C. Wayne Cruse

Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma

BACKGROUND The sentinel lymph node (SLN), the first node draining the primary tumor site, has been shown to reflect the histologic features of the remainder of the lymphatic basin in patients with melanoma. Intraoperative localization of the SLN, first proposed by Morton and colleagues, has been accomplished with the use of a vital blue dye mapping technique. Technical difficulties resulting in unsuccessful explorations have occurred in up to 20% of the dissections. OBJECTIVES The authors aimed to define the SLN using gamma detection probe mapping and to determine whether intraoperative radiolymphoscintigraphy using technetium sulfur colloid and a hand-held gamma-detecting probe could be used to improve detection of all SLNs for patients with melanoma. METHODS To ensure that all initial nodes draining the primary site were removed at the time of selective lymphadenectomy, the authors used intraoperative radiolymphoscintigraphy to confirm the location of the SLN, which was determined initially with the preoperative lymphoscintigram and the intraoperative vital blue dye injection. PATIENT POPULATION The patient population consisted of 106 consecutive patients who presented with cutaneous melanomas larger than 0.75 mm in all primary site locations. RESULTS The preoperative lymphoscintigram revealed that 22 patients had more than one lymphatic basin sampled. Two hundred SLNs and 142 neighboring non-SLNs were harvested from 129 basins in 106 patients. After the skin incision was made, the mean ratio of hot spot to background activity was 8.5:1. The mean ratio of ex vivo SLN-to-non-SLN activity for 72 patients who had SLNs harvested was 135.6:1. When correlated with the vital blue dye mapping, 139 of 200 (69.5%) SLNs demonstrated blue dye staining, whereas 167 of 200 (83.5%) SLNs were hot according to radioisotope localization. With the use of both intraoperative mapping techniques, identification of the SLN was possible for 124 of the 129 (96%) basins sampled. Micrometastases were identified in SLNs of 16 of the 106 (15%) patients by routine histologic analysis. CONCLUSION The use of intraoperative radiolymphoscintigraphy can improve the identification of all SLNs during selective lymphadenectomy.

Redefinition of Cutaneous Lymphatic Drainage With the Use of Lymphoscintigraphy for Malignant Melanoma

Lymphoscintigraphy was performed on 82 patients with melanoma registered at the University Melanoma Clinic. From these data, precise lymphatic drainage basins could be drawn for the head, neck, shoulder, and trunk. These drawings differed significantly from the classic anatomic studies, providing a functional look at the cutaneous lymphatic drainage. This new method correlates much better with clinical experiences and demonstrates much larger areas of ambiguous drainage than previously reported. Data from the lymphoscintigrams also emphasize the individuality of cutaneous lymphatic flow. The implications of these data in planning elective node dissections for intermediate thickness melanomas are obvious, since it is estimated that up to 59% of the dissections for trunk and head and neck primary melanomas may be misdirected if based on classic anatomic studies. The data indicate that all patients with head, neck, and shoulder lesions should undergo lymphoscintigraphy to define possible drainage basins at risk for metastatic disease. Similarly, truncal lesions require scintigrams except when they are within four well-defined areas with an extremely low probability of ambiguous drainage. Lesions in these areas show very reliable and predictable drainage to a single nodal group.

The Augsburg consensus

SUMMARY The techniques of lymphatic mapping and sentinellymphadenectomy have been increasingly popular inthe 8 years since their introduction. 1 The techniqueswere initially developed for the management of pa-tients with cutaneous melanoma, but are now widelyapplied in breast carcinoma and are under investiga-tion in the management of other forms of cancer.Despite this wide enthusiasm there is little unanimityregarding the exact details of the technical steps thatare required for successful application of the ap-proach, and published guidelines remain few. Withthis in mind, a conference on sentinel lymphadenec-tomy in cutaneous malignancies was held in Augs-burg, Germany, in March 1999, following which agroup of individuals who had extensive experiencewith the approach convened a committee of expertsand was charged with developing a consensus on thetechniques necessary for the optimum application of theapproach. This article is the result of these deliberationsand provides detailed and practicable recommendationson patient selection, preoperative and intraoperative lo-calization of the SLNs, pathologic assessment of theSLNs, and the correct disposition of lymph node tissuesfor diagnostic and investigative purposes.

Age as a prognostic factor in the malignant melanoma population

AbstractBackground: The incidence of malignant melanoma is increasing faster than any other cancer, and the state of Florida has one of the highest incidence of melanoma in the United States. This increased incidence is thought to be due to the intense sunlight exposure and ultraviolet radiation exposure in the elderly population. With the increased emphasis on issues of aging, it is appropriate to study the role of age as a prognostic factor for malignant melanoma in the Florida population. Methods: A retrospective, computer-aided search identified 442 consecutively registered patients with malignant melanoma at the Cutaneous Oncology Program. All patients had stage 1 or 2 disease (cutaneous disease only) at diagnosis. Prognostic variables analyzed included the most powerful factors for stage 1 and 2 melanoma, tumor thickness, ulceration, and Clark level of invasion. Other prognostic variables included in the analysis were the clinical variables of sex and primary site (axial vs. extremity). The population was divided into patients ≤65 and >65 years of age. Results: Significant disease-free survival differences were encountered in the older population, with only 55% of the elderly population being disease free at 5 years compared with 65% for the younger population (p=0.0073). However, a greater percentage of patients with melanoma who were >65 years of age had ulcerated lesions (17.5% vs. 12.9%) and a greater percentage of thick lesions at diagnosis (67.2% vs. 62.7%). Both of these prognostic factors would bias the older population with a poorer survival. A stepwise regression analysis of the entire population was performed, treating age as a continuous variable. Surprisingly, increasing age along with tumor thickness were the only significant predictors for disease-free survival. After inclusion of these two prognostic variables, none of the other prognostic factors, including Clark level, ulceration, sex, and primary site, added to the prognostic model. Conclusions: From this analysis, it is apparent that geriatric patients with melanoma have a worse prognosis than a younger control population, even after the correction for the more commonly cited prognostic factors. This information should be used in mathematical modeling to identify high-risk populations who are candidates for perhaps more aggressive primary or adjuvant therapies.

Results of complete lymph node dissection in 83 melanoma patients with positive sentinel nodes.

AbstractBackground: The technique of sentinel lymph node (SLN) biopsy for melanoma provides accurate staging information because the histology of the SLN reflects the histology of the entire basin, particularly when the SLN is negative. Methods: We combined two mapping techniques, one using vital blue dye and the other using radiolymphoscintigraphy with a hand-held gamma Neoprobe, to identify the SLN in 600 consecutive patients with stage I–II melanoma. The SLNs were examined using conventional histopathology and immunohistochemistry for S-100. Results: Eighty-three (13.9%) patients had micrometastatic disease in the SLNs. Thirty percent of patients with primary melanomas greater than 4.0 mm in thickness had positive SLNs, followed by 48 of 267 (18%) of patients with tumors between 1.5 mm and 4 mm, and 12 of 169 (7%) of those with lesions between 1.0 mm and 1.5 mm. No patient with a tumor less than 0.76 mm in thickness had a positive SLN. Sixty-four of the 83 SLN-positive patients consented to undergo complete lymph node dissection (CLND), and five of 64 (7.8%) of the CLNDs were positive. All patients with positive CLNDs had tumor thicknesses greater than 3.0 mm. Conclusions: The rate of SLN-positive patients increases with increasing thickness of the melanoma. SLN-positive patients with primary lesions less than 1.5 mm in thickness may have disease confined to the SLN, thus rendering higher-level nodes free of disease, and may not require a CLND.

The Progression of Melanoma Nodal Metastasis Is Dependent on Tumor Thickness of the Primary Lesion

Background: Recent results of several clinical trials using the technique of intraoperative lymphatic mapping and sentinel lymph node (SLN) biopsy confirm the validity of the concept of there being an order to the progression of melanoma nodal metastases. This report reviews the H. Lee Moffitt Cancer Center experience with this procedure, one of the largest series described to date. These data demonstrate that the involvement of the SLNs, as well as higher-echelon nodes, is directly proportional to the melanoma tumor thickness, as measured by the method of Breslow.Methods: The investigators at the H. Lee Moffitt Cancer Center retrospectively reviewed their experience using lymphatic mapping and SLN biopsies in the treatment of malignant melanoma. All eligible patients with primary malignant melanomas underwent preoperative and intraoperative mapping of the lymphatic drainage of their primary sites, along with SLN biopsies. All patients with positive SLNs underwent complete regional basin nodal dissection. For 20 consecutive patients with one positive SLN, all of the nodes from the complete lymphadenectomy were serially sectioned and examined by S-100 immunohistochemical analysis, to detect additional metastatic disease.Results: Six hundred ninety-three patients consented to undergo lymphatic mapping and SLN biopsy. The SLNs were successfully identified and collected for 688 patients, yielding a 99% success rate. One hundred patients (14.52%) showed evidence of nodal metastasis. The rates of SLN involvement for primary tumors with thicknesses of <0.76 mm, 0.76–1.0 mm, 1.0–1.5 mm, 1.5–4.0 mm, and >4.0 mm were 0%, 5.3%, 8%, 19%, and 29%, respectively. Eighty-one patients underwent complete lymph node dissection after observation of a positive SLN, and only six patients with positive SLNs demonstrated metastatic disease beyond the SLN (7.4%). The tumor thicknesses for these six patients ranged from 2.8 to 6.0 mm. No patient with a tumor thickness of <2.8 mm was found to have evidence of metastatic disease beyond the SLN in complete lymph node dissection. All 20 patients with a positive SLN for whom all of the regional nodes were serially sectioned and examined by S-100 immunohistochemical analysis failed to show additional positive nodes.Conclusions: These results suggest that regional lymph node involvement may be dependent on the thickness of the primary tumor. As the primary tumor thickness increases, so does the likelihood of involvement of SLNs and higher regional nodes in the basin beyond the positive SLNs.

Multiple primary melanomas: Implications for screening and follow-up programs for melanoma

AbstractBackground: Once individuals are diagnosed with malignant melanoma, they are at an increased risk of developing another melanoma when compared with the normal population. Methods: To determine the impact of an intensive follow-up protocol on the stage of disease at diagnosis of subsequent primary melanomas, a retrospective query was performed of an electronic medical record database of 2,600 consecutively registered melanoma patients. Results: Sixty-seven patients (2.6%) had another melanoma diagnosed at the time of presentation to the clinic or within 2 months (synchronous) and another 44 patients (1.7%) developed a second primary melanoma during the follow-up period (metachronous). For the 44 patients diagnosed with metachronous lesions, the Breslow mean tumor thickness for the first invasive melanoma was 2.27 mm compared with 0.90 mm for the second melanoma. The first melanomas diagnosed are thicker by an average of 3.8 mm (p=0.008). The mean Clark level for the initial melanoma was greater than the mean level for subsequently diagnosed melanomas (p=0.002). Twenty-three percent of the initial melanomas were ulcerated, whereas only one of the second primary lesions showed this adverse prognostic factor (p=0.002). Conclusions: Once individuals are diagnosed with melanoma, they are in a high-risk population for having other primary site melanomas diagnosed and should be placed in an intensive follow-up protocol consisting of a complete skin examination.

Evaluation of new putative tumor markers for melanoma

AbstractBackground: The early diagnosis of recurrent melanoma can contribute to better outcome if the disease can be surgically resected or if the metastases are responsive to systemic therapies. Lipid-associated sialic acid (LASA-P) and the S-100 protein (S-100) were evaluated as tumor markers for melanoma with the goal of early detection of recurrence. Methods: Sixty-seven patients were identified who had levels of S-100 and LASA-P drawn during their clinical course. A multivariate regression analysis was performed to determine the significance of the serum markers in relation to other prognostic factors for melanoma. Results: After a median follow-up of 30 months, 58 patients had recurrences, and 49 patients died of disease. LASA-P elevation was not associated with the time to recurrence (p=0.2176) or survival (p=0.2507). S-100 positivity was a significant predictor of recurrence (p<0.0001) and survival (p=0.0059). The median time to recurrence for S-100-positive and S-100-negative patients was 7.6 and 33.8 months, respectively. The median survival time was 59.2 months for S-100-negative patients and 29.6 months for patients positive for S-100. Conclusions: Serum S-100 shows significant correlations to both time to recurrence and survival and could be useful in the clinical detection of malignant melanoma.

Lymphoscintigraphy as a predictor of lymphatic drainage from cutaneous melanoma

AbstractBackground: If cutaneous lymphoscintigraphy (CL) is accurate in predicting the draining lymph node basins at risk from primary axial melanomas, then regional metastases should only occur in those lymph node basins identified by CL. Methods: This study is a retrospective review of patients undergoing CL for primary axial melanomas from June 1, 1985, until June 31, 1992. Data retrieved included age, gender, number of basins identified, location of basins identified, management of basins, recurrence in lymphatics, development of distant disease, and long-term follow-up. Results: A total of 181 patients underwent elective LND, and 48 patients (27%) had melanoma in the nodes within the dissected basin. Of these 181 patients, seven developed nodal metastases as their site of first recurrence. All seven recurrences were seen at sites dissected or at sites indicated by CL, which the primary surgeon elected not to treat initially. Of the 116 patients observed, 16 (14%) developed lymph node metastases as their first site of recurrence. Fifteen of these 16 patients had their site of lymph node metastases predicted by CL. In this study, CL predicted 98.6% of all lymph node metastases. Conclusions: The high overall reliability of CL as demonstrated by long-term follow-up indicates that the information obtained by CL can be reliably used to guide intervention. Initial evaluation of patients with high-risk cutaneous melanomas at sites with ambiguous lymphatic drainage must include CL in order to determine the draining lymph node basins and to plan therapy.

The Role of Selective Lymphadenectomy in the Management of Patients with Malignant Melanoma

background A novel surgical technique based on selective lymphadenectomy was used to stage 132 patients with intermediate and thick cutaneous malignant melanoma. Preoperative and intraoperative lymph node mapping techniques were used to ascertain regional lymph node basins at risk for metastasis, and to identify the first node(s) the afferent lymphatics encounter in the basin, defined as the “sentinel” node(s). It has been shown that the histology of the sentinel node reflects the histology of the rest of the nodal basin, and according to preliminary studies using this technique, the likelihood of bypassing the sentinel node(s) to “higher” level nodes is less than 2%. Epidemiologic studies indicate that the long‐term survival of patients with melanomas of intermediate thickness or greater is significantly compromised if regional lymph nodes are involved. Yet, the utility of performing lymph node dissections for the purposes of staging only is controversial, not only because of the morbidity and expense of the procedure, but the lack of proven survival benefit. objective In the present study, we performed preoperative and intraoperative lymphatic mapping, harvested clinically normal sentinel nodes, and examined them for micrometastasis by light microscopy. Both conventional stains and immunocytochemistry for S‐100 protein and HMB‐45 antibodies were performed, and only those patients with documented micrometastasis received complete lymph node dissections. results The sentinel node(s) was identified in each of the patients. Micrometastasis disease was detected in 31 (23%) of the patients by selective lymphadenectomy, and the sentinel node(s) was the only node involved in 83% of the cases upon subsequent complete nodal dissection. conclusion Our preliminary results suggest that selective lymphadenectomy following lymphatic mapping is an effective procedure for staging melanoma patients with lesions of intermediate thickness or greater. Our results indicate that sentinel lymph nodes may be successfully identified and harvested in the majority of patients, and that they may be examined for the first evidence of micrometastasis without the need of a complete nodal dissection. Information as to whether micrometastases are present in the sentinel node would be valuable in staging patients, and identifying candidates for complete nodal dissections. We are participating in a National Cancer Institute‐sponsored multicenter trial to ascertain whether this surgical approach can impact on the recurrence rate and survival of patients with stage 1 and 2 melanoma.