PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Ectopic islands of gastric-like epithelium mucosa referred to as Barrett mucosa have the potential and predisposition to undergo neoplastic change to adenocarcinomas.
PERSPECTIVE AND PATTERNS OF SPREAD
The esophagus in its lowermost third is a transitional organ as it passes through the diaphragm exiting the thorax and entering the abdomen. The stratified squamous epithelium at the cardia becomes glandular as it transforms into the stomach. Ectopic islands of gastric-like epithelium mucosa referred to as Barrett mucosa have the potential and predisposition to undergo neoplastic change to adenocarcinomas (Fig. 23.1; Table 23.1). These esophagogastric junctional (EGJ) adenocarcinomas often arise in association with a clinical triad: hiatal hernia, gastric reflux, and persistent ulceration of the cardia junction. There is dispute as to the true origin of EGJ adenocarcinomas, particularly those without ectopic mucosa. In the sixth edition of the American Joint Committee on Cancer (AJCC) AJCC Cancer Staging Manual, EGJ cancers are referred to as types I, II, and III by Siewert, depending on the amount of esophagus and stomach involvement. In clinical practice, if >2 cm of the esophagus is involved, it is considered to be esophageal; if the lesion occupies 2 cm of the esophagus, a gastric origin is assigned.
Alcohol and tobacco abuse are predisposing factors leading to a field carcinogenesis effect and multifocal mucosal lesions. The pattern of spread, once the cancer invades into the wall, follows the muscle layers, encircling the lumen and then migrating longitudinally with the milking action of peristalsis (Fig. 23.2; Table 23.2). Often masquerading as a sliding hiatal hernia with gastric reflux, the diagnosis is made once endoscopic examination reveals islands of pink mucosa in the distal esophagus and biopsy establishes abnormal columnar mucosa with goblet cells similar to gastric mucosa. Once adenocarcinoma develops, it can be exophytic, polypoid, or ulcerated; when mainly endophytic and infiltrative submucosally, they are difficult to diagnose, mimic achalasia, and may be missed endoscopically. Once the tumor penetrates into the submucosa, lymph node metastases are 30%; into the muscularis mucosa, 60%; and into the adentitia, nearly universal.
Figure 23.1 | Barrett esophagus. A. The presence of the tan tongues of epithelium interdigitating with the more proximal squamous epithelium is typical of Barrett esophagus. B. The specialized epithelium has a villiform architecture and is lined by cells that are foveolar gastric type cells and intestinal goblet type cells.
Figure 23.2 | A. Patterns of spread. B. T categories. The patterns of spread and the primary tumor classification are similarly color coded: Tis (cancer in situ of mucosa), yellow; T1 (infiltrates the submucosa), green; T2 (penetrates the muscularis externa), blue; T3 (reaches the adventitia), purple; and T4 (invades through the adventitia into a neighboring viscera), red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 23.2.
Invasion anteriorly into pericardium could produce a fistula resulting in pericardial effusion and results in cardiac tamponade with pulsus paradoxus. Posteriorly, invasion of thoracic duct can lead to a chylous ascites (Table 23.2). If it invades the descending aorta, the onset of an esophageal– aortic fistula starts with gross hemoptysis and is disastrous. Exsanguination occurs rapidly, within hours of onset.
PATHOLOGY
At one time, adenocarcinomas of the EGJ were uncommon with only 1% to 5% incidence, but have been on the increase and currently account for 34% of all esophageal cancers. Although this has occurred mainly in white males, adenocarcinomas also are on the rise in African Americans. This is attributed to metaplasia of Barrett epithelium becoming dysplastic and then truly neoplastic. The overall risk with Barrett epithelium for giving rise to an adenocarcinoma is 125 times normal. Knowledge of progression from intestinal metaplasia to adenocarcinoma has implicated the p53 gene, a key suppressor gene, and can be mutated in 70% of esophageal cancers. Abnormal variants of the interleukin IL1 gene are also associated with adenocarcinoma in gastric cardia (Table 23.1; Figure 23.1).
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The normal EGJ is a zigzag line, which divides the whitish stratified esophageal squamous mucous membranes from the pinkish glandular gastric mucosa. The longitudinal esophageal folds fade into the gastric rugal folds. Spasm, obstruction, and regurgitation occur with cardia dysfunction. Eventually, persistent inflammation results with the mucosal transformation to malignancy. Perforation is rare because thickening of the dual muscular layers of the distal esophagus is reinforced as in muscle layers of the stomach. The staging of esophageal cancers has not changed and relates to the standard hollow organ model in which depth of penetration of the wall rather than size determines stage—that is, T1, mucosa; T2, muscular; T3, serosa; and T4, extraesophageal (Fig. 23.3). Dysplastic Barrett mucosa is substaged in terms of length: short versus long segment based on whether the lesion is 3 cm or >3 cm long, respectively, from the zigzag line of the EGJ.
Generally, there is no overarching principle or context design for the digestive system (gastrointestinal tract) or major digestive glands. Stages are frequently expanded to six by subdividing a stage into A and B. The T and N categories are assigned to a stage grouping, specifically for division of a stage into more (a) versus less (b) favorable groupings. This occurs at different stages for different sites.
The esophagogastric junction has 6 to 8 stages; Stages I and II have A and B categories. Stage III has three substages, A, B and C. The initial-stage progression (I/II/III) is due to advancement of the primary, and the late-stage progression (III/IV) is by nodal involvement: IIB is N1. Regional nodes are either stage II or III, and nonregional nodes are stage IV. There are 3 nodal categories, N1, N2, N3.
The staging system for esophagogastric adenocarcinoma is entirely new in the seventh edition AJCC and differs not only in the specific T and N definitions but in stage grouping them from esophageal squamous cell cancer. Thus, the main features relate to the clustering of T and N categories and to the additional cancer grade (Table 23.3).
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Tumor location is simplified, and esophagogastric junction and proximal 5 cm of stomach are included.
• Tis is redefined and T4 is subclassified.
• Regional lymph nodes are redefined. N is subclassified according to the number of regional lymph nodes containing metastasis.
• M is redefined.
• Separate stage groupings for squamous cell carcinoma and adenocarcinoma.
• Stage groupings are reassigned using T, N, M, and G classifications.
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 23.3).
ESOPHAGOGASTRIC JUNCTION ADENOCARCINOMA
Figure 23.3 | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Esophagogastric junction cancers are adenocarcinomas. Note juxtaregional nodes as M1a; celiac nodes, although considered metastatic when resected, offer a better chance for 5-year survival (10%) than visceral metastases (black). Stage 0, yellow; stage I, green; stage II, blue; stage III, purple; stage IV, red; and stage IV (metastatic), black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The anatomic isocenter for the EGJ cancers is at T9/T10. These EGJs are posterior in location for both the mediastinum and the abdominal cavity (Fig. 23.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views. A. Coronal, B. Sagittal, C. Transverse axial (Fig. 23.5).
The esophagus consists of three principal regions: the cervical, thoracic, and cardiac portions.
• Cervical esophagus extends from the pharyngeal–esophageal sphincter to the level of the thoracic inlet, about 18 cm from upper incisor teeth (UIT).
• Upper thoracic esophagus extends from the thoracic inlet to the level of the tracheal bifurcation, about 24 cm from UIT.
• Midthoracic esophagus extends from the tracheal bifurcation toward the esophagogastric junction, about 32 cm from UIT.
• Lower thoracic esophagus is ductal, 3 to 8 cm in length, includes the esophageal gastric junction, and is about 40 cm from UIT.
The esophagus is a muscular tube that consists of two layers of smooth muscle—one longitudinal and the other circular—and this is carried through into the rest of the gastrointestinal system. Peristalsis is initiated with swallowing, and the major function is to propel food into the stomach. There are two sphincters in the esophagus, and these are at the cricopharyngeous muscle at its inlet and the cardiac sphincter at the cardia of the stomach. These sphincters have been extensively studied from the physiologic point of view and are common sites of both benign and neoplastic disease.
The course of the esophagus is from slightly to the right of the midline to the left as it pierces the diaphragm through its own opening. It is in continual contact with the right lung; on the left side, the descending aorta is in continual contact. The azygos vein provides a partial shield on the right and posteriorly. Pulmonary veins would be expected to be in more intimate contact because they drain to the left auricle, which is posterior to the ventricle. The thoracic duct is posterior to the esophagus along its course, which is the reverse of the esophagus coursing from the right side of midline to the left as it ascends. When the esophagus comes anterior to the descending aorta, it is suspended by the mesoesophagus, which allows it to curve forward before it passes through the diaphragm (Fig. 23.4).
• Coronal: The EGJ is usually located to the left of the mid-line, at the 11th thoracic vertebra, and the pylorus is usually located at the L1 vertebral level to the right of the midline at the transpyloric plane; the angular incisura separates the body from the pyloric region of the stomach.
• Sagittal: The peritoneal cavity consists of the greater sac and omental bursa. The superior recess of the omental bursa is between the liver and the posterior attachment of the diaphragm. The inferior recess of the omental bursa is between the two double layers of the greater omentum. In the adult, the inferior recess usually only extends inferiorly as far as the transverse colon because of fusion of the two double peritoneal layers at birth.
• Transverse: The gastrosplenic and splenorenal ligaments tether the spleen in place between the stomach and the kidney; the ligaments from a pedicle (stalk) through which blood vessels run to and from the hilum of the spleen. These ligaments are double layers of peritoneum that form the left boundary of the omental bursa (lesser sac); the inner layer consists of peritoneum lining the omental bursa, and the outer layer consists of peritoneum lining the peritoneal cavity (greater sac).
Figure 23.4 | Orientation and overview of oncoanatomy. The anatomic isocenter for the esophagogastric junction (EGJ) cancers is at T9/T10. A. Coronal. B. Sagittal.
Figure 23.5 | T-oncoanatomy. Connecting the dots: Structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 23.3) and patterns of spread (Fig. 23.2) and SIMLAP table (Table 23.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Esophagogastric cancers frequently lead to lymphatic involvement not only of mediastinal nodes, but also of celiac and para-aortic nodes (Table 23.4). The AJCC/International Union Against Cancer numbering of mediastinal and abdominal nodes is unique and is different from the International Anatomy Terminology. The percentage of positive lymph nodes in the celiac area increases as the cancer location migrates from the upper esophagus to the EGJ (Fig. 23.6A), namely, from 32% to 70%.
The regional lymph nodes for the cervical esophagus are the cervical and supraclavicular nodes. For the thoracic esophagus, the regional nodes are the adjacent mediastinal lymph nodes. Involvement of more distant nodes is considered distant metastasis. Retrograde and prograde lymphatic spread usually places all of the lymph node stations in the neck, mediastinum, and abdomen at risk.
One of the major problems with control of this cancer is the frequency with which lymph node invasion occurs and the rapidity of its dissemination to other, distant anatomic areas. Esophageal cancer is therefore a disease not only of the chest, but also of the neck and abdomen. Because of its lymphatic drainage, esophageal cancer is a formidable tumor to encompass by locoregional modalities of therapy. The percentage of positive nodes found at surgery staging—both mediastinal and abdominal—indicates that at all levels of the primary, infradiaphragmatic nodes are frequently involved (Fig. 23.6B).
Figure 23.6 | N-oncoanatomy. A. The percentage of positive lymph nodes found at surgery for esophageal carcinoma in the upper, middle, and lower esophagus. B. Sentinel nodes of esophagogastric junction include thoracic and abdominal nodes. C. M-oncoanatomy. Note that the esophagogastric has a duel venous drainage. (i) The esophageal vein connects with the azygos vein and drains into the right heart, resulting in lung metastases. (ii) The left gastric vein drains the junction of esophagus and stomach, which in turn drains into the portal vein, resulting in liver metastases.
M-ONCOANATOMY
A rich plexus of venous anastomoses exists with stomach, liver, pancreas, and adrenals (Fig. 23.6C). Therefore, the liver, lung, and adrenals are the most common sites of distant metastases. Remote metastasis from the carcinoma of the esophagus, although ultimately fatal, often carries a better prognosis than when the primary lesion has extended locally outside the esophagus into mediastinal structures, a condition that is rapidly fatal. The incidence of liver metastases exceeds that of other sites. According to a variety of reports in the literature, the range is 30% to 100% at autopsy. Other sites are mainly bone metastases (20% to 35%) and lung metastases (40% to 60%), with only occasional metastases to brain.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Because the esophagus is not accessible to direct physical examination, endoscopy and imaging play a vital role in determining the stage of esophageal cancer. Barium esophagram with air contrast is able to detect the cancer, but to determine the depth of penetration, endoluminal ultrasound (EUS) can define the layers of the esophageal wall. Computed tomography (CT) of the chest and abdomen can determine invasion of surrounding structures, as well as metastatic lesions in lung and liver (Table 23.5; Fig. 23.7).
Pathologic Staging
The surgically resected esophagus and associated lymph nodes removed are assessed. Tumor extension and location of both primary and nodes should be documented. Accurate radial margins should be marked and recorded and are defined “as the surgically dissected surface adjacent to the deepest point of tumor invasion beyond the wall of the gut.” The completeness of resection depends on the clearing of the deepest point of invasion: R0, complete; R1, microscopic; and R2, macroscopic.
Oncoimaging Annotations
• Ninety percent of adenocarcinomas occur near the EGJ.
• Recognition of early mucosal and submucosal lesions can be done with double-contrast studies.
• CT, EUS, and magnetic resonance imaging (MRI) provide a complete picture of invasion. EUS is more accurate in staging penetration of five esophageal layers in its walls, and CT is better for detection of invasion to adjacent structures.
• Positron emission tomography is better for finding metastases.
• EUS demonstrates hyperechoic alternately with hypoechoic layers of esophageal wall.
• MRI and gadolinium diethylenetriaminopentaacetic acid show extensions into mediastinal and diaphragmatic tissues.
• EUS is most accurate in identifying T3 and T4 advanced invasion.
• EUS for nodal staging is less accurate than for T staging and it is best for periesophageal nodes and decreases as nodal distance from esophagus increases.
• Size more than an echogenic signal distinguishes benign from malignant nodes (i.e., size >1 cm vs. hypoechogenicity).
• EUS fine needle aspiration improves and verifies metastatic lymph nodes but ranges in sensitivity from 53% to 98% and in specificity from 77% to 100%.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Table 23.6.
CANCER STATISTICS AND SURVIVAL
The majority of digestive systems neoplasms are successfully treated with multimodal treatment. The number of new patients with cancers are 275,000 of which 50% (140,000) survive. The incidence is slightly greater in males than females 54% vs. 46% i.e., 150,000 vs. 1260,000. The death rates over the past five decades have most dramatically decreased in stomach and colon rectum cancers and are unchanged for pancreas and liver. The deaths are also greater in males than females: 56% vs. 44% i.e. 80,000 vs. 60,000.
An overview of digestive system cancers and their incidence of new patients and their death rates are tabulated according to ACS Cancer Facts and Figures 2010 (Tables 22.6 and 22.7).
The largest gains in survival are in colon and rectum, followed by stomach. The poorest results are those in pancreas and liver. The gains other sites vary depending on early detection of cancer in a localized stage in esophago-gastric junction or where chemoradiation is very effective i.e. anal cancers.
Specifically, the esophagus accounted for 16,640 new cancer cases, 14,500 cancer deaths (93%), with a survival (5-year) rate improvement over the last 3 decades of (1975–2005) of 14%. Currently, relative 5-year survival for all stages is 19%, but when localized, it improves to 29.1%. Chemoradiation in RTOG trials has resulted in 27% 5-year survival with local control at 68% and with esophageal preservation. For adenocarcinoma of the EJG, the best 5-year survival after chemoradiation and surgery is 40% in an intergroup study.
Figure 23.7 | Axial CTs of T9 and T10 level correlate with the T-oncoanatomy transverse section (Figure 23.5C). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. A, aorta; Spl, spleen.
With careful monitoring of EGJ Barrett and a finding of dysplasia, endoscopic resection offers the best chance for cure. Once invasive, if unresectable, the 5-year survival drops between 5% and 20%.
Figure 23.8 | Bar graph showing 5-year survival. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)