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1638
Positron Emission Tomography of Esophageal
Carcinoma Using 11C-Choline and
18
F-Fluorodeoxyglucose
A Novel Method of Preoperative Lymph Node Staging
Oichiro Kobori, M.D.1
Yujiro Kirihara, M.D.1
Noboru Kosaka, M.D.2
Toshihiko Hara, M.D.2
1
Department of Surgery, International Medical
Center of Japan, Tokyo, Japan.
2
Department of Radiology, International Medical
Center of Japan, Tokyo, Japan.
BACKGROUND. Accurate preoperative staging is an important but difficult problem
in determining therapy for patients with esophageal carcinoma. Positron emission
tomography (PET) is used with [methyl-11C]choline (11C-choline) and 2-[18F]fluoro-2deoxy-D-glucose (18F-FDG) to detect a variety of malignancies. The authors used
PET with both of these agents to detect lymph node metastases in patients with
esophageal carcinoma.
METHODS. Lymph node metastases in 33 patients with biopsy-proven esophageal
carcinoma (16 patients with tumors classified as T1 and 17 patients with tumors
classified as T2– 4) was examined by PET using 11C-choline and 18F-FDG, and the
accuracy of the results was correlated with pathology findings after surgery.
RESULTS. 11C-choline PET was more effective than 18F-FDG PET and computed
tomography (CT) in detecting very small metastases localized in the mediastinum.
It was ineffective, however, in detecting metastases localized in the upper abdomen, because of the normal uptake of 11C-choline in the liver. 18F-FDG PET was
superior to CT in detecting metastases in the mediastinum and the upper abdomen, whereas 11C-choline PET was superior to 18F-FDG PET in detecting metastases in the mediastinum. When 11C-choline PET and 18F-FDG PET were used in
combination, they were very effective in evaluating the lymph node status in both
the mediastinum and the upper abdomen, and detected 85% of the metastatic
lymph nodes (n 5 46).
CONCLUSIONS. In this study, the combination of 11C-choline PET and 18F-FDG PET
was very effective in evaluating the lymph node status of patients with esophageal
carcinoma preoperatively. Cancer 1999;86:1638 – 48.
© 1999 American Cancer Society.
KEYWORDS: esophagus, carcinoma, diagnosis, staging, lymph node, positron emission tomography, 11C-choline, 18F-fluorodeoxyglucose.
Supported in part by the Science and Technology
Agency of Japan and the Japanese Smoking Research Foundation.
Address for reprints: Toshihiko Hara, M.D., Department of Radiology, International Medical Center of
Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162,
Japan.
Received November 23, 1998; revision received
June 1, 1999; accepted June 1, 1999.
© 1999 American Cancer Society
T
he chance of finding esophageal carcinoma at an early stage is
increasing as the result of remarkable progress both in endoscopic
technology and medical industries. Once it is found and treatment is
considered, the next step is a survey of lymph node metastases.
Recently, a cooperative study of 1740 patients with superficial esophageal carcinoma (T1 tumor) in which we are participating has elucidated that lymph node metastasis starts to increase as the tumor
advances to the layer of lamina muscularis mucosae, a thin layer
between the mucosa and the submucosa (unpublished data). This
and other studies1– 4 are indicating that lymph node metastases are
not rare events with the T1 tumor. The presence or absence of
PET of Esophageal Carcinoma with Choline and FDG/Kobori et al.
metastases determines the mode of surgical procedure. If there are no metastases, then endoscopic
mucosal resection or esophagectomy without thoracotomy (i.e., transhiatal esophagectomy) are the treatments of choice. If there are any lymph node metastases, then esophagectomy with thoracotomy is the
most justifiable treatment, but serious complications
may ensue postoperatively.
Endosonographic examination is imperfect in
evaluating lymph node metastases of esophageal carcinoma,5–12 although it is useful in estimating the
depth of invasion. Other noninvasive methods, including computed tomography (CT), are inaccurate in
detecting lymph node metastases. Although thoracoscopic and laparoscopic examination seem to be the
most reliable procedures for estimating lymph node
metastases, they are invasive. Postoperative pathologic examination is still the gold standard for the
staging of lymph node status.
Positron emission tomography (PET) is a noninvasive imaging technique that can be used to identify
focal areas of increased metabolism associated with
malignancies. Primary tumor and metastases can be
visualized by the increased focal uptake of a positronemitting tracer, 2-[18F]fluoro-2-deoxy-D-glucose (18FFDG), that is detected by PET scanning. The application of this method to esophageal carcinoma has been
reported by Luketich et al.13,14 and Block et al.15
Recently, we introduced [methyl-11C]choline (11Ccholine) as another tumor-seeking tracer and successfully visualized brain tumor, prostate carcinoma, and
other malignancies using PET.16,17 Choline is a natural
blood constituent and penetrates cell membranes.
11
C-choline is incorporated in kidney and liver, converted to betaine, liberated into circulation again, then
used for transmethylation reactions in various organs.
In tumors, however, the only metabolic pathway of
11
C-choline is its integration into phospholipids. 11Ccholine is phosphorylated within tumor cells, and,
after several biosynthetic processes, finally is integrated into phosphatidylcholine (lecithin), a major
component of cell membrane phospholipids. Once
11
C-choline is phosphorylated within tumor cells, it
remains there: This constitutes another “chemical
trap.” Because tumor cells duplicate very fast, the
biosynthesis of cell membranes also is very fast. It
follows that the uptake rate of 11C-choline in tumors is
proportional to the rate of tumor duplication.
The principles of tumor imaging using 18F-FDG
are as follows. Tumor cells frequently, but not always,
consume a great deal of glucose, because they are
inclined toward anaerobic glycolysis. 18F-FDG, a glucose analogue, is incorporated into tumors, but the
immediate metabolic product, 18F-FDG-6-phosphate,
1639
is not metabolized further and is “chemically trapped”
within tumor cells.18 Thus, 18F-FDG accumulates in
tumors, thereby enabling their detection by PET.
We performed PET studies in patients with esophageal carcinoma using 11C-choline and 18F-FDG, and
the results were compared with those from CT scans.
The radioactivity concentration in tumors and lymph
nodes was measured in terms of the standardized
uptake value (SUV). Finally, the effectiveness of these
imaging techniques was evaluated compared with the
pathologic findings obtained after surgery.
MATERIALS AND METHODS
Patients
The PET studies using 11C-choline and 18F-FDG were
performed in 33 patients with esophageal carcinoma
(28 males and 5 females; ages, 50 – 81 years; mean age,
63.9 years; 16 patients with T1 tumors and 17 patients
with T2–T4 tumors according to the TNM classification), of which the diagnosis was given in advance by
esophageal endoscopy and biopsy. Informed consent
was obtained from the patients. The PET study was
performed before noon, when the patient was abstaining from breakfast.
Radiopharmaceuticals
11
C-choline and 18F-FDG were prepared using a cyclotron and automated synthetic apparatuses that we
constructed.19,20 Dosimetry of 11C-choline (decay halflife, 20 minutes) in 4 normal human subjects was
performed by using the MIRD method21 (calculation
by Dr. K. Fukushi of the National Institute of Radiological Sciences, Japan), and the results were as follows: 18.0 3 10212 Sv/Bq in kidney, 17.3 3 10212 Sv/Bq
in liver, and 2.8 3 10212 Sv/Bq in the whole body, in
which kidney and liver are the target organs.
PET Imaging and Calculation
PET images were obtained using a PET camera (6-mm
spatial resolution; Headtome IV; Shimadzu, Kyoto, Japan) equipped with three rings producing five slices at
13-mm intervals. For 11C-choline PET scans, transmission scans and injection of 11C-choline (370 MBq)
were followed immediately by emission (emission
scan started 5 minutes after injection). For 18F-FDG
PET scans, transmission scan was performed before
injection of 18F-FDG (370 MBq), then, after 40 minutes, the patient was put back into the previous position, and the emission scan was performed.
Both the transmission scans and the emission
scans measured the whole range from liver to neck by
shifting the bed position 6 times, with a scan time of 3
minutes each. By combining the emission and transmission data in a computer, attenuation-corrected
1640
CANCER November 1, 1999 / Volume 86 / Number 9
emission images (PET images) were obtained. The
image of horizontal slices was presented on a computer screen by color display.
The specific color represented the radioactivity
concentration in each pixel (4 mm 3 4 mm 3 6 mm in
real size) using the SUV, which is defined as
SUV 5
Regional radioactivity concentration
Total injected dose/bod y weight
where the radioactivity concentration in a pixel (Bq/
mL) is to be determined from an apparent pixel count
(cps/pixel volume) and a predetermined cofactor. The
numeric value of the SUV in a region of interest (ROI)
was provided by the computer. The reading of the PET
image (interpretation and calculation) was performed
by a group of radiologists who knew nothing more
than the localization of the primary tumor.
Surgery and Pathology
After the PET study, all patients underwent surgery for
esophageal carcinoma by esophagectomy and regional lymph node dissection. The esophagectomy
was performed through a right thoracotomy followed
by laparotomy and left neck incision. After labeling,
the resected esophagus and the tissues adjacent to the
esophagus that possibly contained metastatic lymph
nodes were transferred to a pathology room. After
surgery, the surgeons separated lymph nodes from the
resected esophagus and the adjacent tissues and assigned specified numbers to them for indication of
localization (according to the guidelines of the Japanese Society for Esophageal Diseases22) in the Pathology Department. All subsequent procedures were carried out in this department. The surgical specimens
were fixed, embedded, sectioned, stained with hematoxylin and eosin, and finally examined microscopically. Small lymph nodes (,5 mm) were processed as
a whole. Larger lymph nodes were cut into two pieces
after being fixed, and one of them was submitted to
further procedures. One section plane in each lymph
node was examined microscopically. Dr. Michiyo
Nasu, a pathologist who is experienced in esophageal
carcinoma, reviewed all specimens. The total numbers
of the examined lymph nodes were in the range of
20 –77 lymph nodes in each surgical case. The results
of the lymph node metastases and localization were
recorded according to the above-mentioned guideline. The status of the lymph node aggregation was not
recorded, which is commonplace; however, this posed
a problem later, when we wanted to compare pathologic findings with PET images. Their localizations
finally were allotted to anatomic regions as described
in the guidelines discussed above, i.e., cervical, upper
thoracic, midthoracic, lower thoracic, and abdominal
regions (equivalent to TNM classification).
Superficial esophageal tumors in the T1 category
were classified according to the depth of invasion.
Esophageal carcinoma confined to the epithelium was
called ep-cancer, tumors remaining within the muscularis mucosae were referred to as mm-cancer, and
tumors involving the submucosa were called sm-cancer.22 Lymph node metastases of esophageal carcinoma were recorded as such, without applying the M
category of the new (1987) TNM classification to the
distant lymph node metastases.
RESULTS
Time Course of
Carcinoma
11
C-Choline Uptake in Esophageal
A stable tumor image was obtained by carrying out the
PET scan when the tumor activity remained constant.
With 11C-choline, the scan was started 5 minutes after
injection, because the tumor activity reached a maximum in 5 minutes and stayed at a constant level
afterward, whereas the blood activity (within the right
ventricle) decreased rapidly then continued to be very
low (Fig. 1). With 18F-FDG, however, the most stable
image was obtained 40 – 60 minutes after injection.23
Case Presentation and Overall Results
Typical cases from three patients are presented in
Figures 2– 4. The overall results in detecting primary
tumors are shown in Table 1. 11C-choline was superior
to 18F-FDG in sensitivity for detecting small tumors.
Concerning the T1 tumors (n 5 16), 15 tumors were
visualized with 11C-choline (with 1 negative result for
a tumor localized in the upper abdomen, which was
indistinguishable from the normal liver), whereas only
6 tumors were visualized with 18F-FDG. Concerning
the tumors with higher classifications (T2–T4; n 5 17),
16 tumors were visualized with 11C-choline (with 1
negative result for a tumor in the upper abdomen),
and all 17 tumors were visualized with 18F-FDG. If
11
C-choline PET and 18F-FDG PET were used in combination, then all primary tumors were detected.
The overall results in detecting lymph node metastases are shown in Table 2, in which the lymph
nodes are assigned to pertaining anatomic regions.
With regard to lymph node metastases in the mediastinum (n 5 32 lymph nodes), 11C-choline PET was
positive in 28 lymph nodes and negative in 4 lymph
nodes (sensitivity, 88%), whereas 18F-FDG PET was
positive in 11 lymph nodes and negative in 21 lymph
nodes (sensitivity, 34%). Concerning lymph node metastases in the upper abdomen (n 5 14 lymph nodes),
11
C-choline PET was completely ineffective because of
the high uptake of 11C-choline in the liver (sensitivity,
PET of Esophageal Carcinoma with Choline and FDG/Kobori et al.
FIGURE 1. Time course of radioactivity concentration (standardized uptake
value [SUV]) in the blood pool of the right ventricle and in a tumor after
intravenous injection of [methyl-11C-]choline into a patient with esophageal
carcinoma.
0%), whereas 18F-FDG PET was positive in 11 lymph
nodes and negative in 3 lymph nodes (sensitivity,
79%). If 11C-choline PET and 18F-FDG PET were used
in combination for the metastatic lymph nodes both
in the mediastinum and in the upper abdomen (n 5
46 lymph nodes), then it was positive in 39 lymph
nodes and negative in 7 lymph nodes (sensitivity,
85%). The minimal size of the metastatic lymph nodes
detected by PET was 4 mm with 11C-choline and 8 mm
with 18F-FDG.
The sensitivity of 18F-FDG PET for lymph node
metastases was high (79%) in the abdominal region
and low (34%) in the mediastinum. This difference
was accounted for by the difference in the size of the
lymph nodes, which are larger in the abdomen and
smaller in the mediastinum.
DISCUSSION
The survival rate for patients with esophageal carcinoma is dismal, with 6 –11% of all patients alive 5 years
after diagnosis and treatment.24 Those esophageal
carcinoma patients with a good prognosis, in general,
have squamous cell carcinoma at an early stage. This
1641
FIGURE 2-1.
Clinical and pathologic findings of the primary tumor. (A)
Barium film. (B) Endoscopy (elevated lesion, 2 cm 3 1 cm). (C) Gross view of
the esophagus (Lugol stain; unstained area, 6.5 cm 3 3.0 cm). (D) Histology
(H & E, low magnification. (E) Histology (high magnification, 3 100).
FIGURE 2-2. PET images with 11C-choline and 18F-FDG. (A) Primary tumor.
(B) Lymph node metastasis.
FIGURE. 2.
Esophageal carcinoma of the midesophagus. There were no
abnormal findings on computed tomography (CT) scan in this patient. [Methyl-
11
C]choline (11C-choline) positron emission tomography (PET) and [18F-fluoro2-deoxy-D-glucose (18F-FDG) PET showed high uptake in the primary tumor
and lymph node metastasis (Patient 9 in Tables 1 and 2).
1642
CANCER November 1, 1999 / Volume 86 / Number 9
FIGURE 3-1. Clinical and pathologic findings of the primary tumor. (A) Lugol
stain (unstained area, 3.7 cm 3 12 cm). (B) Endoscopy. (C) Histology (H & E,
low magnification). (D) Histology (high magnification, 3 100).
FIGURE 3-2. PET images with 11C-choline and 18F-FDG. (A) Primary tumor.
(B) Lymph node metastasis.
FIGURE. 3.
Esophageal carcinoma of the midesophagus. There were no
abnormal findings on CT in this patient. 11C-choline PET showed high uptake
in the primary tumor and lymph node metastasis. 18F-FDG PET showed no high
uptake (Patient 13 in Tables 1 and 2).
FIGURE 4-1.
Clinical and pathologic findings of the primary tumor. (A)
Barium film. (B) Endoscopy (elevated lesion, 1.5 cm 3 1.5 cm). (C) Macroscopic view of the elevated lesion with ulceration. (D) Histology (H & E, low
magnification). E. Histology (high magnification, 3 100).
FIGURE 4-2. PET images with 11C-choline and 18F-FDG. (A) Primary tumor.
(B) Lymph node metastasis. In addition, 11C-choline PET showed high uptake
in bone marrow (resulting in a positive bone scan 4 months later), and 18F-FDG
PET showed normal high uptake in myocardium.
FIGURE. 4. Esophageal carcinoma of the midesophagus. CT scan showed a
slightly thickened esophageal wall but no lymph node enlargement. Both
11
C-choline PET and 18F-FDG PET showed high uptake in the primary tumor
and many lymph node metastases (Patient 10 in Tables 1 and 2).
PET of Esophageal Carcinoma with Choline and FDG/Kobori et al.
1643
TABLE 1
Esophageal Carcinoma in Patients: Pathologic Location and Extent of the Primary Tumor and its Histologic
Type Compared with the Findings of [Methyl-11C]Choline, Positron Emission Tomography, [18F]Fluoro-2Deoxy-D-Glucose, and Computed Tomography
Primary tumor
11
18
F-FDG
PET SUV
CT
wall thickness
(mm)
—
—
—
2.59
—
—
—
—
3.45
3.13
3.46
1.44
—
—
—
0.97
5.49
3.54
2.02
3.09
2.67
2.18
6.78
3.60
2.78
6.18
3.31
3.83
6.24
5.61
4.70
5.82
9.88
—
—
—
—
—
—
—
13
—
6
—
—
—
—
—
—
—
32
13
16
10
17
44
64
33
45
30
17
18
19
13
61
23
Patient
Region
Pathology extent
Histology
C-choline
PET SUV
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Lower thoracic
Midthoracic
Midthoracic
Abdominal
Midthoracic
Midthoracic
Lower thoracic
Midthoracic
Midthoracic
Midthoracic
Lower thoracic
Midthoracic
Midthoracic
Midthoracic
Upper thoracic
Midthoracic
Midthoracic
Midthoracic
Midthoracic
Midthoracic
Midthoracic
Midthoracic
Midthoracic
Lower thoracic
Lower thoracic
Midthoracic
Abdominal
Midthoracic
Lower thoracic
Midthoracic
Upper thoracic
Lower thoracic
Midthoracic
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (sm)
T1 (mm)
T1 (mm)
T1 (mm)
T1 (mm)
T2
T2
T3
T3
T3
T3
T3
T3
T3
T3
T3
T3
T3
T3
T3
T3
T4
Well
Mod
Mod
Mod
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Mod
Mod
Mod
Mod
Mod
Mod
Well
Well
Well
Mod
Mod
Poor
Poor
Poor
Poor
Poor
Mod
2.59
2.61
1.78
—
3.14
2.84
2.15
1.76
2.22
3.04
3.49
2.50
3.31
1.34
1.41
1.46
3.22
3.70
2.05
2.90
3.43
3.23
3.56
3.42
3.33
2.56
—
2.60
4.52
3.38
3.89
3.19
4.49
PET: positron emission tomography; 18F-FDG: [18F]fluoro-2-deoxy-D-glucose; CT: computed tomography; 11C-choline: [methyl-11C]choline; SUV: uptake rate in the
PET image; T1, T2, T3, T4: tumor extent according to TNM classification; sm: submucosa; mm: muscularis mucosae (esophageal thickness at the tumor site); poor:
poorly differentiated squamous cell carcinoma; well: well-differentiated squamous cell carcinoma; mod: moderately differentiated squamous cell carcinoma; —:
negative.
kind of esophageal carcinoma has been called either
superficial esophageal carcinoma (not infiltrated beyond the submucosa) or early esophageal carcinoma
(a subset of superficial esophageal carcinoma without
regional lymph node metastases).22 Excellent 5-year
survival rates in the range of 56.7–78% have been
reported in patients undergoing surgical treatment of
early-stage squamous cell carcinoma.1–3,25–30 It has
been reported that the 5-year survival rate in these
patients decreases progressively as invasion progresses from intraepithelial, to intramucosal, to sub-
mucosal.26,29,31 It also has been reported that the likelihood of lymph node metastases increases in
association with invasion of deeper esophageal wall,
with the incidence of lymph node metastases in 5– 8%
of patients with intramucosal squamous cell carcinoma.1– 4 Therefore, early identification and prompt
surgical management of patients with superficial
esophageal carcinoma before dissemination by way of
lymphatics are crucial if survival rates from this lethal
disease are to be improved.
About one-half of the patients with esophageal
1644
CANCER November 1, 1999 / Volume 86 / Number 9
TABLE 2
Lymph Node Metastasis in Patients with Esophageal Carcinoma: Pathologic Location and Size of Metastasized Lymph Nodes Compared with the
Findings of [Methyl-11C]Choline Positron Emission Tomography, [18F]Fluoro-2-Deoxy-D-Glucose, and Computed Tomography
Lymph node metastasis
Pathology
Patient/region
Diameter (mm)
11
1
2
3
4
5
6
—
—
—
10
—
—
12
5
20
—
9, 5, 4
15, 13
10, 10
20, 14, 13, 10, 10, 8
17, 5, 4
—
20, 14, 10, 7, 7, 6
19
4
—
8, 7
6
—
—
13
—
14, 10, 8
9
13
11, 6, 4
—
13, 11, 10, 10, 6
6, 5, 4
—
16, 5, 5
10
10, 8, 6, 6
—
14
5
10, 6
13, 8, 8, 6, 6, 5
8
7
4
16, 5, 5
10, 6, 6
9, 4
—
6, 6, 5, 4, 4
17, 13, 5
18, 7, 4
13
—
3.28, 3.14, 3.03
2.06
—
—
2.99
3.11
3.22
—
2.59
—
2.20, 1.97, 1.50
1.82, 1.65
3.84
2.68, 2.16, 2.01
1.78
3.20, 3.02, 2.71, 2.53, 2.25
3.41
—
2.62
4.22
2.39
—
2.33
—
—
2.71
2.37
—
2.24, 1.73
—
3.34, 2.72
2.56
3.23
—
3.06
—
—
1.56
1.58
—
—
2.11
1.72
—
—
1.72
1.91, 1.83
2.27
—
—
2.59
—
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
No
Midthoracic
Lower thoracic
Abdominal
No
Cervical
Upper thoracic
Lower thoracic
Abdominal
Midthoracic
Abdominal
Upper thoracic
Midthoracic
Lower thoracic abdominal
Upper thoracic
Midthoracic
Cervical
Midthoracic
Abdominal
Lower thoracic
Lower thoracic
Midthoracic
No
Cervical
Lower thoracic
No
Upper thoracic
Lower thoracic
Abdominal
Upper thoracic
No
Cervical
Upper thoracic
Midthoracic
Abdominal
Midthoracic
Abdominal
No
Upper thoracic
Midthoracic
Lower thoracic
Abdominal
Upper thoracic
Midthoracic
Lower thoracic
Abdominal
Upper thoracic
Midthoracic
Lower thoracic
Abdominal
Abdominal
Upper thoracic
Abdominal
C-choline PET SUV
18
F-FDG PET SUV
—
—
2.41
2.43
—
—
—
—
3.11
—
1.48
1.57, 1.38
1.37
3.98
3.26
—
3.71, 3.44
—
—
—
2.26
—
—
2.67
—
—
—
—
2.52
2.34
—
2.45
—
1.17
1.25
—
3.37, 3.10
—
—
—
—
2.03
—
—
—
2.71
—
—
—
—
2.52, 2.45
3.63
3.64
CT diameter (mm)
—
—
—
—
—
—
—
—
13
—
—
14
11
19, 13, 10
—
—
13
—
—
—
12
—
—
—
—
—
12
—
12
12
—
13
12
—
—
10
10
—
15
—
—
12, 11
—
—
—
25
—
—
—
—
18
—
—
(continued)
PET of Esophageal Carcinoma with Choline and FDG/Kobori et al.
1645
TABLE 2
(continued)
Lymph node metastasis
Pathology
Patient/region
Diameter (mm)
11
31 Cervical
Upper thoracic
Abdominal
32 Upper thoracic
Midthoracic
Lower thoracic
Abdominal
33 No
10, 8
20, 5
13
8, 7, 6
6
9
5
—
3.01
3.17, 3.01
—
2.90, 2.77
—
3.04
—
—
C-choline PET SUV
18
F-FDG PET SUV
—
—
2.09
1.68, 1.66
—
5.06
—
—
CT diameter (mm)
—
—
—
—
—
—
—
—
11
C-choline: [methyl-11C]choline; PET: positron emission tomography; 18FDG: [18F]fluoro-2-deoxy-D-glucose; SUV: standardized uptake value (uptake rate in the PET image); CT: computerized tomography;
Diameter: greatest dimension of the lymph node.
carcinoma have a resectable tumor at first presentation.32,33 However, in one-half of all tumors, lymph
node metastases are present already.34,35 If lymph
node metastases are present, then the principle of
oncologic radicality commands that one should aim
not only at resecting the esophagus with primary tumor but also at dissecting the draining lymphatic system extensively. The main cause of death in patients
with esophageal carcinoma, unlike other tumors of
the gastrointestinal tract, is not hematogenous distant
metastases but local recurrence, which is reported to
be up to 80% in some series.36 About one-half of these
recurrences seem to be attributable to lymph node
metastases that were left behind.34 The consequence
is that adequate lymphadenectomy is very important
in surgery for patients with esophageal carcinoma.
Since the first successful removal of a tumor of the
thoracic esophagus by Turner37 in 1933, esophagectomy without thoracotomy (transhiatal approach), a
procedure of bluntly stripping the esophagus from the
mediastinum, has long been accepted as a standard
procedure in esophagectomy. The disadvantage of this
procedure is the inadequate removal of tumor-affected regional lymph nodes, if any. An alternative
procedure is esophagectomy with thoracotomy (transthoracic approach), but the majority opinion holds
that esophagectomy without thoracotomy obviously is
safer than esophagectomy with thoracotomy if postoperative complications are taken into account.38 – 48 If
there are no regional lymph node metastases, then
esophagectomy without thoracotomy (and endoscopic resection of esophageal mucosa as well) seems
to be the option of choice. In this case, however,
confirmation of the absence of metastases is manda-
tory. If there are lymph node metastases, however,
then esophagectomy with thoracotomy is required.
Surgical therapy yields the best results in esophageal carcinoma. For obtaining a good result, precise
preoperative staging is essential: The patients should
be evaluated carefully concerning the operability of
their tumors, and the most appropriate surgical procedure should be applied.
CT is not accurate enough for evaluating lymph
node metastases in the esophageal carcinoma, with an
accuracy rate of 51– 67%.6,7,10,49 –52 Endoscopic ultrasonography has a high accuracy rate for estimating the
depth of primary esophageal carcinoma, but it is inaccurate in evaluating lymph node status.5–12 Recently, a combination of thoracoscopy and laparoscopy has been introduced for detecting locoregional
and distant metastases11,52,53 and achieved high accuracy rates of 93% in thoracoscopy and 94% in laparoscopy,52 but this is an invasive methodology.
Luketich et al.13,14 applied the 18F-FDG PET
method for detecting regional lymph node metastases
and distant metastases in esophageal carcinoma patients. They found that, for regional lymph node metastases, the sensitivity was 45%, the specificity was
100%, and the accuracy rate was 48%. Small regional
lymph node metastases (mean greatest dimension, 5.2
mm; range, 2–10 mm) were not visualized by this
method. Block et al.15 also applied this method to
esophageal carcinoma staging. They reported that, in
58 patients with esophageal carcinoma who underwent surgery, 21 patients had lymph node metastases
in resected specimens, and PET visualized the metastases in 17 patients, whereas CT was positive only in 5
patients.
1646
CANCER November 1, 1999 / Volume 86 / Number 9
We previously introduced 11C-choline PET for imaging brain tumor, lung carcinoma, esophageal carcinoma, colon carcinoma, prostate carcinoma, bladder
carcinoma, and their metastases.17,18,54 11C-choline
PET has a very high sensitivity compared with 18FFDG PET for the detection of small lymph node metastases. Conversely, 18F-FDG PET has a low sensitivity
for the detection of small tumors. It seems that 18FFDG is incorporated actively in tumors only under the
conditions that 1) the tumor is relatively large, 2) the
blood supply (i.e., the oxygen supply) is short, and 3)
the tumor is obtaining most of its energy from glycolysis.55– 60 If the blood supply is not deficient in the
tumor, as in small tumors, then 18F-FDG may not be
incorporated actively. In contrast, the rate of 11C-choline uptake is simply proportional to the rate of cell
membrane synthesis, i.e., the rate of cell division, irrespective of the oxygen supply.17,18,61– 66 We have
demonstrated again in the current study that 11Ccholine PET is more sensitive than 18F-FDG PET for
the detection of small tumors.
The current work was undertaken to evaluate the
sensitivity of detecting the regional lymph node metastases involved with esophageal carcinoma using
11
C-choline PET and 18F-FDG PET. Pathologic findings
were taken as the gold standard. However, it was possible that some of the small lymph nodes may have
eluded pathologic detection, although surgeons elaborately carried out lymph node dissection (during and
after surgery), and pathologists were meticulous in
their work. An international congress has suggested
that, for achieving accurate pathologic staging in patients with esophageal carcinoma, at least 15 lymph
nodes, including both mediastinal and abdominal
lymph nodes, should be examined.67 We examined
20 –77 lymph nodes in each case. Nevertheless, there
were a number of high uptake areas with 11C-choline
(sometimes together with 18F-FDG) for the areas that
were possibly not dissected and not examined pathologically. This is a “sampling error”. In most of the
cases, these areas were localized contralateral to the
side of the surgical incision (Patients 2, 3, 6, 7, 9, 11,
15, 19, and 28 in Table 2).
11
C-choline PET was superior to 18F-FDG PET in
its sensitivity for detecting small metastatic lymph
nodes in the mediastinum. The minimal size of the
metastatic lymph nodes detected with 11C-choline
PET was 4 mm in greatest dimension. However, 11Ccholine PET was useless in imaging metastatic lymph
nodes in the upper abdomen, because the uptake of
11
C-choline in the liver prevented the imaging of
them. In contrast, 18F-FDG PET was effective in visualizing metastatic lymph nodes in the upper abdomen. However, it was not as effective as 11C-choline
PET for detecting metastatic lymph nodes in the mediastinum, because 1) it could not visualize very small
tumors in the mediastinum, and 2) sometimes, 18FFDG was incorporated into normal myocardium even
in the fasting state, resulting in interference with the
imaging of mediastinal lymph nodes. When 11C-choline and 18F-FDG were used in combination, the
above-mentioned disadvantages were compensated,
and lymph node metastases were detected in most
cases regardless of their localization. We believe that
the combined use of 11C-choline and 18F-FDG for PET
will afford very reliable patient evaluation of regional
lymph node metastases when the best surgical procedure is to be considered.
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