Oesophageal cancer

• Oesophageal cancer is a cancer of the tube that carries food to the stomach, and almost all cases are one of two very different diseases: squamous cell carcinoma of the upper and middle oesophagus and adenocarcinoma of the lower oesophagus.
• Squamous cell carcinoma is commonest in Africa and Asia and is driven mainly by tobacco, alcohol, very hot drinks and chronic irritation; adenocarcinoma is rising in Western countries and arises from Barrett oesophagus and chronic reflux, in obese white men.
• It presents with progressive difficulty swallowing, weight loss and sometimes pain on swallowing or hoarseness; symptoms appear late, so most patients are diagnosed at an advanced stage.
• Endoscopy with biopsy makes the diagnosis; computed tomography, positron-emission tomography and endoscopic ultrasound then stage it.
• Early disease can be cured endoscopically or with surgery; locally advanced disease needs multimodal treatment (perioperative FLOT for adenocarcinoma, preoperative chemoradiotherapy for squamous cell carcinoma); advanced disease needs systemic therapy, with palliation for swallowing wherever needed.

By the end of this page you should be able to:

1. Name the two main histological types, where each usually arises, and their main risk factors.
2. Explain the typical symptoms from the tumour's position and the mechanism of each.
3. Plan the investigation and staging of a patient with suspected oesophageal cancer.
4. Outline stage-directed treatment for early, locally advanced and metastatic disease, including adjuvant immunotherapy.
5. Describe palliative care and nutrition support for these patients.
6. Recognise the particular problems of oesophageal cancer in low-resource settings.

Oesophageal cancer is a malignant neoplasm arising from the epithelium of the oesophagus. Almost all cases are either squamous cell carcinoma (cancer of the squamous lining, arising in the upper and middle oesophagus) or adenocarcinoma (cancer of glandular epithelium, arising in the lower oesophagus, often from Barrett oesophagus, a metaplastic columnar lining that replaces the normal squamous mucosa after chronic reflux).^[2] Rare types such as small cell carcinoma and mesenchymal tumours exist but make up a small minority.

The location of the tumour is not just descriptive; it dictates presentation, staging investigations and treatment. Tumours at the gastro-oesophageal junction are treated on the adenocarcinoma pathway, while high or cervical tumours often need definitive chemoradiotherapy rather than surgery.

Oesophageal cancer is very common and very lethal. One widely used estimate calls it the seventh most common cancer and sixth most common cause of cancer death worldwide; survival is generally poor.^[5] In developed countries the 5-year survival rate is only 15 to 20%.^[2] In high-risk developing countries, where most cases occur, it is usually less than 10%.^[6]

Although squamous cell carcinoma remains the commonest type globally, especially in Asia and eastern Africa, its incidence has been falling in several regions, while adenocarcinoma of the lower oesophagus has risen sharply in developed countries and now exceeds squamous cell carcinoma in North America, Europe and Australia.^[2] In the 2012 estimates about 88% of incident oesophageal cancers were squamous cell carcinoma and 12% adenocarcinoma.^[4]

About 90% of squamous cell carcinoma arises in two high-incidence belts: central Asia from the Caspian Sea to north central China, and the eastern side of Africa down to the Eastern Cape of South Africa.^[4][5][6] Within these belts up to 10-fold differences in incidence occur over short distances, and age-adjusted rates above 100 cases per 100,000 inhabitants per year have been reported in some areas.^[6] In much of the low-risk world the incidence is below 10 per 100,000 per year.^[6]

Demographically, squamous cell carcinoma affects more men than women (about 69% versus 31%),^[4] although the sex ratio is more balanced in high-incidence areas such as China, Iran and parts of eastern Africa, and in some African populations more women than men are affected.^[4] Adenocarcinoma is strongly male; in lower-risk populations the male-to-female ratio is usually 3 to 4 to 1 and is higher still in developed countries.^[6] China alone accounts for about half of all squamous cell carcinoma cases worldwide, and in some counties of its high-risk regions oesophageal cancer is the leading cause of death, with incidence above 125 per 100,000 per year.^[4]

In these belts up to 18% of patients present under the age of 40, and a few before the age of 20, an age pattern not explained by population structure and not seen elsewhere.^[5] About 80% of all oesophageal cancer occurs in developing countries, where most patients present late.^[5][6]

In Spain about 1,883 new cases of oesophageal cancer were estimated for 2025.^[2] Ranking estimates vary with the data year; the consistent message is a common cancer with a large, largely preventable burden in poorer regions.

Squamous cell carcinoma is a multifactorial disease whose causes vary by population; no single exposure explains every high-incidence area.^[4]

Tobacco, alcohol and their interaction. In low-risk countries smoking and alcohol drinking dominate. In the USA over 90% of squamous cell carcinoma cases are attributed to these two exposures alone.^[6] In Western series smokers have a 3 to 9-fold relative risk and heavy drinkers 3 to 9-fold, and the two interact to raise risk beyond their combined effect.^[4] In high-incidence areas tobacco and alcohol contribute much less because consumption is low; in one Chinese cohort the effect of even modest alcohol was unclear.^[4]

Very hot drinks. Thermal injury from mate, tea, soup or porridge taken very hot is a confirmed risk factor.^[4] In Tanzania hot tea is often consumed above 70 degrees Celsius, in northern Iran very hot tea is typical, and in parts of South America large volumes of mate are taken hot. Harm is thought to come from thermal irritation cooperating with chemical carcinogens, so modestly cooling drinks, rather than abolishing them, may reduce risk.^[4]

Diet, environment and poverty. Diets low in fruits and vegetables, traditional vegetable pickling, micronutrient deficiency (especially selenium and zinc), poor oral health, low socioeconomic status and air pollution are repeatedly associated with disease in high-incidence areas.^[4][6] In eastern Africa one strongly suspected mechanism is indoor cooking with biomass fuel in poorly ventilated kitchens, producing very high exposure to polycyclic aromatic hydrocarbons, particularly in women, together with poor oral health, tobacco, alcohol, hot beverages and poverty.^[5]

Chronic irritation and structural disease. Achalasia carries a relative risk of about 28. In a Dutch cohort 3.3% of patients with achalasia developed oesophageal cancer over a mean of 11 years, an incidence of about 0.34% a year.^[4] Caustic ingestion with stricture, and squamous cancer of the head and neck, are also strong risk markers.^[6]

Specific syndromes. Plummer-Vinson syndrome (iron deficiency anaemia with oesophageal webbing), tylosis (familial palmoplantar keratoderma from mutations in RHBDF2, with penetrance for oesophageal cancer as high as 90%)^[4], and Fanconi anaemia all carry high relative risks.^[4] Betel quid chewing in South and South-East Asia is a confirmed risk factor with relative risk roughly 2.2 to 5.6.^[4]

Adenocarcinoma is a disease of chronic reflux and adiposity. Its principal risk factors are Barrett oesophagus, gastro-oesophageal reflux, obesity and cigarette smoking, in white men.^[6] Central obesity raises intra-abdominal pressure and promotes reflux, and the rise of adenocarcinoma in Western populations over four decades tracks the rise of obesity and reflux. Progression from Barrett oesophagus to cancer is not inevitable and is monitored by surveillance as described below.^[8]

In high-risk belts squamous dysplasia is the silent precursor; an endoscopic survey in Kenya found moderate to severe squamous dysplasia in 3% of asymptomatic adults.^[5] Barrett oesophagus is the precursor of adenocarcinoma.

Most patients have no symptoms until the tumour significantly narrows the lumen or invades deeply, because the oesophagus is very distensible; this is why presentation is late and diagnosis is often advanced.^[6] Tumour spread follows the lymphatics of the oesophagus to mediastinal, cervical and para-aortic nodes, and distant spread to liver, lung, bone and adrenal gland is common. Direct invasion into the trachea or bronchi can form fistulas, leading to aspiration pneumonia and coughing on swallowing.

• Progressive dysphagia is the cardinal symptom: solids first, then soft foods, and finally liquids as the lumen narrows. This pattern distinguishes mechanical obstruction from a motility disorder, which affects solids and liquids from the start.
• Weight loss follows decreased intake and is usually marked by the time of diagnosis.
• Odynophagia, pain on swallowing, suggests ulceration or deeper invasion.
• Hoarseness suggests recurrent laryngeal nerve involvement, typically with a left-sided tumour near its course, and means locally advanced disease.
• Regurgitation, retrosternal pain and chest fullness are common.
• Bleeding arises from surface ulceration and may present as haematemesis or melaena, leading to iron deficiency anaemia.
• Anaemia may be the only clue in an older patient, with fatigue and occult bleeding.
• Persistent cough and aspiration pneumonia suggest tracheobronchial involvement.

Examination may show wasting, pallor from anaemia, a palpable left supraclavicular lymph node (Virchow's node) suggesting metastatic spread, or hepatomegaly and ascites with liver metastases. There are no pathognomonic signs, and a single small fixed node may be the only finding.

High-definition video endoscopy is the diagnostic test.^[3] All suspicious lesions are biopsied, and 6 to 8 samples should be obtained to ensure adequate representation and enough tissue for molecular analysis.^[2] In Barrett oesophagus, biopsies follow the Seattle protocol: careful inspection of the segment with biopsies of any visible lesions, followed by 4 quadrant biopsies at intervals of no more than 2 cm from the lower oesophageal sphincter to the squamocolumnar junction.^[8] Chromoendoscopy with Lugol's iodine for squamous mucosa, or digital filter methods, improves detection of dysplasia and early carcinoma and should be used in at-risk patients.^[3]

Molecular testing follows histology. For squamous cell carcinoma, test PD-L1 expression, reported as combined positive score, tumour proportion score or tumour area positivity. For adenocarcinoma, test mismatch-repair or microsatellite-instability status, HER2 expression, PD-L1, and, at the gastro-oesophageal junction, claudin 18.2.^[2]

Staging aims to separate patients who can be cured from those who need palliation. Every newly diagnosed patient needs endoscopy, blood tests (full blood count and renal and hepatic panel), a complete physical examination, nutritional and performance-status assessment, and CT of the chest and abdomen.^[2][3]

For candidates for surgery or radical treatment, further staging follows:

• Endoscopic ultrasound (EUS) for T (depth of invasion) and N (regional nodal) stage, because T and N largely drive treatment choice.^[2][3]
• Positron emission tomography with CT (PET-CT) for distant metastases in locally advanced (cT2 to 4, N+) disease where curative treatment is still intended.^[2][3]
• Flexible bronchoscopy for locally advanced tumours in contact with the tracheobronchial system at or above the carina.^[2][3]
• CT of the chest and abdomen with oral and intravenous contrast for all patients.^[3]
• Exploratory laparoscopy and peritoneal washings for distal oesophageal and junctional adenocarcinoma of cT3 to 4 or node-positive disease, especially with signet ring or diffuse type histology.^[2][3]

The disease is staged by the 8th edition (2017, UICC-AJCC) TNM classification.^[2]

Stage groups are assigned separately for squamous cell carcinoma and adenocarcinoma in the 8th edition. In outline: stage 0 is carcinoma in situ; stage I covers mucosal and, for adenocarcinoma, limited submucosal disease; stage II covers T2 and selected T3, N0 disease; stage III covers deeper local invasion with nodal disease; stage IVB is any T or N with M1. Treatment is driven more by the TNM group than by the Roman numeral: early disease is cT1 N0 M0; locally advanced resectable disease is cT2 to cT4 or cN1 to 3 with M0; metastatic disease is M1.

Every treatment decision is made in a multidisciplinary tumour conference, weighing stage, comorbidity, nutritional status and patient preference.^[2][3] Performance status (ECOG), geriatric assessment in older patients, and nutritional status are recorded at baseline.^[2]

Endoscopic resection (endoscopic mucosal resection or submucosal dissection) is curative for adenocarcinoma cT1a to cT1b sm1, and for squamous cell carcinoma cT1a, when no high-risk features (vascular invasion, ulceration, grade 3, large size, positive margin) are present.^[2] Surgery is favoured for adenocarcinoma T1b sm2 to 3, or T1 with high-risk features, and for squamous cell carcinoma T1b or T1 with high-risk features.^[2] After curative endoscopic resection the surrounding Barrett mucosa should be ablated to prevent metachronous lesions.^[2][3]

Endoscopic follow-up is intensive after an endoscopic cure: after 3 months, then every 6 months for 2 years, then annually.^[3] Subtotal transthoracic oesophagectomy with two-field lymphadenectomy is the operation of choice for T1b to T2 tumours.^[2] Surgery is performed in hospitals carrying out at least 20 complex oesophageal resections a year.^[3]

All locally advanced resectable disease (cT2 to 4 or N1 to 3, M0) needs multimodality therapy.^[1][2] For adenocarcinoma of the oesophagus or gastro-oesophageal junction, perioperative chemotherapy with FLOT (5-fluorouracil, leucovorin, oxaliplatin and docetaxel), then surgery, is the preferred option.^[1][2] In the ESOPEC comparison of perioperative FLOT with preoperative chemoradiotherapy (the CROSS regimen) in oesophageal adenocarcinoma, FLOT gave a median overall survival of 66 months versus 37 months with chemoradiotherapy (hazard ratio 0.70, 95% confidence interval 0.53 to 0.92), with 3-year and 5-year overall survival of 57.4% and 50.6% versus 50.7% and 38.7%, and 90-day post-operative mortality of 3.1% versus 5.6%.^[1] Pathological complete response was higher with chemoradiotherapy (17% versus 8%), but overall survival was not improved.^[1]

Neoadjuvant chemoradiotherapy may be considered if a patient is not suitable for FLOT.^[1][2] Preoperative paclitaxel and carboplatin with radiotherapy and surgery is an alternative.^[2] The CROSS schedule uses radiotherapy to 41.4 Gy in 23 fractions with concurrent carboplatin and paclitaxel, usually over 5 weeks.^[9] FLOT is usually given as 4 neoadjuvant cycles followed by 4 adjuvant cycles.^[9] A new exclusion of distant metastases should be obtained before surgery, and restaging is used to time the operation.^[3]

Neoadjuvant antibody treatment is not recommended with preoperative therapy.^[3]

For cT3 or cT4 resectable or cN1 to 3 squamous cell carcinoma, preoperative chemoradiotherapy followed by complete resection is the standard.^[2][3] Neoadjuvant chemotherapy alone is not recommended.^[3] Definitive chemoradiotherapy, with or without salvage surgery, is an alternative and may be preferred for cT3 or cT4 tumours and for tumours of the cervical oesophagus; definitive chemoradiotherapy is given irrespective of histology when the tumour is unresectable, when the patient is functionally inoperable, or when the patient declines surgery.^[2][3] Chemotherapy plus radiotherapy without surgery is superior to radiotherapy alone.

After neoadjuvant chemoradiotherapy and R0 resection, if residual tumour is present in the specimen (at least ypT1 or ypN1), adjuvant nivolumab should be given for 1 year in both squamous cell carcinoma and adenocarcinoma.^[2][3]

The goal of resection is complete removal of the tumour (oral, aboral and circumferential) with regional lymphadenectomy.^[3] Two-field lymphadenectomy (abdominal and thoracic) is standard; cervical dissection is added for upper tumours.^[3] Distal and middle thoracic tumours are managed by right transthoracic subtotal oesophagectomy; distal or gastro-oesophageal junction tumours by extended transhiatal gastrectomy or transthoracic oesophagectomy according to infiltration; cervical tumours by a cervical approach or total oesophagectomy.^[3] Reconstruction uses gastric pull-up with high intrathoracic anastomosis, or colonic interposition when the stomach is unsuitable.^[3] Minimally invasive or hybrid techniques are used when safe.^[3]

Concomitant surgery or medical conditions may add risk; patient fitness, comorbidity and nutritional status should be assessed before neoadjuvant treatment and before surgery.^[2][3] Imaging staging is repeated before the operation.

Nutrition is part of oncological care, not an afterthought. All patients are screened for malnutrition before neoadjuvant therapy and before surgery; severe malnutrition may justify preoperative nutritional therapy even if surgery must be delayed.^[3] Nutritional counselling is offered during neoadjuvant treatment regardless of baseline status.^[3] After oesophagectomy enteral nutrition (including via a fine-needle catheter jejunostomy) should begin within 24 hours if the clinical state allows, with parenteral supplementation if less than half of energy needs are met enterally.^[3] Early palliative care referral and nutritional support are also recommended in advanced disease.^[7]

First-line treatment of squamous cell carcinoma depends on PD-L1 status and drug access:

• Platinum-fluoropyrimidine chemotherapy if PD-L1 is negative or low.^[2]
• Chemotherapy plus pembrolizumab if the combined positive score is at least 10.^[2]
• Chemotherapy plus nivolumab, or nivolumab plus ipilimumab, if the tumour proportion score is at least 1%.^[2]
• Chemotherapy plus tislelizumab if the tumour area positivity is at least 5%.^[1][2]
• Chemotherapy plus toripalimab may be used regardless of PD-L1 expression.^[2]

For adenocarcinoma and junctional cancer the backbone is platinum-fluoropyrimidine; immunotherapy is added for PD-L1-positive disease (nivolumab when the combined positive score is at least 5, pembrolizumab when it is at least 10, tislelizumab when tumour area positivity is at least 5).^[2][7] HER2-positive disease is treated with chemotherapy plus trastuzumab.^[2][7] Mismatch-repair-deficient or microsatellite-unstable tumours receive anti-PD-1 therapy.^[2] Claudin 18.2-positive adenocarcinoma extending across the junction may receive zolbetuximab with chemotherapy.^[2] In later lines, taxane or irinotecan monotherapy is used for adenocarcinoma, while tislelizumab (regardless of PD-L1) or nivolumab (squamous cell carcinoma only, after platinum-fluoropyrimidine) are options.^[2] Trastuzumab deruxtecan is an option in HER2-positive disease after prior trastuzumab-based therapy.^[7]

Palliation targets swallowing, nutrition and pain. Self-expanding metal stents relieve dysphagia but should not be used when curative neoadjuvant chemoradiotherapy is planned, or as a bridge to surgery, because of a high complication rate in that setting.^[3] Palliative radiotherapy, and intraluminal brachytherapy where available, can relieve dysphagia and bleeding. Systemic therapy in advanced disease, as above, commonly prolongs survival. Early palliative care referral, together with nutritional support, improves quality of life.^[7] Feeding tubes and intravenous fluids may be needed when obstruction is complete.

Barrett oesophagus is the precursor of adenocarcinoma, and its management is treated in detail on the gastro-oesophageal reflux disease page; the key surveillance steps are summarised here:

• Seattle protocol biopsies as above, with dysplasia of any grade confirmed by a second expert pathologist.^[3][8]
• Barrett longer than 1 cm is required for diagnosis; non-dysplastic Barrett under 3 cm is re-endoscoped every 5 years and 3 cm or more every 3 years.^[8]
• Indefinite dysplasia is repeated within 6 months after optimising acid suppression; if persistent, annually.^[8]
• Low-grade dysplasia, if surveilled rather than treated, is checked at 6 months, 12 months, then annually.^[8]
• After complete endoscopic eradication of Barrett, follow-up is histology-guided: every 1 year, then 3 years, then 2-yearly after low-grade dysplasia; and 3, 6 and 12 months, then annually, after high-grade dysplasia or intramucosal carcinoma.^[8]

Screening endoscopy is suggested once, for patients with chronic reflux symptoms plus 3 or more additional risk factors (male sex, age above 50, white race, smoking, obesity, family history); it has low yield in women.

• Progressive luminal obstruction with weight loss, dehydration and aspiration pneumonia.
• Local invasion into the trachea or bronchi, sometimes with fistula.
• Bleeding from ulcerated tumour, leading to iron deficiency anaemia.
• Lymphatic and haematogenous spread to liver, lungs, bones and adrenal glands.
• Post-treatment anastomotic leakage, stricture and dumping after surgery; post-chemoradiotherapy strictures.
• Recurrent or metastatic disease after initial curative treatment.

Prognosis is driven by stage. The 5-year survival rate overall is only 15 to 20% in developed countries.^[2], and under 10% in high-risk developing countries, where most patients present late.^[6] Early disease treated endoscopically or surgically can be cured; even locally advanced disease in trial populations of adenocarcinoma achieved around half of patients alive at 3 to 5 years after multimodality therapy.^[1]

There is no universal population screening. In high-risk belts, programmes of Lugol chromoendoscopy and, experimentally, capsule sponge cytology for squamous dysplasia are being developed; in the West, screening is targeted at Barrett oesophagus as above. Modifiable steps include smoking and alcohol cessation, avoiding very hot drinks, improving oral health and nutrition, and treating Barrett oesophagus. Chemoprevention with selenium or multivitamins is not recommended.

Oesophageal cancer is a leading cancer in low-resource settings: about 80% of cases occur in developing countries, squamous cell carcinoma dominates, and patients are often younger than elsewhere.^[5][6] Endoscopy capacity is severely limited; one eastern African report found one endoscopist per 400,000 to 2,000,000 people and only two functioning gastroscopes per facility.^[5] Diagnostic delays of months are common, and 5-year survival is under 10%.^[6]

Practical implications:

• Suspect the disease in any adult with progressive dysphagia, especially in endemic regions and in younger adults than expected. Referral for endoscopy and biopsy should not wait for absolute dysphagia.
• Where endoscopy is unavailable, barium swallow and careful clinical assessment can triage; nutritional rehabilitation and pain control should start while arranging transfer.
• Histology is ideal but often impossible; if unavailable, clinical diagnosis plus compatible imaging guides care, with awareness that benign strictures can mimic cancer.
• Squamous cell carcinoma is usually the working diagnosis in an endemic area; empirical dilatation or stenting can be palliative, though tumours may be bulky and friable.
• Palliative self-expanding metal stents can relieve obstruction and allow eating; access programmes exist in parts of Africa.^[5] Stents should still be avoided as a bridge to curative chemoradiotherapy.

• Oesophageal cancer is essentially two diseases: squamous cell carcinoma of the upper and middle oesophagus (about 85% of new cases globally) and adenocarcinoma of the lower oesophagus (about 15%).
• Squamous cell carcinoma dominates Africa and Asia and is driven by tobacco, alcohol, very hot drinks, poverty and environmental exposures; adenocarcinoma is rising in the West and is driven by reflux, Barrett oesophagus, obesity and male sex.
• Symptoms arrive late because the oesophagus distends; the classic progression is solids, then soft foods, then liquids, with weight loss.
• Endoscopy with biopsy makes the diagnosis; CT, PET-CT and endoscopic ultrasound stage it; PET-CT and bronchoscopy matter for treatment decisions.
• Early disease is treated by endoscopic resection or surgery; after curative endoscopic resection the remaining Barrett mucosa is ablated.
• Locally advanced adenocarcinoma is treated with perioperative FLOT followed by surgery (preferred over CROSS-type chemoradiotherapy in ESOPEC).
• Locally advanced squamous cell carcinoma is treated with preoperative chemoradiotherapy and surgery, with definitive chemoradiotherapy an alternative, especially for cervical or unresectable tumours.
• Adjuvant nivolumab for 1 year is given after neoadjuvant chemoradiotherapy and R0 resection when residual tumour (ypT1 or ypN1) remains.
• Metastatic disease is treated with platinum-fluoropyrimidine chemotherapy plus immunotherapy guided by PD-L1, with trastuzumab for HER2-positive disease.
• Barrett surveillance intervals and Seattle biopsies matter for finding adenocarcinoma early.
• Nutrition, palliative care and early stenting where safe are essential throughout.
• Low-resource nations carry most of the burden, with younger patients and less than 10% 5-year survival.

Related topics (plain text): gastro-oesophageal reflux disease and Barrett oesophagus; oesophageal motility disorders; dysphagia and odynophagia; gastric cancer; palliative care and nutrition support.