In South Africa oesophageal cancer is the eighth most common cancer in men and the eleventh in woman. In the early 20th century esophageal cancer was an uncommon disease in South Africa (37). From the 1940s, there was a rapid rise in the number of EC cases until esophageal cancer became the third most commonly diagnosed cancer in Black South Africans (38–40). In the African population group the ASR was 22.3 per 100,000 in males and 11.7 per 100,000 in females (41). In the African or mixed ancestry population group EC is the fourth highest cause of death in males (42). The area with the highest incidence is the Transkei region (43) with an ASR of 46.7/100,000 for males and 19.2/100,000 for females (44). When this disease is defined by sex and race, a slightly different picture emerges. A decrease in both SCC and AC becomes evident, especially when comparing African males and females with their non-African counterparts (37,45). However, other studies have found that there has only been a decrease in the prevalence of AC in South Africa (8). The areas in South Africa with the highest incidence of OC include the former Transkei region. This area was then a homeland settlement, with limited healthcare resources.

The increased incidence of EC in South Africa over the last decades is largely due to changes in lifestyle, diet, and the exposure to carcinogens (43). EC rates are highest in the 60 to 70-year age group. The two most important risk factors include cigarette fuming and extreme alcohol use (46). Approximately 17.6%, of adult South Africans use tobacco, 29.2% of males and 7.3% in females (47). South Africans consume >53 g of ethanol per day, which leads to a 5 times greater risk of developing esophageal cancer in comparison to non-drinkers. Smoking and drinking together lead to an 8.5 times greater risk of developing oesophageal cancer (48). Most of the studies on oesophageal cancer in South Africa have been performed in large urban areas like Johannesburg and Cape Town. Investigations performed amongst rural populations in South Africa, is more challenging hence, such data from is limited in South African databases.

Other risk factors include exposure to environmental smoke (cooking fires) (49), HPV infection (43) and diet. Helicobacteraceae infection may be related to OC risk as it was discovered in roughly 50% of South African patients with oesophageal carcinoma (50). Dietary risk factors include the use of wild herbs such as Solanum nigrum, the brewing and consumption of traditional maize based beer brewed with maize that may contain fungal mycotoxins or nitrosamines (37), and most importantly the shift to a Western diet. This diet is defined by an increase in the consumption of fats and animal protein (37). High-risk individuals in both the Transkei and KwaZulu-Natal province, are typically poorer with inadequate diets, and consume some class of alcohol and tobacco (51–53). In the Eastern Cape and Transkie, high risk of oesophageal cancer is associated with a diet low in green leafy vegetables and fruit (54). and is associated with low plasma concentrations of vitamins A, E, B12, folic acid and selenium (55). The increased consumption of maize compared to a more traditional diet which is based on other grains such as sorghum, may present additional risks. The maize-rich diet leads to increased levels of prostaglandin E₂ (PGE2) in gastric fluid, an enzyme which increases Wnt signaling and proliferation (56).

Like all countries in the Eastern and Southern Africa cancer corridor, Tanzania has a high incidence of esophageal cancer. The age-standardized rate of EC incidence in Tanzania is 9.2 per 10,0000 (57). Generally esophageal carcinoma affects people at a young age in Tanzania, approximately 40 years and older. This is twenty years younger than the average seen in most developed countries (58). The region of Tanzania with the highest number of EC patients is the Kilimanjaro region, with the eastern and central parts of the country having a higher incidence rate of EC compared to the western parts (57). The control of esophageal cancer in Tanzania is hampered by the lack of educational and screening programs as well as a lack of facilities capable of diagnosing and treating the disease (58). There is only one specialized cancer treatment facility in Tanzania, the Ocean Road Cancer Institute (ORCI), located in Dar es Salaam (57). A study of patient numbers being diagnosed at ORCi compared with those receiving treatment showed that over 20% of EC patients did not receive treatment due to a lack of resources (57). As in other countries, the consumption of hot beverages has been linked to esophageal cancer in Tanzania. In this, case the consumption of hot milky tea (59). Oesophageal cancer in Kenya, especially in the regions bordering Tanzania, is a major health problem. In Kenya oesophageal cancer is more prevalent amongst people living in low socio-economic conditions, and is affected by the level of education and general living conditions (60).

OC is also a major health problem in India; particularly in snow-capped Kashmir valley and North-eastern states and is associated with peculiar food and drinking habits such as the drinking of hot salted tea which contains carcinogenic compounds like nitrosamines (29,61,62). Besides salted tea, tobacco smoking (Hukkah or water-pipe), sun dried vegetables are also very common in Kashmir valley and has been shown to be a potential risk factors for increased incidence of OC. In addition, high risk HPV type infection has also been reported form areas of OC cases in India (63,64).

China is also included in the oesophageal c cancer corridor. China accounts for more than half of all new cases of oesophageal cancer and is the fourth most frequently diagnosed cancer (65). The highest incidence is found in the rural areas (66). Certain areas of China, in Central North China, have the highest oesophageal cancer incidence rate in the world (over 100 per 100 000) (67,68). In China, oesophageal cancer occurs 20–30 times more than in the United States (69). SCC is the major type of oesophageal cancer and more than half of the global SCC cases occur in China (13). Oesophageal cancer is the fourth leading cause of cancer related death in China (65). The Chinese, government is still trying to improve the quality of the cancer registration data in rural areas (13). Like developed countries, an increase in the number of AC cases and a decrease in the number of SSC cases has been observed in China. The rise in the incidence of AC in China was reported in both urban and rural areas (70).

Apart from alcohol consumption and tobacco use is a high risk factors for oesophageal cancer in China include nutritional factors such as the consumption of fatty meat, salted and pickled vegetables and mouldy food as well as nutritional deficiencies. The populations from many of the areas in China with high oesophageal cancer rates were found to have a diet lacking in selenium, zinc, folate, riboflavin, and vitamins A, C, E, and B12 (71). These areas also contained high levels of nitrates and nitrosamines in local sources of drinking water and samples of food from local suppliers (72). A relationship also exists between the consumption of hot green tea and the risk of developing oesophageal cancer (73). Lifestyle factors include passive smoking, oesophageal lesions, and infection with Helicobacter pylori, low socioeconomic status and poor oral hygiene. However, a family history of cancer is also an important risk factor associated with increased risk of ESCC (52) and this points to a genetic component. Gastric atrophy, the replacement of dying of gastric cells with intestinal tissues, was also found to be an indication of increased risk for developing oesophageal cancer in Chines populations (74).

Tobacco use amongst Chinese males is currently estimated to be approximately 49.2–56.1% while it is estimated that only between 2.2–2.6% of Chinese females smokes (75). Alcohol is a Group 1 carcinogen and the body relies on alcohol dehydrogenases (ADHs) to convert alcohol into acetaldehyde, which is then converted to acetic acid by aldehyde dehydrogenase-2 (ALDH2). Mutations and polymorphisms in either of the genes encoding these two enzymes may decrease the ability to detoxify ethanol leading to cells being exposed to high levels of carcinogens (76). These mutations and polymorphisms are frequently found in individuals that originate from East Asia. ALDH2 mutations lead to the development of a rash or flush response when they consume alcohol. These individuals are at an increased risk of developing oesophageal cancer. A study performed in China, in the Shanxi Province, gave one of the strongest indications that genetics and familial history play a role in oesophageal cancer. This study showed that families with a history of oesophageal cancer were more likely to report a new case within ten years of the first case (77).

Brazil is a good example of a country with social and healthcare inequalities across geographic regions. Parts of Brazil have the highest incidence of oesophageal cancer in the Western hemisphere. As in other countries alcohol and tobacco consumption are the main factors contributing to this high incidence rate. In the South of Brazil the consumption of hot mate (78). The incidence of oesophageal cancer in Brazil ranges from one to 18 per 100,000 inhabitants and is higher in the southern part of Brazil where it ranges from nine to 18 per 100 000 (79). The incidence of oesophageal cancer is intermediate in the central western and North Eastern regions where it ranges from 4 to 9 per 100,000 and is low in the Northern region, where it ranges from 1 to 2 per 100,000 (80). In Brazil cases are mainly diagnosed in individuals over the age of 30, which is similar to what is seen in Asian countries (81).

The pattern of oesophageal cancer is rapidly changing worldwide. In Western countries, adenocarcinoma of the lower oesophagus has overtaken the previously more prevalent squamous cell carcinoma (82). Adenocarcinoma is the predominant type in Western countries (82). In the US, adenocarcinoma of the oesophagus is reported to be the most common malignancy with the fastest growing incidence, having increased six times in three decades (82,83). This contrasts with studies from the US in which adenocarcinoma accounted for 81% and squamous cell carcinoma for 17% (84). In another study among Asian/Pacific Islanders in the US, the rate of oesophageal squamous cell carcinoma was 81% higher than in white populations (85).

The characteristics of oesophageal cancer differ between Asian and western populations (Table III). These differences have been reported to play an important role in the disease (86). In future, studies and clinical practices must consider these ethnic and histological differences and molecular epidemiologic studies may will be helpful in investigating high-risk populations.

Literature on SC particularly SCC identified candidate genes that are involved in alcohol metabolism, detoxification of carcinogens, DNA repair, apoptosis and cell proliferation (98,99), but their results are not consistent across different populations. This lack in consistency indicates the role played by environmental differences between populations, differences in the level of exposure to different carcinogens as well as differences in sample sizes (98). Genome wide association studies (GWAS) successfully founded hundreds of genetic polymorphisms that are associated with complex diseases including cancer (96). SCC GWAS were conducted in four Asian populations, three in Chinese population and one in a Japanese population (100–103). Two SCC associated single nucleotide polymorphisms (SNPs) were identified in the Japanese study. These were SNPs in alcohol dehydrogenase 1B (rs1229984) and aldehyde dehydrogenase 2 (rs671) gene. These genes encode for metabolic enzymes that are involved in the metabolism of alcohol. Un-metabolised or partially metabolised alcohol is a carcinogen associated with altered SCC risk. The study also indicated gene environmental interactions of rs1229984 and rs671 with alcohol drinking and in the case of rs671, with smoking (101). Two of the Chinese genome association studies reported two susceptibility loci rs2274223 in phospholipase C and rs13042395 in chromosome 20 (104). In a larger GWAS of 2043 cases and 2063 controls in Chinese Han individuals, three new SNPs associated with SCC were identified. These were, rs10052657 in phosphodiesterase 4D, rs2014300 in runt related transcription factor 1and rs10484761 close to unc5 homolog C (100). No SNP has been identified that plays a larger role than environmental factors. SNPs have been identified in different population groups in South Africa that are associated with increased risk for developing oesophageal cancer. These studies targeted black Africans and mixed ancestry populations of South Africa and investigated the occurrence of 12 SNPs and one insertion/deletion variant from 8 genes, known to be associated with oesophageal cancer. These studies have indicated that several genetic variants in alcohol metabolism and DNA repair genes are known to contribute to genetic susceptibility to SCC in mixed ancestry populations but not in black South African populations of South Africa or Brazil. This shows that the differences in genetic variants may be explained by genetic history and different environmental exposures (97). This indicates that in low and middle countries more investigations are required that will involve more black populations than white and mixed ancestries populations, since caucasians and those of a mixed ancestry share some genetic history. Mixed population composition differs in genetic, epidemiological and socio demographical characteristics and these may result in association variation between smoking and different types of cancer (105). These differences in different populations are demonstrated in Table III, which shows different incidence rates of OC in different countries with different genetic history and environmental factors.

The prevention of OC differs depending on cell type. The best way to prevent oesophageal cancer is to avoid exposure to environmental risks. In the case of SCC, it is important to reduce or quit tobacco usage and alcohol consumption. Reports indicated that no particular risk factor is responsible for the rise of OC incidence and several strategies are under investigations using agents such as nonsteroidal anti-inflammatory drugs, selenium, alpha-di-fluoro-methyl-ornithine, and retinoids (123). Vegetable and fruit intake are reported to be important preventive strategies, in the case of obesity, which is reported as a risk factor for AC). Follow up of patients with precancerous lesions is recommended. Surveillance, endoscopic screening and surgical resection are important approaches that are suggested to prevent the progression of high-grade dysplasia patients (9). Monitoring the weight of obese patients is also an important strategy of prevention. In Asian and African countries such as China and South Africa, there are preventive approaches of cancer related diseases and OC is one of them, which are under investigation such as using medicinal plant extracts to induce apoptosis. Both China and African countries have a history of using traditional herbs to treat diseases. These plants are currently being assessed scientifically for their medicinal value. This involves the extraction and purification of crude plant extracts. The purified compounds can then be tested for their ability to treat diseases. For instance, the effectiveness of these compounds in cancer treatment can be assessed by exposing cancer cells to these compounds. This is one of the important strategies required to treat OC in low and middle countries such as China, India, Brazil and South Africa. These compounds may serve as lead targets for the development of new drugs for the treatment of SCC or even AC in developed countries. Table III, indicates that low and middle-income countries are having high incidence of OC (124).

Surgical treatment is divided into six types, endoscopic procedures, resection, lymph-node dissection, and minimally invasive oesophagectomy, neoadjuvant chemotherapy with surgical resection, neoadjuvant chemoradiotherapy surgery, and surgery with adjuvant chemotherapy, radiation or chemoradiation (128). OC may require surgical resection, which includes traditional oesophagostomy and transthoracic approaches (127,128). This surgical option depends on the location of the tumour and the preference of the surgeon (35). Lymph-node dissection surgery is required for patients with oesophageal carcinoma that may be prone to spreading. An oesophagostomy targets the abdominal lymph nodes and the thoracic lymph nodes. This type of dissection is commonly performed in Japan, where incidence of SCC is high (129). It has been noticed that a mortality rate of 1–23% is associated with oesophagostomy. In order, to reduce the morbidity and mortality associated with oesophagostomy, minimally invasive oesophagostomy was introduced (130).

Avoiding the immune system is one of the hallmarks of cancer. Inducing or sustaining the immune system to act against cancer cells, is a promising therapeutic strategy. This has led to the development of immunotherapies to treat oesophageal cancer. Different classes of compounds have shown promising results. These include cancer vaccines and immune checkpoint inhibitors (ICI) (131). The development of cancer vaccines is based on the identification of immunogenic cancer antigens (ICA) Cancer vaccines work by initiating antigen specific cytotoxiv T lymphocyte killing of cancer cells. One approach is to use dendritic cells loaded with multiple Tumor specific antigens, leading to the activation of multiple population of T cells (131). Novel ICAs for ESCC have been identified which match the criteria for being good UCAs as they hive high expression levels in ESCC. They are also essential molecules for the survival of the cancer cells/Despite this, no cancer vaccine has been approved for the treatment of ESCC yet.

As mentioned previously, another type of immunotherapy is the use of immune checkpoint inhibitors. The response of T cells to cancer cells is regulated by immune checkpoints. This checkpoints are regulated through the binding of inhibitory or stimulatory molecules to receptors, examples of which include Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) (131). Both of these checkpoint receptors are expressed on T cells and act to inhibit T cells by inhibiting the activity of receptors such as CD28, which activate T cells (131) An ICI named ipilimumab is an anti-CTLA-4 mAb, that is able to treat metastatic melanoma. PD-1 binds to the death-ligand receptor 1 (PD-L1) on cancer cells to induce apoptosis in T cells. PD-L1 is, therefore, an inhibitory B7 family member and is up-regulated in ESCC. Four anti-PD1 mAbs, nivolumab, avelumab, pembrolizumab and atezolizumab are used to treat cancer. Anti-CTLA-4 mAb (ipilimumab) and anti-PD-1 mAb (nivolumab), have both demonstrated the ability to decrease in tumor size (131,132).

It was suggested that the spread of OC could be controlled by the combination of both chemotherapy and surgery (133). This type of surgery has encountered some problems since patients with SCC or adenocarcinoma shown conflicting results. However, a UK Medical Research Council Oesophageal cancer Working Group study tested the effectiveness of surgery combined with chemotherapy. This study identified a significant improvement in 3-year survival compared with surgery alone (134).

Neoadjuvant chemoradiotherapy and surgery is commonly used in the USA for locally advanced oesophageal cancer. Most randomised studies of this surgery have shown non-significant results. Two studies performed indicated significant survival benefit of this commination treatment (135,136). It has been predicted that adjuvant chemotherapy treated with primary resection might be beneficial especial in patients with node-positive disease (133,137–139). In several randomised trials performed by the Japanese Clinical Oncology Group compared surgery with or without chemotherapy in SCC patients (137,138). In one study, 5-year disease-free survival indicated that combined therapy was favoured (137).

Non-surgical treatment are divided into six treatment approaches, namely: Radiotherapy; concurrent definitive chemoradiation; salvage oesophagectomy after definitive chemoradiation; advanced metastatic or recurrent disease; biological and targeted therapies; and endoscopic treatment. It is well known that external beam radiotherapy played an important role in the management of un-resectable oesophageal carcinoma. Sustained remission and long-term survival are rarely achieved, although radiotherapy is used in palliative treatment for dysphagia. The preferred approach is chemo-radiotherapy for patients suitable for combined therapy as it provides better palliation than radiotherapy alone and improves the likelihood of long-term progression-free survival (140). Radiotherapy against chemo-radiotherapy was assessed with cisplatin and fluorouracil in patients with 90% SCC. Chemo-radiotherapy group had an estimated 5-year survival of 27% and there was no 5-year survival observed in those patients who received radiotherapy alone. It was suggested that although chemo-radiotherapy without surgery is accepted as a SCC treatment, local control is improved when performed with surgery (141).

Salvage oesophagostomy has a higher morbidity and mortality than regular oesophagostomy performed in neoadjuvant methods. A 5-year survival estimation of 25% in selected patients has shown an increase in perioperative risks. So Salvage oesophagostomy was suggested to be considered for selected patients. It is only an option for patients that respond to chemo-radiotherapy. In most cases by the time of diagnosis of oesophageal carcinoma. The tumour has already started to spread and metasasise (142). Combined short-acting and long-acting narcotics and local radiotherapy are used to treat pain. The effectiveness of chemotherapy or chemo-radiation is observed in approximately 50% of patients; however, management of pain is effective in almost all patients. Cisplatin and fluoroucil combination play a vital role as supportive care in SCC patients (143). Agents consisting of small molecules and antibodies were created and incorporated into multimodal therapies for tumours (144). The commonly used agents include the angiogenesis inhibitor bevacizumab and the inhibitors of epidermal growth factor receptor; panitumumab; cetuximab; and erlotinib (23).

Endoscopic therapies are used to treat advanced or inoperative cancers and have been suggested as curative approaches for early-stage oesophageal carcinomas. Barrett's oesophagus and early stage cancer might be treatable endoscopically with resection or ablation. Nonsurgical treatment seem to be less reliable than surgical treatment. These treatment options are also more common in well-developed countries. In low and middle countries due to lack of funds and experienced personnel (23).