**2. Etiological differences between esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)**

Esophageal carcinoma is seen in two major histological subtypes: adenocarcinoma and squamous cell carcinoma (SCC). These subtypes are very different in terms of risk factors and epidemiology. According to GLOBOCAN 2012, there were an estimated 400,000 cases of ESCC and 50,000 cases of EAC of the esophagus in 2012 worldwide [4].

#### **2.1. Global incidence of ESCC**

In 2012, the global incidence of ESCC was 5.2 per 100,000 people. Most affected regions were located in Eastern and South-East Asia, followed by sub-Saharan Africa and Central Asia [4]. About 80% of global ESCC cases occur in Central and South-East Asian regions. China alone provided more than 50% of the global cases. Areas of high incidence of ESCC have been identified in Northern Iran, Central Asia, and China (together forming the so-called "esophageal cancer belt") as well as parts of Eastern Africa. ESCC is more common and the rate of ESCC is about 95% in Japan [3].

#### **2.2. Risk factor of ESCC**

Generally, chronic inflammation of the esophageal mucosa is postulated to increase the risk of ESCC. Two major risk factors are smoking and alcohol consumption, which have been found to account for more than 75% of all SCC cases in high-income countries [5]. On the other hand, frequent consumption of extremely hot beverages is a common risk factor for ESCC in lessdeveloped regions [4]. Consumption of hot mate drinks in Latin America and hot beverages in Southern China are associated with the risk of ESCC [4, 5].

In Iran, opium use has been found to increase mortality from esophageal cancer by 50%. High-incidence areas in Africa suggest that smoking, occupational exposures and nutritional deficiencies may be responsible for the high burden of ESCC [4].

Alcohol drinking is a well-established risk factor for esophageal cancer. International Agency for Research on Cancer (IARC) referred to acetaldehyde, an oxidative metabolite of ethanol, as a potential causative agent behind alcohol-induced carcinogenesis based on evidence of interaction between alcohol consumption and acetaldehyde dehydrogenase (ALDH2) enzyme gene polymorphisms [6, 7]. Oze et al. showed that acetaldehyde dehydrogenase Glu504Lys polymorphism had strong effect modification with alcohol drinking and concluded that there is convincing evidence that alcohol drinking increases the risk of esophageal cancer in the Japanese population [8]. Half of the Japanese population is heterozygous or homozygous for the \*2 allele of ALDH2, showing respectively, peak blood acetaldehyde concentrations in post-alcohol consumption 6- and 19-fold higher than homozygous wide-type individuals [9]. As a result, ALDH2\*2/\*2 homozygous carriers show facial flushing and nausea after alcohol consumption that deters them from drinking, whereas heterozygotes exhibit less severe reactions [9]. Fang et al. indicated that individuals heterozygous for the \*2 variant allele of aldehyde dehydrogenase 2 (ALDH2\*1/\*2) frequently detected in Asia had an increased risk of esophageal cancer, especially among heavy drinkers, because inactive ALDH2 fails to metabolize acetaldehyde rapidly, leading to excessive accumulation of acetaldehyde in blood and repeated high exposure to acetaldehyde after drinking. Drinking clearly modifies the effect of ALDH2 on esophageal cancer risk in Asians [6].

#### **2.3. Global incidence of EAC**

and occasionally cervical lymph nodes, is suggested as a standard surgical method because systematic dissection of metastatic lymph nodes is thought to improve survival and lead

Consequently, recommending complete lymphadenectomy of the upper mediastinum is an essential component in radical esophagectomy for esophageal squamous cell carcinoma (ESCC). Three-field lymphadenectomy (3FL) is the ultimate surgical procedure in the pursuit of complete lymph node dissection for thoracic esophageal cancer. However, lymph node dissection along the recurrent laryngeal nerve (RLN) is difficult because severance of nerves

The prone position provides better visualization in the subaortic arch and subcarinal and supraphrenic regions, but the working space in the left upper mediastinum for dissecting the lymph nodes along the left recurrent laryngeal nerve is limited. Some investigators, including us, have shown how to obtain a good operative field in the upper mediastinum for lymph adenectomy. Osugi reported that tracheobronchus must be retracted ventrally to visualize the left side of the trachea and developed the retractor that provides exposure of the entire mediastinum and esophagus in left lateral position [3]. In eastern countries, surgeons also describe lymphadenectomy along the left recurrent laryngeal nerve, but few surgeons in western countries have discussed lymphadenectomy of esophageal adenocarcinoma (EAC). Here, we describe differences in lymph node metastasis between ESCC and EAC and procedures for lymph node dissection along the recurrent laryngeal nerve in ESCC.

**2. Etiological differences between esophageal squamous cell carcinoma** 

Esophageal carcinoma is seen in two major histological subtypes: adenocarcinoma and squamous cell carcinoma (SCC). These subtypes are very different in terms of risk factors and epidemiology. According to GLOBOCAN 2012, there were an estimated 400,000 cases of ESCC

In 2012, the global incidence of ESCC was 5.2 per 100,000 people. Most affected regions were located in Eastern and South-East Asia, followed by sub-Saharan Africa and Central Asia [4]. About 80% of global ESCC cases occur in Central and South-East Asian regions. China alone provided more than 50% of the global cases. Areas of high incidence of ESCC have been identified in Northern Iran, Central Asia, and China (together forming the so-called "esophageal cancer belt") as well as parts of Eastern Africa. ESCC is more common and the rate of ESCC

Generally, chronic inflammation of the esophageal mucosa is postulated to increase the risk of ESCC. Two major risk factors are smoking and alcohol consumption, which have been found

by electrical devices can easily lead to paralysis [1, 2].

**(ESCC) and esophageal adenocarcinoma (EAC)**

and 50,000 cases of EAC of the esophagus in 2012 worldwide [4].

**2.1. Global incidence of ESCC**

is about 95% in Japan [3].

**2.2. Risk factor of ESCC**

to cure.

74 Esophageal Abnormalities

The global incidence of EAC is 0.7 per 100,000 people. Highest incidence rates by region were found in Northern and Western Europe, North America, and Oceania [4]. On the national level, the highest rates were seen in the UK, the Netherlands, Ireland, Iceland, and New Zealand. The burden of AC is the highest in Northern and Western Europe, North America, and Oceania, accounting for 46% of all global AC cases [4, 10, 11].

#### **2.4. Risk factor of EAC**

The strongest known risk factor for EAC is gastroesophageal reflux disease and its more severe manifestation, Barrett's esophagus (BE). Obesity promotes the development of gastroesophageal reflux and also acts as an independent risk factor for EAC.

In North America and Northern and Western Europe, prevalence of *Helicobacter pylori* (H pylori) infection is among the lowest and incidence of EAC is higher [4, 10, 11].

*Helicobacter pylori* (H pylori) lowers gastric acid secretion and decreases gastric esophageal reflux [10, 11]. In more recent years, prevalence of the latter has leveled out in high-prevalence countries such as the Netherlands and the UK [4].
