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10.1245/ASO.2006.03.092
Annals of Surgical Oncology 13:198-204 (2006)
© 2006 Society of Surgical Oncology
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Original Article

American Joint Committee on Cancer Clinical Stage as a Selection Criterion for Sentinel Lymph Node Biopsy in Thin Melanoma

Julio Vaquerano, MD1, William G. Kraybill, MD1, Deborah L. Driscoll, BA1, Richard Cheney, MD2 and John M. Kane, III, MD1

1 Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
2 Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263

Correspondence: Address correspondence and reprint requests to: John M. Kane III, MD; E-mail: john.kane{at}roswellpark.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: A significant proportion of newly diagnosed melanomas are thin lesions (≤ 1.00 mm). Because tumor thickness correlates with the risk for nodal metastases, sentinel lymph node (SLN) biopsy in this subset is controversial. Incorporating other prognostic factors (Clark level and ulceration), we evaluated the 6th edition American Joint Committee on Cancer (AJCC) clinical stage as a simple and widely applicable guideline for offering SLN biopsy for thin melanoma.

Methods: This study was a review of a prospective melanoma SLN database from 1993 to 2003 with emphasis on SLN positivity rates based on the 6th edition AJCC primary tumor thickness intervals and clinical stage.

Results: Three hundred five patients underwent SLN biopsy, with an overall positivity rate of 17.7%. By the 6th edition AJCC, lesions ≤ 1.00 mm had an SLN positivity rate of 6.6%. By 6th edition clinical stage, SLN positivity rates were 4.9% for stage IA and 10.4% for stage IB. By using stage IA as the criterion for not offering SLN biopsy, this procedure would have been avoided in 46% (39 of 85) of ≤ 1.00-mm melanoma patients with a negative SLN.

Conclusions: Sixth edition AJCC clinical stage IB as a selection criterion for performing SLN biopsy in thin melanoma identifies most patients with a positive SLN while also avoiding a negative SLN biopsy in many patients. Until additional widely accepted and validated selection criteria are available, SLN biopsy for clinical stage IB, but not stage IA, thin melanomas is a reasonable approach.

Key Words: Thin melanoma • Sentinel lymph node • Clinical stage • Prognostic factors


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Regional lymph node status plays an important role in predicting outcome and guiding therapy for patients with melanoma. In general, the 5-year overall survival decreases to approximately 61% for even one microscopic nodal metastasis.1 For known nodal metastatic disease, lymphadenectomy is performed for therapeutic intent. In addition, the potential use of most adjuvant therapies (interferon alfa, vaccines, and so on) has often been limited to patients with nodal metastases.2–4

Since its introduction by Morton et al.5 in 1992, sentinel lymph node (SLN) biopsy has revolutionized the staging of melanoma. This technique is extremely accurate for determining the presence of clinically occult nodal metastatic disease with limited morbidity. As with any diagnostic procedure, there is a cost to the patient and society (resource utilization, monetary expense, and risk of complications). Consequently, the routine use of SLN biopsy for thin melanoma (≤ 1.00 mm) has been somewhat controversial because of reported positivity rates of only 1.4% to 8.3%.6–15

Although the risk of nodal metastases directly correlates with primary tumor thickness, other factors (ulceration, deeper Clark level, vertical growth phase, regression, sex, primary tumor site, increased mitotic rate, and younger age) have also been associated with a more aggressive tumor biology and an increased risk for nodal metastases in patients with thin melanoma.7,16–20 Because of these multiple and sometimes contradictory findings, it has been difficult to develop widely accepted criteria for performing SLN biopsy in patients with thin melanoma.

Our institution has routinely offered SLN biopsy to melanoma patients with a primary tumor thickness >.75 mm and lesions ≤ .75 mm with other traditional poor-prognostic factors, such as Clark level IV or V, ulceration, or regression. The changes in the 6th edition of the American Joint Committee on Cancer (AJCC) staging for melanoma incorporated Clark level IV or V and ulceration into the staging of melanoma ≤ 1.00 mm.21 In the new system, the biologic behavior and outcome of a thin melanoma with either of these prognostic factors are similar to those of nonulcerated melanoma 1.00 to 2.00 mm. Given that SLN biopsy would be offered to patients with melanomas in the 1.00- to 2.00-mm range, the purpose of our study was to determine whether a preoperative clinical stage of IA versus IB in the new 6th edition AJCC system would be a simple and practical selection criterion for offering SLN biopsy in thin melanoma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After approval by the institutional review board at Roswell Park Cancer Institute, analysis of our prospective melanoma SLN database identified 305 patients who underwent successful SLN biopsy between 1993 and 2003. Demographic information, primary tumor characteristics, and the pathologic status of the SLNs were reviewed for each patient. SLN positivity rates were examined with respect to 6th edition AJCC melanoma staging primary tumor thickness categories and preoperative clinical stages. The techniques of melanoma SLN biopsy and the pathologic evaluation at our institution have been previously described the literature but are briefly summarized below.22

Lymphoscintigraphy
Preoperative lymphoscintigraphy was routinely performed 2 to 4 hours before surgery in the nuclear medicine department to identify the lymphatic drainage patterns and the location of SLN(s). 99mTc-medronate (.5 mCi) was administered intravenously 30 minutes before lymphoscintigraphy to provide a background of anatomical landmarks. 99mTc-sulfur colloid was then injected (.25 mCi of .22 µ pore filtered) into four quadrants immediately surrounding the primary tumor site for a total of 1 mCi. The nodal basins were scanned dynamically for 10 minutes, and static views of all basins containing a SLN (including possible interval nodes) were obtained.

SLN Biopsy
In the operating room before SLN biopsy, 1% isosulfan blue dye (Lymphazurin; US Surgical Corp., Norwalk, CT) was injected intradermally via a 25-gauge needle in the same four quadrants used for the 99mTc-sulfur colloid injections to a total of 2 to 4 mL. By using a handheld gamma probe (Neoprobe Corp., Dublin, OH), the previously marked nodal basins containing a SLN were examined to determine the exact location for SLN biopsy. The lymph node with the greatest radioactive counts and/or all visualized blue lymph nodes were removed and labeled as SLNs. In addition, all other radioactive lymph nodes with counts >10% of the most radioactive SLN were also removed and labeled as SLNs. Wide local excision of the primary tumor site was performed after all SLNs had been removed. Occasionally, wide excision of the primary tumor site was performed before SLN biopsy if the nodal basin containing the SLN was in close proximity to the primary tumor site (to remove the confounding high radioactive counts from the 99mTc injections).

Pathologic SLN Evaluation
All excised SLNs were submitted for pathologic examination. Intraoperative frozen section and touch preparation analysis were not routinely performed. The SLNs were measured and visually inspected to detect gross tumor nodules. Serial sectioning (in general, at least three levels) and routine hematoxylin and eosin staining were performed to identify meta-static disease. In addition, S-100 and HMB-45 immunohistochemistry (Dako Corp., Carpenteria, CA) were used in all cases in which permanent hematoxylin and eosin evaluation was negative for metastatic disease.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median age of the 305 patients who underwent successful melanoma SLN biopsy was 52 years (range, 22–88 years). Fifty-five percent (168 of 305) of patients were male. The median primary tumor thickness was 1.60 mm (range, .27–20.00 mm). The primary tumor site was 56% extremities (n = 171), 36% trunk (n = 111), and 8% head and neck (n = 23). Most (76%) tumors were nonulcerated. The Clark level was II in 4% (n = 12), III in 22% (n = 65), IV in 68% (n = 208), V in 4% (n = 13), and unknown in 2% (n = 7). The median number of SLNs identified per patient was 2 (range, 1–13). Eighty-two percent of patients (250 of 305) had SLNs identified in only 1 nodal basin, 17% (53 of 305) had SLNs localized to 2 nodal basins, and only 1% (2 of 305) had 3 separate nodal basins containing SLNs. The overall SLN positivity rate for the entire group of patients was 17.7% (54 of 305). The median number of positive SLNs identified per patient was 1 (range, 1–2).

The rates of SLN positivity by the 6th edition AJCC tumor thickness intervals are listed in Table 1Go. In the group of patients with a melanoma thickness ≤ 1.00 mm, 6.6% (6 of 91) had a positive SLN. This represented approximately 11% (6 of 54) of the total number of patients with a positive SLN in our entire database. The SLN positivity rates by 6th edition AJCC preoperative clinical stage are listed in Table 2Go. For patients with stage IA melanoma (T1a: ≤ 1.00 mm, nonulcerated, Clark level II/III), the rate of SLN positivity was 4.9% (2 of 41). This represented only 3.7% (2 of 54) of the total number of SLN-positive patients in our database. In contrast, the positivity rate for clinical stage IB (T1b [≤ 1.00 mm with ulceration or Clark level IV/V] and T2a [nonulcerated and 1.00–2.00 mm]) increased to 10.4%. This represented 25.9% (14 of 54) of the total number of SLN-positive patients in our database. For the subset of stage IB ≤ 1.00 mm with ulceration or Clark level IV/V (T1b), the rate of SLN positivity was 8.0% (4 of 50).


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  		TABLE 1. Melanoma sentinel lymph node positivity rates by 6th edition AJCC tumor thickness intervals
 

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  		TABLE 2. Melanoma sentinel lymph node positivity rates by 6th edition AJCC preoperative clinical stage
 
Overall, there were 6 patients with a positive SLN and 85 patients with a negative SLN biopsy in the thin melanoma (≤ 1.00 mm) group. The effect of various criteria for not offering SLN biopsy on the rate of missed positive SLNs and the number of negative SLN biopsies avoided was determined. For a thickness cutoH of ≤ 1.00 mm, none of the negative SLN patients would have undergone the procedure, but all positive SLNs would have been missed. If clinical stage IA had been used as the criterion for not offering SLN biopsy, only 33% (2 of 6) of all positive SLNs would have been missed, and 46% (39 of 85) of SLN-negative patients would have been spared the procedure.

Demographic and additional pathologic factors for the six patients with thin melanoma (≤ 1.00 mm) and a positive SLN are listed in Table 3Go. Most patients were male, and only two were younger than 35 years of age. The primary tumor location was equally distributed across anatomical sites. Four of the patients had Clark level IV tumors, and only one patient had ulceration (also Clark level IV). When categorized by 6th edition AJCC clinical stage, 66% (4 of 6) were stage IB. None of the patients had regression, and the pathologic assessment of mitotic rate was low (<1 in 10 high-power fields) for the entire group. Because the original slides were available for five of the six patients, mitotic rate was reassessed and found to be 0 to 1/mm2 in all five patients. Patient 3 (the only one with ulceration) died of melanoma 26 months after SLN biopsy. At a median follow-up of 5.2 years (range, 4.1–6.2 years), the other five patients are alive with no evidence of recurrent melanoma.


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  		TABLE 3. Characteristics of the six patients with a thin melanoma (≤ 1.00 mm) and a positive sentinel lymph node
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because of heightened public awareness of melanoma combined with screening programs, the proportion of melanoma patients with a new diagnosis and thin lesions is increasing. In our study, 30% of patients undergoing SLN biopsy had a thin melanoma (≤ 1.00 mm). In other series, thin lesions account for 10% to 33% of the total group of patients. 1,15,20,23,24 Although most patients with thin melanoma will have a good long-term prognosis, a small proportion will develop metastatic disease. The ability to identify this subset is important for both prognostication and determination of appropriate candidates for additional therapy.

The list of potential poor-prognostic factors for thin melanoma is complex and sometimes contradictory. In one study of 884 patients with ≤ 1.00-mm melanoma, mitotic rate, vertical growth phase, sex, ulceration, anatomical site, and tumor-infiltrating lymphocytes were associated with an increased risk for metastases at 10 years, whereas tumor thickness, patient age, and Clark level were not significant. 25 A prognostic tree analysis also showed that mitotic rate, sex, and vertical growth phase alone could accurately stratify patients into four distinct risk groups. These findings are contrary to an earlier study in which axial location, regression, and Clark level were predictive of metastatic risk in <.76-mm melanoma, whereas sex, ulceration, and mitotic rate were not significant.17 The largest thin melanoma (≤ 1.00 mm) cohort analyzed for prognostic factors was 5299 patients studied by Balch et al.1 In that study, Clark level, ulceration, increasing age, site, and sex were all independent prognostic factors for survival. Although rare in thin melanoma, ulceration (8%) and Clark level IV or V (16%) were the most significant factors. The relationship of mitotic rate to overall prognosis has been shown in several studies.25–27 However, Francken et al.28 recently concluded that although mitotic rate is one of the independent predictors of survival in melanoma, the most powerful predictor is still AJCC stage (thickness and ulceration).

Because primary tumor thickness strongly predicts the risk for nodal metastatic disease, thin melanomas were often excluded in the era of elective or prophylactic lymph node dissection because too few patients would have potentially benefited from the procedure to outweigh the morbidity.29,30 With the introduction of SLN biopsy by Morton et al.,5 the vast majority of melanoma patients can now be accurately staged with regard to their nodal status. For clinically node-negative patients, SLN status is very predictive of survival, but other factors (thickness, ulceration, Clark level, and age) may also be informative.24,31 Overall, the rate of complications after SLN biopsy has been considered acceptable at 0% to 18%.32–34

One of the lingering questions is whether all melanoma patients should undergo SLN biopsy. If early detection and removal of clinically occult nodal metastatic disease are therapeutic, then SLN biopsy would clearly be warranted in all patients, including those with thin lesions. Although the Multicenter Selective Lymphadenectomy Trial was performed to address this question, the mature data have yet to be presented and evaluated. 35 As a consequence, there is currently no conclusive scientific evidence to support an absolute survival benefit from SLN biopsy. If the alternative conclusion is that SLN biopsy is prognostic but not therapeutic, then its use should be somewhat selective. Given an added monetary charge of approximately $1,800 to $15,000 per SLN biopsy and less tangible costs (postoperative pain, emotional stress while awaiting the biopsy results, and time lost from work or personal pursuits), it would not be unreasonable to consider excluding certain low-risk groups from this procedure.6,7

In 2002, the 6th edition AJCC melanoma staging system was restructured to emphasize the use of integer-based thickness intervals, the upstaging effect of ulceration, the importance of deeper Clark levels in thin melanoma, and a subcategory of micrometastatic nodal disease.1,21 In the new staging system, the overall survival of patients with ≤ 1.00-mm, nonulcerated, Clark level II or III (T1a) melanoma is 95% and 88% at 5 and 10 years, respectively.21 For the same tumor thickness but with ulceration or Clark level IV or V (T1b), 5- and 10-year overall survival rates decrease to 91% and 83%, respectively, and are almost identical to the overall survival for a 1.00- to 2.00-mm nonulcerated (T2a) melanoma (89% at 5 years and 79% at 10 years). The similar prognosis for these two subsets of patients led to the incorporation of both groups into clinical stage IB.

The 6th edition AJCC clinical stage has been shown to predict the risk for a positive SLN in patients with clinically negative nodes.16 In that study, tumor thickness, ulceration, age ≤ 50 years, and an axial primary tumor site were also independently predictive of SLN metastases. For ≤ 1.00-mm melanoma, the overall SLN positivity rate was 4%, with a significant difference between nonulcerated (3%) and ulcerated (16%) lesions. When stratified by AJCC T stage, the rates of SLN positivity were 2% for T1a, 6% for T1b, and 11% for T2a. This translated into clinical stage rates of 2% for stage IA and 9% for stage IB; these rates are similar to our findings.

The accuracy of SLN biopsy must also be considered when potential patients are selected for this procedure. Reported false-negative rates (nodal recurrence after a previous negative SLN biopsy) vary from 4.5% to 13.3%.13,33,36–39 Clinically, identifying a false-positive result (nodal nevi or incorrect staining mistakenly interpreted as metastases) is almost impossible because many patients with a true microscopic SLN metastasis will still have a good prognosis. This false-positive concept becomes more apparent for extremely sensitive assessments, such as polymerase chain reaction, in which SLN positivity rates of 49% to 63% greatly exceed the observed negative clinical outcome for these groups of patients.40–43

For any diagnostic test, as the prevalence of the finding in the population decreases, the positive predictive value (PPV; true positives/true positives + false positives) will also decrease. Conversely, the negative predictive value (true negatives/false negatives + true negatives) will increase. In the case of SLN biopsy for thin melanoma (for which the prevalence or absolute number of patients with a positive node will be small), the PPV will be low, and the negative predictive value will be high. Given that detecting clinically occult SLN metastases is what dramatically changes the expected prognosis and treatment plan for otherwise low-risk thin melanoma patients, a low PPV will result in patients being mislabeled as having nodal metastases and potentially undergoing unnecessary additional treatment (completion node dissection and adjuvant therapy). For the same sensitivity and specificity, SLN biopsy in patients with thicker melanoma (for which the prevalence of nodal disease is higher) will be more accurate and will have much greater diagnostic/prognostic value (because of the higher PPV).

A potential criticism of our study is that not all patients with ≤ 1.00-mm melanoma underwent SLN biopsy. This selection bias might have produced SLN positivity rates that do not accurately reflect the true rate of nodal metastases in this population. However, our decision to selectively perform SLN biopsy in patients with thin melanoma was based on previously accepted negative prognostic factors (Clark level, ulceration, and regression). By selecting higher-risk patients before we even performed the procedure, the true overall rate of SLN positivity in this group should actually be even lower than our observed findings. The 6.6% rate of SLN positivity in our study is also very similar to the 1.4% to 8.3% rate reported by others for thin melanoma (Table 4Go). Therefore, our patients seem to be comparable to thin melanoma populations at other institutions.


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  		TABLE 4. Reported results for sentinel lymph node biopsy in thin melanoma
 
Similar to overall survival, the reported risk factors for predicting a positive SLN in thin melanoma are also somewhat confusing and conflicting. Although some studies have suggested that ulceration, Clark level, mitotic rate, vertical growth phase, and perhaps younger age are predictive of a positive SLN, others have shown that these factors and most traditional high-risk features (regression, sex, and disease site) are not helpful.7,9–12 Recently, Sondak et al.20 developed a probabilistic model in which tumor thickness, mitotic rate, and age <35 years were most predictive of a positive SLN and no other features (including ulceration) were of additional prognostic value. One of their conclusions was that even thin melanoma patients who were younger and had a high mitotic rate may be appropriate candidates for SLN biopsy. Unfortunately, mitotic rate is not uniformly reported in the literature (mitoses per 10 high-power fields vs. 5 high-power fields vs. square millimeters, counted in the fields with the most mitoses vs. the entire dermal component). Regarding age, there is an apparent paradox in the literature in which younger melanoma patients have a higher rate of SLN positivity but an improved overall survival as compared with older patients.1,16,19,20,24,28,44,45 These findings may partially dilute the overall prognostic value of a positive SLN in younger patients, including those with thin melanoma.

A provocative finding from our study was that 83% of the thin melanoma patients with a positive SLN are alive and disease free >4 years from diagnosis. In a much larger SLN study by Bleicher et al.7 of 512 patients with ≤ 1.50-mm melanoma, the overall survival for the SLN-positive group was 100% (n = 25; median follow-up, 25 months) versus 97% for the SLN-negative group (n = 487; median follow-up, 45 months). Similar results were noted by Statius Muller et al.24; their 3-year disease-free survival for all 78 of their ≤ 1.00 mm melanoma patients undergoing SLN biopsy was 100%, despite an 8% SLN positivity rate. Several other studies also report a 100% disease-free survival for thin melanoma patients with a positive SLN.6,8,10,13 These results suggest that a positive SLN in thin melanoma patients may be less predictive of overall survival.

In the future, a standard prognostic model will likely be developed to accurately predict the risk for nodal or distant metastatic disease in patients with newly diagnosed melanoma. This model will probably contain a combination of clinical, pathologic, and newer molecular variables (as determined by micro-arrays, proteomics, and so on). Currently, the 6th edition AJCC clinical stage is readily accepted and very predictive for the risk of a positive SLN in patients with thin melanoma. Clinical stage IB as a selection criterion for performing SLN biopsy in thin melanoma strikes a balance in that it identifies most thin melanoma patients with a positive SLN while avoiding a negative SLN biopsy in many low-risk patients. Realistically, this guideline is simply a framework for stratifying risk. The judgment of the treating physician in regard to additional variables or patient preference should ultimately determine the appropriateness of an SLN biopsy for an individual patient with a thin melanoma.

Received for publication March 23, 2004. Accepted for publication August 25, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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