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NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES |
From Winship Cancer Institute (GWC, DRM, CAS, AH, CC), Emory University School of Medicine; and Department of Biostatistics (RHL), Rollins School of Public Health, Emory University, Atlanta, Georgia.
Correspondence: Address correspondence and reprint requests to: Grant W. Carlson, MD, Winship Clinic, 1365B Clifton Road, Atlanta, GA 30322; Fax: 404-778-4255; E-mail: grant_carlson{at}emory.org
ABSTRACT
Background: The amount of metastatic disease in the sentinel lymph node (SLN) is examined as a prognostic factor in malignant melanoma.
Methods: SLN mapping was performed on 592 patients with stage I and II malignant melanoma from March 1, 1994, through December 31, 1999. One hundred four patients were found to have 134 sentinel SLNs containing metastatic melanoma. The slides were reviewed, and the size of the metastatic melanoma in each SLN was measured. The size of the metastatic deposit was defined as macrometastasis (>2 mm), micrometastasis (
2 mm), a cluster of cells (10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1 to 
20 individual cells) in subcapsular sinuses.
Results: The number of metastases in each SLN was isolated melanoma cells, n = 5 (3.7%); cluster of cells, n = 35 (26.1%); 2 mm, n = 45 (33.6%); and >2 mm, n = 49 (36.7%). Seventy-nine patients (76%) had a single positive SLN. The size of the largest nodal metastasis was used to stratify patients with multiple positive SLNs. The overall 3-year survival for patients with SLN micrometastases was 90%, versus 58% for patients with SLN macrometastases (P = .004).
Conclusions: The amount of metastatic melanoma in an SLN is an independent predictor of survival. Patients with SLN metastatic deposits >2 mm in diameter have significantly decreased survival.
Key Words: Sentinel lymph node • Melanoma • Metastatic disease • Prognosis
The presence or absence of lymph node metastasis is the most significant prognostic factor for survival and recurrence in malignant melanoma. Lymph node disease decreases the 5-year survival by 40% to 50% compared with patients with no evidence of metastasis. The number of metastatic lymph nodes has been found to correlate with survival in several studies.1–3 Balch et al.4 reported an analysis of 1150 patients with nodal metastases in the American Joint Committee on Cancer (AJCC) Melanoma Database. The number of metastatic nodes and whether nodal metastases were clinically occult or apparent were independent predictors of survival.
Sentinel lymph node (SLN) mapping and biopsy has revolutionized the surgical management of primary malignant melanoma. It allows accurate nodal staging, which targets patients who may benefit from regional lymphadenectomy and systemic therapy. The new version of the AJCC staging system for cutaneous melanoma was adopted in 2002.5 Nodal staging is in part based on the presence of micrometastases after sentinel lymphadenectomy. In this study, the amount of metastatic disease in the SLN was examined as a predictor of residual nodal disease and prognosis.
PATIENTS AND METHODS
A retrospective review was performed on 592 consecutive patients (354 men and 238 women) with clinical AJCC stage I and II malignant melanoma who were treated with dynamic lymphoscintigraphy and gamma probe–guided SLN biopsy from January 1, 1994, to December 31, 1999, at Emory University Hospital.
SLN Mapping
Lymphatic mapping with dynamic lymphoscintigraphy and gamma probe–guided SLN biopsy were performed as previously described.6 All patients underwent cutaneous lymphoscintigraphy with filtered technetium 99mTc-labeled sulfur colloid (100–450 µCi; CIS-US, Inc., Bedford, MA). The radioactive tracer was injected intradermally around the circumference of the primary melanoma or biopsy site. Dynamic lymphoscintigraphy was performed with planar gamma camera imaging every 10 seconds for 10 minutes to identify focal areas of accumulation, followed by multiple 5-minute static images up to 60 minutes. In some patients, 2-hour postinjection delayed images were obtained. A mark was placed on the skin overlying these areas to correlate with intraoperative localization.
Measurements of radioactivity in the radiolabeled lymph nodes were made during surgery with a handheld gamma probe, and SLNs demonstrated increased focal radiotracer uptake (hot spots). Counts were accumulated during a 10-second interval and recorded. Areas of increased activity, or hot spots, were removed, and individual lymph nodes were dissected out to find focal uptake of radioactivity. Ex vivo counts of the SLNs were obtained and compared with the nodal bed counts after removal. Vital blue dye injected at the time of surgery was used routinely only in the last 2 years of the study period.
SLN Analysis
All harvested SLNs were carefully labeled, and after serial 5-µm sectioning, they were examined histopathologically by using routine hematoxylin and eosin and immunohistochemical staining for S-100 protein and melanoma-associated antigen HMB-45. The slides were reviewed, and the size of each metastatic deposit in an SLN was measured with an ocular micrometer. The SLN tumor burden was stratified into four groups: macrometastasis (>2 mm), micrometastasis (2 mm), a cluster of cells (COC; 10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (IMC; 1 to 20 individual cells) in subcapsular sinuses7,8 (Figs. 1–3
).
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2 test for general association. When indicated, Kaplan-Meier survival curves were compared via the log-rank test. Multivariate analysis was performed with the Cox proportional hazards regression model, with age, sex, primary location, tumor thickness, ulceration, SLN status, and SLN tumor burden as categorical predictor variables. All P values were two tailed, and P values <.05 were considered statistically significant. RESULTS
The clinicopathologic characteristics of the study group are listed in Table 1. There were 354 men and 238 women, with a mean age of 51.8 years (range, 19–85 years). The primary disease sites were head and neck (n = 86; 14.5%), trunk (n = 247; 41.7%), and extremities (n = 259; 43.8%). The pathologic data included only patients who underwent successful SLN mapping and biopsy. The mean follow-up was 39.6 months (median, 37.2 months). Of the 592 patients, there were 111 relapses and 75 deaths due to disease. Among the 104 patients with positive SLNs, the numbers of relapses and deaths were 45 and 31, respectively. Tumor site was strongly associated with tumor thickness (P = .002), with a higher proportion of head and neck tumors classified as T4. Ulceration was highly associated with tumor thickness and with SLN positivity (P < .001 for both).
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2 mm deposits and 41% for patients with >2 mm deposits (P = .036). The 3-year OS rate for patients with IMC/COC was 86%, versus 90% for patients with 2 mm deposits and 57% for patients with >2 mm deposits (P = .004; Fig. 6).
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2 mm (including IMC and COC) and >2 mm. Patients with positive lymph nodes were then stratified into groups for analysis: group 1, 2 mm and one +SLN; group 2, 2 mm and more than one +SLN; group 3, >2 mm and one +SLN; and group 4, >2 mm and more than one +SLN, with SLN-negative patients as the reference category. Age >52 years, sex, head and neck location, tumor thickness, and ulceration were included as prognostic factors assessed by multivariable Cox regression analysis (Table 6). SLN burden >2 mm was an independent predictor of survival, regardless of the number of metastatic nodes involved.
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Multivariate analysis was then performed among only the 67 patients who had single isolated SLN metastases (Table 7). This was an attempt to negate the effects of multiple lymph node involvement when analyzing SLN tumor burden. SLN tumor burden was a predictor of OS (P = .012) but not of RFS (P = .19).
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The detection of microscopic lymph node metastasis in melanoma has prognostic significance. In nonrandomized retrospective studies, there seems to be a survival advantage if metastatic lymph nodes are removed before they become clinically apparent. Piepkorn et al.9 recently reviewed several series comparing survival for patients with positive elective lymph node dissections versus therapeutic dissections. He noted a 20% improvement in the median 5-year survival for those with clinically negative but histologically positive nodes as opposed to those who presented with grossly involved lymph nodes. The new AJCC melanoma staging system stratifies lymph node metastases into micrometastases and macrometastases on the basis, in part, of analysis of the AJCC Melanoma Database.4 Micrometastases are defined as being diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable lymph node metastases that are confirmed by therapeutic lymphadenectomy or when any lymph node metastasis exhibits gross extracapsular extension.
Three studies have attempted to quantitate the amount of metastatic melanoma in lymph nodes. Cochran et al.10 measured the aggregate diameter of melanoma in all tumor-positive lymph nodes by using an ocular micrometer and compared this with the aggregate diameter of entire lymph nodes identified in 28 node-positive patients. When the aggregate diameter of the positive nodes was <15% of the total lymph node diameter, only 2 (15%) of 13 patients had a recurrence after lymphadenectomy. Ten (67%) of 15 patients with aggregate tumor diameter of >15% experienced recurrences.
Wagner et al.11 measured the maximal diameter of tumor deposits within melanoma SLNs. Aggregate tumor volume was calculated and found to correlate weakly with tumor thickness. Starz et al.12 classified +SLNs in 62 patients with metastatic melanoma by 2 morphometric measurements: the number of tumor-involved 1-mm slices of the SLNs and the depth of metastatic cell invasion, in millimeters. The number of involved 1-mm slices of SLN and the depth of metastatic cell invasion were found to be predictive of distant metastasis and survival.
The method of tumor quantification in this study was introduced in the evaluation of metastatic breast cancer. It is reproducible and easy to perform on a limited number of lymph nodes. Micrometastases are defined as being 2 mm in greatest dimension. They are believed to occur when there has been arrest and implantation of tumor cells in the lymph node.8 Isolated tumor cells or COCs do not exhibit penetration of the lymph sinus wall or extrasinusoidal stromal reaction or proliferation. The presence of isolated tumor cells in an SLN was found in only 3.7% (five SLNs) of the positive SLNs. This is similar to a report by Cascinelli et al.,13 who reported finding IMCs in 6.6% of isolated SLN metastases. In this study, IMCs were found in the SLNs of four patients (one patient had two SLNs containing IMCs). One patient with a single IMC-containing SLN was found to have four additional metastatic nodes on CLND. This patient subsequently died of metastatic disease, but the remaining three patients in this subgroup have remained free of recurrent disease.
Minimal disease in a metastatic melanoma SLN detected by nonmorphological methods may have prognostic significance. The detection of tyrosinase expression by reverse transcriptase-polymerase chain reaction (RT-PCR) assay has been shown to be a highly sensitive marker for the detection of melanoma cells in lymph nodes. It cannot, however, differentiate between melanoma cells and benign nevus cells, which can be identified in 5% of lymph nodes. Shivers et al.14 detected tyrosinase expression in 47 (52%) of 91 patients with pathologically negative nodes. Recurrences developed in 13% of patients whose results were pathologically negative but RT-PCR positive. Forty-one patients whose nodes were negative by routine histology and RT-PCR had a recurrence rate of only 1% (P = .017). In this study, there was a stratification of minimal, micrometastases, and macrometastases for disease-free survival. The 3-year RFS for patients with minimal disease was 81%, versus 57% for patients with micrometastases and 41% for those with macrometastases (P = .036). In OS, the minimal and micrometastasis groups came together but were statistically better than the macrometastasis group (Fig. 6). The 3-year OS for the micrometastasis group was 90%, versus 57% for the macrometastasis group (P = .004).
The number of tumor-containing lymph nodes in malignant melanoma correlates with survival and has resulted in a revision of the AJCC staging system.2,4,15,16 In one study, the 5-year survival was 47% when patients had three or fewer positive lymph nodes versus 21% when four or more nodes were involved.2 The proposed new staging system classifies nodal metastases into three groups: N1, one involved node; N2, two to three involved nodes; and N3, four or more nodes involved. In this study, the 3-year OS rate for patients with one lymph node metastasis was 85%, whereas patients with more than one lymph node metastasis had a 3-year OS rate of 63% (P = .016; Fig. 5).
An attempt was made to compare the prognostic significance of the amount of metastasis against the number of positive lymph nodes. The average difference in risk associated with increasing the number of positive nodes while holding the amount of metastases constant did not reach significance for OS (P = .39). The differences in risk associated with increasing the size of the largest metastasis while holding the number of positive nodes constant was significant for OS (P = .019). This implies that the size of the metastatic deposit in the SLNs may be as important as the total number of lymph nodes involved with metastases.
The incidence of additional positive nodes from CLND in +SLN patients has been reported to range from 7.8% to 33%.17–19 Joseph et al.19 reviewed the results of CLND in 83 patients with +SLNs. Overall, 5 (7.8%) of 64 patients had residual disease at the time of CLND. All five had primary tumor thickness >3.0 mm. The authors suggested that it might be possible to omit CLND in select patients. Starz et al.12 found a correlation between SLN tumor volume and residual nodal disease on CLND. In this study, 16 (15.4%) of the 104 patients had residual nodal disease at the time of CLND. Two of these patients had a primary melanoma tumor thickness of 1 mm (1 mm and .95 mm) and had minimal disease (IMC/COC) in isolated +SLNs. The number of +SLNs and the size of nodal metastases did not influence the likelihood of residual nodal metastases, as depicted in Tables 3 and 5
. This would imply that it is impossible to predict which patients do not require a complete lymph node dissection after a +SLN biopsy.
CONCLUSIONS
SLN mapping removes >80% of metastatic lymph nodes in a draining basin, but the amount of metastatic melanoma is not predictive of residual nodal disease. The amount of metastatic melanoma in an SLN is an independent predictor of survival. Patients with SLN metastatic deposits >2 mm in diameter have significantly decreased survival.
Footnotes
Sentinel lymph node (SLN) mapping removes >80% of metastatic lymph nodes in a draining basin, but the amount of metastatic melanoma is not predictive of residual nodal disease. The amount of metastatic melanoma in an SLN is an independent predictor of survival.
Received for publication March 19, 2002. Accepted for publication February 10, 2003.
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