NEOPLASMS OF THE OESOPHAGUS
The oesophagus is a hollow tubular organ with primary physiologic functions related to contraction to permit propulsion of solid and liquid food contents into the stomach. The mucosa is a stratified squamous epithelium that covers the submucosa and muscle; the latter is skeletal muscle in the proximal oesophagus and smooth muscle in the mid-distal oesophagus. Cancers of the oesophagus may be classified broadly into epithelial versus nonepithelial. There are benign epithelial tumours referred to as squamous cell papillomas. Malignant epithelial tumours are classified into two main subtypes: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Other, less common, oesophageal epithelium-derived cancers include verrucous squamous cell carcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma. Benign nonepithelial tumours include leiomyoma, granular cell tumours, fibrovascular polyp, haemangioma, lymphangioma, lipoma, and fibroma. Malignant nonepithelial tumours include leiomyosarcoma and other sarcomas, metastatic carcinoma (originating from breast, lung), and lymphoma.
Oesophageal squamous cell carcinoma is the more common type of oesophageal cancer worldwide and represents a leading cause of cancer-related mortality in men. Oesophageal squamous cell carcinoma may have rates of up to 100 per 100,000 population in what is often termed the Central Asian belt , including regions around the Caspian Sea, Iran, India, and China; other areas of high incidence include some Mediterranean countries and South Africa. In the United States, oesophageal squamous cell carcinoma is more common among African American males than white males, with risks of 15.1 per 100,000 compared with 2.9 per 100,000, respectively. Overall, although the U.S. incidence of oesophageal squamous cell carcinoma is low in males or females younger than 50 years, it does increase with advancing age.
Cancers in general are viewed in the context of hereditary or inherited forms versus sporadic or seemingly random diseases that are related to age, environmental exposures, and genetic alterations. That being said, the hereditary basis for oesophageal squamous cell carcinoma is exceedingly rare, consisting of a desquamating condition termed tylosis palmaris et plantaris . As implied, the desquamation most dramatically affects the hands and feet, but this extends to the oesophagus as well. Another uncommon condition, Plummer-Vinson syndrome or Paterson-Brown Kelly syndrome, entails glossitis, cervical oesophageal webs, and iron deficiency anaemia. In both conditions, it is likely that chronic inflammation triggers the cascade of events that culminate in oesophageal dysplasia and oesophageal squamous cell carcinoma.
- Oesophageal squamous cell cancer
- Tylosis palmaris et plantaris
- Plummer-Vinson syndrome
- Cigarette smoking
- Chronic lye ingestion
- Human papillomavirus infection
- Radiation injury
- Celiac sprue
- Oesophageal adenocarcinoma
- Gastroesophageal acid reflux
- Bile reflux
- Barrett oesophagus
The preponderance of oesophageal squamous cell carcinoma cases are attributable to cigarette smoking or alcohol, but especially so in combination, because there appear to be synergistic deleterious effects of various chemical carcinogens in both, including N -nitroso compounds, polycyclic aromatic hydrocarbons, and aromatic amines. The relative risk for oesophageal squamous cell carcinoma is 6.2 in those who smoke more than 25 cigarettes on a daily basis. Cessation of cigarette smoking is helpful in attenuating risk after 10 years of abstinence. Cigarette smokers who partake in beer and whiskey have a 10- to 25-fold enhanced risk of developing oesophageal squamous cell carcinoma. Indeed, it is the type of alcohol and the manner of distillation that are most critical. In endemic areas of the world, deficiencies of vitamins A, B12 , C, and E, folic acid, and certain minerals (zinc, selenium, molybdenum) are important risk factors. All these vitamins and minerals exert direct or indirect antioxidant effects, and their deficiencies impair epithelial and tissue homeostasis and regeneration.
Other risk factors for oesophageal squamous cell carcinoma include achalasia, a disorder that involves agangliosis of Auerbach’s plexus, resulting in dysphagia, chest pain, and weight loss, among other symptoms. The emergence of oesophageal squamous cell carcinoma may be observed 10 to 20 years after the identification of achalasia in patients. Because head and neck squamous cell carcinoma (HNSCC) shares many of the environmental and lifestyle risk factors with oesophageal squamous cell carcinoma, particularly alcohol and tobacco smoking, HNSCC and oesophageal squamous cell carcinoma may occur synchronously or metachronously. In different parts of the world, oesophageal squamous cell carcinoma is also associated with chronic oesophageal stricture due to lye ingestion, consumption of maté (a hot herb-based beverage), celiac sprue, human papillomavirus (HPV) infection (especially genotypes HPV-16, HPV-18, and HPV-33), and radiation injury.
Oesophageal squamous cell carcinoma involves the transition from normal squamous epithelium to squamous dysplasia to cancer. Oesophageal squamous cell carcinoma initiation, progression, and metastasis are associated with a number of genetic alterations. Among these genetic alterations are overexpression of epidermal growth factor receptor (EGFR) and cyclin D1 oncogenes, and inactivation of TP53, p16INK4A, E-cadherin, and p120-catenin (p120ctn) tumour suppressor genes. The frequency of these changes varies greatly based upon various studies, but the oncogenic alterations generally appear early in dysplasia and early oesophageal squamous cell carcinoma, whereas the inactivation of tumour suppressor genes appear as later events in established primary and metastatic oesophageal squamous cell carcinoma. From a genomic viewpoint, the SOX-2 transcription factor, important in the pluripotent capacity of somatic cells, has been shown to be an important gene involved in oesophageal squamous cell carcinoma pathogenesis and transformation by virtue of SOX-2 amplification. The ability to model oesophageal squamous cell carcinoma in vitro and in vivo has witnessed great strides in recent years through the advent and characterization of three-dimensional organotypic culture models, xenograft transplantation mouse models, and genetically engineered mouse models. For example, conditional knockout of the p120ctn tumour suppressor gene in the oesophagus of mice results in invasive oesophageal squamous cell carcinoma.
Although oesophageal squamous dysplasia is typically not associated with symptoms, oesophageal squamous cell carcinoma, which has a predilection for the proximal to midoesophagus, may be associated with dysphagia, odynophagia, atypical or typical chest pain, gastrointestinal bleeding, nausea, vomiting, weight loss, and malnutrition. Oesophageal squamous cell carcinoma may metastasize to local lymph nodes, lung, liver, and bone. Symptoms attributable to metastatic oesophageal squamous cell carcinoma may involve bone-related pain, dyspnoea, and evidence of jaundice and liver failure, depending upon the extent of metastatic disease.
The patient should be evaluated for changes in hair, skin integrity, and nail beds as a reflection of malnutrition. Weight loss may result in general cachexia and muscle wasting. There may be lymphadenopathy in the anterior cervical and superclavicular regions. Hepatomegaly and complications of liver disease may be present with metastatic disease to the liver.
There may be progressive iron deficiency anaemia due to chronic indolent upper gastrointestinal bleeding. Additional abnormalities may be reflected in metabolic disturbances, such as metabolic alkalosis due to vomiting and hypernatremia due to dehydration. Liver enzyme abnormalities, both hepatocellular and cholestatic, may reflect metastasis to the liver. There are no specific markers for oesophageal squamous cell carcinoma, but an elevated carcinoembryonic antigen (CEA) level may be used to aid in monitoring disease recurrence after therapy.
Barium swallow radiography is useful for the diagnosis of oesophageal squamous cell carcinoma, with depiction of a filling defect due to the mucosal lesion or impaired transit of barium due to luminal growth. However, definitive diagnosis involves direct visualization with upper endoscopy; once the mass is visualized, biopsies are necessary for confirmation by histopathology and immunohistochemistry for cytokeratins associated with proliferation and differentiation. Oesophageal squamous cell carcinoma may involve local lymph nodes, which are best detected by endoscopic ultrasound (EUS); as needed, samples can then be analysed by cytopathology following fine-needle aspiration (FNA). In high-volume centres in the United States, the cytopathologist will be in the procedure room with the gastroenterologist to provide an initial evaluation of the specimens obtained through FNA. Evaluation of metastatic disease involves chest and abdominal computed tomography (CT) scans. Bone scan might be useful in patients who are symptomatic with bone-related pain. Positron emission tomography (PET) has become increasingly used in some settings. In totality, these diagnostic modalities also allow for staging of oesophageal squamous cell carcinoma, which is important in guiding therapeutic options.
Surgery is the cornerstone of therapy for curative intent. Technical advances have led to improvements in both operative mortality and postoperative morbidity. The different surgical techniques include transthoracic, transhiatal, and radical en bloc resections. Depending upon the location of the oesophageal squamous cell carcinoma, either total esophagectomy or subtotal esophagectomy is pursued. For the latter, jejunal or colonic interposition can be done. Although there is currently a lack of high-quality studies comparing minimally invasive esophagectomy (MIE) to conventional approaches, MIE can achieve equivalent or better perioperative mortality, morbidity, and oncologic outcomes compared to open surgery in selected patients.
Depending upon the stage of disease, there is some variation in whether to proceed with preoperative (neoadjuvant) chemoradiation therapy (preferred for early stage) or postoperative (adjuvant) chemoradiation therapy.
A study in which patients were randomized to receive surgery alone or surgery plus postoperative chemotherapy with 5-fluorouracil and leucovorin and concurrent radiation therapy revealed that the median survival was 36 months for patients in the adjuvant arm compared with 26 months for those in the surgery-only arm. The 3-year overall survival rates were 50% (surgery plus adjuvant therapy) compared with 40% (surgery alone), respectively.
TNM staging system for cancer of the oesophagus (American Joint Committee on Cancer Criteria)
- Primary tumour (T)*
- Primary tumour cannot be assessed
- No evidence of primary tumour
- High-grade dysplasia†
- Tumour invades lamina propria, muscularis mucosae, or submucosa
- Tumour invades lamina propria or muscularis mucosae
- Tumour invades submucosa
- Tumour invades muscularis propria
- Tumour invades adventitia
- Tumour invades adjacent structures
- Resectable tumour invading pleura, pericardium, or diaphragm
- Unresectable tumour invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
- *(1) At least maximal dimension of the tumour must be recorded, and (2) multiple tumours require the T(m) suffix.
- † High-grade dysplasia includes all non-invasive neoplastic epithelia that was formerly called carcinoma in situ.
- Lymph node (N)*
- Regional lymph nodes cannot be assessed
- No regional lymph node metastasis
- Metastasis in 1-2 regional lymph nodes
- Metastasis in 3-6 regional lymph nodes
- Metastasis in 7 or more regional lymph nodes
- *Number must be recorded for total number of regional nodes sampled and total number of reported nodes with metastasis.
- Distant metastasis (M)
- Metastasis cannot be assessed
- No distant metastasis
- Distant metastasis
The 5-year survival for treated oesophageal squamous cell carcinoma is dependent upon stage and types of therapies used. For stages T1 and T2 without lymph node involvement, surgery alone may be curative in more than 60% of cases. The occurrence of major postoperative complications, which occur in about one third of patients, exerts a long-lasting negative effect on health-related quality of life in patients who survive for 5 years after esophagectomy for cancer. Dyspnoea, fatigue, eating restriction, sleep difficulty, and gastroesophageal reflux progressively worsen more during follow-up in those who suffer such major postoperative complications compared with those without major surgical complications. For patients with metastatic disease, therapy is palliative, involving endoscopically placed expandable prosthetic stents to open the nearly obstructed lumen for passage of food contents, percutaneous endoscopic gastrotomy tubes for delivery of nutrition to the stomach distal to the mass lesion, total parenteral nutrition, pain control, and systemic chemotherapy.
Oesophageal adenocarcinoma affects whites more than African Americans and males much more than females (3 : 1 to 5.5 : 1); it increases in incidence after the age of 40 years. The age-adjusted incidence annually is 1.3 per 100,000. The incidence of oesophageal adenocarcinoma is increasing dramatically in developed countries, especially in the United States (by 4 to 10% annually) and Western/Northern Europe.
Obesity (central) is an important risk factor for oesophageal adenocarcinoma. This may be related to either mechanical factors that foster greater gastroesophageal reflux disease (GERD) or the release of proinflammatory cytokines and chemokines that track to the oesophagus, or both. The major recognized precursor of oesophageal adenocarcinoma is Barrett oesophagus. Barrett oesophagus is the replacement of the normal stratified squamous epithelium by an incomplete small intestinal epithelium (metaplasia) in the distal oesophagus, projecting from the GE junction in a distal-proximal gradient. In turn, it has been demonstrated that Barrett oesophagus is fostered by GERD but also by an admixture of bile acids in the acid refluxate. Patients with scleroderma may be at increased risk for Barrett oesophagus. A small subset of Barrett oesophagus patients may progress to oesophageal adenocarcinoma through intermediate stages of low-grade and high-grade dysplasia. In Barrett oesophagus, one case of oesophageal adenocarcinoma is estimated to arise in 55 to 441 patient-years, which corresponds to an approximately 125-fold increased risk for oesophageal adenocarcinoma compared with that in the general population.
Barrett oesophagus involves transdifferentiation from normal oesophageal epithelium to an epithelium of the small intestine with columnar enterocytes and secretory goblet cells, but without Paneth cells and enteroendocrine cells—hence the designation of incomplete intestinal metaplasia. By itself, the metaplasia of Barrett oesophagus cannot become oesophageal adenocarcinoma. However, if and when Barrett oesophagus transitions to low-grade and high-grade dysplasia, there is the aforementioned risk for oesophageal adenocarcinoma. Barrett oesophagus is associated with abnormal DNA ploidy based on flow cytometry analysis, and certain genetic alterations in epidermal growth factor receptor signalling, TP53, and p16INK4A. Microsatellite instability may be noted as well. Whole genome approaches are revealing gains and losses of chromosomal regions that might lead to identification of known and previously unknown genes critical in the pathogenesis of oesophageal adenocarcinoma. Recent advances in genetically engineered mouse models have allowed the phenocopying of Barrett oesophagus and oesophageal adenocarcinoma through the direct targeting of interleukin (IL)-1β to the oesophagus; and in another approach, through the global knockout of p63 (an important marker of stem cells and progenitor cells), Barrett oesophagus is evident in the postnatal period.
It is estimated that 5 to 15% of GERD patients may develop Barrett oesophagus, but such population-based studies are difficult to pursue because vast millions of people are affected with GERD, and most GERD patients do not undergo upper endoscopy. Patients with Barrett oesophagus may or may not have symptoms related to GERD. Chronic GERD with Barrett oesophagus may be associated with distal oesophageal strictures. With oesophageal adenocarcinoma, patients may suffer from dysphagia, odynophagia, upper gastrointestinal bleeding, chest pain, nausea, vomiting, early satiety, weight loss, and malnutrition.
Examination of the patient may reveal signs consistent with malnutrition and weight loss. Lymph adenopathy should be explored. There may be hepatomegaly. Paraneoplastic syndromes are unusual with oesophageal adenocarcinoma (as well as with oesophageal squamous cell carcinoma). Nevertheless, it is important to ensure that oesophageal adenocarcinoma is not mistaken for a benign entity such as a primary oesophageal motility disorder.
Patients with oesophageal adenocarcinoma may have iron deficiency anaemia, metabolic derangements, and abnormal liver enzyme tests owing to metastatic disease. CEA may be elevated as a tumour serologic marker.
Barium swallow radiography may lead one to the suspicion of Barrett oesophagus and can diagnose luminal mass lesions consistent with oesophageal adenocarcinoma in the distal oesophagus. However, the mainstay of diagnosis is upper endoscopy. At that time, a characteristic salmon-coloured mucosa is visualized at the GE junction, with frondlike projections in a proximal direction. If the extent of Barrett oesophagus is 3 cm or less, it is termed short-segment Barrett oesophagus; if it is more than 3 cm, it is referred to as long-segment Barrett oesophagus. This distinction is important in that the risk for oesophageal adenocarcinoma in long-segment Barrett oesophagus is greater than in short-segment Barrett oesophagus. Noting that the normal oesophageal mucosa is more pinkish-white in hue, one can visually distinguish the two different types of epithelia, with the caveat that the gastric cardia mucosa at the GE junction should not be mistaken for Barrett oesophagus. Endoscopic mucosal biopsies from the Barrett oesophagus region (with control biopsies from the normal oesophagus and gastric cardia) are required for histopathologic diagnosis. Features of dysplasia are best appreciated in the absence of reflux-related esophagitis that can lead to nuclear architectural distortion; hence, suppression of acid production with proton pump inhibitor therapy for 6 to 8 weeks is needed, with a view to repeat biopsies.
If the patient has Barrett oesophagus metaplasia, upper endoscopy should be repeated every 3 years. However, low-grade dysplasia (with confirmation by an expert pathologist) requires surveillance endoscopy every 6 to 12 months. High-grade dysplasia, if properly evaluated by the pathologist, may require reconfirmation, but then leads to either medical (radio frequency ablation [RFA], endoscopic mucosal resection) or surgical intervention because of the possibility of missed contiguous oesophageal adenocarcinoma. EUS may be helpful in discriminating between high-grade dysplasia and oesophageal intramucosal adenocarcinoma.
The principles are very similar to those applied to oesophageal squamous cell carcinoma in terms of surgery. Preoperative chemoradiotherapy (carboplatin titrated to achieve an area under the curve of 2 mg/mL/min and paclitaxel 50 mg/m 2 for 5 weeks) and concurrent radiotherapy (at 41.4 Gy in 23 fractions, 5 days per week) significantly improves median survival from 24 months to 49 months among patients with potentially curable oesophageal or esophagogastric-junction cancer. Overall prognosis for oesophageal adenocarcinoma is not too dissimilar from that noted in oesophageal squamous cell carcinoma. Major improvements in the treatment options for Barrett oesophagus, the main precursor of oesophageal adenocarcinoma, have witnessed dramatic growth. RFA reduces progression of Barrett oesophagus with low-grade dysplasia or possibly high-grade dysplasia to cancer. Endoscopic mucosal resection (EMR) is used for Barrett oesophagus–related high-grade dysplasia or Barrett oesophagus associated with intramucosal oesophageal adenocarcinoma. For advanced, unresectable tumours, self-expanding stents, often with localized brachytherapy, can provide palliation.