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Positron Emission Tomography: Another Useful Test for Staging Esophageal Cancer

Columbia University College of Physicians and Surgeons New York, NY

LOCATION, LOCATION, location—in evaluating real estate, the word is usually repeated three times to emphasize its importance. Location also continues to be the key factor in defining the prognosis and guiding the management of esophageal cancer. The three locations in this case are T (primary tumor depth of invasion), N (regional lymph node metastases), and M (distant metastases), as codified in the almost identical staging systems of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).^1,2 At the present time, there is no biochemical test or molecular marker that has proven equal to the tumor-node-metastasis description of the anatomical extent of disease for esophageal cancer staging.

No distinction is made in the AJCC and UICC classifications between the pathologic stage (the gold standard) and the clinical stage. Attempting to stage esophageal cancer using clinical tests with an accuracy rate approaching the pathology standard has proven to be a difficult and expensive enterprise. The usual clinical tools of physical examination, blood tests, and chest x-rays remain important but are of limited value. The burden of staging esophageal cancer has fallen on modern imaging methods. As imaging methods have continued to improve, clinical staging has become increasingly effective but often falls short of pathologic perfection.

In this issue of the Journal of Clinical Oncology, Flamen et al³ report results on the use of positron emission tomography (PET) scans using the radiolabeled glucose analog 18-F-fluoro-deoxy-D-glucose (FDG) for esophageal cancer staging. The test is different from the strictly structural information obtained from other imaging studies and seems related to the increased transport and metabolism of glucose in some tumors, including esophageal cancer. The data seem honestly convincing that PET is a useful test, and Flamen et al also carefully evaluated PET in the context of the other major staging modalities, helical (spiral) computed tomography (CT) and endoscopic ultrasonography (EUS).^4,5 The questions posed by the clinician are as follows: what is to be gained by using PET for esophageal cancer staging, when should it be used, and can it replace either CT, EUS, or both?

CT of the chest and abdomen is pretty much everybody’s first test for staging esophageal cancer. Magnetic resonance imaging, in most cases, seems to add little if anything to the staging information that can be obtained using CT. Furthermore, CT is widely available in the United States, and CT body imaging has been the best test for the detection of distant metastatic disease (M1, stage IV). The presence of stage IV disease precludes the use of radical surgery and usually is an indication for a palliative approach to management.^6,7

If a CT scan is negative for distant metastases (M0), then EUS is often used as the next step for the most accurate locoregional staging. EUS uses endoscopy-guided high frequency ultrasound transducers inside the esophageal lumen to produce detailed images of the esophageal wall and structures close to the esophagus. At the usual ultrasound frequencies of 7.5 MHz, structures up to approximately 5 cm from the esophagus can be imaged. Higher frequencies produce more detailed images, but with a more limited field.⁸

The great advantage of EUS for staging is the ability to image distinct wall layers with histologic correlates. EUS at 7.5 MHz or 12 MHz produces a five-layer image of the esophageal wall: the first layer corresponds to the boundary echo and superficial mucosa, the second layer to the mucosa (including the muscularis mucosae), the third layer to the submucosa, the fourth layer to the muscularis propria, and the fifth layer to the adventitia. Primary esophageal cancer is usually imaged as a hypoechoic disruption of the wall layers. The EUS wall images are highly compatible with the AJCC/UICC classification for T, depth of esophageal cancer invasion.

EUS has consistently outperformed CT and magnetic resonance imaging for locoregional staging of esophageal cancer. Even the new faster scanners and helical CT do not image the esophageal wall as a series of layers. It has become clear that staging the depth of tumor invasion on the basis of wall thickness and contour is open to frequent error. The thickness of the normal esophageal wall is variable because of its distensibility, and the presence of hiatal hernia compounds the difficulty in the distal esophagus even with oral contrast agents.

Lymph nodes greater than 8 to 10 mm in diameter on CT are generally considered to be metastatic. Similar measurements have been used to assess lymph nodes on EUS, but additional EUS criteria for malignancy are nodes that are uniformly hypoechoic, sharply demarcated from surrounding fat, and rounded. Benign nodes, particularly in the mediastinum, may be greater than 10 mm but are often elongated with distinct cortical and medullary areas and are more hyperechoic with less distinct borders. These are subjective criteria and prone to greater diagnostic error than the depth of tumor invasion.

Based on sizable accumulated data, the accuracy of EUS for staging depth of tumor invasion (T) is 85% compared with surgical pathology, and for staging regional lymph node metastases (N) the accuracy is 75%.^8,9 The lower accuracy for N relates to the difficulty in distinguishing benign from malignant nodes. EUS with its limited depth of field is not generally useful for staging distant metastases (M) except for celiac axis lymph nodes. Because locoregional staging has little importance if distant metastases are present, CT scan should be the initial staging test. In patients with esophageal cancer, the combination of CT and EUS has been reported to have an overall stage accuracy in the range of 85%.^8,9 Flamen et al³ did not achieve that degree of accuracy in their current study but admittedly introduced some bias associated with patient selection.

What would PET scanning add to staging accuracy? Flamen et al³ present convincing data that PET significantly improves the detection of distant lymph node and organ metastases (stage IV). In the United States, most patients present with the symptoms of dysphagia and weight loss, indicating the presence of advanced locoregional disease, usually stage IIB or III.¹⁰ One treatment option for these patients is to undertake aggressive multimodality therapy, including esophagectomy. This is not appropriate for patients with stage IV disease, and PET should be useful in this situation to help exclude patients with stage IV disease from this type of management.

Because current PET scans can produce false-negative results, PET cannot replace CT of the chest and abdomen at this point. PET can also produce false positive findings, and biopsy, cytology, or at least radiologic confirmation of positive areas on PET scans should be obtained if possible. The problem for all imaging modalities is detecting very small foci of cancer in lymph nodes or other distant sites and in differentiating enlarged lymph nodes that are reactive or inflammatory from those replaced by metastatic disease.

Some surgical investigators have suggested that thoracoscopy and laparoscopy should be routinely used for maximum accuracy in esophageal cancer staging, but there is significant morbidity and expense associated with these procedures. Their use might be more appropriately limited to confirm positive findings on CT and PET scans. EUS-guided fine-needle aspiration for cytology can be carried out with relative ease and has an accuracy in the 90% range, and this procedure should also be a consideration when tissue confirmation is needed.¹¹

PET scan also cannot replace EUS staging for depth of tumor invasion. EUS is increasingly available in the United States, and new thinner EUS probes, some wire-guided, can traverse almost any malignant stricture to stage the entire tumor. It has been reported that surgical management alone offers little benefit if EUS shows invasion of adjacent structures or organs (T4).¹²

A striking change in the epidemiology of esophageal cancer has occurred in the United States and other Western countries during the past 30 years. The incidence of squamous cell cancer has decreased, and the incidence of adenocarcinoma of the esophagus and esophagogastric junction has dramatically increased.¹³ Squamous cell cancers have largely been attributed to alcohol and tobacco use, whereas esophageal adenocarcinomas are strongly associated with gastroesophageal reflux disease and Barrett’s esophagus.

Endoscopic surveillance of Barrett’s esophagus is widely practiced in the United States, and an increasing number of patients are being diagnosed with high-grade dysplasia and early-stage cancer.¹⁴ Accurate staging is important in these patients, because the depth of tumor invasion is correlated with the probability of regional lymph node metastases. New high-frequency (up to 30 MHz) EUS probes can be used to distinguish disease involving the mucosa (T1m) with a less than 10% risk of nodal metastases from cancer penetrating the submucosa (T1sm), where the risk of nodal disease increases to the 40% to 50% range. Optical coherence tomography, capable of imaging with 10-µm resolution, is a new endoscopic tool that has the potential to be even more accurate for this purpose.¹⁵

Earlier diagnosis, new drugs, and new treatment combinations are beginning to have an impact on the pervasive therapeutic nihilism associated with esophageal cancer. Stage-directed therapy offers a rational approach to management. Accurate staging of esophageal cancer is also critical to new clinical trials, so that the treatment groups can be demonstrated to be comparable or appropriately stratified. As shown by Flamen et al,³ PET is a noninvasive method that improves detection of distant metastases and regional nodal metastases. Technical advances will no doubt ensue. At this time, PET cannot replace either CT or EUS, but PET has clearly emerged as another useful test for esophageal cancer staging.

REFERENCES

1. Beahrs OH, Henson DE, Hutter RVP, et al: American Joint Committee on Cancer: Manual for Staging of Cancer (ed 3). Philadelphia, PA, JB Lippincott, 1998, pp 63-67

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3. Flamen P, Lerut A, Van Cutsem E, et al: Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 18: 3202-3210, 2000[Abstract/Free Full Text]

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5. Thompson WM, Halvorsen RA Jr: Staging of esophageal carcinoma: II. CT and MRI. Semin Oncol 21: 447-452, 1994[Medline]

6. Clark GW, Peters JH, Ireland AP, et al: Nodal metastasis and sites of recurrence after en bloc esophagectomy of adenocarcinoma. Ann Thorac Surg 58: 646-654, 1994[Abstract]

7. Hölscher AH, Bollschweiler E, Bumm R, et al: Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma of the esophagus. Surgery 118: 845-855, 1995[Medline]

8. Rösch T: Endosonographic staging of esophageal cancer: A review of literature results. Gastrointest Endosc Clin N Am 5: 537-547, 1995[Medline]

9. Dancygier H, Lightdale CJ (eds): Endoscopic Sonography in Gastroenterology. Stuttgart, Germany, Thieme, 1999

10. Lightdale CJ: Esophageal cancer: Practice guidelines. Am J Gastroenterol 94: 20-29, 1999[Medline]

11. Chang KJ, Katz KD, Durbin TE, et al: Endoscopic ultrasound-guided fine-needle aspiration. Gastrointest Endosc 40: 694-699, 1994[Medline]

12. Chak A, Canto M, Gerdes H, et al: Prognosis of esophageal cancers preoperatively staged to be locally invasive (T4) by endoscopic ultrasound (EUS): A multicenter retrospective cohort study. Gastrointest Endosc 42: 501-506, 1995[Medline]

13. Lagergren J, Bergstrom R, Lindgren A, et al: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340: 825-831, 1999[Abstract/Free Full Text]

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15. Tearney G, Brezinski M, Bouma B, et al: In vivo endoscopic optical biopsy with optical coherence tomography. Science 276: 2037-2039, 1997[Abstract/Free Full Text]

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