Imaging Recommendations for Diagnosis, Staging, and Management of Esophageal Cancer

Abstract Early staging and treatment initiation affect prognosis of patients with esophageal and esophagogastric junction cancer; hence, it is imperative to have knowledge of proper choice of imaging modality for staging of these patients, to effectively convey relevant imaging findings to the treating physician/surgeon. It is also essential to be aware of pertinent imaging findings that need to be conveyed to the treating physician/surgeon at staging, and after treatment, including post-therapy complications (if any), so as to provide timely management to such patients. In this article, we have provided imaging guidelines for diagnosis, staging, post-therapy response evaluation, follow-up, and assessment of post-therapy complications of esophageal and esophagogastric junction cancer in a systematic manner. Besides, risk factors and clinical workup have also been elucidated. We have also attached comprehensive staging and post-therapy contrast-enhanced computed tomography and fluorodeoxyglucose-positron emission tomography/computed tomography-based synoptic reporting formats “ECI-RADS” and “pECI-RADS,” respectively, for esophageal and esophagogastric junction cancer in the supplement, for effective communication of imaging findings between a radiologist and the treating physician/surgeon.


Introduction
Esophageal cancer (EC) is the seventh most common cancer in the world (GLOBOCAN 2020). 1,2 As per American Joint Committee on Cancer (AJCC), ECs have been divided into those located in the cervical, upper thoracic, middle thoracic, and lower thoracic esophagus (including the esophagogastric junction and up to 2 cm of gastric cardia). 3,4 Squamous cell carcinoma (SCC) is the predominant EC subtype usually seen in the middle third and lower third of esophagus, while most of the adenocarcinomas (ACs) occur in the distal esophagus. 3,5 Two to ten percent of all the cancers are located in the cervical esophagus and are of SCC subtype. 6,7

Risk Factors and Etiopathogenesis
Major risk factors for SCC include tobacco chewing and smoking and alcohol consumption. Achalasia and consumption of hot beverages are other predisposing factors. Main risk factors for AC include gastroesophageal reflux disease, Barrett's esophagus, obesity, and tobacco. Poor nutrition, mineral and vitamin deficiencies due to low intake of fruits and vegetables, radiotherapy for thoracic malignancies, and caustic ingestion predispose to both SCC and AC. [8][9][10] Various somatic mutations implicated in the pathogenesis of EC have been identified, and most notable of them being mutations of TP53, a major tumor-suppressor gene, and PIK3CA. 10

Epidemiology and Clinical Presentation
EC peaks in the seventh and eighth decades with 70% cases occurring in men. 1,11 In the West, the incidence of SCC has declined, with AC now being the dominant subtype. 12 As per GLOBOCAN 2020 data, EC is the fifth most common cancer in terms of incidence and mortality in India, and ranks seventh and sixth, respectively, in terms of incidence and mortality worldwide. 13,14 Patients are asymptomatic in early stages, in advanced stage, present with progressive dysphagia (solids then liquids), weight loss, hematemesis, melena, and hoarseness from recurrent laryngeal nerve involvement. 15

Imaging Referral Guidelines
National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology, AJCC, National Cancer Grid, and Indian College of Radiology and Imaging (ICRI) recommend endoscopic ultrasound (EUS) and contrast-enhanced computed tomography (CECT) with oral contrast for locoregional staging and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) for distant metastatic workup. 4,[16][17][18][19] ICRI specifically recommends the use of EUS only in early stage primary tumor evaluation of the middle third EC. 19 In addition, American College of Radiology recommends the use of single water-soluble contrast esophagogram on fluoroscopy in the immediate postoperative period to detect fistula or leaks, and suggests CT scan for negative esophagogram when clinical suspicion is high. 20 Imaging-based clinical (cTNM) staging proposed by 8th edition AJCC is followed for esophagus and gastroesophageal junction (GEJ) epithelial cancers. 4 ►Fig. 1 shows the NCCN imaging algorithm and ►Table 1 shows the 8th edition AJCC staging for EC. 4,16 EUS can differentiate the various layers of esophageal wall and has a sensitivity of 92 and 82%, respectively, for cT4 tumors and cT1 tumors. 16,21 CECT best detects invasion of adjacent structures (pleura, pericardium, azygous vein, diaphragm, peritoneum, aorta, trachea, and vertebra). 2,21,22 CT has a low accuracy for N staging showing a sensitivity of 30 to 60%, specificity of 60 to 80%, and accuracy 27 to 86% for lymph node more than 1cm. 21 Whereas the sensitivity of PET/CT for detection of locoregional nodal involvement is also low (51%). 16 EUS has a better sensitivity of 85% than either CT or PET/CT for the detection of nodal involvement. 16 Metastasis that is occult on CT can be detected on FDG-PET/ CT. 16 PET/CT has a sensitivity and specificity of 69 and 93%, respectively, for M stage. 4 Clinical/Diagnostic Workup (Excluding Imaging) All patients should have a thorough history and clinical examination with particular reference to weight loss. Grade III/IV dysphagia points toward bulky primary and probably T3/T4 stage. Upper gastrointestinal (GI) endoscopy with multiple biopsies is required to have sufficient tissue for histopathological examination and biomarker testing. 23 Differentiation between squamous and AC histology has prognostic and therapeutic implication. 24 In case of esophageal SCC, ear nose throat (ENT) examination to evaluate oral cavity, oropharynx, and hypopharynx should be done by an ENT specialist. In case of tumors located at or above tracheal bifurcation, a tracheobronchoscopy should be done to rule out tracheal invasion and a synchronous cancer in aerodigestive tract. 17 In locally advanced AC of GEJ, approximately 15% patients have peritoneal metastasis. Laparoscopy is advised in locally advanced GEJ AC to prevent futile surgeries. 25 For patients with metastatic disease, human epidermal growth factor receptor 2 testing by immunohistochemistry or fluorescence in situ hybridization for AC, mismatch repair deficiency/microsatellite instability, program death-ligand 1 (PD-L1) expression, and neurotrophic-tropomyosin receptor kinase fusion are advised to decide for targeted therapy/immunotherapy. 26 Imaging Guidelines a) Screening: Routine screening for EC is not recommended. b) Diagnosis: Upper GI endoscopy-guided biopsy is used for the diagnosis of primary tumor. 23 There are two types of echoendoscopes available: radial and linear array. EUS using linear array echoendoscopes have a limited field but have the important ability to visualize a needle in real time and hence are used for tissue sampling. Endoscopy also helps in guiding nasogastric tube insertion for feeding when needed. In patients having clinically palpable and significant appearing supraclavicular node or liver metastasis, tissue diagnosis can be obtained from node or liver metastasis, when planned for palliative therapy.

Role of EUS
On EUS, five layers of the esophageal wall described are layer 1 (hyperechoic) superficial mucosa, layer 2 (hypoechoic) deep mucosa, layer 3 (hyperechoic) submucosa, layer 4 (hypoechoic) muscularis propria, and layer 5 (hyperechoic) adventitia. Tumors appear as hypoechoic lesions involving the wall layers, and malignant lymph nodes are typically seen in the vicinity of the tumor, appearing hypoechoic and round with smooth borders, and may be more than 10 mm in size. 27 The standard 7.5 to 12 MHz frequency transducers do not have adequate resolution to accurately "T" stage very early stage disease with mucosal involvement or superficial submucosal involvement, and a 20 MHz radial mini-probe may be needed for scanning in such cases. The accuracy of EUS increases with increasing T stage. EUS can be performed in patients with early-stage EC prior to endoscopic resection (ER) or in patients planned for upfront surgery, mainly to rule out lymph-node metastases in selected high-risk cases. Although EUS is the only modality for distinguishing different layers of esophageal wall, ER is more accurate than EUS for the staging of T1a/T1b EC and may also be therapeutic in some cases. 16 When high-definition whitelight or image-enhanced endoscopy is suggestive of a small nodular lesion with high grade dysplasia or earlystage EC, a staging ER is encouraged. 16,28 An EUS-guided fine-needle aspiration can be performed for suspicious lymph nodes if they can be sampled without traversing the tumor or major blood vessels and if the result will change management. 16 Most patients with stenotic tumors are likely to have locally advanced disease where an EUS may be unnecessary. 29 If at all an EUS is indicated in stenotic tumors, a smaller caliber wire-guided probe or mini-probe can be used; however, availability and cost may be an issue. ►Fig. 2(A-C) shows EC staging on EUS with malignant regional node.

Role of CT
CECT thorax and abdomen with oral contrast is recommended for EC staging. CT of the pelvic region should be included for esophagogastric junction tumors or if clinically indicated. Upper third EC including cervical EC requires additional evaluation with CECT neck. CT thorax protocol for EC is shown in ►Table 2. 19 On CECT, differentiation of T1 and T2 is not possible. 21,22 T3 stage on CT presents as mural thickening (> 3mm) and periesophageal fat infiltration without any loss of fat plane/invasion of adjacent structures. 2 CT most accurately provides the craniocaudal length of the tumor (along with the corresponding vertebral level) that is essential for deciding upon the surgical resection margins. 2,3 CT plays a significant role in T4 staging of tumor. Involvement of pleura, pericardium, azygous vein, diaphragm, or peritoneum (for esophagogastric junction EC) is considered as T4a stage, whereas, aorta, vertebral body, or tracheal involvement upgrades the lesion to T4b stage. 2,4 Specific signs of tracheobronchial involvement by EC on CT are fistula formation with the airway, intraluminal extension of tumor within the airway, and tracheobronchial mural thickening. 3,22 Focal loss of fat plane of the EC with the airway with preserved fat planes proximal and distal to it also likely suggests tracheobronchial involvement. 22 More than 90-degree contact of EC with aorta, loss of triangular fat between esophagus, aorta, and spine, suggests aortic involvement on CECT. 2,3,22 Pericardial involvement may be suggested by pericardial thickening/effusion. 3,22 CECT helps in assigning Siewert category to esophagogastric junction AC tumors that have management and prognostic implications. 16 Besides, CECT is important for the detection of metastasis to liver and lungs. 22 ►Fig. 3 (A-E) shows EC staging on CECT.

Role of FDG-PET/CT
Following intravenous injection of 18F-FDG-PET-CT images are acquired from skull base to mid-thigh. Both oral and intravenous contrast is used for the acquisition of CT images. The predominant role of FDG-PET/CT is to detect distant metastases including metastasis to bones and distant nodal metastasis when no metastasis is detected on CECT scan. 16 PET-CT is the modality of choice  to diagnose occult metastasis to various organs that thus help in avoiding futile surgeries. [30][31][32] Besides, PET-CT is also useful to detect second primary tumor and studies have indicated that FDG-PET/CT is superior to conventional anatomical imaging to evaluate synchronous tumors (especially head and neck cancers and colon neoplasm) during primary staging of esophageal SCC. 33 PET/CT also plays an important role in radiation therapy treatment planning of EC. 34,35 PET-CT-based intensitymodulated radiation therapy offers several advantages that includes (1) dose escalation to target (tumor), (2) minimizes dose delivery to normal tissue, (3) decrease acute toxicity, (4) lessens long-term toxicity by optimizing treatment delivery to target tissue, thereby achieving better therapy outcome. ►Fig. 4 (A and B) shows EC staging on FDG-PET/CT.

Role of Other Modalities
Magnetic resonance imaging (MRI) plays a pertinent role in detecting the status of spinal cord, when there is intraspinal extension of the tumor with involvement of vertebrae. Also, when there is doubt on CT regarding pericardial and aortic wall involvement, MRI can come to the rescue. One of the studies has shown that PET-MR has comparable sensitivity with EUS in staging primary esophageal involvement, and offers higher diagnostic accuracy compared with EUS and PET/CT. 36 However, due to limited availability and cost factor, PET-MR is not routinely used. ►Table 3 enlists the role of each modality in staging of EC. [2][3][4]16,22,[30][31][32]

d) Response Assessment
A retrospective multicenter study demonstrated that use of short axis diameter (instead of the usual longest diameter) in the Response Evaluation Criteria in Solid Tumors (RECIST) for EC after neoadjuvant chemotherapy correlates well with pathological response and is significantly associated with survival. 37 On comparison with

e) Follow-Up
In the post-treatment setting, most of the recurrences (95%) are known to occur within the first 2 years after bimodality therapy (definitive chemoradiotherapy) and first 3 years after trimodality therapy (chemoradiotherapy and surgery). 41 There are no well-established guidelines for follow-up; however, CT scan of chest and abdomen with contrast is recommended every 6 months for first 2 years at least. 16 Along with this, 3 monthly follow-up with history and physical examination, upper GI tract endoscopy at 3 months, followed by at 1 year, and then every 3 yearly are recommended. From 2 to 5 years, follow-up can be 6 monthly (clinical) with annual imaging, and after 5 years annual clinical follow-up with imaging only if indicated clinically. 17 ►Table 5 shows the follow-up guidelines for EC. 16,17

Principles of Management
For mucosal tumors, treatment options include ER and/or ablation (high-grade dysplasia, AC limited to mucosa, small   tumor [<2cm] that are asymptomatic and non-circumferential). 42 Upper third EC are best treated with definitive chemoradiation (CTRT). In middle and lower third, patients with T2N0 or less may be operated upfront without any neoadjuvant therapy. 16 Any localized disease greater than T3N0 mandates neoadjuvant therapy despite being upfront resectable. As of today, the best evidence is for neoadjuvant chemoradiotherapy(NACTRT) with CROSS protocol for SCC and perioperative chemotherapy with Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel (FLOT) regimen for AC. 43 For early-stage resectable tumors, either transhiatal or transthoracic (Ivor-Lewis) total esophagectomy or extended-3 field lymphadenectomy is performed depending upon the location or extent of tumor. 44 CTRT is given for T4b stage, except when trachea, great vessels, vertebra or heart, are involved, in which case, palliative chemotherapy is the only option. Depending on HER 2 overexpression and PD-L1 expression, targeted therapy or immunotherapy respectively, are given. 16 Overall EC is very aggressive disease with poor prognosis. Five-year overall survival for localized disease is 39 and 4% for metastatic disease. SCC histology has poor outcome as opposed to AC histology. 45 Nutritional rehabilitation and cardiopulmonary evaluation are vital components in the overall management of EC patients.
►Fig. 6 depicts an algorithm for the management of EC. Location/stage-wise treatment of EC is presented in ►Table 6. 16,43

Follow-Up Imaging and Management of Recurrent Disease
Anastomotic leak is suspected in presence of fever, tachycardia, tachypnea, or arrhythmia in immediate postoperative period. Also, a close watch needs to be kept on the neck wound (for erythema /swelling) and nature of drain output (bilious/ purulent) in the postoperative period. CECT detects immediate post-surgical complications like fistulization of neoesophagus with airway and anastomotic leaks, and is also useful for the detection of esophageal edema after definitive concurrent chemoradiotherapy. 2,46 CECT thorax assists in diagnosis by showing oral contrast extravasation and or air fluid level in pleural/mediastinum. CECT thorax also helps in draining out the collection by guiding pigtail.
Esophagogram on fluoroscopy can also be used in the immediate postoperative period to detect fistula or leaks, and a negative test warrants CECT, if clinical suspicion is high. 20 Delayed post-therapy imaging includes detection of recurrence and post-surgery/RT stricture. ►Fig. 7 (A and B) CECT images show post-NACTRT stricture formation in midesophagus (in supplement). Mantziari et al found FDG-PET/ CT parameters (SUVmax, total lesion glycolysis and MTV) to be quite useful in predicting tumor recurrence and diseasefree survival in patients with EC. 47 CECT may show new onset enhancing esophageal mural thickening suggestive of recurrence. Post-RT esophageal stricture occurs 3 to 8 months later and can be seen as esophageal luminal narrowing with proximal dilatation and air-fluid levels. 2,48 Localized recurrences after surgery are best treated with CTRT. Residual or recurrent disease after CTRT is considered for salvage surgery. Various systemic therapy options exist for both histologies. For palliation of dysphagia, local radiation (external beam or brachytherapy), feeding procedures (nasojejunal/gastric tube), or esophageal or airway stenting (for tracheobronchial infiltration) are feasible options.

Summary of Recommendations
1. Differentiation of T1a and T1b is best achieved by ER. 16 2. EUS is the modality of choice for T staging of EC and for regional lymph node assessment. 16