Sentinel Node Tumor Load Assessment in Melanoma: Dilemmas and Clinical Management

Malignant Melanoma is the most aggressive form of skin cancer. Worldwide, the incidence of melanoma has risen sharply of the past three decades. On the 1st of January 2007, there were nearly 800,000 people alive in the USA alone, who were diagnosed wi

Surgical outcomes of lymph node dissections for stage III melanoma after neoadjuvant systemic therapy are not inferior to upfront surgery

BackgroundNeoadjuvant systemic therapy has shown promising results in the treatment of high-risk stage III melanoma; however, the effects on surgery are currently unknown. This study aims to compare the surgical outcomes, in terms of postoperative complications, postoperative morbidity, duration of surgery and textbook outcomes, of patients with high-risk stage III melanoma who received neoadjuvant systemic therapy followed by lymph node dissection with patients who received an upfront lymph node dissection.MethodsIn this retrospective cohort study, patients with high-risk stage III melanoma treated with neoadjuvant anti-PD1 and anti-CTLA4 in the OpACIN (NCT02437279) and OpACIN-neo (NCT02977052) trial between October 2014 and August 2018 were included and compared to patients who received upfront surgery in the same time period.ResultsA total of 120 patients were included in this study, of whom 44 received neoadjuvant systemic therapy and 76 underwent upfront surgery. There was no significant difference in the overall rate of postoperative complications between the neoadjuvant group and the upfront surgery group (31.8% versus 36.8%, p = 0.578) and neither in rate of postoperative morbidity (seroma 56.8% versus 57.9%, p = 0.908) (lymphedema 22.7% versus 13.2%, p = 0.175). There was a non-significant difference towards a slightly longer duration of surgery after neoadjuvant immunotherapy (105 versus 90 min, p = 0.077). There were no differences in textbook outcomes (50% versus 49%, p = 0.889).ConclusionThis study shows that the surgical outcomes for patients who underwent a lymph node dissection after neoadjuvant systemic immunotherapy or underwent upfront lymph node dissection for high-risk stage III melanoma are comparable.Otorhinolaryngolog

Ultrasound-guided fine needle aspiration cytology as an addendum to sentinel lymph node biopsy can perfect the staging strategy in melanoma patients

Background Ultrasound guided fine needle aspiration cytology (US-guided FNAC) can identify microscopic involvement of lymph nodes as in breast cancer and avoid surgical sentinel node (SN). Its utility in melanoma patients is controversial and subject of this study. Methods Between 2001 and 2010 over 1000 stage I/II consecutive melanoma patients prospectively underwent US-FNAC prior to SN biopsy. All patients underwent lymphoscintigraphy prior to US-FNAC. The Berlin US morphology criteria: Peripheral perfusion (PP), loss of central echoes (LCE) and balloon shaped (BS) were registered. FNAC was performed in case of presence of any of these factors. SN tumour burden was measured according to the Rotterdam criteria. All patients underwent SN or lymph node dissection (LND) in case of positive FNAC. Findings Mean/median Breslow thickness was 2.58/1.57 mm. Mean/median follow-up was 56/53 months (1-132). SN positivity rate was 21%. US-FNAC Sensitivity was 71% (US only) and 51% (US-FNAC). Sensitivity of US-FNAC was highest for T4 (76%) and ulcerated melanomas (63%). PP, LCE and BS had sensitivity of 69%, 24% and 24% respectively. Sensitivity of US-FNAC increased with increasing SN tumour burden. PP was an early sign of metastasis (58% in <0.1 mm metastases). Threshold size of a metastasis for FNAC was 0.3 mm. Five-year survival correlated to US-FNAC status (95% in negative and 59% in positive). Interpretation Ultrasound guided FNAC (US-FNAC) according to the Berlin morphology criteria could correctly identify at least half of all tumour positive sentinel nodes, prior to the surgical SN procedure. Peripheral perfusion is an early sign of metastasis, which is very sensitive, but with lower positive predictive value (PPV). It is responsible for the sensitivity of the procedure. Balloon shape is a sign of advanced metastases, with lower sensitivity, but high PPV. US-FNAC sensitivity correlated with increasing T-stage, ulceration of the primary and increasing SN tumour burden. US-FNAC status accurately predicts survival

Gamma probe and ultrasound guided fine needle aspiration cytology of the sentinel node (GULF) trial

Background: Sentinel node (SN) biopsy (SNB) detects clinically occult metastases of breast cancer and melanoma in 20-30%. Wound infections, seroma and lymph edema occur in up to 10%. Targeted ultrasound (US) of the SN, (with fine needle aspiration cytology (FNAC) if appropriate) has been investigated as a minimally invasive alternative, but reported sensitivity rates are too low to replace SNB. Our hypothesis is that the use of a handheld gamma probe concomitant with US may improve sensitivity. Our aim is to provide an overview of the current literature on preoperative nodal staging of clinical N0 melanoma patients, report on a pilot, and present a study protocol for a minimally invasive alternative to the SNB: Gamma probe and Ultrasound guided Fine needle aspiration cytology of the sentinel node (GULF trial). Methods: The GULF trial is a multicenter open single arm observational trial. Newly diagnosed cT1b-4N0M0 cutaneous melanoma or cT1-3N0M0 breast cancer patients, aged >18years, presenting for SNB are eligible. 120 patients will be included for preoperative targeted gamma probe guided US and FNAC of the SN. Afterwards all patients proceed to surgical SNB. Primary endpoint is the sensitivity of FNAC. Secondary endpoints include SN identification rate and the histopathological compatibility of Core Needle Biopsy and FNAC vs. SNB. Secondary endpoints were investigated in a pilot with 10 FNACs and marker placements, and 10 FNACs combined with Core Needle Biopsy. Results: A pilot in 20 patients showed that SN identification rate was 90%, supporting the feasibility of this technique. Discussion: There is broad experience with US (in combination with FNAC) prior to SNB, but sensitivity and specificity are too low to completely abandon SNB. Promising alternative techniques potentially will replace SNB in the future but more evidence is needed in the form of prospective studies. Accurate identification of the SN for US-FNAC has been proven feasible in our pilot. When adequate sensitivity can be reached, US-FNAC provides a minimally invasive alternative for the surgical SNB procedure. Trial registration: The GULF trial is registered in the Netherlands Trial Registry (NTR), ID: NRT5193. May 1st 2015

Risk Factors for Positive Deep Pelvic Nodal Involvement in Patients with Palpable Groin Melanoma Metastases: Can the Extent of Surgery be Safely Minimized?: A Retrospective, Multicenter Cohort Study

Background: Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient. Aim: The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future. Methods: This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992–2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] ± positron emission tomography [PET], or PET − low-dose CT). Results: Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11–46 months). Median Breslow thickness was 2.10 mm (IQR 1.

Optimal extent of completion lymphadenectomy for patients with melanoma and a positive sentinel node in the groin

Background: The optimal extent of groin completion lymph node dissection (CLND) (inguinal or ilioinguinal dissection) in patients with melanoma is controversial. The aim of this study was to evaluate whether the extent of groin CLND after a positive sentinel node biopsy (SNB) is associated with improved outcome. Methods: Data from all sentinel node-positive patients who underwent gr

Avelumab for advanced Merkel cell carcinoma in the Netherlands: a real-world cohort

Background Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported. Methods Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progressionfree survival (PFS), overall survival (OS), and toxicity. Results Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5–35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3–22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6–15.5) months, and the median OS was 25.8 (95% CI 9.1–42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4–5 toxicity was seen. Conclusions In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC

Molecular Characterization and Patient Outcome of Melanoma Nodal Metastases and an Unknown Primary Site

Background Melanoma of unknown primary site (MUP) is not a completely understood entity with nodal metastases as the most common first clinical manifestation. The aim of this multicentric study was to assess frequency and type of oncogenic BRAF/NRAS/KIT mutations in MUP with clinically detected nodal metastases in relation to clinicopathologic features and outcome. Materials and Methods We analyzed series of 103 MUP patients (period: 1992-2010) after therapeutic lymphadenectomy (LND): 40 axillary, 47 groin, 16 cervical, none treated with BRAF inhibitors. We performed molecular characterization of BRAF/NRAS/KIT mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 53 months. Results BRAF mutations were detected in 55 cases (53 %) (51 V600E, 93 %; 4 others, 7 %), and mutually exclusive NRAS mutations were found in 14 cases (14 %) (7 p.Q61R, 4 p.Q61K, 2 p.Q61H, 1 p.Q13R). We have not detected any mutations in KIT. The 5-year overall survival (OS) was 34 %; median was 24 months. We have not found significant correlation between mutational status (BRAF/NRAS) and OS; however, for BRAF or NRAS mutated melanomas we observed significantly shorter disease-free survival (DFS) when compared with wild-type melanoma patients (p = .04; 5-year DFS, 18 vs 19 vs 31 %, respectively). The most important factor influencing OS was number of metastatic lymph nodes >1 (p = .03). Conclusions Our large study on molecular characterization of MUP with nodal metastases showed that MUPs had molecular features similar to sporadic non-chronic-sun-damaged melanomas. BRAF/NRAS mutational status had negative impact on DFS in this group of patients. These observations might have potential implication for molecular-targeted therapy in MUPs

Development and validation of a nomogram to predict recurrence and melanoma-specific mortality in patients with negative sentinel lymph nodes

Background: Patients with melanoma and negative sentinel nodes (SNs) have varying outcomes, dependent on several prognostic factors. Considering all these factors in a prediction model might aid in identifying patients who could benefit from a personalized treatment strategy. The objective was to construct and validate a nomogram for recurrence and melanoma-specific mortality (MSM) in patients with melanoma and negative SNs. Methods: A total of 3220 patients with negative SNs were identified from a cohort of 4124 patients from four EORTC Melanoma Group centres who underwent sentinel lymph node biopsy. Prognostic factors for recurrence and MSM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across the four centres. A nomogram was developed for graphical presentation. Results: There were 3180 eligible patients. The final prediction model for recurrence and the calibrated model for MSM included three independent prognostic factors: ulceration, anatomical location and Breslow thickness. The c-index was 0·74 for recurrence and 0·76 for the calibrated MSM model. Cross-validation across the four centres showed reasonable model performance. A nomogram was developed based on these models. One-third of the patients had a 5-year recurrence probability of 8·2 per cent or less, and one-third had a recurrence probability of 23·0 per cent or more. Conclusion: A nomogram for predicting recurrence and MSM in patients with melanoma and negative SNs was constructed and validated. It could provide personalized estimates useful for tailoring surveillance strategies (reduce or in

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node–positive melanoma without the need for completion lymph node dissection

Purpose: Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). Methods: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. Results: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. Conclusions: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making