Fluorine-18 fiuorodeoxyglucose (FDG) positron emission tomography (PET) scanning has a well-established role in the diagnosis, initial staging, and restaging of esophageal carcinoma. In this overview, the authors will discuss this role and illustrate the additional value of hybrid PET/computed tomography (CT) imaging as applied to these indications.

Esophageal cancer invades locally, spreads to local lymph nodes, and then metastasizes throughout the body. More than 90% of esophageal cancers are either squamous-cell carcinomas or adenocarcinomas; these histologies have approximately equal occurrences. On rare occasions, other carcinomas, melanomas, leiomyosarcomas, carcinoids, and lymphomas may also occur.1

The esophagus is divided into four regions: cervical, upper thoracic, midthoracic, and lower thoracic. The cervical esophagus begins at the cricopharyngeus muscle at the level of the cricoid cartilage and extends 6 cm to the thoracic inlet. The intrathoracic esophagus extends for another 20 to 25 cm to the gastroesoph-ageal junction. Approximately three quarters of all adenocarcinomas are found in the distal esophagus (Figure 1), whereas squamous cell carcinomas are more evenly distributed between the middle and lower third.1,2

FIGURE 1.
FIGURE 1. A large primary esophageal adenocarcinoma in the mid-lower esophagus, without evidence of metastases to regional lymph nodes or distant sites. Intense uptake is seen in the mid-lower esophagus in the (A) coronal, (B) transaxial, and (C) sagittal views. Intense uptake in the tumor makes it difficult to detect lymph nodes in the vicinity of the tumor. (B) Transaxial positron emission tomography (PET) image shows intense uptake in the lower esophagus as well as normal uptake in the left ventricle. (C) Sagittal PET image shows uptake in the lower esophagus and stomach (arrow). Such an uptake in the stomach can be due to wall contraction; however, it may be difficult to differentiate it from malignancy. High intensity of F-18 fluorodeoxyglucose uptake is seen in the right colon (A), which was proved to be false positive by colonoscopy. The completely normal colonoscopy reinforces the need for caution when interpreting regions of enhanced bowel uptake.

The pathogenesis of esophageal cancer remains unclear. Tobacco and alcohol abuse have a synergistic effect and are very strong risk factors for squamous-cell carcinoma and moderate risk factors for adenocarcinoma.3 Gastroesophageal refiux disease, which is often associated with obesity, promotes the formation of Barrett’s esophagus, which has an annual rate of transformation to esophageal adenocarcinoma of approximately 0.5%.4-6 Radiotherapy to the mediastinum also predisposes patients to both histologic types of esophageal cancer that typically develop ≥10 years after exposure.7

Once cancer develops, it may spread rapidly. Adenocarcinoma often spreads via transverse esophageal penetration, whereas squamous-cell carcinoma tends to spread linearly in a submucosal fashion.8 Lymph node metastasis occurs in 14% to 21% of submucosal cancers (T1 lesions) and 38% to 60% of cancers that invade muscle (T2 lesions).9 Prognosis is best with tumors <5 cm in size, with tumors involving the upper third of the esophagus, and in females younger than 65 years.10 Conversely, weight loss, low Karnofsky performance status, deep ulceration of tumor, sinus tract formation, and fistula formation have all been found to be poor prognostic factors.10

The most common presenting symptoms of esophageal cancer are dysphagia and weight loss. Less common symptoms include odynophagia, cachexia, melena, retrosternal pain, and hoarseness.11 Cancers of the esophagus must involve at least 75% of the circumference before the sensation of food “sticking” or blockage is experienced. At the time of the diagnosis of esophageal cancer, >50% of patients have either unresectable tumors or radiographically visible metastases.9 Because of the poor prognosis for patients with esophageal cancer (Figure 2) and the risks associated with surgical intervention, accurate staging is essential for optimal treatment planning.12

FIGURE 2.
FIGURE 2. Hybrid positron emission tomography (PET)/computed tomography (CT) images showing progression of esophageal squamouscell carcinoma despite therapy. (A) This PET image shows evidence of increased metabolic activity associated with esophageal cancer at the level of the aortic arch. (B) The CT image shows thickening of the esophageal wall (arrow) without evidence of regional lymph node involvement that corresponds to the area of increased metabolic activity. (C) PET scan obtained 2 months later shows increased metabolic activity in the midesophagus, representing progression of the disease despite chemotherapy and radiation therapy. (D) A fused PET/CT image at the same level as (C). Fusion images overlay both physiology and anatomy in one display.

Staging of esophageal cancer

Clinical staging takes into account the amount of disease that is present before treatment and is based on history, physical examination, biopsy, laboratory studies, endoscopic examination, and imaging, such as endoscopic ultrasound (EUS), CT, and PET.

The stage of the disease (Table 1) is defined in terms of the primary tumor invasion into the esophageal and surrounding tissues (T status), the involvement of regional nodes (N status) and the presence of distant metastasis (M status). Because the extent of wall penetration and lymph node metastases are the most important prognosticators of survival, only the depth of penetration is taken into account for the T staging, not the length of the tumor, extent of involved circumference, or degree of lumen narrowing.

TABLE 1. Staging of esophageal cancer by TNM classification

Given the importance of mural invasion, EUS has been a primary means to diagnose and stage esophageal cancer. Using the radial echoendoscope, 360˚ visualization of the layers of esophageal wall is possible, and tumor involvement of adjacent structures, such as the aorta and the trachea, can be assessed.13-15 Further, EUS allows fine-needle aspiration and histologic verification of identified lymph nodes.16,17 A meta-analysis of 27 studies and a review of the literature supports an overall accuracy for EUS of approximately 85% for T staging and 75% for N staging.18,19 Due to limited EUS depth-of-view, however, it would be expected that the utility of EUS in detecting distant metastases other than celiac metastases is low.

In contrast to EUS, CT scanning is excellent for identifying distant metastases in the chest and abdomen. However, CT cannot differentiate the depth of the esophageal wall invasion (T status) or accurately assess regional lymph node disease (N status).20 Hence, CT accurately predicts the T stage in only 70% of cases and N stage in about 50% to 70% of cases.21-23

Positron emission tomography provides a molecular view of the glucose metabolism of esophageal cancer. Both primary squamous-cell carcinoma and adenocarcinoma of the esophagus demonstrate avid FDG uptake, which has been shown to correlate with tumor growth rate.24 Mildly elevated uptake is occasionally seen in the normal esophagus, possibly due to swallowed saliva or smooth muscle contraction. Significant FDG uptake can be seen in the gastric mucosa, which may lower accuracy in detecting tumors of the gastroesophageal junction.25

The principal limitation of FDG-PET is its relatively poor resolution (Figure 3) and reduced sensitivity (24% to 72%) to esophageal wall invasion and local nodal metastases adjacent to the primary tumor.26-28 The accuracy of FDG-PET in the staging of locoregional nodal metastatic disease varies from 24% to 90%, whereas the accuracy of CT in these same patients ranges from 40% to 73%.26-29

FIGURE 3.
FIGURE 3. Positron emission tomography (PET)/computed tomography (CT) scans of moderately differentiated esophageal cancer failing to detect lesions <1 cm. (A) A fused PET/CT image shows diffuse uptake of the radiotracer in the mid- to lower esophagus without evidence of local or distant metastases. (B) Transaxial PET image showing a single metastasis in the right pleura and increased metabolic activity in the esophagus but no evidence of FDG uptake in the lungs. (C) Lung window CT scan showing thickening of the esophageal wall with multiple small pulmonary metastatic nodules throughout both lung fields. The sensitivity of PET is limited for detecting lesions <0.7 cm.

The major advantage of FDG-PET over anatomic imaging modalities is the ability to detect distant metastases (Figure 4).6-9 Distant metastatic disease has a significant impact on patient management because these patients are no longer suitable for surgical resection. In three studies with a total population of 97 patients with esophageal cancer, PET revealed distant metastatic disease that was not seen at conventional imaging in 21 patients (21.6%).26-28 For the evaluation of distant metastases, FDG-PET has a sensitivity of 69% to 100%, a specificity of 84% to 90%, and an accuracy of 84% to 91%.12

FIGURE 4.
FIGURE 4. Positron emission tomography (PET)/computed tomography (CT) scanning of recurrent esophageal adenocarcinoma with bone and visceral metastasis. This patient is status post-esophagectomy with gastric pull-through, followed by chemotherapy and radiation therapy. (A) Coronal PET image shows evidence of tumor recurrence in the mediastinum and metastases to the left shoulder, left chest wall, right adrenal gland, and the iliocecal region. (B) CT scan showing pleural reaction with enlarged lymph nodes and subcarinal fullness and a softtissue mass in the left posterolateral chest wall. (C) A fused PET/CT image shows increased metabolic activity in the subcarinal region, right pleural area, and left posterolateral chest wall.

FDG-PET has proved valuable in determining the resectability of esopha-geal cancer. Kole et al22 prospectively evaluated 26 patients and found the diagnostic accuracies in determining resectability to be 65% for CT, 88% for PET, and 92% for CT and PET together. After esophagectomy, a photopenic defect or region of moderate activity may be noted to the right of the mediastinum that results from the gastric pull-up procedure (Figure 4). Surgery performed 4 weeks before scanning may result in false-positive FDG uptake in areas of active infiammation, hence it is best to evaluate postsurgical patients at least 6 weeks after surgery.

Hybrid PET/CT imaging

Dual-modality PET/CT, or hybrid imaging systems (Figures 2 through figure 9), permit the combined acquisition of functional and morphologic datasets within a single examination. Based on accurate image fusion, FDG-PET/CT further increases staging accuracies for many malignancies when compared with either PET alone, or with PET and CT viewed side by side. Bar-Shalom et al30 found PET/CT to be of additional value over CT alone and PET alone in 49% of patients with different oncologic diseases. In this study, patient management was altered by PET/CT in 14% of patients who had been previously studied with PET and CT alone.30

FIGURE 5.
FIGURE 5. Staging and restaging positron emission tomography (PET)/computed tomography (CT) scans in moderately differentiated lower esophageal adenocarcinoma. Endoscopy showed fungating mass in the distal esophagus. (A) Coronal and (D) transaxial PET images show intense metabolic activity in the lower esophageal region without evidence for metastatic disease elsewhere. (B) Coronal and (E) transaxial PET images show complete resolution of the esophageal tumor 3 months following chemotherapy and radiation therapy. (C) Coronal and (F) transaxial fused PET/CT images show complete resolution of the metabolic activity in the esophagus
FIGURE 6.
FIGURE 6. Biopsy-proven recurrent esophageal adenocarcinoma with good response to combined chemotherapy and radiation. (A) Coronal positron emission tomography (PET) image shows uptake in both the hila and left suprahilar region, with normal uptake in the left ventricle and physiologic uptake in the bowel due to contraction. (B) Follow-up PET scan shows complete resolution of the tumor from the hila and left suprahilar region. (C) Contrast-enhanced computed tomography (CT) image shows gastric pull-through on the right side of the chest with two prevascular lymph nodes, which are not metabolically active on (D) the fused PET/CT image, indicating successful treatment
FIGURE 7.
FIGURE 7. Positron emission tomography (PET)/computed tomography (CT) scan showing disease recurrence following therapy of esophageal adenocarcinoma with widespread metastasis. This patient had chemotherapy and radiation followed 1 year later by esophagectomy. Esophageal cancer can metastasize to almost any organ in the body. (A) Coronal PET image shows evidence for widespread metastases in the left upper cervical region, anterior mediastinum, right adrenal gland, left upper flank, left thigh, supracondylar region of the left femur, left midthoracic paraspinal region, left gluteus medius muscle, right flank muscle, right inguinal region, and right gluteus muscles. (B) Nonenhanced CT scan image shows a mass in the right adrenal gland that corresponds to increased metabolic activity in (C) the fused PET/CT image. (D) CT scan image illustrates metastases in the soft tissues of the right upper thigh, which corresponds to increased metabolic activity (E) on the PET/CT image. (F) CT scan image represents osteoblastic metastasis in the supracondylar region of the left femur, which corresponds to increased metabolic activity on (G) the PET scan.
FIGURE 8.
FIGURE 8. Restaging positron emission tomography (PET)/computed tomography (CT) scan of esophageal adenocarcinoma showing biopsyproven new hepatic lesions with complete resolution of the primary tumor. (A) Coronal PET image shows no evidence of residual esophageal tumor but evidence of metastatic disease in the liver and left gluteus maximus muscle. The primary tumor in the esophagus responded to chemotherapy and radiation therapy but there was no effect on the distant metastases. (B) Contrast-enhanced CT scan of the abdomen faintly delineates the metastases in the liver, which are metabolically active and seen very clearly on (C) the fused PET/CT image. Liver biopsy confirmed an esophageal cancer metastasis. (B) The CT scan shows negative oral contrast in the stomach with normal wall contour. Negative oral contrast (water) is used with IV contrast to delineate the stomach wall and to minimize attenuation artifact on PET imaging. (D) CT image of the pelvis shows evidence of soft-tissue metastasis, which corresponds to increased metabolic activity on (E) the fused PET/CT image
FIGURE 9.
FIGURE 9. Biopsy-proven recurrence of esophageal squamous-cell carcinoma in the neck with no evidence left of the primary tumor. This patient was rendered cured for 2 years until a mass was noted on the left side of the neck. (A) Nonenhanced CT scan of the head and neck shows a large mass in the left posterior triangle (B), which corresponds to a site of increased metabolic activity. Normal uptake is seen at the orbital muscle insertions and nasopharynx. (C) PET/CT fused image show increased metabolic activity in the left posterior triangle.

Differentiation of physiologic FDG uptake from pathologic localization may be very difficult, especially in the abdomen and pelvis. Even a small degree of misregistration may lead to a misinterpretation of physiologic uptake. Several advantages are associated with combined PET/CT imaging compared with retrospective or prospective software-based approaches to align complementary image data. Most importantly, the patient undergoing a combined PET/CT examination is not moved between CT and PET acquisition, thus limiting misalignment from repositioning. Dual-modality PET/ CT systems thus provide intrinsic alignment of PET and CT datasets.

A diagnostic, contrast-enhanced PET/ CT scan can increase the value of the CT study beyond anatomic correlation and attenuation correction for PET. The availability of contrast-enhanced CT data improves confidence to accurately localize a PET-positive lesion in approximately 25% of patients.31,32 CT contrast agents and FDG, therefore, do not compete, but rather complement each other in combined PET/CT imaging.

PET/CT can improve the accuracy of PET imaging in distinguishing recur-rent disease from benign posttherapy changes, delineating the anatomic location of metastatic disease, and monitoring therapy response by solving a myriad of problems inherent in the posttherapy assessment of cancer.33 With the use of the pattern of enhanced metabolic activity to facilitate field definition (Figure 10), PET/CT also promises to improve the accuracy of radiation treatment planning.

FIGURE 10.
FIGURE 10. Utilization of positron emission tomography (PET)/computed tomography (CT) fused images for radiation treatment planning in a patient with moderately differentiated lower esophageal adenocarcinoma. (A) Sagittal view. The blue and orange lines show anteroposterior (AP) and posteroanterior (PA) beams, respectively. The red contour delineates gross target volume (GTV). The green contour encloses region of the esophagus superior to the metabolically active GTV to account for possible microscopic disease. (B) Coronal view. The blue and orange contours represent radiating field by AP and PA beams, respectively. Once again, the red contour represents GTV and the green contour is planned to encompass microscopic disease.

Evaluation of response to therapy

Metabolic imaging allows the detection of biochemical changes within tumor cells as a means to differentiate between responders and non-responders early in the course of therapy follow-up (Figures 2, and figure 5 through figure 9). This aspect is important, because approximately 50% of patients do not respond to currently available chemotherapy regimens. Early determination of nonresponders is of prime importance, given that modifications in therapy regimens may improve patient outcome and reduce unnecessary therapy toxicity.34

In contrast to histopathologic techniques, PET allows noninvasive quantitative assessment of the entire tumor mass. Furthermore, changes in biologic parameters during therapy can be determined easily by serial PET studies. The use of FDG for monitoring cytotoxic therapy is supported by experimental and patient data that show rapid reduction of metabolic activity during chemotherapy.35-38

There is now evidence that FDG-PET is a sensitive and specific method for determining therapy response and for providing important prognostic information for esophageal cancer. In patients with squamous-cell carcinoma of the esophagus, Nakamura et al39 showed a significant difference in FDG median uptake values between patients who failed to respond and those who had a complete response to radiation therapy. The quantitative decrease in FDG uptake seen after neoadjuvant therapy has been correlated with histopathologic assessment of viable tumor cells, time to disease progression, and overall survival.40-42 Weber et al42 reported that metabolic measurements with 18F-FDG–PET allow early differentiation of responders from nonresponders during preoperative chemotherapy. Clinical response was evaluated after 3 months of therapy with endoscopy and anatomic imaging modalities. The reduction of tumor FDG uptake after 14 days of therapy for responding tumors was significantly different from that for nonresponding tumors. FDG-PET predicted therapy response with a sensitivity and a specificity of 93% and 95%, respectively. The mean survival of responders was not reached during the 2-year period, whereas the mean survival for nonresponders was 13 months.42

The metabolic response measured by changes in posttherapy FDG uptake ratios was found to be a stronger prognostic factor for overall survival than was the extent of lymph node involvement determined by pretherapy FDG-PET.43 After neoadjuvant radiotherapy, the decline in FDG uptake can characterize tumor response; however, differentiating partial responders from complete responders can be difficult during or immediately after radiation therapy because of infiammatory changes. In patients who have under- gone recent radiotherapy, 8 to 12 weeks should elapse before an FDG-PET study is done to avoid false-positive findings of radiation-induced esophagitis.44

The accurate spatial localization offered by PET/CT provides an even better assessment of the response to treatment and changes clinical management in up to 30% of cancer patients.45 After therapy, subtle PET findings falsely attributed to physiologic uptake may be correctly identified as residual disease after correlation with simultaneously acquired morphologic data. Alternatively, equivocal CT findings of either recurrent tumor or posttherapy fibrosclerosis now can be distinguished with the help of the additional information provided by FDG-PET data.33

Conclusion

Positron emission tomographic scanning has a well-established role in the diagnosis, initial staging, and restaging of esophageal carcinoma. FDG-PET provides an excellent means to detect distant metastases and has had significant impact on patient management. Hybrid PET/CT can improve the accuracy of PET imaging in distinguishing recurrent disease from benign posttherapy changes, delineating the anatomic location of metastatic disease, and monitoring therapy response. Contrast-enhanced PET/CT can provide fully diagnostic morphologic and functional data in a single session, rendering additional diagnostic CT unnecessary. CT contrast agents and FDG complement each other in combined PET/CT imaging. Finally, there is strong evidence that FDG-PET can determine esophageal cancer therapy response and provide important prognostic information. As the technology of hybrid imaging advances with new positron emitting radiopharmaceuticals and multidetector CT systems, the impact on the diagnosis and management of esophageal cancer will continue to grow.