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LYMPHATIC MAPPING AND DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER
0022-5347/01/1663-0812/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 166, 812– 815, September 2001 Printed in U.S.A.
Original Articles LYMPHATIC MAPPING AND DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER A. SHERIF,* M. DE LA TORRE, P.-U. MALMSTRÖM
AND
M. THÖRN
From the Departments of Urology, Pathology and Surgery, University Hospital, Uppsala, Sweden
ABSTRACT
Purpose: We examined the possibility for detecting sentinel nodes in patients with bladder cancer and whether the histopathological status of identified sentinel nodes reflected that of the lymphatic field. Materials and Methods: A total of 13 patients with bladder cancer who met the criteria qualifying them for radical cystectomy had intravesical injections of radioactive tracer and blue dye marker around the tumor followed by lymphoscintigraphy to visualize lymphatic drainage and detect sentinel nodes. Sentinel nodes were identified preoperatively by the blue color and increased radioactivity and were compared histopathologically with other routinely excised lymph nodes. Results: Sentinel nodes were detected in 85% (11 of 13) of patients. There were 4 patients who had sentinel nodes containing tumor cells, and each metastasis was only seen in the detected sentinel node. There were no false-negative sentinel nodes. Of the metastatic sentinel nodes 3 were located outside the normally excised lymph nodes of the obturator fossa. Conclusions: Sentinel nodes can be detected in patients with bladder cancer. The histopathological status of the identified sentinel nodes was diagnostic for all other excised lymph nodes. Sentinel nodes often seem to be located outside the obturator lymphatic field, which is normally examined during preoperative staging of bladder cancer. KEY WORDS: bladder neoplasms, lymph node excision, radionuclide imaging, cystectomy
Studies of prognostic factors in patients with muscle invasive bladder cancer show the histological status of regional lymph nodes as one of the most important predictors of survival.1 Surgical treatment of invasive bladder cancer includes cystectomy and removal of regional lymphatic nodes, although it is not clear whether lymph node dissection leads to better survival or solely improves staging. The sentinel node concept first introduced by Cabanas proposed that lymphatic drainage from a primary tumor goes to a particular regional lymph node called the sentinel node and then continues to other nodes.2 The sentinel node is specific for each individual, and the tumor status of it can reflect that of the regional lymphatic field. Use of lymphatic mapping and sentinel node biopsy to identify patients with lymph node metastasis is well established in those with malignant melanoma and intensively studied in those with breast cancer.3, 4 The method has also been applied in patients with gastrointestinal cancer.5 Of the markers 2 types are used to identify the sentinel node, dye and radioactive tracer. These makers are usually injected near the tumor, transported in the lymph capillaries and accumulate through phagocytosis by macrophages in the
sentinel node. In the pioneering work regarding melanoma and breast cancer blue dye, including patent blue or lymphazurine blue, was the only marker of the sentinel node.6, 7 Alex et al used radioactive tracer and identified the sentinel node preoperatively with a handheld a˜-detection tube.8 Currently, preoperative lymphoscintigraphy is often part of the method for locating the sentinel node in malignant melanoma and breast cancer and finding the draining regional lymph node basin in some cases, such as midline melanoma,. During surgery the sentinel node is identified with a handheld a˜-detection tube to measure high radioactivity compared with the background radioactivity in the operative field. It is also recognized with dye and visualizing blue colored lymph vessels leading into a blue colored gland. We applied this technique in patients with invasive bladder cancer who were candidates for cystectomy, including lymph node dissection. We examined whether sentinel nodes can be identified in these patients, evaluated the aforementioned different techniques of detection and investigated whether the histological status of the identified sentinel node reflected that of the routinely excised lymphatic field.
Accepted for publication March 2, 2001. MATERIALS AND METHODS Supported by grants from the Swedish Society of Medicine, the Swedish Society of Cancer, and Johanna Hagstrands and Sigfrid Patients. This pilot study was approved by the ethics comLinne´rs Foundation, Stockholm, Sweden. mittee at Uppsala University. All 13 patients gave informed * Requests for reprints: Department of Urology, University Hos- consent and were included in our study. Of these patients 12 pital, SE-751 85 Uppsala, Sweden. were examined with preoperative injection of radioactive Editor’s Note: This article is the first of 5 published in this tracer with lymphoscintigraphy and injection of dye marker issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions right before surgery. One patient was evaluated with dye marker only. The indication for major surgery was invasive on pages 1066 and 1067. 812
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER
FIG. 1. Injection of radioactive tracer or patent blue dye into bladder wall at 4 sites surrounding tumor or residue tumor base.
urothelial bladder cancer (stage T2-T4) in 10 cases and high grade urothelial bladder cancer (stage T1G3) that was multifocal in 3. Lymphoscintigraphy. Before major surgery the patient under general anesthesia was reassessed with cystoscopy and bimanual palpation. Radioactive tracer consisting of 1 ml. Albures (Scanflex, Nycomed Amersham, Milan, Italy), approximately 50 MBq./ml., was injected and divided into 4 equal parts at 4 different sites around the visible tumor or tumor base (fig. 1). A 3.7Fr, 35 cm. long Williams cystoscopy needle (Cook Urological, Spencer, Indiana) directed by an Albarran bridge was used. According to our earlier experience with different techniques in cases of gastrointestinal tumors, we injected the tracer into the muscular wall of the bladder and caution was used not to place it directly beneath the mucous membrane.5 However, care was taken not to penetrate the muscular wall and risk deposing the tracer around the bladder. The patient received an indwelling catheter to empty the bladder before scintigraphy and also wash out excess tracer from the bladder cavity. About an hour after injection the patient underwent lymphoscintigraphy at the department of nuclear medicine. Scintigrams were done in 2 planes, including frontal and lateral views. To enhance the a˜ -camera sensitivity and detect the sentinel node, the primary injection site with high counts of radioactivity was
FIG. 2. Lymphoscintigraphy in patient with bladder cancer. A, frontal view shows prominent sentinel node close to bladder and lymphatic drainage that continues in cranial direction to second lymph node with less uptake of radioactivity. B, lateral view.
813
covered with a lead shield (fig. 2). In those cases in which a sentinel node was not seen after about an hour following injection scintigraphy was repeated after an additional 3 hours. The spreading of tracer indicating the route of lymphatic drainage and suspected sentinel nodes were described for each case. Injection of dye. If major surgery was performed the second day, considering the 6 hour half lifetime of the original tracer, additional tracer was not injected at that time. If more than 24 hours had passed after lymphoscintigraphy, injection of tracer was repeated preoperatively. On the day of major surgery 1.0 ml. patent blue dye was transurethrally injected around the tumor using the same technique aforementioned. After injection the patient was repositioned and redressed for cystectomy. Surgery. According to current practice, lymph node dissection was the first step in which the lymph nodes in the obturator fossa were dissected on each side with a preperitoneal approach. Sentinel nodes were identified by the blue color of the gland and lymph vessels leading into them or by increased radioactivity, as measured with the handheld a˜ detection tube in 5 cases. Dissection also proceeded around the bladder for detection of any sentinel nodes. The nodes overlying the iliac vein up to the iliac bifurcation were examined with the same procedure. Cystectomy was performed thereafter according to regular surgical treatment. Histopathological investigation. The tumor specimen, sentinel node and excised lymph nodes were carefully examined by the pathologist. The histopathological status of the sentinel node was compared with that of all other excised nodes. RESULTS
Sentinel nodes were detected in 11 (85%) patients with lymphoscintigraphy and preoperative investigation based on blue dye or radioactivity. In 2 cases we could not identify any sentinel node with either method (see table). Of the 12 eligible cases sentinel nodes were visible preoperatively with lymphoscintigraphy in 8. All 8 of these patients had only 1 sentinel node and 7 had sentinel nodes that were identified at surgery. In 3 patients lymphoscintigraphy was negative but only dye marker showed the sentinel node in 1, and preoperative examination with the handheld ␥-detection tube identified the sentinel node despite negative dye marker in the other 2. The average number of excised lymph nodes in each patient was 8.5 and median number was 8 (range 5 to 22). Of the 13 patients 4 had lymph node metastases, including 1 metastatic sentinel node and, surprisingly, all other lymph
FIG. 3. Localization of metastatic sentinel nodes
814
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER Patient characteristics
Pt. No. — Pt. Age — Sex 1— 2— 3— 4— 5— 6— 7— 8— 9— 10 — 11 — 12 — 13 —
77 54 60 67 68 57 56 67 55 70 39 70 75
—M —M —M —M —M —M —M —M —F —M —M —M —F
Tumor Stage
Lymphoscintigraphy
Dye Marker
Preop. ␥-Detection
Metastatic Sentinel Node
T2 T3 T1 T4 T4 T2 T2 T1 T3 T2 T1 T3 T4
Not done Neg. Pos. Neg. Neg. Pos. Pos. Pos. Pos. Pos. Pos. Pos. Neg.
Pos. Pos. Pos. Neg. Neg. Pos. Neg. Pos. Pos. Neg. Pos. Neg. Neg.
Not done Not done Not done Not done Not done Not done Not done Not done Pos. Pos. Pos. Pos. Pos.
Yes No No No No Yes No No Yes No No Yes No
nodes were without metastasis. There were no cases of falsenegative sentinel nodes. Only 1 of the metastatic sentinel nodes was in the obturator fossa. The other 3 nodes were around the bladder above the common iliac vein bifurcation and in the pelvic region medial to the obturator fossa, respectively (fig. 3). DISCUSSION
Diagnosis of muscle infiltrating bladder cancer is based on transurethral resection of the bladder tumor, including deeper parts of the bladder wall, and histopathological investigation. Computerized tomography of abdomen and thorax is often used to evaluate extravesical growth and distant metastasis but the sensitivity for detecting nodal metastasis has been low.9 Magnetic resonance imaging has been somewhat better than computerized tomography, with a mean sensitivity of 74% and specificity of 100% in regard to lymph node staging.10 In a study with positron emission tomography, a new imaging modality, the smallest detected lymph node metastasis was a micrometastasis, with a diameter of 0.9 cm. No false-positive results were obtained, but falsenegative cases were seen and positron emission tomography was not considered superior to other techniques.11 Therefore, the presently available imaging techniques have not proved reliable for accurate lymph node staging, and the possibility for detecting sentinel nodes as indicators of lymph node involvement deserves to be evaluated. Radical cystectomy starts with dissection of the regional lymph nodes. This procedure is not controversial, but there are some issues regarding it, including the anatomical extent and possibility to cure patients with lymph node metastasis with surgery alone. Thus, 2 major modifications have evolved regarding the procedure, including limited and extended dissection. Advocated by some, limited dissection consists of removing the lymphatic tissue in the obturator fossa distal to the bifurcation of the common iliac vessels.12 Extended surgery also usually involves the tissue along the common iliac vessels. There are some reports of good prognosis in patients with limited lymphatic spreading that have stimulated the proponents of extended dissection.13, 14 In a recent retrospective study of 447 patients who underwent radical cystectomy the mean number of excised lymph nodes was 14.7 (range 1 to 46).15 The number of lymph nodes removed varied significantly among different surgeons in contrast to the number of those recovered by different pathologists. There was significantly better survival of patients with minimal node positive disease in whom more than 16 nodes were removed compared to those with less removed. Thus, the proponents of extended dissection usually advocate the possibilities of cure with this approach and the minor risk of increased morbidity.14 However, no controlled studies exist supporting the curative value of lymph node dissection. Therefore, only limited dissection as a staging procedure is currently recommended in Sweden and most European countries (unpublished data). The mean number of excised lymph
nodes in our present study was 8.5 nodes (range 5 to 22), which was somewhat smaller than that of Leissner et al.15 Use of the sentinel node method to locate and find lymph node metastasis may imply the diagnosis of it preoperatively and, thus, the possibility to consider extended dissection. Our findings of lymph node metastasis outside the obturator fossa also support the choice for extended dissection. We applied 3 detection methods in our study. Advantages of lymphoscintigraphy include preoperative visualization of lymphatic drainage from the primary tumor with localization of the sentinel node and the possibility of planning lymph node dissection. Disadvantages of the technique include the time and cost of examination, and sometimes the difficulties interpreting the pictures, especially when the sentinel node is located close to the primary tumor, which is hard to outline from the radioactivity of injection sites. Using the dye marker is easy and cost effective in cases of a positive result. It is important to use small amounts (1 ml.) of dye and inject the bladder muscular wall or otherwise risk finding the whole operating area blue colored. Detection of radioactive tracer with a handheld a˜ -detection tube during surgery often improves identification of the sentinel node. It may also be helpful to examine excised sentinel nodes at a distance from the operating area to avoid interference with radioactivity from the primary tumor. For various reasons we were not able to use a a˜ -detection tube at the beginning of our investigation. In the 5 cases in which we used this equipment the sentinel node was always identified. Based on our limited study we hypothesize that regional lymph node metastasis, if present, is located in the sentinel node. Extensive lymph node dissection may not be beneficial to patients in whom no metastases are found in sentinel nodes. In our series we have found that of 4 patients 3 had lymph node metastasis located outside the obturator nodes. Thus, detection of sentinel node may provide us with a correct estimation of lymph node involvement, and lead us to more specific and individually tailored approaches for performing major surgery. It is noteworthy that of the 4 detected lymph node metastases 1 was confined to the perivesical boundary of the bladder. Routine histopathological investigation of cystectomy specimens is usually restricted to the bladder tumor itself and parts of the bladder mucosa but seldom to the exterior, macroscopically unaffected bladder wall. Therefore, identification of sentinel nodes in direct conjunction to the external bladder wall may improve staging in these patients.
CONCLUSIONS
To our knowledge this is the first study of sentinel node detection in patients with bladder cancer. We have demonstrated that sentinel nodes can be identified in these patients with a technique based on lymphoscintigraphy and dye marker as aforementioned. In our small series we found that regional lymph node metastases were solely confined to cor-
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER
responding sentinel nodes. In only 1 case was the lymph node metastasis located in the obturator fossa. When the technique was developed for malignant melanoma and breast cancer, detection rates were around 66%.6, 7 Thus, having a higher detection rate in our first study of the sentinel node technique for bladder cancer encourages us to investigate the procedure further. Dr. Mikael Ka¨ llner provided technical support. REFERENCES
1. Ghoneim, M. A., El-Mekresh, M. M., Mokhtar, A. A. et al: A predictive model of survival after radical cystectomy for carcinoma of the bladder. BJU Int, 85: 811, 2000 2. Cabanas, R. M.: An approach for the treatment of penile carcinoma. Cancer, 39: 456, 1977 3. Reintgen, D., Balch, C. M., Kirkwood, J. et al: Recent advances in the care of the patient with malignant melanoma. Ann Surg, 225: 1, 1997 4. McMasters, K. M., Giuliano, A. E., Ross, M. I. et al: Sentinellymph-node biopsy for breast cancer—not yet the standard of care. N Engl J Med, 339: 990, 1998 5. Tho¨ rn, M.: Lymphatic mapping and sentinel node biopsy: is the method applicable to patients with colorectal and gastric cancer? Eur J Surg, 166: 755, 2000 6. Morton, D. L., Wen, D. R., Wong, J. H. et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg, 127: 392, 1992 7. Guiliano, A. E., Kirgan, D. M., Guenther, J. M. et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer.
815
Ann Surg, 220: 391, 1994 8. Alex, J. C., Weaver, D. L., Fairbank, J. T. et al: Gamma probeguided lymph node localization in malignant melanoma. Surg Oncol, 2: 303, 1993 9. Paik, M. L., Scolieri, M. J., Brown, S. L. et al: Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol, 163: 1693, 2000 10. See, W. A. and Fuller, J. R.: Staging of advanced bladder cancer. Current concepts and pitfalls. Urol Clin North Am, 19: 663, 1992 11. Heicappell, R., Muller-Mattheis, V., Reinhardt, M. et al: Staging of pelvic lymph nodes in neoplasms of the bladder and prostate by positron emission tomography with 2-[(18) F]–2– deoxy–Dglucose. Eur Urol, 36: 582, 1999 12. Wishnow, K. I., Johnson, D. E., Ro, J. Y. et al: Incidence, extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical cystectomy for bladder cancer. J Urol, 137: 408, 1987 13. Lerner, S. P., Skinner, D. G., Lieskovsky, G. et al: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastasis: long-term results. J Urol, 149: 758, 1993 14. Poulsen, A. L., Horn, T. and Steven, K.: Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol, 160: 2015, 1998 15. Leissner, J., Hohenfellner, R., Thuroff, J. W. et al: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int, 85: 817, 2000
Vol. 166, 812– 815, September 2001 Printed in U.S.A.
Original Articles LYMPHATIC MAPPING AND DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER A. SHERIF,* M. DE LA TORRE, P.-U. MALMSTRÖM
AND
M. THÖRN
From the Departments of Urology, Pathology and Surgery, University Hospital, Uppsala, Sweden
ABSTRACT
Purpose: We examined the possibility for detecting sentinel nodes in patients with bladder cancer and whether the histopathological status of identified sentinel nodes reflected that of the lymphatic field. Materials and Methods: A total of 13 patients with bladder cancer who met the criteria qualifying them for radical cystectomy had intravesical injections of radioactive tracer and blue dye marker around the tumor followed by lymphoscintigraphy to visualize lymphatic drainage and detect sentinel nodes. Sentinel nodes were identified preoperatively by the blue color and increased radioactivity and were compared histopathologically with other routinely excised lymph nodes. Results: Sentinel nodes were detected in 85% (11 of 13) of patients. There were 4 patients who had sentinel nodes containing tumor cells, and each metastasis was only seen in the detected sentinel node. There were no false-negative sentinel nodes. Of the metastatic sentinel nodes 3 were located outside the normally excised lymph nodes of the obturator fossa. Conclusions: Sentinel nodes can be detected in patients with bladder cancer. The histopathological status of the identified sentinel nodes was diagnostic for all other excised lymph nodes. Sentinel nodes often seem to be located outside the obturator lymphatic field, which is normally examined during preoperative staging of bladder cancer. KEY WORDS: bladder neoplasms, lymph node excision, radionuclide imaging, cystectomy
Studies of prognostic factors in patients with muscle invasive bladder cancer show the histological status of regional lymph nodes as one of the most important predictors of survival.1 Surgical treatment of invasive bladder cancer includes cystectomy and removal of regional lymphatic nodes, although it is not clear whether lymph node dissection leads to better survival or solely improves staging. The sentinel node concept first introduced by Cabanas proposed that lymphatic drainage from a primary tumor goes to a particular regional lymph node called the sentinel node and then continues to other nodes.2 The sentinel node is specific for each individual, and the tumor status of it can reflect that of the regional lymphatic field. Use of lymphatic mapping and sentinel node biopsy to identify patients with lymph node metastasis is well established in those with malignant melanoma and intensively studied in those with breast cancer.3, 4 The method has also been applied in patients with gastrointestinal cancer.5 Of the markers 2 types are used to identify the sentinel node, dye and radioactive tracer. These makers are usually injected near the tumor, transported in the lymph capillaries and accumulate through phagocytosis by macrophages in the
sentinel node. In the pioneering work regarding melanoma and breast cancer blue dye, including patent blue or lymphazurine blue, was the only marker of the sentinel node.6, 7 Alex et al used radioactive tracer and identified the sentinel node preoperatively with a handheld a˜-detection tube.8 Currently, preoperative lymphoscintigraphy is often part of the method for locating the sentinel node in malignant melanoma and breast cancer and finding the draining regional lymph node basin in some cases, such as midline melanoma,. During surgery the sentinel node is identified with a handheld a˜-detection tube to measure high radioactivity compared with the background radioactivity in the operative field. It is also recognized with dye and visualizing blue colored lymph vessels leading into a blue colored gland. We applied this technique in patients with invasive bladder cancer who were candidates for cystectomy, including lymph node dissection. We examined whether sentinel nodes can be identified in these patients, evaluated the aforementioned different techniques of detection and investigated whether the histological status of the identified sentinel node reflected that of the routinely excised lymphatic field.
Accepted for publication March 2, 2001. MATERIALS AND METHODS Supported by grants from the Swedish Society of Medicine, the Swedish Society of Cancer, and Johanna Hagstrands and Sigfrid Patients. This pilot study was approved by the ethics comLinne´rs Foundation, Stockholm, Sweden. mittee at Uppsala University. All 13 patients gave informed * Requests for reprints: Department of Urology, University Hos- consent and were included in our study. Of these patients 12 pital, SE-751 85 Uppsala, Sweden. were examined with preoperative injection of radioactive Editor’s Note: This article is the first of 5 published in this tracer with lymphoscintigraphy and injection of dye marker issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions right before surgery. One patient was evaluated with dye marker only. The indication for major surgery was invasive on pages 1066 and 1067. 812
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER
FIG. 1. Injection of radioactive tracer or patent blue dye into bladder wall at 4 sites surrounding tumor or residue tumor base.
urothelial bladder cancer (stage T2-T4) in 10 cases and high grade urothelial bladder cancer (stage T1G3) that was multifocal in 3. Lymphoscintigraphy. Before major surgery the patient under general anesthesia was reassessed with cystoscopy and bimanual palpation. Radioactive tracer consisting of 1 ml. Albures (Scanflex, Nycomed Amersham, Milan, Italy), approximately 50 MBq./ml., was injected and divided into 4 equal parts at 4 different sites around the visible tumor or tumor base (fig. 1). A 3.7Fr, 35 cm. long Williams cystoscopy needle (Cook Urological, Spencer, Indiana) directed by an Albarran bridge was used. According to our earlier experience with different techniques in cases of gastrointestinal tumors, we injected the tracer into the muscular wall of the bladder and caution was used not to place it directly beneath the mucous membrane.5 However, care was taken not to penetrate the muscular wall and risk deposing the tracer around the bladder. The patient received an indwelling catheter to empty the bladder before scintigraphy and also wash out excess tracer from the bladder cavity. About an hour after injection the patient underwent lymphoscintigraphy at the department of nuclear medicine. Scintigrams were done in 2 planes, including frontal and lateral views. To enhance the a˜ -camera sensitivity and detect the sentinel node, the primary injection site with high counts of radioactivity was
FIG. 2. Lymphoscintigraphy in patient with bladder cancer. A, frontal view shows prominent sentinel node close to bladder and lymphatic drainage that continues in cranial direction to second lymph node with less uptake of radioactivity. B, lateral view.
813
covered with a lead shield (fig. 2). In those cases in which a sentinel node was not seen after about an hour following injection scintigraphy was repeated after an additional 3 hours. The spreading of tracer indicating the route of lymphatic drainage and suspected sentinel nodes were described for each case. Injection of dye. If major surgery was performed the second day, considering the 6 hour half lifetime of the original tracer, additional tracer was not injected at that time. If more than 24 hours had passed after lymphoscintigraphy, injection of tracer was repeated preoperatively. On the day of major surgery 1.0 ml. patent blue dye was transurethrally injected around the tumor using the same technique aforementioned. After injection the patient was repositioned and redressed for cystectomy. Surgery. According to current practice, lymph node dissection was the first step in which the lymph nodes in the obturator fossa were dissected on each side with a preperitoneal approach. Sentinel nodes were identified by the blue color of the gland and lymph vessels leading into them or by increased radioactivity, as measured with the handheld a˜ detection tube in 5 cases. Dissection also proceeded around the bladder for detection of any sentinel nodes. The nodes overlying the iliac vein up to the iliac bifurcation were examined with the same procedure. Cystectomy was performed thereafter according to regular surgical treatment. Histopathological investigation. The tumor specimen, sentinel node and excised lymph nodes were carefully examined by the pathologist. The histopathological status of the sentinel node was compared with that of all other excised nodes. RESULTS
Sentinel nodes were detected in 11 (85%) patients with lymphoscintigraphy and preoperative investigation based on blue dye or radioactivity. In 2 cases we could not identify any sentinel node with either method (see table). Of the 12 eligible cases sentinel nodes were visible preoperatively with lymphoscintigraphy in 8. All 8 of these patients had only 1 sentinel node and 7 had sentinel nodes that were identified at surgery. In 3 patients lymphoscintigraphy was negative but only dye marker showed the sentinel node in 1, and preoperative examination with the handheld ␥-detection tube identified the sentinel node despite negative dye marker in the other 2. The average number of excised lymph nodes in each patient was 8.5 and median number was 8 (range 5 to 22). Of the 13 patients 4 had lymph node metastases, including 1 metastatic sentinel node and, surprisingly, all other lymph
FIG. 3. Localization of metastatic sentinel nodes
814
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER Patient characteristics
Pt. No. — Pt. Age — Sex 1— 2— 3— 4— 5— 6— 7— 8— 9— 10 — 11 — 12 — 13 —
77 54 60 67 68 57 56 67 55 70 39 70 75
—M —M —M —M —M —M —M —M —F —M —M —M —F
Tumor Stage
Lymphoscintigraphy
Dye Marker
Preop. ␥-Detection
Metastatic Sentinel Node
T2 T3 T1 T4 T4 T2 T2 T1 T3 T2 T1 T3 T4
Not done Neg. Pos. Neg. Neg. Pos. Pos. Pos. Pos. Pos. Pos. Pos. Neg.
Pos. Pos. Pos. Neg. Neg. Pos. Neg. Pos. Pos. Neg. Pos. Neg. Neg.
Not done Not done Not done Not done Not done Not done Not done Not done Pos. Pos. Pos. Pos. Pos.
Yes No No No No Yes No No Yes No No Yes No
nodes were without metastasis. There were no cases of falsenegative sentinel nodes. Only 1 of the metastatic sentinel nodes was in the obturator fossa. The other 3 nodes were around the bladder above the common iliac vein bifurcation and in the pelvic region medial to the obturator fossa, respectively (fig. 3). DISCUSSION
Diagnosis of muscle infiltrating bladder cancer is based on transurethral resection of the bladder tumor, including deeper parts of the bladder wall, and histopathological investigation. Computerized tomography of abdomen and thorax is often used to evaluate extravesical growth and distant metastasis but the sensitivity for detecting nodal metastasis has been low.9 Magnetic resonance imaging has been somewhat better than computerized tomography, with a mean sensitivity of 74% and specificity of 100% in regard to lymph node staging.10 In a study with positron emission tomography, a new imaging modality, the smallest detected lymph node metastasis was a micrometastasis, with a diameter of 0.9 cm. No false-positive results were obtained, but falsenegative cases were seen and positron emission tomography was not considered superior to other techniques.11 Therefore, the presently available imaging techniques have not proved reliable for accurate lymph node staging, and the possibility for detecting sentinel nodes as indicators of lymph node involvement deserves to be evaluated. Radical cystectomy starts with dissection of the regional lymph nodes. This procedure is not controversial, but there are some issues regarding it, including the anatomical extent and possibility to cure patients with lymph node metastasis with surgery alone. Thus, 2 major modifications have evolved regarding the procedure, including limited and extended dissection. Advocated by some, limited dissection consists of removing the lymphatic tissue in the obturator fossa distal to the bifurcation of the common iliac vessels.12 Extended surgery also usually involves the tissue along the common iliac vessels. There are some reports of good prognosis in patients with limited lymphatic spreading that have stimulated the proponents of extended dissection.13, 14 In a recent retrospective study of 447 patients who underwent radical cystectomy the mean number of excised lymph nodes was 14.7 (range 1 to 46).15 The number of lymph nodes removed varied significantly among different surgeons in contrast to the number of those recovered by different pathologists. There was significantly better survival of patients with minimal node positive disease in whom more than 16 nodes were removed compared to those with less removed. Thus, the proponents of extended dissection usually advocate the possibilities of cure with this approach and the minor risk of increased morbidity.14 However, no controlled studies exist supporting the curative value of lymph node dissection. Therefore, only limited dissection as a staging procedure is currently recommended in Sweden and most European countries (unpublished data). The mean number of excised lymph
nodes in our present study was 8.5 nodes (range 5 to 22), which was somewhat smaller than that of Leissner et al.15 Use of the sentinel node method to locate and find lymph node metastasis may imply the diagnosis of it preoperatively and, thus, the possibility to consider extended dissection. Our findings of lymph node metastasis outside the obturator fossa also support the choice for extended dissection. We applied 3 detection methods in our study. Advantages of lymphoscintigraphy include preoperative visualization of lymphatic drainage from the primary tumor with localization of the sentinel node and the possibility of planning lymph node dissection. Disadvantages of the technique include the time and cost of examination, and sometimes the difficulties interpreting the pictures, especially when the sentinel node is located close to the primary tumor, which is hard to outline from the radioactivity of injection sites. Using the dye marker is easy and cost effective in cases of a positive result. It is important to use small amounts (1 ml.) of dye and inject the bladder muscular wall or otherwise risk finding the whole operating area blue colored. Detection of radioactive tracer with a handheld a˜ -detection tube during surgery often improves identification of the sentinel node. It may also be helpful to examine excised sentinel nodes at a distance from the operating area to avoid interference with radioactivity from the primary tumor. For various reasons we were not able to use a a˜ -detection tube at the beginning of our investigation. In the 5 cases in which we used this equipment the sentinel node was always identified. Based on our limited study we hypothesize that regional lymph node metastasis, if present, is located in the sentinel node. Extensive lymph node dissection may not be beneficial to patients in whom no metastases are found in sentinel nodes. In our series we have found that of 4 patients 3 had lymph node metastasis located outside the obturator nodes. Thus, detection of sentinel node may provide us with a correct estimation of lymph node involvement, and lead us to more specific and individually tailored approaches for performing major surgery. It is noteworthy that of the 4 detected lymph node metastases 1 was confined to the perivesical boundary of the bladder. Routine histopathological investigation of cystectomy specimens is usually restricted to the bladder tumor itself and parts of the bladder mucosa but seldom to the exterior, macroscopically unaffected bladder wall. Therefore, identification of sentinel nodes in direct conjunction to the external bladder wall may improve staging in these patients.
CONCLUSIONS
To our knowledge this is the first study of sentinel node detection in patients with bladder cancer. We have demonstrated that sentinel nodes can be identified in these patients with a technique based on lymphoscintigraphy and dye marker as aforementioned. In our small series we found that regional lymph node metastases were solely confined to cor-
DETECTION OF SENTINEL NODES IN PATIENTS WITH BLADDER CANCER
responding sentinel nodes. In only 1 case was the lymph node metastasis located in the obturator fossa. When the technique was developed for malignant melanoma and breast cancer, detection rates were around 66%.6, 7 Thus, having a higher detection rate in our first study of the sentinel node technique for bladder cancer encourages us to investigate the procedure further. Dr. Mikael Ka¨ llner provided technical support. REFERENCES
1. Ghoneim, M. A., El-Mekresh, M. M., Mokhtar, A. A. et al: A predictive model of survival after radical cystectomy for carcinoma of the bladder. BJU Int, 85: 811, 2000 2. Cabanas, R. M.: An approach for the treatment of penile carcinoma. Cancer, 39: 456, 1977 3. Reintgen, D., Balch, C. M., Kirkwood, J. et al: Recent advances in the care of the patient with malignant melanoma. Ann Surg, 225: 1, 1997 4. McMasters, K. M., Giuliano, A. E., Ross, M. I. et al: Sentinellymph-node biopsy for breast cancer—not yet the standard of care. N Engl J Med, 339: 990, 1998 5. Tho¨ rn, M.: Lymphatic mapping and sentinel node biopsy: is the method applicable to patients with colorectal and gastric cancer? Eur J Surg, 166: 755, 2000 6. Morton, D. L., Wen, D. R., Wong, J. H. et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg, 127: 392, 1992 7. Guiliano, A. E., Kirgan, D. M., Guenther, J. M. et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer.
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