Hot dots - which nodes should be removed in sentinel lymph node biopsy for melanoma?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a critical staging tool for melanoma patients. The optimal number of lymph nodes removed in SLNB remains unclear. In this study, we retrospectively analysed and tested different criteria for selecting sentinel lymph nodes (SLNs) by radiotracer uptake and blue dye, and their impact on nodal staging. We also evaluated the association between SLN tumour burden and radiotracer uptake. METHODS: The study population consisted of melanoma patients undergoing SLNB. During the operation all radioactive and blue nodes were removed and sent for histopathological analysis. The ex vivo radioactive count and presence of blue dye of each node were recorded, and these were correlated with presence and size of metastasis in each SLN. RESULTS: Altogether 175 patients with clinically occult metastasis presented with one or more positive, i.e. metastatic, SLNs. The mean number of lymph nodes removed was 4.5, and the mean number of positive lymph nodes was 1.5 per patient. The most radioactive or hottest node was negative in 38 patients (22%). By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients would have been staged correctly. In five patients, metastasis was found solely in a SLN with radioactivity <10% of the hottest node. Of all 267 positive nodes removed, 125 (47%) contained blue dye. Patients with a negative hottest node were associated with lower SLN tumour burden. CONCLUSIONS: By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients with SLN metastases are correctly staged with or without using blue dye.

High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma.

Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients' cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.

Sentinel lymph node biopsy in high-risk cutaneous squamous cell carcinoma of the head and neck.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) shows malignant behaviour in 3-4% of patients with locoregional metastases and a poor prognosis, metastases that are difficult to predict clinically. Therefore, sentinel lymph node biopsy (SLNB) has been assessed, with contradictory findings thus far. We aimed to clarify the prognostic value of SLNB in high-risk cSCC patients. PATIENTS AND METHODS: We completed a retrospective clinical study amongst 63 patients, preoperatively classified as N0 with a high-risk primary cSCC of the head and neck who underwent SLNB between 2001 and 2014 at Helsinki University Hospital (Finland). Considered high risk, the inclusion criteria comprised at least two of the following characteristics: tumour diameter ≥10 mm and/or thickness ≥4 mm and a specific tumour location, such as the lips, ear, scalp and central face. Patients were followed-up postoperatively for a median of 4.1 years (0.2-13.8 years). RESULTS: Only four (6.3%) patients had positive sentinel nodes. One of these patients died of cSCC, while the other three ultimately survived their disease. Five (7.9%) patients showed a negative SLNB, but developed recurrence within one year postoperatively. Recurrence appeared in the neck lymph nodes concurrently with locoregional soft-tissue invasion in all patients. Amongst these patients, three died for cSCC and the remaining two from other causes. Comparing the SLNB-positive and SLNB-negative groups with recurrence, we identified no significant differences in terms of patient or tumour characteristics. CONCLUSIONS: SLNB appears to carry no prognostic value for identifying recurrent disease amongst high-risk cSCC in the head and neck area.

Pelvic sentinel lymph nodes have minimal impact on survival in melanoma patients.

BACKGROUND: Lower limb or trunk melanoma often presents with femoral and pelvic sentinel lymph nodes (SLNs). The benefits of harvesting pelvic lymph nodes remain controversial. In this retrospective study, the frequency and predictors of pelvic SLNs (PSLNs), and the impact of PSLNs on survival and staging was investigated. METHODS: Altogether 285 patients with cutaneous melanoma located in the lower limb or trunk underwent sentinel lymph node biopsy of the inguinal/iliac lymph node basin at Helsinki University Hospital from 2009-2013. Patient characteristics, detailed pathology reports and follow-up data were retrieved from hospital files. Subgroups of patients categorized by presence of PSLNs were compared for outcome parameters including progression-free survival, melanoma-specific survival and groin recurrence. RESULTS: Superficial femoral/inguinal SLNs were present in all patients and 199 (69.8 per cent) also had PSLNs removed. Median number of SLNs per patient was five and median number of PSLNs was two. Sixty-three patients (22.1 per cent) had metastases in their SLNs and seven (2.5 per cent) had metastases in PSLNs. A single patient had metastases solely in PSLNs, while superficial SLNs remained negative. Harvesting PSLNs or the number of PSLNs retrieved had no impact on progression-free survival or overall survival. The removal of PSLNs did not affect the risk of postoperative seroma or lymphoedema. The only predictor of positive PSLNs was radioactivity count equal to or more than that of the hottest superficial SLNs. CONCLUSION: Pelvic SLNs have minimal clinical impact on the outcome of melanoma patients especially in cases with negative superficial femoral/inguinal SLNs. Removal of PSLNs should be considered when they are the most radioactive nodes or equal to the hottest superficial femoral/inguinal SLNs in lymphoscintigraphy or during surgery.Preliminary results were presented in part at the International Sentinel Node Society Biennial Meeting, Tokyo, Japan, 11-13 October 2018.

BRAF immunohistochemistry predicts sentinel lymph node involvement in intermediate thickness melanomas.

BACKGROUND: Sentinel node biopsy (SNB) is an important step in melanoma staging and prognostication. It is commonly performed for patients with intermediate thickness melanomas, based on clinicopathological features. However, only 20-25% of patients eventually demonstrate nodal involvement. The aim of this study was to evaluate whether tissue biomarkers with links to melanoma biology, together with clinicopathological parameters, could aid in the prediction of sentinel node involvement and improve selection of patients for SNB. In addition, we examined the role of these clinical or biological markers in disease outcome. METHODS: We collected a case-control cohort of 140 intermediate thickness (Breslow 0,9-4,0mm) melanoma patients with or without SNB involvement matched for age, gender, Breslow thickness and location. From this cohort, we tested the predictive value of common clinicopathological parameters (ulceration, mitotic count and tumor regression) and FMNL-2, ezrin and BRAF V600E immunoreactivity, for sentinel node involvement and survival. We further analyzed the correlations in the superficial spreading melanoma subtype. RESULTS: Based on our case control analysis, of the markers, BRAF V600E status (p = 0.010) and mitotic count (p = 0.036) correlated with SNB involvement. SNB status was a strong independent prognosticator for recurrence free survival (RFS p<0.001), melanoma specific survival (MSS p = 0.000) and overall survival (OS p = 0.029). In the superficially spreading melanoma subgroup, BRAF V600E positivity indicated poorer RFS (p = 0.039) and OS (p = 0.012). By combining the Breslow thickness, mitotic count and BRAF immunohistochemistry, we identified a group of superficially spreading melanomas with an excellent survival probability independent of SNB status. CONCLUSIONS: These results demonstrate that BRAF immunohistochemistry could serve as a useful addition to a marker panel for selecting intermediate thickness melanoma patients for SNB.

Sentinel lymph node biopsy in cN0 squamous cell carcinoma of the lip: A retrospective study.

BACKGROUND: The purpose of this study was to assess the use of sentinel lymph node biopsy (SLNB) in clinically lymph node-negative (cN0) squamous cell carcinoma (SCC) of the lip deemed high risk for occult nodal metastasis. METHODS: Twenty-six patients with cT1 to T2 cN0 with SCC of the lip underwent SLNB at a tertiary referral center between January 2001 and March 2012. Initial staging methods were clinical examination only (65.4%), ultrasound (23.1%), or CT (11.5%). Operations were performed with the patients under local anesthesia with sedation (50%) or general anesthesia (50%). RESULTS: The mean follow-up time was 53 months. Three patients (11.5%) had a positive sentinel node and were upstaged. One SLNB-related complication was observed. Regional recurrence occurred in 2 patients (7.7%). The relationship between regional status and both tumor diameter and tumor thickness was statistically significant (p < .05). CONCLUSION: SLNB can be a viable staging technique in SCC of the lip. Tumor diameter of ≥ 20 mm and increasing tumor thickness seem to delineate higher risk for regional disease in our study. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1375-E1380, 2016.

[Excision of a naevus]. / Iholuomen poisto näytteeksi.

Skin biopsy due to a changed appearance of a skin mole is a common cause for visiting a doctor. Skin biopsy is a surgical procedure involving the usual surgical complications that can be avoided with careful planning. Histological microscopic examination is the indication for skin biopsy. The main principle should be that if the patient or the physician is concerned about the skin tumor, it should be removed and referred for further analysis and definitive diagnosis.

Outcome following local recurrence or in-transit metastases in cutaneous melanoma.

Defining clinical factors influencing outcome after local recurrence or in-transit metastasis may help us to improve treatment and develop follow-up guidelines. A retrospective review of melanoma patients with local recurrence in the primary tumor scar or with in-transit metastasis was carried out. Outcome and survival were analyzed for 99 patients. In univariate analysis, factors related to overall survival following local recurrence at the time of the first relapse were initial stage [P=0.002, hazard ratio (HR) 1.9], site of primary tumor (P=0.02, HR 1.1), Breslow thickness (P=0.002, HR 1.2), Clark classification (P=0.01, HR 1.7), ulceration (P=0.01, HR 2.1), presence of satellite tumor (P=0.03, HR 2.7), and development of lymph node or distant metastases during follow-up (P<0.001, HR 7.0). Local recurrence within 2 years after surgery of primary melanoma correlated with worse survival (P=0.02, HR 2.1). Patients with local recurrence as first relapse often have a poor prognosis if the disease recurs within 2 years after primary surgery.

Ki-67, Bcl-2 and p53 expression in primary and metastatic melanoma.

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.

Ezrin in primary cutaneous melanoma.

Ezrin is a member of the ezrin-radixin-moesin family of proteins that link the actin-containing cytoskeleton to the plasma membrane. Ezrin is also connected to signaling molecules involved in the regulation of cell survival, proliferation and migration. Here, we examined the expression of ezrin in 95 primary cutaneous melanomas and correlated ezrin expression with conventional prognostic factors and biomarkers. From 12 patients metastatic tissue samples were also examined. In addition to ezrin staining, Mib-1 proliferation antigen, p53 and Bcl-2 were evaluated. Ezrin immunoreactivity was seen in most tumors; only 19 (20%) melanomas were negative. A total of 48 (51%) tumors had weak immunoreactivity and 28 (29%) strong immunoreactivity. The intensity of ezrin immunoreactivity was associated with tumor thickness (Breslow, P=0.0008) and with tumor invasion level (Clark, P=0.004), thicker tumors having stronger immunoreactivity. Also, there was a correlation between higher Mib-1 index in tumors and strong ezrin expression. All metastatic samples (n=12) showed positive ezrin immunoreactivity. In univariate analysis of survival, patients (n=76) with positive ezrin immunoreactivity had worse clinical disease behavior than those (n=19) without ezrin immunoreactivity, but the difference was not significant (P=0.19). In multivariate analysis of survival, the ezrin immunoreactivity was not a significant marker. The results indicate that ezrin is expressed in most primary melanomas of the skin and in all metastatic tumors. Ezrin expression correlates with tumor thickness and level of invasion suggesting an association between ezrin expression and tumor progression.