Diagnostic Applications of Nuclear Medicine: Esophageal Cancers
Esophageal cancer is the eighth most commonly diagnosed malignancy worldwide. This chapter will review the epidemiology, environmental factors, genetic predisposition, and underlying biomolecular changes of the disease. The staging of esophageal cancer will be reviewed as well as the roles of conventional diagnostic imaging and nuclear imaging in this staging. Finally, the efficacy of these modalities in assessing response to the various treatments described in the chapter and in the long term surveillance for disease recurrence will be addressed.
KeywordsEsophageal cancer Conventional diagnostic imaging [18F]FDG-PET/CT [18F]FDG-PET/MRI Staging Assessment of therapeutic response Surveillance
American Joint Committee on Cancer
Gene encoding for adenomatous polyposis coli
Gene encoding for a transcription factor (a multifunctional, nuclear phosphoprotein involved in cell cycle progression, apoptosis, and cellular transformation)
X-ray computed tomography
- erb B-2
Gene encoding for the receptor tyrosine-protein kinase erbB-2 (also known as CD340 or proto-oncogene Neu)
Gastrointestinal reflux disease
Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)
Metastasis status according to the AJCC/UICC TNM staging system
Mega-Becquerel (106 Becquerel)
Maximum intensity projection
Lymph node status according to the AJCC/UICC TNM staging system
Protein encoded by the CDKN2A gene (also known as cyclin-dependent kinase inhibitor 2A or multiple tumor suppressor 1)
Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)
Positron emission tomography response criteria in solid tumors
Positron emission tomography
Positron emission tomography/computed tomography
Positron emission tomography/magnetic resonance
Gene encoding for the retinoblastoma protein
Response evaluation criteria in solid tumors
Squamous cell carcinoma
Standardized uptake ratio (ratio of tumor SUV and blood pool SUV)
Standardized uptake value
Standardized uptake value at point of maximum
Tumor status according to the AJCC/UICC TNM staging system
Union Internationale Contre le Cancer (International Union Against Cancer)
Epidemiology and Environmental Factors
Esophageal cancer is the eighth most commonly diagnosed malignancy worldwide. It is also the sixth most common cause of cancer death, with a 5-year survival of approximately 15–20%. Over 16,000 new cases are estimated to be diagnosed in the United States in 2016, with over 15,000 deaths. Worldwide, over 450,000 new cases were diagnosed in 2012, with over 400,000 deaths. Esophageal cancer is three to four times more common among men than among women, with a lifetime risk in the United States of about 1 in 125 in men and about 1 in 435 in women [1, 2].
Over 95% of esophageal malignancies are squamous cell carcinoma (SCC) or adenocarcinoma, with lymphomas, sarcomas, neuroendocrine tumors, and metastatic disease largely accounting for the remainder. For most of the twentieth century, squamous cell carcinoma was the dominant histologic type, accounting for over 90% of cases and is still the dominant esophageal malignancy worldwide. However, over the past several decades in the Western world, the incidence of esophageal adenocarcinoma has risen significantly and now accounts for over 60% of esophageal cancers in the United States .
Esophageal SCC and adenocarcinoma differ in both typical tumor location and risk factors. Esophageal SCCs occur most frequently in the mid to distal third of the esophagus, while adenocarcinomas are more prevalent in the distal third of the esophagus and gastroesophageal junction. Smoking and excessive alcohol intake are the major risk factors for esophageal SCC. The incidence of esophageal SCC increases with age, peaking in the seventh decade of life. Demographically, the incidence of esophageal SCC is three times higher in black people than in whites . In the highest-risk region in the world for esophageal SCC, which stretches from Iran to China (the so-called esophageal cancer belt), major risk factors are poorly understood but are thought to include poor nutrition, diets lacking in fruits and vegetables, and the drinking of hot beverages . Human papillomavirus (HPV), particularly subtypes 16 and 18, has also been implicated in the pathogenesis of esophageal SCC .
Esophageal adenocarcinomas arise from a region of metaplastic epithelium, commonly known as Barrett’s esophagus, which replaces the squamous epithelium in the presence of gastrointestinal reflux disease (GERD) and progresses to dysplasia. Obesity and smoking are also known risk factors for esophageal adenocarcinoma . The dramatic increase in incidence rates of esophageal adenocarcinoma in Western countries is in part tied to increases in the known risk factor of obesity. With regard to demographics, white people develop esophageal adenocarcinoma five times more often than black people, while men are affected eight times more often than women .
The role that hereditary factors play in the development of esophageal cancer remains unclear. However, familial aggregations have been described in regions with a high incidence of esophageal SCC, such as China . Familial aggregations of Barrett’s esophagus have also been described with regard to development of esophageal adenocarcinoma .
Genetic analysis of esophageal cancers has revealed frequent chromosomal losses, chromosomal gains, and occasional gene amplifications . Gene polymorphism has also been studied. For example, polymorphisms of the epidermal growth factor gene have been found to be associated with a higher risk of esophageal adenocarcinoma, especially in patients with Barrett’s esophagus .
Underlying Biomolecular Changes
A large number of molecular events have been implicated in the development and progression of both esophageal SCC and adenocarcinoma. Studies have indicated that activation of cyclin D1, erb B-2, and c-myc oncogenes and inactivation of p53, Rb, APC, and p16 tumor suppressor genes are frequently involved .
Barrett’s esophagus develops when stratified squamous epithelium that normally lines the distal esophagus is replaced by metaplastic columnar epithelium as a result of chronic inflammation from GERD. Carcinogenesis in these metaplastic cells begins with genetic alterations that either activate some of the oncogenes and/or disable some of the tumor suppressor genes described above. It is thought that the first genetic changes that lead to adenocarcinoma in regions of Barrett’s esophagus are abnormalities in p53 and p16 that permit proliferation of clones of premalignant and/or malignant cells .
Staging and Prognostic Classification
The TNM staging system of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is universally used. The most recent TNM staging system implemented in 2010 created separate histological stage groupings for esophageal SCCs and adenocarcinomas while maintaining similar definitions for tumor, nodal, and metastatic categories. For esophageal SCCs, staging is in part determined by the location of the superior edge of the primary tumor, with upper and middle esophageal malignancies arising above the lower border of the inferior pulmonary vein and lower esophageal malignancies arising below that level. Tumors arising in the gastroesophageal junction and in the proximal 5 cm of the gastric cardia that extend to the gastroesophageal junction or esophagus (which includes almost all esophageal adenocarcinomas) are classified and staged as esophageal cancers.
Tumor (T) staging relates to the depth of invasion of the tumor in the esophageal wall and correlates with prognosis. While patients with disease limited to the mucosa/submucosa (T1) have a relatively high cure rate, patients with disease that has spread through the esophageal wall to the adventitia (T3) or to structures surrounding the esophagus (T4) have a much poorer prognosis. The T4 stage is further classified to indicate whether the cancer is invading adjacent structures such as the pleura, pericardium, or diaphragm (T4a) where surgical resection may still be possible or if it invades structures such as the aorta, carotid vessels, azygos vein, trachea, left main bronchus, or a vertebral body, which would preclude surgical resection (T4b).
Local lymph node invasion occurs relatively early in esophageal cancers because the esophageal lymphatics are located in the lamina propria, as opposed to being located beneath the muscularis mucosa elsewhere in the gastrointestinal tract . For the nodal (N) staging system, regional lymph nodes for all esophageal cancers include the supraclavicular, upper paraesophageal, mediastinal, lower paraesophageal, diaphragmatic, pericardial, left gastric, and celiac stations. Data has demonstrated that the number of regional lymph nodes containing metastatic disease (positive nodes) is more important than the location of these positive nodes. N0 indicates no positive nodes, N1 indicates one to two positive nodes, N2 indicates three to six positive nodes, and N3 indicates seven or more positive nodes. These groupings are relatively arbitrary, and the presence of each additional positive lymph node is thought to increase risk and worsen prognosis.
Distant metastatic disease (M1) includes sites of malignancy not in direct contact with the esophagus and includes parenchymal (e.g., liver or lung) involvement and non-regional lymph node involvement, including the hilar and pulmonary lymph node stations.
Conventional Diagnostic Imaging Staging
Both esophageal SCC and adenocarcinoma have similar clinical presentations, with early esophageal cancer often presenting with nonspecific symptoms such as weight loss, hoarseness, and/or coughing. Dysphagia is usually described in more locally advanced cases.
The initial workup of these nonspecific symptoms suggesting esophageal disease usually consists of a barium swallow fluoroscopic examination and/or an upper GI endoscopy. While infiltrating or ulcerated mucosal masses visualized on endoscopy are nearly pathognomonic of esophageal cancer, biopsy is needed to confirm the diagnosis.
Once the diagnosis of a primary esophageal cancer is established via biopsy, the initial staging usually starts with a contrast-enhanced diagnostic CT scan of the chest and abdomen in order to evaluate the region of the primary tumor for local invasion of mediastinal structures and peritumoral lymph node metastases and to search for any distant metastases.
With regard to T staging, diagnostic CT scan is significantly limited in the identification of esophageal wall layers and is thus unable to accurately assess more superficial tumors (T1–T3). However, CT can provide important information on more invasive tumors, either by excluding the presence of T4 disease or by characterizing any adjacent mediastinal structures the tumor may invade and thus determining potential resectability (T4a vs. T4b disease). Regarding nodal metastases, CT scans have relatively poor diagnostic performance as they rely mostly on size criteria. Enlarged lymph nodes on CT may be reactive in nature, while normal-sized nodes may be positive for metastases . Finally, while diagnostic CT can readily identify large distant metastases, it has limited sensitivity for smaller ones, particularly in the lungs, liver, and peritoneum.
Endoscopic ultrasonography (EUS) is also part of the initial staging workup for esophageal cancers. EUS uses high-frequency ultrasound to provide detailed images of the five layers of the esophageal wall and the paraesophageal environment. EUS is still regarded as the most accurate imaging technique for locoregional staging of esophageal cancer. The overall accuracy of EUS for T staging is 80–90%, and it can accurately delineate both superficial (T1, T2) and invasive (T3, T4) tumors . EUS is also effective in demonstrating peritumoral and paraesophageal metastatic lymph nodes. Findings suggestive of malignant lymph nodes include width greater than 10 mm, round shape, smooth border, and hypoechoic appearance. Of these, hypoechoic appearance and width greater than 10 mm appear to be the most specific for malignancy. When all four suspicious features are present in a visualized lymph node, there is an 80–100% chance of metastatic involvement . Fine needle aspiration , which can be performed in conjunction with EUS, further increases the accuracy of diagnosing lymph node involvement. However, aspiration is only possible when the nodes are accessible and where the primary tumor does not block the path of the aspiration needle. EUS does have its limitations, most notably when there is a tumor-related stenosis in the esophagus that the ultrasound transducer cannot traverse. Since the entire tumor and more distal nodal stations are not visualized, EUS may understage the malignancy in these cases.
Nuclear Imaging Staging
Fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) has been shown to be of great value in the primary staging of esophageal cancer in conjunction with EUS. [18F]FDG-PET/CT scanning has shown to add value to conventional staging methods consisting of both CT and EUS.
The potential prognostic value of the staging [18F]FDG-PET/CT has been explored. Studies have suggested that patients with [18F]FDG-avid nodal disease at baseline have a worse prognosis than those with undetectable nodal disease on [18F]FDG-PET, suggesting that the PET N stage may be an appropriate parameter for determining whether to start a more aggressive treatment regimen than would be normally considered . Several studies have investigated whether a relationship exists between the degree of [18F]FDG uptake of the primary tumor, as measured by maximum standardized uptake value (SUVmax), and prognosis, with inconclusive results. A recent study reported that [18F]FDG-PET provides independent prognostic information for overall survival and distant metastasis-free survival based on the staging tumor-to-blood standardized uptake ratio (SUR), a ratio of the tumor SUV and blood pool SUV. However, this parameter was not found to be prognostic with regard to locoregional tumor control . Finally, studies evaluating intratumoral [18F]FDG uptake heterogeneity, or “textural feature analysis,” have suggested that baseline regional tumor uptake heterogeneity may predict poorer responses to traditional therapy. It is postulated that tumors exhibiting a heterogeneous, as opposed to a homogeneous, [18F]FDG distribution may respond less favorably to uniformly distributed radiotherapy. Likewise, baseline tumor [18F]FDG heterogeneity could also reflect underlying tumor neoangiogenesis, which if present, could reduce the effectiveness of conventional chemotherapy .
Although [18F]FDG-PET/CT scanning is the mainstay of nuclear imaging for staging of esophageal cancer, initial investigations have been made into the utility of the newer and rapidly evolving hybrid modality of PET/MR. In one such study, EUS was once again found to demonstrate the highest accuracy in T staging, followed by PET/MR using [18F]FDG, followed by diagnostic CT. While EUS appears to remain the gold standard for T staging, [18F]FDG-PET/MR was somewhat accurate in characterizing higher T stage lesions, and the MR images were able to identify esophageal wall layers, which are poorly evaluated on diagnostic CT scan and unable to be evaluated on non-contrast-enhanced [18F]FDG-PET/CT. Furthermore, [18F]FDG-PET/MR demonstrated the highest efficacy in diagnosing regional nodal metastases, followed by EUS, [18F]FDG-PET/CT, and diagnostic CT, thought to be related to the excellent soft-tissue contrast of MR combined with the ability to quantitatively measure metabolic activity of the nodes. The diagnostic efficacy of M staging was not evaluated in this study, due to the time and cost involved in performing whole-body MR imaging over a large area comparable to [18F]FDG-PET/CT imaging .
The best option for curative treatment for patients with esophageal cancer is radical surgery consisting of esophagectomy with en bloc lymphadenectomy. The main contraindication for surgery is distant metastatic disease (M1) in which there are parenchymal metastases and/or distant metastatic lymph nodes or nodules. Unresectable invasive disease extending into the mediastinum (T4b) is also a contraindication for surgery. Despite improvements in perioperative care, esophagectomy carries significant morbidity and mortality risks and is thus contraindicated in patients with severe associated comorbid conditions (e.g., cardiovascular disease, respiratory disease). Medical care is reserved for nonsurgical candidates, with the main goal being the palliation of dysphagia, allowing patients to eat. Options include chemotherapy and/or radiotherapy, laser therapy, manual dilatation, metallic stenting, and photodynamic therapy.
After exclusion of distant metastases and/or unresectable locally invasive disease, the selection of the therapeutic regimen depends on the T stage. Localized tumors (T1/T2) have a high likelihood of curative resection, and primary esophagectomy is the most frequent treatment. In locally advanced tumors (T3/T4a, N+), surgery is also the mainstay of therapy, but it has been shown that preoperative chemotherapy or chemoradiotherapy provides a survival benefit of 7–13% over surgery alone . Neoadjuvant therapy typically consists of a combination of radiotherapy (approximately 45 Gy) and chemotherapy (commonly cisplatin and 5-fluorouracil). This combination therapy is usually administered over a 45-day period and is followed by esophageal resection after an interval of approximately 4 weeks. The goal of neoadjuvant therapy is to improve survival results related to surgery alone. Neoadjuvant chemotherapy is aimed at the eradication of lymphatic and/or hematogenous micrometastases and metastases, with improvement of survival. Neoadjuvant radiotherapy is aimed at shrinkage of the primary tumor, leading to an improved resectability rate.
Assessing Efficacy of Treatment
PET response criteria in solid tumors (PERCIST) represent a standardized method for evaluation of metabolic tumor response. Under these criteria, progression on [18F]FDG-PET scan is defined as an increase in [18F]FDG uptake (as measured by SUV) of greater than 20% in a region 1 cm or larger in diameter, while response to treatment is defined as a decrease in uptake of greater than or equal to 30% . Studies evaluating therapeutic response have compared PERCIST to RECIST (Response Evaluation Criteria in Solid Tumors), the more widely used solid tumor response metric based on changes in morphologic size . One such study evaluating response to neoadjuvant therapy for locally advanced esophageal cancer demonstrated that PERCIST was found to be the strongest independent predictor of outcomes .
Even in those patients with esophageal cancer treated with curative intent, 5-year survival rates remain relatively poor, ranging from 34% to 47% . Most recurrences occur within the first 2 years after surgery, with a median time to recurrence of slightly less than a year. Isolated distant systemic recurrences are diagnosed in about 50% of these patients, mainly involving the liver, lung, or bone. Locoregional recurrence (14%) or locoregional recurrence along with distant recurrence (35%) occurs less frequently . After esophageal cancer recurs, very poor median survival rates of 3–9 months have been reported .
Because recurrences of esophageal cancer tend to occur at distant sites, [18F]FDG-PET/CT may be useful in the postoperative surveillance period. In one recent meta-analysis, pooled estimates for [18F]FDG-PET and [18F]FDG-PET/CT scans calculated a high sensitivity (96%) and moderate specificity (78%) for detection of recurrent esophageal cancer after primary treatment with curative intent, indicating that [18F]FDG-PET/CT is a valuable test in clinical practice for surveillance of patients with esophageal cancer after surgery .
Endoscopic ultrasound is effective for the detection of locoregional recurrence with high sensitivity, but both endoscopy and ultrasound do not evaluate for the distant metastases that are of the most concern in this setting. Diagnostic CT scans can detect distant metastases but are limited in evaluating for recurrence at the site of resection due to anatomic distortion related to surgery and any prior radiotherapy. [18F]FDG-PET/CT itself is somewhat limited in evaluating the resection site due to the possible presence of chronic inflammation associated with fibrotic scar tissue. As the false-positive rate on [18F]FDG-PET/CT surveillance scans is not insignificant, histopathologic confirmation of suspected [18F]FDG-avid lesions remains required.
Due to the limited amount of adequate treatment options after recurrent esophageal cancer is detected, presymptomatic surveillance with imaging is not universally performed. However, newer salvage chemotherapy regimens and surgical resection of isolated recurrent metastases have been associated with improved survival rates . In this setting, [18F]FDG-PET/CT may prove to be a reliable imaging modality for routine surveillance of treated esophageal cancer patients prior to development of symptoms given its high sensitivity.
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