Esophageal cancer is one of the most aggressive malignancies and ranks eighth globally in cancer-related mortality. The most common types of esophageal cancer include squamous cell carcinoma (approximately 95%) and adenocarcinoma (around 3%). Rare forms include carcinosarcoma, small-cell carcinoma, and melanoma. In the United States, the incidence of esophageal cancer is approximately 4.2 cases per 100,000 people per year, with a higher prevalence in men compared to women.

Adenocarcinoma is considered one of the fastest-growing forms of esophageal cancer in North America and Europe, while squamous cell carcinoma is more prevalent in developing countries. This distribution correlates with regional variations in risk factors for these cancer types.

There is no single cause for the development of malignant esophageal tumors. Oncologists identify persistent irritation of the esophageal mucosa as a primary etiological factor. This irritation may occur due to:

• Thermal irritation from consuming very hot food or beverages.
• Chemical exposure to carcinogens in food, various chemicals, or medications.
• Mechanical injury from hard or coarse food.

Risk factors for esophageal adenocarcinoma include:

• Genetic abnormalities.
• Poor dietary habits or unhealthy nutrition.
• Alcohol and tobacco abuse.
• Chronic inflammation of the esophagus.
• Consuming non-food substances.

Can acid reflux cause cancer?

Yes, chronic acid reflux (GERD) can increase the risk of developing esophageal cancer, specifically a type called esophageal adenocarcinoma. This happens because repeated acid exposure can damage the esophageal lining and lead to Barrett’s esophagus, a precancerous condition.

Key prevention steps:

• Treat acid reflux symptoms promptly
• Get regular check-ups if you have chronic GERD
• Make lifestyle changes (weight management, avoiding trigger foods)
• Take prescribed medications as directed

Additional risk factors

1. Barrett’s Esophagus:
   A condition where normal squamous epithelial cells in the esophagus are replaced by glandular cells. This process, called intestinal metaplasia, occurs due to chronic exposure to stomach acid in patients with gastroesophageal reflux disease (GERD) and hiatal hernias.
2. Obesity:
   Associated with increased intra-abdominal pressure, which can contribute to GERD and subsequently Barrett’s esophagus.
3. Achalasia and Cardiospasm:
   Disorders that impair the esophagus’s ability to move food to the stomach, increasing the risk of chronic irritation and malignancy.

Classification

The classification of esophageal adenocarcinoma is conducted according to the criteria of the TNM (8th edition) international classification of malignant tumors:

T (Tumor)

• Tis: Carcinoma in situ/high-grade dysplasia.
• T1: Tumor invades the lamina propria or submucosa:
  • T1a: Invasion into the lamina propria or muscularis mucosae.
  • T1b: Invasion into the submucosal layer.
• T2: Tumor invades the muscular layer.
• T3: Tumor invades the adventitia.
• T4: Tumor invades adjacent structures:
  • T4a: Involvement of the pleura, peritoneum, pericardium, or diaphragm.
  • T4b: Involvement of adjacent organs, including the aorta, vertebrae, or trachea.

N (Lymph Nodes)

• N0: No regional lymph node metastasis.
• N1: Metastasis in 1–2 regional lymph nodes.
• N2: Metastasis in 3–6 regional lymph nodes.
• N3: Metastasis in 7 or more regional lymph nodes.

M (Metastasis)

• M1: Presence of distant metastases.

Regional lymph node groups include:

• Prescalene.
• Internal jugular.
• Upper and lower cervical.
• Cervical periesophageal.
• Supraclavicular (bilateral).
• Pretracheal (bilateral).
• Hilar lymph nodes (bilateral).
• Upper paraesophageal (above the azygos vein).
• Bifurcation nodes.
• Lower paraesophageal (below the azygos vein).
• Posterior mediastinal.
• Diaphragmatic.
• Perigastric (right and left cardiac nodes, nodes along the lesser and greater curvature of the stomach, suprapyloric, infrapyloric, and nodes along the left gastric artery).

Involvement of celiac lymph nodes does not contraindicate chemoradiotherapy or surgical treatment.

Differentiation grades

• GX: The grade of differentiation cannot be determined.
• G1: Well-differentiated tumor.
• G2: Moderately differentiated tumor.
• G3: Poorly differentiated tumor.
• G4: Undifferentiated tumor.

Esophageal adenocarcinoma includes cardia-related cancer, which develops at the gastroesophageal junction and cardia region.

Siewert classification

Esophagogastric junction adenocarcinomas are subdivided into three types based on the Siewert classification:

1. Type I: Adenocarcinoma of the distal esophagus (often associated with Barrett’s esophagus), with the tumor center located 1–5 cm above the cardia (Z-line).
2. Type II: True adenocarcinoma of the esophagogastric junction (true cardia cancer), with the tumor center located 1 cm above to 2 cm below the cardia (Z-line).
3. Type III: Subcardial gastric cancer, with the main tumor mass located 2–5 cm below the Z-line and potential involvement of the distal esophagus.

What are the symptoms of esophageal cancer?

The early stages of esophageal adenocarcinoma often proceed asymptomatically in the absence of esophageal lumen narrowing and are frequently an incidental finding during endoscopic examinations conducted for other esophageal conditions. Special attention should be given to routine, dynamic endoscopic examinations in patients with gastroesophageal reflux disease (GERD) and Barrett’s esophagus, who are at increased risk of developing esophageal adenocarcinoma.

What are the first symptoms?

As the tumor grows and narrows the esophageal lumen (typically when the narrowing is less than 15 mm), the primary clinical manifestation is dysphagia syndrome, which includes:

• Difficulty swallowing food and food becoming stuck in the esophagus (dysphagia).
• Unexplained weight loss due to reduced food intake.
• Regurgitation of swallowed food.
• A feeling of pressure and discomfort in the chest area, often described as a tightness or heaviness.
• Pain while swallowing food (rare).
• Excessive salivation (rare).

When the tumor progresses further, obstructing the esophageal lumen and compressing adjacent organs, additional symptoms develop:

• Difficulty swallowing—initially solid foods, then liquids.
• Choking while drinking.
• Persistent coughing.
• Vomiting.
• Pain behind the sternum.
• Loss of appetite and weight loss.
• Hoarseness.
• Numbness of chest skin.
• Muscle twitching.
• Swelling of the cervical veins.
• Esophageal bleeding.

Such symptoms require urgent investigation and immediate treatment.

Signs of advanced esophageal cancer

Advanced stages of the disease are characterized by:

• Progressive dysphagia (ranging from difficulty swallowing solid foods to an inability to swallow liquids and saliva).
• Significant weight loss, up to and including the development of cachexia (severe wasting).
• Fever.
• Bone pain.
• Shortness of breath.
• Pain behind the sternum or in the back.
• Signs of gastrointestinal bleeding (vomiting blood, black stool (melena), anemia in blood tests).

Metastatic spread

Esophageal carcinoma metastasizes via lymphatic and hematogenous pathways. Initially, lymph nodes are affected, followed by the dissemination of cancer cells to distant organs. Symptoms of organ dysfunction may appear, such as:

• Liver: Yellowing of the skin (jaundice), ascites.
• Bones: Pain, pathological fractures.
• Lungs: Shortness of breath.
• Brain: Various neurological symptoms.

Diagnostic methods

The optimal diagnostic plan for establishing a diagnosis, determining the clinical stage, and developing a treatment plan should include the following procedures:

1. Esophagogastroduodenoscopy (EGD) is the primary diagnostic method. It allows for obtaining material for morphological confirmation of the diagnosis and assessing the extent of the primary tumor in the esophagus. To enhance the informativeness of this method, techniques such as chromoendoscopy, narrow-band imaging (NBI), and autofluorescence may be employed.
2. Endoscopic ultrasound (EUS) is the most informative method for evaluating the depth of tumor invasion into the esophageal wall (T stage). It also enables highly accurate assessment of regional lymph nodes (sensitivity 0.8 and specificity 0.7). For more precise preoperative staging and treatment planning, fine-needle aspiration biopsy of mediastinal lymph nodes may be performed.
3. Barium contrast study of the esophagus.
   • X-ray of the esophagus with barium in a patient with esophageal cancer.
4. CT scan of the chest and abdominal organs with intravenous contrast.
   • This is performed to assess the condition of regional lymph nodes and to exclude distant metastases. Compared to EUS, CT has lower sensitivity (0.5) but higher specificity (0.83) in diagnosing regional metastases. For distant metastases, sensitivity and specificity are 0.52 and 0.91, respectively.
5. Positron emission tomography (PET) combined with computed tomography (CT), utilizing 18F-fluorodeoxyglucose (18F-FDG).
   • PET/CT is less informative for determining T and N status but demonstrates higher sensitivity and specificity for detecting distant metastases compared to CT. PET/CT is recommended if CT shows no evidence of distant metastases (M1).
6. Fibrobronchoscopy is performed to exclude invasion into the trachea and main bronchi in cases of esophageal tumors located at or above the level of its bifurcation.

Pre-surgical functional assessment

In preparation for surgical treatment, additional functional tests may be conducted to assess functional status based on indications. These include:

• Echocardiography.
• Holter monitoring.
• Pulmonary function tests.
• Doppler ultrasound of blood vessels.
• Coagulation studies.
• Urine tests.
• Consultations with specialists (cardiologist, endocrinologist, neurologist, etc.).

Treatment for esophageal cancer

• Type I and II tumors: Treated according to protocols for esophageal cancer.
• Type III tumors: Treated following guidelines for gastric cancer.

Surgical treatment

Indications for surgical treatment include localized (early) forms of esophageal cancer without involvement of surrounding structures: I-IIA (T1-3N0M0). Surgery is also indicated for high-grade dysplasia in Barrett’s esophagus, which is considered carcinoma in situ (CIS).

Surgical treatment includes:

• Endoscopic mucosectomy (removal of the mucosa of the esophagus) when malignant cells are confined to the mucosa. Endoscopic resection is the method of choice for carcinoma in situ and severe dysplasia. Additionally, this method is successfully used for esophageal tumors that do not extend beyond the mucosa, in patients at significant risk for surgical complications. In this case, the 5-year survival rate is 85-100%.
• Subtotal esophagectomy with simultaneous gastric tube or colon segment reconstruction.

The main type of surgery is transthoracic subtotal esophagectomy with simultaneous intrapleural reconstruction using a gastric pedicle or colon segment, combined with bilateral two-zone mediastinal lymphadenectomy through a combined laparotomy and right thoracotomy access (Lewis type).

In some clinics, as an alternative, transhiatal esophagectomy is performed, but these cannot be considered radical. They should not be used in patients with thoracic esophageal cancer, as adequate mediastinal lymphadenectomy cannot be performed via the laparotomy approach above the tracheal bifurcation.

Another way to reduce the number of surgical complications is minimally invasive (thoraco-laparoscopic) or hybrid (thoracotomy + laparoscopy or thoracoscopy + laparotomy) esophagectomy or robot-assisted esophagectomy.

Results from surgical treatment alone for more advanced stages remain unsatisfactory, with only about 20% of patients surviving 5 years. To improve outcomes, various combinations of drug and radiation therapies are used (neoadjuvant chemotherapy, neoadjuvant chemoradiation, standalone chemoradiation).

Chemotherapy

Most common methods of treatment:

• Neoadjuvant chemotherapy;
• Adjuvant chemotherapy.

For adenocarcinoma of the lower thoracic esophagus or esophagogastric junction, perioperative chemotherapy is most justified, with 2-3 courses of chemotherapy before surgery and 3-4 courses after. If HER 2neu hyperexpression is detected, trastuzumab is included in the therapy regimen in standard doses.

For adenocarcinoma of the lower thoracic esophagus or esophagogastric junction, adjuvant chemotherapy is indicated if it was administered preoperatively. Standalone adjuvant chemotherapy for esophageal adenocarcinoma is not recommended.

Radiation treatment

Performing radiation therapy (without chemotherapy) before or after surgery is not indicated due to its low efficacy.

A. Neoadjuvant chemoradiation

Before chemoradiation, 1-2 courses of chemotherapy may be conducted to reduce dysphagia in most patients and preplan radiation therapy.

It is highly recommended to perform external beam radiation therapy using linear accelerators. The single focal dose is 1.8-2 Gy, with a total dose of up to 44-45 Gy. Chemotherapy based on cisplatin or carboplatin is conducted during radiation therapy. If there is significant dysphagia, endoscopic electrorecanalization/argon plasma recanalization or percutaneous gastrostomy is performed before radiation.

Surgery is usually performed 6-8 weeks after chemoradiation.

The optimal chemoradiation regimen is weekly administration of paclitaxel and carboplatin during 5 weeks of radiation therapy. This neoadjuvant regimen (compared to surgery alone) achieves complete pathomorphosis in 23% of adenocarcinoma patients. The postoperative mortality rate is 4%, and 5-year survival improves from 34% to 47%.

B. Postoperative chemoradiation

Postoperative chemoradiation may be given to patients in satisfactory condition with micro or macroscopically residual tumor (after R1 or R2 resection). The regimens and doses are similar to those of preoperative chemoradiation.

Standalone сhemoradiation

An alternative to surgical treatment of operable locally advanced esophageal cancer is chemoradiation, which can achieve a comparable 5-year overall survival rate of 20-27%. In a direct comparative study of standalone chemoradiation using cisplatin and 5-fluorouracil infusion versus surgery alone, no significant differences were found in long-term outcomes, while the toxicity and mortality of conservative treatment were significantly lower.

It is highly recommended to perform conformal 3D CRT external beam radiation therapy on linear accelerators with energy between 6-18 MeV, or on proton complexes working with 70-250 MeV energy. The single focal dose is 1.8-2 Gy, with a total dose of up to 50-55 Gy. Increasing the total dose does not improve results but increases mortality.

Chemotherapy is conducted during radiation therapy, often using cisplatin and 5-fluorouracil infusion. If there is significant dysphagia, endoscopic electrorecanalization or percutaneous microgastrostomy is performed before radiation. Chemoradiation often leads to radiation esophagitis and worsens dysphagia, further aggravating the patient’s nutritional deficiency and reducing tolerance to treatment. In such cases, partial or complete transition to parenteral nutrition and temporary percutaneous microgastrostomy may be required.

The choice between standalone chemoradiation or surgery (with or without preoperative chemoradiation) depends on tumor location, the patient’s functional condition, and the surgeon’s experience. For patients with preserved health and tumor localization in the middle or lower third of the esophagus, surgery is preferred.

If a viable tumor remains after chemoradiation or a local recurrence occurs, salvage esophagectomy may be performed.

Palliative treatment for esophageal cancer

The main goals of treatment for patients with metastatic esophageal cancer are to alleviate painful symptoms and increase life expectancy.

Evaluating the effectiveness of various chemotherapy regimens for esophageal cancer is difficult due to the lack of randomized studies. Therefore, it is hard to assess the benefit of chemotherapy compared to supportive care.

Chemotherapy is recommended for patients in satisfactory condition without severe (III-IV) dysphagia, which impedes adequate nutrition. In the latter case, restoring esophageal patency (stenting, recanalization) is indicated as the first step. In cases of Grade I-II dysphagia, starting chemotherapy can reduce the severity of dysphagia in some patients by the end of the first course.

Palliative therapy includes:

• Radiation of the tumor to reduce its size;
• Surgery to ensure normal passage of food, including gastrostomy;
• Adequate pain relief;
• Psychological support;
• Antiemetics.

Esophageal stenting

The most active drugs for both histological variants are cisplatin, fluoropyrimidines, and taxanes. Additionally, oxaliplatin, irinotecan, and trastuzumab (in cases of HER-2 neu overexpression) are also effective in adenocarcinomas.

After treatment

• Examination

Patients after radical treatment (surgery or chemoradiotherapy) should be examined every 3-6 months during the first 2 years, then every 6-12 months during the next 3-5 years, and then annually.

• Tests

Blood tests and instrumental examinations are prescribed only based on clinical indications (appearance of complaints or symptoms of progression).

• EGD

Patients with early-stage cancer who underwent endoscopic mucosal resection should undergo EGD every 3 months in the first year, every 6 months in the second and third years, and then annually.

Prognosis and survival rate

The prognosis for esophageal adenocarcinoma is determined by the stage of the disease. Unfortunately, the anatomical features of the esophagus, the high risk of metastasis, and the absence of specific clinical symptoms in the early stages of the disease lead to the fact that two-thirds of patients, at the time of diagnosis, have stage 3 or 4 cancer. This is either a locally advanced, inoperable process or distant metastases in the lungs, liver, or bones. In this case, the 12-month survival rate is only 38%.

For localized stages, the 5-year survival rate can reach 47%, for regional lymph node involvement – 25%, and for distant metastases, it does not exceed 5%.

The survival prognosis is determined for a 5-year period. It depends on the stage at which the adenocarcinoma was diagnosed and the extent of treatment:

• Stage 0-1 — 85-90% of patients survive 5 years or more;
• Stage 2 — 70-80%;
• Stage 3 — 50-60%;
• Stage 4 — less than 50%.

Without surgery, 80-90% of patients die within the first three years after diagnosis.

• Esophageal cancer prevention includes the following measures:
• Rational nutrition with minimal carcinogen content;
• Avoiding the consumption of non-food liquids;
• Avoiding the consumption of alcohol and cigarettes;
• Maintaining the optimal temperature of food and drinks;
• Observing safety procedures when working with chemicals;
• For those with chronic esophageal inflammatory diseases, annual check-ups with a gastroenterologist.Secondary prevention is aimed at reducing the risk of recurrence. Patients are on lifelong dispensary observation by an oncologist. The doctor schedules preventive examinations every 2 years, and annually if there is a high risk of recurrence.