Clinically, most EC manifests late in the course of the disease. Dysphagia and odynophagia are the most common presenting symptoms, and affected individuals tend to lose weight. Aspiration and emesis are frequent complications of EC. Patients may describe a loss of appetite, too, and progress to anorexia. Pain may be reported, and because the majority of EC develop in the distal esophagus, it is usually located retrosternally [Berry] [Jain].

Additional findings such as palpable lymphadenopathy or subcutaneous masses suggest metastatic disease, but the likelihood of regional metastases is high already when EC becomes symptomatic. No specific symptoms are to be expected in EC patients.

Endoscopy is most frequently employed to visualize the primary tumor and to obtain tissue samples for further examination. Conventional white light imaging endoscopy is of adequate sensitivity in symptomatic EC patients, but additional procedures should be considered when the endoscopy is performed as a screening or surveillance. In this context, chromoendoscopy significantly augments the rate of detection of mucosal irregularities and potential neoplasms. EC may furthermore be characterized by ulcerations or exophytic growth, and they may cause strictures of the esophagus. Biopsies should be taken from all suspect areas and histologically classified and graded according to the criteria of the World Health Organization [Bosman] [Lordick]. Both squamous cell carcinoma and adenocarcinoma can show variable differentiation, and immunohistochemical analyses may be required to identify poorly differentiated tumors. In any case, EC should be unequivocally differentiated from precursor lesions such as squamous cell dysplasia, intestinal metaplasia with or without dysplasia, and chronic esophagitis, but these conditions do warrant continuous monitoring for the development of malignancies [Jain].

EC is staged according to the classical TNM system. With regards to the size and growth behavior of the neoplasm, T may be categorized as Tis, T1a (mucosal carcinoma), T1b (submucosal carcinoma), T2 (reaching the muscular layer), T3 (extending into the periesophageal tissue), or T4. N and M indicate the involvement of regional lymph nodes and the presence or absence of metastatic disease. In order to assess the presence of metastases, patients should undergo a computed tomographic scan of the chest and abdomen with both oral and intravenous contrast. If metastases aren't revealed by computed tomography, positron emission tomography may be considered to improve the sensitivity of tumor staging [Berry].

Endoscopic resection is the recommended treatment in mucosal adenocarcinoma without histological risk factors such as vascular invasion, lymphatic invasion, and high tumor grade. The same approach may be considered for submucosal adenocarcinoma, but is restricted to middle layer mucosal neoplasms in the case of squamous cell carcinoma [Mönig]. If EC is confined to the mucosa, radiofrequency ablation, cryotherapy, and photodynamic therapy may also prove to be effective [Berry].

Beyond the aforementioned limits, surgical resection is the preferred method of treatment. An appropriate procedure should be chosen depending on the affected site and tumor stage, and may consist in transthoracic or transhiatal subtotal or total esophagectomy. Because lymphogenic metastases develop early in the disease process, any surgical resection of EC should be complemented with lymphadenectomy [Mönig]. In case of advanced-stage disease, neoadjuvant radiotherapy and/or chemotherapy is recommended to prepare the patient for surgery [Jain] [Lordick]. On the other hand, patients with residual EC may benefit from post-resection radiation [Berry].

Palliative treatment is recommended for EC patients with distant metastases. This type of treatment may include chemotherapy, clinical trial enrollment, and best supportive care. The latter may consist in symptom management, esophageal dilation and stenting, and the use of feeding tubes. In general, metastatic EC is related to a poor outcome irrespective of the treatment strategy, so optimal regimens should be established depending on the patient's general conditions and objectives of therapy [Berry].

The 5-year survival rate for T1a and T1b carcinomas has been estimated at 87 and 66%, respectively. The chances of survival are roughly halved by the presence of lymph node metastases, and many patients do present regional metastases at the time of diagnosis [Hölscher]. Hence, median survival times are far below five years: 35, 15, and 6 months have been informed for patients diagnosed with localized, regional and distant metastatic disease, respectively. While 73% of EC patients with tumors in situ achieve cure, this applies to only 37, 12, and 2% of those with localized disease, lymph node and distant metastases, respectively [Dubecz].

EC is a general term comprising a wide variety of malignant neoplasms of the esophagus. The vast majority of cases corresponds to squamous cell carcinoma and adenocarcinoma, but there are subtypes of squamous cell carcinoma and adenocarcinoma and rare variants of EC, such as non-epithelial EC [Bosman]:

• Squamous cell carcinoma, well differentiated, moderately differentiated, or poorly differentiated
• Basaloid squamous cell carcinoma
• Spindle cell squamous carcinoma/carcinosarcoma
• Verrucous squamous carcinoma
• Adenosquamous carcinoma
• Adenocarcinoma, well differentiated, moderately differentiated, or poorly differentiated
• Adenoid cystic carcinoma
• Mucoepidermoid carcinoma
• Mixed adenoneuroendocrine carcinoma
• Neuroendocrine carcinoma, possibly small cell or large cell
• Undifferentiated carcinoma, possibly with squamous or glandular components
• Leiomyosarcoma
• Malignant gastrointestinal stromal tumor
• Malignant neurogenic tumor, e.g., malignant schwannoma, peripheral nerve sheath tumor
• Hemangiosarcoma
• Liposarcoma
• Lymphoma
• Malignant melanoma
• Secondary malignancies of any type

This list may not be complete, and other types of malignancy may be detected in the esophagus.

Both genetic and environmental influences have been identified as risk factors for the individual types of EC [El-Zimaity].

• On the one hand, tylosis is associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus. Tylosis is a rare inherited condition otherwise characterized by hyperkeratotic changes of the palmar and plantar skin. It may also be referred to as hyperkeratosis palmaris et plantaris or Howel–Evans syndrome, is inherited in an autosomal dominant manner and has complete penetrance [Blaydon]. On the other hand, esophageal squamous cell carcinoma has been related to infections with human papillomavirus, Epstein–Barr virus, and polyoma viruses [El-Zimaity]. Generally speaking, this type of EC is more commonly diagnosed in those with a history of alcohol abuse and tobacco consumption [Wheeler].
• Adenocarcinoma of the esophagus has been associated with inherited polymorphisms of the EGF gene, with human papillomavirus and bacterial infections [Wheeler]. Helicobacter pylori is related to alterations in the production of gastric acid and peptic ulcer disease, and these conditions may predispose to gastroesophageal reflux disease, Barrett esophagus, dysplasia, and adenocarcinoma. Remarkably though, others argue the involvement of H. pylori in the development of atrophic gastritis may render it protective against EC [Polyzos]. Regardless of their pathogenesis, obesity, gastroesophageal reflux disease, and Barrett esophagus have traditionally been considered the most important risk factors for adenocarcinoma of the esophagus. Any other condition resulting in the relaxation or dilation of the lower esophageal sphincter as well as Zollinger-Ellison syndrome may have similar consequences.

EC is the eighth most common cancer worldwide, but the incidence of distinct types of EC varies largely depending on the geographic region, gender, race, and medical history of the patient [El-Zimaity] [Wheeler]. Adenocarcinoma is more commonly diagnosed in Western Europe, North America, and Australia, while squamous cell carcinoma is frequently reported in South East Africa, Iran, China, and Brazil. Accordingly, Caucasians are usually found to suffer from the former, while blacks are more susceptible to the latter. In sum, adenocarcinoma and squamous cell carcinoma account for >90% of all cases [Berry]. General risk factors for EC are advanced age and male gender; the median age at the time of diagnosis is 68 years, and more than three-fourths of EC patients are male [Dubecz].

The development of EC appears to occur through the progressive accumulation of genetic abnormalities such as the mutational inactivation of genes TP53 and CDKN2A, cell cycle abnormalities and aneuploidy [Jain]. In that respect, major differences in the genetic profiles of squamous cell carcinoma and adenocarcinoma should be taken into account: Genes ERBB2, VEGFA, GATA4, and GATA6 are commonly amplified in adenocarcinoma, whereas the amplification of CCND1, SOX2, and TP63 has frequently been determined in squamous cell carcinoma [Nature]. TP53 and CDKN2A are affected in >80% of either type of EC [Talukdar]. The precise causes of mutations remain unknown, but a wide variety of dietary and environmental carcinogens may be involved in the process of tumorigenesis.

Patients may reduce their individual risk of developing EC by avoiding the consumption of tobacco, alcohol, and extremely hot beverages. Any measure to obviate gastric reflux may contribute to lowering the risk of EC by eliminating the noxious effect of gastric acid on the mucous membrane of the esophagus, and by preventing alterations of the esophageal flora. Indeed, in view of the infectious causes of EC, the maintenance of the esophageal microbiome may generally prove beneficial in the prevention of EC [El-Zimaity].

With regards to the detrimental outcome of EC, diagnostic techniques facilitating the early recognition of the disease are urgently needed. About two-thirds of EC patients are diagnosed with metastatic disease, and the chances for cure drastically decreases upon the formation of metastases [Dubecz]. In this context, all patients with new dysphagia, recurrent aspiration or emesis, loss of appetite or weight, or gastrointestinal hemorrhages should undergo an upper intestinal endoscopy [Lordick]. Those who are found to have precursor lesions should receive adequate treatment to prevent the progression to EC. In this context, the ablation or endoscopic resection of abnormal mucosa should be considered.

EC is the eighth most common cancer worldwide and the sixth most common cause of cancer-related death [Mönig]. Distinct malignancies may develop in the esophagus, but adenocarcinoma and squamous cell carcinoma account for the vast majority of cases. Both have in common the late clinical presentation; about two-thirds of EC patients are diagnosed after metastases have formed. The complete removal of the neoplasm constitutes the only chance for cure and is increasingly difficult when the tumor has spread to the regional lymph nodes or, even more so, to distant organs. The late diagnosis of EC is considered the major cause of the poor prognosis associated with this disease, and additional research is required to improve the rate of early detection. The latter, however, is not feasible if patients at risk and those with precursor lesions are not included in surveillance and monitoring programs.

Esophageal cancer (EC) is the eighth most common cancer in the world. There are two main types of EC, namely squamous cell carcinoma and adenocarcinoma. These types of esophageal carcinoma differ with regards to their origins and risk factors, and they are known to affect distinct people. Casually speaking, the obese white male with gastroesophageal reflux disease is more prone to develop adenocarcinoma, while the malnourished black male smoker with a history of alcohol abuse is the prime example for the patient with esophageal squamous cell carcinoma. Several conclusions regarding preventive strategies can be drawn from this concept:

• Gastric reflux is a main contributor to EC development in the Western world. The noxious effect of gastric acid reflects in abnormalities of the esophageal mucosa that may later turn into cancer.
• Obesity favors the onset of gastroesophageal reflux disease and thus the development of EC.
• The consumption of tobacco, alcohol, and extremely hot beverages should be avoided.

Preventive measures are of utmost importance since the majority of EC patients remains asymptomatic for prolonged periods of time. When swallowing difficulties, pain, loss of appetite and weight do manifest, most esophageal malignancies have already formed metastases, and the spread of EC to regional lymph nodes or distant organs largely reduces the chances for cure. In general, cure may be achieved if the primary tumor (and all its metastasis) can be removed in their entirety.

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