Population Based Time Trends in the Epidemiology and Mortality of Gastroesophageal Junction and Esophageal Adenocarcinoma

Abstract

Background

Limited data are available on the epidemiology of gastroesophageal junction adenocarcinoma (GEJAC), particularly in comparison to esophageal adenocarcinoma (EAC). With the advent of molecular non-endoscopic Barrett’s esophagus (BE) detection tests which sample the esophagus and gastroesophageal junction, early detection of EAC and GEJAC has become a possibility and their epidemiology has gained importance.

Aims

We sought to evaluate time trends in the epidemiology and survival of patients with EAC and GEJAC in a population-based cohort.

Methods

EAC and GEJAC patients from 1976 to 2019 were identified using ICD 9 and 10 diagnostic codes from the Rochester Epidemiology Project (REP). Clinical data and survival status were abstracted. Poisson regression was used to calculate incidence rate ratios (IRR). Survival analysis and Cox proportional models were used to assess predictors of survival.

Results

We included 443 patients (287 EAC,156 GEJAC). The incidence of EAC and GEJAC during 1976–2019 was 1.40 (CI 1.1–1.74) and 0.83 (CI 0.61–1.11) per 100,000 people, respectively. There was an increase in the incidence of EAC (IRR = 2.45, p = 0.011) and GEJAC (IRR = 3.17, p = 0.08) from 2000 to 2004 compared to 1995–1999, plateauing in later time periods. Most patients had associated BE and presented at advanced stages, leading to high 5-year mortality rates (66% in EAC and 59% in GEJAC). Age and stage at diagnosis were predictors of mortality.

Conclusion

The rising incidence of EAC/GEJAC appears to have plateaued somewhat in the last decade. However, both cancers present at advanced stages with persistently poor survival, underscoring the need for early detection.

Introduction

Population based studies have shown that the incidence of esophageal adenocarcinoma (EAC) and gastroesophageal junction adenocarcinoma (GEJAC) has risen rapidly over the last 3 decades [1–3]. A recent international study predicted an increase in the incidence of EAC by approximately 75% between 2005 and 2030 [4]. Outcomes for EAC and GEJAC remain dismal, with 5-year survival rates of less than 20% [2, 3].

The classification of GEJAC has historically been complicated by variable definitions and interpretations of site of origin. Siewert et al. proposed a GEJAC classification scheme in 1996, based on the location relative to the gastroesophageal junction (GEJ)—Types I–III [5, 6]. Specifically, Type I are tumors of distal esophagus that infiltrate the GEJ from above, Type II originate from the cardia, and Type III being carcinoma of the subcardia that infiltrate the GEJ from below [6].

Due to their anatomic proximity, comparisons between EAC and GEJAC have previously shown smoking, obesity, and the presence of gastro-esophageal reflux disease (GERD) symptoms to be associated with an increased risk of both malignancies [3]. Siewert Type I adenocarcinomas have histological and epidemiological features similar to EAC [7]. On the other hand, Siewert Type III GEJAC more closely resemble non-cardia gastric cancers. Type II tumors demonstrate characteristics intermediate between those of Type I and Type III cancers [7]. Localized, superficial disease may be managed endoscopically for both GEJAC and EAC [8]. Unfortunately, 5-year survival rates are poor especially in those presenting with advanced disease [3].

Barrett’s esophagus (BE) is a well recognized precursor for most EACs [9, 10]. Hence, BE screening in those with risk factors and endoscopic surveillance to detect dysplasia in BE patients, are recommended by all gastroenterological societies. On the other hand, there are no clearly guideline-defined screening recommendations for GEJAC, despite the similar risk factors, association with intestinal metaplasia, and overlap of cell of origin with EAC [11]. Screening for BE has gained more attention with the advent of minimally invasive non-endoscopic screening techniques [12–14]. Swallowed, esophageal cell collection devices allow sampling from both the esophagus and GE junction [15].

It is unclear what epidemiologic trends of EAC or GEJAC have occurred with recommendations for BE screening and surveillance over the recent decades. Furthermore, comparative trends between GEJAC and EAC regarding survival outcomes are also unknown. We therefore investigated trends in the incidence and survival of GEJAC and EAC using a population-based cohort from southeastern Minnesota from 1976 to 2019. We also compared demographic characteristics of EAC and GEJAC patients as well as factors associated with mortality in the same cohort.

Materials and Methods

The Institutional Review Boards of Mayo Clinic and Olmsted Medical Center approved this study.

Rochester Epidemiology Project

The Rochester Epidemiology Project (REP), formed in 1966, is an initiative of the Mayo Clinic, Olmsted Medical Center, and the Rochester Family Medicine Clinic in Olmsted County, Minnesota, containing a linked database of medical information for all residents of Olmsted County, Minnesota. Beginning in 2010, this medical record linkage system was serially expanded to include counties in southern Minnesota and western Wisconsin. A high percentage of all medical records of residents in these counties are captured by the REP; all medical data are available for 400,065 patients in this area with a population of 473,064 (84.5%) according to the 2017 US Census [16]. The availability of a centralized index to access patient medical records makes this database well-suited for conducting population-based observational studies [16–19].

Search Strategy and Data Abstraction

For this study, we included patients from the 11 counties (Olmsted, Dodge, Mower, Goodhue, Fillmore, Wabasha, Winona, Houston, Freeborn, Steele, and Rice) of southeastern Minnesota. Incidence calculation was done using only patients from Olmsted County, due to inconsistent coverage by the REP records of the residents from other counties for the period of 1976–2010. Cases of primary malignant neoplasm of esophagus and cardia (except malignant lymphomas) were identified from 1976 to 2019 by performing an electronic search of the REP using the International Classification of Diseases, Ninth Edition and Tenth Edition codes for malignant neoplasm of esophagus (150.0–150.9 and C15.0–15.9, respectively) and malignant neoplasm of cardia (151 and C16, respectively).

GEJAC was categorized according to the classification proposed by Siewert et al. based on the results of endoscopy with retroflexed view of the esophagogastric junction, contrast radiography, computed tomography and intraoperative findings [5]. Type I was defined as tumors in which the center was located 1 cm to 5 cm above the GEJ. Type II was defined as tumors, in which the center is located between 1 cm above and 2 cm below the GEJ, and Type III, in which the center was located 2 cm to 5 cm below the GEJ. EAC was categorized as tumors centered 5 cm above the GEJ. Given the similar features between Siewert Type I adenocarcinomas and EAC, our patients were divided into two cohorts: EAC (consisting of patients with EAC and Type I GEJAC) and GEJAC (consisting of patients from Type II and Type III GEJAC) [5, 6]. Categorization was completed after detailed review of endoscopic and pathology reports performed in conjunction with the senior author PGI). The presence of BE was determined by review of endoscopic and pathology reports, with both endoscopic and histologic criteria required for diagnosis.

Electronic medical records of all cases were reviewed, and the following were abstracted: demographics, symptoms at presentation, endoscopic findings, histology, depth of tumor invasion (T stage), presence of lymph node metastasis (N stage), presence of distant metastasis (M stage), overall stage at diagnosis, treatment (endoscopic resection, surgery, chemotherapy and radiotherapy or palliative treatment) and survival status. To standardize disease staging, we opted to convert all staging to localized (Tis and T1), locally advanced (T2–T4 + N0/N1 + M0), and metastatic (any T + any N + M1). Lesions which belonged to Paris Type I and IIA-IIC, were < 20 mm in diameter and moderately to well differentiated were treated endoscopically [20]. Lesions which were excavated, with undifferentiated cancer, malignant lymphadenopathy on EUS and advanced tumor stage (> T1) were treated with surgery alone or chemoradiation therapy, according to treatment guidelines.

Statistical Analysis

Data were summarized as mean (± standard deviation) for quantitative variables and proportions (%) for discrete variables. Baseline group comparisons were done using the Wilcoxon rank-sum test for quantitative variables and Pearson’s chi-square test for discrete variables. The Poisson distribution was used to calculate incidence rates per 100,000 person-years with 95% confidence intervals. Poisson regression models were used to compare incidence between time periods in Olmsted County, and assess risk factors. Incidence rate ratios and 95% confidence intervals are reported as summaries from these models. The Kaplan–Meier method was used to estimate death rates post-diagnosis and Cox proportional hazards models (univariate and multivariate) were used to assess the association of risk factors with risk of death post cancer diagnosis. All analyses were done using SAS version 9.4 (SAS Institute, Cary, NC). A p value less than 0.05 was considered statistically significant.

Results

A total of 443 patients (287 EAC patients and 156 GEJAC) were included in the study. Baseline variables are shown in (Table 1). The groups had comparable baseline characteristics, with male predominance, and comparable mean BMI and mean age at diagnosis. The majority of patients (61% in EAC vs 62% in GEJAC, p = 0.81) in both groups had associated BE and had symptoms suggestive of GERD (heartburn, regurgitation and acid reflux; 61.3% in EAC vs 60.9% in GEJAC, p = 0.93). Concerningly, a significant portion of patients in both cohorts presented at an advanced stage, with more than one-third in each cohort presenting with distant metastasis (35.5% in EAC vs 36.5% in GEJAC, p = 0.62).

Table 1.

Baseline characteristics of patients with esophageal adenocarcinoma (EAC) (EAC and Siewert I tumors) and gastroesophageal junction adenocarcinoma (GEJAC) (Siewert II and III tumors) diagnosed in Southeastern Minnesota

	EAC (N = 287)	GEJAC (N = 156)	Total (N = 443)	p value
Male sex, N (%)	228 (79.4%)	132 (84.6%)	360 (81.3%)	0.1826
Mean (SD) age at diagnosis	65.3 (13.1)	64.8 (13.3)	65.1 (13.2)	0.9665
Mean (SD) BMI	27.2 (6.2)	27.5 (6.0)	27.3 (6.2)	0.3584
History of smoking	173 (61.6%)	81 (51.9%)	254 (58.1%)	0.0503
History of alcohol use	160 (55.7%)	85 (54.5%)	245 (55.3%)	0.7986
Presence of BEa	175 (61.0%)	97 (62.2%)	272 (61.4%)	0.8037
Presence of Diaphragmatic Hernia	112 (39.0%)	60 (38.5%)	172 (38.8%)	0.9076
Presence of GERD symptoms	176 (61.3%)	95 (60.9%)	271 (61.2%)	0.9299
T stage at diagnosis
T0 or T1	34 (16.0%)	27 (22.3%)	61 (18.3%)	0.4246b
> T1	178 (83.9%)	94 (77.7%)	272 (81.7%)
N stage at diagnosis
N1	120 (56.6%)	78 (65.0%)	198 (59.6%)	0.1341
M stage at diagnosis
M1	99 (35.1%)	56 (36.1%)	155 (35.5%)	0.8307
Stage				0.6173
Localized	29 (10.1%)	20 (12.8%)	49 (11.1%)
Locally advanced	156 (54.4%)	79 (50.6%)	235 (53.0%)
Metastatic	102 (35.5%)	57 (36.5%)	159 (35.9%)

^aDefined as endoscopic and/or histologic criteria

^bp value computed using all individual staging categories

In Olmsted County, 77 and 46 patients had EAC and GEJAC, respectively. These values were utilized for calculation of incidence rates. The overall incidence of EAC and GEJAC in Olmsted County during 1976–2019 was 1.40 (95% CI 1.1–1.74) and 0.83 (95% CI 0.61–1.11) per 100,000 person-years, respectively. There was a statistically significant increase in the incidence of EAC from 1990–1994 to 1995–1999 (IRR 4.71, CI 1.04–21.25, p = 0.04) and from 1995–1999 to 2000–2004 (IRR 2.45, CI 1.23–4.88, p = 0.01) (Table 2) (Fig. 1). Similar increase was observed, though less pronounced, for GEJAC during the same time frame (1990–1994 to 1995–1999 IRR 1.28, CI 0.21–7.64, p = 0.79; 1995–1999 to 2000–2004 IRR 3.17, CI 0.88–11.36, p = 0.08) (Table 3) (Fig. 1). The EAC incidence decreased (2000–2004 to 2005–2009 IRR 0.31, p < 0.001) to approximately the same level as GEJAC from 2005 onward, where both stayed relatively constant. Older age was associated with a significant increase in the incidence of both EAC (IRR 1.05, p < 0.01) and GEJAC (IRR 1.06, p < 0.01). Male gender was also found to be significantly associated with an increased incidence of EAC (IRR 3.72, p < 0.01) and GEJAC (IRR 10.64, p < 0.01) (Tables 2, 3).

Table 2.

Poisson regression model for predicting incidence trends for esophageal adenocarcinoma (EAC)

	IRR (95% CI)	p value
1990–1994 vs 1985–1989	1.79 (0.16–19.69)	0.64
1995–1999 vs 1985–1989	8.41 (1.09–65.14)	0.042
2000–2004 vs 1985–1989	20.64 (2.81–151.22)	0.003
2005–2009 vs 1985–1989	6.36 (0.82–49.27)	0.077
2010–2014 vs 1985–1989	5.11 (0.65–39.92)	0.12
2015–2019 vs 1985–1989	5.04 (0.65–39.09)	0.12
1995–1999 vs 1990–1994	4.71 (1.04–21.25)	0.044
2000–2004 vs 1995–1999	2.45 (1.23–4.88)	0.011
2005–2009 vs 2000–2004	0.31 (0.15–0.61)	0.001
2010–2014 vs 2005–2009	0.80 (0.34–1.89)	0.62
2015–2019 vs 2010–2014	0.99 (0.42–2.32)	0.98
Age per 1 year	1.05 (1.04, 1.07)	< 0.0001
Male vs female	3.72 (2.23, 6.21)	< 0.0001

The bold reflects statistical significance

Cases: 1985–1989: 1, 1990–1994: 2, 1995–1999: 11, 2000–2004: 31, 2005–2009: 11, 2010–2014: 10, 2015–2019:11; Total county population person-years = 5,510,541

Fig. 1.

Population based incidence of EAC and GEJAC in Southeastern Minnesota from 1976 to 2019

Table 3.

Poisson regression model for predicting incidence trends for gastroesophageal junction adenocarcinoma (GEJAC)

	IRR (95% CI)	p value
1995–1999 vs 1990–1994	1.28 (0.21–7.64)	0.79
2000–2004 vs 1990–1994	4.04 (0.90–18.25)	0.07
2005–2009 vs 1990–1994	3.17 (0.69–14.48)	0.14
2010–2014 vs 1990–1994	3.06 (0.68–13.83)	0.15
2015–1019 vs 1990–1994	2.24 (0.48–10.38)	0.30
2000–2004 vs 1995–1999	3.17 (0.88–11.36)	0.08
2005–2009 vs 2000–2004	0.78 (0.33–1.85)	0.58
2010–2014 vs 2005–2009	0.97 (0.41–2.27)	0.94
2015–2019 vs 2010–2014	0.73 (0.30–1.76)	0.49
Age per 1 year	1.06 (1.04, 1.07)	< 0.0001
Male vs female	10.64 (4.20–26.99)	< 0.0001

The bold reflects statistical significance

Cases: 1985–1989: 0, 1990–1994: 2, 1995–1999: 3, 2000–2004: 11, 2005–2009: 10, 2010–2014: 11, 2015–2019:9; Total county population person-years = 5,510,541

In total, 290 patients died during follow-up with a the median follow-up time of 7.0 years. Patients with EAC appeared to have poorer survival than those with GEJAC, but this was not statistically significant (univariate p = 0.19, Table 4). The Kaplan–Meier curve (Fig. 2) shows that the cumulative mortality rate at 1 and 5 years for GEJAC was 26.5% and 59.1% compared to 37.5% and 65.7% for EAC. Median survival time for GEJAC was 2.70 years (IQR = 0.93–12.86) and 1.75 years (IQR = 0.55–11.29) for EAC. Univariate and multivariate predictors of mortality are shown in (Table 4). In a multivariable model, older age at diagnosis (HR 1.03, p < 0.01) and metastatic disease stage (HR 2.61 vs localized, p < 0.0001) were found to be significant predictors of death. The risk of death was not significantly influenced by the type of tumor (GEJAC or EAC), gender, BMI, history of smoking, history of alcohol use, presence of diaphragmatic hernia, or presence of BE (Table 4).

Table 4.

Univariate and multivariate Cox models for predicting risk of death after diagnosis of esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma

Variable	Univariate Hazard ratio (95% CI)	Univariate p value	Multivariate Hazard ratio (95% CI)	Multivariate p value
GEJAC vs EAC	0.85 (0.66,1.08)	0.1864	0.91 (0.71,1.16)	0.4395
Male sex	1.06 (0.78,1.44)	0.7056	1.15 (0.83,1.58)	0.3988
Age at diagnosis	1.02 (1.01,1.03)	< 0.0001	1.03 (1.02,1.04)	< 0.0001
BMI	0.99 (0.97,1.007)	0.2000	0.99 (0.97,1.01)	0.5243
History of smoking	1.06 (0.83,1.34)	0.6434	1.12 (0.88,1.43)	0.3623
History of alcohol use	1.02 (0.80, 1.28)	0.8990	1.03 (0.81, 1.30)	0.8217
Presence of Diaphragmatic Hernia	1.00 (0.79,1.28)	0.9702	0.94 (0.73,1.20)	0.6173
Presence of BEa	0.87 (0.69,1.11)	0.2684	0.95 (0.74,1.21)	0.6534
Staging
Localized	Reference	–	Reference	–
Locally advanced	1.30 (0.85, 1.97)	0.2271	1.42 (0.91, 2.19)	0.1193
Metastatic	2.44 (1.60, 3.74)	< 0.0001	2.61 (1.68, 4.07)	< 0.0001

The bold reflects statistical significance

^aDefined as endoscopic and/or histologic criteria

Fig. 2.

Overall mortality of patients with EAC and GEJAC diagnosed from 1976 to 2019 in Southeastern Minnesota

A subset analysis demonstrated that the presence of BE was not significantly associated with mortality of patients with GEJAC (HR 0.70, p = 0.09) or EAC (HR 0.99, p = 0.95). Diagnosis year was also not significantly associated with 5-year patient survival when comparing 5-year diagnosis time groups (overall p = 0.18) or by year (HR 0.99, CI 0.97–1.01, p = 0.17).

Discussion

This population-based study demonstrates trends in the incidence of EAC and GEJAC from 1976 to 2019 and risk factors associated with mortality for these malignancies. Overall, our study displays that the incidence of GEJAC and EAC appears to have risen and subsequently plateaued in the last four decades, with climbing incidence until 2004 and then relative stability since that time. Regarding disease risk factors, our study postulates that EAC and GEJAC may share many of the same core predilections.

The incidence trends of EAC and GEJAC that we present, mirror those from previous studies [3, 21]. Data from the SEER registry, also demonstrate a substantial increase in the incidence of EAC and a more gradual increase in the incidence of GEJAC, both of which stabilized after 1990 [3]. Our study showed a similar, however temporally shifted, trend in which there was an increase in the incidence of EAC and GEJAC during the 2000s with a subsequent plateau after 2009. Similar increases in incidence have been reported in Sweden, Canada, Great Britain and much of Europe [22–25]. However, it is important to note that previous studies have stated that the true incidence of GEJAC is difficult to confidently ascertain due these inconsistencies in classification [26, 27]. As previously mentioned, the Siewert classification scheme was not published until 1996 and even then, was not always consistently adopted thereafter [5]. Discrepancies in classification could impact incidence especially considering the close overlap with EAC. However, we actively mitigated this concern. In our study all pathology, imaging, and clinical notes were manually reviewed to ensure correct, and standardized, classification of lesions. As such, the epidemiologic shifts we report are unlikely to be due to misclassification of disease.

We also demonstrated a plateau in the incidence of EAC and GEJAC after 2009. There are several potential explanations for this finding. First, increased endoscopic surveillance of BE has led to earlier detection and treatment of dysplasia potentially slowing rates of disease progression [28]. Widespread availability and use of proton pump inhibitors may also be a factor in this phenomenon, as this class of medications has been associated with slower rates of BE progression [29, 30]. Lastly, decreasing rates of tobacco use (a known risk factor for EAC and GEJAC) may have also contributed to this stabilization of neoplasia incidence [31–33].

Our study found several similarities amongst the general characteristics of EAC and GEJAC patients. These included GERD, male gender, older age and elevated BMI. These characteristics are also included in BE screening recommendations. Indeed, over 60% of both EAC and GEJAC patients had associated BE [21, 34]. Given their physical proximity, it is not surprising that GEJAC and EAC would share many risk factors. While many studies have reported an association between GERD and both EAC and GEJAC [35, 36], this association appears to be stronger with EAC compared to GEJAC [34].

In our study, the five-year overall survival rates for EAC and GEJAC were higher than previously reported in a 2012 population-based study (5-year survival rate of 27% and 33% for EAC and GEJAC) [37]. While other studies have reported improvements in survival rates over the last five decades [2, 3, 38, 39] we did not observe a similar phenomenon. It is possible that the higher survival rates observed by us reflects access to a high quality, quaternary referral center for diagnosis and treatment. Given the population-based nature of this study, selection bias is unlikely to account for the noted improved survival. The only factors found to significantly increase the risk of death in both cohorts were older age and metastases at diagnosis, further supporting the importance of early detection.

Our study has many strengths. We used a medical record linkage system (REP) which contains the medical records of most residents in SE Minnesota capturing all residents, regardless of age, sex, ethnicity, disease, socioeconomic, or insurance status and has been consistently used to conduct population-based studies [16–19]. Another asset of this database is that it allowed for longer length of follow-up (dating back to 1976), and construction of a multivariate model that considered several factors that could affect the risk of death from EAC/GEJAC.

Limitations of our study include the lack of availability of a larger cohort of patients suffering from Type III GEJAC. This prevented us from comparing Type III demographic trends to that of Type I and Type II GEJAC. Also, BMI and GERD status are not available yearly for all county residents, so we were not able to evaluate the effect of these variables on the incidence of EAC and GEJAC in our study. Lastly, as the AJCC classification has evolved over the years, classifying cases according to one classification schema might have affected the internal validity of our results. However, this was mitigated by manual review and a standardized staging classification.

In conclusion, the incidence of EAC and GEJAC in SE Minnesota has significantly increased during the time period of 1976–2009, appearing plateauing after 2009. Overall, EAC was not associated with poorer outcomes than those with GEJAC. In both entities, age at diagnosis and advanced disease stage were found to be significant predictors of death. Older age, male sex, elevated BMI, and GERD symptoms appeared to be shared risk factors. These findings support, the efforts for early detection, especially in those who carry multiple risk factors for these diseases.

Abbreviations

BE

Barrett’s esophagus

BMI

Body Mass Index

CCD

Cell collection device

CI

Confidence interval

EAC

Esophageal adenocarcinoma

EGD

Esophagogastroduodenoscopy

GEJAC

Gastro-esophageal junction adenocarcinoma

GERD

Gastro-esophageal reflux disease

IQR

Inter-quartile range

IRR

Incidence rate ratio

REP

Rochester Epidemiology Project

SD

Standard deviation

SEER

Surveillance epidemiology and end-results