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Neoplasms of the Esophagus and Stomach
Neoplasms of the Esophagus
Definition
The esophagus ( Chapter 124 ) 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 esophagus and smooth muscle in the mid-distal esophagus. Cancers of the esophagus may be classified broadly into epithelial versus nonepithelial cancers. Benign epithelial tumors are referred to as squamous cell papillomas. Malignant epithelial tumors are classified into two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Other, less common, esophageal epithelium-derived cancers include verrucous squamous cell carcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma. Benign nonepithelial tumors include leiomyoma, granular cell tumors, fibrovascular polyp, hemangioma, lymphangioma, lipoma, and fibroma. Malignant nonepithelial tumors include leiomyosarcoma and other sarcomas, metastatic carcinoma (e.g., originating from breast or lung), and lymphoma.
Esophageal Squamous Cell Carcinoma
Epidemiology
Esophageal squamous cell carcinoma is the more common type of esophageal cancer worldwide and is a major cause of cancer-related mortality. Esophageal 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 Eastern Africa. In the United States, esophageal squamous cell carcinoma is more common among Black males than White males, with risks of 15.1 per 100,000 compared with 2.9 per 100,000, respectively. Rates are 2 to 3 times higher in men than in women. Although the U.S. incidence of esophageal squamous cell carcinoma is low in both men and women younger than age 50 years, the incidence increases with advancing age.
Risk Factors
Hereditary esophageal squamous cell carcinoma is exceedingly rare, and is associated with a desquamating condition termed tylosis palmaris et plantaris . This desquamation most dramatically affects the hands and feet but extends to the esophagus as well. Another uncommon condition, Plummer-Vinson syndrome or Paterson-Brown Kelly syndrome, entails glossitis, cervical esophageal webs, and iron deficiency anemia. In both conditions, it is likely that chronic inflammation triggers the cascade of events that culminate in esophageal squamous dysplasia and esophageal squamous cell carcinoma.
Most esophageal squamous cell carcinoma cases are related to cigarette smoking or alcohol consumption, especially in combination, because their deleterious effects appear to be synergistic. Chemical carcinogens that are present in both include N -nitroso compounds, polycyclic aromatic hydrocarbons, and aromatic amines. The relative risk for esophageal squamous cell carcinoma is 6.2-fold higher in persons who smoke more than 25 cigarettes daily. Cessation of cigarette smoking is helpful in attenuating risk after 10 years of abstinence. Cigarette smokers who drink beer and whiskey have a 10- to 25-fold enhanced risk of developing esophageal squamous cell carcinoma. Vitamins A, B 12 , C, and E; folic acid; and certain minerals (zinc, selenium, molybdenum) exert direct or indirect antioxidant effects, and their deficiencies impair epithelial and tissue homeostasis and regeneration.
Other risk factors for esophageal squamous cell carcinoma ( Table 178-1 ) include achalasia ( Chapter 124 ), which is a disorder that involves agangliosis of the Auerbach plexus, thereby resulting in dysphagia, chest pain, and weight loss, among other symptoms. The emergence of esophageal squamous cell carcinoma may be observed 10 to 20 years after the identification of achalasia. Because head and neck squamous cell carcinoma ( Chapter 176 ) shares many of the same environmental and lifestyle risk factors with esophageal squamous cell carcinoma, particularly alcohol use and tobacco smoking, head and neck squamous cell carcinoma and esophageal squamous cell carcinoma may occur synchronously or metachronously. In different parts of the world, esophageal squamous cell carcinoma is also associated with chronic esophageal stricture due to lye ingestion, consumption of maté (a hot herb-based beverage), celiac sprue, infection with human papillomavirus (HPV) (especially genotypes HPV-16, HPV-18, and HPV-33), and radiation injury.
TABLE 178-1
RISK FACTORS FOR ESOPHAGEAL CANCER
Esophageal squamous cell cancer
Esophageal adenocarcinoma
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Pathobiology
Esophageal squamous cell carcinoma involves the transition from normal squamous epithelium to squamous dysplasia to cancer. The initiation, progression, and metastatic potential of esophageal squamous cell carcinoma are associated with a number of genetic alterations, including overexpression of epidermal growth factor receptor ( EGFR ) and cyclin D1 oncogenes, as well as inactivation of TP53 , p16INK4A , and p120-catenin ( p120ctn ) tumor suppressor genes. The frequency of these changes varies greatly based upon various studies, but the oncogenic alterations generally appear early in dysplasia and early esophageal squamous cell carcinoma, whereas the inactivation of tumor suppressor genes appears as later events in established primary and metastatic esophageal squamous cell carcinoma. From a genomic viewpoint, the SOX-2 transcription factor, which is important in the pluripotent capacity of somatic cells, is an important gene involved in the pathogenesis of esophageal squamous cell carcinoma. Conditional knockout of the p120ctn tumor suppressor gene in the esophagus of mice results in invasive esophageal squamous cell carcinoma. Deep DNA sequencing has confirmed these genetic alterations and revealed a lower frequency of other alterations, such as inactivation of chromatin-modifying enzymes.
Clinical Manifestations
Symptoms and Signs
Although esophageal squamous dysplasia is typically not associated with symptoms, esophageal squamous cell carcinoma, which has a predilection for the proximal to mid-esophagus, may be associated with dysphagia, odynophagia, atypical or typical chest pain, gastrointestinal bleeding, nausea, vomiting, weight loss, and malnutrition. Esophageal squamous cell carcinoma may metastasize to local lymph nodes, lung, liver, and bone. Symptoms attributable to metastatic esophageal squamous cell carcinoma may include bone-related pain, dyspnea, and evidence of jaundice and liver failure, depending upon the extent of metastatic disease.
Physical Examination
Weight loss may result in general cachexia and muscle wasting. The patient should be evaluated for changes in hair, skin integrity, and nail beds as a reflection of malnutrition. Lymphadenopathy may be detected in the anterior cervical and supraclavicular regions. Hepatomegaly and complications of liver disease may herald metastatic disease to the liver.
Laboratory Studies
A progressive iron deficiency anemia may be 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. Paraneoplastic hypercalcemia is uncommon. Esophageal squamous cell carcinoma has no specific markers, but an elevated carcinoembryonic antigen (CEA) level and levels of cell-free DNA from tumor cells may be used to aid in monitoring for recurrent disease after therapy.
Diagnosis
An upper gastrointestinal contrast radiographic study can show a filling defect due to the mucosal lesion or impaired transit of contrast due to luminal growth ( Chapter 119 ). However, definitive diagnosis involves direct visualization with upper endoscopy ( Chapter 120 ). Once the mass is visualized, biopsies are necessary to confirm the diagnosis and to enable genomic studies. Fine-needle aspiration can provide a rapid diagnostic assessment in the procedure room. Esophageal squamous cell carcinoma may involve local lymph nodes, which are best detected by endoscopic ultrasound; as needed, samples can then be analyzed by cytopathology following fine-needle aspiration. Endoscopic ultrasound is routinely used also to gauge depth of invasion, which guides the use of neoadjuvant therapy in node-negative localized cases.
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) is increasingly used to assess metastatic disease. In totality, these diagnostic modalities also allow for staging of esophageal squamous cell carcinoma, which is important in guiding therapeutic options.
Treatment
Surgical Therapy
Surgery is the cornerstone of therapy for curative intent, but adjuvant chemotherapy or chemoradiation markedly improves outcomes. Depending upon the location of the esophageal squamous cell carcinoma, either total esophagectomy or subtotal esophagectomy is pursued. For the latter, jejunal or colonic interposition can be done.
Surgical techniques include transthoracic, transhiatal, and radical en bloc resections. Increasing surgical proficiency in performing esophagectomy improves short-term as well as long-term mortality results in esophageal cancer. In selected patients, minimally invasive esophagectomy can provide equivalent or better perioperative mortality, morbidity, and oncologic outcomes compared with open surgery.
In patients who are medically unfit for surgery or in whom surgery is likely to result in high morbidity (e.g., tumors in the cervical esophagus), definitive chemoradiation is often pursued as an alternative to surgical therapy. Salvage esophagectomy after definitive chemoradiotherapy can offer acceptable short- and long-term outcomes in selected patients whose esophageal cancers are treated at experienced centers.
Medical Therapy
Neoadjuvant or adjuvant combination chemoradiotherapy under expert supervision is more effective than surgery alone for improving the survival of patients with resectable esophageal cancer. For patients who have localized node-positive or more advanced esophageal cancer, outcomes are improvedby neoadjuvant chemoradiation with about 40 Gy of radiation plus either carboplatin with paclitaxel or cisplatin with vinorelbine. Adjuvant nivolumab can enhance survival in patients who have residual disease despite chemoradiation and surgery.
In patients who have metastatic esophageal squamous cell carcinoma, first-line platinum-containing cytotoxic chemotherapy should be combined with immune checkpoint inhibition using nivolumab, , camrelizumab, toripalimab, or pembrolizumab. For patients who have unresectable or metastatic disease, palliative therapy includes endoscopically placed expandable prosthetic stents (to open the nearly obstructed lumen and to allow passage of food contents), percutaneous endoscopic gastrotomy tubes (to deliver nutrition to the stomach distal to the mass lesion), total parenteral nutrition, pain control, and systemic chemotherapy.
Prognosis
The 5-year survival for treated esophageal 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. Major postoperative complications, which occur in about one third of patients, exert a long-lasting negative effect on health-related quality of life in patients who survive for 5 years after esophagectomy for cancer. Dyspnea, fatigue, eating restrictions, sleep difficulty, and gastroesophageal reflux progressively worsen more during follow-up in patients who suffer such major postoperative complications compared with patients without major surgical complications.
Esophageal Adenocarcinoma
Epidemiology
Esophageal adenocarcinoma has an age-adjusted annual incidence of 1.3 per 100,000. It affects Whites more than Blacks, males much more than females (3:1 to 5.5:1), and increases in incidence after age 40 years. The incidence of esophageal adenocarcinoma is increasing dramatically in developed countries, especially in the United States (by 4 to 10% annually) and Western/Northern Europe.
Risk Factors
Obesity (central) is an important risk factor for esophageal adenocarcinoma (see Table 178-1 ), perhaps because it is related to either mechanical factors that foster greater gastroesophageal reflux disease (GERD) or, more likely, the release of proinflammatory adipokines, cytokines, and chemokines that track to the esophagus. The major recognized precursor of esophageal adenocarcinoma is Barrett esophagus ( Chapter 124 ), which is the replacement of the normal stratified squamous epithelium by an incomplete small intestinal epithelium (metaplasia) that projects from the gastroesophageal junction into the distal esophagus in a distal-proximal gradient ( Chapter 124 ). In turn, Barrett esophagus is fostered by GERD as well as by an admixture of bile acids in the acid refluxate. A small subset of patients with Barrett esophagus may progress to esophageal adenocarcinoma through intermediate stages of low-grade and high-grade dysplasia. In Barrett esophagus, one case of esophageal adenocarcinoma is estimated to arise in every 55 to 441 patient-years, a rate that corresponds to an approximately 125-fold increased risk for esophageal adenocarcinoma compared with the risk in the general population.
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