Alimentary Pharmacology and Therapeutics
Oesophageal signet 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. E-mail:
[email protected]
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 signet ring cell cancers constitute a complication of gastro-oesophageal reflux disease. Methods In a large national database of histopathology records, we accumulated 91 802 patients with Barrett’s oesophagus (BE), 2817 with oesophageal nonsignet ring adenocarcinoma (EAC) and 278 with oesophageal signet 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 signet ring cell carcinoma. Patients with oesophageal adenocarcinoma and signet 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 signet ring cell carcinoma, rather than the usual type of oesophageal adenocarcinoma, remain unknown. Aliment Pharmacol Ther 2015; 42: 1222–1231
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ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13395
Oesophageal signet 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, signet 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 signet ring cell cancers are unrelated to those found in the stomach.1 Previous studies of this oesophageal signet 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 signet ring cells, those with the signet ring cell type have a worse prognosis.3–8 Because of the relatively infrequent occurrence of oesophageal signet 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
(a)
(b)
histopathological features of rare conditions. In the recent past, this database has been utilised for a variety of patho-epidemiological studies.9–15 We hypothesised that oesophageal signet 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 signet ring cells. Accordingly, the aim of the present cross-sectional study was to use the Miraca database to compare the clinical epidemiology of oesophageal signet ring cell carcinoma with three groups of patients: those with signet ring cell cancer of the stomach, nonsignet 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
(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 signet ring cells. Aliment Pharmacol Ther 2015; 42: 1222–1231 ª 2015 John Wiley & Sons Ltd
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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 signet ring cell carcinoma, gastric signet 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 1224
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, signet ring, papillary, with neuroendocrine differentiation, with squamous differentiation).18 Signet ring cell cancer is a histological subtype of adenocarcinoma that consists predominately (more than 50%) or exclusively of signet 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 90% 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 signet ring cell carcinoma or oesophageal adenocarcinoma without features of signet ring cells to patients who harboured Barrett’s oesophagus alone. In addition, we compared patients with oesophageal to those with gastric signet 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 Aliment Pharmacol Ther 2015; 42: 1222–1231 ª 2015 John Wiley & Sons Ltd
Oesophageal signet ring cell cancer oesophageal signet 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 signet ring cell carcinoma than oesophageal adenocarcinoma. Besides the aforementioned symptoms, patients with oesophageal adenocarcinoma and signet 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 signet ring cell cancers were associated with less dysphagia, but more pain, weight loss, dyspepsia, nausea and vomiting than oesophageal signet 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 signet ring cell carcinoma respectively. The average family income was $48 000, $46 000 and $46 000 respectively. In all three patient groups alike, the average percentage of Whites and Blacks was 79% and 10% respectively. All four parameters were equally distributed among patients with Barrett’s oesophagus, oesophageal adenocarcinoma and signet ring cell carcinoma. Compared to patients with
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 487 587 patients who had EGD with biopsies during the study period, we extracted a group of 95 155 patients: 91 802 (967%) with Barrett’s oesophagus, 2817 (3.0%) with oesophageal nonsignet ring adenocarcinoma, 278 (0.3%) with oesophageal signet ring cell carcinoma and 258 with gastric signet ring cell carcinoma. Thus, of the 3095 patients with oesophageal adenocarcinoma, 9.0% had signet 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 signet 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 signet ring cell carcinoma were 3.1 years older. Thus, the age distribution of oesophageal signet 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
Table 1 | Age and sex comparisons of the four patient groups Age
N
Mean
SD
t-value
P-value
Barrett’s oesophagus Oesophageal adenocarcinoma Oesophageal signet ring cell cancer Gastric signet ring cell cancer*
91 802 2817 278 258
63.69 68.03 66.74 65.34
11.95 11.17 11.81 13.41
Reference 20.303 4.306 1.282
