Esophageal Cancer Diagnosis and Staging

Epidemiology

The incidence of esophageal cancer has increased in recent decades, with an estimated 17,990 new cases in the United States in 2013. Histologically, in the United States esophageal adenocarcinoma is the fastest-growing subtype, surpassing the incidence of esophageal squamous cell carcinoma (SCC), in contrast to worldwide incidence where SCC still predominates. There is a marked variation in histologic incidence of esophageal cancer with respect to race, sex, geographic area, and economical status. SCC is three times more frequent in blacks as compared with whites. In the United States, the age-adjusted incidence among whites is up to 5 per 100,000 versus 12.5 per 100,000 in France versus more than 100 per 100,000 in some parts of China. In most countries the male-to-female ratio is 6 to 1. Genetic predisposition has also been clearly established; however, other risk factors, such as smoking and alcohol, have been strongly associated with SCC, and gastroesophageal reflux disease (GERD) has been associated with Barrett esophagus and adenocarcinoma.

Esophageal cancer remains one of the deadliest cancers with an overall 5-year survival rate estimated to be less than 18%. Esophagectomy has historically been the gold standard for regional invasive cancers; however, less invasive therapy such as endoscopic mucosal resection (EMR) has become an accepted alternative treatment for intramucosal carcinoma. Moreover, multimodality therapy (neoadjuvant chemotherapy, or chemoradiotherapy followed by esophagectomy) has shown increased survival benefits when compared with surgery alone in locally advanced cases. Therefore, accurate staging is essential for a stage-directed treatment approach, for prognostication, for quality control in clinical trials, and for proper communication among health care workers as well as patients.

Both invasive and noninvasive staging techniques are employed. Although new technologies have upgraded staging accuracy, the best overall approach remains controversial. This chapter describes the current staging classifications and methods for esophageal cancer and highlights some of the difficulties and controversies.

Anatomy

The esophagus is approximately 20 to 30 cm in length and is located in the posterior mediastinum. It extends from the hypopharynx, posterior to the trachea and the heart, to the stomach, passing through the esophageal hiatus. Through its descent, three critical anatomic points of narrowing are identified: the cricopharyngeus muscle, the bronchoaortic constriction, and the esophagogastric junction, which are also the most common sites of iatrogenic and mechanical perforation. The esophagus, a muscular tube, is composed of three general layers as follows: mucosa (stratified squamous epithelium), submucosa, and muscularis propria. The tissue immediately attached to the esophagus is called the adventitia.

The esophagus is divided into three anatomic areas comprising cervical, upper and middle thoracic, and lower thoracic/esophagogastric junction ( Fig. 36.1 ). The esophagus also can be divided into thirds with 50% of adenocarcinoma occurring in the lower third. The location of the tumor is an important prognostic element and has been included in the tumor, node, metastasis (TNM) seventh edition staging system of the SCC. Tumors in the middle or upper esophagus are considered higher stage compared with the lower one-third of the esophagus.

• 1

  The cervical esophagus extends from the esophageal orifice (lower border of the cricoid cartilage) to the sternal notch (or thoracic inlet). Typical endoscopic measurements for the cervical esophagus from the incisors are from 15 to less than 20 cm.

• 2

  The upper thoracic esophagus extends from the sternal notch to the azygos vein arch. Typically, this is located from 20 to less than 25 cm from the incisors. The middle thoracic esophagus is bordered superiorly by the lower border of the azygos vein and inferiorly by the inferior pulmonary vein. Typical endoscopic measurements from the incisors are from 25 to less than 30 cm.

• 3

  The lower thoracic esophagus extends from below the inferior pulmonary vein to the gastroesophageal junction (GEJ). Typical measurements from the incisors are from 30 to 40 cm.

Lymph node involvement and the number of lymph node metastases are important prognostic factors. The esophagus has a complex pattern of a dense and rich interconnected network of lymphatic vessels deep within submucosa that communicate freely longitudinally and transversally with the lymphatics of the muscular layers; thus, the pattern of lymph node metastases is very complex. Lymphatic channels in the submucosa facilitate the longitudinal spread of neoplastic cells along the esophageal wall. They can drain to cervical, tracheobronchial, mediastinal nodes, and gastric and celiac nodes.

Many patients will present late in the disease process with unresectable tumors or distant metastasis. The most common metastatic sites are retroperitoneal or celiac lymph nodes, liver, lungs, and adrenals. Metastatic disease can also manifest as malignant pleural effusion, ascites, and bone pain of the affected site in bone metastasis or as hypercalcemia secondary to paraneoplastic syndrome. Adenocarcinomas most frequently metastasize to intraabdominal sites, while metastases from SCCs more commonly spread to intrathoracic or cervical locations.

Nomenclature

Different-stage nomenclatures are used to define the state of the disease at specific phases in the care of the cancer patients. These include pretreatment stage or clinical stage , and postsurgical or pathologic stage . In addition, stage is further classified according to neoadjuvant therapy or at the time of recurrence.

The clinical stage or pretreatment stage is the extent of disease defined by diagnostic studies such as physical examination, imaging tests, endoscopic examination, biopsies of the primary tumor, and surgical exploration without resection of the affected areas. The nomenclature for clinical staging is cT, cN, and cM.

The pathologic stage is defined by the same diagnostic studies used for clinical staging supplemented by findings from surgical resection and histologic examination of the surgically removed tissues. This pathologic extent of disease is expressed as pT, pN, and pM.

The posttherapy stage documents the extent of the disease after neoadjuvant therapy or when systemic therapy or radiation is the only treatment. The posttherapy stage may be recorded as clinical or pathologic, depending on the source of posttreatment information. The nomenclature is recorded by adding the prefix “yc” or “yp” such as: ycT, ycN, ycM, ypT, ypN, and ypM.

Restaging is used to determine the extent of the disease following the completion of neoadjuvant therapy, and if a cancer recurs after treatment. This is done to determine if additional treatment is warranted or appropriate.

In addition to the TNM components, residual tumor and surgical margins are two important elements that may have a prognostic implication on the cancer patients after surgery. Residual tumor is denoted by the symbol “R”; it reflects the effect of therapy and the completeness of surgical resection, and is a strong predictor of prognosis. Although not formally integrated into TNM staging, “R” status is an important component of the pathologic record within the cancer registry.

The “R” categories for the primary tumor site are as follows:

• R0 no residual tumor

• R1 microscopic residual tumor

• R2 macroscopic residual tumor

• RX presence of residual tumor cannot be assessed

It should be noted that the “R1” designation varies between countries. In the United States, which uses the American College of Pathology designation of R1, it is “tumors at the surgical margin.” In the United Kingdom, the definition of the Royal College of Pathology is used, which designates R1 as a “tumor within 1 mm of the surgical margin.”

Histologic Type

Esophageal cancers are histologically classified as SCC or adenocarcinoma. Adenocarcinoma is a malignant epithelial tumor with glandular differentiation arising predominantly from Barrett esophagus mucosa in the lower third of the esophagus. Occasionally they originate from heterotopic gastric mucosa in the upper esophagus, or from mucosal and submucosal glands. SCC is a malignant epithelial tumor with squamous cell differentiation, microscopically characterized by keratinocyte-like cells with intercellular bridges and/or keratinization. SCC and adenocarcinoma are assumed to have different biologic behaviors, which might influence treatment choices. SCC seems to be more sensitive to chemotherapy, chemoradiation, and radiotherapy than adenocarcinoma, but the long-term outcome of therapy appears to be similar. Adenocarcinoma may be associated with a better long-term prognosis after resection than SCC. Another histologic subtype that has been reported is the primary mixed adenosquamous carcinoma. It is a rare kind of malignancy characterized by mixed glandular and squamous differentiation as well as a propensity for aggressive clinical behavior.

Histologic Grade

The tumor grade reflects the histologic aggressiveness of the cancer. It can be an indicator of how quickly a tumor is likely to grow and spread. Cancers that are “well-differentiated” tend to grow and spread at a slower rate than tumors that are “undifferentiated” or “poorly differentiated.” Tumor grade is defined by numbers: 1, 2, 3, or 4 or by X depending on the amount of abnormality, shown as :

• GX: Grade cannot be assessed (undetermined grade)

• G1: Well differentiated (low grade)

• G2: Moderately differentiated (intermediate grade)

• G3: Poorly differentiated (high grade)

• G4: Undifferentiated (high grade)

Tumor, Node, Metastasis Classification and Updates in the Seventh Edition

The TNM staging system for all solid tumors was devised by Pierre Denoix between 1943 and 1952. Currently, it is maintained and developed by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). The TNM staging system is updated every 6 to 8 years to include advances in our understanding of cancer prognostication. The TNM system classifies and groups cancers primarily by the extent of local tumor invasion into the esophageal wall and advanced invasion into adjacent structures (T), the status of regional draining lymph nodes (N), and the presence or absence of distant metastases (M). The T stage is assessed by evaluation of the depth of invasion into the four distinct layers involving the esophageal wall and adventitia according to the following nomenclature:

• TX: Primary tumor cannot be assessed

• T0: No evidence of primary tumor

• Tis: High-grade dysplasia

• T1: Tumor invading mucosal lamina propria, muscularis mucosae, or submucosa

  • T1a: Tumor invading into the lamina propria or muscularis mucosae

  • T1b: Tumor invading submucosa

• T2: Tumor invading muscularis propria

• T3: Tumor invading adventitia

• T4: Tumor invading adjacent structures

  • T4a: Resectable tumor invading pleura, pericardium, or diaphragm

  • T4b: Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, or trachea.

T stage is important in the prognostication and is crucial to determining suitability for surgical resection and establishing a treatment plan.

The nodal classification (N) is one of the most controversial aspects in TNM staging. Different N stages are defined as:

• N0: No positive node

• N1: 1 to 2 nodes

• N2: 3 to 6 nodes

• N3: 7 or more nodes

There is no consensus on the ideal number of nodes that must be resected for optimal staging. Data suggest that the number of lymph nodes recovered—rather than their location—is an independent predictor of survival after esophagectomy. In the Surveillance, Epidemiology, and End Results (SEER) database, when 12 lymph nodes were examined, significant reduction in mortality was noted compared with no lymph node evaluation. Moreover, patients who had 30 or more lymph nodes examined had significantly lower mortality than any other groups. This may be secondary to enhanced N staging, or to a therapeutic effect of lymphadenectomy. In addition, the number of involved lymph nodes can be used to predict the likelihood of systemic disease. There is general agreement that a two-field lymph node dissection should be done in an invasive cancer. For lymph node mapping, a lymph node map that extends the nomenclature and numbering system used for the staging of non–small cell lung cancer can be used ( Fig. 36.2 ).

Distant metastasis is simply designated as:

• M0: no distant metastases

• M1: distant metastases.