Complications of sentinel lymph node biopsy for melanoma – A systematic review of the literature

Purpose

The complications reported after sentinel lymph node biopsy (SLNB) for melanoma is highly variable in the worldwide literature; the overall complication rate varies between 1.8% and 29.9%. With heterogeneous reporting of morbidity data, no ‘average’ complication rates of this procedure have been reported. This systematic review aims to determine the complications rates associated with SLNB.

Is complete lymph node dissection after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? A meta-analysis

Background

The current recommendation for patients with cutaneous melanoma and a positive sentinel lymph node (SLN) biopsy is a complete lymph node dissection (CLND). However, metastatic melanoma is not present in approximately 80% of CLND specimens. A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive in patients with melanoma.

Methods

A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google scholar, Science Direct, and Web of Science. The search identified 54 relevant articles reporting the frequency of NSN metastases in melanoma. Original data was abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI).

Findings

The pooled estimates that were found to be significantly associated with the high likelihood of NSN metastases were: ulceration (OR: 1.88, 95% CI: 1.53–2.31), satellitosis (OR: 3.25, 95% CI: 1.86–5.66), neurotropism (OR: 2.51, 95% CI: 1.39–4.53), >1 positive SLN (OR: 1.77, 95% CI: 1.2–2.62), Starz 3 (old) (OR: 1.83, 95% CI: 0.89–3.76), Angiolymphatic invasion (OR: 2.46, 95% CI: 1.34–4.54), extensive location (OR: 2.22, 95% CI: 1.74–2.81), macrometastases >2 mm (OR: 1.95, 95% CI: 1.61–2.35), extranodal extension (OR: 3.38, 95% CI: 1.79–6.40) and capsular involvement (OR: 3.16, 95% CI: 1.37–7.27). There were 3 characteristics not associated with NSN metastases: subcapsular location (OR: 0.51, 95% CI: 0.38–0.67), Rotterdam Criteria <0.1 mm (OR: 0.29, 95% CI: 0.17–0.50) and Starz I (new) (OR: 0.44, 95% CI: 0.22–0.91). Other variables including gender, Breslow thickness 2–4 mm and extremity as primary site were found to be equivocal.

Interpretation

This meta-analysis provides evidence that patients with low SLN tumor burden could probably be spared the morbidity associated with CLND. We identified 9 factors predictive of non-SLN metastases that should be recorded and evaluated routinely in SLN databases. However, further studies are needed to confirm the standard criteria for not performing CLND.     

What is a sentinel node? Re‐evaluating the 10% rule for sentinel lymph node biopsy in melanoma

INTRODUCTION: Many surgeons use the "10% rule" to define whether a lymph node is a sentinel node (SLN) when staging malignant melanoma. However, this increases the number of SLN removed and the time and cost of the procedure. We examined the impact of raising this threshold on the accuracy of the procedure. METHODS: We reviewed the records of 561 patients with melanoma (624 basins) who underwent SLN with technetium Tc99 labeled sulfur colloid using a definition of a SLN as 10% of that of the node with the highest counts per minute (CPM). RESULTS: Of the 624 basins, 154 (25%) were positive for metastases. An average of 1.9 nodes per basin were removed (range 1-6). Metastases were found in the hottest node in 137 cases (89% of positive basins, 97% of basins overall). Increasing the threshold above 10% decreased the number of nodes excised and the costs involved, but incrementally raised the number of false negative cases above baseline (a 4% increase for a "20% rule," 5% for a "30% rule," 6% for a "40% rule," and 7% for a "50% rule"). Taking only the hottest node would raise the false negative rate by 11%. CONCLUSIONS: Although using thresholds higher than 10% for the definition of a SLN will minimize the extent of surgery and decrease the costs associated with the procedure, it will compromise the accuracy of the procedure and is not recommended.     

Improved immunohistochemical evaluation of micrometastases in sentinel lymph nodes of cutaneous melanoma with 'MCW Melanoma Cocktail' – A mixture of monoclonal antibodies to MART-1, melan-A,and tyrosinase

Background  

MART-1, Melan-A, and Tyrosinase have shown encouraging results for evaluation of melanoma micrometastases in sentinel lymph nodes, as compared to conventionally used S-100 protein and HMB-45. To achieve higher sensitivity, some studies recommend evaluation of three sections, each at intervals of 200 μ. This would mean, routine staining of three adjacent sections in each of the three clusters at intervals of 200 μ, requiring nine slides resulting in added expense. If a cocktail of these antibodies could be used, only one section would be required instead of three generating significant cost savings.     

Intra-operative imprint cytology for assessing the sentinel node in breast cancer – Results of its routine use over 8 years

Introduction

Intra-operative imprint cytology (IIC) for analysing sentinel lymph node/s (SLN) in breast cancer allows definitive axillary surgery as a one-step procedure. Most reported studies are research oriented. This study reports long-term results of IIC done as routine clinical practice.

Materials and methods

Eight hundred ninety-six female, operable breast cancer patients underwent SLN biopsy over an 8-year period (January 1999–December 2006). Data were extracted retrospectively from medical records. SLNs were sent intra-operatively to the laboratory where they were bisected, touch imprinted and stained with Hematoxylin & Eosin. Patients with positive IIC had axillary clearance. Formal histological analyses of SLNs were compared with IIC findings. The impact of routine pre-operative axillary ultrasound (introduced in 2003) on IIC sensitivity and specificity was also assessed.

Results

Median age was 61 years (26–89) and median tumour size was 18 mm (2–100). A total of 244/896 patients had SLN metastases on final paraffin histology of which 177 were correctly detected by IIC (67 false negatives). 39/67 false negatives could be attributed to sampling error. The overall sensitivity and specificity of IIC for the identification of SLN metastases was 73% and 100%, respectively. The sensitivity of IIC after introduction of pre-operative axillary ultrasound decreased from 75% to 71%.

Discussion

Routine use of IIC for analysis of the SLN in breast cancer allows complete axillary surgery during a single anaesthetic for a majority of patients undergoing SLN biopsy. Almost two thirds of positive axillae were spared a second operation. False negative results are frequent and patients should be warned about the potential need for further axillary surgery.     

The analysis of the outcomes and factors related to iliac–obturator involvement in cutaneous melanoma patients after lymph node dissection due to positive sentinel lymph node biopsy or clinically detected inguinal metastases

Background

We assessed clinical–pathological features and outcomes of cutaneous melanoma patients after ilio-inguinal lymph node dissection (LND) in relation to the presence of metastases in iliac–obturator nodes.

Methods

We analyzed 390 consecutive patients who underwent ilio-inguinal therapeutic LND [TLND] (237) due to clinical/cytologically detected metastases or after completion LND [CLND] (153) due to positive SLN biopsy (in one cancer centre 1994–2009). Median follow-up time was 60 months.

Results

The 5-year overall survival (OS) rate was 49% and median OS – 52 months in the entire group of patients. According to univariate analysis following factors had significant negative influence on OS: presence of metastases to iliac–obturator nodes (5-year OS for positive versus negative: 54.5% and 32%, respectively), macrometastases, higher Breslow thickness, ulceration, higher Clark level, male gender, number of metastatic lymph nodes, extracapsular extension, and, additionally in the CLND group – micrometastases size ≥0.1 mm according to the Rotterdam criteria and non-subcapsular location of micrometastases. Iliac–obturator involvement was also negative factor for OS in multivariate analysis. The presence of iliac–obturator nodal metastases correlated with the following factors: type of LND–CLND versus TLND (15% versus 27.5%) of iliac–obturator involvement, respectively), higher Breslow thickness, extracapsular extension of nodal metastases, male gender. We have not identified any metastases in iliac–obturator nodes in group of patients with micrometastases size ≤1.0 mm and primary tumour Breslow thickness <4.0 mm or no ulcerated primary tumours.

Conclusions

Metastases to iliac–obturator nodes have additional negative prognostic value for melanoma patients with inguinal basin involvement. We are able to identify the subgroup of patients after positive SLN biopsy without metastases to iliac–obturator nodes, probably requiring only inguinal LND.     

Clinical outcome of breast cancer patients with N3a (��10 positive lymph nodes) disease: has it changed over years?

It has been shown that breast cancer patients with N3a (10 positive lymph nodes) had a poor prognosis. We planned to investigate the clinical outcome BC patients who presented with N3a disease and had no evidence of systemic metastasis at the time of diagnosis. We made a retrospective chart review of breast cancer patients who had ??10 positive lymph nodes and received adjuvant systemic therapy in Marmara University Hospital between 1998 and 2008. We recorded clinical, pathologic and treatment characteristics of the patients and analyzed the survival outcome. We identified 73 patients with N3a disease who were treated in Marmara University Hospital between 1998 and 2008. The median age was 52. Most (75%) of the patients had invasive ductal histology, 75% had T2/T3 tumors, 36% had grade 3 tumors. The median number of metastatic lymph nodes was 15. Estrogen and progesterone receptors were both positive in 61% and both negative in 16+ tumors. Her-2/neu status was assessed in 68% of the tumors; 18% of patients had 3+ and 50% had negative scores. Six patients had triple negative tumors. All patients except one received adjuvant chemotherapy and radiotherapy. Seventy-four percent of patients received anthracycline/taxane-based chemotherapy. Fifty-nine patients received adjuvant endocrine therapy, 42% them received aromatase inhibitors. Five of the 13 Her-2 positive patients received adjuvant trastuzumab. With a median follow-up of 47 months, 5-year disease and overall survival rates were 66 and 81%, respectively. Twenty-four patients had relapsed and 14 patients died. Her-2 status and the number of lymph nodes (<20 vs. ??20) had significant impact on disease-free survival in the univariate analysis (P?=?0.03 and 0.05, respectively) and Her-2 retained its significant impact on disease-free survival in the multivariate analysis (P?=?0.05). The prognosis of BC patients with N3a disease has changed favorably in the past decade with the current standards of care.     

Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities – Long-term follow-up of a randomised trial

Introduction: Isolated limb perfusion (ILP) is a treatment option most commonly used in the treatment of melanoma in-transit metastases of the extremities. The principle idea is to surgically isolate a region of the body and then deliver a high concentration of a chemotherapeutic agent together with hyperthermia. There have been three randomised trials exploring whether adjuvant ILP to patients with recurrent or high-risk primary melanomas increases survival; one of these trials has now been updated with a 25-year follow-up.

Methods: The original study randomised 69 patients (between 1981 and 1989) with their first satellite or in-transit recurrence to either wide excision (WE group, n?=?36 patients) or to WE and adjuvant ILP (WE?+?ILP group, n?=?33 patients). Follow-up data 25 years later concerning survival and cause of death was retrieved from the Swedish National Cause of Death Register.

Results: In the WE?+?ILP group there were 20 deaths (61%) due to melanoma compared with 26 deaths (72%) in the WE group (p?=?0.31). Median melanoma-specific survival was 95 months for WE?+?ILP compared to 38 months for the WE group, an almost 5 year benefit without statistical significance (p?=?0.24).

Discussion: There is no evidence that adjuvant ILP prolongs survival in patients with high-risk or recurrent melanoma; however, the existing randomised trials are largely underpowered to detect such a difference. New studies are exploring systemic immunological effects of ILP, and a combination of regional therapy and immunotherapy may serve as a rationale for new trials using ILP in the future.     

Irradiation after surgery for breast cancer patients with primary tumours and one to three positive axillary lymph nodes: yes or no?

Objective and Methods

We retrospectively analyzed clinicopathologic features and survival in breast cancer patients who had T1 or T2 primary tumours and 1–3 histologically involved axillary lymph nodes and who were treated with modified radical mastectomy without adjuvant radiotherapy (rt). We also explored prognosis to find the high- and low-risk groups.

Results

From May 2001 to April 2005, 368 patients treated at Tianjin Tumor Hospital met the study criteria. The 5- and 8-year rates were 7.2% and 10.7% for locoregional recurrence (lrr), 85.1% and 77.7% for disease-free survival (dfs), and 92.8% and 89.3% for overall survival (os). Multivariate Cox regression analysis showed that age, tumour size, estrogen receptor (er) status, and lymphovascular invasion (lvi) were independent prognostic factors for lrr and dfs. Based on 4 patient-related factors that indicate poor prognosis (age < 40 years, tumour > 3 cm, er negativity, and lvi), the high-risk group (patients with 3 or 4 factors, accounting for 12.5% of the cohort) had 5- and 8-year rates of 24.3% and 36.9% for lrr, 57.2% and 39.2% for dfs, and 74.8% and 43.8% for os compared with 5.0% and 7.1% for lrr, 88.9% and 83.1% for dfs, 91.6% and 83.4% for os in the low-risk group (patients with 0–2 factors, accounting for 87.5% of the cohort; p < 0.001).

Conclusions

Our study identified several risk factors that correlated independently with a greater incidence of lrr and distant metastasis in patients with T1 and T2 breast cancer and 1–3 positive nodes. Patients with 0–2 risk factors may not be likely to benefit from post-mastectomy rt, but patients with 3–4 risk factors may need rt to optimize locoregional control and improve survival.     

Sentinel lymph node biopsy for cutaneous melanoma: results of 10 years’ experience in two regional training hospitals in the Netherlands

Background and objective

The Multicenter Selective Lymphadenectomy Trial (MSLT-I) demonstrated that the sentinel node (SN) status in cutaneous melanoma affects prognosis and that completion lymphadenectomy in SN-positive patients may improve survival. Our objective was to evaluate sentinel lymph node biopsy (SLNB) in two regional hospitals in the Netherlands.

Methods

Patients with localized melanoma were planned for wide excision and SLNB. Completion lymphadenectomy was recommended for positive SN status. Data were compared with the MSLT-I.

Results

A median of 2 (1–7) SNs were identified in 305 patients and complications occurred in 11%. Fifty-four patients (18%) demonstrated SN metastases and 45 underwent completion lymphadenectomy (20% additional metastases). Six patients with initially negative SN developed lymph node metastases (sensitivity 90%). Overall disease-free survival was 83% (SN-negative 91% vs. SN-positive 41%; p < 0.001) and melanoma-specific survival was 93% (SN-negative 97% vs. SN-positive 62%; p < 0.001). Multivariate regression analysis revealed the SN status to be the most significant predictor for recurrence and melanoma-related death.

Conclusion

Our results of SLNB are comparable to data from high-volume centers participating in MSLT-I. From a patient perspective, the false-negative SN rate of 10% and complication rate of 11% should be weighed against being informed about prognosis and having a possible therapeutic benefit from completion lymphadenectomy.     

How should tracers be injected to detect for sentinel nodes in gastric cancer – submucosally from inside or subserosally from outside of the stomach?

Background

In sentinel node (SN) detection for cases of early gastric cancer, the submucosal dye injection method appears to be more reasonable than the subserosal injection. To compare the two injection methods, we have focused on the rate of concordance between hot nodes (HNs) obtained from the radioisotope (RI) method and green nodes (GNs) obtained from the dye-guided method in addition to the number and distribution of GNs detected, and the sensitivity of metastatic detection.

Methods

The subjects of this study were 63 consecutive patients with gastric cancer (sT1–T2, sN0, tumor diameter ≦ 4 cm) in whom we attempted SN detection using a combination of RI and dye methods. ^99mTc-tin colloid was injected a day before the surgery, and indocyanine green was injected either submucosally (n = 43) with endoscopes or subserosally (n = 20) by direct vision.

Results

An average of hot and green nodes (H&G: 4 ± 3 vs. 4 ± 3), hot and non-green nodes (H&NG: 2 ± 3 vs. 1 ± 2), cold and green nodes (C&G: 2 ± 2 vs. 3 ± 4), and the rate of concordance (H&G/H&G + H&NG + C&G: 45 + 27% vs. 48 ± 30%) were not significantly different between the submucosal and subserosal injection methods. The spread of GNs to tier 2 stations (24% vs. 30%) and metastatic detection sensitivity (86% vs. 100%) were also not different between the submucosal and subserosal injection methods.

Conclusion

The tracer injection sites do not have to be limited to the submucosa.     

Are the effects of cognitive behavior therapy for severe fatigue in cancer survivors sustained up to 14 years after therapy?

Purpose

Cognitive behavior therapy (CBT) reduces cancer-related fatigue (CRF) in cancer survivors in the short term. We examined fatigue levels up to 14 years after CBT.

Methods

Eligible participants of two randomized controlled trials who had completed CBT for CRF and a post-treatment assessment were contacted (n?=?81). Fatigue was assessed with the subscale “fatigue severity” of the Checklist Individual Strength (CIS-fatigue). The course of fatigue over time was examined with linear mixed model analyses. Fatigue levels of participants were compared to matched population controls at long-term follow-up. We tested with multiple regression analysis if fatigue at follow-up was predicted by the patients’ fatigue level and fatigue-perpetuating factors directly after CBT (post-CBT).

Results

Seventy-eight persons completed a follow-up assessment (response rate?=?96%, mean time after CBT?=?10 years). The mean level of fatigue increased from 23.7 (SD?=?11.1) at post-CBT to 34.4 (SD?=?12.4) at follow-up (p?<?0.001). Population controls (M?=?23,9, SD?=?11.4) reported lower fatigue levels than participants. Half of the patients (52%) who were recovered from severe fatigue at post-CBT (CIS-fatigue <?35) were still recovered at long-term follow-up. Patients with lower fatigue levels at post-CBT were less likely to show relapse.

Conclusion

Despite initial improvement after CBT, levels of fatigue deteriorated over time. Half of the patients who were recovered from severe fatigue after CBT still scored within normal ranges of fatigue at long-term follow-up.

Implications for Cancer Survivors

It should be explored how to help patients with a relapse of severe fatigue following an initially successful CBT. They may profit from CBT again, or another evidence-based intervention for fatigue (like mindfulness or exercise therapy). Future research to gain insight into reasons for relapse is warranted.

     

Are PROMs sufficient to record late outcome of breast cancer patients treated with radiotherapy? A comparison between patient and clinician reported outcome through an outpatient clinic after 10 years of follow up

Aim

To investigate whether breast cancer patients’ visits to an outpatient clinic for late outcome (OCLO) can be replaced by patient reported outcome measures (PROMs), by comparing late toxicity scored at the OCLO with PROMs.

A double-blind placebo-controlled study to evaluate endometrial safety and gynaecological symptoms in women treated for up to 5 years with tamoxifen or placebo – A substudy for IBIS I Breast Cancer Prevention Trial

Aims of the studyThis prospective study was performed to investigate the effects of 5-year’s use of tamoxifen in preventive setting on endometrium and gynaecological symptoms.Material and methodsAltogether 96 women were treated either with tamoxifen (TAM, n = 45) or placebo (PLA, n = 51) for up to 5 years in a randomised, double-blind IBIS I breast cancer prevention trial, clinically followed-up for an additional year and for the occurrence of malignancies at least 9 years between 2/1995 and 7/2009 in Finland. The gynaecological follow-up with trans-vaginal ultrasound and endometrial biopsies were performed at baseline, at 2.5 and 5 years and at the 6 years follow-up visit.ResultsWomen in the TAM group discontinued the treatment significantly more often (44% versus 22%; p = 0.017) and earlier (at 15 versus 30 months; p = 0.044), than those in the PLA group. In postmenopausal women the median endometrial thickness was significantly increased at five years in the TAM group (median 4.3 versus 2.0 mm, p = 0.011), but there was no difference between the groups at one year after the treatment. There were also statistically significantly more referrals to hospitals due to gynaecological findings in the TAM group (risk rates (RR) 3.15; 95% confidence intervals (CI) 1.12–10.10), but no differences in hysterectomy rates or other serious adverse event rates were observed.ConclusionsThe discontinuation rate in the TAM group was high, and the discontinuations also occurred early. Even though there were significantly more non-serious gynaecological events during the TAM treatment, routine gynaecological follow-up cannot be recommended.