0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Study |

Prognostic Usefulness of Sentinel Lymph Node Biopsy for Patients Who Have Clinically Node Negative, Localized, Primary Invasive Cutaneous Melanoma:  A Bayesian Analysis Using Informative Published Reports FREE

Arthur R. Rhodes, MD, MPH
[+] Author Affiliations

Author Affiliation: Department of Dermatology, Rush Medical College, Rush University, Chicago, Illinois.


Arch Dermatol. 2011;147(4):408-415. doi:10.1001/archdermatol.2010.371.
Text Size: A A A
Published online

Objective  To assess the prognostic value of sentinel lymph node biopsy status for patients with localized, clinically node negative, primary invasive cutaneous melanoma.

Design  Predictive value of positive or negative sentinel lymph node biopsy (SLNB) results for melanoma-related death, using raw numbers from informative publications.

Setting and Participants  Reports comprising 50 patients with cutaneous melanoma who had undergone SLNB, based on PubMed search (January 1, 1993, through June 3, 2010).

Main Outcome Measure  Melanoma-related death.

Results  For the 2 informative reports of patients with tumors of intermediate thickness (1-4 mm), risk of melanoma-related death ranged from 26.2% to 31.6% for node-positive cases and from 9.7% to 15.6% for node-negative cases. Based on 4 informative reports of patients with thin tumors (≤1 mm), risk of melanoma-related death ranged from 0% to 0.6% for both node-positive and node-negative cases. For the single informative report of patients with thick tumors (≥4 mm), risk of melanoma-related death was 32.5% for node-positive cases and 30.1% for node-negative cases. For 19 informative case series with any tumor thickness, risk of melanoma-related death ranged from 0% to 47.8% for node-positive cases and from 0% to 13.3% for node-negative cases.

Conclusion  Prognostic information provided by SLNB status may be variably useful for patients who have tumors of intermediate thickness (1-4 mm) and not very useful for patients who have thin (≤1 mm) or thick (≥4 mm) tumors.

The combined procedures of lymphatic mapping and sentinel lymph node biopsy (SLNB) have been devised as minimally invasive alternatives to elective lymph node dissection to identify occult metastases in patients with clinically node-negative localized primary invasive cutaneous melanoma (CM) and who might benefit from therapeutic lymph node dissection (TLND).1,2 An international randomized cohort study of patients with primary CM of intermediate thickness, the Multicenter Selective Lymphadenectomy Trial (MSLT),3 was designed to determine the survival impact of lymphatic mapping plus SLNB (and immediate TLND for positive cases), compared with nodal observation. According to this study,3 there was no significant difference in disease-specific survival when the 2 groups were compared. Retrospective studies by other groups have shown similar results.48

Not infrequently, published reports of randomized controlled trials that demonstrate nonsignificant primary outcomes provide optimistic interpretations of secondary outcomes to suggest that the experimental treatment is beneficial when in fact it is not.9 For instance, despite the lack of therapeutic efficacy (primary outcome measure),3 SLNB procedures are still being recommended for patients with CM to provide staging and prognostic information, prevent nodal recurrence, and improve recurrence-free survival,3,1013 despite questions raised about the appropriateness of subset analyses conducted by the authors of the MSLT.14 The goal of the present analysis was to assess the usefulness of SLNB status in providing clinically relevant prognostic information for asymptomatic patients with CM, relying on raw numbers obtained from informative published reports and using CM-related death as the outcome.

LITERATURE SEARCH

The English-language Medline database was searched electronically using PubMed for original reports containing the terms cutaneous melanoma and sentinel lymph node biopsy, published between January 1, 1993, and June 3, 2010. Abstracts were searched for indications of CM-related prognosis based on SLNB results, and potentially informative publications were reviewed in their entirety. For a report to be included, the following information was required: inclusion of at least 50 patients with invasive melanoma, distribution of tumor thickness, raw numbers of patients who had undergone lymphatic mapping plus SLNB, number of patients who had a negative or positive SLNB result, numbers of SLNB-negative and SLNB-positive patients who died from CM, and stated follow-up. Studies could include invasive tumors of any thickness.

DEFINITIONS

For purposes of this analysis, SLNB is regarded as a diagnostic and prognostic test, and risk of CM-related death based on SLNB status was assessed in terms of sensitivity and specificity of the test and positive and negative predictive value (PV),15 ie, the chance that a positive or negative result predicts CM-related death or no CM-related death, respectively.

For CM-related death, PV positive (PV+) is defined as the ratio of the number of patients who have a positive SLNB result and who ultimately die from CM (true positives), to the total number of patients who have a positive SLNB result whether or not they die from CM (true positives plus false positives). Predictive value negative (PV−) is defined as the ratio of the number of patients who have a negative SLNB result and who do not die from CM (true negatives), to the total number of patients who have a negative SLNB result whether or not they die from CM (true negatives plus false negatives). Estimates of PV+ and PV− are dependent on disease prevalence (prior probability) in the population tested. For this analysis, disease prevalence represents CM-related death within a stated follow-up interval for patients with CM who had undergone SLNB. Cutaneous melanoma–related death rate is defined as the number of SLNB patients who died from CM divided by the total number of SLNB patients within a given cohort, multiplied by 100%.

Sensitivity of SLNB for CM-related death is defined as the number of patients who had a positive SLNB result and who died from CM (true positives), divided by the total number of patients who ultimately died from CM whether the SLNB result was positive or negative (true positives plus false negatives). Specificity of SLNB for CM-related death is defined as the number of patients who had a negative SLNB result and who did not die from CM (true negatives), divided by the total number of patients who did not die from CM whether the SLNB result was negative or positive (true negatives plus false positives). Equations for PV+ and PV− are derived using these definitions for sensitivity and specificity of SLNB for CM-related death and disease prevalence (ie, CM-related death rate)15:

Equation 1

PV+ = [Prev × Sens] ÷ {(Prev × Sens) + [(1 − Prev)(1 − Spec)]}

Equation 2

PV− = [(1 − Prev)(Spec)] ÷ [{(1 − Prev)(Spec)} +{(Prev)(1 − Sens)}],

where Prev indicates prevalence; Sens, sensitivity; and Spec, specificity.

RISK OF CM-RELATED DEATH BASED ON RESULTS OF SLNB

Raw numbers were gleaned from informative reports to calculate CM-related death rate, sensitivity, and specificity of SLNB for CM-related death and risk of CM-related death based on SLNB status. Sample calculations are described in the eAppendix.

ELECTRONIC LITERATURE SEARCH

The search yielded 480 publications. Eliminations included 104 reviews, 27 articles whose main focus was not CM, 13 reports that included individual cases or small case series, and 19 letters and commentaries. Of the remaining 317 reports, available abstracts provided an indication of prognosis based on SLNB status in 145. These 145 reports were reviewed in their entirety and were included for analysis if at least 50 patients with CM with invasive tumors were available in the cohort, clinically evident regional lymph nodes or distant metastases were absent at the time of CM diagnosis, and the required raw numbers were available for calculations. Of these 145 reports, 25 provided numbers for calculations of sensitivity and specificity of SLNB for CM-related death. Numbers in the report by Gomez-Rivera et al,16 which comprised 113 patients whose tumors were thicker than 1 mm (or less if Clark level IV or V or ulceration was present), were also used for calculations of PV+ and PV− for a subset of 83 patients who had tumors of intermediate thickness (1-4 mm). Informative reports were segregated into limited tumor thickness (thin [≤1 mm], intermediate [1-4 mm], and thick [≥4 mm]) (eTable 1) and any thickness (eTable 2). It is noted that the tumor thickness ranges are overlapping at 1 mm and 4 mm, a limitation of available data and the manner that tumor thickness ranges are displayed in the informative reports used for analysis.

DERIVED ESTIMATES OF PV
Patients With Tumors of Intermediate Thickness

For the single informative prospective case series of patients with tumors of intermediate thickness (1.2-3.5 mm) on any anatomic site reported by Morton et al,3 the CM-related death rate was 12.3%, sensitivity and specificity of SLNB for CM-related death were 34.0% and 86.6%, respectively, and risk of CM-related death was 26.2% for cases with a positive SLNB result and 9.7% for cases with a negative SLNB result. For a retrospective case series of tumors of intermediate thickness (1-4 mm) only on head and neck sites reported by Gomez-Rivera et al,16 the CM-related death rate was 19.3%, sensitivity and specificity of SLNB for CM-related death were 37.5% and 80.6%, respectively, and risk of CM-related death was 31.6% for cases with a positive SLNB result and 15.6% for cases with a negative SLNB result. Follow-up was a median of 48.4 months in the report by Morton et al,3 and a median of 34 months in the report by Gomez-Rivera et al.16 To summarize findings for patients with tumors of intermediate thickness based on 2 informative reports,3,16 risk of CM-related death ranged from 26.2% to 31.6% for cases with a positive SLNB result, and 9.7% to 15.6% for cases with a negative SLNB result (eTable 1).

Patients With Thin Tumors

For patients with thin tumors (eTable 1), the CM-related death rate ranged from 0% to 1.1%, sensitivity of SLNB for CM-related death was 0% in 3 studies1719 and 50% in 1 study,20 and specificity of SLNB for CM-related death ranged from 88.5% to 96.8%. The risk of CM-related death ranged from 0% to 0.6% for both SLNB-positive and SLNB-negative cases. Follow-up for these latter 4 studies ranged from a median of 26.3 to 74 months for 3 studies17,19,20 and a mean of 27 months in 1 study.18 The range of follow-up was stated for 3 studies: 15 to 84 months,17 6 to 60 months,18 and 12 to 108 months.19 Tumor location included any cutaneous site for all 4 studies. To summarize findings for patients who have a thin primary CM, the risk of CM-related death was less than 1% for both SLNB-positive and SLNB-negative cases.

Patients With Thick Tumors

For the single informative report of patients with a 4-mm or thicker CM on any cutaneous site by Essner et al21 (eTable 1), with a follow-up of 2 to 73 months (median, 31 months), the CM-related death rate was 31.0%, sensitivity and specificity of SLNB for CM-related death were 37.1% and 65.4%, respectively, and the risk of CM-related death was 32.5% for cases with a positive SLNB result and 30.1% for cases with a negative SLNB result. Thus, for patients who have thick tumors, based on this report,21 the risk of CM-related death was approximately 1 in 3 for both SLNB-positive and SLNB-negative cases.

Patients With Any Tumor Thickness

eTable 2 presents 19 case series16,2239 of patients with any tumor thickness. The risk of CM-related death ranged from 0% to 47.8% for cases with a positive SLNB result and 0% to 11.9% for cases with a negative SLNB result. Median and mean follow-up for these 19 studies ranged from 13.2 to 72 months and 22 to 42 months, respectively. The range of follow-up was available for 13 studies. Distribution of tumors according to cutaneous site was variable among the 25 studies (data not shown), unavailable for 2 studies,36,39 and available only for cases with a positive SLNB result (any cutaneous site) in 1 study.20 Tumors were confined to head and neck sites in 2 studies.16,36

DISTRIBUTION OF TUMOR THICKNESS

eTable 3 gives the distribution of tumor thickness for informative case series of patients with invasive CM that included any tumor thickness. The proportion of thin tumors ranged from a low of 1.1%24 to a high of 30.4%.26 The proportion of thick tumors ranged from a low of 5.3%25 to a high of 30.3%.24 In 3 reports,34,36,39 distribution of tumor thickness was not provided.

DISTRIBUTION OF PATIENT SEX AND AGE

Patient sex was included in all but 2 reports.17,20 Age range was available for all but 7 reports. Ethnicity was stated for only 1 report (eTable 4).16

A clinical test40 that accurately predicts patient outcome for localized primary invasive CM would be invaluable. In practice, SLNB is being used worldwide for this purpose. According to numerous studies,22,4144 overall survival, disease-free survival, and disease-specific survival are significantly worse for patients with a positive SLNB result compared with those with a negative SLNB result. However, patients may survive or die from CM regardless of SLNB status. The goal of the present study was to assess the prognostic usefulness of SLNB status in predicting CM-related death.

In the assessment of any diagnostic or prognostic test for CM, choices of patient outcome may include disease-specific survival (ie, CM-related death), overall survival, and disease-free survival. In the analysis herein, CM-related death rather than recurrence (disease-free and recurrence-free survival) was used to assess prognostic usefulness of SLNB status. The prognostic usefulness of SLNB status in predicting CM-related death is dependent on the CM-related death rate in the cohort being studied and sensitivity and specificity of SLNB for CM-related death. Therefore, a Bayesian approach15,40 was used to attach a probability value for CM-related death according to SLNB status. This probability value becomes a useful measure of validity of SLNB as a diagnostic and prognostic test. Had disease-free survival been used instead of CM-related death, SLNB status as a predictive test would have been obfuscated by sites of recurrence, ie, local, in-transit, regional node, or distant. If regional node recurrence is included in disease-free survival, then surgical removal of regional nodes will strongly influence sites of recurrence and thus rates of disease-free survival. Disease-free survival will be worse in patients whose tumors recur in regional nodes compared with patients who have had TLND for microscopic disease. Reliance on CM-related death rate according SLNB status instead of disease-free survival eliminates this potential bias and will more likely permit replication in validation studies.

USEFULNESS OF SLNB IN PREDICTING CM-RELATED DEATH

For tumors of intermediate thickness, only 2 informative reports were found with available raw numbers for risk of CM-related death calculations based on SLNB status, one a prospective randomized controlled trial3 and the other a retrospective series.16 Based on raw data from the Multicenter Selective Lymphadenectomy Trial3 for patients who had undergone an SLNB for a primary localized CM of intermediate thickness (range, 1.2-3.5 mm) (eTable 1) on any cutaneous site and were followed up for a median of 48.9 months, risk of CM-related death was 26.2% for cases with a positive SLNB result and 9.7% for cases with a negative SLNB result. For a subset of 83 patients reported by Gomez-Rivera et al16 with primary CM 1 to 4 mm thick on the head or neck,16 risk of CM-related death was 31.6% for cases with a positive SLNB result and 15.6% for cases with a negative SLNB result, with a median follow-up of 34 months.

Based on 4 informative reports of patients with thin tumors (eTable 1),1720 the CM-related death rate was 0% to 1.1% for follow-up intervals ranging from a median of 2 years to 6 years. The risk of CM-related death was less than 1% for both SLNB-positive and SLNB-negative cases. According to a meta-analysis of SLNB for tumors 1-mm thick or less, reported by Warycha et al45 for 34 studies comprising 3651 patients, the pooled rate of SLNB positivity was 5.6%, with significant heterogeneity among studies; only 4 deaths were reported, despite the fact that 6.1% of tumors were ulcerated, 31.5% demonstrated regression, and 47.5% were Clark level IV or V. According to Morris et al,46 even for patients whose thin primary tumors had significant histopathologic regression, rates of SLNB positivity, local recurrence, systemic recurrence, and overall survival were not significantly worse than for patients whose thin primary tumors showed no regression. In a multicenter study in Italy reported by Testori et al,47 the presence of regression appeared to be inversely correlated with SLNB positivity. A lack of consistent definitions further obfuscates the prognostic significance of regression. It may be concluded that for patients with thin CM, rates of SLNB positivity are approximately 6%, and SLNB status may be useless in predicting CM-related death, even in cases with adverse histopathologic features.

While clinically node-negative patients with 4-mm or thicker tumors have a 60% to 70% risk of regional micrometastatic disease and a 70% risk of occult systemic disease at the time of presentation,48 multiple authors make a case for SLNB in this subgroup because SLNB status is a powerful predictor of overall survival by univariate and multivariate analysis.4854 For the single informative case series of patients with thick tumors reported by Essner et al,21 in which the CM-related death rate for the cohort was 31.0%, risk of CM-related death was 32.5% for cases with a positive SLNB result and 30.1% for cases with a negative SLNB result, with a median follow-up of 31 months (range, 2-73 months) (eTable 1). In this report, tumor status of the SLNB was predictive of disease-free survival but not overall survival.21 In patients with thick tumors, SLNB status is probably not useful for predicting CM-related death.

Differences in CM-related death rates for patients with thin (0%-1.1%), intermediate (12.3%-19.3%), and thick (31.0%) tumors account for striking differences in risk of CM-related death based on SLNB status, demonstrating the importance of prior probability in calculations of predictive value.

Based on informative case series composed of patients with any tumor thickness (eTable 2), CM-related death ranged from 0% to 47.8% for cases with a positive SLNB result and 0% to 13.3% for cases with a negative SLNB result. The wide range of CM-related death according to SLNB status observed for CM case series including any tumor thickness is influenced by varying composition of tumor thickness (eTable 3), patient age, distribution of tumors according to anatomic location, and duration of patient follow-up (see “Limitations” subsection). The proportion of thick tumors ranges from a low of 5.3% to a high of 30.3% (eTable 3). Tumor thickness is a prime determinant of SLNB positivity and CM-related death.10 Calculations of risk of CM-related death based on SLNB status for informative reports of patients with any tumor thickness (eTable 2) provide no useful conclusions.

FALSE-NEGATIVE RATE FOR SLNB

The false-negative rate for SLNB may be defined as the chance of obtaining a negative result when in fact the SLNB result is positive for tumor, for which regional lymph nodes become clinically and histopathologically tumor positive during follow-up. The false-negative rate for SLNB has been defined in various ways, likely accounting for wide variations in reported results, from 3.4% to 21.0%.14,55,56 A false-negative result obfuscates the prognostic usefulness of SLNB and may be due to flawed lymphatic mapping evaluation, lymphatic drainage disruption related to tumor excision, reduced sentinel lymph node detection during surgical exploration, less than optimal histopathological examination of lymph node(s), suboptimal lymphatic function (particularly in older patients), and unknown factors that influence malignant cells in lymphatic channels from reaching the sentinel lymph node.56

CURRENT MANAGEMENT PRACTICES

Multiple factors influence decisions about recommending SLNB, including tumor location, economic costs, and surgical morbidity. Other factors include patient age, comorbidities, insurance availability, and ethnicity.5762 It is not surprising that according to population-based studies, no more than half of patients with tumors at least 1-mm thick undergo SLNB.5759 According to recent surveys of surgical units treating patients with CM, only 31% to 76% of respondents reported using SLNB in their practices.60,61 Based on results of 44 548 patients with primary CM in the US National Cancer Data Base,62 only 50% of 2942 patients with a positive SLNB result underwent TLND.

COMPLICATIONS RELATED TO SLNB

According to studies by Kretschmer et al63 in Germany, the overall rate of at least 1 complication following SLNB for axillary or inguinal lymph node regions in 315 patients was 13.8%, while the rate of complications after TLND for these nodal regions was 65.5%, with a significantly higher complication rate for patients 70 years or older and inguinal lymph node involvement. According to Ling et al64 in Australia, the complication rate for 147 patients undergoing SLNB was 10.9% (16 of 147), related to higher body weight and body mass index and groin location.

While procedures related to SLNB (and TLND) are not free of complications, it has been observed that patients who develop clinically palpable inguinal lymph node recurrence during nodal observation have a greater number of involved nodes, more often 4 or more involved nodes, and a greater incidence of extranodal extension, wound complications, and lymphedema, compared with patients with a positive SLNB result (microscopic disease) who undergo TLND.65 To determine the validity of this argument, it will be necessary to compare surgical morbidity rates of TLND among patients who develop advanced regional node disease during routine nodal observation compared with patients in whom regional node disease is discovered based on frequent clinical examinations with the use of ultrasonography.55

ECONOMIC CONSIDERATIONS

Additional costs related to SLNB for a patient undergoing SLNB in England, reported in the year 2000 by Hettiaratchy et al,66 was £1420. For 138 patients with a primary CM less than 1.2-mm thick undergoing SLNB at Ohio State University between 1994 and 2002,67 physician and hospital charges per patient for SLNB procedures ranged from $10 096 to $15 223 (mean, $12 193), compared with $1000 to $1740 (mean, $1466) for outpatient wide excision alone performed at the same institution. Only 2 of the 138 patients were identified as having tumor in the SLNB, resulting in an estimated cost to identify a single patient with a positive SLNB result ranging from $696 600 to $1 051 1000.67 The 2007 Medicare reimbursement rate for SLNB procedures was reported to be $19 000.68 Costs related to TLND are considerably more than for SLNB, with longer hospital stays, more complications, higher physician charges, and greater lost patient income and patient downtime.

LIMITATIONS

The present analysis relied on available informative English-language reports in which raw numbers were available for risk of CM-related death calculations based on SLNB status. Dozens of otherwise useful reports were excluded because raw numbers were not provided. Additional informative reports, in English and other languages, may have been missed in the literature search.

The informative studies reported herein were not uniform with regard to interpretation of histopathologic features of primary tumors and lymph nodes. There were wide variations in CM-related death rate, duration of follow-up, distribution of tumors according to thickness and anatomic site, and distribution of patient age. Cutaneous melanoma–related death rate is dependent on tumor thickness and length of patient follow-up, and SLNB positivity is dependent on tumor thickness and patient age.25,69,70 Gutzmer et al53 found that among patients with primary CM at least 4-mm thick undergoing SLNB, patients with a positive SLNB result had a median age 7 years younger than patients with a negative SLNB result. Vuylsteke et al25 reported that patients younger than 20 years usually had a very good prognosis despite having a 30% to 80% positive SLNB rate. According to an analysis of 3076 patients enrolled in the Sunbelt Melanoma Trial and followed for a median of 19 months,70 a worse prognosis was associated with increased patient age, increased tumor thickness, and increased incidence of ulceration despite a lower incidence of SLNB positivity; risk of a positive SLNB result was 23% in patients younger than 30 years, compared with 12% in patients aged 61 to 70 years. According to Statius Muller et al,69 a positive SLNB rate was 37% for patients aged 18 to 30 years vs 17% for patients aged 71 to 84 years. Thus, SLNB status may be less useful prognostically in older (>60 years) and younger (<20 years) patients. Also, older patients are more likely to be excluded from procedures of SLNB and TLND because of increased comorbidities, thus age-biasing patient composition. Age distribution was available for only 4 of the informative reports21,24,31,39 in the present analysis (eTable 4).

Reluctance to include all patients with CM for SLNB regardless of tumor location may further bias studies. For instance, tumors on the head, neck, and mid thorax often have more than 1 lymphatic drainage site. Sentinel lymph nodes may be more difficult to locate given multiple drainage sites, and there may be reluctance to conduct multiple SLNBs in patients whose tumors have multiple drainage sites. For head and neck CM, SLNB presents unique challenges of complicated lymphatic drainage, difficulties locating the sentinel lymph node(s), radiation overlap between primary tumor and sentinel lymph node(s), less frequent visualization of the blue dye, and higher morbidity related to proximity of nodes to neurovascular structures.

In 5 of the 25 informative studies used for risk of CM-related death calculations based on SLNB status,29,32,3537 reverse transcriptase–polymerase chain reaction (RT-PCR) was used to increase sensitivity of tumor detection. For purposes of the present analysis, SLNB cases that were histopathologically negative but RT-PCR positive were designated SLNB negative. In cases with histopathologically negative but positive RT-PCR results, capsular nevi are often found on further histopathologic investigation.32 Detection of tyrosinase messenger RNA by RT-PCR alone did not appear to increase the likelihood of short-term disease recurrence in one study,32 but was significant in predicting disease-free survival adversely in other studies.35,36 Preliminary findings of the Sunbelt Melanoma Trial revealed no difference in disease-free survival and overall survival when patients with positive RT-PCR but histopathologically negative (and immunohistochemically negative) SLNB results were randomized to observation, TLND, or TLND and 4 weeks of high-dose intravenous interferon therapy.71

Patient follow-up is critical to any analysis of treatment effect on CM-related death rate. With longer follow-up, CM-related death rate may be expected to increase regardless of SLNB status. Long-term natural history studies are useful to determine the minimum follow-up necessary for assessment of any treatment effect on CM-related death rate. Gamel et al72 reported on 5342 patients with localized melanoma at the Duke Comprehensive Cancer Center who underwent surgical excision between 1978 and 1996 and who had a maximum follow-up of 23 years. Of the 1486 patients who died within 23 years, 65.5% (974 of 1486) died within 5 years, 91.9% (1365 of 1486) died within 10 years, and 98.8% (1468 of 1486) died within 15 years; of the 1365 patients who died within 10 years, 43.4% (592 of 1365) died within 3 years, and 71.4% (974 of 1365) died within 5 years. For the informative reports in the analysis, only median and mean follow-up intervals were usually reported. The mean or median follow-up interval was less than 3 years in 16 reports and less than 2 years in 3 reports (eTable 1 and eTable 2). In future studies, follow-up intervals of at least 5 years for all study patients (unless death intervenes) will be required to assess the effect of SLNB (and TLND for positive cases) on CM-related death rate within well-defined age and tumor thickness groups.

In the present analysis, wide ranges in CM-related death rate and risk of CM-related death based on SLNB status were notable for informative case series including tumors of any thickness. Only 2 informative reports were available for tumors of intermediate thickness (1-4 mm),3,16 4 for thin tumors (≤1 mm),1720 and only 1 for thick (≥4 mm) tumors,21 with overlap in tumor thickness limits (≤1 mm, 1-4 mm, and ≥4 mm). Additional studies with narrowly defined categories of tumor thickness and raw numbers of CM-related death according to SLNB status, including large numbers of patients pooled from multiple centers, will be required to corroborate or refute the findings presented.

Sentinel lymph node biopsy is being offered for not only prognostic purposes but also based on the presumption that all microscopic nodal disease progresses to bulky nodal disease. When nodal tumor burden is small, SLNB may be curative,73 but therapeutic usefulness may be impossible to assess, ie, the clinical equivalent of the Heisenberg principle.74 Nevertheless, there is no current evidence that SLNB (and TLND for positive cases) enhances disease-specific or distant disease-free survival.75

Based on current practices, there may be hesitancy in exposing the majority of patients who would never progress to regional metastatic disease to the potential morbid complications of SLNB (and TLND for positive cases) in efforts to assess prognosis and prevent bulky regional recurrence. Alternative methods of preventing bulky regional recurrence warrant further evaluation.76 The present analysis suggests that prognostic information provided by SLNB status may be variably useful for patients who have tumors of intermediate thickness and not very useful for patients who have thin or thick tumors. If SLNB is being offered to obtain prognostic information, patients need to be informed how SLNB status will be used to predict CM-related mortality and guide treatment options.

Correspondence: Arthur R. Rhodes, MD, MPH, Department of Dermatology, Rush University Medical Center, 1653 W Congress Pkwy, Annex Bldg, Ste 220, Chicago, IL 60612 (Arthur_Rhodes@Rush.edu).

Accepted for Publication: October 11, 2010.

Published Online: December 20, 2010. doi:10.1001/archdermatol.2010.371. This article was corrected online on April 11, 2011, for errors in the text in the “Results” section and correspondence address.

Financial Disclosure: None reported.

Funding/Support: Support was provided by the Department of Dermatology, Rush University Medical Center, Chicago.

Additional Contributions: On a very preliminary version of the manuscript, Martin A. Weinstock, MD, PhD, provided invaluable comments that gave the impetus for a more complete study. Without Dr Weinstock's suggestions and encouragement, this study may not have been pursued nor completed.

Morton  DLWen  DRWong  JH  et al.  Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127 (4) 392- 3991558490
Morton  DLCochran  AJ The case for lymphatic mapping and sentinel lymphadenectomy in the management of primary melanoma. Br J Dermatol 2004;151 (2) 308- 31915327537
Morton  DLThompson  JFCochran  AJ  et al. MSLT Group, Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355 (13) 1307- 131717005948
Koskivuo  ITalve  LVihinen  PMäki  MVahlberg  TSuominen  E Sentinel lymph node biopsy in cutaneous melanoma: a case-control study. Ann Surg Oncol 2007;14 (12) 3566- 357417924169
Leiter  UBuettner  PGBohnenberger  K  et al.  Sentinel lymph node dissection in primary melanoma reduces subsequent regional lymph node metastasis as well as distant metastasis after nodal involvement. Ann Surg Oncol 2010;17 (1) 129- 13719866238
Gutzmer  RAl Ghazal  MGeerlings  HKapp  A Sentinel node biopsy in melanoma delays recurrence but does not change melanoma-related survival: a retrospective analysis of 673 patients. Br J Dermatol 2005;153 (6) 1137- 114116307648
Kingham  TPPanageas  KSAriyan  CEBusam  KJBrady  MSCoit  DG Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol 2010;17 (2) 514- 52019924486
Wong  SLMorton  DLThompson  JF  et al.  Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol 2006;13 (6) 809- 81616604476
Boutron  IDutton  SRavaud  PAltman  DG Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA 2010;303 (20) 2058- 206420501928
Balch  CMGershenwald  JESoong  S-J  et al.  Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27 (36) 6199- 620619917835
Balch  CMCascinelli  N Sentinel-node biopsy in melanoma. N Engl J Med 2006;355 (13) 1370- 137117005955
Sondak  VKZager  JSMessina  JLThomas  JM Sentinel lymph node biopsy as the standard of care for cutaneous melanoma. Clin Adv Hematol Oncol 2007;5 (6) 483- 49017679922
Sondak  VKMessina  JL Lymphangiogenesis: host and tumor factors in nodal metastasis. Arch Dermatol 2008;144 (4) 536- 53718427050
Kanzler  MH The current status of evaluation and treatment of high-risk cutaneous melanoma: therapeutic breakthroughs remain elusive. Arch Dermatol 2007;143 (6) 785- 78717576947
Vecchio  TJ Predictive value of a single diagnostic test in unselected populations. N Engl J Med 1966;274 (21) 1171- 11735934954
Gomez-Rivera  FSantillan  A McMurphey  AB  et al.  Sentinel node biopsy in patients with cutaneous melanoma of the head and neck: recurrence and survival study. Head Neck 2008;30 (10) 1284- 129418704971
Cecchi  RBuralli  LInnocenti  SDe Gaudio  C Sentinel lymph node biopsy in patients with thin melanomas. J Dermatol 2007;34 (8) 512- 51517683380
Jacobs  IAChang  CKDasGupta  TKSalti  GI Role of sentinel lymph node biopsy in patients with thin (<1 mm) primary melanoma. Ann Surg Oncol 2003;10 (5) 558- 56112794023
Starz  HBalda  B-R Benefit of sentinel lymphadenectomy for patients with nonulcerated cutaneous melanomas in the Breslow range between 0.76 and 1 mm: a follow-up study of 148 patients. Int J Cancer 2007;121 (3) 689- 69317397029
Ranieri  JMWagner  JDWenck  SJohnson  CSColeman  JJ  III The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol 2006;13 (7) 927- 93216788753
Essner  RChung  MHBleicher  RHsueh  EWanek  LMorton  DL Prognostic implications of thick (≥4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002;9 (8) 754- 76112374658
Moehrle  MSchippert  WRassner  GGarbe  CBreuninger  H Micrometastasis of a sentinel lymph node in cutaneous melanoma is a significant prognostic factor for disease-free survival, distant-metastasis-free survival, and overall survival. Dermatol Surg 2004;30 (10) 1319- 132815458529
Topar  GEisendle  KZelger  BFritsch  P Sentinel lymph node status in melanoma: a valuable prognostic factor? Br J Dermatol 2006;154 (6) 1080- 108716704637
Kettlewell  SMoyes  CBray  C  et al.  Value of sentinel node status as a prognostic factor in melanoma: prospective observational study. BMJ 2006;332 (7555) 1423- 142516735303
Vuylsteke  RJCLMvan Leeuwen  PAMStatius Muller  MGGietema  HAKragt  DRMeijer  S Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results. J Clin Oncol 2003;21 (6) 1057- 106512637471
Rex  JParadelo  CMangas  C  et al.  Single-institution experience in the management of patients with clinical stage I and II cutaneous melanoma: results of sentinel lymph node biopsy in 240 cases. Dermatol Surg 2005;31 (11, pt 1) 1385- 139316416605
Mangas  CHilari  JMParadelo  C  et al.  Prognostic significance of molecular staging study of sentinel lymph nodes by reverse transcriptase-polymerase chain reaction for tyrosinase in melanoma patients. Ann Surg Oncol 2006;13 (7) 910- 91816788751
Lock-Andersen  JHorn  JSjøstrand  HNürnberg  BMStokholm  KH Sentinel node biopsy in cutaneous melanoma. Scand J Plast Reconstr Surg Hand Surg 2006;40 (1) 24- 3116428210
Romanini  AManca  GPellegrino  D  et al.  Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome. Ann Oncol 2005;16 (11) 1832- 184016107497
Roka  FKittler  HCauzig  P  et al.  Sentinel node status in melanoma patients is not predictive for overall survival upon multivariate analysis. Br J Cancer 2005;92 (4) 662- 66715700039
Oliveira  AFSantos  IDTucunduva  TC  et al.  Sentinel lymph node biopsy in cutaneous melanoma. Acta Cir Bras 2007;22 (5) 332- 33617923951
Tatlidil  CParkhill  WSGiacomantonio  CAGreer  WLMorris  SFWalsh  NM Detection of tyrosinase mRNA in the sentinel lymph nodes of melanoma patients is not a predictor of short-term disease recurrence. Mod Pathol 2007;20 (4) 427- 43417334354
Jansen  LNieweg  OEPeterse  JLHoefnagel  CAOlmos  RAKroon  BB Reliability of sentinel lymph node biopsy for staging melanoma. Br J Surg 2000;87 (4) 484- 48910759748
Wells  KERapaport  DPCruse  CW  et al.  Sentinel lymph node biopsy in melanoma of the head and neck. Plast Reconstr Surg 1997;100 (3) 591- 5949283554
Blaheta  H-JEllwanger  USchittek  B  et al.  Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 2000;114 (4) 637- 64210733666
Shivers  SJakub  JPendas  SReintgen  D Molecular staging for patients with malignant melanoma. Expert Rev Anticancer Ther 2007;7 (11) 1665- 167418020932
Manca  GRomanini  APellegrino  D  et al.  Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med 2008;49 (11) 1769- 177518927334
Gad  DHøilund-Carlsen  PFBartram  PClemmensen  OBischoff-Mikkelsen  M Staging patients with cutaneous malignant melanoma by same-day lymphoscintigraphy and sentinel lymph node biopsy: a single-institutional experience with emphasis on recurrence. J Surg Oncol 2006;94 (2) 94- 10016847917
Howman-Giles  RShaw  HMScolyer  RA  et al.  Sentinel lymph node biopsy in pediatric and adolescent cutaneous melanoma patients. Ann Surg Oncol 2010;17 (1) 138- 14319672660
Sox  HC  Jr Probability theory in the use of diagnostic tests: an introduction to critical study of the literature. Ann Intern Med 1986;104 (1) 60- 663079637
Cascinelli  NBombardieri  EBufalino  R  et al.  Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol 2006;24 (27) 4464- 447116983115
Gershenwald  JEThompson  WMansfield  PF  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- 98310071292
Berk  DRJohnson  DLUzieblo  AKiernan  MSwetter  SM Sentinel lymph node biopsy for cutaneous melanoma: the Stanford experience, 1997-2004. Arch Dermatol 2005;141 (8) 1016- 102216103331
Nowecki  ZIRutkowski  PNasierowska-Guttmejer  ARuka  W Sentinel lymph node biopsy in melanoma patients with clinically negative regional lymph nodes—one institution's experience. Melanoma Res 2003;13 (1) 35- 4312569283
Warycha  MAZakrzewski  JNi  Q  et al.  Meta-analysis of sentinel lymph node positivity in thin melanoma (≤1 mm). Cancer 2009;115 (4) 869- 87919117354
Morris  KTBusam  KJBero  SPatel  ABrady  MS Primary cutaneous melanoma with regression does not require a lower threshold for sentinel lymph node biopsy. Ann Surg Oncol 2008;15 (1) 316- 32218004626
Testori  ADe Salvo  GLMontesco  MC  et al. Italian Melanoma Intergroup, Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol 2009;16 (7) 2018- 202719132446
Gershenwald  JEMansfield  PFLee  JERoss  MI Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (≥4 mm) primary melanoma. Ann Surg Oncol 2000;7 (2) 160- 16510761797
Vermeeren  Lvan der Ent  FWCSastrowijoto  PSHHulsewé  KWE Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33 (11) 2464- 246819649757
Gajdos  CGriffith  KAWong  SL  et al.  Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma? Cancer 2009;115 (24) 5752- 576019827151
Ferrone  CRPanageas  KSBusam  KBrady  MSCoit  DG Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9 (7) 637- 64512167577
Carlson  GWMurray  DRHestley  AStaley  CALyles  RHCohen  C Sentinel lymph node mapping for thick (≥4-mm) melanoma: should we be doing it? Ann Surg Oncol 2003;10 (4) 408- 41512734090
Gutzmer  RSatzger  IThoms  K-M  et al.  Sentinel lymph node status is the most important prognostic factor for thick (≥4 mm) melanomas. J Dtsch Dermatol Ges 2008;6 (3) 198- 20318093216
Thompson  JFShaw  HM The prognosis of patients with thick primary melanomas: is regional lymph node status relevant, and does removing positive regional nodes influence outcome? Ann Surg Oncol 2002;9 (8) 719- 72212374653
Rossi  CRPasquali  SMocellin  S Actual false-negative rate prompts the routine use of ultrasound scan before and after sentinel node biopsy in melanoma. Ann Surg Oncol 2008;15 (10) 2976- 29771854604310.1245/s10434-008-9999-6
Sondak  VKZager  JS Who is to blame for false-negative sentinel node biopsies in melanoma? Ann Surg Oncol 2010;17 (3) 670- 67319953329
Stitzenberg  KBThomas  NEBeskow  LMOllila  DW Population-based analysis of lymphatic mapping and sentinel lymphadenectomy utilization for intermediate thickness melanoma. J Surg Oncol 2006;93 (2) 100- 10816425313
Grange  FVitry  FGranel-Brocard  F  et al.  Variations in management of stage I to stage III cutaneous melanoma: a population-based study of clinical practices in France. Arch Dermatol 2008;144 (5) 629- 63618490589
Cormier  JNXing  YDing  M  et al.  Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol 2005;23 (25) 6054- 606216135473
Garreau  JRNelson  JCook  D  et al.  Geographic variation in sentinel node adaptation by practicing surgeons in Oregon. Am J Surg 2005;189 (5) 616- 62015862507
Lens  MBDawes  MNewton-Bishop  JAGoodacre  T Management of regional lymph nodes in patients with malignant melanoma: questionnaire survey of UK current practice. Br J Plast Surg 2002;55 (5) 372- 37512372363
Bilimoria  KYBalch  CMBentrem  DJ  et al.  Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol 2008;15 (6) 1566- 157618414952
Kretschmer  LThoms  K-MPeeters  SHaenssle  HBertsch  HPEmmert  S Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res 2008;18 (1) 16- 2118227703
Ling  ADawkins  RBailey  M  et al.  Short-term morbidity associated with sentinel lymph node biopsy in cutaneous malignant melanoma. Australas J Dermatol 2010;51 (1) 13- 1720148833
Sabel  MSGriffith  KAArora  A  et al.  Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy. Surgery 2007;141 (6) 728- 73517560249
Hettiaratchy  SPKang  NO’Toole  GAllan  RCook  MGPowell  BW Sentinel lymph node biopsy in malignant melanoma: a series of 100 consecutive patients. Br J Plast Surg 2000;53 (7) 559- 56211000070
Agnese  DMAbdessalam  SFBurak  WE  JrMagro  CMPozderac  RVWalker  MJ Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 2003;134 (4) 542- 54814605613
Kanzler  MH Lymphatic mapping and sentinel node biopsy: the data unclouded by speculation—in reply. Arch Dermatol 2008;144 (5) 688- 689
Statius Muller  MGvan Leeuwen  PAMde Lange-De Klerk  ES  et al.  The sentinel lymph node status is an important factor for predicting clinical outcome in patients with Stage I or II cutaneous melanoma. Cancer 2001;91 (12) 2401- 240811413531
Chao  CMartin  RC  IIRoss  MI  et al.  Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 2004;11 (3) 259- 26414993020
McMasters  KMRoss  MIReintgen  DS  et al.  Final results of the Sunbelt Melanoma Trial [abstract]. J Clin Oncol 2008;26 (15S) ((May 20 suppl)) 9003
Gamel  JWGeorge  SLEdwards  MJSeigler  HF The long-term clinical course of patients with cutaneous melanoma. Cancer 2002;95 (6) 1286- 129312216097
van Akkooi  ACJNowecki  ZIVoit  C  et al.  Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg 2008;248 (6) 949- 95519092339
Heisenberg  W Über den anschaulichen Inhalt der quantentheoretischen Kinematik und Mechanik [English translation: Wheeler JA, Zurek H. Quantum Theory and Measurement. Princeton, NJ: Princeton University Press; 1983:62-84]. Zeitschrift für Physik 1927;43172- 198
Thomas  JM Concerns relating to the conduct and statistical analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT-1) in patients with melanoma. J Plast Reconstr Aesthet Surg 2009;62 (4) 442- 44619246272
Testori  ARastrelli  MDe Fiori  E  et al.  Radio-guided ultrasound lymph node localization: feasibility of a new technique for localizing and excising nonpalpable lymph nodes ultrasound suspicious for melanoma metastases. Melanoma Res 2010;20 (3) 197- 20220216241

Figures

Tables

References

Morton  DLWen  DRWong  JH  et al.  Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127 (4) 392- 3991558490
Morton  DLCochran  AJ The case for lymphatic mapping and sentinel lymphadenectomy in the management of primary melanoma. Br J Dermatol 2004;151 (2) 308- 31915327537
Morton  DLThompson  JFCochran  AJ  et al. MSLT Group, Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355 (13) 1307- 131717005948
Koskivuo  ITalve  LVihinen  PMäki  MVahlberg  TSuominen  E Sentinel lymph node biopsy in cutaneous melanoma: a case-control study. Ann Surg Oncol 2007;14 (12) 3566- 357417924169
Leiter  UBuettner  PGBohnenberger  K  et al.  Sentinel lymph node dissection in primary melanoma reduces subsequent regional lymph node metastasis as well as distant metastasis after nodal involvement. Ann Surg Oncol 2010;17 (1) 129- 13719866238
Gutzmer  RAl Ghazal  MGeerlings  HKapp  A Sentinel node biopsy in melanoma delays recurrence but does not change melanoma-related survival: a retrospective analysis of 673 patients. Br J Dermatol 2005;153 (6) 1137- 114116307648
Kingham  TPPanageas  KSAriyan  CEBusam  KJBrady  MSCoit  DG Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol 2010;17 (2) 514- 52019924486
Wong  SLMorton  DLThompson  JF  et al.  Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol 2006;13 (6) 809- 81616604476
Boutron  IDutton  SRavaud  PAltman  DG Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA 2010;303 (20) 2058- 206420501928
Balch  CMGershenwald  JESoong  S-J  et al.  Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27 (36) 6199- 620619917835
Balch  CMCascinelli  N Sentinel-node biopsy in melanoma. N Engl J Med 2006;355 (13) 1370- 137117005955
Sondak  VKZager  JSMessina  JLThomas  JM Sentinel lymph node biopsy as the standard of care for cutaneous melanoma. Clin Adv Hematol Oncol 2007;5 (6) 483- 49017679922
Sondak  VKMessina  JL Lymphangiogenesis: host and tumor factors in nodal metastasis. Arch Dermatol 2008;144 (4) 536- 53718427050
Kanzler  MH The current status of evaluation and treatment of high-risk cutaneous melanoma: therapeutic breakthroughs remain elusive. Arch Dermatol 2007;143 (6) 785- 78717576947
Vecchio  TJ Predictive value of a single diagnostic test in unselected populations. N Engl J Med 1966;274 (21) 1171- 11735934954
Gomez-Rivera  FSantillan  A McMurphey  AB  et al.  Sentinel node biopsy in patients with cutaneous melanoma of the head and neck: recurrence and survival study. Head Neck 2008;30 (10) 1284- 129418704971
Cecchi  RBuralli  LInnocenti  SDe Gaudio  C Sentinel lymph node biopsy in patients with thin melanomas. J Dermatol 2007;34 (8) 512- 51517683380
Jacobs  IAChang  CKDasGupta  TKSalti  GI Role of sentinel lymph node biopsy in patients with thin (<1 mm) primary melanoma. Ann Surg Oncol 2003;10 (5) 558- 56112794023
Starz  HBalda  B-R Benefit of sentinel lymphadenectomy for patients with nonulcerated cutaneous melanomas in the Breslow range between 0.76 and 1 mm: a follow-up study of 148 patients. Int J Cancer 2007;121 (3) 689- 69317397029
Ranieri  JMWagner  JDWenck  SJohnson  CSColeman  JJ  III The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol 2006;13 (7) 927- 93216788753
Essner  RChung  MHBleicher  RHsueh  EWanek  LMorton  DL Prognostic implications of thick (≥4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002;9 (8) 754- 76112374658
Moehrle  MSchippert  WRassner  GGarbe  CBreuninger  H Micrometastasis of a sentinel lymph node in cutaneous melanoma is a significant prognostic factor for disease-free survival, distant-metastasis-free survival, and overall survival. Dermatol Surg 2004;30 (10) 1319- 132815458529
Topar  GEisendle  KZelger  BFritsch  P Sentinel lymph node status in melanoma: a valuable prognostic factor? Br J Dermatol 2006;154 (6) 1080- 108716704637
Kettlewell  SMoyes  CBray  C  et al.  Value of sentinel node status as a prognostic factor in melanoma: prospective observational study. BMJ 2006;332 (7555) 1423- 142516735303
Vuylsteke  RJCLMvan Leeuwen  PAMStatius Muller  MGGietema  HAKragt  DRMeijer  S Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results. J Clin Oncol 2003;21 (6) 1057- 106512637471
Rex  JParadelo  CMangas  C  et al.  Single-institution experience in the management of patients with clinical stage I and II cutaneous melanoma: results of sentinel lymph node biopsy in 240 cases. Dermatol Surg 2005;31 (11, pt 1) 1385- 139316416605
Mangas  CHilari  JMParadelo  C  et al.  Prognostic significance of molecular staging study of sentinel lymph nodes by reverse transcriptase-polymerase chain reaction for tyrosinase in melanoma patients. Ann Surg Oncol 2006;13 (7) 910- 91816788751
Lock-Andersen  JHorn  JSjøstrand  HNürnberg  BMStokholm  KH Sentinel node biopsy in cutaneous melanoma. Scand J Plast Reconstr Surg Hand Surg 2006;40 (1) 24- 3116428210
Romanini  AManca  GPellegrino  D  et al.  Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome. Ann Oncol 2005;16 (11) 1832- 184016107497
Roka  FKittler  HCauzig  P  et al.  Sentinel node status in melanoma patients is not predictive for overall survival upon multivariate analysis. Br J Cancer 2005;92 (4) 662- 66715700039
Oliveira  AFSantos  IDTucunduva  TC  et al.  Sentinel lymph node biopsy in cutaneous melanoma. Acta Cir Bras 2007;22 (5) 332- 33617923951
Tatlidil  CParkhill  WSGiacomantonio  CAGreer  WLMorris  SFWalsh  NM Detection of tyrosinase mRNA in the sentinel lymph nodes of melanoma patients is not a predictor of short-term disease recurrence. Mod Pathol 2007;20 (4) 427- 43417334354
Jansen  LNieweg  OEPeterse  JLHoefnagel  CAOlmos  RAKroon  BB Reliability of sentinel lymph node biopsy for staging melanoma. Br J Surg 2000;87 (4) 484- 48910759748
Wells  KERapaport  DPCruse  CW  et al.  Sentinel lymph node biopsy in melanoma of the head and neck. Plast Reconstr Surg 1997;100 (3) 591- 5949283554
Blaheta  H-JEllwanger  USchittek  B  et al.  Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 2000;114 (4) 637- 64210733666
Shivers  SJakub  JPendas  SReintgen  D Molecular staging for patients with malignant melanoma. Expert Rev Anticancer Ther 2007;7 (11) 1665- 167418020932
Manca  GRomanini  APellegrino  D  et al.  Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med 2008;49 (11) 1769- 177518927334
Gad  DHøilund-Carlsen  PFBartram  PClemmensen  OBischoff-Mikkelsen  M Staging patients with cutaneous malignant melanoma by same-day lymphoscintigraphy and sentinel lymph node biopsy: a single-institutional experience with emphasis on recurrence. J Surg Oncol 2006;94 (2) 94- 10016847917
Howman-Giles  RShaw  HMScolyer  RA  et al.  Sentinel lymph node biopsy in pediatric and adolescent cutaneous melanoma patients. Ann Surg Oncol 2010;17 (1) 138- 14319672660
Sox  HC  Jr Probability theory in the use of diagnostic tests: an introduction to critical study of the literature. Ann Intern Med 1986;104 (1) 60- 663079637
Cascinelli  NBombardieri  EBufalino  R  et al.  Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol 2006;24 (27) 4464- 447116983115
Gershenwald  JEThompson  WMansfield  PF  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- 98310071292
Berk  DRJohnson  DLUzieblo  AKiernan  MSwetter  SM Sentinel lymph node biopsy for cutaneous melanoma: the Stanford experience, 1997-2004. Arch Dermatol 2005;141 (8) 1016- 102216103331
Nowecki  ZIRutkowski  PNasierowska-Guttmejer  ARuka  W Sentinel lymph node biopsy in melanoma patients with clinically negative regional lymph nodes—one institution's experience. Melanoma Res 2003;13 (1) 35- 4312569283
Warycha  MAZakrzewski  JNi  Q  et al.  Meta-analysis of sentinel lymph node positivity in thin melanoma (≤1 mm). Cancer 2009;115 (4) 869- 87919117354
Morris  KTBusam  KJBero  SPatel  ABrady  MS Primary cutaneous melanoma with regression does not require a lower threshold for sentinel lymph node biopsy. Ann Surg Oncol 2008;15 (1) 316- 32218004626
Testori  ADe Salvo  GLMontesco  MC  et al. Italian Melanoma Intergroup, Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol 2009;16 (7) 2018- 202719132446
Gershenwald  JEMansfield  PFLee  JERoss  MI Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (≥4 mm) primary melanoma. Ann Surg Oncol 2000;7 (2) 160- 16510761797
Vermeeren  Lvan der Ent  FWCSastrowijoto  PSHHulsewé  KWE Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33 (11) 2464- 246819649757
Gajdos  CGriffith  KAWong  SL  et al.  Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma? Cancer 2009;115 (24) 5752- 576019827151
Ferrone  CRPanageas  KSBusam  KBrady  MSCoit  DG Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9 (7) 637- 64512167577
Carlson  GWMurray  DRHestley  AStaley  CALyles  RHCohen  C Sentinel lymph node mapping for thick (≥4-mm) melanoma: should we be doing it? Ann Surg Oncol 2003;10 (4) 408- 41512734090
Gutzmer  RSatzger  IThoms  K-M  et al.  Sentinel lymph node status is the most important prognostic factor for thick (≥4 mm) melanomas. J Dtsch Dermatol Ges 2008;6 (3) 198- 20318093216
Thompson  JFShaw  HM The prognosis of patients with thick primary melanomas: is regional lymph node status relevant, and does removing positive regional nodes influence outcome? Ann Surg Oncol 2002;9 (8) 719- 72212374653
Rossi  CRPasquali  SMocellin  S Actual false-negative rate prompts the routine use of ultrasound scan before and after sentinel node biopsy in melanoma. Ann Surg Oncol 2008;15 (10) 2976- 29771854604310.1245/s10434-008-9999-6
Sondak  VKZager  JS Who is to blame for false-negative sentinel node biopsies in melanoma? Ann Surg Oncol 2010;17 (3) 670- 67319953329
Stitzenberg  KBThomas  NEBeskow  LMOllila  DW Population-based analysis of lymphatic mapping and sentinel lymphadenectomy utilization for intermediate thickness melanoma. J Surg Oncol 2006;93 (2) 100- 10816425313
Grange  FVitry  FGranel-Brocard  F  et al.  Variations in management of stage I to stage III cutaneous melanoma: a population-based study of clinical practices in France. Arch Dermatol 2008;144 (5) 629- 63618490589
Cormier  JNXing  YDing  M  et al.  Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol 2005;23 (25) 6054- 606216135473
Garreau  JRNelson  JCook  D  et al.  Geographic variation in sentinel node adaptation by practicing surgeons in Oregon. Am J Surg 2005;189 (5) 616- 62015862507
Lens  MBDawes  MNewton-Bishop  JAGoodacre  T Management of regional lymph nodes in patients with malignant melanoma: questionnaire survey of UK current practice. Br J Plast Surg 2002;55 (5) 372- 37512372363
Bilimoria  KYBalch  CMBentrem  DJ  et al.  Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol 2008;15 (6) 1566- 157618414952
Kretschmer  LThoms  K-MPeeters  SHaenssle  HBertsch  HPEmmert  S Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res 2008;18 (1) 16- 2118227703
Ling  ADawkins  RBailey  M  et al.  Short-term morbidity associated with sentinel lymph node biopsy in cutaneous malignant melanoma. Australas J Dermatol 2010;51 (1) 13- 1720148833
Sabel  MSGriffith  KAArora  A  et al.  Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy. Surgery 2007;141 (6) 728- 73517560249
Hettiaratchy  SPKang  NO’Toole  GAllan  RCook  MGPowell  BW Sentinel lymph node biopsy in malignant melanoma: a series of 100 consecutive patients. Br J Plast Surg 2000;53 (7) 559- 56211000070
Agnese  DMAbdessalam  SFBurak  WE  JrMagro  CMPozderac  RVWalker  MJ Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 2003;134 (4) 542- 54814605613
Kanzler  MH Lymphatic mapping and sentinel node biopsy: the data unclouded by speculation—in reply. Arch Dermatol 2008;144 (5) 688- 689
Statius Muller  MGvan Leeuwen  PAMde Lange-De Klerk  ES  et al.  The sentinel lymph node status is an important factor for predicting clinical outcome in patients with Stage I or II cutaneous melanoma. Cancer 2001;91 (12) 2401- 240811413531
Chao  CMartin  RC  IIRoss  MI  et al.  Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 2004;11 (3) 259- 26414993020
McMasters  KMRoss  MIReintgen  DS  et al.  Final results of the Sunbelt Melanoma Trial [abstract]. J Clin Oncol 2008;26 (15S) ((May 20 suppl)) 9003
Gamel  JWGeorge  SLEdwards  MJSeigler  HF The long-term clinical course of patients with cutaneous melanoma. Cancer 2002;95 (6) 1286- 129312216097
van Akkooi  ACJNowecki  ZIVoit  C  et al.  Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg 2008;248 (6) 949- 95519092339
Heisenberg  W Über den anschaulichen Inhalt der quantentheoretischen Kinematik und Mechanik [English translation: Wheeler JA, Zurek H. Quantum Theory and Measurement. Princeton, NJ: Princeton University Press; 1983:62-84]. Zeitschrift für Physik 1927;43172- 198
Thomas  JM Concerns relating to the conduct and statistical analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT-1) in patients with melanoma. J Plast Reconstr Aesthet Surg 2009;62 (4) 442- 44619246272
Testori  ARastrelli  MDe Fiori  E  et al.  Radio-guided ultrasound lymph node localization: feasibility of a new technique for localizing and excising nonpalpable lymph nodes ultrasound suspicious for melanoma metastases. Melanoma Res 2010;20 (3) 197- 20220216241

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Prognostic Usefulness of Sentinel Lymph Node Biopsy for Patients Who Have Clinically Node Negative, Localized, Primary Invasive Cutaneous Melanoma: A Bayesian Analysis Using Informative Published Reports
Arch Dermatol.2011;147(4):408-415.eSupplement

eSupplement -Download PDF (256 KB). This file requires Adobe Reader®.

eAppendix. Sample calculations

eTable 1. Intermediate Thickness, Very Thick, and Very Thin Invasive Primary Cutaneous Melanoma: Tumor-Related Death According to Sentinel Lymph Node Biopsy Status

eTable 2. Any Tumor Thickness, Informative Case Series of Invasive Primary Cutaneous Melanoma: Tumor-Related Death According to Sentinel Lymph Node Biopsy Status

eTable 3. Distribution of Microscopic Tumor Thickness for Informative Case Series of Patients With Invasive Primary Cutaneous Melanoma and Sentinel Lymph Node Biopsy, Comprised of Any Tumor Thickness

eTable 4. Distribution of Gender and Age: Informative Case Series of Patients with Invasive Primary Cutaneous Melanoma and Sentinel Lymph Node Biopsy
Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 6

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Sentinel-node biopsy in melanoma. N Engl J Med 2014;370(22):2148.
Sentinel-node biopsy in melanoma. N Engl J Med 2014;370(22):2148-9.