Disease Overview
Subdivisions
Signs & Symptoms
Causes
Affected Populations
Disorders with Similar Symptoms
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Esophageal Cancer

Last updated: 8/13/2024
Years published: 2019, 2024

Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Peter C. Enzinger, MD, Director, Center for Esophageal and Gastric Cancer, Associate Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.

Disease Overview

Summary

Esophageal cancer is a rare type of cancer that starts in the esophagus, the tube that carries food from the throat to the stomach. In this disease, cells in the esophagus grow uncontrollably, forming a tumor that can make swallowing difficult. Esophageal cancer can spread to other parts of the body, including the liver, lungs, bones and brain.

There are several types of esophageal cancer based on the kind of cells involved. The most common types are:

Squamous cell carcinoma: This type starts in the flat cells that line the esophagus. It’s more common in East Asia and the Middle East.
Adenocarcinoma: This type begins in cells that produce mucus and is more common in the lower part of the esophagus, especially in Western countries.

In the early stages, esophageal cancer might not cause any symptoms. As it progresses, symptoms may include difficulty swallowing (dysphagia), pain when swallowing (odynophagia), unintended weight loss, heartburn or indigestion that doesn’t improve with treatment and chest pain. Other symptoms may include anemia, vomiting or coughing blood, hoarseness, persistent hiccups or back pain and, in rare cases, an abnormal passage (fistula) between the esophagus and the windpipe that may result in breathing problems.

The cause of esophageal cancer isn’t fully understood, but it likely involves a combination of genetic and environmental factors.

Treatment depends on the stage of the disease and includes surgery to remove the tumor, chemotherapy, radiotherapy, targeted therapies and supportive measures.

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Subdivisions

adenocarcinoma of the esophagus
esophageal adenocarcinoma
esophageal squamous cell carcinoma
squamous cell carcinoma of the esophagus

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Signs & Symptoms

In the early stages, esophageal cancer often doesn’t cause any noticeable symptoms (asymptomatic). However, as the tumor grows, it may start to block the esophagus, leading to difficulty swallowing, especially solid foods—a condition known as dysphagia.

Affected people may feel that certain foods like meat, apples, or bread feel like they are “sticking” in their throat. As the tumor enlarges, even swallowing liquids can become difficult.

As the cancer progresses, additional symptoms may develop:

Pain when swallowing (odynophagia) which is often felt with dry foods and can help distinguish esophageal cancer from less serious causes of swallowing difficulty
Unintended weight loss, one of the most common symptoms associated with esophageal cancer
Indigestion and heartburn that does not improve with medication
Chest pain, often worsening after eating

Anemia and blood loss can lead to iron deficiency anemia, a condition where the body has too few red blood cells to carry oxygen effectively. Symptoms of anemia include:
Fatigue and weakness
Pale skin
Lightheadedness
Dark and sticky stools, which may indicate gastrointestinal bleeding that has gone unnoticed

Some symptoms are less common but may still occur as the cancer advances:

Swollen lymph nodes, particularly in the neck (cervical lymphadenopathy)
Vomiting blood (hematemesis)
Coughing up blood (hemoptysis)
Hoarseness caused by the tumor compressing the vocal cords
Hiccups or spinal pain which can occur if the tumor presses on nearby nerves

In rare cases, esophageal cancer can cause a tracheoesophageal fistula (TEF), which is an abnormal connection between the esophagus and the windpipe. This can allow food and liquids to enter the lungs, leading to severe breathing problems and pneumonia.

Esophageal cancer can spread (metastasize) to other parts of the body, with the liver, lungs, bones and brain being the most common sites. Symptoms vary depending on where the cancer has spread:

Fever
Enlargement of the liver (hepatomegaly)
Chronic cough, shortness of breath, or fluid buildup around the lungs (pleural effusion)
Bone pain
Headaches, confusion, or seizures

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Causes

The cause isn’t fully understood, but it likely involves a combination of genetic and environmental factors.

Most esophageal cancers result from genetic changes that happen during a person’s life, not from inherited gene variants. These genetic changes can be caused by environmental factors such as smoking, or they may occur randomly without any clear cause.

Certain genes can become altered leading to cancer:

Oncogenes: These are genes that normally help cells grow. When altered, they can cause uncontrolled cell growth, leading to cancer.
Tumor suppressor genes: These genes usually work to slow down cell growth or stop it when needed. When variants in these genes occur, they lose their ability to control cell growth, which can result in cancer.

Variants in specific genes have been found in people with esophageal cancer including:

TP53 and CDKN2A genes, often altered in both major types of esophageal cancer (squamous cell carcinoma and adenocarcinoma)
ERBB2 (HER2/neu), altered in about 20% of people with esophageal adenocarcinoma
VSIG10L gene, altered in people with Barrett’s esophagus and esophageal cancer that runs in families (About 9% of cases of esophageal adenocarcinoma are linked to a family history of Barrett’s esophagus.)
Several other genes have been noted to be altered in a few people

Familial esophageal cancer is when the disease appears in multiple family members, but this is uncommon. Even if esophageal cancer runs in a family, it does not necessarily mean that it is inherited. Sometimes, people in the same family share environmental exposures, such as smoking or diet, which might increase their cancer risk.

Esophageal cancer can develop due to several risk factors, but it’s important to understand that having a risk factor doesn’t guarantee a person will develop the disease. Likewise, some people without any known risk factors can still get esophageal cancer. Some of the identified factors that can increase the risk:

Smoking, especially cigars and pipes, is the most significant risk factor for esophageal cancer. It is strongly linked to squamous cell carcinoma.
Heavy alcohol use is another major risk factor for squamous cell carcinoma. The risk is even higher for people who smoke and drink.
Long-term gastroesophageal reflux disease (GERD), where stomach acids frequently flow back into the esophagus, can increase the risk of adenocarcinoma.
- Most people with GERD do not develop cancer, but a few may develop Barrett’s esophagus, which raises the risk of adenocarcinoma.
  - Barrett’s esophagus is a condition where chronic acid reflux causes the lower esophageal tissue to change and resemble the lining of the stomach (although only few people with Barrett’s esophagus develop cancer).
- Obesity raises the risk of adenocarcinoma, possibly due to the increased chances of GERD and other metabolic changes that affect the esophagus.
- Diet is also potentially associated with a decreased or increased risk of esophageal cancer, for example, processed meat may increase the risk, fruits and vegetables may lower the risk and regularly drinking very hot beverages (over 149°F or 65°C) may increase the risk of squamous cell carcinoma.
- Certain medical conditions may increase the risk of developing esophageal cancer:

- Achalasia: Characterized by impaired ability of the esophagus to move food toward the stomach and this increases the risk of squamous cell carcinoma

Tylosis: Characterized by thickened skin on the hands and feet and wart-like growths in the esophagus. Tylosis with esophageal cancer is known as Howel-Evans syndrome and is caused by variants in the RHBDF2 gene, leading to an increased risk for squamous cell esophageal cancer.
Bloom syndrome, characterized by short stature, cancer predisposition and genomic instability, caused by variants in the BLM These patients have a higher risk of developing squamous cell esophageal cancer.
Fanconi anemia: A rare condition that can be caused by variants in certain FANC genes and can lead to a higher risk of many cancers including squamous cell cancer of the esophagus.

- Plummer-Vinson syndrome: Characterized by thin membranes forming in the esophagus, which can narrow the esophagus and increase the risk of squamous cell carcinoma in about 10% of patients.
- Human papillomavirus (HPV) infection: This has been linked to an increased risk of squamous cell carcinoma in East Asia.

Radiation therapy: Previous radiation treatment to the chest or upper abdomen, often for other cancers like lymphoma or breast cancer, increases the risk of developing esophageal cancer later in life.

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Affected populations

Esophageal cancer is a rare type of cancer, making up about 1% of cancer cases in the United States. The rate of new cases per year is about 4 for every 100,000 people. In other parts of the world, esophageal cancer is more common. In the United States, esophageal adenocarcinoma is more common than esophageal squamous cell carcinoma and makes up about 80% of esophageal cancer cases.

The American Cancer Society estimates for esophageal cancer in the United States for 2024 are: About 22,370 new esophageal cancer cases diagnosed (17,690 in men and 4,680 in women).

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Diagnosis

Diagnosis

A diagnosis of esophageal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis is usually confirmed by a biopsy, in which a small piece of tissue is taken and studied under a microscope to identify cancerous cells. The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist).

Clinical Testing and Workup

Doctors may order the following exams to help diagnose esophageal cancer and how much the cancer has spread through the body:

Upper endoscopy: A thin, flexible tube with a camera (endoscope) is passed down the throat to examine the esophagus and stomach connection. It helps detect abnormal growths, such as plaques, nodules, or ulcers. A small tissue sample (biopsy) can be taken during this procedure to confirm if cancer is present.
Endoscopic ultrasonography: This test uses ultrasound waves to create detailed images of the esophagus and surrounding tissues. It helps determine how deeply a tumor has penetrated and if it has spread to nearby lymph nodes.
X-rays and barium swallow: Drinking a barium solution coats the esophagus, making it visible on X-rays. This helps outline any abnormalities in the esophagus, such as narrowing or masses, especially if an endoscopy isn’t feasible.
CT scan: This imaging technique uses X-rays and a computer to create cross-sectional images of the chest and abdomen. A liquid contrast may be used to enhance the images. CT scans help determine the size, location and spread of the cancer.
PET/CT scan: This combines PET and CT scans to provide information on both the structure and metabolic activity of tissues. Radioactive sugar is injected into the body, and cancer cells, which consume more sugar, appear as bright spots on the scan. This test is crucial for detecting if cancer has spread to other areas, such as bones.

Staging
When an individual is diagnosed with esophageal cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging.

Once diagnosed, the cancer is staged to determine its spread, which guides treatment options. Staging is done using a system called TNM:

T (Tumor): Size and extent of the tumor
N (Nodes): Whether cancer has spread to lymph nodes
M (Metastasis): Whether cancer has spread to other body parts

It is a complex staging system. For more information on this staging system for esophageal cancer, visit the American Cancer Society webpage: Esophageal Cancer Stages.

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Standard Therapies

Treatment varies by cancer stage and may include:

Surgery: Removal of the tumor and possibly part of the esophagus or stomach
Chemotherapy and radiation: Often combined to shrink the tumor before surgery or as the main treatment if surgery isn’t possible
Targeted therapy: Drugs like monoclonal antibodies target specific cancer cells and boost the immune system.
- Monoclonal antibodies are lab-made proteins that specifically attack cancer cells and can deliver drugs directly to them, typically given via infusion and can be combined with other treatments.
Palliative care: Focuses on symptom relief, pain management and nutritional support

Stage 0 (high-grade dysplasia)

Surgery or endoscopic mucosal resection to remove abnormal cells before they turn invasive

Stage I

Chemoradiation followed by surgery to shrink the tumor before surgery
Surgery alone may be sufficient in some patients

Stage II

Chemoradiation or chemotherapy followed by surgery is common
Chemoradiation alone if surgery isn’t an option

Stage III

Chemoradiation followed by surgery is often the main treatment
Chemoradiation alone when surgery isn’t feasible

Stage IV

Chemotherapy and immunotherapy to manage symptoms and slow cancer progression
Palliative therapies including laser therapy, esophageal stents and radiation to relieve symptoms

Recurrent Cancer

Palliative care to improve quality of life
Immunotherapy and clinical trials for new treatment options

Screening is not generally recommended unless the patient is at high risk, such as having Barrett’s esophagus, in which case regular monitoring is advised.

The National Cancer Institute provides detailed information about esophageal cancer treatment.

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Clinical Trials and Studies

Many several research studies are ongoing to test various targeted therapies for esophageal cancer. More research is necessary to determine all of the specific genetic factors (e.g. altered genes) play a role in the development esophageal cancer and what types of targeted therapies may be possible to treat these tumors.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2019;8:49-58. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813492/

Mondaca S, Margolis M, Sanchez-Vega F, et al. Phase II study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer. Gastric Cancer. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30088161

Cohen NA, Strong VE, Janjigian YY. Checkpoint blockade in esophagogastric cancer. J Surg Oncol. 2017;118:77-85. https://www.ncbi.nlm.nih.gov/pubmed/29878357

Di Pietro M, Canto MI, Fitzgerald RC. Endoscopic management of early adenocarcinoma and squamous cell carcinoma of the esophagus: screening, diagnosis, and therapy. Gastroenterology. 2018;154:421-436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104810/

Huang FL, Yu SJ. Esophageal cancer: risk factors, genetic association, and treatment. Asian J Surg. 2018;41:210-215. https://www.ncbi.nlm.nih.gov/pubmed/27986415

Smyth EC, Lagergren J, Fitzgerald RC, et al. Oesophageal cancer. Nat Rev Dis Primers. 2017;3:17048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168059/

Sanford NN, Catalano PJ, Enzinger PC, et al. A retrospective comparison of neoadjuvant chemoradiotherapy regimens for locally advanced esophageal cancer. Dis Esophagus. 2017;30:1-8. https://www.ncbi.nlm.nih.gov/pubmed/28475728

Abdo J, Agrawal DK, Mittal SK. “Targeted” chemotherapy for esophageal cancer. Front Oncol. 2017;7:63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377046/

Short MW, Burgers KG, Fry VT. Esophageal cancer. Am Fam Physician. 2017;95:22-28. https://www.aafp.org/afp/2017/0101/p22.html

Rice TW, Gress DM, Patil DT, et al. Cancer of the esophagus and esophagogastric junction – major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:304-317. https://www.ncbi.nlm.nih.gov/pubmed/28556024

Sohda M, Kuwano H. Current status and future prospects for esophageal cancer treatment. Ann Thorac Cadiovasc Surg. 2017;23:1-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347481/

Zimmerman TG. Common questions about Barrett esophagus. Am Fam Physician. 2014;89:92-98. https://www.aafp.org/afp/2014/0115/p92.html

Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesphageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681-692. https://www.ncbi.nlm.nih.gov/pubmed/21684205

Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241-2252. https://www.ncbi.nlm.nih.gov/pubmed/14657432

INTERNET
Esophageal Cancer. National Cancer Institute. My Part. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-digestive-system-tumors/esophageal Accessed August 12, 2024.

Esophageal Cancer Treatment (PDQ®)–Health Professional Version. National Cancer Institute. August 9, 2024. https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq Accessed August 12, 2024.

American Cancer Society. Esophageal Cancer. Available at: https://www.cancer.org/cancer/esophagus-cancer.html Accessed August 12, 2024.

Choi NC, Gibson MK. Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancer of the esophagus. UpToDate, Inc. Jan 23, 2023. Available at: https://www.uptodate.com/contents/radiation-therapy-chemoradiotherapy-neoadjuvant-approaches-and-postoperative-adjuvant-therapy-for-localized-cancers-of-the-esophagus Accessed August 12, 2024.

Gibson MK. Epidemiology and pathobiology of esophageal cancer. UpToDate, Inc.Feb 27, 2024. Available at: https://www.uptodate.com/contents/epidemiology-and-pathobiology-of-esophageal-cancer Accessed August 12, 2024.

Saltzman JR, Gibson MK. Clinical manifestations, diagnosis, and staging of esophageal cancer. UpToDate, Inc. May 31, 2023. Available at: https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-esophageal-cancer August 12, 2024.

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Programs & Resources

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/