On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.2 Rio de Janeiro Mar./Apr. 2004
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
The role of sentinel node mapping in malignant melanoma: experience with 99mTc-phytate and a review of the literature*
Marcelo T. SapienzaI; Marcia G. M. TavaresII; Irene S. EndoII; Guilherme C. Campos NetoII; Margarida M. M. F. LopesIII; Sérgio NakagawaIII; Francisco A. BelfortIII; Jose Soares Jr.I; Shlomo LewinII; Marilia M. S. MaroneI
PhD, Bone Densitometry and Diagnosis Unit - Uddo, São Paulo - Brasil
IIMD, Bone Densitometry and Diagnosis Unit - Uddo, São Paulo - Brasil
IIIMD, Brazilian Cancer Control Institute - IBCC, São Paulo - Brasil
Sentinel lymph node (SLN), corresponding to the first lymph node draining the
tumor, is usually the first one to receive its metastasis, and its biopsy is
used to define the status of the whole lymphatic basin.
OBJECTIVE: The aim of this paper is to describe the use 99mTc-Fitato in SLN localization in malignant melanoma patients, and to review the main indications and information provided by SLN biopsy.
METHOD: A total of 92 patients with malignant melanoma was studied. Lymph node scintigraphy was carried out after the subdermal injection of 99mTc-Phytate. After 18-24 hours, intra-operative SLN localization was carried out using the gamma-probe and lymph node dissection was then performed.
RESULTS: Lymphoscintigraphy identified the sentinel node in all studies and intra-operative detection using gamma-probe was reached in 98.8% of the cases. The SLN was involved in 23 patients (26%). The method's negative predictive value was 100%, and there were no side effects related to 99mTc-Phytate.
CONCLUSION: Scintigraphic and intra-operative sentinel node detection was satisfactorily performed using 99mTc-Phytate, an easily available and low cost radiopharmaceutical. SLN mapping allows the use of more accurate tumor staging techniques and reduces surgical morbidity.
Keywords: sentinel lymph biopsy; radionuclide imaging; melanoma.
The incidence of malignant melanoma is growing worldwide. Three-thousand fifty new cases are detected in Brazil yearly, which results in 1,085 deaths (1.7 new cases and 0.57 deaths per 100,000 inhabitants).1 The treatment of primary melanoma of the skin begins by resection with an ample margin of the tumor. Resection may lead to a cure in cases of localized disease. However, the likelihood of ganglionar involvement increases with thicker lesions, notably affecting 20% of melanoma patients who have intermediary Breslow thickness (1-4 mm). The removal of the entire lymphatic basin may be carried out as complementary treatment in these patients. There is no clear impact of this procedure upon survival rates, apart from its morbidity factor-for lymphedema frequently ends up developing. This is why its indication has been questioned.2
The outcome of treatment basically depends on the initial stage of the disease, because most systemic treatments (including chemistry and immunotherapy) have little impact upon survival. The exception here is high-dose interferon-alpha treatment, which has shown encouraging results.3,4 The main prognosis factors of cutaneous melanoma are tumor thickness, presence of ulceration and detection of ganglionar metastases.5,6 The five-year survival rate is also related to the number of lymph nodes affected, and the presence of micro- or macroscopic affection.7
The concept of sentinel lymph node (SNL) was widely used during the last decade. It has had a large impact upon the staging and prognosis of diverse tumors, including melanoma. SNL corresponds to the first lymph node of the lymphatic basin to receive drainage from a determined region. The latter virtually always corresponds to the first tumoral implantation site (Figure 1), since dissemination typically occurs in an orderly and sequential way. Nevertheless, SNL analysis allows one to define the status of the entire lymphatic basin. Beyond lower morbidity rates resulting from resection of the entire lymphatic basin, ganglion staging starting from the sentinel lymph node may prove to have greater accuracy than a complete resection, for it allows a guided use of existing techniques, such as immunohistochemistry.
The very first SNL studies were performed by Cabanas in 1977. They evidenced lower mortality in patients with penile carcinoma when the first lymph node draining the tumor proved to be disease free.8 In 1992, Morton and cols. undertook SNL mapping of melanoma patients with a preoperative injection of blue dye in the lesion. This was followed by mapping the lymphatic and stained lymph node pathways during surgery.9
The use of dyes has shown good results,10 though within certain limits only. Visual analysis as a means of identifying stained lymph nodes is based upon the assumption that the tumor's drainage basin is known beforehand. Such is not usually the case (especially in patients with melanoma of the trunk). Likewise, lymph node detection in atypical localizations can also be difficult. The required interval for the appearance of dye in the lymph node varies. This leads to an increased risk of lymphatic dissection prior to the staining of SNL or after the dye's progression to a larger number of lymph nodes.
In 1993, Alex and Krag proposed intradermal injection of colloidal sulfur marked with 99mTc-Phytate around the melanoma, followed by scintigraphy to determine the lymphatic drainage path and identify SNL.11 Marking the lymph node projection on the skin prior to surgery helps guide surgeons. Furthermore it allows for less aggressive incisions and dissections. Development of a portable radiation detector, a.k.a. the gamma-probe, allows intraoperative application of radioisotope techniques to localize sentinel lymph nodes. A combined use of lymphoscintigraphy and the probe enhances detection rates and allows rapid access to the ganglionic chain with a lower mortality rate.
SNL detection in patients with malignant melanoma was one of the first situations in which the SNL concept gained validity. These initial studies have been widely confirmed ever since.6,12,13 Improved staging and prognostic information obtained from SNL biopsies are extra reasons for explaining the speed with which the technique has acquired such widespread acceptance. This paper describes the group's experience in detecting SNL by the use of 99mTc-Phytate. It also offers revised indications, and discusses the main information gathered from a SNL biopsy.
MATERIAL AND METHODS
Lymphoscintigraphy used for detecting SNL was carried out on 92 patients (32 male and 60 female, 54±14.3 years of age) between March 1998 and July 2002. The Institution's Ethics Board approved the study, and patients were previously informed as to the procedures involved.
None of the patients subjected to melanoma resection showed any suspected clinical ganglionar involvement. The first lesion was localized on the trunk in 38 patients, lower limbs in 35, upper limbs in 15 and the throat in four cases. The medial depth of the tumor was 4 mm ± 3.9 (varying from 0.4-20 mm), with a level of Clark equal to I for 1.5% of lesions, II for 13%, III for 42%, IV for 25% and V for 18%.
Lymphoscintigraphy was carried out after subdermal injection of 0.8 ml of Phytate marked with the 99mTechnique (Ipen, São Paulo), set at 55-74 MBq (1.5-2 mCi). The injection was applied to four or more points around the resection wound of the primary tumor.
Lymph node scintigraphy was carried out with a model SPX-6 scintigraphy camera (Elscint, Haifa) with a low-energy, high-resolution collimator, at the UDDO/Brazilian Cancer Control Institute Nuclear Medicine Service. The study's dynamic phase consisted of 30-second images obtained over five minutes after injection of the radiopharmaceutical. Static images were obtained in 10-60 minute intervals after the injection. When SNL identification within the first hour of study was not possible, images were obtained up to four hours later. The patient's position varied according to the progression observed during the study's dynamic phase and localization of the primary lesion (trunk, thorax/axilla and basin projections; lower limbs-basin projections; upper limbs-thorax/axilla projections; head and throat-thorax, axilla and cranial projections). Additional images of the popliteal region and elbows were taken for the tumors found at the extremities. Lymph nodes identified by scintigraphy were marked on the skin. Moreover, it is preferable for the patient to be in the position designated for surgery.
Surgery was performed 18-24 hours after lymph node scintigraphy. The intraoperative localization of SNL was made with the use of patent blue dye and the gamma-probe. The GAMMED II (Eurorad) gamma-probe was used to assess the number of radioactive counts detected on the skin (a region previously marked during the lymphoscintigraphy). This procedure thus confirmed the SNL position prior to the initial incision. The probe was then covered by a sterile protector and utilized by the surgeon to guide the intraoperative SNL mapping. The number of SNL counts in vivo, and following the resection, was measured and registered. Should radioactivity persist during surgery at over 1/10 of the counts detected prior to the SNL removal, mapping and resection would then have to be performed on the other traced lymph nodes. By the end of SNL mapping, the peritumoral margin had grown. At the initial phase of implementing the procedure, total resection of the ganglionic chain was also performed on all of the 36 patients.
After SNL removal, we moved on to macroscopic analysis of the tumor, and measured its three diameters and longitudinal incision. The lymph node was then embedded in paraffin, thus obtaining 3 µm cuts and hematoxylin-eosine staining. Immunohistochemical techniques were not applied systematically with this group due to routine unavailability at the hospital.
Lymphoscintigraphy with 99mTc-Phytate revealed rapid progression of the radiopharmaceutical. SNL identification was still in the dynamic phase for most patients (Figure 2). There were no local or systemic adverse reactions observed after injecting the radiopharmaceutical.
Simultaneous draining of two or more lymphatic basins was observed in nine patients. Draining of unexpected basins by lesion topography was found in six, and popliteal lymph nodes detected in seven cases (Figure 3). Of the seven patients with sentinel lymph nodes in popliteal areas (always associated with inguinal lymph nodes), two showed tumor involvement, while in one, the inguinal chain was free from disease.
Intraoperative SNL detection with the gamma probe was performed in 88 patients. It was not performed on four individuals since the equipment was not available on the day set aside for surgery. SNL was identified and achieved in 87 cases (98.8%) (Figure 4), with an average of 2.1 sentinel lymph nodes per patient. The sole patient in whom SNL was not found, either by the gamma-probe or blue staining, showed a tumor on the medial line of the high dorsal region. Lymphoscintigraphy revealed drainage to the posterior cervical chain.
The SNL biopsy revealed lymphatic dissemination of the melanoma in 23 patients. SNL resection was followed by removal of the whole ganglionic chain in 36 patients, including those who had disease-free SNL during the initial phase of implementing the method at our service. Among these 36 patients there was no single case of SNL false negative results from conventional histopathological analysis. And the SNL was the sole lymph node affected by a tumor in 16 cases (44%). The histopathological analysis of SNL, nonetheless, proved to have a predictive potential over whether or not the basin would be affected in all of the 36 patients (Table 1).
Lymphoscintigraphy and radiopharmaceuticals used in SNL detection
The skin shows a rich network of lymphatic vessels localized primarily in the most superficial layer of the dermis, i.e. near the epidermis.14 Sub- or intra-dermal injections of different substances allow the study of lymphatic drainage and a few variations in draining velocity and lymphatic retention that depend on the physical characteristics of the injected composite. Progression in the lymphatic pathways depends primarily on particle size. Particles with the highest molecular weight are among the least and slowest to progress. On the other hand, low molecular weight composites are not retained in lymph nodes, as opposed to particulate materials (such as colloids), which are retained most likely by phagocytosis. Colloids consist of the majority of radiopharmaceuticals used to detect sentinel lymph nodes. SNL detection is made possible because a colloid is linked to a radioactive tracer, usually the 99mTc. The radioactivity of latter may be detected in images obtained by the scintillation camera or gamma probe.
Lymphoscintigraphy is an essential step in studying SNL. The images obtained allow an assessment of the draining pattern and accurate identification of one or more related chains at the injection site. As such, the gamma probe (or even the dye) may provide better guidance in its use during surgery. Atypical or unexpected draining patterns were often observed, above all in patients with trunk lesions. The use of lymphoscintigraphy has shown that areas with ambiguous draining are far more extensive than those classically described along the head to truck medial line, and in the thoracic-abdominal transition (areas described in Sappey's studies).15 In this latter study, 15 patients (16%) showed drainage in more than one lymphatic basin, or in an unexpected basin with respect to the primary lesion site. Another seven showed sentinel lymph nodes in the popliteal region, which is a common finding in cases of tumors in the extremities, though seldom found in reports in the literature.16
The literature does show relatively homogenous results in SNL detection with radioisotopes in spite of many methodological differences. The most frequent variations match up with the use of different radiopharmaceuticals, radioactivity, volumes and administration pathways. There is almost unanimous agreement to recommend administration of small volumes (0.2 ml) around the primary lesions or surgical wound via intra- or subdermal pathways.
What is also considered ideal is the use of particles (20-500 nm in diameter),17 since the use of large diameter particles is limited by a slow lymphatic progression. On the other hand, small diameter particles do not experience phagocytosis and may engulf the entire basin. Among the most common radiopharmaceuticals, albumin nanocolloids are used in Europe and antimony composites in Oceania, as well as modified/filtered colloidal sulfur in the USA. Still, availability of the first two radiopharmaceuticals cited is very limited in Brazil. This situation highlights the lack of uniformity and the technical difficulties involved in preparing colloidal sulfur. It is most likely for this reason that we see radiopharmaceuticals being used here more than Dextran and 99mTc-Phytate.
In spite of how hard it is to measure the particle diameter correctly, about five years ago 99mTc-Phytate was cited as possibly becoming an alternative in SNL detection. This suggestion was raised due especially to how phytate biodistribution resembles nanocolloids in the reticuloendothelial system. 99mTc-Phytate was initially described in a study of the reticuloendothelial system in 1973, which has a colloid formation in vivo after a calcium ion reaction. 18 The measures undertaken after adding calcium in a 1:1 or 2:1 molar relation to 99mTc-Phytate, and performed with the electron microscope and conductibility studies, indicate the formation of particles <500 nm in diameter.19,20 The spleen imaging observed after intravenously administering the 99mTc-Phytate in patients is similar to what has been observed with nanocolloids and poorer than with colloidal sulfur. These results confirm the lower-diameter particle formation.
The use of 99mTc-Phytate for lymphoscintigraphy has already been described.21,22 The specific use of SNL detection was reported for the group by the authors.23 The fast-moving progression of 99mTc-Phytate in the initial phase, with SNL identification still at the dynamic phase in the initial minutes of the study, may be related to migrating low-weight molecular composites prior to the colloid's formation in vivo. On the other hand, retention and concentration of radiopharmaceuticals in SNL, only slowly progressing to the rest of the basin, indicates that colloid formation occurs in the course between the subcutaneous layer and SNL.
Impact of the SNL biopsy on the staging and prognosis of the melanoma
The intraoperative mapping of SNL is widely indicated for patients with thick (>1-mm) lesions and with no clinical evidence of ganglionic metastasis. Roughly 20% of tumor patients showing a 1-4 mm Breslow have SNL metastasis. This value rises to 34% among patients with >4 mm index, and falls to 4.7% in patients with <1 mm index in association with ulcerated lesions or level of Clark IV.6 The SNL status has achieved such widespread acceptance that it is now included in the staging proposed by the American Joint Committee on Cancer for Malignant Cutaneous Melanoma.24,25
SNL detection may also be indicated for patients with more superficial lesions (<1mm),26,27 in spite of the obvious fact that deeper tumors are more likely to show ganglionar dissemination.28,29 The prognostic value of sentinel node biopsy is confirmed for thick (>/=4-mm) tumors.30
Proper intraoperative SNL identification is described in 98% of cases with radiomarked colloids, 75-80% with dyes and 98-99% with a combination of both.25 Also described is a greater than 98% accuracy rate from SNL biopsy to predict the affection of the entire lymphatic basin.6,12,13 In a recent review of 1,135 melanoma cases, SNL was detected with radioisotopes in 97% of patients, with a negative predictive value of 100%.31 The results shown in the present study are similar, with rates of 98 and 100%, respectively.
The mapping of ganglion affection at SNL may be even greater than at the access to the entire basin, thereby allowing a more detailed study and the use of techniques aiming at detecting micrometastases. The lower number of analyzed lymph nodes allows the pathologist not only to boost the number of sections per lymph node, but also to apply more sensitive techniques, such as immunohistochemistry or PCR (polymerase chain reaction).32,33 Immunohistochemistry with antibodies directed at S100 and HMB45 antigens enhances the sensitivity of metastasis detection by roughly 14%,34,35 though it was not routinely available for the study of patients at the institution.
The latest recommendations by the American Joint Committee on Cancer for Malignant Cutaneous Melanoma include SNL status in the staging, in addition to using the term "micrometastasis" for lymph nodes that show no macroscopic involvement.24 The clinical significance of a micrometastasis (mainly when detected only by PCR) and its impact on survival rates, however, remain controversial.32,33
The infiltration of SNL is recognized to be the most important prognostic factor for primary melanoma patients (in the absence of metastases at other sites). SNL involvement is a strong predictor of recurrence and survival. A mortality rate of 6% is found in SNL-negative patients compared to 30% in SNL-positive patients who received follow-up for an average of 37 months.2,36 Gershenwald2,36 has reported that SNL is the most important survival indicator in stage I and II melanoma patients. It is therefore more significant than Breslow thickness and presence of ulceration. The percentage of patients who are free of disease for an interval of three years dropped from 96.8 to 69.9% when receiving SNL follow up. Even among patients with thicker melanoma, there is a significant reduction in recurrence when SNL is negative (37 vs. 73% of patients free of disease for three years).7
A negative SNL biopsy, however, does not guarantee the patient against showing recurrence in the future. Various authors report recurrence in 1-6% of SNL-negative patients36,37,38,39 Regional recurrence among SNL-negative patients might be even less when using more sensitive techniques. It has been noted that the review of SNL cuts elucidates a large part of the recurrences in cases initially interpreted to be SNL-negative.40 Also, it ought to be observed that 5% frequency rate of close regional recurrence is similar to what can be seen to occur following elective lymphadenectomy,41 and that complete resection of the basin did not noticeably increase survival rates in melanoma and SNL-negative patients.28,31
The indications for elective lymphadenectomy are still controversial. Their impact upon survival is not clear when considering a population with a roughly 20% likelihood of ganglionic affection. The best selection of patients for elective lymphadenectomy might perhaps be performed by means of assessing the SNL. SNL-negative patients would thus be exempted from the procedure. In this case, the main cause of morbidity in elective lymphadenectomy would be reduced, since lymphedema is described in only 1.7% of patients after SNL biopsy.42
The fact of micrometastasis patients showing better survival than those with macroscopic involvement43 suggests that early removal of the affected lymph nodes may improve the patient's course. Nevertheless, three clinical randomized trials failed to show significant differences in overall survival rates for SNL-positive patients subjected to a complementation of ganglionic emptying.44,45,46 These trials were discussed by Balch,47 who highlighted the fact that most patients had not undergone preoperative scintigraphy to confirm the correct identification of the draining basin. These data are crucial when considering the high frequency of draining to more than one lymphatic basin or unexpected localizations. New clinical studies meant to assess the therapeutic results of selective lymphadenectomy based on SNL detection are being carried out.48 These considerations, namely on the need for better patient stratification to assess therapeutic response, are being applied not only to lymphadenectomy, but also to other protocols, such as interferon or vaccine use.
SNL biopsy showed a high degree of accuracy for the ganglionic staging of patients with malignant melanoma. It has also proved to be an important prognostic factor. Correctly defining lymphatic staging, then, may have therapeutic implications. The latter specifically include whether the most required indication is to resection the entire lymphatic basin, or use systemic therapies.
The results obtained in SNL detection with 99mTc-Phytate, which is a widely available radiopharmaceutical in Brazil, were comparable to those described in the literature. q
1. Estimativa da incidência e mortalidade por cancer no Brasil. INCA - Ministério da Saúde 2002: [ Links ]
2. Fife K, Thompson, JF. Lymph-node metastases in patients with melanoma: what is the optimum management? Lancet Oncol 2001;2(10):614-621. [ Links ]
3. Agarwala SS, Kirkwood JM. Update on adjuvant interferon therapy for high-risk melanoma. Oncology (Huntingt) 2002;16(9):1177-1187. [ Links ]
4. Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001;19(9):2370-2380. [ Links ]
5. Morton DL, Wanek L, Nizze JA, Elashoff RM, Wong JH. Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic. Ann Surg 1991;214(4):491-499. [ Links ]
6. Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17(3):976-983. [ Links ]
7. Cherpelis BS, Haddad F, Messina J, Cantor AB, Fitzmorris K, Reintgen DS, Fenske NA et al. Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 2001;44(5):762-766. [ Links ]
8. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39(2):456-466. [ Links ]
9. Morton DL, Wen DR, Wong JH, Economou,JS, Cagle LA, Storm FK et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127(4):392-399. [ Links ]
10. Bostick PJ, Giuliano AE. Vital dyes in sentinel node localization. Semin Nucl Med 2000;30(1):18-24. [ Links ]
11. Alex JC, Weaver DL, Fairbank,JT, Rankin BS, Krag DN. Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 1993;2(5):303-308. [ Links ]
12. Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F et al. The orderly progression of melanoma nodal metastases. Ann Surg 1994;220(6):759-767. [ Links ]
13. Thompson JF, McCarthy WH, Bosch CM, O'Brien CJ, Quinn MJ, Paramaesvaran S et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 1995;5(4):255-260. [ Links ]
14. Lubach D, Ludemann W, Berens VR. Recent findings on the angioarchitecture of the lymph vessel system of human skin. Br J Dermatol 1996;135(5):733-737. [ Links ]
15. Uren RF, Howman-Giles R, Thompson JF. Patterns of lymphatic drainage from the skin in patients with melanoma. J Nucl Med 2003;44(4):570-582. [ Links ]
16. Thompson JF, Hunt JA, Culjak G, Uren RF, Howman-Giles R, Harman CR. Popliteal lymph node metastasis from primary cutaneous melanoma. Eur J Surg Oncol 2000;26(2):172-176. [ Links ]
17. Eshima D, Fauconnier T, Eshima L, Thornback JR. Radiopharmaceuticals for lymphoscintigraphy: including dosimetry and radiation considerations. Semin Nucl Med 2000;30(1):25-32. [ Links ]
18. Strand SE, Persson BR. Quantitative lymphoscintigraphy I: Basic concepts for optimal uptake of radiocolloids in the parasternal lymph nodes of rabbits. J Nucl Med 1979;20(10):1038-1046. [ Links ]
19. Campbell J, Bellen JC, Baker RJ, Cook DJ. Technetium-99m calcium phytate--optimization of calcium content for liver and spleen scintigraphy: concise communication. J Nucl Med 1981;22(2):157-160. [ Links ]
20. Galvez AJ, Garcia SC, Garcia DR, Moreno, FJ. [99mTc]Ca-phytate: some colloidal characteristics related to the optimal preparation conditions. Int J Appl Radiat Isot 1983;34(12):1647-1649. [ Links ]
21. Alavi A, Staum MM, Shesol BF, Bloch PH. Technetium-99m stannous phytate as an imaging agent for lymph nodes. J Nucl Med 1978;19(4):422-426. [ Links ]
22. Kaplan WD, Davis MA, Rose CM. A comparison of two technetium-99m-labeled radiopharmaceuticals for lymphoscintigraphy: concise communication. J Nucl Med 1979;20(9):933-937. [ Links ]
23. Tavares MG, Sapienza MT, Galeb NA, Belfort FA, Costa RR, Osorio CA et al. The use of 99mTc-phytate for sentinel node mapping in melanoma, breast cancer and vulvar cancer: a study of 100 cases. Eur J Nucl Med 2001;28(11):1597-1604. [ Links ]
24. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19(16):3635-3648. [ Links ]
25. Mariani G, Gipponi M, Moresco L, Villa G, Bartolomei M, Mazzarol G et al. Radioguided sentinel lymph node biopsy in malignant cutaneous melanoma. J Nucl Med 2002;43(6):811-827. [ Links ]
26. Bedrosian I, Faries MB, Guerry D, Elenitsas R, Schuchter L, Mick R et al. Incidence of sentinel node metastasis in patients with thin primary melanoma (< or = 1 mm) with vertical growth phase. Ann Surg Oncol 2000;7(4):262-267. [ Links ]
27. Lowe JB, Hurst E, Moley JF, Cornelius LA. Sentinel lymph node biopsy in patients with thin melanoma. Arch Dermatol 2003;139(5):617-621. [ Links ]
28. Caggiati A, Potenza C, Gabrielli F, Passarelli F, Tartaglione G. Sentinel node biopsy for malignant melanoma: analysis of a four-year experience. Tumori 2000;86(4):332-335. [ Links ]
29. Gennari R, Bartolomei M, Testori A, Zurrida S, Stoldt HS, Audisio RA et al. Sentinel node localization in primary melanoma: preoperative dynamic lymphoscintigraphy, intraoperative gamma probe, and vital dye guidance. Surgery 2000;127(1):19-25. [ Links ]
30. Carlson GW, Murray DR, Hestley A, Staley CA, Lyles RH, Cohen C. Sentinel Lymph Node Mapping for Thick (>/=4-mm) Melanoma: Should We Be Doing It? Ann Surg Oncol 2003; 10(4):408-415. [ Links ]
31. Chan AD, Morton DL. Sentinel node detection in malignant melanoma. Recent Results Cancer Res 2000;157:161-177. [ Links ]
32. Krag DN, Weaver DL. Pathological and molecular assessment of sentinel lymph nodes in solid tumors. Semin Oncol 2002;29(3):274-279. [ Links ]
33. da Silva AM, Oliveira Filho RS, Ferreira LM, Saconato H. Relevance of micrometastases detected by reverse transcriptase-polymerase chain reaction for melanoma recurrence: systematic review and meta-analysis. Sao Paulo Med J 2003;121(1):24-27. [ Links ]
34. Cochran AJ, Wen DR, Morton DL. Occult tumor cells in the lymph nodes of patients with pathological stage I malignant melanoma. An immunohistological study. Am J Surg Pathol 1988;12(8):612-618. [ Links ]
35. Baisden BL, Askin FB, Lange JR, Westra WH. HMB-45 immunohistochemical staining of sentinel lymph nodes: a specific method for enhancing detection of micrometastases in patients with melanoma. Am J Surg Pathol 2000;24(8):1140-1146. [ Links ]
36. Cascinelli N, Belli F, Santinami M, Fait V, Testori A, Ruka W et al. Sentinel lymph node biopsy in cutaneous melanoma: the WHO Melanoma Program experience. Ann Surg Oncol 2000;7(6):469-474. [ Links ]
37. Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998;16(6):2253-2260. [ Links ]
38. Landi G, Polverelli M, Moscatelli G, Morelli R, Landi C, Fiscelli O et al. Sentinel lymph node biopsy in patients with primary cutaneous melanoma: study of 455 cases. J Eur Acad Dermatol Venereol 2000;14(1):35-45. [ Links ]
39. Statius Muller MG, Borgstein PJ, Pijpers R, Van Leeuwen PA, Van Diest PJ, Gupta A et al. Reliability of the sentinel node procedure in melanoma patients: analysis of failures after long-term follow-up. Ann Surg Oncol 2000;7(6):461-468. [ Links ]
40. Clary BM, Brady MS, Lewis JJ, Coit DG. Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence. Ann Surg 2001;233(2):250-258. [ Links ]
41. Shen P, Guenther JM, Wanek LA, Morton DL. Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences? Ann Surg Oncol 2000;7(2):114-119. [ Links ]
42. Wrone DA, Tanabe KK, Cosimi AB, Gadd MA, Souba WW, Sober AJ. Lymphedema after sentinel lymph node biopsy for cutaneous melanoma: a report of 5 cases. Arch Dermatol 2000;136(4):511-514. [ Links ]
43. McMasters KM, Reintgen DS, Ross MI, Gershenwald JE, Edwards MJ, Sober A et al. Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 2001;19(11):2851-2855. [ Links ]
44. Balch CM, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 2000;7(2):87-97. [ Links ]
45. Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc 1986;61(9):697-705. [ Links ]
46. Veronesi U, Adamus J, Bandiera DC, Brennhovd O, Caceres E, Cascinelli N et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 1982;49(11):2420-2430. [ Links ]
47. Balch CM. The John Wayne Clinical Research Lecture. Surgical management of melanoma: results of prospective randomized trials. Ann Surg Oncol 1998;5(4):301-309. [ Links ]
48. McMasters KM. Sentinel Lymph Node biopsy for melanoma. Melanoma Res 2001;11(suppl 1):s5-s7. [ Links ]
Marcelo Tatit Sapienza
Serviço de Medicina Nuclear - Hospital Samaritano
Rua Conselheiro Brotero, 1486
01232-010 São Paulo SP
Tel.: (11) 3825-4433
in June, 13th of 2003
Approved by the Consultive Council and accepted for publication in October, 07th of 2003
* Work done at "Unidade de Diagnóstico e Densitometria Óssea - Uddo, São Paulo" and "Instituto Brasileiro de Controle do Câncer - IBCC, São Paulo".