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Diagnostic Applications of Nuclear Medicine: Esophageal Cancers

  • Christopher G. Sakellis
  • Heather A. Jacene
  • Annick D. Van den Abbeele
Living reference work entry

Abstract

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.

Keywords

Esophageal cancer Conventional diagnostic imaging [18F]FDG-PET/CT [18F]FDG-PET/MRI Staging Assessment of therapeutic response Surveillance 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

AJCC

American Joint Committee on Cancer

APC

Gene encoding for adenomatous polyposis coli

c-myc

Gene encoding for a transcription factor (a multifunctional, nuclear phosphoprotein involved in cell cycle progression, apoptosis, and cellular transformation)

CT

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)

EUS

Endoscopic ultrasonography

GERD

Gastrointestinal reflux disease

GI

Gastrointestinal

Gy

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)

HPV

Human papillomavirus

M

Metastasis status according to the AJCC/UICC TNM staging system

MBq

Mega-Becquerel (106 Becquerel)

MIP

Maximum intensity projection

MR

Magnetic resonance

N

Lymph node status according to the AJCC/UICC TNM staging system

p16

Protein encoded by the CDKN2A gene (also known as cyclin-dependent kinase inhibitor 2A or multiple tumor suppressor 1)

p53

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)

PERCIST

Positron emission tomography response criteria in solid tumors

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PET/MR

Positron emission tomography/magnetic resonance

Rb

Gene encoding for the retinoblastoma protein

RECIST

Response evaluation criteria in solid tumors

SSC

Squamous cell carcinoma

SUR

Standardized uptake ratio (ratio of tumor SUV and blood pool SUV)

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

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 [3].

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 [4]. 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 [5]. Human papillomavirus (HPV), particularly subtypes 16 and 18, has also been implicated in the pathogenesis of esophageal SCC [6].

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 [7]. 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 [8].

Genetic Predisposition

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 [9]. Familial aggregations of Barrett’s esophagus have also been described with regard to development of esophageal adenocarcinoma [10].

Genetic analysis of esophageal cancers has revealed frequent chromosomal losses, chromosomal gains, and occasional gene amplifications [11]. 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 [12].

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 [13].

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 [14].

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 [15]. 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 [16]. 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 [17]. 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 [18]. 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.

With regard to T staging, [18F]FDG-PET/CT cannot accurately assess depth of tumor invasion. In fact, the sensitivity of [18F]FDG-PET/CT in detecting biopsy-proven T1 tumors involving the mucosa and/or submucosa ranges approximately between 40% and 60%, likely due to the smaller size of the tumors and/or lower malignant cellularity (Fig. 1). [18F]FDG-PET sensitivity for detection of more invasive tumors progressively rises from 83% in T2 tumors (involving the muscularis propria), to 97% in T3 tumors, to 100% in T4 tumors [19].
Fig. 1

[18F]FDG-PET/CT of a 73 year old man with history of gastric bypass surgery presenting with recently diagnosed intramucosal adenocarcinoma of the distal esophagus in the background of Barrett’s esophagus. The relatively mild associated uptake in the distal esophagus may relate to the primary tumor’s small size and could even reflect inflammation in the setting of Barrett’s esophagus. There is no evidence of regional or distant metastatic disease

[18F]FDG-PET/CT has demonstrated some advantages over traditional imaging in the staging of nodal metastases. Regional lymph nodes that are equivocal in size on diagnostic CT scan will be suspicious for metastatic sites of involvement if metabolically active on [18F]FDG-PET/CT scan (Fig. 2). EUS does not evaluate for distal metastatic nodal disease. A meta-analysis performed by van Vliet et al. suggested that [18F]FDG-PET/CT scanning is more sensitive for the detection of distant metastatic nodal disease than diagnostic CT alone [20]. However, with regard to regional nodal disease, [18F]FDG-PET/CT has shown a similar, but slightly decreased, sensitivity when compared with EUS. This may be in part due to the [18F]FDG uptake of lymph nodes in the immediate vicinity of the primary tumor being obscured by the primary tumor’s uptake or by limitations in the spatial resolution of PET leading to false-negative results in small regional nodes (Fig. 3). Also, the [18F]FDG uptake of the primary esophageal cancer has been shown to affect the detectability of nodal metastases, as they have similar histologies. Thus, if the primary lesion presents with a low baseline [18F]FDG uptake, nodal metastases will have relatively low [18F]FDG uptake as well, potentially resulting in a false-negative appearance [21].
Fig. 2

(a) [18F]FDG-PET/CT maximum intensity projection (MIP) image of a 67 year old man with newly diagnosed upper esophageal adenocarcinoma, represented by contiguous intense [18F]FDG uptake in the upper thorax (arrow). (b) CT and PET images of an associated subcentimeter right supraclavicular lymph node (arrow). (c) CT and PET images of the primary tumor at the thoracic inlet and an associated subcentimeter node (arrow). (d) CT and PET images showing the more inferior extent of the primary tumor and an associated subcentimeter left paratracheal lymph node (arrow). The small [18F]FDG-avid lymph nodes described in b, c, and d could all be considered equivocal on CT scan alone. The relatively intense [18F]FDG uptake of these nodes on PET scan is strongly suggestive of regional nodal metastatic disease

Fig. 3

[18F]FDG-PET/CT scan of a 56 year old man with newly diagnosed distal esophageal adenocarcinoma. There is an enlarged paraesophageal lymph node immediately adjacent to the [18F]FDG-avid primary tumor. This lymph node is likely a site of regional metastatic spread but is not significantly [18F]FDG-avid, likely due to the dominance of the intense uptake (SUVmax 22) of the adjacent tumor

The primary advantage [18F]FDG-PET/CT demonstrates over EUS and diagnostic CT evaluation is in the detection of distant metastatic disease (M1). In addition to non-regional nodal metastases, distant metastatic disease includes parenchymal spread to the lungs and liver but may also include spread to more atypical sites difficult to evaluate on anatomic imaging such as the pleura, musculature, and skeleton (Fig. 4). Several studies have demonstrated that [18F]FDG-PET and PET/CT have significantly higher sensitivities for the detection of distant metastatic disease than CT scans alone. [18F]FDG-PET has been shown to upstage the disease in approximately 20% of patients first evaluated with CT/EUS, with the benefit of preventing unnecessary surgery [20, 22]. Another study demonstrated that staging with [18F]FDG-PET significantly changed management in 38% of patients [23]. Given its superior sensitivity in detecting metastatic disease (and precluding expensive curative surgery), [18F]FDG-PET combined with EUS, despite being more expensive, appears to be the more cost-effective method of staging patients compared to CT and EUS [24].
Fig. 4

(a) CT and PET images from an [18F]FDG-PET/CT demonstrate a primary esophageal adenocarcinoma (arrow) arising at the gastroesophageal junction in a 74 year old man. (b) There is a single associated [18F]FDG-avid celiac axis lymph node (arrow), which is considered regional disease. (c) There are bilateral [18F]FDG-avid pulmonary nodules present (arrows) which are considered distant metastases (M1)

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 [25]. 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 [26]. 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 [27].

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 [28].

Common Therapies

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 [29]. 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

Many studies have shown that significant decrease in [18F]FDG uptake of the primary tumor as well as resolution of [18F]FDG-avid regional lymph nodes following neoadjuvant therapy correlates with favorable long-term prognosis following surgery. Complete metabolic response (defined as a reduction of SUVmax greater than 80%) after completion of preoperative chemotherapy has been shown to predict favorable long-term outcome (Figs. 5 and 6) [30].
Fig. 5

(a) MIP images of [18F]FDG-PET/CT scans performed on a patient with localized esophageal adenocarcinoma involving the gastroesophageal junction and gastric cardia. Baseline images prior to therapy show an intensely [18F]FDG-avid mass with SUVmax 22. (b) Following completion of neoadjvant chemoradiotherapy, there is still some mild [18F]FDG uptake at the gastroesophageal junction with SUVmax 3, but there has been a greater than 80% drop in uptake which has been shown to correlate with a more favorable long-term outcome. The patient went on to have an esophagectomy, and continued to be followed up with diagnostic CT. He is currently disease-free 6 years after the completion of trimodal therapy

Fig. 6

[18F]FDG-PET/CT MIP images of a 55 year old man who presented with metastatic gastroesophageal junction adenocarcinoma. (a) Baseline PET scan demonstrates the [18F]FDG-avid primary tumor (arrow) along with extensive [18F]FDG-avid metastatic lymphadenopathy above and below the diaphragm, in addition to liver metastases. (b) A follow up scan was performed two months after starting chemotherapy. There had been some response to treatment with significant decrease in size and uptake of the widespread lymphadenopathy and resolution of most of the liver metastases. The [18F]FDG uptake of the primary tumor only decreased about 30% (from SUVmax 14.2 to 9.8), and there was persistent mild [18F]FDG uptake in a single lesion in the caudate lobe of the liver (arrow), findings which did not suggest a favorable prognosis. (c) A follow up scan performed two months later demonstrated that the metabolic activity of the primary tumor had continued to slightly decrease but was still quite significant. There was also an increase in size and [18F]FDG uptake of the caudate lesion as well as a new [18F]FDG-avid lesion in the right hepatic lobe (arrow). These findings were consistent with progression of disease

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% [31]. 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 [32]. 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 [33].

Surveillance

Even in those patients with esophageal cancer treated with curative intent, 5-year survival rates remain relatively poor, ranging from 34% to 47% [34]. 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 [35]. After esophageal cancer recurs, very poor median survival rates of 3–9 months have been reported [36].

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 [37].

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 [38]. 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.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7.CrossRefPubMedGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87.CrossRefPubMedGoogle Scholar
  3. 3.
    Pohl H, Sirovich B, Welch HG. Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer Epidemiol Biomarkers Prev. 2010;19(6):1468.CrossRefPubMedGoogle Scholar
  4. 4.
    Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut. 2005;54 Suppl 1:i1–5.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gholipour C, Shalchi RA, Abbasi M. A histopathological study of esophageal cancer on the western side of the Caspian littoral from 1994 to 2003. Dis Esophagus. 2008;21(4):322.CrossRefPubMedGoogle Scholar
  6. 6.
    Shuyama K, Castillo A, Aguayo F, Sun Q, Khan N, Koriyama C, Akiba S. Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China. Br J Cancer. 2007;96(10):1554.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Engel LS, et al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst. 2003;95(18):1404.CrossRefPubMedGoogle Scholar
  8. 8.
    Hur C, Miller M, Kong CY, Dowling EC, Nattinger KJ, Dunn M, Feuer EJ. Trends in esophageal adenocarcinoma incidence and mortality. Cancer. 2013;119(6):1149–58.CrossRefPubMedGoogle Scholar
  9. 9.
    Chang-Claude J, Becher H, Blettner M, Qiu S, Yang G, Wahrendorf J. Familial aggregation of oesophageal cancer in a high incidence area in China. Int J Epidemiol. 1997;26(6):1159.CrossRefPubMedGoogle Scholar
  10. 10.
    Chak A, Lee T, Kinnard MF, Brock W, Faulx A, Willis J, Cooper GS, Sivak Jr MV, Goddard KA. Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut. 2002;51(3):323.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.CrossRefPubMedGoogle Scholar
  12. 12.
    Lanuti M, Liu G, Goodwin JM, Zhai R, Fuchs BC, Asomaning K, Su L, Nishioka NS, Tanabe KK, Christiani DC. A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and esophageal adenocarcinoma risk and outcome. Clin Cancer Res. 2008;14(10):3216.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kuwano H, et al. Genetic alterations in esophageal cancer. Surg Today. 2005;35(1):7–18.CrossRefPubMedGoogle Scholar
  14. 14.
    Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, Rabinovitch PS, Reid BJ. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet. 1999;22(1):106.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Meltzer SJ. The molecular biology of esophageal carcinoma. Recent Results Cancer Res. 1996;142:1.CrossRefPubMedGoogle Scholar
  16. 16.
    Yoon YC, et al. Metastasis to regional lymph nodes in patients with esophageal squamous cell carcinoma: CT versus FDG PET for presurgical detection - prospective study. Radiology. 2003;227:764–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am. 1995;5(3):537.PubMedGoogle Scholar
  18. 18.
    Catalano MF, Sivak Jr MV, Rice T, Gragg LA, Van Dam J. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc. 1994;40(4):442.CrossRefPubMedGoogle Scholar
  19. 19.
    Kato H, Miyazaki T, Nakajima M, et al. The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma. Cancer. 2005;103(1):148–56.CrossRefPubMedGoogle Scholar
  20. 20.
    van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD. Staging investigations for oesophageal cancer: a meta-analysis. Br J Cancer. 2008;98(3):547.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Manabe O, et al. Diagnostic accuracy of lymph node metastasis depends on metabolic activity of the primary lesion in thoracic squamous esophageal cancer. J Nucl Med. 2013;54(5):670–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Pierre AM, et al. Detection of distant metastases in esophageal cancer with F-18 FDG PET. J Nucl Med. 2004;45(6):980–7.Google Scholar
  23. 23.
    Chatterton BE, et al. Positron emission tomography changes management and prognostic stratification in patients with oesophageal cancer: results of a multicentre prospective study. Eur J Nucl Med Mol Imaging. 2009;36(3):354–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Wallace MB, et al. An analysis of multiple staging management strategies for carcinoma of the esophagus: computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy. Ann Thorac Surg. 2002;74(4):1026–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Yasuda, et al. The impact of F-18 FDG PET positive lymph nodes on postoperative recurrence and survival in resectable thoracic esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19:652–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Butof, et al. Prognostic value of pretherapeutic tumor-to-blood standardized uptake ratio in patients with esophageal carcinoma. J Nucl Med. 2015;56(8):1150–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Tixier, et al. Intratumor heterogeneity characterized by textural features on baseline F-18 FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer. J Nucl Med. 2011;52(3):369–78.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lee G, et al. Clinical implication of PET/MR imaging in preoperative esophageal cancer staging: comparison with PET/CT, endoscopic ultrasonography, and CT. J Nucl Med. 2014;55(8):1242–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Gebski, et al. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007;8:226–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Kim MK, Ryu JS, Kim SB, et al. Value of complete metabolic response by F-18-fluorodeoxyglucose-positron emission tomography in oesophageal cancer for prediction of pathologic response and survival after preoperative chemoradiotherapy. Eur J Cancer. 2007;43:1385–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S–50.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMedGoogle Scholar
  33. 33.
    Yanagawa M, et al. Evaluation of response to neoadjuvant chemotherapy for esophageal cancer: PET response criteria in solid tumors versus response evaluation criteria in solid tumors. J Nucl Med. 2012;53(6):872–80.CrossRefPubMedGoogle Scholar
  34. 34.
    Omloo JM, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg. 2007;246:992–1000.CrossRefPubMedGoogle Scholar
  35. 35.
    Mariette C, et al. Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer. 2003;97:1616–23.CrossRefPubMedGoogle Scholar
  36. 36.
    Abate E, et al. Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing. J Am Coll Surg. 2010;210:428–35.CrossRefPubMedGoogle Scholar
  37. 37.
    Goense L, et al. Diagnostic performance of F-18 FDG PET and PET/CT for the detection of recurrent esophageal cancer after treatment with curative intent: a systematic review and meta-analysis. J Nucl Med. 2015;56(7):995–1002.CrossRefPubMedGoogle Scholar
  38. 38.
    Kubota K, et al. Surgical therapy and chemoradiotherapy for postoperative recurrent esophageal cancer. Hepatogastroenterology. 2013;60:1961–5.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Christopher G. Sakellis
    • 1
    • 2
    • 3
    • 4
    • 5
  • Heather A. Jacene
    • 1
    • 2
    • 3
    • 4
    • 5
  • Annick D. Van den Abbeele
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of ImagingDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of RadiologyBrigham and Women’s HospitalBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Center for Biomedical Imaging in OncologyDana-Farber Cancer InstituteBostonUSA
  5. 5.Tumor Imaging Metrics CoreDana-Farber/Harvard Cancer CenterBostonUSA

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