Isolated limb perfusion with melphalan for melanoma.

Isolated limb perfusion with melphalan is a well-established and effective treatment for inoperable melanoma metastases of the extremities, with an overall response rate of 80% and a complete response rate of 54%. The surgical technique is complex and serious morbidity can occur, but with attention to detail major side effects can be kept to a minimum. This article reviews the technique, results and other aspects of this sophisticated form of treatment.

Five-year follow-up of 16 melanoma patients with a Starz I-involved sentinel node in whom completion lymph node dissection was omitted.

The aim of the study was to determine the incidence of lymph node recurrence in 16 melanoma patients with a minimal metastasis (Starz level I) in a sentinel node in whom a completion lymph node dissection was omitted. A secondary aim was to examine whether other melanoma-related recurrences developed. Sixteen melanoma patients with an SI-involved sentinel node, who did not undergo completion lymph node dissection, were followed for a median of 66 months. Lymph node recurrences did not occur. One of the 16 patients developed a local recurrence and another developed satellite metastases. None of the 16 patients with an SI-positive sentinel node developed a nodal recurrence, which suggests that the risk of refraining from node dissection in such patients is small. This option could be considered and discussed with the patient in terms of the risk of nonsentinel node involvement and the unsolved problem of unknown overall survival advantage.

T-cell immune function in tumor, skin, and peripheral blood of advanced stage melanoma patients: implications for immunotherapy.

PURPOSE: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms. EXPERIMENTAL DESIGN: CD8(+) T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2(+) patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied. RESULTS: Higher percentages of melanocyte antigen-specific CD8(+) T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8(+) T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function. CONCLUSIONS: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy.

Less false-negative sentinel node procedures in melanoma patients with experience and proper collaboration.

BACKGROUND AND OBJECTIVES: The aims of the study were to determine the percentage of false-negative sentinel node procedures in melanoma patients, to investigate the time cohort of these recurrences, whether a learning phase was involved and to search for causes of the failures. METHODS: Between December 1993 and December 2008, 708 melanoma patients underwent a sentinel node biopsy. The procedure was considered false-negative if a recurrence developed in the basin from which a tumor-free sentinel node had been removed. Of all false-negative cases, the pre-operative images, operative report and pathology slides were reviewed. RESULTS: Sentinel node biopsy was positive in 164 (23%) of the patients and false-negative in 10 (1.4%), which results in a false-negative rate of 5.7%. Five of the 10 failures occurred in the first year after the sentinel node biopsy was introduced. Causes for these false-negative procedures could be attributed once to the nuclear medicine physician, once to the surgeon and twice to the pathologist. CONCLUSION: The sentinel node procedure failed to identify involvement in 5.7% of the patients with lymph node metastases. Half of the false-negative biopsies took place in the first year after the procedure was introduced, illustrating the existence of a learning period.

Utility of preoperative 18F-FDG PET/CT and brain MRI in melanoma patients with palpable lymph node metastases.

BACKGROUND: The aims of this prospective study were to determine the diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and brain MRI in melanoma patients with palpable lymph node metastases and to assess the impact of these imaging modalities on their management. MATERIALS AND METHODS: Between October 2006 and March 2009, PET/CT and brain MRI were performed in 70 melanoma patients with palpable nodal lymph node metastases and without evidence of systemic dissemination after physical examination. Hypermetabolic PET/CT lesions were examined by histology or cytology or were imaged further and followed if no pathology confirmation could be obtained. RESULTS: PET/CT findings changed the intended regional node dissection in 26 patients (37%). PET/CT was false negative in 4 patients (6%) and false positive in 1 (1%). This resulted in a sensitivity of 87%, specificity of 98%, accuracy of 93%, positive predictive value of 96%, and negative predictive value of 91%. MRI revealed brain metastases in 5 patients (7%). The overall survival of patients without additional lesions on PET/CT was 84% after 2 years, which was better than the 56% in patients with additional metastases (P < .001). CONCLUSIONS: PET/CT has an 87% sensitivity and 98% specificity in the detection of other metastases in melanoma patients with palpable lymph node involvement. PET/CT leads to a change in the planned regional node dissection in 37% of the patients in this study. MRI revealed brain metastases in 5 patients (7%). PET/CT findings correlate with survival.

Utility of FDG PET/CT and brain MRI in melanoma patients with increased serum S-100B level during follow-up.

BACKGROUND: The serum level of the S-100B protein is increasingly used as a tumor marker in melanoma patients. The aims of this study were to assess the clinical relevance of increased S-100B during follow up of high-risk melanoma patients and to determine the value of subsequent whole-body PET/CT and brain MRI. MATERIALS AND METHODS: A retrospective analysis was performed of all 46 melanoma patients with a normal history and physical examination who were found to have an elevated serum S-100B level (> or =0.10 microg/L) during follow-up between August 2006 and March 2009. Suspicious lesions on FDG PET/CT were biopsied for histological or cytological confirmation or were imaged further and followed if no pathology confirmation could be obtained. RESULTS: The positive predictive value of an elevated serum S-100B was 50%. PET/CT revealed hypermetabolic lesions in 27 of the 46 patients (59%). PET/CT was never false negative as confirmed by median follow-up of 1 year but was false positive in 4 patients. MRI revealed brain metastases in 1 patient (2%). Of the 23 patients with a true positive PET/CT scan, 6 (26%) received surgical treatment with curative intent; the other 17 (74%) received palliative treatment or supportive care. The survival of patients with a normal PET/CT was longer than patients with a positive PET/CT (P = .002). CONCLUSIONS: An elevated serum S-100B during follow-up of high-risk melanoma patients has a modest 50% positive predictive value for recurrent disease. Subsequent PET/CT and MRI can identify patients with recurrent disease.

Lymphatic drainage patterns from the treated breast.

INTRODUCTION: Lymphatic drainage patterns from the breast have been described in the past. Drainage may change after treatment of a breast or axilla, and this may have implications for lymphatic mapping. The aim of this study was to determine the lymphatic drainage patterns in breast cancer patients with a previously treated ipsilateral breast. METHODS: Between January 1999 and November 2008, 115 sentinel node procedures were performed in breast cancer patients who had undergone treatment of the ipsilateral breast in the past. Lymphatic drainage patterns were analyzed based on preoperative lymphoscintigraphy and sentinel lymph node biopsy. Patients were divided into subgroups according to their previous treatment. RESULTS: Sentinel nodes were found in 84% of the patients: in 81 patients (70%) in the axilla, 43 patients (37%) had drainage to more than one site, and in 18 patients (16%) no drainage was detected. The percentage of drainage outside the axilla was higher than in a series of untreated breast cancer patients from our institution (51% versus 33%, P = 0.01). The 16% nonidentification rate was also higher than the 3.1% in patients without previous treatment (P = 0.003). Four patients (3.5%) had lymphatic drainage to the contralateral axilla. Twelve patients (10%) had involved sentinel nodes; these were harvested from the contralateral axilla in two of them. No lymph node recurrences were observed during a median follow-up time of 39 months. CONCLUSION: Lymphatic mapping yields a lymph node in 84% of breast cancer patients who have undergone previous treatment of the breast. Nonidentification and extra-axillary nodes are more frequently encountered than in patients without treatment of the breast in the past. The finding of involved nodes suggests that sentinel node biopsy improves staging. Long-term follow-up will determine the sensitivity of the procedure in this specific situation.

SPECT/CT for preoperative sentinel node localization.

The value of SPECT/CT for detection and localization of sentinel nodes is reviewed. SPECT/CT depicts extra sentinel nodes and identifies non-nodal tracer accumulation. SPECT/CT is indicated in patients with complex lymphatic drainage as often present in patients with head, neck and scapular melanoma, breast cancer patients with extra-axillary sentinel nodes and patients with tumors draining to pelvic nodes. SPECT/CT also clarifies the drainage pattern of inconclusive conventional images (non-visualization or unclear location of the nodes).

Reevaluation of the locoregional recurrence rate in melanoma patients with a positive sentinel node compared to patients with palpable nodal involvement.

BACKGROUND: The main aims of this study were to evaluate the occurrence of the various forms of locoregional recurrence in sentinel node-positive melanoma patients, to determine whether the different definitions that are being used to describe in-transit metastases influence this rate, and to identify factors associated with locoregional recurrence. A comparison was made with the rate of locoregional recurrence in patients who underwent lymph node dissection for palpable metastases. METHODS: Between December 1993 and December 2008, a total of 141 patients underwent completion lymph node dissection because of a tumor-positive sentinel node. In the same period, 178 patients underwent a regional lymph node dissection for palpable nodal metastases. RESULTS: In the sentinel node-positive patients, the local recurrence rate was 5%, the rate of satellite metastasis was 2%, and for in-transit metastasis, it was 15%. In patients with palpable nodal involvement, these values were 3%, 2%, and 14%, respectively. There was no statistically significant difference in locoregional recurrence-free rates between these two groups of node-positive patients (P = .172). Breslow thickness was the only predictive factor for locoregional recurrence (P = .015). CONCLUSIONS: The rate of locoregional metastases in patients with a tumor-positive sentinel node and patients with palpable nodal involvement is similar. The present study refutes the suggestion that a positive sentinel node indicates a predisposition for developing in-transit metastases.

Evaluation of lymphatic drainage patterns to the groin and implications for the extent of groin dissection in melanoma patients.

INTRODUCTION: Early conventional lymphoscintigrams can distinguish sentinel nodes from second-tier nodes and the new SPECT/CT technology shows their precise anatomical location. The purpose of the study was to analyze lymphatic drainage patterns to the groin using these techniques and to determine the implications for a potential groin dissection. METHODS: Fifty-five groins in 50 patients were analyzed using lymphoscintigrams and SPECT/CT. The superficial groin was divided in five Daseler-zones, and the pelvic region in three zones. RESULTS: A total of 106 sentinel nodes were depicted: 10% in the superior lateral, 13% superior medial, 42% inferior medial, 26% central, and 8% in the external iliac zone. The second-tier nodes were mostly visualized in the external iliac zone (54%). No drainage at all was seen to the inferior lateral zone. In lower trunk melanoma, 81% of the sentinel nodes were in the superior and central zones, and no second-tier nodes were observed in the inferior zones. Twelve sentinel nodes were involved: ten in the inferior medial and two in the central zone. CONCLUSIONS: Most (involved) sentinel nodes were found in the inferior medial and central zones. The high frequency of pelvic second-tier nodes indicates the need for a deep completion groin dissection in the majority of patients with positive sentinel nodes. In none of the patients, lymphatic drainage was seen to the inferior lateral zone, which suggests that this area need not be included in a completion dissection. In patients with lower trunk melanoma, the inferior medial zone may not need to be removed either.

Comparison of three micromorphometric pathology classifications of melanoma metastases in the sentinel node.

OBJECTIVE: The purposes of this study were to determine which classification best predicts additional lymph node disease and survival, and to suggest a threshold below which a completion dissection may be omitted. SUMMARY BACKGROUND DATA: Three micromorphometric parameters of melanoma sentinel node metastases were compared: invasion depth from the capsule (Starz-classification), maximum diameter (Rotterdam-criteria), and location within the node (Dewar-classification). METHODS: The pathology slides of 116 patients with tumor-positive sentinel nodes were reviewed. The follow-up data were obtained from the prospectively kept database. The median follow-up duration was 53 months. RESULTS: Metastases with an invasion depth under 0.3 mm or diameter less than 0.1 mm were not associated with additional involved nodes. Four percent of the patients with metastases with an invasion depth of 0.3 to 1.0 mm had other involved nodes and 3% of the patients with metastases with a diameter of 0.1 to 1.0 mm. Other nodes were involved in 3% of subcapsular metastases, 9% of both subcapsular and parenchymal metastases, and 33% in case of multifocal or extensive disease. The smallest tumor invasion depth and diameter associated with additional involved nodes was 0.4 mm. Only 5-year overall survival in the 3 successive invasion depth categories were statistically significant: 92%, 83%, and 68%. Five-year overall survival was 81% in patients with one involved sentinel node and 60% if there were more. CONCLUSIONS: Invasion depth and diameter of the metastasis correlate best with the presence of additional nodal disease. Invasion depth best predicts overall survival. It seems justified to refrain from completion dissection in patients with a sentinel node tumor invasion depth up to 0.4 mm.

Lymphatic drainage patterns in breast cancer patients who previously underwent mantle field radiation.

BACKGROUND: Lymphatic drainage may change after radiation of a breast or its regional lymph node basins, and this may have implications for lymphatic mapping afterward. The aim of this study was to determine the lymphatic drainage patterns in breast cancer patients who had undergone mantle field radiation for Hodgkin's lymphoma in the past. METHODS: Between January 1999 and November 2008, 22 breast cancer patients underwent a sentinel node procedure after previous mantle field radiation. Lymphatic drainage patterns were analyzed based on lymphoscintigraphy and sentinel node biopsy. The results were compared with the drainage patterns in patients without previous treatment from an earlier study. RESULTS: Sentinel nodes were found in the axilla in 19 patients (86%) and 9 patients (41%) also had drainage toward extra-axillary regions. Sentinel nodes were more often found outside the axilla compared to the patients in our earlier study (33%, P = 0.04), and the nonidentification rate was also higher (14% vs. 3%, P = 0.01). Sentinel nodes were involved in 5 patients (23%). These were harvested from the internal mammary chain in two of them. No lymph node recurrences were observed during a median follow-up time of 49 months. CONCLUSION: Lymphatic mapping is feasible and yields a lymph node in 86% of the breast cancer patients after previous mantle field radiotherapy for Hodgkin's lymphoma. Nonvisualization and extra-axillary nodes are more frequently encountered than in patients without a history of mantle field radiation. The finding of involved nodes suggests that sentinel node biopsy improves staging. Long-term follow-up will determine the sensitivity of the procedure in this specific situation.

Is completion lymph node dissection needed in case of minimal melanoma metastasis in the sentinel node?

OBJECTIVE: The purpose of this study was to evaluate the micromorphometric Starz-classification in melanoma patients. SUMMARY BACKGROUND DATA: The micromorphometric Starz-classification suggests that melanoma patients with a sentinel node metastasis invading no more than 0.3 mm (S-I) or 0.31 to 1.0 mm (S-II) below the capsular level can be spared further surgery, while invasion of the metastasis of more than 1.0 mm (S-III) implies a need for completion dissection. METHODS: Seventy patients with sentinel node metastases were studied. Twenty patients with an S-I or S-II classification were spared further surgery and 50 S-III patients underwent completion dissection. The median follow-up time was 33 months. RESULTS: No lymph node recurrences were detected in the 20 S-I, II patients. Six of the 50 S-III patients (12%) had additional involved nodes in the dissection specimen. In these patients no recurrences developed in the cleared regional basins. Overall 3-year survival was 100% in the S-I, II patients and 80% in the S-III patients (P = 0.04). Three-year disease-free survival rates were 83% and 60%, respectively (P = 0.40). CONCLUSIONS: : This study suggests that further surgery is unnecessary in S-I and S-II patients, while it does seem prudent to carry out completion dissection in S-III patients. The distinct survival difference between the 2 groups of patients suggests that the S-classification also has prognostic implications.

The yield of SPECT/CT for anatomical lymphatic mapping in patients with melanoma.

BACKGROUND: The hybrid single-photon emission computed tomography camera with integrated CT (SPECT/CT) fuses tomographic lymphoscintigrams with anatomical CT data. SPECT/CT shows the exact anatomical location of a sentinel node and may detect additional drainage. The purpose of this study was to explore its potential in patients with melanoma. METHODS: We studied 85 patients with melanoma with conventional lymphoscintigrams that were difficult to interpret (51 patients), that showed an unusual drainage pattern (33 patients), or with nonvisualization (1 patient). Forty-one patients had melanoma on an extremity, 31 on the trunk, and 14 in the head and neck region. SPECT/CT was performed following late conventional imaging without reinjection of the radiopharmaceutical. RESULTS: Conventional imaging suggested 214 sentinel nodes in 84 of the 85 patients (99%). SPECT/CT showed these same nodes and 12 extra sentinel nodes in seven patients (8%). Ten of these additional nodes were harvested, of which three nodes of two patients harbored metastases. There was a clear advantage of SPECT/CT in 30 patients (35%), resulting in a different incision in 17 patients, an incision at another site in 8, and an extra incision in 5 patients. The value was questionable in 19 patients (22%) in whom sentinel nodes were more clearly visualized by SPECT/CT, although the incision remained unchanged. There was no additional value of SPECT/CT in 36 patients (42%). CONCLUSIONS: SPECT/CT detects additional drainage and shows the exact anatomical location of sentinel nodes in patients with inconclusive conventional lymphoscintigrams. SPECT/CT facilitates surgical exploration in difficult cases and may improve staging.

The yield of SPECT/CT for anatomical lymphatic mapping in patients with breast cancer.

PURPOSE: The recently introduced hybrid single-photon emission computed tomography camera with integrated CT (SPECT/CT) fuses tomographic lymphoscintigrams with anatomical data from CT. The purpose of this study was to explore this sophisticated technique in lymphatic mapping in breast cancer patients. METHODS: We studied 134 patients who underwent SPECT/CT immediately after late planar imaging when these images showed an unusual drainage pattern (85 patients), a pattern that was difficult to interpret (27 patients), or nonvisualization (22 patients). RESULTS: Planar imaging suggested 271 sentinel nodes in 112 of the 134 patients (84%). SPECT/CT showed 269 of these same nodes and indicated that two sites of radioactivity were caused by skin contamination. SPECT/CT visualized 19 additional sentinel nodes in 15 patients, of whom 11 had non-visualization on planar images. One or more tumour-positive sentinel nodes were seen in 27 patients, and in 4 of these patients (15%), these were visualized only by SPECT/CT. SPECT/CT had no additional value for the surgical approach in 11 patients with persisting nonvisualization (8%), and was of questionable value in 67 other patients (50%). Based on the SPECT/CT images, a more precise incision was made in 48 patients (36%), an extra incision was made in 6 (4%), and an incision was omitted in 2 (1.5%). CONCLUSION: SPECT/CT detected additional sentinel nodes and showed the exact anatomical location of sentinel nodes in breast cancer patients with inconclusive planar images. SPECT/CT was able to visualize drainage in patients whose planar images did not reveal a sentinel node. Therefore, SPECT/CT facilitates surgical exploration in difficult cases and may improve staging.

The hidden sentinel node and SPECT/CT in breast cancer patients.

PURPOSE: In a minority of breast cancer patients, lymphoscintigraphy shows no lymphatic drainage and 'hidden' sentinel nodes may remain undiscovered. The purpose of this study was to explore the additional value of the recently introduced hybrid SPECT/CT in breast cancer patients with axillary non-visualisation on planar images. The role of blue dye and careful palpation of the axilla was evaluated in patients in whom axillary sentinel nodes remained hidden after SPECT/CT. METHODS: Fifteen breast cancer patients with non-visualisation on planar lymphoscintigraphy and 13 women with only extra-axillary sentinel nodes underwent SPECT/CT following late planar imaging without re-injection of the radiopharmaceutical. RESULTS: SPECT/CT visualised lymphatic drainage in eight of the 15 patients (53%) with non-visualisation on planar imaging, depicted nine of the 14 harvested sentinel nodes (64%) and three of five tumour-positive sentinel nodes. In two of the 13 patients (15%) with only extra-axillary sentinel nodes on their planar lymphoscintigram, SPECT/CT showed an axillary sentinel node that appeared to be uninvolved. Careful exploration of the axilla with the combined use of blue dye, a gamma probe and intra-operative palpation revealed an axillary sentinel node in the remaining 18 patients. SPECT/CT showed the exact anatomical location of all visualised sentinel nodes. CONCLUSION: SPECT/CT discovered 'hidden' sentinel nodes in the majority of patients with non-visualisation, but was less valuable in patients with only extra-axillary lymphatic drainage on the planar images. Exploration of the axilla in patients with persistent non-visualisation improved the identification of axillary (involved) sentinel nodes.

Breast cancer patients with extra-axillary sentinel nodes only may be spared axillary lymph node dissection.

BACKGROUND: In breast cancer patients with only extra-axillary sentinel nodes, surgeons typically perform axillary node dissection. The purpose of this study was to evaluate our approach to spare such patients further dissection based on the hypothesis that a sentinel node is not necessarily located in the axilla. METHODS: Between March 11, 1999 and March 5, 2008, 1,949 breast cancer patients underwent lymphatic mapping with preoperative lymphoscintigraphy and intraoperative use of a gamma-ray detection probe and patent blue dye. The tracers were injected into the tumors. RESULTS: Eighty-two of the 1,949 patients had only extra-axillary drainage on their lymphoscintigrams. A sentinel node was harvested from the axilla in 62 patients but not in the remaining 20 patients. No axillary lymph nodes were removed in 4 of these 20 patients, suspicious palpable nodes were excised in another 4 patients, and node sampling was done in the remaining 12. These nodes were all free of disease. All sentinel nodes outside the axilla were removed. Two patients had a metastasis in an internal mammary chain node. No lymph node recurrences were detected in or outside the axilla in any of the 20 patients with a median follow-up time of 49 months. CONCLUSION: 4% of the patients have only extra-axillary drainage on preoperative lymphoscintigrams. It is worthwhile to explore the axilla since a sentinel node can be found in three-quarters. In the remaining 1% without axillary sentinel nodes, axillary sampling seems unnecessary and the approach to refrain from axillary dissection appears valid.

Isolated limb perfusion for melanoma.

Isolated limb perfusion with high-dose chemotherapy is an accepted treatment modality to achieve locoregional control in advanced melanoma of the extremities. The drug of choice is melphalan. Tumor necrosis factor-alpha is frequently added to melphalan in bulky disease, and this combination may be an option for repeat perfusion for recurrent melanoma after a first perfusion. Results of perfusions performed with tissue temperatures between 37 degrees C and 38 degrees C seem to be equivalent to those of the perfusions performed under mild hyperthermic conditions. Perfusion cannot be recommended as an adjunct to wide local excision in patients who have primary melanoma. Adjuvant perfusion in repeatedly recurrent limb melanoma, however, may be of value because it lengthens the limb recurrence-free interval and decreases the number of lesions per recurrence significantly. Regional toxicity of perfusion should be mild when risk factors are taken into account.