HOW I DO IT

Introduction: Sentinel Lymphadenectomy forPatients With Clinical Stage I Melanoma

DONALD L. MORTON, MD*John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California

Approximately 10–60% of patients diagnosed with cu-taneous malignant melanoma have tumor involvement ofthe regional lymph nodes. Their overall rate of 5-yearsurvival is only 30%–40%, reflecting the putative asso-ciation between lymph node involvement and aggressiveprogression to distant metastases. Early identificationand removal of tumor-involved lymph nodes can curtailthe spread of melanoma, but prophylactic or electivelymphadenectomy (ELND) remains controversial. Retro-spective reviews demonstrated a 15–25% improvementin survival [1–3]; prospective randomized trials initiallyshowed no survival advantage but were noted to haveinherent design flaws [4,5]. Recent results from the In-tergroup Melanoma Trial demonstrated no overall sur-vival advantage but identified subsets of patients forwhom ELND appears to be beneficial (patients under 60years old with primary melanomas 1–2 mm in thickness)[6].

In 1990, during a presentation to the Society of Sur-gical Oncology, we introduced intraoperative lymphaticmapping and sentinel lymphadenectomy (SLND) as apotential solution to the controversy surrounding ELNDin patients with clinical stage I malignant melanoma. Asfirst published in our 1992 report [7], SLND uses logicalanatomic and physiologic principles to identify occultregional node metastases. Mastery of SLND eliminatesroutine ELND, thereby reducing overall health care costsand avoiding extensive resection of the lymph node basinin patients with tumor-free lymph nodes (who are un-likely to benefit from the procedure).

As described below, the technique of SLND hasevolved in the hands of its originators at the John WayneCancer Institute (JWCI). It has also been successfullyadopted by surgical oncologists at other centers. In thisissue, Dr. John F. Thompson of the Sydney MelanomaUnit in Australia, Dr. Merrick Ross of M.D. AndersonCancer Center in Houston, Dr. Douglas Reintgen of Mof-fitt Cancer Center in Tampa, and Dr. C.P. Karakousis ofthe Millard Fillmore Hospital/State University of New

York in Buffalo, describe their technique and results forSLND in patients with primary cutaneous melanoma.

PREOPERATIVE LYMPHOSCINTIGRAPHY

At JWCI we always obtain a dynamic preoperativelymphoscintigram before SLND. This is necessary notonly to identify the lymphatic basin(s) draining a cuta-neous melanoma but also to identify and mark the posi-tion of the sentinel node(s) and lymphatic channel(s). Asthe location of the primary moves from the distal extrem-ity to the trunk and the head and neck, historical ana-tomic guidelines become increasingly inaccurate foridentifying the primary lymphatic drainage basin(s)[8,9]. Moreover, approximately 25% of patients havemore than one sentinel lymph node. Each of these sen-tinel nodes may receive drainage from one or more lym-phatic channels, but no single channel drains into morethan one sentinel node. By following the image of thelymphatic channel(s) into the identified sentinel lymphnode(s), dynamic lymphoscintigraphy usually can distin-guish multiple sentinel nodes from a solitary sentinelnode with secondary drainage. In the 3–5% of patientswith in-transit aberrant lymph nodes, lymphoscintigra-phy can visualize nodes outside the lymphatic basinalong the primary lymphatic channel. Multiple views arenecessary to define the lymphatic anatomy and its loca-tion within the draining lymphatic basin.

Lymphoscintigraphy can be performed with a varietyof agents that vary in particle size and composition. Par-ticle size determines the time to optimum visualization:smaller, uniformly labeled particles are visualized fasterthan larger, nonuniform particles. As demonstrated in thefollowing reports from Drs. Thompson, Reintgen andRoss, the timing of colloid injection varies considerably

*Correspondence to: Donald L. Morton, MD, John Wayne CancerInstitute, 2200 Santa Monica Blvd., Santa Monica, CA 90404. Phone:310-829-8781; Fax: 310-582-7185.Accepted 28 August 1997

Journal of Surgical Oncology 1997;66:267–269

© 1997 Wiley-Liss, Inc.

among institutions. At JWCI, we usually perform lym-phoscintigraphy the day before or the morning of sur-gery, so that the mark placed on the skin by our nuclearmedicine colleague (to identify the number and the lo-cation of lymphatic channels and sentinel node[s]) doesnot wear off. Also, when preoperative lymphoscintigra-phy is performed no more than 24 hours before SLND,there is enough residual radioactivity to use the gammaprobe as an adjunct for intraoperative localization of sen-tinel nodes (see below).

INTRAOPERATIVE MAPPING: BLUE DYEAND PROBE

Intraoperative mapping can be carried out with a vitaldye (usually patent blue or isosulfan blue), differentnuclear agents of varying or uniform particle size, or acombination of dye and labeled agent. Although our ini-tial approach to SLND used isosulfan dye alone, in 1993we began using isosulfan blue mixed with radiolabeledhuman serum albumin; in 1994 we presented our resultsto the Society of Surgical Oncology [10]. We believe thata 2:1 combination of vital dye and radiolabeled pharma-ceutical is additive in its ability to localize the sentinelnode, and we now use both agents in every case.

An intradermal injection of 1–2 cc of the localizingagent is administered around the primary lesion. The ex-act volume of dye depends on the distance between theprimary site and the nodal basin. If excisional biopsy haspreceded definitive surgery, care must be taken not toinject the dye into the biopsy cavity. Accurate lymphaticmapping usually is not possible following a wide localexcision using 2-cm margins, especially if local flaps orskin grafts have been used to close the defect [11]. Whenthe dye is used, the interval between dye injection andsurgical incision will vary depending upon the physiol-ogy of the patient and the distance between the site ofinjection and the draining lymphatic basin.

If a radiopharmaceutical is used, it is usually techne-tium-labeled sulfur colloid or human serum albumin. In-traoperative radiolymphoscintigraphy was originally in-troduced due to technical difficulties with the use of dyealone, especially in axillary drainage basins [7,10]. Afterthe radiopharmaceutical is injected at the site of the pri-mary tumor, a hand-held gamma probe is used to map thelymphatic channel(s), lymph node basin(s) and sentinelnode(s) by monitoring the emitted counts in relationshipto the background. No standardization has yet been es-tablished; guidelines for the ratio of counts between thesentinel node(s) and lymph node basin(s) have been pro-posed but vary widely among different authors [12–15].

A concerted effort must be made to identify the lym-phatic channel since this is the key to detecting the truesentinel node(s). Meticulous dissection is employed tofollow the channel both proximally (to rule out anyproximal sentinel nodes) and distally into the sentinel

node. Usually a short segment of the channel is excisedwith the lymph node. Surgical attention to detail andfamiliarity with the procedure have fostered success withSLND among surgeons at JWCI. We define surgical pro-ficiency as 90% accuracy in identifying the sentinelnode, which is usually reached after undertaking 30cases. Most surgeons will achieve 98% accuracy afterexperience with 100 cases.

EXAMINATION OF THE SENTINELLYMPH NODE

Both Drs. Ross and Reintgen stress the importance ofcareful histopathologic evaluation of the sentinel nodespecimen. Even if localization and excision of sentinelnodes are successful, the results of SLND will not beaccurate unless the pathologist undertakes a diligentsearch for nodal micrometastases. At JWCI, we bivalvethe specimen and process its two faces immediately byfrozen section analysis. Standard hematoxylin and eosinstaining (H&E) is performed later on four sections, andall negative results are verified using immunohistochem-ical staining with HMB-45 and S-100 antibodies. Furthersurgical therapy is dictated by the results of histopatho-logical analysis.

Serial sectioning and immunohistochemical analysisare more sensitive in detecting microscopic nodal metas-tases than is standard histopathologic preparation; wecurrently study 12 sections of the serially sectioned sen-tinel node. Results of cell culture of excised lymph nodepreparations have been used to upstage 21% of node-negative patients [16]. However, the time and expertiseof this technique prohibit its general acceptance.

Submicroscopic molecular biologic techniques usingreverse transcriptase polymerase chain reaction (RT-PCR) have been proposed as a method of identifyingsubmicroscopic nodal metastases [17]. One study re-ported that 28% of nodes were upstaged with this mo-dality [18]. Caution is necessary because capsular nevi,Schwann cells, and nerves are present in about 25% ofsentinel nodes and may cause a false-positive tyrosinasesignal [19]. However, Dr. Reintgen has previously re-ported interim follow-up data indicating that the disease-free interval is reduced considerably when nodes areidentified as tumor-positive by standard histopathologyand RT-PCR [20]. The metastatic cells are often found inthe vicinity of the afferent lymphatic, in the subcapsularlymph node space.

SUMMARY

Consistent results with SLND can only be obtainedthrough the combined efforts of the nuclear medicinephysician, the surgeon, and the pathologist. These indi-viduals must have experience with the technical detailsof SLND and must understand and accept the multidis-ciplinary nature of this technique.

268 Morton

The reports in this issue of theJournal of SurgicalOncologyprove that SLND is accurate and reproducible.Drs. Thompson and Karakousis both report a 93% rate ofsentinel node identification, and Dr. Reintgen reports arate of 96%. At JWCI, our overall rate of sentinel nodeidentification has now reached 98%. The ultimate resultsof SLND as a therapeutic procedure in patients withclinical stage I cutaneous melanoma await completion ofour international phase III multicenter trial (‘‘A ClinicalStudy of Wide Excision Alone Versus Wide Excisionwith Intraoperative Lymphatic Mapping and SelectiveLymph Node Dissection in the Treatment of Patientswith Cutaneous Invasive Melanoma’’; D.L. Morton,Principal Investigator), which is now in its third year ofaccrual. At the present time, we believe that lymphaticmapping and selective (sentinel) lymph node dissectionis an investigational procedure whose therapeutic utilityis unproven. Until clinical trials are completed and thereis technique standardization among various centers, thisprocedure should not be used as routine therapy in acommunity hospital outside the setting of a clinical trial.Although intraoperative lymphatic mapping and SLNDmay provide prognostic information, if its therapeuticutility is not demonstrated by current multicenter clinicaltrials, it is likely to be replaced by molecular RT-PCRtechniques that directly measure tumor burden in theblood [21].

REFERENCES1. Balch CM, Soong S-J, Murad TM, Ingalls AL, Maddox WA: A

multifactorial analysis of melanoma: III. Prognostic factors inmelanoma patients with lymph node metastases (stage II). AnnSurg 1981;193:377–388.

2. Morton DL, Wanek L, Nizze JA, Elashoff RM, Wong JH: Im-proved long-term survival after lymphadenectomy of melanomametastatic to regional nodes. Ann Surg 1991;214:491–501.

3. Das Gupta TK: Results of treatment of 269 patients with primarycutaneous melanoma: A five-year prospective study. Ann Surg1977;186:201–209.

4. Sim FH, Taylor WF, Ivins JC, Pritchard DJ, Soule EH: A pro-spective randomized study of the efficacy of routine electivelymph node lymphadenectomy in management of malignant mela-noma: Preliminary results. Cancer 1978;41:948–956.

5. Veronesi U, Adamus J, Bandiera DC, Brennhovd IO, Caceres E,Cascinelli N, et al.: Inefficacy of immediate node dissection instage I melanoma of the limbs. N Engl J Med 1977;297:627–631.

6. Balch CM, Soong S-J, Bartolucci AA, Urist MM, Karakousis CP,Smith TJ, et al.: Efficacy of an elective regional lymph nodedissection of 1 to 4 mm thick melanomas for patients 60 years ofage and younger. Ann Surg 1996;224:255–266.

7. Morton DL, Wen D-R, Wong JH, Economou JS, Cagle LA, StormFK, et al.: Technical details of intraoperative lymphatic mappingfor early stage melanoma. Arch Surg 1992;127:392–399.

8. Fee HJ, Robinson DS, Sample WF, Graham LS, Holmes EC,Morton DL: The determination of lymph shed by colloidal goldscanning in patients with malignant melanoma: a preliminarystudy. Surgery 1978;84:626–632.

9. Morton DL, Wen D-R, Foshag LJ, Essner R, Cochran AJ: Intra-operative lymphatic mapping and selective cervical lymphadenec-tomy for early-stage melanomas of the head and neck. J ClinOncol 1993;11:1751–1756.

10. Essner R, Foshag LJ, Morton DL. Intraoperative radiolympho-scintigraphy: a useful adjunct to intraoperative lymphatic mappingand selective lymphadenectomy in patients with clinical stage Imelanoma. Presented at the Society of Surgical Oncology, Hous-ton, TX: March 1994.

11. Morton DL, Wen D-R, Cochran AJ: Management of early-stagemelanoma by intraoperative lymphatic mapping and selectivelymphadenectomy or ‘‘watch and wait’’. Surg Oncol Clin NorthAm 1992;1:247–259.

12. Albertini JJ, Cruse CW, Rapaport D, Wells K, Ross M, DeContiR, et al.: Intraoperative radiolymphoscintigraphy improves senti-nel lymph node identification for patients with melanoma. AnnSurg 1996;223:217–224.

13. Glass LF, Messina JL, Cruse W, Wells K, Rapaport D, Miliotes G,et al.: The use of intraoperative radiolymphoscintigraphy for sen-tinel node biopsy in patients with malignant melanoma. DermatolSurg 1996;22:715–720.

14. Krag DN, Meijer SJ, Weaver DL, Loggie BW, Harlow SP, TanabeKK, et al.: Minimal-access surgery for staging of malignant mela-noma. Arch Surg 1995;130:654–658.

15. Mudun A, Murray DR, Herda SC, Eshima D, Shattuck LA, Van-sant JP, et al.: Early stage melanoma: Lymphoscintigraphy, re-producibility of sentinel node detection, and effectiveness of theintraoperative gamma probe. Radiology 1996;199:171–175.

16. Heller R, Becker J, Wasselle J, Baekey P, Cruse W, Wells K, etal.: Detection of submicroscopic lymph node metastases in pa-tients with melanoma. Arch Surg 1991;126:1455–1460.

17. Doi F, Chi DDJ, Charuworn BB, Conrad AJ, Russell J, MortonDL, Hoon DSB: Detection ofb-human chorionic gonadotropinmRNA as a marker for cutaneous malignant melanoma. Int JCancer 1996;65:454–459.

18. Wang X, Heller R, Van Voorhis N, Cruse CW, Glass F, Fenske N,et al.: Detection of submicroscopic lymph node metastases withpolymerase chain reaction in patients with malignant melanoma.Ann Surg 1994;220:768–774.

19. Carson KF, Wen D-R, Li P-X, Lana AM-A, Bailly C, Morton DL,Cochran AJ: Nodal nevi and cutaneous melanomas. Am J SurgPathol 1996;20:834–840.

20. Reintgen D: Melanoma nodal metastases: biological significanceand therapeutic considerations. Surg Oncol Clin North Am 1996;5:105–120.

21. Hoon DSB, Wang Y, Dale PS, Conrad AJ, Schmid P, Garrison D,et al.: Detection of occult melanoma cells in blood with a mul-tiple-marker polymerase chain reaction assay. J Clin Oncol 1995;13:2109–2116.

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