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Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning.

AIM
To assess the relationship between preoperative computed tomography (CT) and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data.


METHODS
A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy. Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens. Inter- and intra-observer variations in CT measurements were assessed. Survival data were collected.


RESULTS
There was a weak correlation between CT and pathological tumor length (r = 0.30, P = 0.025). CT lengths were longer than pathological lengths in 68% (38/56) of patients with a mean difference of 1.67 cm (95% CI: 1.18-2.97). The mean difference in measurements by two radiologists was 0.39 cm (95% CI: -0.59-1.44). The mean difference between repeat CT measured tumor length (intra-observer variation) were 0.04 cm (95% CI: -0.59-0.66) and 0.47 cm (95% CI: -0.53-1.47). When stratified, patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length (r = 0.69, P = 0.0014, n = 37) than patients that did (r = 0.13, P = 0.43, n = 19). Median survival with CT tumor length > 5.6 cm was poorer than with smaller tumors, but the difference was not statistically significant.


CONCLUSION
Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.


INTRODUCTION
Tumor length is a recognised independent adverse prog nostic factor following surgery or radiotherapy in patients with esophageal cancer [13] . In a study by Griffiths et al [2] , patients with pathological tumor length > 3.5 cm had a poorer prognosis than those with shorter tumors following esophagogastrectomy for cancer. Tumor dimensions, including length, are included in the United Kingdom Royal College of Pathologist's minimum dataset for the histopathological reporting of the disease [4] . As such, its accurate measurement preoperatively would provide essential information for treatment planning and prognosis.
Contrast enhanced computed tomography (CT) is an important aspect of staging patients with esophageal cancer [58] . However, published studies on the relationship between tumor lengths reported on the preoperative CT scan and the corresponding length on the postoperative pathological specimen are inconsistent. Using pathological length as the gold standard and discounting length differences of 1 cm or less, Drudi et al [9] reported 32% concordance between the two measurement types and CT was found to underestimate tumor length. However, Quint et al [10] reported CT generally overestimated tumor length by 1.57.5 cm. This finding was echoed by Gao et al [11] in which 34 patients with middle and distal third esophageal squamous cell carcinoma were found to have longer tumor length on the preoperative CT scans with a mean CT length of 4.48 cm vs mean pathological length of 3.82 cm.
The extent of gross esophageal tumor impacts on the surgeon's choice of operative approach. Also, delineation of gross tumor volume (GTV) for radiotherapy is reliant on a CT scan performed for the purposes of radiotherapy planning, supplemented by information obtained from clinical staging procedures. The clinical target volume (CTV) will encompass the GTV and additional tissue based on pathological extent of subclinical disease from resected surgical series [11] . It is, therefore, essential to ascertain as accurately as possible the gross tumor extent and staging by CT, barium imaging, endoscopy and endoscopic ultrasound (EUS).
The aims of this work were to compare the level of agreement between pathological and CT length of resected esophageal adenocarcinoma and evaluate the implication of any inter and intraobserver variation in CT measurement. We also assessed any association between tumor length and other clinicopathological factors and the degree of contrast distension of the stomach or esophagus. In principle, good visceral distension by contrast agent should help delineate tumor dimensions but whether this plays a role in optimising the accuracy of CT measurement of tumor length is not clear. The study also investigated the prognostic value of tumor length measured preoperatively using CT.

MATERIALS AND METHODS
The study was retrospective and involved 56 patients who underwent esophagogastrectomy for cancer between September 1999 and June 2007 at the University Hospital of South Manchester, UK. There were eight females (14%) and 48 males (86%), and the median age was 65 years (range 3682 years). Sixtysix percent (37/56) of the patients underwent neoadjuvant chemotherapy. In these cases, the post chemotherapy/presurgery scan was used. All tumors were adenocarcinomas of the distal third of the esophagus. Ethical approval for the study was obtained from the South Manchester Research Ethics Committee.

Radiology methods
All 56 patients underwent intravenous and oral contrast enhanced preoperative staging CT scans of the thorax and upper abdomen. The subjects were scanned at several referring hospitals using a variety of scanners. Different oral contrast preparations were utilised: Gastrografin™ based solution in 55 patients and water based, negative oral contrast in one patient. Slice thickness ranged from 410 mm. The CT carried out closest to the time of tumor resection was reviewed in each case. The mean time from the date of scanning to surgery was 37 d (range 1149 d). All images were reviewed on hard copy axial images.
The slices judged to be tumor free superior and inferior to the cancer were identified, allowing a judgement of the craniocaudal extent of the tumor. The maximal esophageal wall thickness, maximal esophageal diameter, esophageal distension, gastric distension and presence of hiatus hernia were all recorded.
The craniocaudal tumor lengths in the immediate preoperative contrast enhanced axial CT images were estimated independently by two radiologists. A senior trainee radiologist assessed the scans of 56 patients and a specialist consultant radiologist assessed 42 of the 56 patients. The CT tumor lengths of a cohort of the patients were subsequently reestimated independently by both radiologists. This allowed evaluation of inter and intra observer variation.

Pathology methods
During the study period, all esophagogastrectomy speci mens from the operating theatres were immersed in formalin and sent to the Department of Histopathology for analysis. On receipt of the specimen, the pathologists inked the circumferential resection margin (CRM). The esophagus was subsequently opened along its longitudinal axis from proximal to distal extending along the greater curvature of the stomach. The opened specimen was then fixed in formalin for at least 24 h.
Information on whether the specimens were pinned or unpinned was not available. The histopathological tumor details of all the patients in the study were obtained from the computed pathology records. Macroscopic parameters were recorded as detailed in the United Kingdom Royal College of Pathologists minimum dataset for the histopathological reporting of esophageal cancer [4] .

Statistical analysis
Statistical analysis was performed using SPSS ® (SPSS, Chicago, Illinois, USA) Version 11.5 and Stata® (StataCorp, 4905 Lakeway Drive, College Station, TX 77845 USA) Version 9.2. Oneway analysis of variance (ANOVA), the MannWhitney or Spearman's tests were used to assess factors associated with tumor length. Agreement between pathological and CT lengths for each radiologist and inter and intraobserver variation was assessed using the Bland Altman plot [12] . Survival was defined as the time from the date of surgery until death or most recent follow up appointment and was analysed using log rank test. A P ≤ 0.05 was considered to be statistically significant.

RESULTS
Tables 1 and 2 summarise the clinicopathological and radiological details of the 56 patients. No significant associations were found between CT or pathology measu rements of tumor length and patients' age, gender, tumor morphology, differentiation, overall histological stage, resection category (complete microscopic clearance vs microscopic evidence of tumor cells at the resection margins), presence of hiatus hernia, slice thickness and the degree of the gastroesophageal contrast distension. However there was a significant correlation between maximal esophageal thickness and tumor length on the CT scan (P = 0.01).
There was a weak positive correlation between CT and pathology measurements of esophageal tumor lengths (r = 0.30, P = 0.02, n = 56). However, the BlandAltman plots in Figure 1 illustrate the generally poor level of agreement between CT measurements of esophageal tumor lengths and their corresponding pathological lengths. In the Bland Altman plot, the difference between the two measurements is plotted against their meanthe best estimate of the true value. If there is good agreement between the methods, then the results would be close to zero. Preoperative CT   The difference between the two measurements was plotted against their mean. The majority of the points fall above and below the zero line showing a weak agreement.
length was longer than postoperative pathology length in 68% (38/56) of the patients with an average tumor length difference of 1.67 cm (95% CI: 1.182.97). The difference in tumor length between CT and pathological measurements was statistically significant (P < 0.0005, n = 56, paired ttest). There was no relationship between the time from CT scan to surgery (median 37 d, range 1149 d) and the difference in CT and pathological tumor length (r = 0.16, P = 0.25).
In order to address whether the poor agreement between CT and pathology measurements of tumor length was due to a poor reliability in obtaining CT data, a second radiologist measured tumor length in 42 of the patients. Qualitatively similar results were found to the first radiologist. There was a weak positive correlation between CT and pathological tumor length (r = 0.20, P = 0.92, n = 42). The average tumor length difference (CT minus pathology) was 1.52 cm (95% CI: 0.622.68), and CT length was longer in 69% (29/42) of the patients (P = 0.006, n = 42, paired ttest). Agreement between the two radiologists was summarised by calculating the mean difference between their measurements ( Figure 2). This analysis shows a small interobserver difference in measurements of tumor length with a mean difference in the measured tumor length between the two radiologists' being 0.39 cm (95% CI: 0.591.44). However, a large spread in the observations was observed, with radiologist 2 measuring one tumor 6 cm shorter and another tumor 7 cm longer than radiologist 1. As this lack of agreement between CT and pathology measurements can be attributed, at least in part, to variability in obtaining CT measurements, an assessment was made of intraindividual variability in measuring tumor length.  Measurements are in cm.  readings by the two radiologists with the corresponding pathological lengths and Figure 3 illustrates the Bland Altman plot for intraobserver variation or repeatability. For radiologist 1 the mean difference between the two scores was 0.04 cm (95% CI: 0.590.66). For radiologist 2, the mean difference was 0.47 cm (95% CI: 0.531.47). The large 95% CIs for both radiologists suggests it is difficult to measure reliably preoperative esophageal tumor length using CT. When patients were stratified into whether they under went neoadjuvant chemotherapy (n = 19) or not (n = 37), a strong correlation was found between preoperative CT and postoperative pathological measurement of tumor length in the latter (r = 0.69, P = 0.001, n = 37) but not the former (r = 0.13, P = 0.43, n = 19). BlandAltman analysis for inter observer variability revealed a smaller mean tumor length difference between the two radiologists and relatively tighter 95% confidence intervals in the group with no neoadjuvant chemotherapy (0.27 cm; 95% CI: 1.051.59) than those who underwent preoperative chemotherapy (0.36 cm ; 95% CI: 1362.08).
The median CT tumor length was 5.6 cm (n = 56). Despite the difficulty in obtaining repeatable CT measurements of tumor length, survival analysis revealed that the patients with tumor length ≤ 5.6 cm (n = 28) and > 5.6 cm (n = 28) had median survival times of 44 mo and 17 mo respectively. Although the survival difference was large it was not statistically significant ( Figure 4).

DISCUSSION
In this study, we found no association between preopera tive contrast enhanced CT defined tumor length and clinicopathological factors. The preoperative cranio caudal axial CT images of esophageal tumor lengths were longer than their corresponding pathological len gths following esophagogastrectomy in approximately twothirds of the patients. In addition, results of CT measurement of tumor lengths estimated independently by the two radiologists showed marked inter and intra observer variability.
The proximal and distal resection margins of various tumor types have been reported to shrink significantly following formalin fixation. Some example are breast [13] , colorectal [14] , esophageal cancers [15] and cervical intra epithelial neoplasia [16] . However, in all such cases, the proportion of size shrinkage attributable to the tumor itself is negligible [1316] ; and in the case of esophageal cancer, Siu et al [15] reported only 8% shrinkage in the formalin fixed specimen compared to tumor length in-vivo. This suggests that longitudinal tumor length measured in formalin fixed resected specimens is comparable to their nonfixed in-situ state.
The tendency for CT to overestimate esophageal tumor length compared to the corresponding pathological length was also reported by Gao et al [11] . They studied 34 patients with middle and distal third esophageal squamous cell carcinoma and found a statistically signi ficant difference between the two measurement types (mean CT length of 4.48 cm vs mean pathological length of 3.82 cm, P < 0.05). This is in keeping with our finding of mean CT and pathological tumor lengths of 5.9 and 4.2 cm respectively. However, in a study of 22 patients, Drudi et al [9] found tumor length on the preoperative CT to be consistently shorter than the corresponding lengths on the resected specimens. The reasons for this finding were not discussed but may be related to observer error, scanning methodology or inadequate tumor delineation by contrast agent.
Although contrast CT was found to generally over estimate esophageal tumor length, the difference with pathological tumor length measurement was less marked in the cohort of patients who did not undergo neoadjuvant chemotherapy. In contrast, the correlation coefficient and interobserver agreement were both weaker in the group of patients who had neoadjuvant chemotherapy. This finding illustrates the inherent unreliability of contrast CT in assessing tumor length particularly following preo perative chemotherapy.
A number of studies have highlighted the deficiencies of CT in assessing the extent of post chemotherapy esophageal tumor bulk regression. In these studies, the radiological response rates were significantly lower than the pathological response rate to chemotherapy resulting in an apparent upward tumor stage migration [1720] . This in part is due to chemotherapy associated inflammatory and fibrotic changes [17] .
Several factors might contribute to the differences in tumor lengths obtained using the two approaches. Such factors include the difficulty in distinguishing tumor from mural thickening resulting from peritumor fibrosis, edema and gastric folds at the gastroesophageal junction by CT [17,21,22] . Other possible factors contributing to dis parity between CT and pathological tumor lengths are suboptimal coating of the mucosa by contrast agent [23] , movement artefacts during the scanning process such as the respiratory or cardiac cycle [24,25] and difficulty in determining the macroscopic proximal and distal limits of the tumor radiologically. Some of these factors might also   contribute to the intraobserver variability in measuring tumor length using CT. An important implication of this study is the selection of patients for appropriate treatment. Surgical data have shown that longer tumors are associated with increasing Tstage, nodal metastasis, worse overall TNM stage and increased tumor involvement of the resection margins [2] . In addition to selection for treatment and staging, CT is also routinely used as part of the radiotherapy planning process but protocols usually do not include the use of oral contrast medium. As larger radiation treatment volumes are associated with higher radiation doses to normal tissues such as the lungs [2630] resulting in a higher incidence of treatment related morbidity and a poor therapeutic index, radiation therapy protocols usually exclude patients with longer tumor lengths (> 710 cm) from receiving radical radiotherapy. Since overestimation of in vivo tumor length has been commonly observed in our study, we would urge caution in excluding patients from radical radiotherapy treatment on the basis of CT findings alone. It is recommended that determination of treatment intent and target delineation of esophageal tumors during radiotherapy planning should be based on at least a further modality in addition to CT scanning as in the SCOPE (Study of Chemoradiotherapy in Oesophageal cancer Plus or Minus Erbitux) clinical trial, currently recruiting in the UK. In the SCOPE study, where patients with a total tumor length greater than 10 cm are excluded from radical treatment, an endoscopic ultrasound (EUS) is required in addition to CT for determination of tumor length [31] . This stems from the observation that EUS more accurately measures esophageal tumor length and this imaging modality has been investigated in a number of studies [32,33] .
Target definition during radiotherapy planning must be not only precise but also reliable and reproducible to avoid a geographical tumor miss and minimise the volume of normal tissue irradiated. Accurate target definition would also allow radiation doseescalation studies to be carried out which may potentially improve clinical outcome. In a transCanada study in which 58 radiation oncologists were independently asked to determine the craniocaudal length and CTV of esophageal tumors using CT images, Tai et al [34] found significant inter observer variations in the target volume dimensions and also reported low longitudinal overlap of the CTV among the oncologists. They went on to show that specific training of oncologists could reduce the variations seen [35] . Our study echoes the implications of this finding in that imprecise target definition, as evidenced here by marked inter and intraobserver variability of tumor length, may reduce the potential benefits of threedimensional radiotherapy planning and high precision radiation dose delivery. A multidisciplinary approach in target delineation with close cooperation between the radiation oncologist and specialist gastrointestinal CT radiologists may be helpful in this context. Importantly, the use of positron emission tomography in combination with CT (PETCT) in this setting could potentially ameliorate some of the limitations of CT alone, such as distinguishing a metabolically active tumor from peritumor edema, fibrosis and normal gastric rugal folds adjacent to subcardial tumors [3638] . However, as PET acquisition is over several minutes, the tumor extent seen on PET images will include the tumor motion due to movement and patient breathing during the period, in contrast to helical or multidetector CT scans, which are acquired in a few seconds. Methods such as gating of PET images may be helpful in this context.
Finally, survival analysis revealed that patients with CT tumor length ≤ 5.6 cm had a median survival of 44 mo compared with 17 mo for those with tumor lengths > 5.6 cm (P = 0.22). This finding, albeit based on a small number of preoperative CT length measurements, concurs with published work indicating that patients with tumor length > 3.5 cm recorded from the postoperative pathological specimen have a worse prognosis [2] . The failure of our survival analysis to achieve statistical significance may be related to the small number of patients studied. However, the marked survival time difference between the two groups of patients (17 mo vs 44 mo) suggests that accurate measurement of tumor length on the preoperative CT scan in a bigger series could provide useful prognostic information. A sample size of approximately 100 in each arm would be required to have 80% power to detect a difference in survival using the logrank test with a 50% and 70% survival after 12 mo (assuming a constant hazard ratio of 1.9 and a conventional significance level of 0.05).
The strength of this study lies in its relatively large number of patients compared with other series, the involvement of specialist radiologists to measure tumor length and establishing, in an objective way, intra and interobserver variability in the radiological reporting of esophageal tumor length. The two key limitations lie in its retrospective nature and the lack of softcopy review of scans performed on a variety of scanners in referring district general hospitals. Only axial images were reviewed and many were performed on single slice scanners (11 of 56 patients). Where scans were performed on multislice scanners, only hard copy axial images were available for review from the referring hospitals.

CONCLUSION
This study suggests that staging CT assessments generally overestimate macroscopic esophageal tumor length parti cularly when tumor length is assessed following neoad juvant chemotherapy. CT measurements of tumor length can not, therefore, act as a surrogate for pathological measurement. The limitation of CT should be considered when it is used for staging, in the selection of treatment and in radiotherapy planning. In particular, inter and intraobserver variability in CT reporting of esophageal tumor length may result in inappropriate radiotherapy target volume delineation if based on CT scan data alone. Consequently, decisions on whether patients should have palliative or curative radiotherapy may need to be revised. The situation may be ameliorated by supporting information on tumor length provided by complementary modalities and close multidisciplinary collaboration between clinical oncologists, surgeons and radiologists with specialist interest in esophageal cancer.

Background
Tumor length is a recognised predictor of survival in resected esophageal cancer. Studies have shown that patients with longer tumors in the resected specimens have a worse prognosis than those with shorter ones; and this is independent of advanced T-stage, lymph node metastasis and resection margin involvement with cancer cells. Consequently, accurate measurement of tumor length prior to surgery using standard imaging modalities such as computed tomography (CT) may potentially serve two purposes. First, it would provide additional prognostic information prior to surgery. Second, it would enable oncologists to more accurately calculate tumor target volumes for radiotherapy delivery. This study looked at the correlation between esophageal tumor length measured on the preoperative CT scan and the length on the postoperative pathological length (considered the gold standard).

Research frontiers
CT is widely used to stage esophageal cancer. It is also used by radiation oncologists to determine tumor dimensions including tumor length for radiotherapy planning. The research hot spot, therefore, is to investigate the accuracy of CT in determining tumor length and factors that influence the accuracy.

Innovations and breakthroughs
Previous studies correlating tumor length measured using CT (CT tumor length) and on resected specimen (pathological tumor length) did not evaluate interand intra-observer variability. In this study, CT tumor lengths were measured independently by two radiologists and each radiologist measured the same tumor on two different occasions. The key findings were: (1) CT measurements of tumor length are longer than those obtained from pathology specimens, even after allowing for an effect of formalin fixation; and (2) there is a weak correlation between measurements obtained by two radiologists and repeat measurements made by the same radiologist on the same CT image, i.e. inter-and intra-observer variability hampers accurate measurements of esophageal tumor length.

Applications
The study has a number of implications. First, the work highlights the need for a review of the indications for palliative radiotherapy. This study suggests that CT tends to over-estimate the true length of esophageal tumors. In some centres, if the CT tumor length is longer than 7-10 cm, patients are considered unsuitable for radiotherapy with curative intent. Such patients might be incorrectly managed with palliative intent. Second, the high inter-and intra-observer variations in measuring tumor length using CT suggest that in some cases tumor will be excluded from the radiotherapy field-reducing the probability of local control. Third, in most cases CT over-estimation of esophageal tumor length would lead to larger volumes irradiated than required, which would increase the risk of radiation injury to important adjacent organs such as the heart and the lungs.

Terminology
GTV or the gross tumor volume is the volume of tumor that can be seen on imaging (CT scan) or is visible (by endoscopy etc. ) or can be felt. This is the demonstrable extent and location of the malignant growth. CTV or the clinical target volume is the gross tumor volume plus a margin allowing for microscopic spread of the disease.

Peer review
This is a retrospective study in which the authors investigated the correlation between CT and pathology measurements of esophageal tumor length. All tumors were adenocarcinoma of the distal third of the esophagus. In about two-thirds of the cases, the esophageal tumor lengths measured from CT images were longer than measurements made on the resected specimen.