texas Southwestern Medical Center College of Medicine, Dallas, TX, USA. VA Medical Center, Dallas, TX, USA. Oregon Health & Science University, Portland, OR, USA. VA Medical Center, Portland, OR, USA. Correspondence to: Dr A. Sonnenberg, Portland VA Medical, P3-GI, Portland, OR 97239, USA. Publication data Submitted 14 July 2015 First decision 28 July 2015 Resubmitted 2 August 2015 Resubmitted 15 August 2015 Accepted 16 August 2015 EV Pub Online 8 September 2015 This article was accepted for publication after full peer-review. SUMMARY Background Signet ring cell carcinoma occurs as a histological variant of oesophageal adenocarcinoma. Aim In a cross-sectional study, to pursue the hypothesis that oesophageal ring cell cancers constitute a complication of gastro-oesophageal reflux disease. Methods In a large national database of histopathology records, we accumulated patients with Barrett s oesophagus (BE), 2817 with oesophageal non ring adenocarcinoma (EAC) and 278 with oesophageal ring cell carcinoma (SRC). The three groups were compared with respect to their clinical and demographic characteristics, as well as socio-economic risk factors (associated with patients place of residence). Results About 9% of all oesophageal adenocarcinomas harboured features of ring cell carcinoma. Patients with oesophageal adenocarcinoma and ring cell carcinoma were characterised by almost identical epidemiological patterns. Patients with either cancer type were slightly older than those with Barrett s oesophagus (EAC 68.0, SRC 66.7 vs. BE 63.7 years), and both showed a striking male predominance (EAC and SRC 85% vs. BE 67%). Both cancer types were associated with a similar set of alarm symptoms, such as dysphagia, pain and weight loss. The distribution by race (Whites vs. Blacks) and socio-economic parameters, such as levels of college education and family income, were similar among the three groups of patients. Conclusions Signet ring cell carcinoma is a rare variant of oesophageal adenocarcinoma with similar epidemiological characteristics. The reasons why a minority of reflux patients progress to develop ring cell carcinoma, rather than the usual type of oesophageal adenocarcinoma, remain unknown. Aliment Pharmacol Ther 2015; 42: doi: /apt.13395

2 Oesophageal ring cell cancer INTRODUCTION Signet ring cell carcinoma is a histological variant of adenocarcinoma (Figure 1) characterised by a population of loose tumour cells whose cytoplasm appears almost entirely occupied by mucin. The nucleus, compressed and displaced to the periphery of the round, thin-walled cells, has been compared to the bezel of rings used to impress a personal symbol onto the wax that sealed letters and documents. While this subtype is usually associated with an infiltrating type of gastric cancer that results in a thick and rigid gastric wall (linitis plastica), it may arise in other parts of the digestive tract, including the colon and the oesophagus. In rare instances, ring cell carcinoma is found as part of oesophageal cancer without association with any such primary lesion in other areas of the stomach. Though histologically identical, it has been suggested that these oesophageal ring cell cancers are unrelated to those found in the stomach. 1 Previous studies of this oesophageal ring carcinoma have focused mainly on its natural history, prognostic features, and the effects of surgery, radiation and chemotherapy on patient survival. 2, 3 These studies have suggested that, compared to patients with oesophageal adenocarcinoma without features of ring cells, those with the ring cell type have a worse prognosis. 3 8 Because of the relatively infrequent occurrence of oesophageal ring cell carcinoma, these studies were based on small case series and provided few if any insights into its general epidemiology. Miraca Life Sciences manages a large nationwide database of clinico-pathological data. The database affords a unique opportunity to study the epidemiological and histopathological features of rare conditions. In the recent past, this database has been utilised for a variety of patho-epidemiological studies We hypothesised that oesophageal ring cell cancers constitute a complication of gastro-oesophageal reflux disease and would thus reveal similar epidemiological characteristics as Barrett s oesophagus or oesophageal adenocarcinoma without features of ring cells. Accordingly, the aim of the present cross-sectional study was to use the Miraca database to compare the clinical epidemiology of oesophageal ring cell carcinoma with three groups of patients: those with ring cell cancer of the stomach, non ring oesophageal adenocarcinoma and Barrett s oesophagus without cancer. PATIENTS AND METHODS Data source We used a database of subjects who underwent oesophago-gastro-duodenoscopy (EGD) between January 2008 and December 2014 in endoscopy centres distributed throughout the USA and whose mucosal biopsy specimens were evaluated and reported by a single group of histopathologists. The group consists of 35 pathologists with subspecialty training in gastrointestinal pathology who practise in the same environment. Consensus is maintained and updated through daily multi-headed microscope conferences, frequent didactic conferences, a journal club, a terminology and criteria review committee, and ongoing comprehensive quality assurance review. The Miraca Life Sciences internal review board determined that this study would be entirely performed by collecting existing data, documents and reports, and (a) (b) (c) Figure 1 Signet ring cell adenocarcinoma of the oesophagus. (a) Haematoxylin and Eosin (HE) stain, low-power magnification: most of the tumour consists of poorly cohesive individual cells. (b) HE, high-power magnification: almost every cell shows a round, pale cytoplasm and a peripherally located, flattened nucleus. (c) Alcian Blue and Periodic Acid Schiff stain (PAS-D), high-power magnification, highlighting in dark blue the mucin content within the cytoplasm of the ring cells. Aliment Pharmacol Ther 2015; 42:

3 K. O. Turner et al. that the information would be recorded in such a manner that subjects cannot be identified. In accordance with US federal regulations of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), no informed consent was deemed necessary for the present study. All unique patients who had a diagnosis of oesophageal ring cell carcinoma, gastric ring cell carcinoma, oesophageal adenocarcinoma and Barrett s oesophagus without malignancy during the study period were extracted from the database and their demographic, clinical and histopathological data were recorded. In the majority of patients, the clinical data included information about signs and symptoms preceding the endoscopy and the indication for endoscopy itself. Because of the large group of 1500 gastroenterologists who were distributed across the USA and who contributed biopsy specimens, no standardised format for reporting existed and the amount of clinical details varied among individual patients. Medication history, serology and results of other laboratory tests were rarely provided with the pathology specimen. Oesophageal cancers were restricted to Siewert types I and II, that is adenocarcinoma of the distal oesophagus, which arises from an area with Barrett oesophagus (type I) or carcinoma of the cardia arising immediately at the oesophagogastric junction (type II), but not subcardial gastric carcinoma that infiltrates the oesophagogastric junction and distal oesophagus from below (type III). 16 However, the analysis was restricted to biopsy specimens obtained during the EGD and the anatomical descriptions provided by the endoscopist as surgical resection specimens were not available for the present analysis. If a patient had multiple EGDs, only data from the chronologically first procedure were included. Socio-economic information was available from census data associated with the patients postal address and ZIP codes. These data included population size per ZIP code, average annual income, per cent of residents with college education, per cent of White and Black residents per ZIP code. Histopathological criteria Barrett s mucosa is defined as the condition in which any extent of metaplastic columnar epithelium replaces the stratified squamous epithelium that normally lines the distal oesophagus. 17 Pathologists diagnosed Barrett s mucosa when a gastro-oesophageal junction or distal oesophagus sample of mucosa was reported as being suspicious for Barrett s oesophagus by the endoscopist, and in which metaplastic columnar epithelium with goblet cells were identified histologically. Oesophageal adenocarcinoma is a malignant gland-forming tumour that is seen in a variety of grades (well, moderately and poorly differentiated), as well as histological types (NOS, mucinous, ring, papillary, with neuroendocrine differentiation, with squamous differentiation). 18 Signet ring cell cancer is a histological subtype of adenocarcinoma that consists predominately (more than 5) or exclusively of ring cells. 19 In this laboratory, all upper gastrointestinal mucosal biopsy specimens are stained with the Alcian Blue Periodic Acid Schiff stain to enhance the detection of intestinal metaplasia. More than 9 of gastric biopsies are routinely stained with a specific anti-helicobacter monoclonal immunochemical stain (Cell Marque, Rocklin, CA, USA); the remainder are stained with a modified Giemsa stain (HP Blue; Anatech, Ltd., Battle Creek, MI, USA). Gastric biopsy specimens are diagnosed following the guidelines of the Updated Sydney System and the 2002 International Atrophy Consensus. 20, 21 OLGA scores are not routinely used, but the OLGA guidelines for the evaluation of atrophy and metaplasia are followed. 22 Briefly, Helicobacter infection was diagnosed when the characteristic curved organisms were visualised in a gastric biopsy specimen. Intestinal metaplasia was diagnosed in the presence of goblet cells in the columnar mucosa. Chronic inactive gastritis was diagnosed when the lamina propria contained dense populations of lymphocytes and plasma cells. The diagnosis of reactive gastropathy was based on the 2006 guidelines, which includes various combinations of foveolar hyperplasia, regenerative changes in the surface epithelium, oedema or hyperaemia of the lamina propria, erosions, and smooth muscle proliferation. 23 Biopsy sites (corpus or antrum) were assessed according to the endoscopist definition, as previously detailed; thus, a specimen designated as antrum was assigned to the site antrum even if the pathologist determined it to consist of oxyntic (corpus) mucosa. 24 Statistical analysis We compared patients with oesophageal ring cell carcinoma or oesophageal adenocarcinoma without features of ring cells to patients who harboured Barrett s oesophagus alone. In addition, we compared patients with oesophageal to those with gastric ring cell cancer. Patients were characterised by age, sex, ethnicity, presence of various clinical symptoms, presence of various histopathological diagnoses, family income and levels of college education. Differences in 1224 Aliment Pharmacol Ther 2015; 42:

4 Oesophageal ring cell cancer the frequency of categorical variables among the three patient groups were compared calculating odd ratios and their 95% confidence interval. Differences in the magnitude of continuous variables were compared calculating t-values and their associated probability. RESULTS From a total of patients who had EGD with biopsies during the study period, we extracted a group of patients: (967%) with Barrett s oesophagus, 2817 (3.) with oesophageal non ring adenocarcinoma, 278 (0.3%) with oesophageal ring cell carcinoma and 258 with gastric ring cell carcinoma. Thus, of the 3095 patients with oesophageal adenocarcinoma, 9. had ring morphology. On microscopic examination, recognisable areas of Barrett s mucosa (i.e. intestinal metaplasia with goblet cells) were detected in 154 of the 2817 patients with oesophageal adenocarcinoma (5.5%) and in 12 of the 278 patients with oesophageal ring cell carcinoma (4.3%). The age and sex distribution of the four patient groups are shown in Table 1 and Figure 2. Compared to patients with Barrett s oesophagus and no oesophageal carcinoma, those with oesophageal adenocarcinoma were on average 4.3 years older and those with ring cell carcinoma were 3.1 years older. Thus, the age distribution of oesophageal ring cell carcinoma and oesophageal adenocarcinoma was slightly shifted to the right towards older ages (Figure 1, left panel). All three diagnoses were associated with a marked male predominance, which was significantly more pronounced in patients with either cancer type than in those with only Barrett s oesophagus (Figure 1, right pane). Gastric and oesophageal ring cell cancers were characterised by similar age distributions. However, their gender distributions were strikingly different (Figure 2). Table 2 depicts the clinical presentation of patients from the four groups. Figure 3 is focused on the four most common symptoms, that is reflux, dysphagia, pain and weight loss. Dysphagia, pain and weight loss were significantly more common in patients with cancer than with Barrett s oesophagus. Dysphagia, pain and weight loss were also slightly, but not significantly, more prevalent in patients with oesophageal ring cell carcinoma than oesophageal adenocarcinoma. Besides the aforementioned symptoms, patients with oesophageal adenocarcinoma and ring cell carcinoma tended to present more frequently with nausea and vomiting or anaemia, but the absolute difference when compared with Barrett s oesophagus alone was too small to be of any discriminatory value (Table 2). Gastric ring cell cancers were associated with less dysphagia, but more pain, weight loss, dyspepsia, nausea and vomiting than oesophageal ring cell cancers. Figure 4 shows the socio-economic variables associated with the three oesophageal patient groups. The average percentage of college education was 27%, 24% and 26% in patients with Barrett s oesophagus, oesophageal adenocarcinoma and ring cell carcinoma respectively. The average family income was $48 000, $ and $ respectively. In all three patient groups alike, the average percentage of Whites and Blacks was 79% and 1 respectively. All four parameters were equally distributed among patients with Barrett s oesophagus, oesophageal adenocarcinoma and ring cell carcinoma. Compared to patients with Table 1 Age and sex comparisons of the four patient groups Age N Mean SD t-value P-value Barrett s oesophagus Reference Oesophageal adenocarcinoma < Oesophageal ring cell cancer < Gastric ring cell cancer* Sex Female % Male % OR 95% CI Barrett s oesophagus Oesophageal adenocarcinoma , Oesophageal ring cell cancer Gastric ring cell cancer* * Odds ratio (OR) and t-value refer to comparison of gastric with oesophageal ring cell cancer. Aliment Pharmacol Ther 2015; 42:

5 K. O. Turner et al. 35% % Esoph Gastr EAC BE 8 6 F M 15% 4 1 5% BE EAC Esoph Gastric Figure 2 Age (left) and sex (right) distributions of Barrett s oesophagus (BE), oesophageal adenocarcinoma (EAC) oesophageal and gastric ring cell cancer. F, female; M, male. oesophageal ring cell cancers, patients with gastric ring cell cancers showed a lesser predilection for white ethnicity (data not shown separately). In addition to the oesophageal biopsies, in patients, the histopathology results of gastric biopsies were also available for analysis (Table 3). Helicobacterpositive chronic active gastritis was found in 5% of gastric biopsies, Helicobacter-negative chronic active gastritis in 1%, chronic inactive gastritis in 4%, intestinal metaplasia in 4%, gastric atrophy in 0.5% and reactive gastropathy in 19%. Signs of past or present H. pylori infection, as evidenced by presence of H. pylori-positive chronic active gastritis (CAG), chronic inactive gastritis and intestinal metaplasia were more common in both cancer types than in patients with Barrett s oesophagus, whereas reactive gastropathy was less common. There were too few patients with H. pylori-negative chronic active gastritis or gastric atrophy to draw any firm conclusions. Gastric ring cell cancers were associated with a significantly higher fraction of H. pylori-positive gastritis than oesophageal ring cell cancers. DISCUSSION Using the data from a large national database of histopathology records, our study was focused on the prevalence and characteristics of patients with oesophageal ring cell carcinoma. About 9% of all adenocarcinomas at the gastro-oesophageal junction harboured the features of ring cell carcinoma. Overall, patients with oesophageal adenocarcinoma and ring cell carcinoma were characterised by almost identical epidemiological patterns. Patients with either cancer type were slightly older than those with Barrett s oesophagus, and both showed a striking male predominance. Both cancer types were associated with a similar set of alarm symptoms, such as dysphagia, pain and weight loss. Although alarm symptoms tended to be slightly more prevalent in patients with ring cell cancer than adenocarcinoma, the difference was insignificant and far too small to be of any clinical relevance. The distribution by race and socio-economic parameters, such as levels of college education and family income, was similar among the three groups of patients. The similarity in the epidemiological patterns of Barrett s oesophagus, oesophageal adenocarcinoma and ring cell carcinoma suggests that these three diseases represent different expressions of the same underlying condition. Both cancer types were associated with reflux symptoms, albeit less frequently than patients with Barrett s oesophagus. The cancer growth at the gastrooesophageal junction may act as a barrier to acid reflux and can thus lead to improvement in reflux symptoms. The average age difference between patients with Barrett s oesophagus and those with cancer probably reflects on the natural history of the disease and its time-dependent progression from intestinal metaplasia to dysplasia and cancer. In this regard, oesophageal adenocarcinomas tend to behave similarly, irrespective of the ring cell differentiation. Male predominance is a characteristic pattern of all three diagnoses. Although general reflux disease appears to affect both gender groups alike, its more severe expressions, such as erosive oesophagitis, 1226 Aliment Pharmacol Ther 2015; 42:

6 Oesophageal ring cell cancer Table 2 Prevalence of symptoms in the four patient groups Symptom Histopathology Presence of symptom Yes (%) No (%) OR 95% CI Reflux Barrett s oesophagus (40) (60) 1.00 Oesophageal adenocarcinoma 613 (22) 2204 (78) Oesophageal ring cell cancer 59 (21) 219 (79) Gastric ring cell cancer* 56 (22) 202 (78) Dysphagia Barrett s oesophagus (11) (89) 1.00 Oesophageal adenocarcinoma 1497 (53) 1320 (47) Oesophageal ring cell cancer 164 (59) 114 (41) Gastric ring cell cancer* 41 (16) 217 (84) Dyspepsia Barrett s oesophagus 2396 (3) (97) 1.00 Oesophageal adenocarcinoma 96 (3) 2721 (97) Oesophageal ring cell cancer 7 (3) 271 (97) Gastric ring cell cancer* 28 (11) 230 (89) Nausea and vomiting Barrett s oesophagus 2787 (3) (97) 1.00 Oesophageal adenocarcinoma 104 (4) 2713 (96) Oesophageal ring cell cancer 13 (5) 265 (95) Gastric ring cell cancer* 41 (16) 217 (84) Pain Barrett s oesophagus (12) (88) 1.00 Oesophageal adenocarcinoma 370 (13) 2447 (87) Oesophageal ring cell cancer 54 (19) 224 (81) Gastric ring cell cancer* 114 (44) 144 (56) Diarrhoea Barrett s oesophagus 2394 (3) (97) 1.00 Oesophageal adenocarcinoma 39 (1) 2778 (99) Oesophageal ring cell cancer 1 (0) 277 (100) Gastric ring cell cancer* 6 (2) 252 (98) Anaemia Barrett s oesophagus 3991 (4) (96) 1.00 Oesophageal adenocarcinoma 166 (6) 2651 (94) Oesophageal ring cell cancer 14 (5) 264 (95) Gastric ring cell cancer* 23 (9) 235 (91) Haematemesis Barrett s oesophagus 178 (0) (100) 1.00 Oesophageal adenocarcinoma 6 (0) 2811 (100) sophageal ring cell cancer 0 (0) 278 (100) 0.00 Gastric ring cell cancer* 1 (0) 257 (100) Weight loss Barrett s oesophagus 1879 (2) (98) 1.00 Oesophageal adenocarcinoma 418 (15) 2399 (85) Oesophageal ring cell cancer 45 (16%) 233 (84%) Gastric ring cell cancer* 62 (24%) 196 (76%) * Odds ratios (OR) refer to comparison of gastric with oesophageal ring cell cancer. Barrett s oesophagus, and adenocarcinoma clearly show predilection for male gender. 25, 26 Again, a similar pattern was evident regarding both types of oesophageal but not gastric adenocarcinoma. Like Barrett s oesophagus and oesophageal adenocarcinoma, ring cell carcinoma of the oesophagus also appears to affect Whites more frequently than Blacks. The reasons for sex- and 25, 26 race-specific patterns are not fully understood. Only a minority of patients were diagnosed concomitantly with cancer and Barrett s metaplasia. The low rate Aliment Pharmacol Ther 2015; 42:

7 K. O. Turner et al. 10 No Yes Reflux 10 Dysphagia Barrett s esophagus Esoph Gastric Barrett s esophagus Adenocarcinoma Adenocarcinoma Esoph Gastric 10 Pain 10 Weight loss Barrett s esophagus Adenocarcinoma Adenocarcinoma Esoph Gastric Barrett s esophagus Esoph Gastric Figure 3 The prevalence of reflux symptoms, dysphagia, pain and weight loss among patients with Barrett s oesophagus, adenocarcinoma, oesophageal and gastric ring cell cancer. of coincidence probably reflects more on patterns of biopsy taking during endoscopy than on any underlying pathophysiology. In the light of the overwhelming relevance of the cancer diagnosis, few physicians may feel compelled to take additional biopsies from the surrounding mucosa. Moreover, large cancers may have spread to affect most or all of the underlying Barrett s metaplasia, especially if associated with shorter segments of Barrett s oesophagus. This pattern occurred in oesophageal adenocarcinoma and cell ring adenocarcinoma alike. The endoscopists focus on tissue samples from the cancer itself rather than its surrounding mucosa may also explain the relatively low prevalence of H. pylori-positive gastritis associated with gastric cell ring cancer. The spectrum of symptoms associated with oesophageal adenocarcinoma and ring cell carcinoma appeared to be quite similar. The occurrence of dysphagia, pain and weight loss should cause alarm in any patient with reflux disease and initiate an endoscopic work-up. Previous studies have suggested that ring cell carcinoma of the oesophagus leads to a more rapid disease progression than oesophageal adenocarcinoma with a more advanced cancer at the time of diagnosis and shorter life expectancy. Although we found a slight trend for overall more symptoms in patients with ring cell carcinoma than oesophageal adenocarcinoma, these differences did not reach statistical significance. Other symptoms, such as nausea and vomiting or anaemia, were also more frequent in patients with oesophageal adenocarcinoma and ring cell carcinoma, but the absolute difference compared to Barrett s oesophagus was far too small to be of any clinical relevance. In the comparison of gastric with oesophageal ring cell cancer, the difference in the spectrum of symptoms appeared mostly related to their different locations Aliment Pharmacol Ther 2015; 42:

8 Oesophageal ring cell cancer College 3 Income 15% 1 5% 1 0 5% 10 15% 20 25% 30 35% 40 45% 50 55% 60 65% 70 75% 80 85% 0 10K 20 30K 40 50K 60 70K 80 90K K K K 3 Whites 6 Blacks 4 BE EAC 1 Signet % % % % % Figure 4 Distribution of patients with Barrett s oesophagus, adenocarcinoma and oesophageal ring cell cancer by average annual income (US$), per cent college education and per cent Whites or Blacks per residential ZIP code. In patients who also had gastric biopsies, the additional histopathological information failed to provide any clues as to why a small subset of patients with Barrett s oesophagus progress to ring cell carcinoma rather than the general type of adenocarcinoma. This similarity with respect to the accompanying gastric histopathology is consistent with the similarity in the epidemiological patterns of the two cancer types. Other factors than those examined by the present study must contribute to separate pathways taken by dysplastic transformation of the underlying Barrett s mucosa. The different pathway could reflect on a peculiar genetic susceptibility of some patients or on the influence of yet another set of unknown environmental risk factors. Like any database analysis, the present epidemiological study is limited by its reliance on pre-existing data. The description of endoscopic results had to be restricted to information provided by the endoscopist submitting the pathology request. For instance, a detailed description of the macroscopic appearance of the Barrett s oesophagus according to the Prague criteria was not available for the majority of patients. We were careful to select only patients with oesophageal cancer and without evidence for any concurrent gastric cancer. However, one can never rule out with absolute certainty that the oesophageal adenocarcinoma did not originate in the gastric portion of the gastro-oesophageal junction. As in the majority of such studies, the assignment of junctional tumours to either the oesophagus or the proximal stomach sometimes remains an educated guess that rests mainly on the reliability of the endoscopic information available As endoscopic biopsies constitute a Aliment Pharmacol Ther 2015; 42:

9 K. O. Turner et al. Table 3 Prevalence of gastric histopathology in the four patient groups Gastric histopathology Oesophageal histopathology Presence of gastric histopathology Yes (%) No (%) OR 95% CI Helicobacter-positive CAG Barrett s oesophagus 1625 (5) (95) 1.00 Oesophageal adenocarcinoma 57 (7) 742 (93) Oesophageal ring cell cancer 5 (6) 81 (94) Gastric ring cell cancer* 40 (16) 218 (84) Chronic inactive gastritis Barrett s oesophagus 1377 (4) (96) 1.00 Oesophageal adenocarcinoma 37 (5) 762 (95) Oesophageal ring cell cancer 7 (8) 79 (92) Gastric ring cell cancer* 7 (3) 251 (97) Helicobacter-negative CAG Barrett s oesophagus 345 (1) (99) 1.00 Oesophageal adenocarcinoma 8 (1) 791 (99) Oesophageal ring cell cancer 2 (2) 84 (98) Gastric ring cell cancer* 6 (2) 252 (98) Intestinal metaplasia Barrett s oesophagus 1635 (5) (95) 1.00 Oesophageal adenocarcinoma 63 (8) 736 (92) Oesophageal ring cell cancer 7 (8) 79 (92) Gastric ring cell cancer* 29 (11) 229 (89) Gastric atrophy Barrett s oesophagus 139 (0.43) (100) 1.00 Oesophageal adenocarcinoma 2 (0.25) 797 (100) Oesophageal ring cell cancer 0 (0.00) 86 (100) 0.00 Gastric ring cell cancer* 4 (2) 254 (98) Reactive gastropathy Barrett s oesophagus 6113 (19) (81) 1.00 Oesophageal adenocarcinoma 110 (14) 689 (86) Oesophageal ring cell cancer 6 (7) 80 (93) Gastric ring cell cancer* 11 (4) 247 (96) * Odds ratios (OR) refer to comparison of gastric with oesophageal ring cell cancer; CAG, chronic active gastritis. random process, we cannot rule out with certainty that some oesophageal adenocarcinoma harboured foci of ring cells that escaped detection. Other potential limitations of the study relate to the fact that we could not establish socio-economic data for each individual patient, but rather had to rely on socio-economic data associated with the patients ZIP codes. However, such proxy use of ZIP code-associated data has become a common analytical approach in epidemiological studies, as income and education are considered private information that rarely enters the medical record. Because of the nature of our database, which was focused primarily on histopathology, we had little if any access to any additional information about patients occupation, social habits or exposure to other potential environmental risk factors. In summary, our study shows that ring cell carcinoma of the oesophagus constitutes 9% of all oesophageal adenocarcinomas associated with gastro-oesophageal reflux disease. In general, patients with ring cell carcinoma appear to be characterised by the same set of epidemiological and clinical characteristics as patients with regular oesophageal adenocarcinoma. The reasons why a minority of reflux patients progress to develop ring cell carcinoma rather than the usual type of oesophageal adenocarcinoma remain presently unknown. AUTHORSHIP Guarantor of the article: A. Sonnenberg. Author contributions: K. Turner: data analysis; R.M. Genta: database preparation; A. Sonnenberg: study design, data analysis. All authors contributed to writing of the manuscript. All authors approved the final version of the manuscript Aliment Pharmacol Ther 2015; 42:

10 Oesophageal ring cell cancer ACKNOWLEDGEMENTS Declaration of personal interests: Kevin Turner and Robert Genta are employed by Miraca Life Sciences, Irving, TX. Amnon Sonnenberg declares no relevant conflicts of interest. Declaration of funding interests: None. REFERENCES 1. Piessen G, Messager M, Lefevre JH, et al. ; FREGAT Working Group. Signet ring cell adenocarcinomas: different clinical-pathological characteristics of oesophageal and gastric locations. Eur J Surg Oncol 2014; 40: Chirieac LR, Swisher SG, Correa AM, et al. Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma. Clin Cancer Res 2005; 11: Enlow JM, Denlinger CE, Stroud MR, Ralston JS, Reed CE. Adenocarcinoma of the esophagus with ring cell features portends a poor prognosis. Ann Thorac Surg 2013; 96: Patel VR, Hofstetter WL, Correa AM, et al. Signet ring cells in esophageal adenocarcinoma predict poor response to preoperative chemoradiation. Ann Thorac Surg 2014; 98: Nafteux PR, Lerut TE, Villeneuve PJ, et al. Signet ring cells in esophageal and gastroesophageal junction carcinomas have a more aggressive biological behavior. Ann Surg 2014; 260: Yoon HH, Khan M, Shi Q, et al. The prognostic value of clinical and pathologic factors in esophageal adenocarcinoma: a Mayo cohort of 796 patients with extended follow-up after surgical resection. Mayo Clin Proc 2010; 85: Yendamuri S, Huang M, Malhotra U, et al. Prognostic implications of ring cell histology in esophageal adenocarcinoma. Cancer 2013; 119: Schmidt T, Sicic L, Blank S, et al. Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas. Br J Cancer 2014; 110: Sonnenberg A, Lash RH, Genta RM. A national study of Helicobacter pylori infection in gastric biopsy specimens. Gastroenterology 2010; 139: Dellon ES, Peery AF, Shaheen NJ, et al. Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database. Gastroenterology 2011; 141: Gupta S, Balasubramanian BA, Fu T, Genta RM, Rockey DC, Lash R. Polyps with advanced neoplasia are smaller in the right than in the left colon: implications for colorectal cancer screening. Clin Gastroenterol Hepatol 2012; 10: Sonnenberg A, Genta RM. Helicobacter pylori is a risk factor for colonic neoplasms. Am J Gastroenterol 2013; 108: Lebwohl B, Blaser MJ, Ludvigsson JF, et al. Decreased risk of celiac disease in patients with Helicobacter pylori colonization. Am J Epidemiol 2013; 15: Jensen ET, Hoffman K, Shaheen NJ, Genta RM, Dellon ES. Esophageal eosinophilia is increased in rural areas with low population density: Results from a national pathology database. Am J Gastroenterol 2014; 109: Turner KO, Genta RM, Sonnenberg A. Ethnic distribution of microscopic colitis in the United States. Inflamm Bowel Dis 2015; PMID: [Epub ahead of print]. 16. Siewert RJ, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/ topographic classification in 1,002 consecutive patients. Ann Surg 2000; 232: Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ; American Gastroenterological Association. American Gastroenterological Association technical review on the management of Barrett s esophagus. Gastroenterology 2011; 140: e Fenoglio-Preiser CM, Noffsinger AE. Gastrointestinal Pathology: An Atlas and Text. 3rd ed. Philadelphia: Wolters Kluwer, 2007; Bosman FT, ed. WHO Classification of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2010; Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston Am J Surg Pathol 1996; 20: Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment Pharmacol Ther 2002; 16: Rugge M, Correa P, Di MF, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008; 40: Genta RM. Differential diagnosis of reactive gastropathy. Semin Diagn Pathol 2005; 22: Lash JG, Genta RM. Adherence to the Sydney System guidelines increases the detection of Helicobacter gastritis and intestinal metaplasia in sets of gastric biopsies. Aliment Pharmacol Ther 2013; 38: Sonnenberg A. The effects of environment and lifestyle on gastroesophageal reflux disease. Dig Dis 2011; 29: Runge TM, Abrams JA, Shaheen NJ. Epidemiology of Barrett s esophagus and esophageal adenocarcinoma. Gastroenterol Clin North Am 2015; 44: Pera M, Manterola C, Vidal O, Grande L. Epidemiology of esophageal adenocarcinoma. JSurgOncol2005; 92: Marsman WA, Tytgat GN, ten Kate FJ, van Lanschot JJ. Differences and similarities of adenocarcinomas of the esophagus and esophagogastric junction. J Surg Oncol 2005; 92: Chandrasoma P, Wickramasinghe K, Ma Y, DeMeester T. Adenocarcinomas of the distal esophagus and gastric cardia are predominantly esophageal carcinomas. Am J Surg Pathol 2007; 31: Vial M, Grande L, Pera M. Epidemiology of adenocarcinoma of the esophagus, gastric cardia, and upper gastric third. Recent Results Cancer Res 2010; 182: Gertler R, Stein HJ, Loos M, Langer R, Friess H, Feith M. How to classify adenocarcinomas of the esophagogastric junction: as esophageal or gastric cancer? Am J Surg Pathol 2011; 35: Aliment Pharmacol Ther 2015; 42: