In North America and Europe esophageal adenocarcinoma is the predominant type of esophageal cancer. Gastroesophageal reflux disease (GERD) and obesity are the main risk factors. The known precancerous damage is Barrett’s esophagus, which is detected by endoscopy and treated and monitored as such after detection.
Squamous esophageal cancer is the main type of esophageal cancer in blacks in Asia, Africa, South America and North America. Alcohol and tobacco are the main risk factors and squamous heterogeneous esophageal hyperplasia is the main precancerous damage. Although 5-year survival rates for esophageal cancer remain poor over the past decade, they have improved, and the likelihood of long-term survival for patients with early and locally progressive esophageal cancer is improving.
Anil Rustgi and Dr. Hashem B. EI-Serag of the United States published a review in NEJM that focuses on the epidemiology and pathogenesis of two types of esophageal cancer and on prevention and treatment, highlighting recent advances.
Epidemiology of esophageal adenocarcinoma and esophageal squamous carcinoma
There are two major types of esophageal cancer, squamous carcinoma and adenocarcinoma. Although squamous esophageal cancer accounts for 90% of all esophageal cancers worldwide, the mortality and incidence of esophageal adenocarcinoma is increasing and has surpassed squamous esophageal cancer in several regions of North America and Europe. Esophageal cancer is rare in young adults and its incidence increases with age, with a peak incidence of 70 to 80 years. Esophageal adenocarcinoma is more prevalent in men, 3 to 4 times more common than in women, and there is no difference between men and women with esophageal squamous carcinoma.
In the United States, 18,000 new cases of esophageal cancer and 15,000 deaths from esophageal cancer are expected in 2014. Over the past 30 years, the incidence of esophageal squamous cancer is decreasing and the incidence of esophageal adenocarcinoma is gradually increasing (Figure 1).
Figure 1. Trends in esophageal adenocarcinoma incidence and survival
Environmental risk factors
Population-based case-control cohort studies have shown GERD, smoking, and obesity to be major risk factors for esophageal cancer. The absolute risk of developing esophageal adenocarcinoma in individuals older than 50 years of age is approximately 0.04% per year. Up to 40% of patients with esophageal cancer do not have symptoms of GERD.
The risk of esophageal adenocarcinoma is twice as high in smokers as in nonsmokers, and smoking is considered to be a stronger risk factor for esophageal squamous carcinoma than for esophageal adenocarcinoma. Population-based studies have not revealed a relationship between esophageal adenocarcinoma and alcohol. The incidence of esophageal squamous carcinoma in alcohol drinkers is 3-5 times higher than in non-drinkers, and the increased risk is more pronounced when smoking is also associated. Excessive consumption of meat, fat and processed foods increases the risk of both types of esophageal cancer, while increased consumption of fiber, fresh fruits and vegetables reduces the risk.
The increased incidence of esophageal adenocarcinoma has the following hypotheses: increased GERD, increased obesity + GERD, and decreased H. pylori infection. Obesity increases the risk of esophageal adenocarcinoma with risk factors 2.4 to 2.8, especially abdominal obesity increases the risk of Barrett’s esophagus and cancer, probably due to increased pressure in the stomach causing relaxation of the lower esophageal sphincter and formation of esophageal hiatal hernia, which together contribute to aggravate GERD. abdominal obesity is common in men, which explains to some extent the gender difference in cancer risk.
The risk of esophageal adenocarcinoma is reduced in people with H. pylori infection, and the Meta study showed a 41% reduction in the risk of esophageal adenocarcinoma in patients with H. pylori infection. H. pylori causes gastritis, reduces acid production, decreases exposure of the esophageal epithelium to acid components, and reduces the risk of Barrett’s esophagus and adenocarcinoma formation. No clear link between H. pylori and esophageal squamous carcinoma was found.
An association between esophageal adenocarcinoma and the use of sodium allantoin phosphate has been reported, however, further studies have yielded conflicting findings. Human papillomavirus may increase the risk of esophageal squamous carcinoma, but the evidence remains insufficient. There is also a 10-fold increased risk of esophageal squamous carcinoma in patients with esophageal motility disorder – flaccid failure.
Genetic risk factors
Barrett’s esophagus and adenoma are familially clustered, and genome-wide association analysis identified 11% of Barrett’s esophagus and adenoma with embryonic mutations in three candidate genes, MSR1, ASCC1, and CTHRC1.
Mutated MRS1 is associated with cyclinD1 overexpression, leading to rapid cell cycle progression. In another genomic relationship study, susceptibility loci for Barrett’s esophagus and adenoma were identified in CRTC1 (encoding CREB-regulated transcription factor), BARX1 (esophagus-specific associated protein) and FOXP1 (esophageal differentiation-associated protein).
Palmoplantar keratosis, a rare familial esophageal squamous carcinoma, is an autosomal dominant disorder with a missense mutation in RHBDF2 at chromosome 17q21-22, which encodes an inactivating rhodopsin. Genomic relationship studies have identified a series of susceptibility loci in Chinese patients with esophageal squamous carcinoma, implying that esophageal squamous carcinoma is associated with complex genetic and environmental interactions.
A recent study, which analyzed mutational profiles in whole exome sequencing in normal and cancerous tissues of esophageal adenocarcinoma patients, identified a total of 28 mutated genes, five of which were associated with adenocarcinoma pathogenesis: TP53, CDKN2A, SMAD4, ARIS1A, and PIK3GA.
Alterations in these genes and molecular pathways are very common in esophageal adenocarcinoma. Germline-specific factors, especially transcription factors, are very important in esophageal carcinogenesis. Genome-wide and whole-exome sequencing of Chinese esophageal squamous carcinoma patients identified eight mutated genes, six known tumor-associated genes and two newly discovered genes.
Animal models of esophageal cancer
Several animal models of esophageal cancer have now been established. A rodent surgical animal model with gastrectomy followed by esophageal jejunostomy or esophageal duodenal anastomosis to induce bile reflux recapitulates Barrett’s esophagus and tumor progression. Mouse models with P120-linked protein, which is normally used to stabilize E-cadherin on the cell membrane and which, if removed, leads to esophageal squamous carcinoma.
There are also hereditary models of esophageal adenocarcinoma. For example, the fusion of the L2 promoter of the esophagus-specific EB virus with interleukin 1-beta induces an inflammatory factor microenvironment that induces the formation of Barrett’s esophagus. The addition of bile acids to the drinking water of this mouse or crossbreeding with another P16 tumor suppressor gene deficient mouse accelerates esophageal adenocarcinogenesis.
Another approach is to knock out the P63 gene, which is critical for the proliferation of squamous epithelial stem cells or precursor cells, ultimately leading to the conversion of the Barrett-like cell population to squamocolumnar junctional cells.
Three-dimensional cell culture “organotypic culture” complements the animal model to elucidate the pathway of Barrett’s esophagus, where there may be stem cell or precursor cell transformation leading to reprogramming, or squamous esophageal basal cell differentiation, or gastric cardia cell transformation. Barrett’s esophagus cells can appear followed by heterogeneous proliferation and malignancy within the damage. Three-dimensional organotypic culture models have been used to study esophageal squamous cell carcinoma.
Endoscopy and surveillance
It is believed that Barrett’s esophagus is an esophageal adenocarcinoma precursor with differentiated intestinal columnar epithelial cells replacing the normal squamous epithelium. The results of a large cohort study showed that the annual risk of cancer in patients with Barrett’s esophagus without heterogeneous hyperplasia was 0.12-0.40%. The presence of heterogeneous hyperplasia in Barrett’s esophagus damage significantly increased the risk of cancer, with a 1% annual risk of cancer in low-grade heterogeneous hyperplasia and a risk of cancer in high-grade heterogeneous hyperplasia of more than 5%.
80-90% of esophageal adenocarcinomas do not have Barrett’s esophagus. Barrett’s esophagus is found on endoscopy in 6-12% of patients with persistent GERD, most of whom are white men over 50 years of age. Endoscopy is recommended every 3 years for Barrett’s esophagus without heterogeneous hyperplasia. Despite the lack of randomized direct evidence, most observational studies conclude that endoscopic surveillance of Barrett’s esophagus reveals adenomas that are more likely to be cancerous at an early stage, should receive radical treatment, and have a longer survival time than patients who are diagnosed and treated for symptoms.
In addition to being able to detect cancer early. Radiofrequency ablation of Barrett’s damage with low- or high-grade heterogeneous hyperplasia resulted in remission of esophageal chemosis in 77% of cases, remission of heterogeneous hyperplasia in 86%, reduced risk of progression, and fewer cancers. Long-term follow-up has confirmed the persistence of these effects, but ongoing monitoring after radiofrequency ablation therapy is necessary because recurrences can occur, the most common recurrence being non-heterogeneous hyperplasia, which can be treated endoscopically.
Guidelines now do not recommend endoscopic ablation for non-heterozygous hyperplasia Barrett’s esophagus, and ablation should be considered in patients at high risk for long Barrett’s esophagus, severe GERD, Barrett’s esophagus, or family history of adenocarcinoma. Treatment of precancerous lesions is usually individualized without regard to the economic benefit ratio. Although other biomarkers of Barrett’s esophagus progression are available, none show heterogeneous growths as clearly and as accurately as endoscopy.
The preexisting damage of esophageal squamous carcinoma is esophageal squamous heterogeneous hyperplasia. The risk of squamous cell carcinoma increases progressively in patients with mild, moderate, or severe heterogeneous hyperplasia, with risk factors of 3, 10, and 30, respectively, and in some parts of China, esophageal cancer screening methods including endoscopy or cytobrush are also valuable and recommended for patients who are unable to relax or whose esophageal strictures are caused by alkaline solution ingestion, for which there are no guidelines.
Prevention
Proton pump inhibitors
The first observational studies have shown that proton pump inhibitor therapy reduces the risk of high-grade heterogeneous hyperplasia and adenocarcinoma in patients with Barrett’s esophagus. However, these studies had shortcomings, such as selection bias and no adjustment for cofactors. Several retrospective studies have shown that anti-reflux surgery in patients with GERD or Barrett’s esophagus does not reduce the risk of esophageal adenocarcinoma, and the procedure is not recommended for cancer prevention alone.
Aspirin and non-steroidal anti-inflammatory drugs
Observational studies have shown that aspirin and NSAIDs can reduce the risk of esophageal adenocarcinoma and squamous carcinoma by 40-50% and are recommended as cancer prevention in the general high-risk population. However, a randomized trial showed that celecoxib treatment did not reduce the risk of cancer in patients with Barrett’s esophagus and low-grade/high-grade heterogeneous hyperplasia. Another randomized study showed that celecoxib did not affect the progression of squamous heterogeneous growths in the esophagus. Further studies are underway on this issue.
Statins
One analysis showed that statin users reduced the risk of esophageal adenocarcinoma by 28% and the risk of Barrett’s esophagus adenocarcinoma by 41% compared to non-users. However, there were significant inconsistencies in these studies, including dose, duration, or statin type.
The translation of demographic findings into actual prevention recommendations, while logical, lacks evidence, unlike the evidence for smoking bans, weight loss, and dietary modification, which is so clear. Prevention trials conducted in China have shown that nutritional supplementation, such as vitamins and minerals, does not reduce precancerous damage, nor does it reduce incidence or mortality, either in the esophageal cancer, general population, or esophageal squamous heterogeneous hyperplasia population.
Clinical manifestations of esophageal cancer
Esophageal adenocarcinoma and esophageal squamous carcinoma have different demographics and risk factors, but similar clinical presentations and similar endoscopic presentations, except that approximately 3/4 of adenocarcinomas present in the distal esophagus, whereas squamous cell carcinomas frequently present in the proximal or mid esophagus.
Common clinical manifestations include progressive dysphagia, weight loss, heartburn unresponsive to medication, and blood loss. Less frequent symptoms include hoarseness, cough, pneumonia associated with nerve damage or invasion of the tracheobronchus. Patients with squamous cell carcinoma of the head and neck are at increased risk of developing esophageal squamous carcinoma.
Treatment
The treatment of esophageal cancer is summarized in Table 1. The treatment of both tissue types of esophageal cancer is usually similar, but there are several differences in the choice of chemotherapy versus surgical treatment, and adenocarcinoma of the gastroesophageal junction is usually considered to be an extension of esophageal adenocarcinoma.
Table 1, Treatment of esophageal adenocarcinoma
Staging
Esophageal cancer prognosis and treatment rely on precise assessment of the depth of cancer invasion and lymph node invasion (Figure 2). Over the past decade, endoscopic ultrasound and PET have improved staging, with endoscopic ultrasound achieving 70-80% accuracy in assessing tumor and lymph node status, and the addition of fine-needle biopsy to endoscopic ultrasound further improving the sensitivity of lymph node staging. Endoscopic ultrasound is particularly helpful for staging in those who have no obvious local or distant dissemination on chest and abdominal image examination, and endoscopic mucosal resection, which can further improve staging and increase the chance of cure.
Figure 2. Esophageal cancer staging
PET examination is used to identify occult distant metastases, usually in supraclavicular or retroperitoneal lymph nodes, and 10-20% of cases are classified as progressive stage because of PET findings.
Mucosal tumors
Endoscopic mucosal resection with or without ablation has been a major therapeutic advancement in recent years when high-grade heterogeneous hyperplasia or adenocarcinoma in Bsrrett’s esophagus is confined within the mucosal epithelium, especially in small tumors, which are usually asymptomatic and do not have a pericircular switch margin. If Barrett’s esophagus remains incomplete, endoscopic ablation may be added.
The risk of lymph node metastasis is related to the depth of tumor invasion. The risk of lymph node invasion is almost zero in Barrett’s esophagus with high-grade heterogeneous hyperplasia and 1-2% in stage I tumors. There are no randomized trials comparing endoscopic versus surgical treatment, and several observational studies have shown similar cure and survival rates for both approaches.
Endoscopic treatment should be preferred for patients with stage 0 or I adenocarcinoma with no contraindications or comorbidities. For T1b tumors that have invaded the myxomucosa and entered the submucosa, with a 20% risk of lymph node metastasis, radical esophagectomy is the preferred approach, but some treatment centers have expanded the indications for endoscopic treatment to include low-risk submucosal tumors.
Locally Progressive Tumors
Locally progressive tumors, defined as T3N1, are best treated with esophagectomy, and although studies have also shown that cure can be achieved with radical radiotherapy alone, particularly in patients with squamous cell carcinoma, this approach is not supported by evidence from randomized controlled trials and should therefore be limited to patients with declining status or insufficient health to tolerate esophagectomy.
Esophagectomy alone is associated with a high recurrence rate and a very low 5-year survival rate of 5 to 34%. Recent advances in the treatment of patients requiring esophagectomy have been the administration of neoadjuvant radiotherapy or chemotherapy. Randomized controlled trials have shown that neoadjuvant chemoradiotherapy or chemotherapy provides a survival benefit for both types of esophageal cancer compared to surgery alone. Carboplatin combined with paclitaxel or cisplatin combined with fluorouracil-based chemoradiotherapy is becoming the standard of care in the United States, and neoadjuvant chemotherapy alone is the preferred approach in Europe.
Meta-analysis showed that the risk of all-cause mortality was 0.78 in the neoadjuvant group and 0.87 in the neoadjuvant group, with the benefit for adenocarcinoma exceeding that for squamous cell carcinoma. The benefit of receiving chemotherapy both before and after surgery was slightly increased in patients with squamous cell carcinoma.
Other than histologic examination of the resected specimen, there were no other tests that could be trusted to confirm the responsiveness of neoadjuvant therapy, so esophagectomy was necessary. Patients with adenocarcinoma, with residual, positive lymph nodes, have poor outcomes despite complete resection after neoadjuvant therapy, and it is unclear whether adjuvant chemotherapy or radiotherapy would be beneficial in such patients. Adjuvant chemotherapy is used for lymph node positive squamous carcinoma and this approach has shown benefit in several Japanese randomized trials.
Surgical outcomes look better at larger medical centers or with experienced surgeons, and the incidence of postoperative comorbidities and treatment are clearly beneficial. Lymph node dissection in both thoracoabdominal regions is the standard procedure in most European and North American medical centers, and in some countries also in the cervical lymph nodes, which are often invaded by squamous carcinoma. The safety and comorbidities of minimally invasive esophagectomy are similar to those of standard esophagectomy, but the technique is challenging.
Progressive Tumors
Unresectable esophageal cancer causing obstructive symptoms is addressed by endoscopic esophageal stenting or high-dose intraluminal irradiation. Endoscopic placement of a self-filling metal stent is the first-line option to address dysphagia. Self-filling metal stents provide higher symptom relief and less management of comorbidities compared to local treatment. The addition of high-dose internal irradiation to the built-in stent base can moderately prolong survival. Other treatments such as endoscopic expansion or ablation, plastic stents, bypass surgery or radiotherapy are not recommended due to low effectiveness and higher comorbidity.
Palliative chemotherapy is also frequently used to treat unresectable, metastatic or recurrent esophageal cancer in order to prolong survival. Carboplatin or cisplatin in combination with fluorouracil or capecitabine has a 35-45% response rate and prolonged survival for several months, especially in squamous cell carcinoma. Combinations of all three drugs may increase response rates by 5-10%, but are associated with higher toxicity.
Second-line chemotherapy is still under investigation, and the use of gefitinib as second-line therapy in non-selective patients does not improve overall survival. Treatment with docetaxel in combination with ramucirumab is more promising. Trastuzumab increased overall and progression-free survival in progressive esophageal adenocarcinoma by 2.7 months and 1.7 months, respectively.
Prognosis
The 5-year overall survival of patients with esophageal adenocarcinoma in the United States is 17%, which is slightly higher than the 5-year survival of patients with squamous carcinoma. Overall survival and progression-free survival are significantly better in surgically treated patients. Despite the increasing ability to detect early esophageal adenocarcinoma, most tumors are still detected when regional or distant metastases appear, and the 5-year survival rate decreases from 39% for localized esophageal cancer to 4% for distant metastatic esophageal cancer. Moreover, 60-70% of esophageal cancers are not treated with guideline recommendations. Multidisciplinary discussions can improve the treatment of esophageal cancer.
Summary
The main risk factors for esophageal adenocarcinoma are GERD, obesity and smoking, while H. pylori infection reduces the risk of esophageal cancer. Smoking and alcohol consumption are the main risk factors for esophageal squamous carcinoma. Endoscopy can identify Barrett’s esophagus and regular monitoring of Barrett’s esophagus can detect heterogeneous hyperplasia and early esophageal adenocarcinoma.
Endoscopic ablation is an effective treatment for heterogeneous hyperplasia and is the mainstay of treatment for intramucosal adenocarcinoma. Screening for genomic regions and genes can help identify potential pathogenesis of esophageal cancer and contribute to the discovery of new biomarkers and the development of new treatments.