Esophageal Cancer Workup: Approach Considerations, Imaging Studies, Staging

Sections

Workup

Approach Considerations

In 2013, the Society of Thoracic Surgeons released clinical practice guidelines to assist in the diagnosis and treatment of localized esophageal cancer. Their recommendations for diagnosis include the following^[72]:

Flexible endoscopy with biopsy is the primary method for diagnosis of esophageal cancer.
Computed tomography (CT) of the chest and abdomen is an optional test for staging of early-stage esophageal cancer, and a recommended test for staging of locoregionalized esophageal cancer.
Positron emisison tomography (PET) is an optional test for staging of early-stage esophageal cancer, and a recommended test for staging of locoregionalized esophageal cancer.
In patients without metastatic disease, endoscopic ultrasonography is recommended to improve the accuracy of staging
In patients with small, discrete nodules or areas of dysplasia in whom disease appears limited to the mucosa or submucosa as assessed by endoscopic ultrasonography, endoscopic mucosal resection should be considered as a diagnostic/staging tool.
In patients with locally advanced (T3/T4) adenocarcinoma of the esophagogastric junction infiltrating the anatomic cardia or Siewart type III esophagogastric tumors, laparoscopy is recommended to improve the accuracy of staging.

Imaging Studies

Imaging studies used in the diagnosis and staging of esophageal cancer include the following:

CT scanning
PET scanning
Endoscopic ultrasound (EUS)
Bronchoscopy
Barium swallow

Computed tomography

Abdominal and chest computed tomography (CT) scans are useful for helping to exclude the presence of metastases (M staging) to the lungs and liver and may be useful for helping to determine whether adjacent structures have been invaded.^[73](See the image below.)

Esophageal cancer. Chest CT scan showing invasion of the trachea by esophageal cancer.

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Positron emission tomography

PET scanning is also a useful baseline imaging technique and is increasingly becoming standard in the staging of esophageal cancer. It may be particularly useful in detecting occult distant lymph node metastases and bone spread. In addition, the intensity of radiopharmaceutical uptake on PET scans may reflect the biology of the cancer and thus may have prognostic significance.^[68]

Endoscopic ultrasound

EUS is the most sensitive test for determining the depth of tumor penetration (T staging) and the presence of enlarged periesophageal lymph nodes (N staging).^{[74, 75]}

Following are the characteristic features of malignant or inflammatory lymph nodes detected on EUS:

Enlarged in size
Hypoechoic (dark)
Homogeneous
Well circumscribed and rounded

The accuracy of diagnosing nodal disease is significantly increased with the combination of above-mentioned features, but also is confirmed with the use of fine needle aspiration (FNA) biopsy for cytology assessment.^[76]The combined use of EUS and FNA (EUS-FNA) has a greater accuracy than EUS alone in the evaluation of lymph node metastasis.^[77]In a study that compared the role of CT, EUS, and EUS-FNA for preoperative nodal staging in 125 patients with esophageal cancer, EUS-FNA was more sensitive than CT (83% vs. 29%) and more accurate than CT (87% vs. 51%) or EUS (87% vs. 74%) for nodal staging.^[78]

Patients with obstructing tumors are at increased risk for perforation during staging EUS. The risk of perforation can be reduced with the use of wire-guided or mini-EUS probes. In certain cases, the malignant stricture is dilated prior to the staging EUS.The review of CT and PET scans prior to EUS is recommended to evaluate the nodal distribution for a possible FNA biopsy.

Bronchoscopy

Bronchoscopy is indicated for cancers of the middle and upper third of the thoracic esophagus (tumor at or above carina) to help exclude invasion of the trachea or bronchi. It should be performed only if the patient shows no evidence of M1 disease. Laparoscopy and thoracoscopy have a greater than 92% accuracy in staging regional nodes.

Barium swallow

Barium swallow is very sensitive for detecting strictures (see the first image below) and intraluminal masses (see the second image below) but does not allow staging and biopsy. It is now rarely used, but it may be helpful for studying the distal anatomy in obstructive tumors that are inaccessible by endoscopy.

Esophageal cancer. Barium swallow demonstrating stricture due to cancer.

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Esophageal cancer. Barium swallow demonstrating an endoluminal mass in the mid esophagus.

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For more information, see the Medscape article Esophageal Carcinoma Imaging.

Staging

Esophageal cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC).^[79]

No completely satisfactory method is available to clinically stage esophageal cancer. The difficulty of clinically assessing the disease is reflected by changes over time in the AJCC staging system. The 1983 system was based on the length of the intraluminal esophageal tumor, the presence of esophageal obstruction, and the involvement of palpable lymph nodes. This clinical staging system proved to have limited value.

The 1988 revision defined a clinical and pathologic staging system based entirely on the depth of esophageal wall invasion and the presence or absence of local nodal involvement. Neither of those parameters is assessed easily on a clinical basis. Hofstetter et al therefore proposed incorporating the number of involved lymph nodes with regional and nonregional node location.^[80]This modification, which seemed to be simpler and to better predict long-term survival, was adopted into the revised system.

The revised 2010 AJCC staging classification was based on the risk-adjusted random forest analysis of the data generated by the Worldwide Esophageal Cancer Collaboration (WECC) for 4627 patients who were treated with primary esophagectomy without preoperative or postoperative therapy.^[81]In the data reported by the WECC, survival decreased with increasing depth of tumor invasion (T), presence of regional lymph node metastases (N), and the presence of distant metastases (M).^[82]

The 2017 TNM classification for esophageal cancer is shown below (staging is detailed in Tables 2-4, below. T staging is illustrated in the image below). For more information, see Esophageal Cancer Staging.

TNM staging is as follows:

Tis - High-grade dysplasia (malignant cells confined to the epithelium by the basement membrane)
T1 - Tumor invades the lamina propria, muscularis mucosae, or submucosa
T1a - Tumor invades the lamina propria or muscularis mucosae
T1b - Tumor invades the submucosae
T2 - Tumor invades the muscularis propria
T3 - Tumor inades adventitia
T4 - Tumor invades adjacent structures
T4a -Tumor invading into pleura, pericardium, azygos vein, diaphragm, or peritoneum
T4b - Tumor invading other adjacent structures (eg, aorta, vertebral body, trachea)
N0 - No regional lymph node metastasis
N1 - 1-2 regional lymph nodes (N1 is site dependent)
N2 - 3-6 regional lymph nodes
N3 - More than 6 regional lymph nodes
M0 - No distant metastasis
M1 - Distant metastasis

Esophageal cancer. Diagram showing T1,T2 and T3 stages of esophageal cancer. Courtesy of Cancer Research UK and Wikimedia Commons.

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Table 3. Clinical Staging Classification (Squamous Cell Carcinoma) (Open Table in a new window)

Stage 0	Tis	N0	M0
Stage I	T1	N0-1	M0
Stage II	T2	N0	M0
	T3	N0	M0
Stage III	T3	N1	M0
	T1-3	N2	M0
Stage IVA	T4	N0-2	M0
	Any T	N3	M0
Stage IVB	Any T	Any N	M1

Table 4. Clinical Staging Classification (Adenocarcinoma) (Open Table in a new window)

Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
Stage IIA	T1	N1	M0
Stage IIB	T2	N0	M0
Stage III	T2	N1	M0
	T3	N0-1	M0
	T4a	N0-1	M0
Stage IVA	T1-4a	N2	M0
	T4b	N0-2	M0
	Any T	N3	M0
Stage IVB	Any T	Any N	M1

All esophageal tumors, as well as tumors with epicenters within 5 cm of the esophagogastric junction that also extend into the esophagus, are classified and staged according to the AJCC/UICC esophageal scheme. Tumors with an epicenter in the stomach that are more than 5 cm from the esophagogastric junction or those within 5 cm of the esophagogastric junction without extension into the esophagus are staged using the gastric carcinoma scheme.

However, this classification may not work well for patients who have received preoperative therapy. Some other shortcomings associated with the current staging classification are as follows:

Inclusion of proximal 5 cm of the stomach
Lack of guidance for regional resectable and unresectable cancer
Emphasis on the number of nodes rather than their size and anatomic locations/significance.

Other classifications—such as that of the Japanese Society for Esophageal Diseases, which is widely used in Asia—differ from that of the AJCC/UICC, especially regarding lymph node distribution and nomenclature.^[83]

Laboratory Studies

Laboratory studies in patients with esophageal cancer focus principally on patient factors that may affect treatment. These include complete blood count (CBC) and comprehensive metabolic panel. Nutritional status should be evaluated in patients with dysphagia; liver function studies should be performed in patients who abuse alcohol.

Upper GI endoscopy

Upper GI endoscopy allows direct visualization and biopsies of the tumor. (See the image below.)

Esophageal cancer. Endoscopy demonstrating intraluminal esophageal cancer.

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Endoscopy is a very important tool in the diagnosis, staging, and surveillance of patients with esophageal cancer. Most endoscopy procedures are performed under conscious sedation. Patients who are at risk of aspiration during endoscopy may require general anesthesia.

Diagnostic endoscopies are performed to determine the following:

Detection of esophageal tumor
Biopsy of any suspicious lesions
Location of the tumor relative to the teeth and esophagogastric junction
Tumor length
Degree of obstruction

Esophageal tumor length, as assessed by preoperative endoscopy, has been identified as an independent predictor of long-term survival in patients with adenocarcinoma of the esophagus.^[84]The 5-year survival rate was significantly higher for patients with a tumor length of 2 cm or less (78% vs 29% for those with a tumor length of more than 2 cm).

Endoscopic resection

Endoscopic resection (ER) of focal nodules should be performed in the setting of early-stage disease (T1a or T1b) to provide accurate assessment of depth of invasion, degree of differentiation, and the presence of lymphovascular invasion.^[85]Thus, ER is an essential procedure for the accurate staging of early-stage cancer especially in patients with small nodular lesions (≤2 cm).^[86]ER can become a therapeutic procedure if a small lesion (under 2 cm) is fully removed and histopathology reveals that the lesion is well differentiated, with penetration limited to submucosa, absence of lymphovascular invasion, and clear margins.^[87]

Histologic Findings

Histologically, esophageal squamous cell carcinoma is characterized microscopically by keratinocyte-like cells with intercellular bridges or keratinization. Adenocarcinomas that arise from Barrett esophagus mucosa are typically well- or moderately differentiated and have well-formed tubular or papillary structures. In poorly differentiated adenocarcinomas, glandular structures comprise less than half of the tumor; in undifferentiated adenocarcinomas, glandular structures are absent. See the images below.

Esophageal cancer. Micrograph of squamous cell carcinoma of the esophagus (H&E stain). Courtesy of Wikimedia Commons.

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Esophageal cancer. Low-magnification micrograph of an intramucosal esophageal adenocarcinoma (H&E stain). Endoscopic mucosal resection specimen. Courtesy of Wikimedia Commons.

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Treatment & Management

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Media Gallery

Esophageal cancer. Endoscopy demonstrating intraluminal esophageal cancer.
Esophageal cancer. Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
Esophageal cancer. Barium swallow demonstrating stricture due to cancer.
Esophageal cancer. Barium swallow demonstrating an endoluminal mass in the mid esophagus.
Esophageal cancer. Chest CT scan showing invasion of the trachea by esophageal cancer.
Esophageal cancer. Transhiatal esophagectomy in which (a) is the abdominal incision, (b) is the cervical incision, and (c) is the stomach stretching from abdomen to the neck.
Esophageal cancer. Five-year survival for esophageal cancer based on TNM stage.
Esophageal cancer. Hematoxylin and eosin stain, high power, showing junction of benign glands in the lower right, Barrett columnar cell metaplasia with a large goblet cell containing blue mucin in the lower center, and adenocarcinoma on the left.
Esophageal cancer. Macroscopic image of a resection of the gastroesophageal junction. On the right is non-neoplastic esophagus, consisting of tan, smooth mucosa. On the left is the non-neoplastic rugal folds of the stomach. In the center of the picture is an ulcer with a yellow-green fibrinous exudate surrounded by irregular, heaped-up margins with almost a cobblestone appearance. The latter represents mucosal adenocarcinoma with probably some Barrett metaplasia in the background.
Esophageal cancer. Hematoxylin and eosin stain, high power, demonstrating invasive esophageal squamous cell carcinoma. This carcinoma does not form glands and instead shows features of squamous differentiation, including keratinization and intercellular bridges.
Esophageal cancer. Macroscopic image of an esophageal resection. A polypoid squamous cell carcinoma is visible protruding from the esophageal mucosal surface (left center of specimen).
Esophageal cancer. On this positron emission computed tomography (PET) scan, esophageal cancer is evident as a golden lesion in the chest.
Palmoplantar keratoderma (tylosis) of palms (A) and soles (B). Courtesy of The American Journal of Gastroenterology, Nature Publishing Group.
Esophageal cancer. Diagram showing T1,T2 and T3 stages of esophageal cancer. Courtesy of Cancer Research UK and Wikimedia Commons.
Esophageal cancer. Micrograph of squamous cell carcinoma of the esophagus (H&E stain). Courtesy of Wikimedia Commons.
Esophageal cancer. Low-magnification micrograph of an intramucosal esophageal adenocarcinoma (H&E stain). Endoscopic mucosal resection specimen. Courtesy of Wikimedia Commons.

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Table 2. Five-year esophageal cancer survival rates by stage at diagnosis in the US, 2014-2020 ^[60]

Stage	Survival Rate (%)
Localized	48.1
Regional	28.1
Distant	5.3
All Stages	21.6

Table 3. Clinical Staging Classification (Squamous Cell Carcinoma)

Stage 0	Tis	N0	M0
Stage I	T1	N0-1	M0
Stage II	T2	N0	M0
	T3	N0	M0
Stage III	T3	N1	M0
	T1-3	N2	M0
Stage IVA	T4	N0-2	M0
	Any T	N3	M0
Stage IVB	Any T	Any N	M1

Table 4. Clinical Staging Classification (Adenocarcinoma)

Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
Stage IIA	T1	N1	M0
Stage IIB	T2	N0	M0
Stage III	T2	N1	M0
	T3	N0-1	M0
	T4a	N0-1	M0
Stage IVA	T1-4a	N2	M0
	T4b	N0-2	M0
	Any T	N3	M0
Stage IVB	Any T	Any N	M1

Table 5. Hereditary Cancer Predisposition Syndromes Associated with an Increased Risk for Esophageal Cancers.

Syndrome	Gene(s)	Inheritance Pattern	Clinical Manifestation	Surveillance Recommendations
Tylosis (non-Epidermolytic palmoplantar keratosis (PPK) or Howel Evans syndrome)	RHBDF2	Autosomal dominant	Skin thickening of palms and soles. Non-epidermolytic PPK is associated with high risk of developing SCC of esophagus (40-90% by age of 70 years)^{[45, 42]}	Surveillance by upper GI endoscopy is recommended for family members with tylosis after 20 years of age^[45]
Familial Barrett esophagus (FBE)	Genes not identified	Autosomal dominant	Familial aggregation of Barrett esophagus, adenocarcinoma of the esophagus and EGJ^{[136, 137]}	Potential family history of Barrett esophagus, and adenocarcinoma of the esophagus,should be determined for patients presenting with GERD, especially white men older than 40 years of age.
Bloom syndrome	BLM/RECQL3	Autosomal recessive	Increased predisposition to a wide variety of malignancies^[138]. Acute myeloid leukemia, acute lymphoblastic leukemia, lymphoid neoplasms, and Wilms tumor are the predominant cancers diagnosed before 25 years of age, whereas carcinomas of different anatomic sites including SCC of the esophagus are diagnosed after 20 years of age. Chromosomal quadraradials with breakage may be used for the diagnosis of BS^[45]	Screening for GERD with or without endoscopy after 20 years of age may be considered to detect cancer early.
Fanconi anemia (FA)	FANC^[139]	Autosomal recessive	Characterized by congenital malformations, progressive pancytopenia, easy bruising, chromosomal breakage and an increased predisposition to the development of hematologic malignancies as well as solid tumors^[45]. AML is the most common cancer type in patients with FA. However, patients with FA are also at an increased risk of developing SCC of head, neck and esophagus, cervical cancer, and brain tumors.^{[45, 140, 141]}Enhanced mitomycin C–induced chromosomal breakage analysis can help in diagnosis.^[142]	Endoscopy of the esophagus may be considered as a surveillance strategy in individuals identified with FA.