Real-time tissue elastography as promising diagnostic tool for diagnosis of lymph node metastases in patients with malignant melanoma: a prospective single-center experience.

BACKGROUND: Real-time tissue elastography is a new, noninvasive method in ultrasonography, differentiating tissues according to their stiffness. Earlier studies have highlighted this technique as a useful diagnostic tool for the detection of noncutaneous malignancies like breast, prostate and thyroid cancer based on the principle that tumor cells present a higher stiffness compared to the adjacent normal tissue. OBJECTIVE: The purpose of our study was to investigate the value of real-time tissue elastography for the differentiation of benign and metastatic peripheral lymph nodes (LN) in patients with cutaneous melanoma by comparing this technique with conventional B-mode sonography combined with power Doppler sonography (PDS). METHODS: In this prospective study, 36 melanoma patients (23 females and 13 males, mean age 62.7 ± 11.1 years) undergoing LN excision at the Department of Dermatology and Allergy, University of Bonn, were included between July 2011 and July 2012. Real-time tissue elastography was planned prior to surgery and histopathological examination. Elasticity images had been qualitatively scored for the proportion of stiff areas from pattern 1-5 (soft to stiff) on the basis of a newly defined system for LNs. RESULTS: A total of 42 LNs have been removed in 36 patients. Of these 42 LNs, 21 carried melanoma cells and 21 were benign LNs. Significant differences in elastographic patterns were found between metastatic and nonmetastatic LNs. In real-time tissue elastography, 19 (90.5%) of 21 metastatic LNs showed a pattern of 3, 4 or 5. Of all benign LNs, 76.2% had a pattern of 1 or 2 in their elastogram. Sensitivity and specificity of B-mode sonography combined with PDS were 80.9 and 76.2%, respectively, 90.5 and 76.2% for elastography and 95.2 and 76.2% for the combined evaluation. CONCLUSION: An elastography pattern ≥3 was identified as an independent significant factor, predicting a metastatic LN involvement. The combination of elastography with conventional B-mode sonography has the potential to further improve the differentiation between benign and metastatic peripheral LNs in melanoma patients.

Role of high-resolution ultrasound and PET/CT imaging for preoperative characterization of sentinel lymph nodes in cutaneous melanoma.

The purpose of our study was the comparison of high-resolution ultrasound (HRUS) and positron emission tomography combined with computerised tomography (PET/CT) in the preoperative characterization and identification of subclinical nodal metastases focusing on sentinel lymph nodes (SLN) in melanoma patients. Patients with cutaneous melanoma (CM) who received sentinel lymph node biopsy at the Department of Dermatology and Allergy, University of Bonn, between January 2009 and January 2011 had been evaluated with a retrospective computer-aided search concerning preoperative staging procedures. A combination of PET/CT and HRUS had been performed preoperatively in 20 of 123 patients. A total of 59 SLNs had been removed in those 20 patients followed by histopathologic examination. HRUS correctly identified two of 17 positive SLNs whereas PET/CT imaging identified none. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HRUS were 11.8 % (95 % confidence interval [CI] = 3.3-34.3), 100 % (95 % CI = 91.6-100.0), 100.0 % (95 % CI = 34.2-100.0), and 73.7 % (95 % CI = 61.0-83.3), respectively. On the basis of this limited study cohort, HRUS had a better value than PET/CT in preoperative identification of positive SLNs, suggesting a possible diagnostic superiority of HRUS in general characterization of peripheral nodal disease in CM.

Sentinel lymph node status as most important prognostic factor in patients with high-risk cutaneous melanomas (tumour thickness >4.00 mm): outcome analysis from a single institution.

PURPOSE: Sentinel lymph node biopsy (SLNB) is considered the most powerful prognostic indicator of survival in patients with cutaneous melanoma of intermediate thickness (1-4 mm). The use of SLNB in patients with melanoma with a tumour thickness >4.0 mm is still controversial. The purpose of the current study was to determine the prognostic value of SLNB in patients with thick cutaneous melanomas (tumour thickness >4.0 mm) in terms of progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective single-centre study was performed at the Department of Dermatology and Allergy, University of Bonn, and the Department of Nuclear Medicine, University of Bonn, based on data collected between September 2000 and January 2010. A total of 142 patients with cutaneous melanoma of thickness >4.00 mm were identified, and 63 of these patients underwent SLNB. RESULTS: Of the 63 patients in whom SLNB was performed, 25 (39.7 %) had a positive SLN. Ulceration was more frequent in SLN-positive patients (44 %) than in SLN-negative patients (18.4 %). The mean follow-up time for the 63 patients was 50.7 months. Positive SLN status predicted a significantly reduced life expectancy in the analyses of PFS and OS. In SLN-positive patients 5-year OS was 76 % and in SLN-negative patients was 84.2 % (p = 0.048). Patients with a combination of ulcerated tumour and positive SLN had the worst prognosis. CONCLUSION: On the basis of our follow-up data, SLNB has to be recommended in patients with a tumour thickness >4.00 mm after exclusion of lymph node macrometastases or distant metastases. SLN status is the most significant prognostic factor in this group of patients.

Influence of sporting activity and smoking on peripheral lymph nodes in patients with melanoma analyzed by high-resolution ultrasound.

BACKGROUND: The sonographic examination of peripheral lymph nodes (LNs) plays an important role in the preoperative treatment and in the follow-up of patients with melanoma. OBJECTIVE: A prospective study including 200 consecutive patients with a history of invasive cutaneous melanoma was performed at the Department of Dermatology and Allergy, University of Bonn, Germany, to examine the influence of sporting activity, physical workload, interferon alfa therapy, smoking habits, and infections of the upper respiratory tract on morphology and number of LNs analyzed by high-resolution ultrasound. METHODS: Between May 2010 and June 2011, 106 men and 94 women (mean age 51.1 ± 12.8 years) were included in this study. During their follow-up visits for cutaneous melanoma, high-resolution ultrasound examination of cervical, axillary, and inguinal LN regions were performed. LN diameters and volumes were measured and correlated with the above given factors. RESULTS: Sports-active patients had more LNs in inguinal regions, a higher volume and a larger LN diameter, and a higher maximum width of the hypoechoic LN margin in comparison with the nonactive patients. Patients with a hard physical workload in their occupations had a significantly higher volume of the biggest LN. Compared with nonsmoking patients smokers presented higher values in the total quantity of the LNs, in the greatest volume of LN, and in the greatest diameter of LN in the cervical regions. The other factors had no significant influence on the LN parameters. LIMITATIONS: Our study population was too small to comment on influencing factors in more detail especially the influences of different sporting activities or smoking habits. CONCLUSION: Sporting activity, physical workload, and smoking habits as associated cofactors influencing sonomorphologic aspects in patients with cutaneous melanoma should always be considered.

Prognostic value of sentinel lymph node biopsy in 121 low-risk melanomas (tumour thickness <1.00 mm) on the basis of a long-term follow-up.

PURPOSE: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage melanomas with a thickness ≥1 mm. The value of SLNB in thin melanomas is still controversial, especially because long-term observations of these patients are rare. The purpose of the current study was to identify the positive sentinel lymph node (SLN) ratio in low-risk patients with cutaneous melanoma (CM) of thickness less than 1 mm and its possible prognostic value, focusing on long-term follow-up data. METHODS: In a retrospective single-centre study performed at the Department of Dermatology and Allergy, University of Bonn, 121 patients who had received SLNB were identified out of 621 patients with a diagnosis of CM of <1.00 mm thickness presenting between September 2000 and February 2009 (mean follow-up time, 50.9 months). RESULTS: Of the 121 patients, 5 (4.1%) had a positive SLN. All positive SLNs were found in patients with a tumour thickness between 0.90 mm and 1.00 mm. There were no significant differences in the presence of positive SLNs according to Clark level and ulceration status (Clark levels II and III and no ulceration vs. Clark levels IV and V or ulceration), regression, gender or age. Disease-free survival was 100% in the SLN-positive patients. On the other hand, five SLN-negative patients (4.1%) developed disease progression. One of these five progressive patients showed recurrence in the former negative SLN basin (16.7% false-negative rate). CONCLUSION: A positive SLN in thin melanomas is uncommon with a prevalence of 4.1% in our study population. We could not identify reliable clinicopathological risk factors which could predict results of SLNB in thin melanomas. Based on our results, SLNB may be considered in patients with a melanoma of thickness in the range 0.90-0.99 mm, because all SLN-positive patients belonged to this subgroup.

High-resolution ultrasound combined with power Doppler sonography can reduce the number of sentinel lymph node biopsies in cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with cutaneous melanoma. Disadvantages of the SLNB procedure are the overall costs and potential side effects of the operation [J Dtsch Dermatol Ges 2009;7:318-327; J Am Dermatol 2010;62:737-748]. OBJECTIVE: The purpose of our study was to evaluate whether high-resolution ultrasound combined with power Doppler sonography (PDS) is an appropriate tool for preoperative identification and characterization of sentinel lymph nodes (SLNs) in patients with cutaneous melanoma. METHODS: In a prospective study eighty-one consecutive patients with cutaneous melanoma (33 females and 48 males) in whom dissection of SLNs was indicated underwent ultrasound examinations before and after the preoperative lymphoscintigraphy. RESULTS: A total of 170 SLNs (mean 2.1 per patient) were removed and examined by histopathology. High resolution ultrasound combined with PDS correctly identified 2 of 9 positive SLNs. The sensitivity, specificity, positive predictive value, and negative predictive values of ultrasound were 22.2% (95% confidence interval (CI) = 2.8-60.0), 100% (95% CI = 97.7-100.0), 100.0% (95% CI = 15.8-100.0), and 95.8% (95% CI = 91.6-98.3), respectively. CONCLUSIONS: Although high-resolution ultrasound combined with PDS cannot substitute SLNB, this technique offers earlier diagnosis of lymph node involvement in a small subgroup of patients (with subcapsular location of metastases), and introduces the possibility to exclude those patients from SLN procedure and directly prepare them for complete lymph node dissection (CLND).

Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with melanoma. However, there is no consensus concerning the practical consequences of a positive SLN, since a survival benefit of a complete lymph node dissection (CLND) has not yet been demonstrated. OBJECTIVE: We wondered whether we could identify a subgroup of patients with metastatic involvement of the SLN who could be excluded from the recommendation to undergo CLND. METHODS: At the Department of Dermatology at the University of Munich, a total of 213 patients with metastatic SLNs (24.9%) were identified among 854 patients who had undergone SLNB between 1996 and 2007. All SLN-positive patients had been advised to have CLND. Survival analyses were performed by using the Kaplan-Meier approach. RESULTS: A total of 176 (82.6%) of 213 SLN-positive patients underwent CLND. In this group, 26 patients (14.8%) showed metastatic disease in non-sentinel lymph nodes (NSLN). The 5-year overall survival (OS) was 26.1% in NSLN-positive patients and 74% in NSLN-negative patients. SLN-positive patients who refused CLND had a better prognosis than patients with CLND. Breslow tumor thickness was significantly associated with positive CLND status with higher median values in CLND-positive than CLND-negative patients (3.03 vs 2.22 mm). LIMITATIONS: The subgroup of patients with metastatic disease in CLND may have been too small to reach statistical significance for other tumor- or patient-related parameters. Mitotic indices of the primary melanomas had not been determined in this retrospective study; thus a possible correlation with lymph node status could not be tested. CONCLUSION: Among SLN-positive patients, the presence of metastatic NSLN is a highly significant poor prognostic factor. Tumor thickness is a significant prognostic parameter for positive CLND status and might be considered in the decision to perform CLND in case of metastatic SLN.

Dose-dependent development of depressive symptoms during adjuvant interferon-{alpha} treatment of patients with malignant melanoma.

BACKGROUND: Adjuvant IFN-α treatment for patients with malignant melanoma is often complicated by depression. The influence of dosage, however, is unknown. OBJECTIVE: The authors sought to elucidate this dosage effect. METHOD: Using the Zung Self-Rating Depression Scale and the German Bf-S Self-Rating (Affectivity) Scale, the authors prospectively compared the frequency and severity of IFN-α-induced depressive symptoms between a group of 29 patients receiving low-dose and 17 patients getting high-dose induction therapy for 4 weeks. RESULTS: Patients receiving high-dose induction treatment had significantly higher depression scores after 4 weeks, and significantly more patients in the high-dose group developed depression. CONCLUSION: The authors concluded that frequency and severity of IFN-α-associated depression during melanoma treatment are dose-dependent.

Prognostic factors associated with sentinel lymph node positivity and effect of sentinel status on survival: an analysis of 1049 patients with cutaneous melanoma.

Sentinel lymph node biopsy (SLNB) is a widely accepted staging procedure in patients with melanoma. However, it is unclear which factors predict the occurrence of micrometastasis and overall prognosis and whether SLNB should also be performed in patients with thin primary tumors. At our Department of Dermatology, University of Munich (Germany), 1049 consecutive melanoma patients were identified for SLNB between 1996 and 2007, and were followed-up to assess disease-free and overall survival. Of those, a total of 854 patients were analyzed prospectively. Patients with positive SLN were subjected to selective lymphadenectomy. The association of patient characteristics with SLN was assessed by multivariate logistic regression. Survival curves were performed using the Kaplan-Meier method. Cox proportional hazard regression with different adjustments was used to estimate the effect of SLN on survival. The detection rate of SLN was 97.24%, of which 24.9% were metastatic. Significant parameters upon SLN positivity were tumor thickness and nodular type of melanoma. The 5-year overall survival was 90.1 and 58.1% in SLN-negative and SLN-positive patients, respectively. Upon multivariate analysis tumor thickness and SLN status were significant factors influencing both disease-free survival and overall survival. In conclusion, our data confirm that SLNB is relevant as a diagnostic and staging procedure and that tumor thickness is of predictive importance. SLN status should be taken into account when designing clinical trials and informing patients about the probable course of their disease. Our data suggest that in case of a nodular melanoma subtype SLNB should also be considered at a tumor thickness below 1 mm.

The use of high-resolution ultrasonography for preoperative detection of metastases in sentinel lymph nodes of patients with cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) reliably assesses the status of the regional lymph node basins and provides prognostic information in patients with cutaneous melanoma, but is logistically demanding and expensive. OBJECTIVE: The aim of this study was to evaluate the ability of high resolution B-mode ultrasonography (US) for pre-operative identification and characterization of sentinel lymph nodes (SLN) in patients with cutaneous melanoma. PATIENTS AND METHODS: In a prospective trial, the use of high resolution US was assessed in 25 consecutive patients with cutaneous melanoma identified for SLNB, first, for its value in primary detection of SLN, and, second, for its value in the correct assessment of SLN after lymphoscintigraphic mapping. RESULTS: High resolution B-mode US correctly identified two of 6 positive SLN. The sensitivity, specificity, positive predictive value, and negative predictive value of US were 33.3% (95% CI 43.3-77.7), 100.0% (95% CI 88.1-100.0), 100.0% (95%CI 15.8-100.0) and 87.9% (95% CI 71.8-96.6), respectively. CONCLUSION: High resolution B-mode US cannot replace SLNB, especially in the detection of micrometastases, but it remains the most important method to assess the lymph node status for macrometastases presurgically.

Correlation between sICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon-alpha.

Interferon-alpha (IFN-alpha) treatment is frequently complicated by symptoms of depression. The mechanism by which peripherally administered IFN-alpha enters and modulates the central nervous system remains unclear. The cell adhesion molecule ICAM-1 is involved in the regulation of blood-brain barrier (BBB) permeability. ICAM-1 expression was shown to increase during IFN-alpha treatment and recently the expression of ICAM-1 on vascular endothelial cells in the brain was found to be correlated with the development of depression. We therefore hypothesized that soluble ICAM-1 may be involved in the development of IFN-alpha associated depression. In a prospective study, serum levels of soluble ICAM-1 (double sandwich ELISA test) and symptoms of depression (SDS) were measured in 48 patients with malignant melanoma before and during adjuvant IFN-alpha treatment. Both, depression scores and the serum levels of sICAM-1 significantly increased after three months of IFN-alpha treatment compared to baseline levels (p < .001). Patients who developed depression (SDS-index scores > or = 50) after three months of treatment had higher sICAM-1 levels compared to non-depressed patients. Furthermore, sICAM-1 levels were positively correlated with SDS values (r = .367, p = .018). Our data provides evidence for an association between the induction of sICAM-1 and the development of symptoms of depression during IFN-alpha treatment, possibly by enhancing BBB-permeability.

Value of ultrasonography compared with physical examination for the detection of locoregional metastases in patients with cutaneous melanoma.

In several studies the early detection of locoregional metastases in patients with cutaneous melanomas has been shown to be of prognostic value. Physical examination alone often fails to detect locoregional metastases or cannot unambiguously classify palpable lymph nodes. This study aimed to evaluate the usefulness of high resolution ultrasonography for the early detection of locoregional metastases and to compare the sensitivity and specificity of ultrasound and physical examination. A prospective study was performed between January 1997 and June 1999 in 1395 patients (721 men and 674 women) with invasive cutaneous melanoma, treated and followed up at the Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany. A total of 2650 physical and ultrasound examinations of lymphatic drainage areas were performed, and lesions suspicious for metastases were excised and diagnosed by histopathology. The results of physical and ultrasound examinations were compared. Of the 2650 ultrasound examinations, metastases were suspected in 153, whereas 290 of the 2650 physical examinations were suspicious for metastatic disease. A total of 168 patients with suspicious lesions underwent surgery; histopathological examination revealed 112 melanoma metastases and 56 other diagnoses, including one second malignancy, one neurinoma, one haemangioma and 54 reactive lymph nodes. Ultrasonographic diagnosis of melanoma metastases had a sensitivity of 92.2% and a specificity of 98.2%, whereas diagnosis by physical examination had a sensitivity of only 51.3% and a specificity of 90.9%. Thus ultrasound examination was found to be highly effective and superior to physical examination for the early detection of locoregional melanoma metastases.

Cutaneous melanoma in childhood and adolescence: an analysis of 36 patients.

Analysis of data of 6931 patients with cutaneous melanoma seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University of Munich between 1977 and 1998 identified 36 patients in whom cutaneous melanomas developed during childhood or adolescence (age <18 years). Clinical courses of all patients and histopathologic characteristics of the lesions were reviewed. Seventeen patients were boys and 19 patients were girls. The median ages of the boys and girls were 15 and 16 years, respectively (range, 2-17 years). Thirty-one patients presented with nonmetastatic primary melanomas and 5 patients presented with metastatic melanoma. Forty-seven percent of the primary lesions were associated with a nevus (22% with congenital nevi and 25% with acquired nevi). Tumor thickness ranged from 0.24 to 7.0 mm, with a median of 1.29 mm (mean, 1.67 mm). All patients with primary melanomas received surgical therapy; patients with metastatic disease received chemotherapy, radiation therapy, or both. Relative 5-year survival was 87.5% for the group of patients younger than 18 years. Similar to experience in adult patients, survival strongly correlated with tumor thickness and clinical stage at the time of diagnosis. The data emphasize that a high index of suspicion for cutaneous melanoma is needed by clinicians assessing melanocytic lesions in children and adolescents for early diagnosis. Reduction of the melanoma mortality rate in children and adolescents will be achieved through identification of patients at increased risk.