Regional lymph node metastases in cutaneous melanoma: a single-center analysis from southeast europe.

OBJECTIVE: Sentinel lymph node biopsy is the standard of care for nodal staging in clinically node-negative melanoma patients. Our goal was to present 10-year results of sentinel lymph node biopsy at our institution and to evaluate the clinicopathologic factors as potential predictors of sentinel lymph node and non-sentinel lymph node metastatic involvement in patients with cutaneous melanoma. METHODS: We have analyzed clinicopathologic and lymphoscintigraphic characteristics in 420 patients with cutaneous melanoma who underwent sentinel lymph node biopsy between 2010 and 2019. In addition, we have examined the results of group of patients with positive sentinel lymph node biopsy undergoing complete lymph node dissection. RESULTS: The overall detection rate of sentinel lymph node biopsies was 97.1%, of which 18.8% was metastatic. Drainage to one regional basin was seen in 345 patients (83.1%) and to multiple drainage regions in 71 patients (17%). In-transit lymph nodes were detected in 20 patients. On univariate logistic regression analysis, male gender, primary tumor thickness with nodular histology, acral location, presence of ulceration, and the number of nodes harvested were significantly associated with sentinel lymph node biopsy status (p < 0.05). On multivariate analysis, the Breslow thickness was the only independent predictor of sentinel lymph node biopsy status. The metastases in non-sentinel lymph node found in 26 patients with positive sentinel lymph node (35.6%) correlated on univariate, as well as on multivariate logistic regression, with tumor subtype and number of sentinel lymph node harvested. CONCLUSIONS: In addition to the well-established primary tumor thickness as a predictor of sentinel lymph node biopsy positivity, we observed acral location and nodular melanoma subtype to significantly enhance the risk of metastases in sentinel lymph node(s). Primary tumor histology and number of nodes harvested were the only statistically significant variables predicting the non-sentinel lymph node status on multivariate analysis. Lymphoscintigraphy imaging characteristics were not significantly associated with sentinel lymph node status.

DNMT1 and DNMT3B genetic polymorphisms affect the clinical course and outcome of melanoma patients.

The aberrant DNA methylation plays a critical role in a number of different malignancies, including melanoma. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), involved in methylation maintenance (DNMT1) and de novo DNA methylation (DNMT3A and DNMT3B). The current study investigated the association of genetic variants in the DNMT1 and DNMT3B with the clinicopathologic features and the clinical course of melanoma patients. In the present study, DNMT1 (rs2228612, rs2228611, and rs2114724) and DNMT3B (rs406193 and rs2424932) polymorphisms were examined in 123 melanoma patients. Single nucleotide polymorphisms were assessed using TaqMan SNPs Genotyping Assays according to the manufacturer's protocols. The carriers of the variant genotype of DNMT1 rs2228612 had poorer overall survival and recurrence-free survival, (P = 0.000 and 0.000, respectively), and an increased risk for adverse outcome [hazard ratio (HR) = 6.620, 95% confidence interval (CI): 2.214-19.791, P = 0.001]. DNMT1 rs2228612 was also associated with ulceration (P = 0.045), nodal status (P = 0.030), progression (P = 0. 007), and stage of disease (P = 0.003). Univariate analysis indicated that tumor-infiltrating lymphocytes could be a marker of good prognosis in melanoma patients (HR = 0.323, 95% CI: 0.127-0.855, P = 0.025), whereas the genotype distribution of the DNMT3B rs406193 polymorphism correlated significantly with the presence of tumor-infiltrating lymphocytes (P = 0.012). The multivariate analysis showed that the DNMT1 rs2228612 polymorphism (HR = 12.126, 95% CI: 2.345-62.715, P = 0.003) is an independent predictor of poor overall survival in melanoma patients. As expected, disease progression was also found to be an independent prognostic factor in melanoma patients (HR = 37.888, 95% CI: 3.615-397.062, P = 0.002). DNMT1 rs2228612 was found to be an independent predictor of poor overall survival in melanoma patients. DNMTs polymorphisms could serve as a potential target for novel therapeutic approaches.

Time to Procedure, Nuclear Imaging and Clinicopathological Characteristics as Predictive Factors for Sentinel Lymph Node Metastasis in Cutaneous Melanoma: A Single-Center Analysis.

OBJECTIVE: Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored. METHODS: Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1-98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size. RESULTS: Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P < 0.001), primary ulceration lesion (P = 0.001), and lymphovascular invasion (P = 0.006) were strongly correlated with SLN positivity, as well as the site of primary tumor (P = 0.024), tumor-infiltrating lymphocytes (TILs) (P = 0.021), and sex (P = 0.026). In multivariate analysis, Breslow thickness and TILs were found to be significant independent predictors of SLN status (P < 0.05). CONCLUSIONS: Addition of blue dye did not improve SLN detection rate; time to procedure was not found to be associated with higher SLN biopsy positivity rates. Breslow thickness and TILs, as a marker of immune response to tumor, were consistently found to be significant independent predictors of SLN status.

The influence of Dupuytren's disease fingers contracture degree on surgical treatment outcome.

Background/Aim: Dupuytren's disease is a progressive disease of the palmar and digital fascial structures, with functional limitations. There are no clear recommendations about the optimal time of surgical repair, concerning the hand impairment. The aim of our study was to investigate the relation between finger's contracture degree and success of surgical treatment of the Dupuytren's disease. Methods: This prospective analysis included 60 patients operated on due to Dupuytren's contracture. According to preoperative contracture degree of proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joint, patients were divided into three groups: the group 1: < 15°, the group 2: 15−30° and the group 3: > 30°. All the patients underwent operation of partial palmar fasciectomy. Postoperative improvement was expressed with contracture reduction INDEX. Results: There were 60 patients with 85 fingers affected. The groups 1, 2 and 3 had 22 (37%), 37 (62%) and 26 (43%) fingers with MCP contracture and 32 (37.4%), 24 (28.2%) and 29 (34.1%) fingers with PIP contracture, respectively. Postoperative contractures of MCP joint in these groups were 0, 0.135° and 5°, and of PIP joint 0, 2.08 ° and 16.89°, respectively. After six months all MCP contractures resolved, while PIP joint contracture in the group 3 remained 13.62°. The reduction INDEX was 98.85%, 97.62% and 75.52% in the groups 1, 2 and 3, respectively. There was a statistically significant difference in the INDEX value between the groups (p = 0.0001). Conclusion: The degree of PIP joint contracture is related to the outcome of surgical treatment of Dupuytren's disease. Optimal results are achieved when contracture degree is between 15° and 30°. Surgical treatment of MCP joint contracture is successful regardless of the preoperative joint contracture degree.

Validity of ultrasound-guided aspiration needle biopsy in the diagnosis of micrometastases in sentinel lymph nodes in patients with cutaneous melanoma.

Background/Aim: Cutaneous melanoma is one of the most aggressive solid cancers, that develops local, regional and distant metastases. The presence of metastases in lymph nodes is in correlation with Breslow tumor thickness. According to various researches, in melanoma with more than 4 mm Breslow thickness, lymph node micrometastases can be found in 60-70% of cases. Sentinel lymph nodes biopsy is a diagnostic procedure for lymph node micrometastasis detection, which is necessary for disease staging. In recent studies, ultrasound-guided fine needle aspiration with cytology (US FNAC) of the sentinel lymph node was used as less invasive procedure, but is not accepted as the standard procedure. The goal of this work was to define sensitivity, specification and precision of the ultrasound-guided fine needle aspiration method in comparison with standard sentinel lymph node biopsy. Methods: After obtaining the Ethics Committee's permission, from 2012 to 2014 a total of 60 patients with cutaneous melanoma were enrolled, and divided into three groups: group I with thin melanoma, group II with intermediate thickness melanoma and group III with thick melanoma. The presence of micrometastases in sentinel regional lymph nodes was analyzed by US FNAC. The results obtained were compared to sentinel lymph nodes biopsy (SLNB) results. The golden standard for calculating the specific, sensitive and precise characteristics of the method of US FNAC of sentinel lymph nodes was histopathologic lymph node examination of sentinel lymph nodes acquired through biopsy. Results: Detection rate of US FNAC was 0% in the group I, 5% in the group II and 30% in the group III. SLNB detection rates were: 10% in the group I, 15% in the group II, and 45% in the group III. In melanoma thicker than 4 mm, 15% of the patients were false negative by US FNAC. The sensitivity of US FNAC for all the patients was 50%: in the group I, 0%; in the group II, 33.3%; and in the group III, 66.6%. The method specificity for all examined patients was 100% and accuracy 88%: group I, 90%; group II, 90%; group III, 85%. The FNAC and SLNB micrometastasis detection rate was significantly higher in melanoma with Breslow thickness > 4 mm (group 3) in comparison to thin and intermediate thickness tumors. Conclusion: The method of ultrasound-guided fine needle aspiration of sentinel lymph nodes, according to its sensitivity, has a place in the diagnostics of micrometastasis in regional lymph nodes only in thick melanoma, but not in thin and intermediary thickness melanoma. The results must be confirmed in a larger number of patients. If this observation could be confirmed, it would rationalize treatment of patients with thick melanoma, decrease the number of operations and shorten the time to make the diagnosis.

Lymphoscintigraphy and sentinel lymph node biopsy, in cutaneous melanoma staging and treatment decisions.

OBJECTIVE: Sentinel lymph node biopsy (SLNB) is a widely accepted method in the management of clinically localized cutaneous melanomas. The aim of this study was to report the results on patients scheduled for preoperative lymphoscintigraphy and SLNB for staging and further treatment planning. SUBJECTS AND METHODS: Two hundred and one patients (115 male and 86 female, median age 57 years, range 9-81) with cutaneous melanoma having undergone SLB at Military Medical Academy between November 2010 and October 2014, were recruited for retrospective study. Dual labeling method (Tc-99m Nanocolloid (blue dye) was used. In order to delineate the relation between patients' tumors and scintigraphic characteristics with positive SLN findings, we examined all variables by univariate logistic regression with odd ratios representing the size effect. RESULTS: The overall identification rate of SLN was 98.5%. One or more positive SLN were seen in 47 (23.4%) of the patients. Drainage to one regional basin was noticed in 176 (88%) and multiple drainage regions, up to three, was noticed in 24 patients (12%). Transit lymph nodes were detected in 20 patients (10%). The characteristics that were assotiated significatly with sentinel lymph node metastases were Breslow thickness, nodular melanoma histological subtype and acral localization. CONCLUSION: Besides the well established primary tumor thickness being a predictor of SLN malignancy, we observed: acral body site location and nodular melanoma histological subtype to be significant independent factors in increasing the risk for regional metastases. Our results suport the clinical usefulness of SLNB within a multidisciplinary approach (dermatooncology, plastic/head and neck surgery, pathology, nuclear medicine), as a reliable method in staging and for treatment planning in melanoma patients.

Clinicopathological characteristics, diagnosis and treatment of melanoma in Serbia--the Melanoma Focus Study.

BACKGROUND/AIM: Treatment options for metastatic melanoma in Serbia are limited due to the lack of newly approved biologic agents and the lack of clinical studies. Also, there is a paucity of data regarding the treatment approaches in different tertiary centers and efficacy of available chemotherapy protocols. The aim of this study was to obtain more detailed data about treatment protocols in Serbia based on structured survey in tertiary oncology centers. METHODS: Data about the melanoma patients treated in 2011 were analyzed from hospital databases in 6 referent oncology centers in Serbia, based on the structured survey, with the focus on metastatic melanoma patients (unresectable stage IIIC and IV). RESULTS: A total of 986 (79-315 in different centers) patients were treated, with 320 (32.45%) newly diagnosed patients. There were 317 patients in stage IIIC/IV, 77/317 aged < 50 years. At the time of diagnosis 47.3% of patients were < 60 years of age (24.2% < 40 years, 23% 50-59 years, 52.6% > 60 years). At initial diagnosis 12.5% of patients were in stage III and 4.5% in stage IV. The most common type was superficial spreading melanoma (50-660), followed by nodular melanoma (23.5-50%). Apart from the regional and distant lymph node metastases, the most frequent organs involved in stage IV disease were distant skin and soft tissues (12-55%), lungs (19-55.5%), liver (10-60%), and bones (3-10%). The first line therapy in stage IV metastatic melanoma was dacarbazine (DTIC) dimethyl-triazenoimidozole-carboxamide in 61-93% of the patients, while the second line varied between the centers. Disease control (complete response + partial response + stable disease) was achieved in 25.7% of the patients treated with the first line chemotherapy and 23.1% of the patients treated with the second line therapy, but the duration of response was short, in first-line therapy 6.66 +/- 3.36 months (median 6.75 months). More than 90% of patients were treated outside the clinical trials. CONCLUSION: Based on this survey, there is a large unmet need for the new treatment options for metastatic melanoma in Serbia. The development of national guidelines, and greater involvement in international clinical studies could lead to widening of treatment options for this chemotherapy resistant disease.

Interferon alpha-induced reduction in the values of myeloid-derived suppressor cells in melanoma patients.

BACKGROUND/AIM: Interaction between tumor cells and host's immunoregulatory cells in creation of microenvironment that supports tumor progression is the focus of numerous investigations in recent years. Myeloid-derived suppressor cells (MIDSCs) are heterogeneous population of immature dendritic cells, macrophages and granulocytes. In cancer patients, these cells accumulate in tumor microenvironment, tumor-draining lymph nodes, peripheral blood and the liver and their numbers correlate with the stage of the disease and the metastatic disease. The aim of the study was to investigate the effect of interferon alpha on MDSCs percentage in peripheral blood of melanoma patients. METHODS: The interferon treated melanoma patients were given subcutaneously interferon alpha, in optimal dose, for a period of at least 6 months before the analysis. Blood samples were collected from the melanoma patients (n=91) and the age/sex matched healthy controls (n=8). The following anti-human monoclonal antibodies were used for immunostaining: anti-CD15-FITC, anti-CD33-PE, anti-CD45-ECD, anti-HLA-DR PE/Cy5, anti-CD14-FITC, anti-CD16-PE and anti-CD11b-PE. RESULTS: Comparison of myeloid- derived suppressor cells values in the stage 2 melanoma patients with and without interferon alpha therapy did not show a significant difference. When we compared the MDSCs values in the patients within stage 3 melanoma, we found a significant difference in granulocytic subset values between the interferon alpha-treated and the untreated group. Comparison of values of all suppressor cells populations between the interferon alpha-treated patients and healthy controls showed a significant increase in suppressor cells percentage in the melanoma patients. The granulocytic and total MDSCs values were significantly lower in the interferon alpha treated melanoma patients with progression in comparison with untreated patients with stable disease. CONCLUSION: We confirmed that interferon alpha effect in stage 3 melanoma patients was reduction in MDSCs percentage. We also found an unexpected bounce back of these suppressor cells levels, many months after the discontinuation of interferon alpha therapy.

Melanoma in South-East Europe: epidemiological data from the central cancer registry and clinicopathological characteristics from the hospital-based registry in Serbia.

BACKGROUND: Melanoma in South-East Europe shows varying incidence from 1.7 per 100,000 in Albania to 14.5 per 100,000 in Slovenia, but more detailed data from this region are scarce. In this study, we report epidemiological and clinicopathological characteristics of melanoma in central Serbia. MATERIALS AND METHODS: Epidemiological data were retrieved from the Cancer Registry of Central Serbia and clinicopathological data from the hospital-based registry. RESULTS: The ASR(W) incidence rate of melanoma was 4.2/100,000 (males) and 3.9/100,000 (females), and ASR(W) mortality rates were 1.9/100,000 (males) and 1.4/100,000 (females), with recorded rising trends in both of them. Data from the hospital-based registry revealed a total of 266 patients treated from 2005 to 2010, with the median age at diagnosis of 57 (13-86) years. The most frequent histopathological subtype was superficial spreading melanoma (SSM; 63.53%), and ulceration was present in 40.6% of primary tumors. Median Breslow thickness was 3 mm (0.1-25 mm). Primary tumors with thickness of more than 4 mm were found in 31.95% of patients, and in this group statistically significant difference was found for younger age in patients with SSM (55 years vs. 61 years, P = 0.04). CONCLUSION: Low incidence rates in central Serbia and probably other countries of South-East Europe are accompanied by a large percentage of thick tumors and a significant proportion of younger patients with thick tumors. This points to the urgent need for more effective primary and secondary prevention of melanoma in these countries.

Principles of surgical treatment of congenital, developmental and acquired female breast asymmetries.

BACKGROUND/AIM: There is a natural asymmetry in normal female brests. When the difference in the shape, size or position of the breast and nipple-areola complex is visible, surgical correction is the only treatment option and presents one of the greatest challenges for a plastic surgeon. Based on the Nahai classification presented in details, the aim of the study was to present the possibilities of plastic surgery to correct primary (congenital), secondary (developmental) and tertiary (acquired) brest asymmetries. METHODS: We conducted a retrospective analysis of female breast asymmetry surgeries performed in the Clinic for Plastic Surgery and Burns, Military Medical Academy (MMA), Belgrade over the last seven years (January 2002 - January 2009). RESULTS: During the above mentioned period, 82 female patients, 18 - 65 years of age, underwent surgery for breast asymmetry. The most frequent asymmetries were developmental, "pubertal" (n = 43); acquired asymmetries as a consequence of tumor surgery were found in the other 22 patients, while 7 patients were diagnosed with primary asymmetries such as congenital chest-wall asymmetry (Sy. Poland), accessory and tuberous breasts. All patients underwent preoperative ultrasound examination, while hormone status was determined in those with developmental, "pubertal" asymmetries. The selection of surgical procedure for correction of breast asymmetry depended upon clinical examination findings and patient's wish relating to the shape and size of the breasts. The most of breast asymmetries were corrected by a combination of surgical procedures including primary and secondary reconstruction, reduction, suspension or augmentation mammoplasty. Having combined different surgical procedures, we managed to achive satisfactory results. The hypertrophic scar formation after reduction mamoplasty was seen in some cases, however, they caused no significant patient's discomfort. CONCLUSION: Application of plastic, reconstructive and aesthetic surgical principles can considerably contribute to achieving excellent results in corrective surgery for breast asymmetries. In addition to most suitable breast asymmetry surgical procedures choice, motivation of a patient is also very important for achieving satisfactory results.

Denonvilliers' advancement flap in congenital alar rim defects correction.

BACKGROUND: Alar rim defects are mostly acquired, resulting from burns, traumas or tumor excision. Sometimes they can accompany craniofacial clefts. However, isolated congenital alar defects are extremely rare. CASE REPORT: We presented two cases of congenital isolated alar cleft. The defect was closed by the use of an advancement flap, the technique described by Denonvilliers. We achieved both symmetry and appropriate thickness of the nostrils. Skin color and texture of the alar rim were excellent, with scars not excessively visible. CONCLUSION: Denonvilliers' z-plasty technique by using advancement flap provides both functionally and aesthetically satisfying outcome in patients with congenital alar rim defects.