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Annals of Surgical Oncology 9:754-761 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Prognostic Implications of Thick (>=4-mm) Melanoma in the Era of Intraoperative Lymphatic Mapping and Sentinel Lymphadenectomy

Richard Essner, MD, Mathew H. Chung, MD, Richard Bleicher, MD, Eddy Hsueh, MD, Leslie Wanek, DrPH and Donald L. Morton, MD

From the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California.

Correspondence: Address correspondence and reprint requests to: Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404; Fax: 310-449-5259; E-mail: essner{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Lymphatic mapping/sentinel lymphadenectomy (LM/SL) has become a routine part of our treatment algorithm for primary melanoma, yet its role in the management of thick (>=4-mm) lesions is unknown.

Methods: One hundred twenty-one patients with thick primaries underwent LM/SL at our institute. Survival curves were constructed from Kaplan-Meier estimates and analyzed by Cox proportional hazards methods.

Results: Sixty-three percent of patients were men, median age 54 years. The primary tumor sites were trunk (46%), extremities (32%), and head and neck (21%). Primary thickness ranged from 4 to 15 mm (median, 6.0 mm). Forty-five percent of primary tumors were ulcerated. Thirty-five percent of patients had tumor-positive dissections. Median follow-up was 31 months. The overall 5-year survival was no different (P = .726) for ulcerated and nonulcerated lesions. There was no difference (P = .159) in overall survival after tumor-negative (60% ± 7%) and tumor-positive (50% ± 10%) dissections. The 5-year disease-free survival was significantly (P = .012) lower in patients with tumor-positive (34% ± 9%) than tumor-negative (47% ± 7%) dissections.

Conclusions: Although LM/SL has become a popular technique for staging the regional lymph nodes in early-stage melanoma, our results suggest that sentinel node status is predictive of disease-free survival for thick primary tumors but is not yet reflective of overall survival. The role of LM/SL for patients with thick primary tumors is not clearly defined.

Key Words: Malignant melanoma • Lymph node dissection • Sentinel lymph node • Metastasis—Thick primaries


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The management of the regional lymph nodes in early-stage melanoma has remained controversial over the last century. The debate is based on the hypothesis that when melanoma metastasizes, this occurs by sequential progression of cells from the primary tumor to the regional lymph nodes and then to more distant sites. The proponents of elective lymph node dissection (ELND) claim that the metastatic cascade can be halted by removing the regional lymph nodes early in the natural history of the disease.1,2 If so, then patients treated by ELND should have a survival advantage compared with individuals whose lymph nodes are removed only after clinical and pathologic documentation of regional metastasis (delayed therapeutic dissection). Multiple retrospective, nonrandomized studies have demonstrated a survival advantage for patients treated by ELND instead of delayed therapeutic dissection.1–5 However, four randomized prospective clinical trials have failed to demonstrate an overall survival benefit for ELND, in part because a majority (~80%) will not have tumor-positive dissections, thereby diluting any therapeutic value of ELND in these studies. Many investigators support the opposing concept that regional lymph node metastases may only be markers of systemic disease.6–10

The role of ELND for patients with thick (>=4-mm) melanoma is even more controversial, because some studies suggest that the risk of occult distant metastases is so high in these patients that ELND should not be routinely used.11 All of the randomized trials examining the efficacy of ELND have excluded patients with thick primary tumors.

In 1992, Morton et al.12 reported on a minimally invasive alternative to ELND or delayed therapeutic dissection: intraoperative lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND). This procedure is based on the concept that regional lymph node metastases occur by the passage of melanoma cells through afferent lymphatics to the regional basin and to particular identifiable sentinel lymph nodes (SN). Experiments with cutaneous lymphoscintigraphy and subsequent work with several vital dyes in an animal model demonstrated that SN technology was valid.13,14 A large body of literature15 has accumulated over the past 9 years supporting the concepts of the original work by Morton et al.

Although a defined role of LM/SL/SCLND in patient care is unknown, LM/SL has become an increasingly popular alternative to ELND.16 LM/SL/SCLND is attractive to both surgeon and patient because it is minimally invasive and highly accurate for determining lymph node status for staging and directing adjuvant therapy. Patients who have a tumor-positive SN undergo SCLND, whereas those with tumor-negative LM/SL are spared the costs and potential morbidity of complete lymph node dissection.17

Because of the potentially high risk for patients with thick primary tumors to harbor occult distant metastases, LM/SL may not be warranted for patients with thick primary tumors, because the staging of the regional lymph nodes may not be predictive of clinical outcome. We undertook this investigation to evaluate those factors predictive of outcome for patients with thick primary tumors who underwent LM/SL/SCLND.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
One hundred thirty-five patients with clinical stage I melanoma and thick primary tumors who underwent LM/SL/SCLND between 1985 and 2000 were identified from our computer-assisted database. One hundred thirteen patients were used as our sample for data analysis (22 patients were excluded from the study as a result of LM/SL being performed at other facilities). Data were analyzed by patient sex and age, primary tumor site, Breslow thickness, ulceration, and histology of the primary melanoma.18

Before surgery, patients were routinely evaluated by complete history and physical examinations, chest x-ray, and blood profiles, including lactate dehydrogenase. In some cases, computed tomographic scans of the chest, abdomen, and pelvis; magnetic resonance imaging; or positron emission tomography was used for clinical suspicion of distant metastases.19,20 If metastases were identified, patients were excluded from LM/SL.

LM/SL was performed according to the techniques we previously described.12,21,22 In brief, patients underwent cutaneous lymphoscintigraphy with one of three radiopharmaceuticals, either several days before or on the day of the operative procedure.23 The skin site identified by lymphoscintigraphy was marked by the nuclear medicine physician. At the time of surgery, 1.0 to 2.0 mL of isosulfan blue (LymphazurinTM 1%; Tyco International, Exeter, NH) was injected intradermally at the primary tumor site. The skin was gently massaged to enhance the drainage of isosulfan blue into the regional lymphatics. An incision was made over the skin site marked by the nuclear medicine physician. The afferent lymphatics were examined for blue staining followed from the edge of the wound to the first SN. Since 1993, we have routinely used radiolymphoscintigraphy as an adjunct to the blue dye to improve the accuracy of LM/SL. Blue-stained or radioactive SNs were excised and examined for the presence of metastases by review of either frozen (early in our experience) or, more often, by permanent sections with hematoxylin and eosin (H&E) staining. If metastases were not demonstrated by H&E staining of the first sections, then additional sections were cut from the bivalved lymph nodes and stained with the murine monoclonal antibodies HMB-45 and S-100.24 If metastases were identified in the SN, then SCLND was performed. Lymph nodes removed by SCLND were examined only by conventional H&E staining.

After surgery, patients were observed by routine clinical examination, blood work, and chest x-rays. The follow-up time was calculated from initial diagnosis until last follow-up or death. Follow-up ranged from 2 to 173 months (median, 31 months). All LM/SL and SCLND occurred within 3 months of diagnosis of the primary melanoma.

Survival curves were constructed by using Kaplan-Meier estimates.25,26 Differences in survival distributions were tested by the log-rank method. Differences in frequency distributions and proportions were made by using either {chi}2 analysis or Fisher’s exact test. A P value of <.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Most patients were men (63%), and a majority (58%) were >50 years old (range, 20–87 years); 78% of patients had primary tumors on either the trunk or extremities. The mean thickness of the primary lesions was 5.90 mm (range, 4–15 mm; median, 6.0 mm). Eighty-seven percent of the primary tumors were Clark level IV or V, and 45% were ulcerated. Forty-eight percent of the primary tumors had nodular histologies.

One hundred thirteen patients underwent LM/SL, with identification of SN in all cases. Seventy-three (65%) patients had tumor-negative SNs; 22 (30%) of these patients subsequently died. Forty (35%) patients had tumor-positive SNs. SCLND was performed in all cases with tumor-positive SNs. Twenty-nine (73%) patients had one tumor-positive lymph node. Six (15%) patients had two tumor-positive lymph nodes, and in five (12%) cases, three or more positive nodes were identified. Thirteen (32%) patients with tumor-positive SNs died. Although there was a trend toward worsening survival for patients with increasing numbers of tumor-positive lymph nodes, the difference was not statistically significant (data not shown). There was no difference in the distribution of any of the prognostic factors in patients with tumor-positive or -negative SNs (Table 1). The 5-year disease-free survival was significantly (P = .012) worse for patients with tumor-positive (34% ± 9%) than those with tumor-negative (47% ± 7%) dissections (Fig. 1). However, the difference in disease-free survival did not translate to a lower overall 5-year survival (50% ± 10% vs. 60% ± 7%; P = .159) (Fig. 2). Fifty-one (45%) patients had ulcerated primary tumors. Neither disease-free nor overall survival was significantly (P = .915 and P = .726, respectively) different in patients with ulcerated or nonulcerated primary tumors (Figs. 3 and 4).


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  		TABLE 1. Comparison of factors in sentinel node–negative and –positive patients
 


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  		FIG. 1. Disease-free survival estimates for patients with thick (>=4-mm) primary melanoma with tumor-negative (SN-) and -positive (SN+) dissections. The 5-year disease-free survival was significantly (P = .012) better for patients with SN- (47% ± 7%) than for those with SN+ (34% ± 9%) dissections. SLND, sentinel lymph node dissection.

 


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  		FIG. 2. Five-year survival estimates based on lymph node status (SN- vs. SN+). The 5-year survival was no different (P = .159) for the 73 patients with SN- (60% ± 7%) than the 40 with SN+ (50% ± 10%). SN, sentinel lymph node; SLND, sentinel lymph node dissection.

 


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  		FIG. 3. Disease-free survival estimates comparing ulceration status (+ vs. -) for thick (>=4-mm) primary melanoma. The 5-year disease-free survival was no different (P = .915) for patients with nonulcerated (35% ± 17%) versus ulcerated (26% ± 13%) primary tumors.

 


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  		FIG. 4. Overall 5-year survival estimates based on ulceration status (+ vs. -) for patients with thick (>=4-mm) primary melanoma. Five-year survival estimates were determined for patients on the basis of the presence or absence of ulceration of the primary tumor. There was no difference (P = .726) in survival of patients by ulceration status (59% ± 11% ulcerated vs. 56% ± 14% nonulcerated lesions).

 
The incidence and distribution of first site recurrences was quite similar for patients with tumor-negative and tumor-positive dissections. Thirty (41%) of 73 patients with tumor-negative SNs had recurring disease. The majority (73%) of first site recurrences were to distant lymph nodes, skin, or viscera. Three (4.1%) patients had recurrences to the dissected basin. The median time to distant recurrence was 23 months; one patient’s disease recurred 72 months after tumor-negative LM/SL (Table 2).


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  		TABLE 2. Distribution of first site recurrences for 113 patients with thick primary melanoma
 
Twenty-one (52%) of 40 of patients with tumor-positive SNs had recurring disease. Most (67%) of these recurrences were to distant sites and, less often, to regional lymph nodes, in-transit sites, or at the wide excision. The median time to distant recurrence for tumor-positive dissections was 7.6 months (Fig. 5).



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  		FIG. 5. Frequency of distant metastases on the basis of the status of the sentinel lymph node (SN). The time to development of distant skin, lymph node, or visceral metastases was determined from patients with tumor-positive (SN+) and -negative (SN-) dissections. Fourteen (35%) of 40 patients with SN+ had recurring disease, all within 36 months of LM/SL. Thirty-two (30.1%) of 73 patients with SN- developed distant metastases. One patient’s disease recurred 6 years after SN-.

 
Multiple clinicopathologic features were examined for their role in predicting disease-free and overall survival. Sex, age (<=50 vs. >50 years), primary tumor site, Clark level, histology, tumor thickness, and ulceration were not predictive of disease-free survival (Table 3). The tumor status of the SN was predictive of disease-free survival but seemed not to be significant for overall survival (Table 4).


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  		TABLE 3. Univariate and multivariate analyses of factors predicting disease-free survival
 

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  		TABLE 4. Univariate and multivariate analyses of factors predicting overall survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The rationale for ELND in early-stage melanoma is based on the assumptions that (1) lymph node dissection identifies nodal metastases (for staging purposes) and prevents subsequent recurrences in the same (dissected) basin and that (2) a certain percentage of distant metastases occur as the tumor grows in the regional lymph basin from microscopic to palpable disease.1–10 LM/SL/SCLND seems to be a valid alternative to ELND as a procedure that fulfills the first assumption, but we are unaware of any data to support the notion that LM/SL/SCLND has any role in fulfilling the second assumption for ELND.27–29 Thus, we are left with the conclusion that LM/SL/SCLND is a staging procedure, yet in patients with thick primary tumors, the staging of the regional lymph nodes may not be critical when the risk of distant metastases may exceed that of regional lymph node disease.

In our experience, the tumor status of the SN was predictive of disease-free but not overall survival. We suspect that our results are probably related to the relatively similar risk of recurrence (41% vs. 52%) for SN- and SN+ patients, contrasted with the variation in times to recurrence. The median time to recurrence was only 7 months for SN+ dissections and was 23 months for those with SN- dissections. Recurrences at any time seem to be predictive of subsequent patient demise. Yet none of the factors we examined were of prognostic value for determining overall survival. Although these results are contrary to current dogma for early-stage melanoma, patients with thick primary tumors may represent a homogeneous patient population with predictably poor outcomes.

A number of investigators have examined prognostic factors contributing to survival for patients with thick primary tumors. Massi et al.30 determined that tumor thickness, tumor invasion front, ulceration status, and mitotic rate were independent predictors of overall survival. With a median follow-up of 93 months, their cohort of patients had a projected survival similar to that in our group. In 1999, Kim et al.31 from Memorial Sloan-Kettering Cancer Center reported on their experience of 120 patients with thick primary tumors treated with a variety of approaches; a minority had regional lymph node metastases. Although ELND in and of itself was not associated with an improved survival (P > .05), increasing tumor thickness, ulceration status, and nodal metastases were predictive of survival.

However, it is not clear from our series why tumor thickness, ulceration, and nodal status of the SN were not predictive of overall survival. Gershenwald et al.32 reported on 126 patients with thick primary tumors who underwent LM/SL. Thirty-nine percent of patients had tumor-positive dissections, and 50% had ulceration of the primary lesions. With a median follow-up of 3 years, the 3-year estimated survival was significantly (P = .006) worse for SN+ (64%) than for SN- (89%) patients and for those with ulcerated primary tumors (71%) (P < .003) than those without ulceration (86%). Yet even with a slightly shorter median follow-up time, our patients seemed to have similar survival times in terms of SN (3-year estimates: 62% SN+ vs. 80% SN-) and ulceration status (3-year estimates: 72% ulcerated vs. 75% nonulcerated primary tumors). The differences in statistical outcome from our series may result from the lack of adverse events for SN+ patients and those with ulcerated primary tumors. We anticipate that with longer follow-up, more recurrences would be seen in those patients.

We also suspect that the routine use of immunohistochemistry may contribute to the smaller differences in survival between SN- and SN+ patients. Cochran et al.24 demonstrated the importance of immunohistochemical staining for the detection of occult tumor cells in the regional lymph nodes. They reported that routine immunohistochemical staining of ELND specimens with HMB-45 and S-100 murine monoclonal antibodies increased the frequency of positive dissections by at least 14%. Among patients with thick primary tumors, the rate of detection of tumor-positive SNs may be even higher. However, although the prognostic significance of micrometastases is unknown, our current standard for pathology analysis of the SN incorporates both routine H&E and immunohistochemical staining. Seventy-three percent of our patients with tumor-positive dissections had disease limited to a single SN; many incidents were micrometastases. The inclusion in survival statistics of patients with smaller metastases tends to cause a delayed recurrence and may reduce the effect of survival for tumor-positive SNs. Immunohistochemical staining of SNs was not a routine part of the series reported by Gershenwald et al.32.

Recurrences in the dissected basins occurred in three (4%) SN- patients; these occurred as late as 5 years after LM/SL.33 One patient had undergone LM/SL with Lymphazurin alone, and two had a combination of blue dye and a radiopharmaceutical. Although we continue to improve on the accuracy rate of SN identification, the occurrence of dissected basin recurrence reminds us of the flaws possible in a staging modality. The importance of nuclear medicine, pathology, and surgical cooperation cannot be overemphasized for the success of LM/SL. The ongoing Multicenter Selective Lymphadenectomy Trial should provide us with information about the accuracy of this procedure on an international scale.16

Questions remain as to the role of LM/SL/SCLND for patients with thick primary tumors. LM/SL has become a routine part of the management of early-stage melanoma and can provide valuable staging information for guiding the use of adjuvant therapy. LM/SL provides significant prognostic information on disease-free survival for patients with thick primary melanoma, but further follow-up is necessary to determine whether this technique is useful for predicting survival among other factors that may be important.33,34


   Acknowledgments
 
Supported by National Institutes of Health grants CA 12582 and CA 29605, by the California Cancer Research Fund, and by funding from the Saban Family Foundation, Los Angeles, CA.


   Footnotes
 
Presented at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) has become the standard technique for staging the regional lymph nodes in early-stage melanoma. Our results of LM/SL from 113 patients with thick (>=4-mm) primary tumors suggest that the tumor status of the sentinel node is predictive of disease-free but not overall survival.

Received for publication June 19, 2001. Accepted for publication July 18, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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