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Preface

Esophageal cancer is a major cause of cancer-related mortality worldwide. In the

Western world, there has been a change in esophageal cancer presentation due to the
rapidly rising incidence of distal esophageal adenocarcinoma. The heterogeneity of
the disease and its aggressive clinical course has rendered the task of the develop-
ment of an optimal multimodal management approach a challenging one. On the
brighter side, there has been a noted surge in exploring novel therapeutic approaches
in medical, surgical, and radiation therapy, including immune-based and targeted
approaches, as well as palliative and nutritional supportive care.
Esophageal Cancer: Prevention, Diagnosis and Therapy, second edition, pro-
vides a unique and updated comprehensive review of the current epidemiology,
molecular biology, staging, and treatment of cervical, thoracic, and junctional
tumors. In addition, it highlights the differences in etiology, prognosis, and manage-
ment of squamous cell and adenocarcinomas of the esophagus.
Promising novel diagnostic approaches and an in-depth review of cellular and
molecular biology of premalignant lesions, the role of immunotherapy, as well as
palliative and nutritional aspects are discussed in depth. We hope this second edition
will further incite the interest of specialists from various diagnostic and therapeutic
disciplines and will promote further research in the field of esophageal cancer.

Atlanta, GA, USA Nabil F. Saba

Bassel F. El-Rayes

vii
Acknowledgments

The editors acknowledge

Anthea Hammond for editorial contribution

Nefertiti Hawthorne for communication

ix
Contents

1 Epidemiology and Risk Factors for Esophageal Cancer������������������������   1

Keshini Vijayan and Guy D. Eslick
2 Cellular and Molecular Biology of Esophageal Cancer ������������������������ 33
Alfred K. Lam
3 Pathology of Premalignant and Malignant Disease
of the Esophagus���������������������������������������������������������������������������������������� 61
Jessica Tracht, Brian S. Robinson, and Alyssa M. Krasinskas
4 Barrett’s Esophagus: Diagnosis and Management �������������������������������� 83
Adam Templeton, Andrew Kaz, Erik Snider, and William M. Grady
5 Chemoprevention of Esophageal Cancer������������������������������������������������ 113
Elizabeth G. Ratcliffe, Mohamed Shibeika, Andrew D. Higham,
and Janusz A. Jankowski
6 Staging of Cancer of the Esophagus and
Esophagogastric Junction ������������������������������������������������������������������������ 127
Thomas W. Rice and Eugene H. Blackstone
7 Radiologic Assessment of Esophageal Cancer���������������������������������������� 139
Valeria M. Moncayo, A. Tuba Kendi, and David M. Schuster
8 Role of Endoscopy in the Diagnosis, Staging,
and Management of Esophageal Cancer ������������������������������������������������ 159
Michelle P. Clermont and Field F. Willingham
9 Principles and Approaches in Surgical Resection
of Esophageal Cancer�������������������������������������������������������������������������������� 185
Nassrene Elmadhun and Daniela Molena
10 Principles of Radiation Therapy�������������������������������������������������������������� 199
Neil Bryan Newman and A. Bapsi Chakravarthy
11 The Multidisciplinary Management of Early-Stage
Cervical Esophageal Cancer �������������������������������������������������������������������� 221
Jarred P. Tanksley, Jordan A. Torok, Joseph K. Salama,
and Manisha Palta

xi
xii Contents

12 The Multidisciplinary Management of Early-Stage

Thoracic Esophageal Cancer�������������������������������������������������������������������� 237
Brandon Mahal and Theodore S. Hong
13 The Multidisciplinary Management of Early Distal Esophageal
and Gastroesophageal Junction Cancer�������������������������������������������������� 251
Megan Greally and David H. Ilson
14 Systemic Treatment for Metastatic or Recurrent Disease���������������������� 275
Daniel H. Ahn and Tanios Bekaii-Saab
15 Immunotherapy in Esophageal Cancer �������������������������������������������������� 289
Megan Greally and Geoffrey Y. Ku
16 Palliative Approaches in Esophageal Cancer������������������������������������������ 311
Baiwen Li, Shanshan Shen, Cicily T. Vachaparambil,
Vladimir Lamm, Qunye Guan, Jie Tao, Hui Luo, Huimin Chen,
and Qiang Cai
17 Nutritional Support in Esophageal Cancer �������������������������������������������� 323
Tiffany Barrett
Epidemiology and Risk Factors
for Esophageal Cancer 1
Keshini Vijayan and Guy D. Eslick

Introduction

Esophageal cancer has a long and fascinating history and the epidemiology is geo-
graphically dynamic with wide variation from region to region [1]. There have been
several recent publications reporting the global epidemiology of esophageal cancer.
The majority of these published papers have used the International Agency for
Research on Cancer (IARC) databases (e.g., GLOBOCAN 2012) data as the basis
for any data analysis conducted. Esophageal cancer remains the eighth most com-
mon cancer worldwide, with 455,784 new cases in 2012, and it is the sixth most
common cause of death from a cancer with approximately 400,156 deaths annually
[2]. Figures 1.1 and 1.2 show the breakdown of new cases and deaths associated
with esophageal cancer by gender and also comparing developed and developing
countries. Future predictive models estimate that by the year 2035, the number of
new cases of esophageal cancer will almost double to 808,508 and the number who
will die from the disease will reach 728,945 individuals in that year, making it an
enormous cancer burden globally [3]. In fact, it is one of a handful of cancers for
which the number of new cases in some regions of the world is actually increasing
[4], with average annual increase ranging from 3.5% in Scotland to 8.1% in Hawaii
[5]. It is disappointing, given the increases in rates of esophageal cancer and the
continued poor prognosis for this cancer, that it receives very little attention relative
to other cancers; however, there has recently been a call for a greater research focus
and funding for male-dominated cancers like esophageal cancer [6]. There is an
urgent need for cancer research organizations to provide increased and dedicated
funding to gain a greater understanding of the dynamic epidemiology of esophageal
cancer. This will be crucial to determine the causes and risk factors associated with

K. Vijayan · G. D. Eslick (*)

The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney,
Sydney Medical School, Nepean Hospital, Penrith, NSW, Australia
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 1

N. F. Saba, B. F. El-Rayes (eds.), Esophageal Cancer,
https://doi.org/10.1007/978-3-030-29832-6_1
2 K. Vijayan and G. D. Eslick

Estimated New Cases Estimated Deaths

Male Female Male Female

Lung, bronchus, & trachea Breast Lung, bronchus, & trachea Breast
1,241,600 1,676,600 1,098,700 521,900
Prostate Colon & rectum Liver Lung, bronchus, & trachea
1,111,700 614, 300 521,000 491,200
Colon & rectum Lung, bronchus, & trachea Stomach Colon & rectum
746,300 583,100 469,000 320,300
Stomach Cervix uteri Colon & rectum Cervix uteri
631,300 527,600 373,600 265,700
Liver Stomach Prostate Stomach
554,400 320,300 307,500 254,100
Urinary bladder Corpus uteri Esophagus Liver
Worldwide 330,400 319,600 281,200 224,500
Esophagus Ovary Pancreas Pancreas
323,000 238,700 173,800 156,600
Non-Hodgkin lymphoma Thyroid Leukemia Ovary
217,600 229,900 151,300 151,900
Kidney Liver Urinary bladder Esophagus
213,900 228,100 123,100 119,000
Leukemia Non-Hodgkin lymphoma Non-Hodgkin lymphoma Leukemia
200,700 168,100 115,400 114,200
All sites* All sites* All sites* All sites*
7,427,100 6,663,000 4,653,400 3,548,200

Male Female Male Female

Prostate Breast Lung, bronchus, & trachea Lung, bronchus, & trachea
758,700 793,700 416,700 209,900
Lung, bronchus, & trachea Colon & rectum Colon & rectum Breast
490,300 338,000 175,400 197,600
Colon & rectum Lung, bronchus, & trachea Prostate Colon & rectum
398,900 267,900 142,000 157,800
Urinary bladder Corpus uteri Stomach Pancreas
196,100 167,900 106,700 91,300
Stomach Ovary Pancreas Stomach
175,100 99,800 93,100 68,000
Developed Kidney Stomach Liver Ovary
125,400 99,400 80,400 65,900
Countries Non-Hodgkin lymphoma Thyroid Urinary bladder Liver
101,900 93,100 58,900 42,700
Melanoma of skin Pancreas Esophagus Leukemia
99,400 92,800 56,100 40,300
Pancreas Melanoma of skin Leukemia Cervix uteri
94,700 91,700 51,300 35,500
Liver Non-Hodgkin lymphoma Kidney Corpus uteri
92,000 88,500 47,900 34,700
All sites* All sites* All sites* All sites*
3,243,500 2,832,400 1,591,500 1,287,000

Male Female Male Female

Lung, bronchus, & trachea Breast Lung, bronchus, & trachea Breast
751,300 882,900 682,000 324,300
Liver Cervix uteri Liver Lung, bronchus, & trachea
462,400 444,500 440,600 281,400
Stomach Lung, bronchus, & trachea Stomach Cervix uteri
456,200 315,200 362,300 230,200
Prostate Colon & rectum Esophagus Stomach
353,000 276,300 225,100 186,100
Colon & rectum Stomach Colon & rectum Liver
347,400 220,900 198,200 181,800
Developed Esophagus Liver Prostate Colon & rectum
255,300 185,800 165,500 162,500
Countries Urinary bladder Corpus uteri Leukemia Esophagus
134,300 151,700 100,000 103,700
Lip, oral cavity Ovary Pancreas Ovary
130,900 139,000 80,700 86,000
Leukemia Thyroid Non-Hodgkin lymphoma Leukemia
120,400 136,800 74,500 73,800
Non-Hodgkin lymphoma Esophagus Lip, oral cavity Pancreas
115,800 114,400 74,500 65,300
All sites* All sites* All sites* All sites*
4,183,600 3,830,600 3,061,900 2,261,200

Fig. 1.1 The incidence and mortality for all cancers, note esophageal cancer

developing this lethal cancer and, more importantly, form the cornerstone of devel-
oping any prevention strategies.
There are two main histological types of esophageal cancer: adenocarcinoma
and squamous cell carcinoma [7]. The epidemiology and risk factors for esophageal
cancer vary substantially by these two different histological cell types. Published
studies usually categorize esophageal cancer studies into either “adenocarcinoma”
or “squamous cell carcinoma” histological types or a combined “esophageal can-
cer” grouping which contains both histological types.
1 Epidemiology and Risk Factors for Esophageal Cancer 3

Males Females

Eastern Asia 16.9 5.4

Southern Africa 13.7 6.7

Eastern Africa 11.9 7.8

Northern Europe 8.1 2.7

South America 7.0 2.0

Western Europe 6.8 1.6

South-Central Asia 6.5 3.9

Centrl and Eastern Europe 5.6 0.8

Northern America 5.4 1.1

Australia/New Zealand 5.4 1.7

Caribbean 4.6 1.2

Middle Africa 4.2 2.0

Melanesia 3.6 1.4

South-Eastern Asia 3.6 1.0

Southern Europe 3.2 0.6

Micronesia/Polynesia 3.1 0.2

Western Asia 2.9 2.1

Northern Africa 2.4 1.5

Central America 1.7 0.6

Western Africa 0.8 0.4

20 10 0 10 20
Age-standardized rate per 100,000

Fig. 1.2 Age-standardized incidence rates of esophageal cancer among males and females glob-
ally (GLOBOCAN 2012)

Epidemiology

Incidence

Esophageal Adenocarcinoma
The global age-standardized incidence rate of esophageal adenocarcinoma (EAC)
was estimated at 0.7 per 100,000 (1.1 in men and 0.3 in women) in 2012, with
52,000 estimated cases occurring during the year [8]. The highest incidence rates
4 K. Vijayan and G. D. Eslick

were observed in Northern and Western Europe (3.4 in men and 0.6 in women),
Northern America (3.5 in men and 0.4 in women), and Oceania (3.4 in men and
0.6 in women)—contributed to mainly by Australia and New Zealand—while the
lowest rates were found in Eastern/Southeastern and Central Asia (0.6 in men and
0.2 in women) and sub-Saharan Africa (0.4 in men and 0.2 in women) [8]. The high-
est national rates were observed in the UK (7.2 in men and 2.5 in women), the
Netherlands (7.1 in men and 2.8 in women), Ireland (5.4 in men and 2.9 in women),
Iceland (3.9 in men and 2.7 in women), and New Zealand (4.0 in men and 1.5 in
women), while the highest absolute incidence occurred in the United States, with
10,000 cases occurring in 2012, of which 88% were in men [8].
In the United States, there has been a disturbing trend in which the number of
new cases of EAC has been increasing faster than that of any other cancer, and inci-
dence data suggests that this increase commenced sometime in the mid-1970s. The
reasons for this dramatic increase in EAC are multifactorial and complex and are
not explained by known risk factors. Data from the National Cancer Institute (NCI)
Surveillance, Epidemiology, and End Results (SEER) database have shown an
increase in the incidence of EAC from 0.40 cases per 100,000 in 1975 to 2.58 cases
per 100,000 in 2009, with an average annual percentage increase in incidence of
6.1% in men and 5.9% in women during the period from 1975 to 2009 [9].
Interestingly, geographic variability was observed in the incidence of EAC across
the United States, with the highest age-standardized incidence rates observed in the
Northeast and Midwest and the lowest observed in the South and West [10].
Likewise, the annual percentage change over the 10-year period from 1999 to 2008
varied widely, a 3.19% annual increase for men in the Northeast, in contrast to the
0.80% annual increase observed in the West [10]. The increase in EAC incidence is
predicted to continue until 2030 with a plateauing trend, reaching 8.4–10.1 cases
per 100,000 person-years for males and 1.3–1.8 per 100,000 person-years for
females [11].
In Europe, increasing EAC incidence trends were observed in most countries
during the period from 1980 to 2002, with the steepest increases observed in the
male population in Denmark, the Netherlands, England, and Scotland, where the
incidence of EAC has overtaken that of esophageal squamous cell carcinoma [12].
Overall, the age-standardized incidence rate in Northern and Western Europe was
3.4 per 100,000 for men and 0.6 per 100,000 for women in 2012 [8].

 sophageal Squamous Cell Carcinoma

E
Globally, esophageal squamous cell carcinoma (ESCC) is the more commonly
occurring of the two histological subtypes, with 398,000 estimated incident cases in
2012 and a global age-standardized incidence rate of 5.2 per 100,000 (7.7 in men
and 2.8 in women). The highest incidence rates occurred in Eastern/Southeastern
Asia (13.6 in men and 4.3 in women), sub-Saharan Africa (6.4 in men and 4.0 in
women), and Central Asia (5.9 in men and 3.6 in women) [8]. The highest estimated
national rates were calculated for Malawi, Turkmenistan, Kenya, Mongolia, and
Uganda [8]. The lowest incidence regions were North America (1.7 in men and
0.7 in women), Oceania (2.0 in men and 1.2 in women), and Southern Europe (2.4 in
men and 0.4 in women) [8].
1 Epidemiology and Risk Factors for Esophageal Cancer 5

Approximately 80% of ESCC cases in 2012, or 315,000 cases, occurred within

what is termed the “esophageal cancer belt,” an area stretching across Central to
Eastern Asia from the Caspian littoral region through Iran, Iraq, and Kazakhstan to
the northern provinces of China [8]. Additionally, 210,000, more than half of all
ESCC cases, occurred in China in 2012 [8]. This dramatic concentration of ESCC
cases to this particular geographical area is likely to reflect local risk factors.
In China, 2015 data reported that esophageal cancer (predominantly squamous
cell carcinoma) was the fourth most commonly diagnosed and the leading cancer
cause of death for both males and females [13]. Data analyzed between 2000 and
2011 revealed that the incidence of cancer of the esophagus had decreased for both
males (annual percentage change −3.2) and females (annual percentage change
−5.5). Mortality rates also decreased for both males (annual percentage change
−6.1) and females (annual percentage change −6.4) during this period.
In the United States, the national age-standardized incidence rate for ESCC is
4.93 per 100,000 in men and 2.30 per 100,000 in women [10]. In contrast with the
trends observed in EAC, incidence rates of ESCC in the United States have been
decreasing at a rate of around 3% per year in both genders and across regions, which
has generally been attributed to a decrease in the practice of smoking [10, 14].
Figure 1.3 shows that ethnic variation exists within the United States for esophageal
cancer rates. An excellent graph highlights the differences between States in North
America in terms of both EAC and ESCC by gender (Fig. 1.4).
This trend has been mirrored in Europe, where ESCC incidence has been decreas-
ing or stabilizing over the last several decades in most countries [10]. The incidence

AC SCC

African American

Asian and Pacific Islander

American Indian

Caucasian

6.0 4.0 2.0 0.0 2.0 4.0 6.0

Age standardized incidence rate

FEMALE MALE

Fig. 1.3 Incidence rates of esophageal cancer in the United States by ethnic group
6 K. Vijayan and G. D. Eslick

AC SCC

USA, New Hampshire

USA, Maine
USA, Massachuetts
USA, Rhode Island
USA, Wyoming
USA, lowa
USA, West Virginia
USA, Indiana
USA, Pennsylvania
USA, Ohio
USA, Wisconsin
USA, Oregon
USA, Kentucky
USA, Idaho
USA, South Dakota
USA, Nebraska
USA, Michigan
USA, Illinois
USA, Delaware
USA, Missouri
USA, Alaska
USA, Vermont
USA, Oklahoma
USA, Montana
USA, Washington State
USA, Colorado
USA, Connecticut
USA, NPCR (42 states)
USA, New Jersey
USA, North Carolina
USA, Virginia
USA, Tennessee
USA, North Dakota
USA, Alabama
USA, Florida
USA, New York State
USA, Arizona
USA, Utah
USA, Texas
USA, Louisiana
USA, Mississippi
USA, South Carolina
USA, Georgia
USA, Arkansas
USA, New Mexico
USA, California
Canada
8.0 6.0 4.0 2.0 0.0 2.0 4.0
Age standardized incidence rate
FEMALE MALE

Fig. 1.4 Age-standardized incidence rates in the United States and Canada
1 Epidemiology and Risk Factors for Esophageal Cancer 7

rates in most European countries were between 2 and 4 per 100,000 in 2002, with
the exceptions of France, which although experiencing a steep decrease in incidence
over the last couple of decades still had an incidence rate of above 5 per 100,000,
and Slovenia, which has not followed the trend and has actually seen an increase in
ESCC incidence rates from just below 2 per 100,000 in 1980 to around 5 per
100,000 in 2002.

Mortality

In the United States, the estimated number of deaths from esophageal cancer in
2018 was 15,850, with a large male predominance (12,850 male deaths versus 3000
female deaths) [15]. The mortality rate from esophageal cancer increased from 4.67
to 5.44 cases per 100,000 during the period from 1993 to 2007 for white males and
experienced only a minor increase from 0.76 to 0.77 in white females during the
same period [16]. Esophageal cancer mortality rates are predicted to increase in the
United States, with most of the deaths contributed to by EAC [11]. Cause-specific
EAC deaths for years 2011–2030 are estimated to range between 142,300 and
186,298, almost double the number of deaths in the past 20 years, and EAC mortal-
ity rates are estimated to reach 5.4–7.4 cases per 100,000 person-years for males
and 0.9–1.2 cases per 100,000 person-years for females by 2030 [11].
In EU, decreasing trends were observed for esophageal cancer mortality in males
in a number of several southern and western European countries, and in central
Europe mortality has also stabilized or declined since the mid-1990s [12]. In some
northern European countries, mortality rates from esophageal cancer are still
increasing, likely due to the continued increase in EAC observed in that region.
Similar to the situation in the United States, the female mortality rate from esopha-
geal cancer in Europe was comparatively low and remained stable or decreased
[12]. Overall, deaths from esophageal cancer have declined in European men, from
5.34 to 4.99 per 100,000 during the period from 2000 to 2009. European women
also experienced a modest decrease in mortality during this period, from 1.12 to
1.09 per 100,000 [12]. European mortality rates from esophageal cancer are pre-
dicted to decline to 4.46 per 100,000 men (resulting in approximately 22,300 deaths)
and 1.07 per 100,000 women (resulting in approximately 7400 deaths) by 2015
[12]. Significantly, the predicted mortality rate for UK men is 8.51 per 100,000 by
2015, above the European average [12], which again is likely due to the expected
continued increase in EAC incidence.
A recent analysis of esophageal cancer mortality data shows that Bulgaria and
the Philippines have escalating rates of cancer death among females [17]. These
results can be seen in Fig. 1.5, which also shows changes in incidence and mortality
rates for other countries.
8 K. Vijayan and G. D. Eslick

Fig. 1.5 (A) Incidence trend of esophageal cancer in males (left panel) and females (right panel).
(B) Mortality trend of esophageal cancer in males (left panel) and females (right panel)

Survival

Esophageal cancer remains a rapidly fatal disease. The current 5-year survival rates
are 19% in the United States [15] and 12% in Europe, with the highest European
rate observed in Belgium (21.8%) and the lowest occurring in Lithuania (5.7%)
[18]. There is generally no difference reported in survival between the two histo-
logical types, EAC and ESCC [18].
One study which did investigate EAC separately reported improved 5-year rela-
tive age-adjusted EAC survival rates in the United States since 1975, with the great-
est improvement observed in cases with localized disease [9]. The 5-year survival
rate in this group has increased from only 2.1% in 1975 to just over 50% in 2009 [9].
The 5-year survival for all stages of EAC in the United States has increased from
just under 5% in 1975 to just over 20% in 2009 [9].
1 Epidemiology and Risk Factors for Esophageal Cancer 9

Risk Factors

An evidence-based approach has been taken with this section of the chapter. Where
possible, meta-analyses or systematic reviews of the literature were used to sum-
marize the current level of evidence for each risk factor.

Esophageal Adenocarcinoma

The risk factors for EAC are presented diagrammatically in Fig. 1.6 and are dis-
cussed individually below.

Age and Gender

The majority of individuals with EAC are aged 50–60 years [19]. The incidence of
EAC has a strong male preponderance. Globally, the incidence of EAC was

0.29
Proton pump inhibitors
0.56
Helicobacter Pylori infection

0.59
Folate

0.64
Aspirin

0.65
NSAIDs
0.72
Statins

0.73
Fruits

0.76
Vegetables
Risk factors

0.78
Hot food and beverages
0.87
Alcohol consumption

0.91
Dietary flavonoids

1.18
NDMA

1.43
Diabetes

1.45
Vitamin D

1.62
Ex-smokers

1.74
Bisphosphonates

2.10
BMI (>25)

2.32
Current smokers

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Odds Ratio

Fig. 1.6 Risk factors associated with esophageal adenocarcinoma

10 K. Vijayan and G. D. Eslick

estimated to be 1.1 per 100,000 in men and 0.3 per 100,000 in women in 2012, a
difference in incidence of over threefold [8]. The difference was most obvious in the
highest incidence areas of Northern and Western Europe (3.4 in men and 0.6 in
women), Northern America (3.5 in men and 0.4 in women), and Oceania (3.4 in
men and 0.6 in women). Also striking are the predicted incidence rates in 2030,
which are estimated at 8.4–10.1 cases per 100,000 person-years for males and 1.3–
1.8 per 100,000 person-years for females [11].

Ethnicity
Several studies have found that Caucasians are more likely to develop EAC com-
pared to ESCC. Most recently, two studies conducted in 2017 afforded further evi-
dence that Caucasians had a higher risk of developing EAC. The first study compared
Caucasian individuals to Africans, non-white Hispanics, Asians, Pacific Islanders,
and Native Americans, concluding that Caucasians were more likely to develop
EAC (p < 0.002) [20]. The second study confirmed this finding, reaffirming that the
incidence rate of EAC was higher in Caucasians than in Asian and African ethnic
groups upon analysis of the SEER database (p < 0.05) [21]. This study also sug-
gested that molecular patterns associated with the relevant genes for EAC are simi-
lar between Asians and Caucasians (however, small differences do preside) and that
these differences may be crucial in tumorigenesis and personalized treatment.

Eating Disorders

Obesity
A 2015 review found a consistent relationship in which patients with higher-than-­
normal BMIs had a higher risk of developing EAC compared to patients with nor-
mal BMI. Patients with BMI ≥40 kg/m2 had a higher risk of developing this cancer
(OR, 4.76, 95% CI, 2.96–7.66), compared to patients with BMI 35–39.9 kg/m2 (OR,
2.79, 95% CI, 1.89–4.12), BMI 30–34.9 kg/m2 (OR, 2.39, 95% CI, 1.86–3.06), and
BMI 25–29.9 kg/m2 (OR, 1.54, 95% CI, 1.26–1.88) [22].
As discussed above, there has been a dramatic increase in the incidence of EAC
over the last several decades in many Western countries such as the United States, the
UK, and the Netherlands. One of the contributing factors to this increase is thought
to be the obesity epidemic, which has risen to prominence during a similar time
period. Obesity is linked with gastroesophageal reflux disease (GERD) and Barrett’s
esophagus, a precursor lesion to EAC. A meta-analysis conducted in 2012 found a
positive association between a body mass index (BMI) between 25 and 30 and EAC
(relative risk (RR), 1.71, 95% confidence interval (CI), 1.50–1.96) [23]. The risk
increased even further for BMI ≥ 30 (RR, 2.34, 95% CI, 1.95–2.81) [23]. The con-
tinuous RR for a 5-point increase in BMI was RR 1.11 and 95% CI 1.09–1.14 [23].
This is a consistent finding, with an earlier meta-analysis likewise finding an
increased risk of EAC associated with a BMI of over 25 (males, OR, 2.2, 95% CI,
1.7–2.7; females, OR, 2.0, 95% CI, 1.4–2.9) [24]. A population-based study from
Australia which included 367 EAC patients also reported an increased risk for BMIs
of 30–35 (OR, 2.1, 95% CI, 1.4–3.1) which increased almost threefold (OR, 6.1,
95% CI, 2.7–13.6) for BMIs over 40, after adjusting for reflux [25].