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23
Staging for Esophageal Cancer: Positron Emission Tomography, Endoscopic
Ultrasonography
Jarmo A. Salo
metabolism in malignant tumors using a posi- tron camera.6 The sensitivity of PET in detecting primary esophageal carcinoma is high (level of evidence 2−).7 Secondary primary neoplasms can sometimes also be diagnosed with PET.
PET does, however, have a low sensitivity in the diagnosis of small-volume tumors and metasta- ses. Cancer T status, small metastatic lesions in locoregional lymph nodes, and intra-abdominal carcinomatosis are diffi cult to diagnose (level of evidence 2+ to 2−).8–11 These diagnostic limita- tions are partially due to the spatial resolution of PET, which is only 6mm. However, spatial resolu- tion is not the sole limitation of PET because tumors of up to 30mm (mean diameter, 13.5mm) can occasionally go undetected.8,9 Thus, the primary indication for PET is not diagnosis of esophageal cancers, especially small-volume carcinomas.
The sensitivity of PET in diagnosing loco- regional metastases is only 51% and the specifi c- ity is 84% (level of evidence 1−).12 Therefore, PET is unsuitable for detecting loco-regional lymph node metastases (level of evidence 2−).11 In fact, PET is inferior to EUS in this regard (level of evidence 2+).8 PET’s sensitivity and specifi city in diagnosing distant lymph node metastases and hematogenous metastases are 67% and 97%, respectively.11,12 Metastatic sites missed by PET are usually less than 1cm in diameter.11 In addi- tion, peritoneal carcinomatosis is diffi cult to diagnose with this technique.8 The accuracy of PET may be improved by the use of combined PET and computed tomography (CT; level of Survival rates in esophageal cancer are closely
related to the stage of the disease at the beginning of treatment and the completeness of surgical R0 resection. Preoperative staging is reasonable only if it allows selection between different treatment options. Accurate pretreatment staging is critical for optimal choice of treatment. Today’s stage- adjusted treatment of advanced esophageal can- cers requires a meticulous diagnostic workup.
Multimodal therapy may improve the outcome even in more advanced cases.1–3 Hence, the exact role of positron emission tomography (PET) and endoscopic ultrasonography (EUS) in restaging after neoadjuvant treatment needs to be deter- mined. In esophageal cancer, EUS represents the gold standard for T staging, crucial when less radical approaches, such as endoscopic mucosa resection or limited resection for early carci- noma, are considered.4,5 Positron emission tomography is a promising new method based on changes in the glucose metabolism of cancer tissue. However, any advantage offered by PET in the staging of esophageal cancer is unclear, and its supplemental value in the routine clinical pre- operative workup of esophageal cancer patients is unknown.
23.1. Positron Emission Tomography
Positron emission tomography is based on accu- mulation of fl uorinated glucose analog (F-18 fl uo- rodeoxyglucose) in malignant cells.6 The method provides a means of detecting altered tissue
evidence 2−).13 Only a few studies have investi- gated the ability of PET to diagnose cancer recur- rence. In one report, PET gave additional information in 27% of cases (level of evidence 2+).14
The limitations of PET in detecting small car- cinomas can, however, offer benefi ts in clinical practice. Patients with PET-detectable primary tumors are mostly unsuitable candidates for modern, less radical surgical approaches such as endoscopic mucosa resection or limited resec- tion. Adding PET to standard staging improves detection of stage IV esophageal cancer, which is associated with poor survival (level of evidence 2−).9–11,15,16 However, the modest sensitivity for distant lymph node metastases and the false- positive judgment of cervical and supraclavicular nodes must be taken into consideration. Positive PET fi ndings in distant lymph nodes should be verifi ed by histology or cytology before making a diagnosis of inoperability.8,9
23.2. PET in Restaging after Neoadjuvant Therapy
Positon emission tomography is a promising noninvasive tool for the assessment and predic- tion of pathological response in locally advanced esophageal cancer after neoadjuvant treatment.17 The pathological response of an initially highly metabolic tumor correlates with the metabolic response in PET and provides additional infor- mation about the effect of treatment (level of evidence 2−).18,19 In addition, the standardized uptake value of F-18 fl uorodeoxyglucose may be used to predict tumor resectability (level of evi- dence 2+).20 In a systematic review of the litera- ture, PET and EUS offered an equally high accuracy after neoadjuvant treatment, but EUS was not always feasible (level of evidence 2+).21 In restaging patients after neoadjuvant therapy, PET/CT may be more accurate than EUS-assisted fi ne needle aspiration (level of evidence 2−).22
23.3. Endoscopic Ultrasonography
Endoscropic ultrasonography provides a 360º view of all fi ve to nine layers (depending on the feature of the probe) of the esophageal wall and
paraesophageal tissues. Endoscopic ultrasonog- raphy is an effective method for detecting inva- sion depth of esophageal cancer and represents the gold standard for T staging (level of evidence 2−).23–27 The accuracy of EUS in T staging ranges from 63% to 90%,11,21,25,26,28 therefore being better than that of CT scans.26 The EUS probes used and the depth of the tumor infi ltration infl uence the accuracy, which is best in T4 tumors and worst in T1 and T2 tumors (level of evidence 2− to 1−).25,26,29 The low accuracy achieved by standard lower-frequency ultrasound endoscopes in dif- ferentiating T1 (mucosal and submucosal cancer) and T2 may be increased to more than 90% with high-frequency ultrasound probes (level of evi- dence 2−).30–32 This is very important when endo- scopic mucosal resections or limited surgery are being considered. Although high-frequency miniprobes allow better superfi cial visualization, their drawback is limited depth of penetration.
Evaluation of N stage should therefore be per- formed with conventional EUS (level of evidence 2−).33 Overstaging is usually more common than understaging in EUS.25 The most important weakness of EUS in investigating a malignant ste- nosis is that the large probe (dip diameter, 12–
13mm) often cannot pass the tumor. In cases such as this, the accuracy is only half of that of traversable tumors (level of evidence 2−).34 In addition, the evaluation of tracheal or bronchial infi ltration is problematic due to air causing refl ection of the ultrasonic waves.
The EUS procedure is based on the diameter, form, and echoic pattern being different in malig- nant and benign lymph nodes. Metastatic lymph nodes are typically larger than 10mm in diameter and have a round shape, sharp borders, and a uniform hypoechogenicity.35 When all four of these characteristics are present, the accuracy of nodal involvement is supposed to be nearly 100%
(level of evidence 2−).36 However, the diagnostic accuracy of these fi ndings is usually less than 80% (level of evidence 2− to 2+).37,38 The reported higher accuracies of lymph node staging origi- nate from studies including greatly advanced carcinomas with lymph node metastasis.
The loco-regional N staging can be improved (accuracy, sensitivity, and specifi city >90%) by transmural EUS-assisted fi ne needle puncture cytology (level of evidence 2+).39 In the diagnosis
of distant metastases especially, the ability to confi rm malignant involvement of celiac axis lymph nodes (M1 disease) is important (level of evidence 2−).40 In distant metastasis outside the celiac axis, the role of EUS is rather limited.
23.4. EUS in Restaging after Neoadjuvant Treatment
Restaging of esophageal cancer with EUS after neoadjuvant treatment is often diffi cult because scars and infl ammation cannot be distinguished from the primary tumor. Volume reduction of the tumor may be present but is not distinguishable with EUS. This leads to overstaging as well as to understaging because microscopic foci of resid- ual tumor within the esophageal wall are common. After neoadjuvant treatment, the T- stage accuracy with EUS has been found to vary from 27% to 73% and the N-stage accuracy from 38% to 71% (level of evidence 2− to 2+).41–43 Recently, the proportion of reduction of maximal tumor thickness exceeding 30% with EUS was reported to correctly predict 94% of responders (level of evidence 2−).44 The postoperative detec- tion of local tumor recurrence by EUS is also diffi cult because of anatomical changes and scars.
23.5. Summary
The sensitivity of PET in detecting primary esophageal carcinoma is high. Positron emission tomography has, however, a low sensitivity in the diagnosis of small-volume (less than 5mm in diameter) tumors, metastases, and intra-abdom- inal carcinomatosis. Therefore, PET is unsuitable for detecting loco-regional lymph node metasta- ses and is inferior to EUS for this purpose (level of evidence 2− to 1−; recommendation grade B).
PET’s sensitivity and specifi city in diagnosing distant lymph node metastases and hematoge- nous metastases are 67% and 97%, respectively.
Adding PET to standard staging improves detec- tion of stage IV esophageal cancer, which is associated with poor survival (level of evidence 2−; recommendation grade C).
Endoscopic ultrasonography is an effective method for detecting invasion depth of esopha- geal cancer and represents the gold standard for T staging. The accuracy of EUS in T staging ranges from 63% to 90%, therefore being better than that of CT scans (level of evidence 2−; rec- ommendation grade C). The most important weakness of EUS in investigating a malignant ste- nosis is that the large probe (tip diameter, 12–
13mm) often cannot pass the tumor. In restaging patients after neoadjuvant therapy the T-stage accuracy with EUS has been found to vary from 27% to 73% and the N-stage accuracy from 38%
to 71%. In restaging patients after neoadjuvant therapy, PET/CT may be more accurate than EUS-assisted fi ne needle aspiration (level of evi- dence 2−; recommendation grade C).
Positron emission tompgraphy is unsuitable for detecting loco-regional lymph node metas- tases and is inferior to EUS for this purpose (level of evidence 1− to 2−; recommendation grade B).
Adding PET to standard staging improves detection of stage IV esophageal cancer, which is associated with poor survival (level of evi- dence 2−; recommendation grade C).
Endoscopic ultrasonography is an effective method for detecting invasion depth of esoph- ageal cancer and represents the gold standard for T staging (level of evidence 2−; recommen- dation grade C).
In restaging patients after neoadjuvant therapy, PET/CT is more accurate than EUS- assisted fi ne needle aspiration (level of evi- dence 2−; recommendation grade C).
23.6. Personal View
In routine clinical practice, EUS is an essential tool in planning treatment strategy for most patients with esophageal cancer. Ascertaining the exact T stage of the tumor with mucosal or submucosal infi ltration is important before deciding the extent of resection (mucosal or limited resection, or radical surgery with lymph- adenectomy). Endoscopic ultrasonography is
more suitable than PET in diagnosing metastatic loco-regional lymph nodes, fi ndings of which indicate consideration of neoadjuvant treatment.
Use of EUS is not advisable in the diagnosis of distant metastasis, in restaging after neoadjuvant therapy, or in postoperative situations.
Today, we use PET in preoperative staging of most patients with esophageal cancer despite not knowing its actual value in preventing unneces- sary resections or its cost effectiveness. Positron emission tompgraphy does help to diagnose inoperative stage IV cancer and should thus be performed at least in patients with operative risk factors. On the other hand, positive fi ndings in PET suggesting distant metastases in operable patients should be confi rmed by cytology or his- tology, particularly in cases where CT and EUS have negative fi ndings. In restaging after neoad- juvant treatment, in spite of a few sound studies, PET is not yet used to discriminate between responders and nonresponders because of the lack of standardization in cutoff values.
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