Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1148/radiol.2373041578
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suga, K.
Right arrow Articles by Oka, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suga, K.
Right arrow Articles by Oka, M.
(Radiology 2005;237:952-960.)
© RSNA, 2005

Gastrointestinal Imaging

Lymphatic Drainage from Esophagogastric Tract: Feasibility of Endoscopic CT Lymphography for Direct Visualization of Pathways1

Kazuyoshi Suga, MD, Kensaku Shimizu, MD, Yasuhiko Kawakami, MD, Akira Tangoku, MD, Mohammed Zaki, MD, Naofumi Matsunaga, MD and Masaaki Oka, MD

1 From the Department of Radiology (K. Suga, K. Shimizu, Y.K., M.Z., N.M.) and The 2nd Surgery (A.T., M.O.), Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. Received September 12, 2004; revision requested November 18; revision received December 21; accepted February 1, 2005. Supported in part by a grant for Scientific Research (no. 16591206) from the Japanese Ministry of Education, Science, Sports and Culture. Address correspondence to K. Suga (e-mail: sugar{at}po.cc.yamaguchi-u.ac.jp).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate the feasibility of an endoscopic computed tomographic (CT) lymphography technique with submucosal injection of iopamidol for direct visualization of lymphatic drainage pathways in dogs and in patients with operable esophageal cancer.

MATERIALS AND METHODS: With institutional animal committee approval, a total of 2 mL of undiluted iopamidol was injected into the esophageal (n = 6) or gastric (n = 3) submucosa in nine dogs by using a flexible endoscope. Multi–detector row CT images (section thickness, 1.25 mm) were obtained before contrast material injection and during the 10 minutes after injection. The animals were euthanized so that their lymphatic anatomy could be examined. With ethical committee approval and patient informed consent, nine patients with esophageal cancer also underwent CT lymphography with peritumoral injection of 2 mL of iopamidol, followed by esophagectomy and regional lymph node dissection with CT lymphographic guidance. The histopathologic features of dissected nodes, including sentinel lymph nodes (SLNs), were examined.

RESULTS: CT lymphography depicted the direct connection of lymphatic drainage vessels with enhanced and/or unenhanced nodes (ie, SLNs) as early as within 5 minutes after contrast material injection in all subjects. All 13 SLNs in dogs (1.4 nodes per animal) and 18 SLNs in patients (two nodes per patient) were found and dissected at the correct location by using CT lymphographic guidance. In patients, histopathologic examination revealed the high predictive value of CT lymphographic–guided SLN biopsy: Only one of the preoperatively identified SLNs in three patients and both SLNs and adjacent nodes in two patients were positive for metastasis; all resected nodes in the remaining four patients were negative.

CONCLUSION: Endoscopic CT lymphography is a feasible method for visualizing the direct connection between and the accurate anatomic location of SLNs and lymphatic drainage vessels.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The first lymph node (or sentinel lymph node [SLN]) encountered near the lymphatic vessels draining from a primary tumor is most likely the first to be affected by metastasis, and when an SLN is negative for metastasis, it is highly unlikely that other, more distant nodes are affected (1–3). On the basis of the SLN concept, SLN mapping and biopsy are now becoming standard practice in minimally invasive surgery for early stage breast cancer and malignant melanoma (4–6). The SLN concept also appears to be applicable to early stage gastric and esophageal cancers, and SLN detection may contribute to minimally invasive surgery, selective lymphadenectomy, and accurate staging, as indicated by results of pilot studies in which a radiocolloid scintigraphic method with intraoperative gamma probe counting was used (7–18). However, that method cannot be used to preoperatively predict the accurate anatomic location of primary SLNs because the resulting images have limited spatial resolution, which means that the detailed anatomy of the surrounding structures cannot be sufficiently visualized (12–15). Detection of high-uptake lymph nodes adjacent to the injection sites is difficult owing to the shine-through phenomenon (12,13,16,18). Furthermore, this method is not available in the many hospitals that do not have a nuclear medicine department.

Iopamidol is a commercially available nonionic monometric computed tomographic (CT) contrast agent for intravenous use (19–26). CT lymphography performed with submucosal injection of this contrast agent may be of use for SLN mapping and biopsy in early stage esophagogastric cancers by enabling the direct visualization of lymphatic drainage pathways from primary tumor sites. CT lymphography with subcutaneous or intrapulmonary injection of iopamidol enables direct visualization of the lymphatic drainage pathways from the primary tumors of breast and lung cancer, and its use in SLN mapping and biopsy has yielded favorable results (19–25). Thus, the purpose of our study was to evaluate the feasibility of endoscopic CT lymphography with submucosal injection of iopamidol for visualization of the pathways of lymphatic drainage from the esophagogastric tract in dogs and in patients with operable esophageal cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Animal Study
In accordance with guidelines for the care and use of laboratory animals (27) and with approval of our institution's animal use and care administrative advisory committee, nine adolescent male beagle dogs (mean weight, 10.9 kg ± 1.6 [standard deviation]; weight range, 8.6–12.5 kg) were examined. Blood and parasite analyses were performed for these animals by a veterinarian. For cleansing before endoscopy, the dogs were not allowed to eat for 4 hours before the procedure. These animals were anesthetized with 25 mg per kilogram of body weight of sodium pentobarbital (Dai-Nihon Pharmacy, Osaka, Japan) and 20 mg/kg ketamine hydrochloride (Bayer-Sankyo, Tokyo, Japan). The animals were placed in the supine position, intubated by using a 7-mm cuffed endotracheal tube, and connected to a volume-cycled piston ventilator (Harvard Instrument, Cambridge, Mass). The respiratory rate was set at 15 inspirations per minute with a tidal volume of 15 mL/kg. Small supplementary doses of sodium pentobarbital (total dose range, 3.0–5.8 mg/kg) were intermittently administered during the course of the experiment as needed to maintain adequate levels of sedation. After endoscopic CT lymphography, all animals were euthanized with 50 mg/kg sodium pentobarbital to enable postmortem evaluation of lymphatic anatomy. The animal study procedures were performed by three authors (K. Suga, K. Shimizu, and Y.K).

Clinical Study
With the approval of the institutional review board of the Yamaguchi University School of Medicine and after informed consent had been obtained from all patients, nine consecutive male patients (mean age, 66.1 years ± 7.0; range, 55–79 years) with operable superficial esophageal cancer (squamous cell carcinoma) underwent endoscopic CT lymphography between November 2002 and August 2004. The selection criteria for CT lymphography were as follows: (a) Tumors had to be localized (without multiple skip tumors), operable, and superficial without intensive invasion to surrounding structures such as the heart and trachea/bronchus or distant metastasis and (b) apparent signs of lymph node metastases had to not be present at preoperative imaging, including endoscopic ultrasonography (US) and magnetic resonance imaging and/or CT. The tumor was located in the middle part of the esophagus in six patients, in the lower esophagus in two patients, and in the upper esophagus in one patient. At endoscopic US, tumors were seen to have invaded within the lamina propria in three patients and within the submucosa in six patients. All patients underwent a standard esophagectomy and regional lymph node dissection within 1 week after CT lymphography.

Endoscopic CT Lymphography
Endoscopic CT lymphography was performed by using a multi–detector row CT scanner (four 0.5-mm detector rows) (Volume Zoom; Siemens-Asahi Medical, Tokyo, Japan). In the animal study, each anesthetized dog was placed in the supine position on the CT table with the forelimbs extended upward and then tightly fixed to the table with cotton tape. Then, unenhanced CT images were obtained from the neck to the abdomen so that we could evaluate lymphatic enhancement and distinguish nodal enhancement from nodal calcification deposits. CT scanning was performed with the following parameters: 140 kV; 140 mA; matrix, 512 x 512; section width, 1 mm; and table speed, 8 mm/sec. Subsequently, a flexible endoscope was inserted into the esophagus or stomach without repositioning the dog. In six of the nine dogs, the contrast material was injected into the esophageal submucosa. It was injected into the upper third of the esophageal submucosa (31–34 cm from the teeth) in two dogs, the middle third (39–45 cm from the teeth) in three dogs, and the lower third (51 cm from the teeth) in one dog. In the remaining three dogs, the contrast material was injected into the gastric submucosa—into the lesser curvature of the gastric antrum in two dogs and into the lesser curvature of the gastric corpus in one dog.

Once the target point was determined by using the endoscope, the needle injection system was inserted into the rubber port and advanced down the biopsy channel of the endoscope port. The 23-gauge endoscopic injection sclerotherapy needle (Create Medic, Yokohama, Japan) could be seen on the video screen as it exited the distal end of the endoscope. The needle tip was introduced into the submucosal layer in an approach that was as tangential as possible to avoid a transmural puncture of the serosal surface. A total of 2 mL of iopamidol (Iopamiron-370; Nihon Schering, Osaka, Japan) was gently administered into the submucosa at four different areas (with a 0.5-mL dose at each area) that just surrounded the target point (19–25). Adequate submucosal injection of iopamidol was confirmed by observation of bulging of the superficial mucosa surrounding the tumors in proportion to the volume of the injected contrast agent, without seeping of contrast agent into the esophageal lumen. Postcontrast CT images were successively obtained (with the same parameters used for precontrast scanning) 1, 3, 5, 7, and 10 minutes after contrast agent injection. The number of sections ranged between 98 and 127, and the time for one-time CT image acquisition ranged from 23 to 30 seconds. During CT image acquisition, breath holding was used, with the lungs inflated to a tidal inspiration level.

In the clinical study, precontrast CT images from the upper thorax to the abdomen were also initially obtained while patients were in the supine position with their arms extended cranially. CT scanning was performed with the following parameters: 120 kV; 210 mA; matrix, 512 x 512; section width, 1 mm; and table speed, 8 mm/sec. Then, patients were placed in the left lateral position, the endoscope was inserted, and, with the same type of 23-gauge sclerotherapy needle used in the animal study, a total of 2 mL of iopamidol was injected into the submucosal layer at four different areas (with a 0.5-mL dose at each area) that just surrounded the primary tumors. This procedure was performed by two radiologists (K. Suga and K. Shimizu). After the patient was returned to the same supine position used for precontrast CT scanning, postcontrast CT images were successively obtained (with the same parameters used for precontrast scanning) 1, 5, and 10 minutes after contrast material injection. The number of sections ranged between 111 and 132, and the time for one-time CT image acquisition ranged from 26 to 32 seconds. During CT image acquisition, breath holding was performed at a resting tidal inspiration level. The mean time required to complete the CT lymphography procedure was 27 minutes (range, 22–35 minutes). The x-ray exposure dose for one-time CT image acquisition, assessed by using the weighted CT dose index function on the CT monitor, ranged from 13.6 to 18.3 mGy.

After both the animal and the clinical studies were performed, transverse pre- and postcontrast CT images were reconstructed with a section width of 1.25 mm and a section interval of 0.5 mm. Multiplanar reconstruction (MPR) and/or maximum intensity projection (MIP) images were then reconstructed from the transverse postcontrast CT images that showed the greatest enhancement of the lymphatic pathways in each subject.

Image Interpretation and Lymph Node Dissection
CT lymphograms obtained in the animals and patients were interpreted at a viewer unit (Yokogawa-GE Medical, Tokyo, Japan) connected to the CT system. The anatomy of the enhancing lymphatic vessels and the location of the lymph nodes that drained directly from these lymphatic vessels (ie, SLNs) were independently identified by two radiologists (K. Suga and K. Shimizu) who had more than 10 years of experience in CT evaluation of the esophagogastric regions. The location of each SLN in the patients was reported according to definitions in the guidelines for clinical and pathologic studies on carcinoma of the esophagus published by the Japanese Society for Esophageal Disease (28). Working in consensus, the two observers placed regions of interest that ranged in size between 4.5 and 11.2 mm2 in each SLN, and the maximum contrast enhancement (ie, the maximum postcontrast enhancement in Hounsfield units minus the precontrast enhancement in Hounsfield units) was estimated. Lymph node enhancement was judged to be positive if the attenuation of a node on postcontrast images was increased by more than 30 HU compared with the attenuation of the node on precontrast images. This threshold for CT attenuation change was determined according to our previous findings in pulmonary interstitial CT lymphography performed with the same CT scanner (25); in that study, the CT attenuation of the same lymph node in the same subject changed by 30 HU at the most owing to motion artifacts at repeat unenhanced CT scanning.

The size (maximum diameter) of each of the enhanced/unenhanced SLNs was also measured by the two observers in consensus. Visual assessment of the presence or absence of calcification deposits in the SLNs and visual assessment of enhancement in structures other than the lymphatic pathways (eg, the venous system and muscles) were also performed by consensus of these observers.

At postmortem examination of the dogs, two radiologists (K. Suga and Y.K., who had more than 10 years of experience in CT evaluation of the esophagogastric region) working in consensus carefully evaluated the first drainage lymph nodes by referring to the detailed anatomy revealed at CT lymphography to see whether the position and size of these nodes actually corresponded to the position and size of the nodes on CT lymphograms. Subsequently, lymph nodes other than these nodes were searched and dissected at the visceral/parietal thoracic regions and abdomen, and the numbers of these nodes were counted by these observers in consensus.

Surgery in all of the patients with esophageal cancer was performed by two surgeons (A.T., M.O.) with over 20 years of experience in esophageal surgery. As part of a standard esophagectomy, thoracoabdominal lymphadenectomy was performed in three patients; thoracoabdominal and cervical lymphadenectomy was performed in the remaining six patients. In one patient with cancer of the middle part of the esophagus, cervical lymphadenectomy was added to the procedure because the long lymphatic vessels directed to the cervical paraesophageal node had been seen preoperatively on CT lymphograms. With CT lymphographic guidance, the preoperatively identified SLNs were surveyed and resected intraoperatively by the two surgeons working in consensus so that we could evaluate whether the actual position and size of these SLNs corresponded to the position and size seen at preoperative CT lymphography. The other dissected regional lymph nodes were separated from these SLNs, and the number of dissected nodes was recorded by the surgeons.

All of the dissected lymph nodes and esophagogastric tissues from the animals and patients were stored in 10% buffered formalin, processed overnight, embedded in paraffin, and sliced into serial thin slices. All thin slices were stained with hematoxylin-eosin for histopathologic examination by a pathologist with 25 years of experience in histopathologic examination of the esophagus. This pathologist evaluated (a) whether all the dissected nodes were actually lymph nodes, (b) the presence or absence of esophagogastric mucosal damage at the injection sites, and (c) the presence or absence of metastastasis in each dissected node in patients. On the basis of the histopathologic findings in the patient SLNs identified at CT lymphography and the histopathologic findings in other regional nodes, the sensitivity, specificity, accuracy, positive and negative predictive values, and false-negative rate for CT lymphographic–guided SLN biopsy were assessed according to guidelines in the literature (29) by one radiologist (K. Suga) and one surgeon (A.T.) working in consensus.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Animal Study
Endoscopic CT lymphography enabled direct visualization of the lymphatic vessels providing drainage from the injection sites and a total of 13 enhancing lymph nodes (1.4 nodes per animal) directly draining from these lymphatic vessels within 3 minutes after contrast agent injection in all animals (Table 1; Figs 1, 2). These lymphatic pathways were continuously visualized on the subsequent images. Although a small volume of iopamidol occasionally seeped into the esophagogastric lumen, the enhancing lymphatic vessels and nodes could be easily differentiated from the intraluminary contrast agent by identifying the esophagogastric wall. The length and the direction of the enhancing lymphatic drainage vessels showed marked variations in each animal. All of the enhancing oval lymph nodes with diameters that were greater than those of the lymphatic vessels could be easily identified with consistency between the two observers. MPR and/or MIP images often enabled recognition of the three-dimensional anatomy of these lymphatic pathways (Fig 2). The average maximum attenuation, the average maximum enhancement, and the average size of the 13 enhancing nodes were as follows: 132 HU ± 36 (range, 75–194 HU), 101 HU ± 37 (range, 43–163 HU), and 5.7 mm ± 1.3 (range, 3.4–8.2 mm), respectively (Table 1). The average attenuation of these nodes on precontrast CT images was 31 HU ± 4 (range, 22–43 HU), and they did not show visible nodal calcification deposits. No noticeable enhancement of structures other than the lymphatic pathways was visualized.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Summary of Results of CT Lymphography in Dogs

 


View larger version (94K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Transverse endoscopic CT lymphograms in dog 6, which received a submucosal injection of iopamidol in the lower third of the esophagus, show a total of two enhancing lymph nodes (LN) that represent thoracic paraesophageal (top left) and splenic hilar (bottom right) nodes that are directly connected with the lymphatic vessels (unlabeled arrows) that drain the injection site.

 


View larger version (41K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Coronal MPR endoscopic CT lymphograms in dog 7, which received a submucosal injection of iopamidol at the lesser curvature of the gastric antrum, show a single enhanced lymph node (LN) that is directly connected with the lymphatic vessel (arrow in middle image) that drains the injection site.

 
At postmortem examination, all 13 enhancing nodes could be resected at the accurate locations in all animals. On the basis of the detailed anatomy in relation to the surrounding structures seen on CT lymphograms, these nodes could be found with minimal incision and/or removal of the surrounding fat and connective tissues. The actual position and size of these nodes appeared to be consistent with their position and size on CT lymphograms. In addition to these nodes, a total of 51 other nodes (5.6 nodes per animal) were found in the visceral/parietal thoracic regions and abdomen. Results of histologic evaluation confirmed that all dissected nodes were actually lymph nodes. There was no histologic evidence of esophagogastric mucosal damage.

Clinical Study
Contrast agent injection was successfully performed in all patients, without acute or late adverse effects. CT lymphography enabled visualization of the lymphatic vessels draining the peritumoral sites in the esophagus within 5 minutes after contrast agent injection in all patients. These enhancing vessels were persistently visualized on subsequent images, although the enhancement effect typically slightly declined on the images obtained at the latest points after injection (Figs 3 –6). The length and direction of these enhancing lymphatic drainage vessels were different in each patient: There was only upward lymph flow in three patients, only downward lymph flow in two patients, and both upward and downward flow in three patients. In the remaining patient, only the short lymphatic vessels nearest to the primary tumor site were visualized.



View larger version (106K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3a. Patient 1. (a) Transverse and (b) coronal MPR and sagittal MIP endoscopic CT lymphograms in 68-year-old man with upper thoracic esophageal cancer (type 0-IIa + IIc) show lymphatic vessels (unlabeled arrows) directly draining into three enhancing paraesophageal lymph nodes (LN 1, LN 2, LN 4) and one enhancing right supraclavicular node (LN 3). This patient underwent esophagectomy and regional lymphadenectomy that included dissection of lymph nodes in the mediastinum, neck, and abdomen. A total of 12 resected lymph nodes—including the four enhancing SLNs—were negative for metastasis.

 


View larger version (113K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3b. Patient 1. (a) Transverse and (b) coronal MPR and sagittal MIP endoscopic CT lymphograms in 68-year-old man with upper thoracic esophageal cancer (type 0-IIa + IIc) show lymphatic vessels (unlabeled arrows) directly draining into three enhancing paraesophageal lymph nodes (LN 1, LN 2, LN 4) and one enhancing right supraclavicular node (LN 3). This patient underwent esophagectomy and regional lymphadenectomy that included dissection of lymph nodes in the mediastinum, neck, and abdomen. A total of 12 resected lymph nodes—including the four enhancing SLNs—were negative for metastasis.

 


View larger version (88K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. Patient 2. Transverse endoscopic CT lymphograms in 69-year-old man with middle thoracic esophageal cancer (type 0-IIa + IIc) show the lymphatic vessels (unlabeled arrows) draining to an enhancing subcarinal lymph node (LN, top left) and a nonenhancing perigastric node (LN, bottom right). Although the perigastric node is poorly enhanced, this node can be considered to be an SLN because it has a direct connection with the lymphatic drainage vessels. This patient underwent esophagectomy and regional lymphadenectomy that included the lymph nodes of the mediastinum and abdomen. A total of 12 resected lymph nodes—including both the enhancing and the nonenhancing SLNs—were negative for metastasis.

 


View larger version (98K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5a. Patient 3. (a) Transverse (top) and coronal MPR (bottom) endoscopic CT lymphograms and (b) photomicrographs in 62-year-old man with middle thoracic esophageal cancer (type 0-IIb). In a, a long lymphatic vessel (unlabeled arrows) that is directly connected with a single left cervical paraesophageal lymph node (LN) (lymph node 101) is seen draining the injection site. This patient underwent esophagectomy and regional lymphadenectomy that included dissection of lymph nodes in the mediastinum, neck, and abdomen. In b, the enhancing SLN is seen to contain micrometastasis (arrows). The right image is an enlargement of the area of micrometastasis in the left image. Two adjacent left recurrent nerve lymph nodes (nodes 106-recL) also contained macrometastasis (results not shown). A total of 15 remaining dissected lymph nodes—including thoracic paraesophageal nodes that were close to the primary tumor and cervical and abdominal nodes—were negative for metastasis. (Hematoxylin-eosin stain; original magnification of left image, x100; original magnification of right image, x400.)

 


View larger version (97K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5b. Patient 3. (a) Transverse (top) and coronal MPR (bottom) endoscopic CT lymphograms and (b) photomicrographs in 62-year-old man with middle thoracic esophageal cancer (type 0-IIb). In a, a long lymphatic vessel (unlabeled arrows) that is directly connected with a single left cervical paraesophageal lymph node (LN) (lymph node 101) is seen draining the injection site. This patient underwent esophagectomy and regional lymphadenectomy that included dissection of lymph nodes in the mediastinum, neck, and abdomen. In b, the enhancing SLN is seen to contain micrometastasis (arrows). The right image is an enlargement of the area of micrometastasis in the left image. Two adjacent left recurrent nerve lymph nodes (nodes 106-recL) also contained macrometastasis (results not shown). A total of 15 remaining dissected lymph nodes—including thoracic paraesophageal nodes that were close to the primary tumor and cervical and abdominal nodes—were negative for metastasis. (Hematoxylin-eosin stain; original magnification of left image, x100; original magnification of right image, x400.)

 


View larger version (92K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6. Patient 5. Transverse (left) and sagittal MPR (right) endoscopic CT lymphograms in 63-year-old man with middle thoracic esophageal cancer (type 0-Ip) show only a short lymphatic vessel (unlabeled arrow) at the paraesophageal region that is directly connected with the single middle thoracic paraesophageal lymph node (LN) (lymph node 108). This patient underwent esophagectomy and regional lymphadenectomy that included dissection of nodes in the mediastinum and abdomen. The enhancing SLN and an adjacent nonenhancing middle thoracic paraesophageal node were found to be positive for macrometastasis. A total of eight other dissected lymph nodes—including thoracic paraesophageal and abdominal nodes—were negative for metastasis.

 
A total of 18 enhanced/unenhanced lymph nodes (ie, SLNs; two nodes per patient) that had a direct connection with the enhancing lymphatic vessels were identified with consistency by the two observers (Table 2). Of these SLNs, 15 nodes in seven patients were enhanced, with an average maximum attenuation of 104 HU ± 17 (range, 68–132 HU) and an average maximum nodal enhancement of 70 HU ± 16 (range, 43–98 HU). In the remaining two patients, although no noticeable enhancement of lymph nodes was visualized, a total of three SLNs that were directly connected with the enhancing lymphatic vessels could be identified. The average diameter of the 18 SLNs (two nodes per patient) was 6.5 mm ± 1.3 (range, 4.7–9.5 mm). The average attenuation of these nodes on precontrast CT images was 34 HU ± 3 (range, 25–44 HU), and no nodal calcification deposits were visible. No noticeable enhancement of the structures other than the lymphatic pathways was visualized.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Summary of Results of CT Lymphography in Patients with Esophageal Cancer

 
With CT lymphographic guidance, all of the 18 preoperatively identified SLNs in all patients could be found and resected at the correct location by the two surgeons working in consensus. Because the anatomy of the SLN locations in relation to surrounding structures was detailed preoperatively, these nodes could be found with minimal incision and removal of fat and connective tissues. The actual position and size of these nodes appeared to be consistent with their position and size on CT lymphograms. Including these SLNs, between nine and 16 lymph nodes were dissected at regional lymph node dissection in each patient.

At histopathologic examination, all of the dissected nodes were confirmed to be lymph nodes, and metastases were found in five of the nine patients (Table 2). Of these five patients, two had micrometastases (<2 mm in diameter) and one had macrometastasis in only one of the preoperatively identified SLNs, without metastases in the other nodes (Table 2). The other two patients had micrometastases and/or macrometastases in both the SLNs and other adjacent nodes but no metastases in the remaining nodes. In the remaining four patients, all nodes, including the SLNs, were negative for metastasis. As shown in Table 3, the sensitivity, false-negative rate, and accuracy of CT lymphographic–guided SLN biopsy were 100% (five of five patients), 0% (none of five patients), and 100% (nine of nine patients), respectively. There was no histologic evidence of esophageal mucosal damage in any patient.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Pathologic Status of SLNs Identified at Esophageal CT Lymphography and Final Lymph Node Status in Nine Patients with Esophageal Cancer

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the present study, endoscopic CT lymphography enabled visualization of the lymphatic drainage vessels that directly drained the injection sites in the esophagogastric tract and accurately depicted the location of the first drainage lymph nodes (ie, SLNs) in both the animals and the patients with esophageal cancer. Given the detailed depiction of their anatomy on CT lymphograms, all of these nodes could be found at the correct location. At CT lymphographic–guided SLN biopsy in the patients, metastasis could be detected with 100% sensitivity and accuracy, without false-negative results. Although these results are preliminary, this technique has the potential to enable direct visualization of lymphatic drainage pathways in the esophagogastric tract and SLN mapping and biopsy of esophagogastric cancers.

Lymph node metastases in esophagogastric cancers have been reported to widely distribute over various anatomic sites and show unpredictable regional spread patterns because of the complicated lymphatic network in the esophagogastric submucosa (2,7–15,30–34). Therefore, radical esophagectomy or gastrectomy with extended lymphadenectomy has been accepted as the standard surgery. However, more than 80% of patients with early stage esophagogastric cancers have no nodal metastases (2,7–10). Extended surgery to reduce morbidity and mortality would be unwarranted for patients without lymph node metastasis. SLN mapping and biopsy are helpful in determining the suitable extent of lymphadenectomy and in sparing patients with negative SLNs from extensive lymph node dissection. The endoscopic CT lymphography method described in this article can be one of the imaging options for accurately identifying SLNs.

Submucosally injected iopamidol appears to strongly penetrate into the lymphatic system through the clefts in the terminal lymphangioles of the esophagogastric submucosal layer (35,36). The enhanced lymphatic pathways are considered to reflect the main lymphatic stream from the injection sites (22,24). The lymph nodes directly connected with these enhancing lymphatic vessels should be primary SLNs. In the dogs in our study, the anatomy of the enhancing lymph nodes in the thoracic and abdominal regions were consistent with those previously described (18,37). Although some volume of iopamidol may drain into the venous system, this volume appears to be negligible. Selective lymphatic enhancement is advantageous for identifying drainage lymphatic pathways.

An endoscopic scintigraphic method involving the use of radiocolloids and intraoperative gamma-probe counting that has been evaluated in pilot studies (7–18) is available for identification of SLNs in esophagogastric cancers. However, this method has potential disadvantages and pitfalls (12,13,16,18,34,38). The draining lymphatic vessels are usually not clearly visualized because of slow lymphatic migration of radiocolloids, and the location of SLNs cannot be accurately determined because of the low spatial resolution of scintigrams (13–16,18). Resected SLNs often show a degree of uptake that is below the detection sensitivity of a gamma probe (15,38). There is a risk of labeling non-SLNs owing to further migration of radiocolloids to subsequent distant nodes, and lymph nodes with the highest degree of uptake are not necessarily defined as SLNs (15,30). SLN detection is difficult owing to shine-through radioactivity (10–14,38) when such nodes are close to the injection site or to the physiologically high-in-uptake liver.

A blue dye has also been used for SLN biopsy (34,38). However, rapid transit of blue dye through the lymph node chain limits the time for surgery, and blue lymphatic vessels are often not clearly visualized during surgery because mobilization of lymphatic vessels disrupts lymphatic flow (34,38). Detection of unexpectedly distributed blue SLNs over various anatomic sites seems to be difficult (32,33,38).

In contrast to scintigraphic and blue dye methods, the present technique appears to have excellent utility in the identification of primary SLNs by enabling direct visualization of lymphatic pathways over underlying detailed anatomy. This technique can depict SLNs close to primary tumors and enable visualization of even long lymphatic vessels beyond the regional compartments and the multiple lymphatic vessels that course to various locations from a primary tumor. Preoperative assessment of the anatomic distribution of SLNs in patients by using CT lymphograms appears to be largely beneficial for planning the surgical field and the optimal extent of lymphadenectomy. In the present study, pre- and intraoperative relative changes in lymph node position seemed to be minimal and did not interrupt a survey of the SLNs because the preoperatively identified SLNs could be found at accurate locations in our patients. CT lymphography can be performed by using a widely available multi–detector row CT scanner. The radiation exposure to patients can be minimized because only one or two scanning passes performed during the 5 minutes after contrast agent injection may enable the sufficient delineation of lymphatic pathways.

One of the drawbacks of CT lymphography is the CT room time required for the endoscopic procedure. However, the patient may be able to receive the contrast agent injection in an endoscopy procedure room and then be brought into the CT room for scanning, without the acquisition of precontrast images. Visualization of the direct connection between enhancing lymphatic vessels and lymph nodes is not interrupted during the relatively long period of lymphatic enhancement, and such visualization may allow accurate identification of SLNs even if these nodes have an incidental calcification deposit.

The lesser degree of nodal enhancement in the human patients than in the animals that was observed in our study was considered to be caused by the lower dose of iopamidol per kilogram administered to the animals. Optimization of the injection dose for greater nodal enhancement is warranted in attempts to obtain better image quality at CT lymphography. The combined use of conventional contrast agents and contrast agents such as iodinated nanoparticles that have lymphocyte phagocytic properties might facilitate nodal enhancement (39–41). Further studies are also warranted to establish the lymphatic drainage pattern from various sites in the esophagogastric tract of dogs and to clinically evaluate the anatomic and pathologic factors affecting lymphatic enhancement and the utility of CT lymphography in gastric cancer.

In conclusion, the present endoscopic CT lymphography method involving use of a small volume of iopamidol safely and quickly depicted the direct connection between the lymphatic drainage vessels and the first drainage lymph nodes (ie, SLNs) in the esophagogastric tract. The preoperatively identified SLNs could be found at the correct locations, and the good predictive value of CT lymphographic–guided SLN biopsy was histopathologically confirmed in patients with esophageal cancer. Although further studies and validation are warranted, this technique has potential for SLN mapping and biopsy in esophagogastric cancers and may address the disadvantages of the scintigraphic and blue dye methods.


   FOOTNOTES
 

Abbreviations: MIP = maximum intensity projection • MPR = multiplanar reconstruction • SLN = sentinel lymph node

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, K. Suga; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, K. Suga, M.Z., N.M., M.O.; clinical studies, K. Suga, K. Shimizu, A.T., M.O.; experimental studies, K. Suga, K. Shimizu; statistical analysis, K. Shimizu, Y.K.; and manuscript editing, N.M.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39:456–466.[CrossRef][Medline]
  2. Catarci M, Guadagni S, Zaraca F, et al. Prospective randomized evaluation of preoperative endoscopic vital staining using CH-40 for lymph node dissection in gastric cancer. Ann Surg Oncol 1998;5:580–584.[Abstract]
  3. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392–399.[Abstract/Free Full Text]
  4. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 1997;349:1864–1867.[CrossRef][Medline]
  5. Giuliano AE, Jones RC, Brennan M, et al. Sentinel lymphadenectomy in breast cancer. J Clin Oncol 1997;15:2345–2350.[Abstract/Free Full Text]
  6. Bass SS, Cox CE, Ku NN, et al. The role of sentinel lymph node biopsy in breast cancer. J Am Coll Surg 1999;189:183–194.[CrossRef][Medline]
  7. Palaia R, Cremona F, Delrio P, Izzo F, Ruffolo F, Parisi V. Sentinel node biopsy in gastric cancer. J Chemother 1999;11:230–231.[Medline]
  8. Kosaka T, Ueshige N, Sugaya J, et al. Lymphatic routes of the stomach demonstrated by gastric carcinomas with solitary lymph node metastasis. Surg Today 1999;29:695–700.[CrossRef][Medline]
  9. Hiratsuka M, Miyashiro I, Ishikawa O, et al. Application of sentinel node biopsy to gastric cancer surgery. Surgery 2001;129:335–340.[CrossRef][Medline]
  10. Kitagawa Y, Fujii H, Mukai M, et al. The role of the sentinel lymph node in gastrointestinal cancer. Surg Clin North Am 2000;80:1799–1809.[CrossRef][Medline]
  11. Kitagawa Y, Ohgami M, Fujii H, et al. Laparoscopic detection of sentinel lymph nodes in gastrointestinal cancer: a novel and minimally invasive approach. Ann Surg Oncol 2001;8(9 suppl):86S–89S.
  12. Kitagawa Y, Fujii H, Mukai M, Kubota T, Otani Y, Kitajima M. Radio-guided sentinel node detection for gastric cancer. Br J Surg 2002;89:604–608.[CrossRef][Medline]
  13. Kitagawa Y, Kitajima M. Gastrointestinal cancer and sentinel node navigation surgery. J Surg Oncol 2002;79:188–193.[CrossRef][Medline]
  14. Mendez J, Wallace AM, Hoh CK, Vera DR. Detection of gastric and colonic sentinel nodes through endoscopic administration of Tc-99m-DTPA-mannosyl-dextran in pigs. J Nucl Med 2003;44:1677–1681.[Abstract/Free Full Text]
  15. Yasuda S, Shimada H, Chino O, et al. Sentinel lymph node detection with Tc-99m tin colloids in patients with esophagogastric cancer. Jpn J Clin Oncol 2003;33:68–72.[Abstract/Free Full Text]
  16. Cense H, Sloof GW, Klaase JM, et al. Lymphatic drainage routes of the gastric cardia visualized by lymphoscintigraphy. J Nucl Med 2004;45:247–252.[Abstract/Free Full Text]
  17. Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 1998;186:275–283.[CrossRef][Medline]
  18. Baciewicz FA Jr, McNevin MS, Farris RH, Madan SK, Muz J. Lymphoscintigraphic technique to image canine esophageal lymph nodes. J Invest Surg 2000;13:265–271.[CrossRef][Medline]
  19. Suga K, Ogasawara N, Yuan Y, Okada M, Matsunaga N, Tangoku A. Visualization of breast lymphatic pathways with an indirect CT lymphography using a nonionic monometric contrast medium iopamidol: preliminary results. Invest Radiol 2003;38:73–84.[CrossRef][Medline]
  20. Suga K, Ogasawara N, Okada M, et al. Interstitial CT lymphography-guided localization of breast sentinel lymph node; preliminary results. Surgery 2003;133:170–179.[CrossRef][Medline]
  21. Minato M, Hirose C, Sasa M, et al. 3-dimensional computed tomography lymphography-guided identification of sentinel lymph nodes in breast cancer patients using subcutaneous injection of nonionic contrast medium: a clinical trial. J Comput Assist Tomogr 2004;28:46–51.[CrossRef][Medline]
  22. Suga K, Yuan Y, Okada M, et al. Breast sentinel lymph node mapping at CT lymphography with iopamidol: preliminary experience. Radiology 2004;230:543–552.[Abstract/Free Full Text]
  23. Tangoku A, Yamamoto S, Suga K, et al. Sentinel lymph node biopsy using computed tomography-lymphography in patients with breast cancer. Surgery 2004;135:258–265.[CrossRef][Medline]
  24. Ueda K, Suga K, Kaneda Y, Li TS, Ueda K, Hamano K. Preoperative imaging of the lung sentinel lymphatic basin with computed tomographic lymphography: a preliminary study. Ann Thorac Surg 2004;77:1033–1037.[Abstract/Free Full Text]
  25. Suga K, Yuan Y, Ueda K, et al. Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization. Invest Radiol 2004;39:313–324.[CrossRef][Medline]
  26. Grainger RG, Thomas AMK. History of the development of radiological contrast media (1895-1996). In: Dawson P, Cosgrove DO, Grainger RG, eds. Textbook of contrast media. Oxford, England: Isis Medical Media, 1999; 1–14.
  27. National Research Council. Guide for the care and use of laboratory animals. 7th ed. Washington, DC: National Academy, 1996.
  28. Japanese Society for Esophageal Disease. Guidelines for the clinical and pathologic studies on carcinoma of esophagus. 9th ed. Tokyo, Japan: Kanehara, 1999; 11–20.
  29. Fukui Y, Yamakawa T, Taniki T, Numoto S, Miki H, Monden Y. Sentinel lymph node biopsy in patients with papillary thyroid carcinoma. Cancer 2001;92:2868–2874.[CrossRef][Medline]
  30. Chin PL, Medeiros J, Schwarz RE. Use of the sentinel lymph node to determine metastases of gastrointestinal malignancies: a word of caution. J Surg Oncol 1999;71:239–242.[CrossRef][Medline]
  31. Matsubara T, Ueda M, Abe T, Akimori T, Kokudo N, Takahashi T. Unique distribution patterns of metastatic lymph nodes in patients with superficial carcinoma of the thoracic oesophagus. Br J Surg 1999;86:669–673.[CrossRef][Medline]
  32. Ichikura T, Morita D, Uchida T, et al. Sentinel node concept in gastric carcinoma. World J Surg 2002;26:318–322.[CrossRef][Medline]
  33. Nomura T, Onda M, Miyashita M, et al. Wide-spread distribution of sentinel lymph nodes in esophageal cancer [in Japanese]. J Nippon Med Sch 2001;68:393–396.[CrossRef][Medline]
  34. Aikou T, Higashi H, Natsugoe S, Hokita S, Baba M, Tako S. Can sentinel node navigation surgery reduce the extent of lymph node dissection in gastric cancer? Ann Surg Oncol 2001;8(9 suppl):90S–93S.
  35. Casley-Smith J. The structure and functioning of the blood vessels, interstitial tissues and lymphatics. In: Foeldi M, Casley-Smith J, eds. Lymphangiology. Stuttgart, Germany: Schayyauer Verlag, 1983; 27–143.
  36. Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev 1990;70:987–1028.[Abstract/Free Full Text]
  37. Evans HE, Christensen GC. The lymphatic system. In: Miller's anatomy of the dog. 3rd ed. Philadelphia, Pa: Saunders, 1993; 717–757.
  38. Hayashi H, Ochiai T, Mori M, et al. Sentinel lymph node mapping for gastric cancer using a dual procedure with dye- and gamma probe-guided techniques. J Am Coll Surg 2003;196:68–74.[CrossRef][Medline]
  39. Ketai LH, Muggenberg BA, McIntire GL, et al. CT imaging of intrathoracic lymph nodes in dogs with bronchoscopically administered iodinated nanoparticles. Acad Radiol 1999;6:49–54.[CrossRef][Medline]
  40. Wisner ER, Katzberg RW, Koblik PD, et al. Iodinated nanoparticles for indirect computed tomography lymphography of the craniocervical and thoracic lymph nodes in normal dogs. Acad Radiol 1994;1:377–384.[Medline]
  41. McIntire GL, Bacon ER, Illig KJ, et al. Time course of nodal enhancement with CT x-ray nanoparticle contrast agents: effect of particle size and chemical structure. Invest Radiol 2000;35:91–96.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suga, K.
Right arrow Articles by Oka, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suga, K.
Right arrow Articles by Oka, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE