Adverse Reactions to Isosulfan Blue During Selective Sentinel Lymph Node Dissection in Melanoma

Background: Selective sentinel lymph node (SLN) dissection can spare about 80% of patients with primary melanoma from radical lymph node dissection. This procedure identifies the SLN either visually by injecting isosulfan blue dye around the primary melanoma site or by handheld gamma probe after radiocolloid injection.Methods: During selective SLN mapping, 1 to 5 ml of isosulfan blue was injected intradermally around the primary melanoma. From November 1993, to August 1998, 406 patients underwent intraoperative lymphatic mapping with the use of both isosulfan blue and radiocolloid injection. Three cases of selective SLN dissection, in which adverse reactions to isosulfan blue occurred, were reviewed.Results: We report three cases of anaphylaxis after intradermal injection with isosulfan blue of 406 patients who underwent intraoperative lymphatic mapping by using the procedure as described above. The three cases we report vary in severity from treatable hypotension with urticaria and erythema to severe cardiovascular collapse with or without bronchospasm or urticaria.Conclusions: In our series, the incidence of anaphylaxis to isosulfan blue was approximately 1%. Anaphylaxis can be fatal if not recognized and treated rapidly. Operating room personnel who participate in intraoperative lymphatic mapping where isosulfan blue is used must be aware of the potential consequences and be prepared to treat anaphylaxis.     

Use of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma

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Predictors of Completion Axillary Lymph Node Dissection in Patients with Positive Sentinel Lymph Nodes

Background  Completion axillary lymph node dissection (CALND) is routinely performed in breast cancer patients with positive sentinel lymph nodes (SLN). We sought to determine the sociodemographic, pathologic, and therapeutic variables that were associated with CALND. Methods  From 7/1997 to 7/2003, 1,470 patients with invasive breast cancer were SLN positive by intraoperative frozen section or final pathologic exam by hematoxylin–eosin and/or immunohistochemistry (IHC). A comorbidity score was assigned using Adult Comorbidity Evaluation-27 system. Fisher’s exact, Wilcoxon tests, and multivariate logistic regression analysis were used. Results  CALND was performed less often in patients with age ≥ 70 years compared with age < 70 years, moderate or severe comorbidities compared with no or mild, IHC-only positive SLN and breast conservation therapy (BCT compared with mastectomy. Patients who did not undergo CALND were less likely than CALND patients to have grade III disease, lymphovascular invasion multifocal disease, tumor size > 2 cm or to receive adjuvant chemotherapy. However, they were more likely to undergo axillary radiotherapy (RT). On multivariate analysis, age ≥ 70 years [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.26–0.63], IHC-only positive SLN (OR 0.13, 95%CI 0.09–0.19), presence of moderate to severe comorbidities (OR 0.64, 95%CI 0.41–0.99), tumor size ≤ 2 cm (OR 0.44, 95%CI 0.29–0.66), axillary RT (OR 0.39, 95%CI 0.20–0.78), and BCT (OR 0.54, 95%CI 0.37–0.79) were all independently associated with lower odds of CALND. Conclusions  The decision to perform CALND following positive SLN biopsy was multifactorial. Patient factors were a primary determinant for the use of CALND in our study. The decreased use of CALND in the BCT patients probably reflects reliance on the radiotherapy tangents to maintain local control in the axilla.     

Methylene Blue Dye as an Alternative to Isosulfan Blue Dye for Sentinel Lymph Node Localization

Background: Our study describes the use of methylene blue dye as an alternative to isosulfan blue dye to identify the sentinel lymph node (SLN).Methods: A retrospective analysis was performed of 112 breast cancer patients (113 axillae) who underwent SLN biopsy (SLNB) with methylene blue dye and ^99mTc-labeled sulfur colloid for SLN identification. All SLNs were submitted for intraoperative frozen section analysis, hematoxylin and eosin stain, and immunohistochemical evaluation. Patients with a pathologically negative SLN did not undergo further axillary lymph node dissection.Results: Of 112 patients who underwent SLNB, the SLN was identified in 107 (95.5%); 104 (92.8%) were identified by methylene blue dye. In a subset of 99 patients with recorded isotope status in relation to blue nodes, concordant identification with both dye and isotope was observed in 94 (94.9%). Of patients with identified SLNs, 32 (29.9%) of 107 contained metastatic disease, with 31 (96.9%) of 32 identified by methylene blue dye. The SLN was the only positive node in 18 (60.0%) of 30 patients.Conclusions: SLNB with methylene blue dye is an effective alternative to isosulfan blue dye for accurately identifying SLNs in breast cancer patients.Presented at the Society of Surgical Oncologys 55th Annual Cancer Symposium, Denver, Colorado, March 14–17, 2002.     

A Randomized Study Comparing the Effectiveness of Methylene Blue Dye with Lymphazurin Blue Dye in Sentinel Lymph Node Biopsy for the Treatment of Cutaneous Melanoma

Background  Radioactive colloid with a gamma probe is the most effective method of identifying sentinel lymph nodes (SLN). Nevertheless, since vital blue dyes are also helpful for visually identifying SLN during surgical dissection, they are often used together with radioactive colloid. There has occasionally been a shortage of lymphazurin blue (LB) dye for use in sentinel lymph node biopsies (SLNB). There have also been reports of anaphylactic reactions to the use of LB dye. Therefore, we were interested in using methylene (MB) blue dye to aid in the visualization of the SLN for biopsy because of its ready availability and greater safety. The purpose of this study of SLN biopsies was to compare the effectiveness of MB with that of LB dye. Study Design  We randomly assigned 159 consecutive patients with intermediate and high-risk melanomas, who were treated by a single surgeon at the Yale Melanoma Unit between January 10, 2005, and June 13, 2007 with SLN biopsy, with radioactive colloid and either LB or MB. Results  A total of 443 SLN were identified and removed from these 159 consecutive patients. MB dye was found to be as effective as LB dye in visually identifying SLN: blue dye was visible in 62% of SLN in the MB group compared with 58% in the LB group. When the SLN were separated into three anatomic locations the visualization results were LB 36% and MB 72% (P = 0.010) for head and neck, LB 65% and MB 61% (P = 0.919) for axilla, and LB 59% and MB 67% (P = 0.001) for groin. Conclusion  SLN were identified in all 158 patients. Approximately 60% of these SLN were also visibly blue. In the cervical and groin regions, MB dye was more visible in the SLN than was the LB dye, and in the axilla the SLN were equally stained blue by both dyes. Generally, if surgeons wish to use intradermal injections of vital blue dye to help visualize SLN, we have found in this study that MB is at least as effective as LB for the visualization of these SLN. The cost of MB is less than that of LB.     

染料法前哨淋巴结活检治疗乳腺癌进展

本旨在复习前哨淋巴结活检术的发展过程和乳腺的淋巴引流解剖，总结染料法前哨淋巴结活检术在乳腺癌诊治中的临床意义。乳腺癌的淋巴转移常常首先到达腋窝前哨淋巴结，染料法前哨淋巴结活检术对腋窝淋巴结是否受累以及是否需行清扫有确切指导作用。当染料法前哨淋巴结活检阴性时，可不必常规行腋窝淋巴结清扫术，由此可避免后带来的并发症和痛苦。     

Regressed Subungual Melanoma Simulating Cellular Blue Nevus: Managed with Sentinel Lymph Node Biopsy

BACKGROUND: Subungual melanoma, a not uncommon presentation of cutaneous melanoma in Asian populations, is easily overlooked as benign and thus is improperly treated. OBJECTIVE: To present two cases with clinical suspicion of subungual melanoma. Skin biopsies failed to demonstrate the diagnostic features of malignancy. METHODS: Lymphoscintigraphy and sentinel lymph node (SLN) biopsies were performed to determine regional lymph node status. RESULTS: Both hematoxylin-eosin and HMB45 staining revealed melanoma cells in the SLN of the patient. The second patient's SLN was negative for malignant cells, but her excised primary lesion showed extensive regressed melanoma. CONCLUSION: Regression phenomena are not uncommon for subungual melanoma. An extention biopsy techniques are useful for determining nodal basin status in regressed subungual melanoma.     

The Prognostic Importance of Sentinel Lymph Node Biopsy in Thin Melanoma

Background Sentinel lymph node biopsy (SLNB) is prognostically useful in patients with cutaneous melanoma with Breslow thickness >1 mm. The objective of this study was to determine whether sentinel node histology has similar prognostic importance in patients with thin melanomas (≤1 mm). Methods This was a retrospective study of patients who underwent SLNB for clinically localized melanoma at Indiana University Medical Center between 1994 and 2003. SLNB results and traditional melanoma prognostic indicators were studied in univariate log-rank tests. Results One hundred eighty-four patients with melanomas ≤1 mm thick underwent SLNB. SLNB was tumor positive in 12 patients (6.5%). Univariate analysis of SLNB results revealed that Breslow thickness, Clark level of invasion, and mitotic index were associated with SLNB status. Tumor positivity was observed at different rates in tumor thickness subsets: <.75 mm, 2.3%; and .75 to 1.0 mm, 10.2% (P = .0372). Disease-free survival and overall survival were significantly associated with SLNB results in melanomas ≤1 mm (log-rank test: P < .0001 and P = .0125, respectively) at a median follow-up of 26.3 months. Conclusions SLNB histology in melanomas ≤1.0 mm deep is a significant predictor of outcome. SLNB should be considered for selected patients with melanomas .75 to 1.0 mm.     

Delayed Harvesting of Sentinel Lymph Nodes After Previous Wide Local Excision of Extremity Melanoma

Background:Harvesting the sentinel lymph node (SLN) is important in the management of patients with primary cutaneous melanoma. Selective sentinel lymphadenectomy (SSL) is generally performed at the time of wide local excision (WLE). The aim of our study was to determine whether delayed SSL is useful in detecting micrometastasis to the regional basin in patients with previous WLE of an extremity melanoma.Methods:Of 203 patients with a primary melanoma site located on the upper or lower extremity seen at the University of California, San Francisco/Mount Zion Melanoma Center from May 17, 1994, to March 23, 1999, 24 patients had a WLE of their extremity melanoma with adequate margins before referral. SSL was performed to assess micrometastasis in the regional lymph node basin after preoperative lymphoscintigraphy.Results:At least 1 SLN was identified in all 24 patients. At a median follow-up of 3 years, two patients showed micrometastasis in the SLNs. One of these two patients developed recurrence, and all remaining patients showed no evidence of disease.Conclusions:Although it is generally advised that WLE should be performed simultaneously with SSL, delayed SSL after WLE of an extremity melanoma can still provide valuable staging information, which is critical for management of the patient.     

Complete Lymph Node Dissection for Sentinel Node-Positive Melanoma: Assessment of Practice Patterns in the United States

Background Currently, complete lymph node dissection (CLND) is recommended after identification of a metastatic lymph node by sentinel lymph node biopsy (SLNB). Guidelines suggest that CLND should be performed as a separate procedure, and a sufficient number of nodes should be examined. Our objective was to examine the utilization, timing, and adequacy of CLND for melanoma in the United States. Methods From the National Cancer Data Base, patients diagnosed with stage I to III melanoma during 2004–2005 were identified. Multiple logistic regression was used to assess factors associated with CLND utilization, timing (separate operation from SLNB), and adequacy (examination of ≥10 nodes). Results Of the 44,548 patients identified, 47.5% were pathologic stage IA, 23.8% stage IB, 14.1% stage II, and 14.6% stage III. Of the 17% (2942 of 17,524) with nodal metastases on SLNB, only 50% underwent a CLND. Patients were significantly less likely to undergo a CLND after SLNB if >75 years old or had lower extremity melanomas. Of the patients who underwent a CLND, only 42% underwent the CLND at a separate procedure after the SLNB. Of those who underwent a CLND, 69.2% had ≥10 nodes examined. Patients were significantly less likely to have ≥10 nodes examined if they were >75 years old or had lower extremity melanomas. Patients treated at NCCN/NCI-designated centers were significantly more likely to undergo nodal evaluation in concordance with established guidelines. Conclusions Only half of patients with sentinel node-positive melanoma underwent CLND. Quality surveillance measures are needed to monitor, standardize, and improve the care of patients with malignant melanoma. Presented in part at the Society of Surgical Oncology Annual Meeting, March 14, 2008, Chicago, IL.     

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.     

Primary Cutaneous Melanoma with Regression Does not Require a Lower Threshold for Sentinel Lymph Node Biopsy

Introduction Histological evidence of primary tumor regression (RG) is observed in 35% or fewer patients with cutaneous melanoma. Some advocate a lower threshold for sentinel lymph node (SLN) biopsy when RG is present. Methods We identified 1,349 patients presenting to our center with clinically localized cutaneous melanoma between 1995 and 2004. Of these, 344 demonstrated histological RG in their primary melanoma. A retrospective analysis of their medical records was performed to obtain clinical and pathological information. Results The median Breslow depth for the 344 patients with RG was 1.1 mm versus 1.5 mm for 1,005 patients with no regression (NRG) (P < 0.005). SLN biopsy was performed in 64% of patients with RG and 72% without. Positive SLN was more common in those with NRG than in those with RG (18% vs 10%, P = 0.005). Only one RG patient with thin melanoma (≤1 mm, Clark IV) had a positive SLN. When stratified by Breslow depth, patients with RG had lower rates of SLN positivity in all groups (≤1.0mm, >1.0 and ≤2.0mm, >2 and ≤4 mm, and >4.0 mm). Recurrence was more common in patients with NRG (21% vs 12%; P < 0.005). Both local and systemic recurrence occurred more commonly in patients with NRG (4% vs 1%, P = 0.002 and 8% vs 3%, P < 0.005, respectively) Conclusions The presence of histological RG in a primary melanoma predicts neither SLN positivity when stratified by Breslow depth nor increased risk of recurrence when compared with melanomas with NRG.     

Efficacy of Lymphatic Mapping, Sentinel Lymphadenectomy, and Selective Complete Lymph Node Dissection as a Therapeutic Procedure for Early-Stage Melanoma

Background: Lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) is an increasingly popular alternative to elective lymphadenectomy (ELND) for patients with early-stage melanoma. Although several reports have demonstrated the accuracy of the LM/SL technique, there are no data on its therapeutic value.Methods: We performed a matched-pair statistical analysis of 534 patients with clinical stage I melanoma; one half of the patients were treated with LM/SL and the other half were treated with ELND. Patients in the two treatment groups were matched for age (54% were 50 years of age), gender (63% were male patients), site of the primary melanoma (49% were on the extremities, 36% on the trunk, and 15% on the head and neck), and thickness of the primary melanoma (7% were <0.75 mm, 42% between 0.75 and 1.5 mm, 43% between 1.51 and 4.0 mm, and 8% >4 mm). Patients in the LM/SL group underwent complete regional lymphadenectomy (SCLND) only if the LM/SL specimen contained metastatic melanoma.Results: The overall incidences of nodal metastases were no different (P = .18) between LM/SL (15.7%) and ELND (12%) groups, but the incidence of occult nodal disease was significantly (P = .025) higher among patients with intermediate-thickness (1.51–4.0-mm) primary tumors who underwent LM/SL (23.7%) instead of ELND (12.2%). Survival data were compared by the log-rank score test. LM/SL/SCLND and ELND resulted in equivalent 5-year rates of disease-free survival (79 ± 3.3% and 84 ± 2.2%, respectively; P = .25) and overall survival (88 ± 3.0% and 86 ± 2.1%, respectively; P = .98). The LM/SL and ELND groups also exhibited similar incidences of same-basin recurrences (4.8% vs. 2.1%, P = .10, respectively) and in-transit metastases (2.6% vs. 3.8%, P = .48) after tumor-negative dissections. Patients who underwent ELND showed a higher incidence of distant recurrences (8.9% vs. 4.0%, P = .03), but this may be related to the longer follow-up period for these patients (median, 169 months), compared with the LM/SL-treated patients (45 months). Among patients with tumor-positive nodal dissections, the 5-year overall survival rates were higher, and approached significance (P = .077) for patients treated by LM/SL/SCLND (64 ± 12%) compared with ELND (45 ± 10%).Conclusions: These findings suggest that LM/SL/SCLND is therapeutically equivalent to ELND but may be more effective for identifying nodal metastases in patients with intermediate-thickness primary tumors.Supported by National Institutes of Health Grants CA12582 and CA29605 and by funding from the Wrather Family Foundation (Los Angeles, CA). Richard Essner, MD, is the recipient of an American Cancer Society Career Development Award.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–29, 1998.     

Prediction of Residual Nodal Disease at Completion Dissection Following Positive Sentinel Lymph Node Biopsy for Melanoma

Introduction

While recent trial data have demonstrated no survival benefit to immediate completion lymph node dissection (CLND) for positive sentinel lymph node (SLN) disease in melanoma, prediction of non-SLN disease may help risk-stratify patients for more intensive observation of the nodal basin.

Patients and Methods

A retrospective cohort of patients with positive SLN biopsy (SLNB) who underwent CLND was identified (1996–2016). A risk score for likelihood of CLND-positive disease was developed based on factors associated with presence of CLND metastases identified on logistic regression. Survival outcomes were analyzed.

Results

Among 312 patients with positive SLN, 192 underwent CLND and had complete pathologic data for evaluation. The median age of the study cohort was 53 years [interquartile range (IQR) 43–66 years], and 112 (58%) were male. Thirty-one (16%) had non-SLN metastatic disease on CLND. The four factors independently associated with CLND positivity and thus included in the risk score were Breslow thickness?≥?3 mm [odds ratio (OR) 2.56, p?=?0.047], presence of primary tumor-infiltrating lymphocytes (OR 0.33, p?=?0.013),?≥?2/3 positive-to-total SLN ratio (OR 4.35, p?=?0.003), and combined subcapsular and parenchymal metastatic SLN location or metastatic deposit?≥?1 mm (OR 4.45, p?=?0.013). The four-point risk score predicted CLND positivity well with area under the curve of 0.82 (0.80–0.85). Increasing risk score was independently associated with increasingly worse melanoma-specific survival [hazard ratio (HR)?=?1.54, p?=?0.001].

Conclusions

Likelihood of residual nodal disease after positive SLNB and survival can be predicted from primary tumor and SLN characteristics. High-risk patients may warrant more intensive surveillance of the nodal basin to reduce risk of loss of regional control.

     

Limitations of Lymph Node Ratio, Evidence-Based Benchmarks, and the Importance of a Thorough Lymph Node Dissection in Melanoma

Background

Stage III melanoma is currently stratified by number of lymph nodes (LNs) involved. However, given the variability of LN retrieval counts we hypothesize that lymph node ratio (LNR) may also provide prognostic information.

Methods

Retrospective cohort study of 411 patients with stage III melanoma were divided into two groups based on LNR (<0.15, n = 291 and ≥0.15, n = 120).

Results

In multivariate analysis N stage (N3 vs. N1, hazard ratio [HR] = 2.13, p < 0.001), extranodal extension (HR = 1.92, p = 0.002), macrometastasis (HR = 1.70, p = 0.005), non-SLN involvement (HR = 1.65, p = 0.005), risk of N2 disease exceeding 35 % (HR = 1.51, p = 0.03), and LNR ≥0.15 (HR = 1.46, p = 0.03) were associated with overall survival (OS). LNR failed to further stratify stage III melanoma; however, the number of LNs examined was an independent prognostic factor. Patients who had >8 inguinal, >15 axillary, or >20 cervical LNs examined had fewer same nodal basin recurrences (26 [8 %] vs. 20 [20 %], p = 0.0009) and for N1 patients an improved OS (3-year OS 84 % vs. 76 %, 10-year OS 53 % vs. 34 %, p = 0.06) compared with N1 patients who had fewer LNs examined.

Conclusions

LNR is an important prognostic factor in stage III melanoma; however, it was not independent over the current AJCC TNM staging system. Diligence by the surgeon and pathologist to retrieve and examine >8 inguinal, >15 axillary, or >20 cervical LNs is associated with fewer same nodal basin recurrences and improved survival and is critical to reliable prognostication.     

单用蓝染料示踪剂在乳腺癌前哨淋巴结活检中的价值

目的探讨单用蓝染料示踪剂在乳腺癌前哨淋巴结活检术(SLNB)中的临床价值。方法本研究共纳入308例患者,均采用联合法(蓝染料联合核素示踪剂)进行SLNB,分别记录单用蓝染料和联合法行SLNB的相关数据并进行对比分析。结果染料法与联合法行SLNB的成功率(93.5%比99.4%,P=0.000)、假阴性率(14.8%比3.3%,P=0.007)、准确性(89.6%比97.8%,P=0.006)和阴性预测值(74.0%比93.3%,P=0.012)的差异均有统计学意义。2种方法的成功率及假阴性率与患者年龄、肿瘤大小、肿瘤部位、组织学类型、肿瘤切检方式、乳房手术方式以及ER、PR和HER-2状况均无关(均P0.05)。染料法的假阴性率在临床腋淋巴结可疑肿大者中显著升高(P=0.042),并随前哨淋巴结检出数目增多而逐渐降低(P=0.000)。结论与联合法相比,染料法SLNB的成功率、准确性和阴性预测值显著降低,假阴性率显著升高,推荐临床实践中应尽量采用联合法,避免单用染料示踪剂进行SLNB。