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Original Article |
1 Department of Surgery, Hospital of the University of Pennsylvania, 4th Floor, Silverstein Pavilion, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
2 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 631 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania 19104
3 Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
4 Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 6th Floor, Founders Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
5 Pigmented Lesion Group and Melanoma Program, Abramson Cancer Center of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
6 Department of Dermatology, Hospital of the University of Pennsylvania, 2nd Floor, Rhoads Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
7 Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 519 Maloney Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104
Correspondence: Address correspondence and reprint requests to: Francis R. Spitz, MD; E-mail: francis.spitz{at}uphs.upenn.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL. Methods: Clinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree.
Results: The overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness 
.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%.
Conclusions: In patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.
Key Words: Thin melanomas • Sentinel lymphadenectomy • Mitotic rate • Tumor-thickness • SLN positivity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the case of thin melanomas (1.00 mm), however, recommendations for LM/SL have not been established. Thin melanomas are generally considered low-risk lesions with limited metastatic potential and a good long-term prognosis. In addition, the incidence of nodal metastasis in this group of patients is low,10,11,13–17 ranging from 0% to 5%. This low incidence of nodal metastasis has discouraged the routine use of LM/SL in this patient population. However, even in this low-risk population, 10-year melanoma-specific death rates of 12% and 17% have been reported for patients with T1a and T1b lesions.18 Therefore, it may be possible to identify a group of patients at higher risk for nodal metastases in whom LM/SL may provide important prognostic information and guide further therapy. The recent American Joint Committee on Cancer prognostic factor analysis identified a Clark level of IV or higher and ulceration as the two most significant prognostic factors for survival in patients with thin melanomas.8 Although many surgeons have used these prognostic factors to risk-stratify patients with thin melanomas and select patients for LM/SL, it is unclear whether these prognostic factors for survival are also predictors of SLN positivity in this patient population.
The Pigmented Lesion Group (PLG) at the University of Pennsylvania has prospectively compiled a database of >6500 patients with melanoma from 1972 to 2005. In an attempt to develop a prognostic model that more accurately predicts the long-term outcome for patients with thin melanomas, we recently performed a classification and regression tree (CART) analysis of >800 patients with thin melanomas and at least 10 years of follow-up who presented between 1972 and 1991. Mitotic rate (MR) was identified as the first prognostic factor that split this population sample into two groups with different risks of metastasis. In patients with an MR >0, the risk of disease recurrence at 10 years was 19.9%, whereas in those with an MR of 0, the risk of recurrence was 1.8%.19 On the basis of these results, we hypothesized that MR may also be a predictor of SLN positivity in patients with thin melanomas. Because we have previously reported that patients with thin melanomas with a vertical growth phase (VGP) may be at an increased risk for SLN metastases,17 we evaluated MR in a larger and more contemporary cohort of patients with VGP-positive thin melanomas who underwent LM/SL between January 1996 and January 2004. We sought to determine whether MR can be used to risk-stratify patients with thin melanomas and identify those who may benefit from LM/SL.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.00 mm. LM/SL was performed in 227 (20%) of these patients with thin melanomas. Informed consent was obtained from all patients before lymphoscintigraphy (LSG) and surgery. This study was approved by the Institutional Review Board at the University of Pennsylvania.
Clinical and Histopathologic Variables
The following patient and tumor characteristics were examined: age, sex, anatomical location, MR, thickness, Clark level, and ulceration. Variables that were categorized as binary factors included age (60 or >60 years), anatomical location (extremity or axial), MR (0 or >0), thickness (<.76 or .76 mm), and Clark level (II/III or IV/V).
Pathologic Evaluation of Primary Tumors
The characteristics of the primary tumor were determined from initial biopsy and wide local excision (WLE) specimens. VGP lesions had dermal nests of tumor cell aggregates larger than in the epidermis and/or mitotic figures in the dermis.20 Tumor thickness was measured in millimeters from the surface of the granular layer to the deepest point at which malignant cells were present. The anatomical level of invasion was classified according to Clark and associates’21 original definition: level II, invasion of the papillary dermis; level III, tumor extending to the papillary-reticular interface; level IV, invasion of the reticular dermis; and level V, invasion into the subcutaneous fat. MR was reported as either the number of mitotic figures in a specified number of high-power fields or as the number of mitotic figures per unit area (square millimeters). For this analysis, the presence of any lesional cell mitosis in the dermis was categorized as an MR >0. Mitoses in lesional cells in the epidermis or in nonlesional cells were not considered in the rate determination. Ulceration was identified as being present if there was evidence of an area of complete loss of the epidermis over the tumor associated with a host inflammatory response.22
Selection of Patients for LM/SL
The use of LM/SL in patients with thin melanomas is not routinely recommended at our institution. However, we have offered LM/SL to patients with VGP-positive thin melanomas if primary tumor characteristics were present that were considered risk factors for metastasis, for example, a Clark level of IV or higher, ulceration, or regression. In addition, because we have previously reported that patients with VGP-positive thin melanomas have an increased incidence of SLN metastasis,17 the potential risks and benefits of LM/SL were reviewed with all such patients who presented for WLE. A decision about whether to proceed with WLE alone or with the combination of WLE and LM/SL was made on an individual basis.
Radiotracer Injection and LSG
Radiotracer injection and LSG were performed on the day of surgery in all patients. For radiotracer injection, either 99mTc-labeled human serum albumin (Amersham Health, Princeton, NJ) or 99mTc-labeled sulfur colloid (Tyco International Ltd., Mallinckrodt, Phillipsburg, NJ), filtered through a .22-µm filter, was used. Radiotracers were combined with 1 mL of normal saline and injected intradermally surrounding the primary tumor or biopsy site. In the case of axial tumors, radiotracer was injected in equal amounts in four quadrants surrounding the lesion, whereas for extremity tumors, radiotracer was injected on the medial and lateral sides of the lesion.
LSG was performed with a large-field-of-view gamma camera with a high-resolution collimator (Model 2000; General Electric Medical Systems, Waukesha, WI). After the administration of radio-tracer, continuous images were obtained until one or more regional nodal basins with draining lymph nodes were identified. Once these regional nodal basins were identified, static images were obtained in the anteroposterior and lateral projections. In addition, at the completion of LSG, an external source of radioactivity was used to outline the contour of the body and delineate areas with increased radioactivity in relation to the neck, shoulder, axilla, and groin. Within each regional nodal basin, all radiographically identified draining lymph nodes were marked on the overlying skin with indelible ink. If nodal drainage was not identified by 2 hours, the case was considered an LSG failure.
Blue Dye Injection and Operative Procedure
After the induction of anesthesia, 1 mL of 1% isosulfan blue dye (Lymphazurin; Tyco Healthcare, US Surgical, Norwalk, CT) was injected intradermally in equal amounts in four quadrants surrounding the primary tumor or biopsy site. Gentle massage was performed over the primary tumor site after injection. Within 5 to 10 minutes of blue dye administration, the LM/SL procedure was initiated. A gamma-detecting probe (Tyco Healthcare, US Surgical) was used during surgery to identify radioactive nodes. An initial background count was taken with the gamma-detecting probe, and then the nodal basin site with the greatest radioactivity was located. The skin incision was made in the area of the nodal basin with the highest radioactivity. Careful dissection was performed to identify all blue lymphatics and blue nodes (defined as any node that stained blue). Additional dissection was performed with the gamma-detecting probe to identify radioisotope-positive nodes. Radioactive SLNs were defined as nodes with counts at least 3 times background or 10 times ex vivo fat.3,23 Radioisotope-positive nodes were removed until the background counts were <10% of the hottest node removed.24 After completion of the SLN-mapping portion of the procedure, WLE of the primary tumor or biopsy site was performed.
Pathologic Evaluation
All SLNs were submitted for permanent histological evaluation. SLNs were serially divided into approximately 4-mm segments and paraffin-embedded. A central section was taken from each lymph node segment for hematoxylin and eosin (H&E) staining. If initial H&E staining did not reveal metastases, four additional sections were obtained from each lymph node segment for repeat H&E staining and immunohistochemical staining for S-100 and HMB-45, with appropriate positive and negative controls.
Statistical Analysis
Fisher’s exact test was used to evaluate whether there was a significant association between SLN positivity and each of the clinical and histopathologic variables available for this study. Because of the limited number of patients with positive SLNs, multivariate regression models were restricted to those that included only MR and one other factor. Exact methods were used to obtain P values for the coefficients in these models. Logistic regression analyses were performed with SAS (SAS Institute Inc., Cary, NC).
By using CART software (Salford Systems, San Diego, CA), a recursive partitioning algorithm was used to develop the classification tree. The following factors were included as the binary variables previously described: age, sex, anatomical location, MR, thickness, Clark level, and ulceration. In the final tree, each terminal group had at least 30 patients.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.76 mm (50% vs. 50%). Most patients (85%) were 60 years old. Fifty-seven percent of the patients had an MR >0, and 57% had Clark level II/III lesions. Only 5% of patients had evidence of ulceration in the primary tumor.
LM/SL and Completion Lymphadenectomy
LSG was successful in identifying at least one regional nodal basin in all patients before surgery. During surgery, 209 nodal basins were sampled, with successful SLN identification in 206 (99%). A single nodal basin was sampled in 87% of patients. The distribution of anatomical locations for nodal basins sampled is listed in Table 1
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Association of Clinical Variables With SLN Positivity
Clinical variables that were evaluated for association with SLN positivity included age, sex, and anatomical location (Table 2). All patients with positive SLNs were 60 years old. In addition, a greater percentage of patients with positive SLNs were men (67%) or had extremity lesions (67%). Univariate analyses (Table 2) demonstrated no significant association between age, sex, and anatomical location and SLN positivity. Stratified analyses (Table 3) demonstrated that the association between MR and SLN positivity remained significant controlling for each of the clinical factors under investigation: age, sex, and anatomical location. Clinical characteristics of patients with thin melanoma and positive SLNs are listed in Table 4.
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.76 mm (89%) and Clark level IV lesions (67%). Univariate analyses (Table 2
) identified two factors—MR (P = .011) and thickness (P = .033)—as being significantly associated with SLN positivity. Although there was a significant correlation between MR and tumor thickness .76 mm (P < .0001) and MR and Clark level (P = .034; Table 5), stratified analyses (Table 3) demonstrated that the association between MR and SLN positivity remained significant controlling for each of these histopathologic factors. In addition, the association between MR and SLN positivity remained significant controlling for ulceration (Table 3). Histopathologic characteristics of patients with thin melanoma and positive SLNs are listed in Table 4.
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). MR was the first factor selected that split the population sample into two groups—patients with an MR of 0 and patients with an MR >0—with different risks for SLN metastases. In this particular population sample, patients with an MR of 0 had an SLN positivity rate of .0% (minimal-risk group; 95% confidence interval [CI], .0%–4.6%). The population of patients with an MR >0 was further subdivided according to tumor thickness and sex. Patients with an MR >0 and tumor thickness .76 mm had a 12.3% SLN positivity rate (95% CI, 5.5%–22.8%), whereas those with an MR >0 and tumor thickness <.76 mm had a 2.6% SLN positivity rate (95% CI, .1%–13.8%). Three additional risk groups were defined: (1) low risk: MR >0 and thickness <.76 mm (SLN positivity rate, 2.6%; 95% CI, .1%–13.8%); (2) intermediate risk: MR >0, thickness .76 mm, and female sex (8.8%; 95% CI, 1.9%–23.7%); and (3) high risk: MR >0, thickness .76 mm, and male sex (16.1%; 95% CI, 5.5%–33.7%). Although the 95% CIs for these risk groups are broad, with upper bounds in the minimal- and low-risk groups that may be considered sufficient to justify LM/SL, this analysis was limited by the small number of positive events in the study population.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.00 mm) is still unclear. Because of increased awareness and earlier diagnosis, patients with thin melanomas represent a significant proportion of patients who are evaluated for melanoma. Currently at the University of Pennsylvania, >60% of new patients evaluated by the PLG have thin melanomas, and nearly 80% of invasive melanomas reported to the Surveillance, Epidemiology, and End Results Program are thin33. Because the incidence of nodal metastasis in this group of patients is low, the routine use of LM/SL, with the attendant increase in morbidity and costs,15 has not been recommended for all patients. Consequently, there is an ongoing effort to identify patient and tumor characteristics that can be used to risk-stratify patients with thin melanomas and determine those who are at increased risk for nodal metastasis and who should be considered for LM/SL.
Previous studies have identified multiple prognostic factors for disease recurrence and survival in patients with thin melanomas.8,19,25,34,35 In the prognostic factor analysis performed by the American Joint Committee on Cancer in revising the melanoma staging system, tumor thickness and ulceration were identified as significant prognostic factors for outcome in all patients with localized melanoma.8 For thin melanomas, level of invasion was also identified as an independent prognostic factor that was more significant than ulceration in that subset of patients. Slingluff et al.25 evaluated 681 patients with thin melanomas <.76 mm to identify negative risk factors and to develop a prognostic model for this group of patients. Two clinical variables (sex and tumor location) and two histological variables (Clark level and severe regression) were associated with an increased incidence of metastasis and were included in a prognostic model that identified low-, intermediate-, and high-risk populations. In addition, the recent CART analysis performed by the PLG at the University of Pennsylvania on >800 patients with thin melanomas identified MR as the first prognostic factor that split this population sample into two groups with different risks of metastasis. In patients with an MR >0, the risk of disease recurrence at 10 years was 19.9%, whereas for patients with an MR of 0, the risk of recurrence was 1.8%.19 However, because these studies used disease recurrence and survival as end points, it is not clear whether these prognostics factors may also be used to predict the probability of positive SLNs in patients with thin melanomas.
Factors associated with positive SLNs in all patients with melanoma have been variably reported in the literature.2,10–12,14,17,24,28–32 Increasing tumor thickness has consistently been found to predict SLN positivity. Other factors that have also been found to be associated with an increased incidence of positive SLNs include ulceration,2,12,14,24,30–32 age,11,12,24,28,29,32 MR,28–31 Clark level,2,24 anatomical location,32 lymphovascular invasion,14,31 and microsatellitosis.31 MR was identified as an independent predictor of SLN positivity in several recent studies. Wagner et al.30 evaluated SLN results in 275 patients and found that an MR of more than five mitoses per high-power field was a significant predictor of SLN positivity in addition to a Breslow thickness 1.25 mm and ulceration. Mraz-Gernhard et al.31 identified tumor thickness and multiple histological factors, including ulceration, high MR (more than five mitoses per square millimeter), microsatellitosis, and angiolymphatic invasion, as significant predictors of SLN metastases. Finally, Sondak et al.28 identified MR, a younger age, and Breslow depth as factors that were significantly associated with positive SLNs. This study also found that MR was more closely associated with positive SLNs in younger patients (age <35 years), and therefore the authors recommended that younger patients with thin melanomas and primary tumors with a high MR be considered for LM/SL.
Several investigators have specifically focused on factors that may predict SLN metastases in patients with thin melanomas or the role of LM/SL in this patient population. We previously reported17 that VGP is a risk factor for nodal metastasis in patients with thin melanomas, with an overall SLN positivity rate of 5.6%. Notable in this study was a 9.7% SLN positivity rate in patients with tumors .76 to 1.00 mm thick. This suggests that LM/SL may be indicated in that subset of patients. Corsetti et al.34 recommended that patients with thin melanomas and Clark level III or IV lesions be considered for LM/SL because there is an increased risk of recurrence in these patients. Finally, Jacobs et al.16 evaluated SLN positivity in 65 patients with thin melanomas. The incidence of positive SLNs in patients with tumor thickness <.75 mm was 0%, and this led the authors to conclude that LM/SL is not indicated in these patients.
In this article, we report the results of LM/SL in 181 patients with VGP-positive thin melanomas. Although other authors have included thin-melanoma patients in studies evaluating risk factors for SLN positivity, this is one of the largest population samples of thin melanomas to date reported in the literature. We found an overall SLN positivity rate of 5%, which is consistent with the incidence of nodal metastasis in patients with VGP-positive thin melanomas that we have previously reported,17 as well as with that reported by several other authors for patients with thin melanomas.11,28,29,32 However, because there is probably referral bias at our institution, as well as selection bias when patients are chosen for LM/SL, this 5% SLN positivity rate likely does not reflect the actual SLN positivity rate in patients with thin VGP melanomas observed in the general population. By univariate analysis, we identified two factors that were significantly associated with an increased incidence of positive SLNs: MR and tumor thickness. In addition, in a stratified multivariate regression model, the association between MR and SLN positivity remained significant when controlling for all other variables under investigation.
Focusing only on patients with an MR >0, we found an 8.7% SLN positivity rate. In addition, in patients with an MR >0 and tumor thickness .76 mm, the incidence of positive SLNs was 12.3%. These SLN positivity rates are comparable to those reported in several recent studies for patients with intermediate-thickness melanomas in whom LM/SL is routinely offered and recommended. Bleicher et al.11 reported a 7.1% SLN positivity rate in patients with melanomas 1.01 to 1.50 mm thick. In data reported by Cascinelli et al.10 from the World Health Organization, the incidence of SLN metastasis in patients with tumors 1.00 to 1.99 mm thick was 7%, and in patients with tumors 2.00 to 2.99 mm thick it was 13%. In addition, Joseph et al.12 identified positive SLNs in 7% of patients with tumors 1.00 to 1.50 mm thick. Therefore, in patients with thin melanomas, an MR >0 may identify patients who are at a risk for nodal metastasis similar to the risk of some patients with intermediate-thickness melanomas, thus suggesting that further staging with LM/SL should be considered in this group of thin-melanoma patients.
Although other clinical and histopathologic factors, including thickness, age, sex, Clark level, and ulceration, were considered in this study, none was found to be an independent predictor of SLN positivity, and only thickness was found to be associated with SLN positivity by univariate analysis. Whereas thickness has consistently been reported as an independent predictor of SLN positivity, other prognostic factors have been inconsistently associated with an increased incidence of positive SLNs. The inability to demonstrate a significant association between these other prognostic factors and SLN positivity in this study may be due to the limited number of events (positive SLNs) and to the low frequency of ulceration in patients with thin melanomas. In addition, although age is probably an important variable in predicting SLN metastasis, we were unable to demonstrate a significant association between age and SLN positivity because of the small number of patients >60 years of age in our study population. Other potential explanations for the lack of association in this study, as well as the inconsistent findings in other studies, include differences in the clinical and histopathologic variables evaluated, selection bias when considering patients for LM/SL, referral bias, and differences in selection of break points for the various factors evaluated.
In this study, the presence of any mitoses in dermal lesional cells was associated with an increased risk of SLN metastases. Therefore, it is not necessary to determine a formal MR to apply this model. This is an advantage, because pathologists differ in the manner of recording MR. In particular, MR determined as a rate per high-powered field varies according to the microscope used. If a formal rate count is desired, investigators recommend using a microscope calibrated to give a rate per square millimeter, because standardizing the method of recording MR facilitates comparison of data between different study populations.20,29
In summary, we found that there is a definable risk in patients with VGP-positive thin melanomas of having occult nodal disease. The presence of dermal lesional cell mitotic activity (MR >0) seems to be a significant predictor of SLN positivity that may be useful in risk-stratifying patients with thin melanomas and selecting patients for further staging with LM/SL. However, to confirm the significance of this finding, the predictive value of mitosis for SLN metastasis in patients with thin melanomas needs to be externally validated in other thin-melanoma population samples.
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ACKNOWLEDGMENTS |
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Received for publication April 19, 2004. Accepted for publication January 12, 2005.
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