sentinel-lymph-node biopsy for cutaneous melanoma

clinical therapeutics

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;18 nejm.org may 5, 20111738

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,

the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations.

Sentinel-Lymph-Node Biopsy for Cutaneous Melanoma

Jeffrey E. Gershenwald, M.D., and Merrick I. Ross, M.D.

From the Department of Surgical Oncol-ogy, University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Gershenwald at the Uni-versity of Texas M.D. Anderson Cancer Center, Unit 1484, P.O. Box 301402, Hous-ton, TX 77230-1402, or at [email protected].

N Engl J Med 2011;364:1738-45.Copyright © 2011 Massachusetts Medical Society.

A 38-year-old woman presented to her dermatologist with a 2-month history of changes in a mole on her right upper back. The mole had been present for a few years, but recently the patient had noticed episodes of itching and observed blood on her blouse. On skin examination, this pigmented lesion was 8 mm in diameter and had irregular borders and variegated color. An excisional biopsy was performed; pathological examination revealed a superficial spreading melanoma, 2.8 mm thick (i.e., in depth), with ulceration and six mitotic figures per square millimeter. Sub-sequent examination of the patient revealed a healing biopsy site over the right up-per back. There was no clinical adenopathy and no evidence of in-transit or satellite metastases. The patient had no specific symptoms indicative of metastatic disease. A surgical oncologist was consulted, who recommended that the patient undergo wide excision of the primary tumor and sentinel-lymph-node biopsy in the same opera-tive setting.

The Clinic a l Problem

Melanoma is an important public health problem; by 2015, the estimated lifetime risk of the development of cutaneous melanoma will be 1 in 50.1,2 Approximately 68,000 patients were expected to receive a diagnosis of invasive melanoma in the United States in 2010.3 Although melanoma represents only 10% of all skin-cancer diagno-ses, at least 65% of deaths that are related to skin cancer are attributed to melanoma.4

Melanoma is most commonly diagnosed when it is clinically localized to the primary tumor site (American Joint Committee on Cancer [AJCC] clinical stages I and II). At its earliest invasive stage (i.e., stage IA), the prognosis is favorable, with 5-year and 10-year survival estimates of 97% and 93%, respectively (Fig. 1).5 In con-trast, the prognosis for a patient with distant metastasis (stage IV melanoma) is poor; 1-year and 5-year overall survival rates are 45% and 12%, respectively.5

Various clinicopathological factors have been identified that influence the prog-nosis. The most important of these are the following primary tumor characteristics: thickness (defined as the depth of tumor invasion, measured in millimeters with an ocular micrometer),6 presence or absence of ulceration (defined as loss of epidermis overlying the melanoma),7 and mitotic rate (defined as the number of mitoses per square millimeter).5 Collectively, these elements define AJCC staging criteria for stage I and stage II melanoma (Tables 1 and 2 in the Supplementary Appendix, available with the full text of this article at NEJM.org). These factors influence the prognosis largely because they predict the presence of clinically occult nodal metas-tases, which is the most important independent predictor of survival.8,9 Patients in whom palpable regional lymph-node involvement (AJCC stages IIIB and IIIC) develops have a guarded prognosis, with at least a 50% risk of future distant metastases.10

A video showing a sentinel-lymph-

node biopsy is available at

NEJM.org

The New England Journal of Medicine Downloaded from nejm.org at LINKOPING UNIVERSITY on August 19, 2013. For personal use only. No other uses without permission.

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

clinical Ther apeutics

n engl j med 364;18 nejm.org may 5, 2011 1739

PATHOPH YSIOL O GY A ND EFFEC T OF THER A PY

Cutaneous melanoma arises from melanocytes, the pigment-producing cells that are derived from the neural crest and that are found at the dermal–epidermal junction of the skin. The growth and spreading of melanoma have been described as occurring in an initial horizontal-growth or radial-growth phase, in which the melanoma is primarily confined to the epidermis (but may penetrate the papillary dermis), followed by a vertical-growth phase, in which the melanoma acquires the ability to invade deeper into the dermis.11 Metastasis tends to occur first to regional lymph nodes (AJCC stage III) and subsequently to various secondary sites (AJCC stage IV).5,12

Biopsy of a suspicious pigmented lesion fol-lowed by histologic assessment provides defini-tive diagnosis and the essential primary tumor information (i.e., tumor thickness, ulceration, and mitotic rate). Since this information defines the disease stage and predicts the risk of occult re-gional lymph-node metastases, it influences treat-ment recommendations.5

The technique of lymphatic mapping and sentinel-lymph-node biopsy was first proposed in the 1980s as a minimally invasive procedure for identifying patients with clinical stage I and stage II melanoma who have occult (microscop-ic) disease.13,14 The rationale for sentinel-node biopsy relies on the concepts that different regions of the skin have specific patterns of lymphatic drainage to the regional nodes and that, for a given region of skin, there is at least one specific lymph node — that is, the “sentinel” node or nodes — in the regional lymph-node basin or ba-sins to which cutaneous afferent lymphatic ves-sels drain first. Studies have confirmed that the sentinel node is the most likely first site of me-tastasis and have shown that if the sentinel node is histologically negative, the remaining lymph nodes in the mapped basin are unlikely to con-tain disease.14-16 The term “biopsy” is perhaps a misnomer (particularly to patients), since the bi-opsy is excisional in nature and the entire sentinel node is removed and subjected to rigorous his-tologic analysis.

CLINIC A L E V IDENCE

The goals of sentinel-node biopsy include accurate nodal staging, enhanced regional disease control,

and improved survival. In short, the procedure is intended to identify patients with clinically node-negative disease who in fact have occult nodal me-tastases and to improve the outcomes for these patients by preventing the development of clinical (palpable) regional node involvement. The proce-dure is also intended to identify patients with pathologically node-negative disease for whom additional treatment may not be indicated.

The accuracy of nodal evaluation of sentinel-node–biopsy specimens has been assessed. Rates of false negative results, determined by concomi-tant complete lymphadenectomy at the time of sentinel-node biopsy, were reported to be ap-proximately 5%.13-16 These findings have been corroborated by studies that showed rates of recurrence ranging from 3% to 6% in a nodal basin that had been determined to be negative for disease after examination of a sentinel-node–biopsy specimen.8,17,18 Sentinel-node biopsy thus allows more precise staging than does clinical

Surv

ival

(%)

100

80

60

40

20

00 5 10 15 20

Years

B Stage III Melanoma

A Stage I and Stage II Melanoma

Surv

ival

(%)

100

80

60

40

20

00 5 10 15 20

Years

IA (N=9425)

IIA (N=4644)

IIB (N=3228)

IIC (N=1397)

IIIA (N=1196)

IIIB (N=1391)

IIIC (N=720)

IB (N=8918)

Figure 1. Survival Estimates for Stage I and Stage II Melanoma (Panel A) and Stage III Melanoma (Panel B).

Data are from the American Joint Committee on Can-cer melanoma staging database.5





evaluation alone, without the requirement for com-plete lymph-node dissection.

The effectiveness of regional disease control when guided by findings on sentinel-node–biopsy specimens has also been evaluated. Rates of re-currence in a regional nodal basin range from 2% to 10% after treatment with formal lymphadenec-tomy performed because of a positive sentinel-node–biopsy specimen.17,19 In contrast, rates of recurrence in a regional nodal basin range from 20% to 50% among patients who undergo lymph-adenectomy for palpable disease.20,21

The only randomized trial to date to evaluate the potential survival benefit of sentinel-node biopsy is the Multicenter Selective Lymphadenec-tomy Trial I (MSLT I; ClinicalTrials.gov number, NCT00275496).8 In this trial, 1269 patients with a primary melanoma that was at least 1 mm thick were randomly assigned to sentinel-node biopsy (and completion dissection if examination of the biopsy specimen was positive) or nodal observa-tion (and lymphadenectomy if clinical nodal re-currence subsequently developed). At an interim analysis, there was no significant difference be-tween the observation group and the sentinel-node–biopsy group in the primary end point of melanoma-specific survival at 5 years (86.6% vs. 87.1%; hazard ratio, 0.92; 95% confidence inter-val [CI], 0.67 to 1.25; P = 0.58).8 However, in a prespecified analysis, patients in the observation group in whom clinical nodal recurrence devel-oped (and who therefore underwent delayed lymph-adenectomy) had significantly poorer melanoma-specific survival at 5 years than did those in the sentinel-node–biopsy group whose nodes were positive (and who thus underwent early lymph-adenectomy) (52.4% vs. 72.3%; hazard ratio, 0.51; 95% CI, 0.32 to 0.81; P = 0.007). The validity of this comparison rests on the assumption that all mi-crometastases seen on examination of the senti-nel-node–biopsy specimen would have progressed to palpable disease if left untreated; there is some evidence in support of this assumption.22,23 The final analysis of MSLT I has not yet been pub-lished.

CLINIC A L USE

The decision to recommend sentinel-lymph-node biopsy is made principally on the basis of the predicted risk of occult regional nodal disease (see the Supplementary Appendix). Tumor thick-

ness and ulceration are important independent predictors of sentinel-node metastasis.24,25 More recently, a high mitotic rate and lymphovascular invasion have been associated with increased rates of positive sentinel nodes.26-30 In general, we con-sider patients with cutaneous melanoma to be candidates for sentinel-node biopsy if they have a primary tumor that is at least 1 mm thick or if they have a primary tumor that is less than 1 mm thick and has other potentially adverse features, such as ulceration, a high mitotic rate (≥1 mitosis per square millimeter), lymphovascular invasion, invasion of the reticular dermis (Clark level IV) or subcutaneous tissue (Clark level V), or a positive deep margin on examination of a biopsy specimen.

Before surgery, a physical examination should be performed to identify or rule out additional primary melanomas, in-transit or satellite disease (or both), and clinically suspicious regional lymph nodes. Chest radiography, computed tomography (CT), combined positron-emission tomography and CT, and magnetic resonance imaging are generally not recommended in the absence of clinical suspicion, since radiographically detect-able distant metastatic disease in an asymptom-atic patient with early-stage melanoma is unlike-ly.31,32 In patients in whom examination of the regional nodal basin suggests possible clinical in-volvement, ultrasonography should be considered, with fine-needle aspiration biopsy performed if suspicious adenopathy is identified. Regional node metastasis obviates the need for sentinel-node biopsy in that basin; however, a negative fine-needle aspirate does not rule out microscopic disease, and a sentinel-node biopsy is still indi-cated.

Lymphoscintigraphy is performed to estab-lish a preoperative road map of nodal basins that are at risk and to facilitate intraoperative identi-fication of the sentinel nodes (Fig. 2).33 Lympho-scintigraphy facilitates surgical planning, since some primary melanomas, particularly of the trunk and head and neck, may be associated with drainage to multiple nodal basins. In the United States, lymphoscintigraphy is performed by means of intradermal injection of technetium-99m–labeled sulfur colloid. Recently, preopera-tive localization of sentinel nodes has been en-hanced with the use of single-photon-emission CT (SPECT)–CT hybrid imaging, which is particu-larly useful in the head and neck region.34 In some institutions, lymphoscintigraphy is performed just





before surgery; in others, it is performed on a day before surgery and is generally followed by re-peat injection of radiotracer 1 to 2 hours before surgery.

Sentinel-node biopsies are typically performed on an outpatient basis (see video, available at NEJM.org) with the use of intravenous sedation or general anesthesia. After the induction of an-esthesia, isosulfan blue dye is injected intrader-mally around the biopsy site or the residual in-tact melanoma (Fig. 3). The general location of the sentinel node is determined with the use of a handheld scanner with a gamma-sensor probe that detects the technetium-99m–labeled sulfur colloid that was previously injected around the primary melanoma site. An incision is then made over the area of highest radionuclide accumula-tion, and the sentinel node is identified within the incision by inspection; the isosulfan blue dye will usually stain any draining nodes blue. The use of both radionuclide and blue dye for sentinel-node localization has been called the “dual mo-dality” approach.

After excision of the sentinel nodes, wide local excision of the primary tumor is performed to re-duce the likelihood of local recurrence due to the possibility of microscopic spread around the origi-nal primary melanoma. Rescanning of relevant nodal basins (and intervening afferent lymphatic pathways, to identify interval or ectopic sentinel nodes, or both) is performed with the gamma probe to ensure removal of all sentinel nodes.

Detailed examination of the sentinel node or nodes is generally performed with the use of he-matoxylin and eosin staining at multiple levels and immunohistochemically stained sections from each node.35 Although the most appropriate sec-tioning and staining protocol has not been deter-mined, there is consensus that for best results, sentinel-node biopsy requires a coordinated effort among the surgery, pathology, and nuclear medi-cine and diagnostic imaging teams. Sentinel-node evaluation by means of examination of immedi-ate (intraoperative) frozen sections is not recom-mended, because it is less sensitive than postop-erative examination of formalin-fixed tissue.36

For patients with all negative sentinel nodes, no further surgery of regional nodal basins is rec-ommended. For patients with at least one posi-tive sentinel node, completion lymphadenectomy is the standard of care. Although completion lymphadenectomy provides durable control of re-

gional basins, its effect on disease-specific sur-vival remains an area of intense investigation.8,37

Options for adjuvant systemic therapy, including participation in clinical trials and treatment with high-dose interferon alfa, are discussed routinely with patients who have positive sentinel nodes and selectively with a subgroup of patients who have negative sentinel nodes.

In 2003, the cost of sentinel-node biopsy was estimated to be $10,000 to $15,000 at one U.S. center.38 This estimate included all fees for physi-cians, medications, nuclear medicine, pathologi-cal studies, and use of facilities.

A DV ER SE EFFEC T S

Adverse effects of sentinel-node biopsy include wound complications (e.g., infection, wound sep-aration, and formation of seromas or hematomas) and regional complications (e.g., lymphedema, thrombophlebitis, pain, numbness, and loss of range of motion). These complications are less commonly associated with sentinel-node biopsy than with complete lymphadenectomy. In MSLT I, complications involving the surgical site occurred

A B

C D

Figure 2. Lymphoscintigraphic Images from a Patient with a Cutaneous Melanoma in the Middle of the Back.

An anteroposterior view (Panel A) shows the primary melanoma (arrow) and sentinel nodes in the right axilla (black arrowhead) and left axilla (white arrowhead). In a posteroanterior view (Panel B), afferent lymphatics are seen draining from the primary site (arrow) to the axillary nodes in the right axilla (black arrowhead) and left axilla (white arrowhead). A right lateral view (Panel C) shows the primary melanoma (arrow) and sentinel nodes in the right axilla (arrowhead). A left lateral view (Panel D) shows the primary melanoma (arrow) and sentinel nodes in the left axilla (arrowhead).





in 10.1% of patients undergoing sentinel-node biopsy alone and in 37.2% of those undergoing sentinel-node biopsy and complete lymph-node dissection.39 In the Sunbelt Melanoma Trial, over-all complication rates were 4.6% among patients undergoing sentinel-node biopsy alone as com-pared with 23.2% among those undergoing sen-tinel-node biopsy and complete lymph-node dis-section. The most notable complications were wound infection (1.1% vs. 7.0%), lymphedema (0.7% vs. 11.7%), and hematoma or seroma for-mation (2.3% vs. 5.9%).40 In MSLT I, patients who had a positive sentinel-node–biopsy speci-men and underwent completion lymphadenecto-my had a lower incidence of lymphedema and a shorter hospital stay than those who underwent delayed lymphadenectomy for clinical nodal re-currence.41 Allergic reaction to isosulfan blue dye

during sentinel-node biopsy in patients with mel-anoma has been reported, but the incidence is low (0.2% in MSLT I).8,39

Concern has been expressed that sentinel-node biopsy and completion lymphadenectomy in pa-tients with positive sentinel nodes may increase the risk of in-transit metastasis — defined as cu-taneous or subcutaneous deposits of melanoma between the primary tumor and the regional lymph-node basin to which cutaneous afferent lymphatic vessels drain — by the obstruction of lymph flow due to mechanical disruption of the lymphatics.42,43 However, both single-insti-tution studies and the prospective, randomized MSLT I trial show that the development of in-transit melanoma depends on tumor biology (e.g., increasing thickness of the primary tumor, the presence of ulceration of the primary tumor, a

Sentinellymph node

Sentinellymph nodes

Sentinellymph node

Surgical exposure of sentinel lymph node

Primarymelanoma

Afferentlymphaticchannel

Afferentlymphaticchannels

A

Injection site

B

Figure 3. Sentinel-Node Localization.

After the intradermal injection of blue dye around a primary cutaneous melanoma of the left abdominal wall (Panel A), afferent lymphatic drainage to a left inguinal sentinel lymph node and two left axillary sentinel lymph nodes occurs. Panel B shows surgical exposure of the first of two sentinel nodes in the left axilla. Note the two afferent lymphatic vessels entering the sentinel node.





primary tumor on the leg, or sentinel-node me-tastasis) and not on the surgical approach to regional lymph nodes.8,44-47

A r e a s of Uncerta in t y

Controversy exists regarding the role of sentinel-node biopsy in patients with thick primary tumors (>4 mm). Such patients have a high risk of subse-quent distant metastatic disease after treatment of the primary tumor. Nevertheless, sentinel-node status is the most important independent predic-tor of survival, even among these patients.48-50

Efforts have also been made to identify pa-tients with thin primary tumors (<1 mm) who are at high risk for sentinel-node metastasis. Al-though this issue is not completely resolved, primary tumor characteristics, including the pres-ence of ulceration, Clark level IV or V, a mitotic rate of at least 1 mitosis per square millimeter, a thickness of at least 0.75 mm, and lymphovas-cular invasion, have been used as selection crite-ria.51 The use of Clark level IV or V as a selection criterion in patients with thin melanomas is the subject of ongoing debate because of seemingly conflicting data concerning the association of Clark level IV or V with sentinel-node involvement and a recent AJCC analysis5 that failed to con-firm the usefulness of Clark level as an indepen-dent predictor of prognosis. The presence of in-vasive melanoma at the base (deep margin) of a shave-biopsy specimen, particularly extensive in-volvement, may indicate that the recorded mea-surement underestimates the true thickness of the primary tumor and hence the predicted risk of sentinel-node metastasis.

Use of young age as the sole selection crite-rion in patients with thin melanoma represents an ongoing unresolved controversy; definitions of “young age” have been inconsistent, as have data showing an increased risk of sentinel-node metastases.24-26,51 Indications for sentinel-node biopsy among patients with thin primary tumors will most likely continue to evolve, perhaps lead-ing to an approach that is based on assessment of individual patient risk.

Questions have been raised about the accuracy of sentinel-node biopsy in patients who have al-ready had a wide local excision of the primary tumor. In particular, it is unclear whether senti-nel-node biopsy is accurate in patients who have had previous extensive reconstructive rotational f laps, since the lymphatic drainage of the re-

maining skin may be different from that of the skin that was immediately adjacent to the origi-nal primary melanoma.52 Sentinel-node biopsy should be performed at the time of initial wide excision whenever possible.

The majority of patients (approximately 85%) who undergo completion lymphadenectomy after a finding of a positive sentinel-node–biopsy spec-imen do not have additional involved nodes in the lymphadenectomy specimen53; routine com-pletion lymphadenectomy in such patients has therefore been challenged. Potential additional selection criteria, including the size of the senti-nel-node metastases and the thickness of the primary tumor, have been proposed,53,54 but no single factor or combination of factors has defini-tively identified patients who have no risk of ad-ditional positive nodes and for whom comple-tion lymphadenectomy can be safely omitted. MSLT II (NCT00297895), a prospective, multi-center clinical trial, is addressing this important clinical question by randomly assigning patients with sentinel-node involvement to completion lymphadenectomy or nodal observation.

Also unresolved is the use of ultrasonography of the nodal basin with fine-needle aspiration, as an alternative to sentinel-node biopsy. Although one group has reported considerable sensitivity with this approach,55,56 at least one other group has not.57

Guidelines

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma recommend that sentinel-node biopsy should be discussed with and offered to patients with melanoma classified as stage IB (≤1.00 mm thick with ulceration or a mitotic rate ≥1 mitosis per square millimeter, or 1.01 to 2.00 mm thick without ulceration) or stage II (1.01 to 2.00 mm thick with ulceration, or >2.00 mm thick). Although there are no uniformly accepted guide-lines for stage IA melanoma, the NCCN guide-lines suggest that sentinel-node biopsy should be considered for patients with stage IA melanoma and “adverse” features that might portend a high-er risk of sentinel-node involvement, such as tumor thickness of 0.75 mm or more, positive deep mar-gins, lymphovascular invasion, or Clark level IV or V. They also note that, for lower-risk patients, such as those with stage IA or stage IB lesions with a maximum thickness of 0.5 mm and a mi-





totic rate of fewer than 2 mitoses per square mil-limeter, sentinel-node biopsy should generally not be recommended, unless there are specific clini-cal indications. The complete NCCN guidelines (updated February 2011; version 2.2011) are avail-able at www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.32

The AJCC guidelines are consistent with the NCCN guidelines, supporting the use of senti-nel-node biopsy for patients with clinical stage IB to stage IIC primary melanoma.5,58 The Clini-cal Practice Guidelines for the Management of Melanoma in Australia and New Zealand (available at www.nzgg.org.nz/guidelines/dsp_guideline_popup.cfm?guidelineID=141) generally support the concept that sentinel-node biopsy should be dis-cussed with patients who have a risk of a positive sentinel node.

R ecommendations

The patient described in this vignette is an excel-lent candidate for sentinel-node biopsy. The clini-cal stage of her melanoma is IIB (Tables 1 and 2 in the Supplementary Appendix); her predicted risk of microscopic nodal disease is approxi-mately 25 to 30%. We recommend that the pa-tient undergo wide local excision with a 2-cm margin and concomitant sentinel-node biopsy on

an outpatient basis while under general anesthe-sia. To identify nodal basins that are at risk and to facilitate intraoperative sentinel-node localization, preoperative lymphoscintigraphy (with or with-out SPECT–CT imaging) should be performed either on a day before or on the day of surgery.

If there is at least one positive sentinel node, completion lymphadenectomy would be recom-mended after a discussion with the patient about the risk of having additional positive nodes; par-ticipation in MSLT II would be discussed. In col-laboration with our melanoma medical oncology team, adjuvant therapy, including high-dose inter-feron alfa-2b, or participation in a clinical trial would also be considered.

If the sentinel nodes are negative, no addi-tional regional surgery would be recommended, although in view of the patient’s pathological stage IIB diagnosis, we would discuss adjuvant therapy in the context of ongoing clinical trials.

Dr. Gershenwald reports receiving consulting fees from GlaxoSmithKline and Metamark Genetics, lecture fees from Imedex, fees for manuscript preparation from Clinical Care Op-tions, royalties from Mercator Therapeutics, and fees for the development of educational presentations from Schering. Dr. Ross reports receiving consulting fees from GlaxoSmithKline and Genentech, lecture fees from Dava Oncology and Genomic Health, and travel reimbursement from Genentech. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References

1. Ries LAG, Melbert D, Krapcho M, et al. SEER cancer statistics review, 1975-2005. Bethesda, MD: National Cancer In-stitute, 2008. (http://seer.cancer.gov/csr/ 1975_2005.)2. Rigel DS, Russak J, Friedman R. The evolution of melanoma diagnosis: 25 years beyond the ABCDs. CA Cancer J Clin 2010;60:301-16.3. Jemal A, Siegel R, Xu J, Ward E. Can-cer statistics, 2010. CA Cancer J Clin 2010; 60:277-300.4. Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CA. Increasing burden of melanoma in the United States. J Invest Dermatol 2009;129:1666-74.5. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melano-ma staging and classification. J Clin On-col 2009;27:6199-206.6. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prog-nosis of cutaneous melanoma. Ann Surg 1970;172:902-8.7. Balch CM, Wilkerson JA, Murad TM, Soong SJ, Ingalls AL, Maddox WA. The prognostic significance of ulceration of

cutaneous melanoma. Cancer 1980;45: 3012-7.8. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. [Erratum, N Engl J Med 2006;355:1944.]9. Gershenwald JE, Thompson W, Mans-field PF, et al. Multi-institutional mela-noma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma pa-tients. J Clin Oncol 1999;17:976-83.10. Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal mi-crometastases versus macrometastases. J Clin Oncol 2010;28:2452-9.11. Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355:51-65.12. Gershenwald JE, Hwu P. Melanoma. In: Hong WK, Bast RC Jr, Hait WN, et al., eds. Cancer medicine. 8th ed. Shelton, CT: People’s Medical Publishing House, 2010:1459-86.13. Morton DL, Wen DR, Wong JH, et al.

Technical details of intraoperative lym-phatic mapping for early stage melano-ma. Arch Surg 1992;127:392-9.14. Ross MI, Reintgen D, Balch CM. Se-lective lymphadenectomy: emerging role for lymphatic mapping and sentinel lymph node biopsy in the management of early stage melanoma. Semin Surg Oncol 1993;9:219-23.15. Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg 1994;220:759-67.16. Thompson JF, McCarthy WH, Bosch CM, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Mel-anoma Res 1995;5:255-60.17. Chao C, Wong SL, Ross MI, et al. Pat-terns of early recurrence after sentinel lymph node biopsy for melanoma. Am J Surg 2002;184:520-4.18. Gershenwald JE, Colome MI, Lee JE, 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;16:2253-60.





19. Gershenwald JE, Berman RS, Porter G, Mansfield PF, Lee JE, Ross MI. Region-al nodal basin control is not compro-mised by previous sentinel lymph node biopsy in patients with melanoma. Ann Surg Oncol 2000;7:226-31.20. Lee RJ, Gibbs JF, Proulx GM, Kollmor-gen DR, Jia C, Kraybill WG. Nodal basin recurrence following lymph node dissec-tion for melanoma: implications for adju-vant radiotherapy. Int J Radiat Oncol Biol Phys 2000;46:467-74.21. Ballo MT, Ang KK. Radiotherapy for cutaneous malignant melanoma: ratio-nale and indications. Oncology (Williston Park) 2004;18:99-107.22. Morton DL, Cochran AJ, Thompson JF. The rationale for sentinel-node biopsy in primary melanoma. Nat Clin Pract On-col 2008;5:510-1.23. Sentinel-node biopsy in melanoma. N Engl J Med 2007;356:418-21.24. Rousseau DL Jr, Ross MI, Johnson MM, et al. Revised American Joint Com-mittee on Cancer staging criteria accu-rately predict sentinel lymph node positiv-ity in clinically node-negative melanoma patients. Ann Surg Oncol 2003;10:569-74.25. McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in pa-tients with melanoma. Surgery 2001;130: 151-6.26. Sondak VK, Taylor JM, Sabel MS, et al. Mitotic rate and younger age are predic-tors of sentinel lymph node positivity: les-sons learned from the generation of a probabalistic model. Ann Surg Oncol 2004;11:247-58.27. Kruper LL, Spitz FR, Czerniecki BJ, et al. Predicting sentinel node status in AJCC stage I/II primary cutaneous mela-noma. Cancer 2006;107:2436-45.28. Paek SC, Griffith KA, Johnson TM, et al. The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma. Cancer 2007;109: 100-8.29. Doeden K, Ma Z, Narasimhan B, Swetter SM, Detmar M, Dadras SS. Lym-phatic invasion in cutaneous melanoma is associated with sentinel lymph node me-tastasis. J Cutan Pathol 2009;36:772-80.30. Petersson F, Diwan AH, Ivan D, et al. Immunohistochemical detection of lym-phovascular invasion with D2-40 in mela-noma correlates with sentinel lymph node status, metastasis and survival. J Cutan Pathol 2009;36:1157-63.31. Choi EA, Gershenwald JE. Imaging studies in patients with melanoma. Surg Oncol Clin N Am 2007;16:403-30.32. National Comprehensive Cancer Net-work (NCCN) clinical practice guidelines in oncology. Fort Washington, PA: NCCN, 2011. (http://www.nccn.org/professionals/ physician_gls/pdf/melanoma.pdf.)33. Uren RF, Howman-Giles R, Thomp-son JF. Patterns of lymphatic drainage

from the skin in patients with melanoma. J Nucl Med 2003;44:570-82.34. Uren RF. SPECT/CT lymphoscintigra-phy to locate the sentinel lymph node in patients with melanoma. Ann Surg Oncol 2009;16:1459-60.35. Scolyer RA, Prieto VG. Melanoma pa-thology: important issues for clinicians involved in the multidisciplinary care of melanoma patients. Surg Oncol Clin N Am 2011;20:19-37.36. Scolyer RA, Thompson JF, McCarthy SW, Gershenwald JE, Ross MI, Cochran AJ. Intraoperative frozen-section evalua-tion can reduce accuracy of pathologic as-sessment of sentinel nodes in melanoma patients. J Am Coll Surg 2005;201:821-3.37. Wong SL, Morton DL, Thompson JF, et al. Melanoma patients with positive sentinel nodes who did not undergo com-pletion lymphadenectomy: a multi-insti-tutional study. Ann Surg Oncol 2006;13: 809-16.38. Agnese DM, Abdessalam SF, Burak WE Jr, Magro CM, Pozderac RV, Walker MJ. Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 2003;134:542-7.39. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302-11.40. Wrightson WR, Wong SL, Edwards MJ, et al. Complications associated with sentinel lymph node biopsy for melano-ma. Ann Surg Oncol 2003;10:676-80.41. Faries MB, Thompson JF, Cochran A, et al. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphade-nectomy Trial (I). Ann Surg Oncol 2010; 17:3324-9.42. Estourgie SH, Nieweg OE, Kroon BB. High incidence of in-transit metastases after sentinel node biopsy in patients with melanoma. Br J Surg 2004;91:1370-1.43. Thomas JM, Clark MA. Selective lymphadenectomy in sentinel node-posi-tive patients may increase the risk of local/in-transit recurrence in malignant melanoma. Eur J Surg Oncol 2004;30:686-91.44. Pawlik TM, Ross MI, Johnson MM, et al. Predictors and natural history of in-transit melanoma after sentinel lymphad-enectomy. Ann Surg Oncol 2005;12:587-96.45. Kang JC, Wanek LA, Essner R, Faries MB, Foshag LJ, Morton DL. Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in pri-mary melanoma. J Clin Oncol 2005;23: 4764-70.46. van Poll D, Thompson JF, Colman MH, et al. A sentinel node biopsy does not increase the incidence of in-transit metas-tasis in patients with primary cutaneous

melanoma. Ann Surg Oncol 2005;12:597-608.47. Pawlik TM, Ross MI, Thompson JF, Eggermont AM, Gershenwald JE. The risk of in-transit melanoma metastasis de-pends on tumor biology and not the sur-gical approach to regional lymph nodes. J Clin Oncol 2005;23:4588-90.48. Gershenwald JE, Mansfield P, Lee J, Ross M. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or = 4 mm) primary mela-noma. Ann Surg Oncol 2000;7:160-5.49. Gajdos C, Griffith KA, Wong SL, et al. Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma? Cancer 2009;115:5752-60.50. Scoggins CR, Bowen AL, Martin RC II, et al. Prognostic information from sen-tinel lymph node biopsy in patients with thick melanoma. Arch Surg 2010;145:622-7.51. Andtbacka RH, Gershenwald JE. Role of sentinel lymph node biopsy in patients with thin melanoma. J Natl Compr Canc Netw 2009;7:308-17.52. Gannon CJ, Rousseau DL Jr, Ross MI, et al. Accuracy of lymphatic mapping and sentinel lymph node biopsy after previous wide local excision in patients with pri-mary melanoma. Cancer 2006;107:2647-52.53. Gershenwald JE, Andtbacka RH, Prie-to VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchro-nous nonsentinel lymph node involve-ment in patients with melanoma. J Clin Oncol 2008;26:4296-303.54. Cadili A, Scolyer RA, Brown PT, Dabbs K, Thompson JF. Total sentinel lymph node tumor size predicts nonsenti-nel node metastasis and survival in pa-tients with melanoma. Ann Surg Oncol 2010;17:3015-20.55. Voit C, Van Akkooi AC, Schäfer-Hes-terberg G, et al. Ultrasound morphology criteria predict metastatic disease of the sentinel nodes in patients with melano-ma. J Clin Oncol 2010;28:847-52.56. Voit CA, van Akkooi AC, Schäfer-Hes-terberg G, et al. Rotterdam Criteria for sentinel node (SN) tumor burden and the accuracy of ultrasound (US)-guided fine-needle aspiration cytology (FNAC): can US-guided FNAC replace SN staging in patients with melanoma? J Clin Oncol 2009;27:4994-5000.57. Sanki A, Uren RF, Moncrieff M, et al. Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with pri-mary cutaneous melanoma. J Clin Oncol 2009;27:5614-9.58. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Com-mittee on Cancer staging system for cuta-neous melanoma. J Clin Oncol 2001;19: 3635-48.Copyright © 2011 Massachusetts Medical Society.



sentinel-lymph-node biopsy for cutaneous melanoma

Documents