Background

The global burden of esophageal cancer is high, with it ranked as the fifth and eighth most common cause of cancer-related deaths in men and women, respectively, worldwide. In 2012 an estimated 455,800 new cases were diagnosed and the disease resulted in 400,200 deaths. At the time of presentation, almost half of patients have locally advanced or metastatic disease. Because of this rapid spread and late presentation, the 5-year survival is poor, measuring 18.4% overall. Although squamous cell carcinoma (SCC) is the most common type of esophageal cancer worldwide, in Western countries the incidence of SCC has decreased and adenocarcinoma has increased over the past few decades.

Esophageal Cancer Staging

Esophageal cancer staging is defined by the American Joint Committee on Cancer (AJCC) Staging System that establishes tumor-node-metastasis (TNM) subclassifications based on the depth of invasion of the primary tumor (T), lymph node involvement (N), and extent of metastatic disease (M). The 8th edition of the AJCC Cancer staging manual was published in 2017 ( Table 8.1 ) and will be in clinical use in 2018. The TNM components for staging esophageal adenocarcinoma and SCC are the same; however, the AJCC anatomic stage groups differ depending on histologic type because of differing mortality rates between adenocarcinoma and SCC stages.

The esophageal wall has four main layers: the mucosa, submucosa, muscularis propria, and adventitia. The mucosal layer includes the epithelium, lamina propria, and muscularis mucosae and is separated from the submucosa by a basement membrane. T1a cancers are confined within the mucosa and are often called intramucosal cancers; they can invade the lamina propria, as deeply as the muscularis mucosae. T2 tumors invade the muscularis propria and T3 the adventitia, and T4 denotes invasion of adjacent structures. Management is dependent on tumor stage, and accurate preoperative determination of disease stage is therefore essential to select the appropriate treatment for each patient, including endoscopic resection (ER), surgery, chemotherapy, radiation, or palliative care.

Management Pathways in Esophageal Cancer

Tumors limited to the mucosa or submucosa (T1) have a high rate of cure from endoscopic or surgical resection. Outcomes of Tis high grade dysplasia (HGD) and T1a tumors are similar, and ER for staging and therapy has demonstrated efficacy. The goal of endoscopic therapy is the complete removal or eradication of early stage disease. Lesions that are limited to the mucosa (Tis), lamina propria, or muscularis mucosae (T1a) can be removed by ER, with a low risk of lymph node metastases (0% to 3%). In patients with T1b disease, the optimal treatment strategy depends on histopathologic characteristics of the ER specimen and the patient’s clinical status. ER may be a valid alternative to surgery and is recommended in patients who are borderline fit for surgery and if the ER specimen has submucosal invasion less than 500 μm, tumor differentiation grade “well” or “moderate”, no lymphovascular invasion, and no tumor infiltration in the deep resection margin. These tumors are considered “low-risk” T1b cancers, with a risk of lymph node metastasis of less than 2%. However, discussion about comparative risk of esophagectomy versus potential for concurrent nodal disease should be undertaken, especially in cases with larger tumors or deeper invasion.

The most important risk factor predicting lymph node metastasis in both early adenocarcinoma and SCC is the depth of infiltration of the lesion. Survival is significantly worse once the esophageal cancer breaches the submucosa and there is lymphovascular invasion. This is largely related to early lymph node metastases, seen in up to 35% of T1b tumors and 78% to 85% of T3 tumors. The lymphatic drainage of the esophagus is unique in the gastrointestinal (GI) tract, with a freely anastomosing network in the mucosa and submucosa, intermittently piercing the muscularis propria to drain into regional lymph nodes or directly into the thoracic duct. The upper third of the esophagus drains into the paratracheal and internal jugular nodes, the middle third into the mediastinal node, and the lower third into nodes situated around the aorta and celiac axis. This intricate lymphatic system allows bidirectional tumor spread via the thoracic duct to involve the regional and systemic lymph nodes in the abdomen and mediastinum and development of “skip metastases.”

Patients with locally advanced disease which is potentially surgically resectable are usually offered neoadjuvant chemoradiotherapy to improve survival outcomes. Chemoradiotherapy followed by surgery is considered a standard treatment option for patients with stages II, III, and IVa disease. Neoadjuvant chemoradiotherapy rather than chemotherapy is generally used because it confers superior pathologic response and may improve outcomes. For early stage tumors the role of preoperative chemoradiotherapy remains controversial. A randomized controlled trial of 195 patients with early stage cancer (stage I or II) randomized to neoadjuvant chemoradiotherapy followed by surgery or to surgery alone showed no survival advantage with neoadjuvant therapy.

For patients who are either medically inoperable or have unresectable tumors, the efficacy of definitive chemoradiotherapy has been established. For patients with esophageal SCC, definitive chemoradiotherapy may offer equivalent outcomes compared with preoperative chemoradiotherapy followed by surgical resection.

Stage-dependent treatment protocols require the most complete and accurate staging possible, not only to select patients for surgery with or without neoadjuvant chemoradiotherapy, but also to minimize the rate of unnecessary surgery in metastatic disease.

Staging of Newly Diagnosed Esophageal Cancer

The preoperative evaluation of esophageal adenocarcinoma involves a careful endoscopic assessment, with or without the addition of computed tomography (CT), and positron emission tomography (PET)/CT with fluorodeoxyglucose (FDG), and endoscopic ultrasonography (EUS). These modalities have a limited role in the initial work-up of superficial esophageal cancers (Tis and T1) because ER is the best method for determining depth of invasion (T staging) and EUS is less accurate for early stage lesions (T1 or T2) compared with more advanced tumors. In contrast, in advanced esophageal cancers, a multimodality approach to preoperative staging cancer is required to determine a treatment plan and this may reduce the number of unnecessary surgeries performed and potentially improve survival.

Following initial diagnosis using upper endoscopy and tissue biopsy, the National Comprehensive Cancer Network (NCCN) guidelines recommend CT of the chest, abdomen, and pelvis with oral and intravenous contrast as the first staging study ( Table 8.2 ). The prime strength of CT and PET scanning in preoperative staging is the detection of distant metastases that identify patients who are not surgical candidates. CT is limited in defining the local extent and nodal involvement of esophageal cancer but is very useful in identifying patients with metastatic disease. These patients require histologic confirmation of metastatic disease, after which further investigations to evaluate the T and N status are generally not required. If CT is negative or equivocal for metastatic disease, FDG PET/CT is often used because it detects previously unsuspected metastatic disease in 15% to 20% of patients and assesses malignant involvement of any lymphadenopathy detected on CT.

In a prospective study of EUS, CT, and PET in 42 patients with esophageal cancer, accuracy for distant nodal metastasis was significantly higher for FDG PET than the combined use of CT and EUS (86% vs. 62%, P = .0094). However, PET was not as accurate as the combination of EUS and CT for locoregional lymph node staging. A retrospective study of 148 patients who had EUS and FDG PET for esophageal cancer staging found PET was not as accurate as EUS-guided fine-needle aspiration (FNA) and PET identified distant metastases only in those patients with incomplete EUS or who had nodal disease detected by EUS. PET CT has a higher accuracy than CT alone for distant and locoregional metastases but is inferior to EUS for locoregional staging. In a systematic review, FDG PET had a pooled sensitivity and specificity for the detection of locoregional metastases of 0.51 (95% confidence interval [CI], 0.34 to 0.69) and 0.84 (95% CI, 0.76 to 0.91), respectively. For distant metastases, pooled sensitivity and specificity was 0.67 (95% CI, 0.58 to 0.76) and 0.97 (95% CI, 0.90 to 1.0), respectively.

If CT and FDG PET/CT do not demonstrate distant disease, EUS staging should be performed to establish the extent of locoregional disease prior to initiation of treatment. EUS is recognized as the most accurate imaging method for initial locoregional staging in esophageal cancer. Sihvo and coworkers found EUS to be more accurate in detecting locoregional lymph node metastases than PET and CT (72%, 60%, and 58%, respectively). The addition of EUS to CT and PET increased the nodal staging accuracy from 70% to 91% ( P = .008). A study by Pfau and coworkers evaluating EUS, CT, and PET in staging esophageal cancer found that EUS changed management by guiding the need for neoadjuvant therapy in 34.8% of patients. The major impact on treatment plans of EUS was in patients with locally advanced disease: EUS identified a significantly greater number of patients (58.9%) with locoregional nodes than either CT (26.8%, P = .0006) or PET (37.5%, P = .02). In a retrospective study of 29 patients with no metastatic disease on CT and PET scan who underwent EUS, pathology confirmed nodal involvement was correctly identified by CT in 6 of 11 patients (54.5%), by PET in 4 of 11 patients (36.4%), and by EUS in 10 of 11 patients (90.9%). Overall accuracy for N staging was 69% for CT, 56% for PET, and 81% for EUS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of EUS for detection of locoregional lymph node metastasis were 91%, 60%, 83%, 75%, and 81%, respectively.

PET scan, CT, and EUS were performed in a prospective study of 75 patients with newly diagnosed esophageal cancer, with tissue confirmation or FNA used as the “gold standard” of disease. Accurate T stage by CT and PET was seen in 42% of cases and by EUS in 71% ( P = .14). CT, EUS, and PET had a similar performance in nodal staging: the sensitivity and specificity of N staging for CT was 84% and 67%, for EUS was 86% and 67%, and for PET was 82% and 60% ( P = .38), respectively. The sensitivity and specificity for distant metastasis were 81% and 82% for CT, 73% and 86% for EUS, and 81% and 91% for PET ( P = .25), respectively. Another prospective study showed that the addition of FDG PET to EUS and CT did not change management if a complete EUS examination had been performed, but it did offer some benefit in patients with incomplete EUS due to stenosing tumors.

Endoscopic Ultrasound Examination Technique

Obstructing Tumors

The diagnostic benefit of EUS examination in patients with stenotic esophageal tumors is limited. Complete staging EUS examination may be hampered by the presence of malignant stenosis obstructing passage of the scope. The esophagus may be dilated to allow scope passage and imaging through the length of the stricture and beyond. To pass the linear or radial scope, the stricture needs to be dilated to a diameter of 13 to 15 mm. Dilating a tight stricture to this diameter during one endoscopy session carries a significant risk of perforation of up to 24%. Stepwise dilation over more than one endoscopy may reduce this risk ; however, performing multiple procedures to achieve complete EUS staging may be challenging for patients and endoscopy centers to facilitate. The very presence of a stricture that impedes passage of a diagnostic gastroscope may indicate advanced disease, which may require neoadjuvant or definitive chemotherapy, radiotherapy, or a combination of both ( Fig. 8.1 ). In a recent multicenter retrospective cohort study of 100 patients with newly diagnosed nonmetastatic esophageal cancer referred for staging EUS, the diagnostic gastroscope could not pass through the malignant stricture in 46 patients. This had 100% correlation with locally advanced (T3 or T4) disease on EUS.

(A) On gastroscopy a tight stricture is seen at the distal esophagus due to adenocarcinoma. (B) On radial imaging the tumor invades the muscularis layer consistent with T3 disease (T3N0). (C) On “wedging” the linear echoendoscope transducer at the tumor site, additional disease burden such as nodal involvement could be recognized in the same patient (T3N1).

TNM Staging

The echoendoscope examination generally begins after an upper endoscopy. Initial passage of the echoendoscope is done slowly and carefully and largely “by feel” as it passes through the tumor rather than under direct vision. The sequence of staging generally is to examine for metastatic disease, then nodal involvement, followed by tumoral staging. The allows for early identification of disease that may upstage the tumor.

EUS is considered the modality of choice for accurate local staging, with a pooled sensitivity of 81% to 90% and 84.7% to 96.7% for T and N staging, respectively. In Barrett esophagus with high-grade dysplasia and early adenocarcinoma the pooled sensitivity and specificity of EUS for N staging is 71% (95% CI, 49% to 87%) and 94% (95% CI, 89% to 97%), respectively, with a pooled NPV of 96% (95% CI, 93% to 99%). A summary of studies reporting the accuracy of EUS for T and N staging and for EUS compared with other staging modalities are shown in Tables 8.3 and 8.4 , respectively.

TABLE 8.3

Accuracy of Endoscopic Ultrasound in Staging Esophageal Cancers

Study	Design	Number of Patients	Accuracy (%)
			T Stage	N Stage
Nesje (2000) a	Prospective	54	70	90
Heidemann (2000) b	Consecutive	68	79	79
Vazquez-Sequeiros (2001) c	Consecutive	64	Unspecified	70
Kienle (2002) d	Prospective	117	69	79
Chang (2003) e	Prospective	60	83	89
Wu (2003) f	Prospective	31	84	71
Vazquez-Sequeiros and coworkers	Prospective	125	86	87
DeWitt and coworkers	Prospective	102	72	75
Lowe and coworkers	Prospective	75	71	81
Zhang (2005) g	Retrospective	34	79	74
Moorjani (2007) h	Prospective	50	64	72
Shimpi (2007) i	Prospective	42	76	89
Kutup and coworkers	Prospective	214	66	64
Sandha and coworkers	Prospective	16	80	81
Mennigen (2008) j	Prospective	97	73	74
Omloo (2008) k	Prospective	125	76	70
Takizawa (2009) l	Prospective	159	Unspecified	64
Smith (2010) m	Retrospective	95	72	76

 

a Nesje LB, Svanes K, Viste A, et al. Comparison of a linear miniature ultrasound probe and a radial-scanning echoendoscope in TN staging of esophageal cancer. Scand J Gastroenterol . 2000;35:997–1002.

b Heidemann J, Schilling MK, Schmassmann A, et al. Accuracy of endoscopic ultrasonography in preoperative staging of esophageal carcinoma. Dig Surg . 2000;17:219–224.

c Vazquez-Sequeiros E, Norton ID, Clain JE, et al. Impact of EUS-guided fine-needle aspiration on lymph node staging in patients with esophageal carcinoma. Gastrointest Endosc . 2001;53:751–757.

d Kienle P, Buhl K, Kuntz C, et al. Prospective comparison of endoscopy, endosonography and computed tomography for staging of tumours of the oesophagus and gastric cardia. Digestion . 2002; 66:230–236.

e Chang KJ, Soetikno RM, Bastas D, et al. Impact of endoscopic ultrasound combined with fine-needle aspiration biopsy in the management of esophageal cancer. Endoscopy . 2003;35:962–966.

f Wu LF, Wang BZ, Feng JL, et al. Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI. World J Gastroenterol . 2003;9:219–224.

g Zhang X, Watson DI, Lally C, Bessell JR. Endoscopic ultrasound for preoperative staging of esophageal carcinoma. Surg Endosc . 2005;19(12):1618–1621.

h Moorjani N, Junemann-Ramirez M, Judd O, et al. Endoscopic ultrasound in esophageal carcinoma: comparison with multislice computed tomography and importance in the clinical decision making process. Minerva Chir . 2007;62:217–223.

i Shimpi RA, George J, Jowell P, Gress FG. Staging of esophageal cancer by EUS: staging accuracy revisited. Gastrointest Endosc . 2007;66:475–482.

j Mennigen R, Tuebergen D, Koehler G, et al. Endoscopic ultrasound with conventional probe and miniprobe in preoperative staging of esophageal cancer. J Gastrointest Surg . 2008;12: 256–262.

k Omloo JM, Sloof GW, Boellaard R, et al. Importance of fluorodeoxyglucose-positron emission tomography (FDG-PET) and endoscopic ultrasonography parameters in predicting survival following surgery for esophageal cancer. Endoscopy . 2008;40:464–471.

l Takizawa K, Matsuda T, Kozu T, et al. Lymph node staging in esophageal squamous cell carcinoma: a comparative study of endoscopic ultrasonography versus computed tomography. J Gastroenterol Hepatol . 2009;24:1687–1691.

m Smith BR, Chang KJ, Lee JG, Nguyen NT. Staging accuracy of endoscopic ultrasound based on pathologic analysis after minimally invasive esophagectomy. Am Surg . 2010;76(11):1228–1231.

TABLE 8.4

Accuracy of Imaging Modalities in Staging Esophageal Cancer

Study	Number of Patients	Stage	EUS (%)	CT (%)	MRI (%)	PET (%)
Kienle (2002) a	117	T N	69 79	33 67
Wu (2003) b	31	T N	84 71	68 78	60 64
Sihvo and coworkers	55	N	72	58		60
Vazquez-Sequeiros and coworkers	125	T N	86 87	72 51
Lowe and coworkers	69	T N	71 81	42 80		42 76
Sandha and coworkers	16	T N	80 81	69		56
Omloo (2008) c	125	T N	76 70	97 61
Keswani and coworkers	245	N	86			44

 

CT, Computed tomography; EUS, endoscopic ultrasound; MRI, magnetic resonance imaging; PET, positron emission tomography.

a Kienle P, Buhl K, Kuntz C, et al. Prospective comparison of endoscopy, endosonography and computed tomography for staging of tumours of the oesophagus and gastric cardia. Digestion . 2002; 66:230–236.

b Wu LF, Wang BZ, Feng JL, et al. Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI. World J Gastroenterol . 2003;9:219–224.

c Omloo JM, Sloof GW, Boellaard R, et al. Importance of fluorodeoxyglucose-positron emission tomography (FDG-PET) and endoscopic ultrasonography parameters in predicting survival following surgery for esophageal cancer. Endoscopy . 2008;40:464–471.

T Stage

T staging can be assisted by techniques to improve acoustic coupling and identification of the wall layers. These include using a balloon on the tip of the echoendoscope or low-volume water insufflation of the esophagus once the scope is in position over the tumor. Care must be taken to minimize the risk of aspiration with the latter technique, including using a small volume of water, raising the head of the bed, and regularly suctioning the stomach. It is important to avoid tangential imaging because it might lead to overstaging of the tumor.

The esophageal wall has five layers ( Table 8.5 ) on imaging with the curvilinear and radial EUS scope using frequencies of 5 to 10 MHz ( Fig. 8.2 ). The first hyperechoic layer corresponds to the superficial mucosa, the second hypoechoic layer to deep mucosa, the third hyperechoic layer to submucosa, the fourth hypoechoic layer to muscularis propria, and the fifth hyperechoic layer to adventitia. Tumors appear as a hypoechoic expansion, and the degree of infiltration of the tumor through the esophageal wall layers determines the tumor stage. Expansion of layers 1 to 3 corresponds with infiltration of the superficial and deep mucosa and submucosal layers, which is T1 disease. Expansion of layers 1 to 4 correlates with penetration into the muscularis propria, which is T2 disease. Expansion beyond the smooth outer border of the muscularis propria correlates with invasion of the adventitia, corresponding to T3 disease. Loss of a bright tissue plane between the area of tumor and surrounding structures such as the pleura, diaphragm, and pericardium correlates with T4a disease, whereas invasion of surrounding structures such as the trachea, aorta, lungs, or heart correlates with T4b disease ( Fig. 8.3 ).

TABLE 8.5

Esophageal Wall Layers With the Radial and Curvilinear Echoendoscope

EUS Layer	Esophageal Wall Layer	Echogenicity
1	Interface between lumen and mucosa	Hyperechoic
2	Deep mucosa including muscularis mucosa	Hypoechoic
3	Submucosa	Hyperechoic
4	Muscularis propria	Hypoechoic
5	Adventitia interface	Hyperechoic

 

EUS, Endoscopic ultrasound.

Schematic representation of the normal esophageal and gastric wall as examined using a radial echoendoscope and a high-frequency miniprobe.

A bulky esophageal tumor was identified, with pleural (A) and left atrium (B) invasion and a peritumoral lymph node (C). This was consistent with T4bN1 disease.

N Stage

The survival of patients with esophageal carcinoma depends largely on the presence or absence of lymph node involvement at the time of diagnosis. In patients who have surgery, stage for stage, survival is worse if a lesser lymphadenectomy is done. This survival difference is likely due to the result of stage migration because the probability of identifying positive lymph nodes is directly correlated to the adequacy of the lymphadenectomy.

EUS has an important role in identifying malignant lymph nodes, to help plan a treatment pathway, and for predicting the prognosis. Several nodal characteristics are associated with malignant involvement: size greater than 5 to 10 mm, round shape, sharp boarders, and hypoechoic (dark) pattern. The accuracy of this diagnosis correlates with the number of EUS criteria present. The presence of all four features has a sensitivity of 89% and specificity of 92% for lymph node metastasis.

Modified lymph node criteria were proposed by Vazquez-Sequeiros and coworkers, with the addition of three EUS features: lymph node in the celiac region, ≥5 nodes identified, and T3-T4 disease. The modified EUS criteria were more accurate than standard criteria, with 86% accuracy achieved when ≥3 of the 7 modified EUS criteria were used. Multivariable logistic regression analysis found that the EUS lymph node criteria of size ≥5 mm, rounded shape, ≥5 lymph nodes identified, and tumor stage T3-T4 best predicted malignant nodal involvement.

Malignant involvement is also confirmed by FNA for cytology assessment. FNA of suspicious lymph nodes should be performed without traversing the primary tumor or major blood vessels because this can lead to false-positive results, bleeding, and potentially risk tumor seeding. Furthermore, FNA should only be performed if it will impact treatment decisions.

EUS alone is insufficient for lymph node staging because metastatic lymph nodes may be beyond the depth of ultrasound penetration, past a stricturing tumor, or involve distal lymph nodal groups without regional lymph node disease. A combination of EUS, CT, and FDG PET/CT is often used to minimize the risk of understaging. EUS detects more locoregional node involvement than CT or PET and has a specificity of 70% (95% CI, 65% to 75%) and a sensitivity of 80% (95% CI, 75% to 84%). The combination of EUS FNA with CT further improves the diagnostic accuracy of local lymph node involvement.

M Stage

Imaging begins in the duodenum and antrum of the stomach to examine the liver and portal and peripancreatic lymph nodes. The area surrounding the fundus and cardia of the stomach are scanned to look for perigastric, peripancreatic, and celiac axis lymphadenopathy. Other sites of metastases include the left adrenal gland and peritoneum, which is suggested by free peritoneal fluid (ascites). Metastases to the left liver lobe (median size, 5 mm) or collections of malignant pleural fluid unsuspected at CT were diagnosed by EUS FNA in 3% to 5% of patients in a prospective and a retrospective study that together included a total of 207 patients.

Role of Fine-Needle Aspiration in Staging

Tissue confirmation of nodal involvement or metastatic disease is important for selecting appropriate treatment pathways ( Fig. 8.4 ). The presence of nodal involvement in T1-T2 disease determines whether patients receive neoadjuvant chemoradiotherapy or proceed directly to surgery, and confirmation of metastatic disease may determine whether treatment will be of curative or palliative intent.

(A) Celiac lymph node identified in a patient with esophageal cancer using a radial echoendoscope. (B and C) Linear echoendoscope passed to perform fine-needle aspiration for cytology confirmation.

The addition of FNA to EUS improves identification of malignant lymph nodes compared with EUS alone. In a prospective blinded comparison study in 125 patients, EUS, EUS FNA, and helical CT results were compared with the pathologic evaluation of resected lymph nodes. The accuracy of EUS FNA for lymph node staging (87%) was higher than that of EUS alone (74%, P = .01) or helical CT (51%, P < .001). Furthermore, EUS FNA significantly modified tumor stage determined by helical CT in 38% of patients, usually towards a higher stage. Clinical treatment plan is also impacted by performing FNA on suspicious lymph nodes. In a prospective cohort study of 109 patients referred for EUS, FNA was performed in 13% and the cytology results impacted management plan in all patients.

Early Esophageal Cancer

Esophageal cancer is termed “early” if it involves the mucosal (T1a) or submucosal (T1b) layers and does not invade the muscularis propria (T2 disease). Three distinct layers are described in the esophageal mucosa: the epithelium (m1), the lamina propria (m2), and the muscularis mucosae (m3). In Barrett esophagus, because of the existence of a newly formed muscularis mucosae beneath the Barrett epithelium, the mucosal layer is divided into four layers. In the operative specimen the submucosa is divided into three sections of equivalent thickness and termed sm1, sm2, and sm3. The muscularis propria is not present in an ER specimen; therefore submucosal invasion is described using a micrometric scale starting from the muscularis mucosae.

Cancer invading only the superficial mucosal levels (m1 and m2) can be treated by ER, and invasion into deep submucosa levels (sm2 and sm3) usually requires surgery. Middle level invasion (m3 and superficial submucosa) requires balancing of clinical factors with patient performance status and operative risks, and ER may be suitable for select patients with “low risk” submucosal invasion. The critical depth assessment of early esophageal neoplasia is to distinguish T1a from T1b lesions.

The risk of nodal involvement in early adenocarcinoma confined to the mucosa (T1a) ranges between 0% and 3%, and when the lesion extends into the submucosal layer (T1b) this risk is up to 30%. Early adenocarcinoma behaves less aggressively than SCC, for which the risk of lymph node metastasis starts to increase with invasion of the muscularis mucosa (m3), and surgery is generally recommended if any submucosal invasion is seen.

The main role for EUS in staging early esophageal cancer is to exclude suspicious lymph nodes in “high-risk” lesions with conventional EUS followed by FNA, if necessary ( Fig. 8.5 ). Its utility in staging prior to endoscopic or surgical treatment in early neoplasia is debatable. Isolated thickening of the mucosal layer alone may be difficult to see on EUS, resulting in loss of sensitivity of EUS for superficial disease. Similarly, standard EUS scopes (frequency 7.5 to 12 MHz) have a higher penetration, which is important for lymph node staging, but a lower resolution which limits its ability to accurately distinguish tumor penetration through the muscularis mucosa, or superficial from deep penetration of the submucosa. The main risk is overstaging in early disease. In a single center retrospective review of 109 patients with Barrett neoplasia, EUS classified lesions as suspicious for invasion in 19 patients; 84% of them had no evidence of invasion in final pathology.

Esophageal tumor invasion of the submucosa is seen, with an adjacent enlarged, rounded and hypoechoic lymph node (T1N1).

Restaging After Neoadjuvant Therapy

Neoadjuvant therapy is recommended for most patients with locally advanced disease. The objectives of neoadjuvant therapy are to decrease the tumor burden which may enable more patients to undergo potentially curative surgical resection, and diminish the risk of recurrence. Patients need to be restaged after completing neoadjuvant therapy to determine whether they are suitable for resection or should be referred for palliative management. Endoscopic biopsies performed after chemotherapy or radiotherapy may miss residual disease, and endoscopic evaluation requires careful examination for mucosal surface changes, with multiple biopsies taken of any visualized abnormalities and strictures.

Although EUS has clear benefits in the initial staging of esophageal cancer, it is not as reliable for restaging after neoadjuvant therapy. This is due to the local inflammatory and fibrotic responses to chemotherapy and radiation, which cause hypoechoic wall thickening on EUS. This can lead to overestimation of the depth of tumoral invasion and potentially exclude suitable patients from surgical resection.

EUS FNA has lower accuracy than integrated FDG PET/CT for lymph node restaging after neoadjuvant therapy but has similar accuracy in distinguishing between T1-3 and T4 disease. In a prospective trial of 48 consecutive patients who had undergone neoadjuvant chemoradiotherapy, the accuracy for nodal disease was 78%, 78%, and 93% for CT scan, EUS FNA, and FDG PET/CT, respectively ( P = .04). The accuracy of each test for distinguishing pathologic T4 from T1-T3 disease was 76%, 80%, and 80% for CT scan, EUS FNA, and FDG PET/CT, respectively. Fifteen (31%) patients were complete responders, and FDG PET/CT accurately predicted complete response in 89% compared with 67% for EUS FNA ( P = .045) and 71% for CT ( P = .05). It is unclear whether EUS FNA should be performed for cytologic confirmation if suspicious lymph nodes or areas of wall thickening are seen on FDG PET/CT or CT.

Imaging characteristics may predict the likelihood of a pathologic response following neoadjuvant chemoradiotherapy. In a retrospective study of 103 patients, reduced EUS mass size (0.7 vs. 1.7 cm, P = .01), reduction in esophageal wall thickness on CT (13.3 vs. 15.3 mm, P = .04), and lower PET standardized uptake value (SUV) (3.1 vs 5.8, P = .01) correlated with pathologic response, which was defined as ≤10% viable cells.

Influence of Endoscopic Ultrasound on Patient Management

The use of EUS in staging esophageal cancer changes patient management in up to 38% of cases. The change in management is most commonly by increasing the tumor stage, by detecting malignant lymph nodes or metastatic disease.

EUS FNA was used in a prospective study to select the surgical approach in patients with resectable distal esophageal cancer and mediastinal lymph nodes visualized on EUS: EUS FNA changed the management in 23% of 48 patients, by allocating patients with positive lymph nodes to transthoracic esophagectomy, and those without lymph node involvement to transhiatal resection, which has limited ability to resect lymph nodes.

Cost-Effectiveness of Endoscopic Ultrasound in Esophageal Cancer

EUS has been shown to be economical in multiple studies. EUS staging prior to treatment saves an average of $US 3443 per patient, by identification of stage I and stage IV tumors, which prevented unnecessary neoadjuvant chemoradiotherapy or surgery, respectively. In a study looking at whether initial CT or EUS costs less to diagnose advanced esophageal cancer, CT was the initial staging test of choice in most settings, but in a referral center EUS found advanced disease (T4 and/or M1) more frequently than CT (44% vs 13%, P < .0001) and was the least costly strategy. Another study found that in patients without metastatic disease, EUS was the most cost-effective staging modality, at $US 13,811, versus CT-guided FNA at $US 14,350, and surgery at $US 13,992. Another cost-saving method is selective rather than routine use of FNA for suspicious lymph nodes during EUS.

Impact of Endoscopic Ultrasound on Survival

A randomized trial of 223 patients with nonmetastatic gastroesophageal cancer was performed to assess whether the addition of EUS to usual staging tests changes treatment. EUS significantly improved participant survival, with a hazard ratio of 0.706 (95% CI from 0.501 to 0.996) and an increase of 121 days in estimated median survival: from 1.63 years in the group that had standard work-up to 1.96 years in the group that included EUS. Quality-adjusted survival was significantly higher (66 days), and there was a substantial, although nonsignificant, net saving of £2,800 per trial participant. Combining these survival and economic findings, there was a 96.6% probability of being cost-effective by National Institute for Health and Care Excellence (NICE) criteria. The use of EUS also increased the proportion of tumors completely resected from 80% (44 of 55) to 91% (48 of 53) ( P = NS). Two retrospective studies examined the effect of EUS staging on patient survival. The first study reported significantly better survival and reduced recurrence rate, due to improved selection of patients for surgery and neoadjuvant treatment. The second study found no survival advantage from EUS staging, but it reported only on patients suitable for surgery.

Learning Curve and Procedural Volume

Accuracy of tumoral staging by EUS is dependent in part on the learning curve of the endosonographer, with a study suggesting that at least 100 examinations are required to provide accurate T staging in patients with esophageal cancer. In addition, the location where the EUS is performed may affect preoperative staging. A comparison study of outcomes in a low– and high–EUS volume hospital showed higher sensitivity and specificity of staging in a high-volume compared with low-volume center.

Background

In 2017 the American Cancer Society estimates 28,000 new diagnoses and 10,960 deaths due to gastric cancer will occur in the United States. Globally, gastric cancer is the fourth most common cancer and the second most common cause of cancer-related death. There have been significant improvements in survival rates in the United States over the past 40 years; however, the 5-year relative survival rate remains low at 30%. Potential targets for disease prevention include Helicobacter pylori infection, diet, smoking and alcohol use, and early neoplasia detection through population screening in high-incidence countries.

Role of Endoscopic Ultrasound

Noninvasive imaging studies such as CT are widely available, but they lack accuracy for assessing the depth of tumor invasion or lymph node involvement. EUS is the most reliable nonsurgical method available for evaluating the depth of invasion of primary gastric cancers, is relatively low risk, and provides a more accurate prediction of T and N stage than CT imaging. Moreover, EUS-guided FNA of both regional and distant lymph nodes adds to the accuracy of nodal staging. Small metastatic deposits in the left lobe of the liver or low-volume malignant ascites can be diagnosed by EUS FNA, obviating the need for staging laparoscopy by establishing nonoperative diagnosis. EUS does not add to patient management in patients with metastatic gastric cancer identified by CT, and the role of EUS in restaging after chemotherapy or radiation therapy is unclear.

Gastric Cancer Work-Up ( Fig. 8.6 )

Most gastric cancers are diagnosed on endoscopy, with multiple biopsies taken for histology and the cancer location in the stomach, and the relationship to the esophagogastric junction (EGJ) for proximal tumors documented. In addition, endoscopic examination enables identification of complications such as luminal obstruction or bleeding. Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of superficial lesions can be performed to provide a larger specimen for histology assessment of the degree of differentiation, presence of lymphovascular invasion, and the depth of infiltration. EMR and ESD provide both accurate T staging for early cancers and have the potential to be therapeutic, as is discussed later.

National Comprehensive Cancer Network Guidelines for the work-up of gastric cancer. CT, Computed tomography; GI, gastrointestinal; PET, positron emission tomography.

(Adapted from the National Comprehensive Cancer Network Guidelines V 1.2017, Gastric Cancer.)

A CT of the chest, abdomen, and pelvis with oral and intravenous contrast is performed to determine the extent of disease, followed by an EUS if no metastatic disease is seen on CT. In patients being considered for surgical resection without neoadjuvant therapy, laparoscopy to detect radiologically occult metastatic disease in patients with T3 or node-positive disease can be considered. In patients planned for neoadjuvant therapy, laparoscopy with peritoneal washings should be considered.

Gastric Cancer Staging

Gastric cancer staging is defined by the AJCC Staging System and is shown in Table 8.7 . The 8th edition includes changes to the definition of the anatomic boundary between esophagus and stomach, a subdivision of N3 disease according to the number of involved nodes, reclassification of T4aN2 and T4bN0 tumors as stage IIIA disease, and separate prognostic stage groups for clinical and pathologic staging, including pathologic staging after neoadjuvant therapy.

TABLE 8.7

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