Localized Melanoma Research Articles

A melanoma odyssey - a conversation with Vernon Sondak about a career in melanoma treatment and research.

VERNON SONDAK* SPEAKS TO LAURA MCGUINNESS, MANAGING COMMISSIONING EDITOR: Vernon Sondak is Chair of the Department of Cutaneous Oncology and Director of Surgical Education at the H Lee Moffitt Cancer Center and Research Institute in Tampa, FL, USA. He is also a Professor in the Departments of Oncologic Sciences and Surgery at the University of South Florida Morsani College of Medicine. His research interests include the surgical treatment of malignant melanoma in adults and children; the surgical treatment of Merkel cell carcinoma, desmoid tumors and cutaneous soft-tissue sarcomas, including dermatofibrosarcoma protuberans; the adjuvant therapy of melanoma; and the evaluation of new therapies for patients with localized or disseminated melanoma. Sondak has also been a leader in studies of the surgical treatment of melanoma and other cutaneous malignancies, particularly in the application of sentinel lymph node biopsy to the staging of melanoma and Merkel cell carcinoma. He is actively involved in ongoing analyses in order to determine which patients with thin melanomas are most likely to benefit from sentinel node biopsy, as well as which patients with sentinel node metastases are most likely to have further metastases identified in other regional lymph nodes. Sondak is the author or coauthor of over 300 articles in peer-reviewed publications, 165 abstracts, eight books and 67 book chapters.

Salvage Proton Beam Therapy in Local Recurrent Uveal Melanoma

To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy. Retrospective, interventional case series. We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates. The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment. Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis.

BIOPSIA DE GÂNGLIO SENTINELA EM PORTUGAL – EXPERIÊNCIA DE UM CENTRO DE REFERÊNCIA

Introdução: A biopsia de gânglio sentinela é o método de escolha actual para o correcto estadiamento de doentes com melanoma cutâneo localizado. As guidelines do National Comprehensive Cancer Network (NCCN) reforçam o papel do status do gânglio sentinela como o factor de prognóstico mais importante na sobrevivência.Objectivos: Investigamos factores preditivos de gânglio sentinela positivo e factores que influenciam a sobrevivência na nossa população.Material e métodos: Realizámos um estudo retrospectivo de 221 doentes que foram submetidos a biopsia de gânglio sentinela durante o período entre 2004 e 2010 na Unidade de Cirurgia Dermatológica do Centro Hospitalar e Universitário de Coimbra. Foram aplicados métodos de análise estatística univariada e multivariada.Resultados: Os doentes do sexo feminino representavam 61% da população estudada e a idade média era de 59,3 anos. A maioria das lesões localizava-se nos membros inferiores (43%), sobretudo no pé (21,3% de todas as lesões). A biopsia de gânglio sentinela foi positiva em 48 casos (21,7%). A análise univariada determinou os seguintes factores preditivos de biopsia de gânglio sentinela positiva: sexo masculino, espessura de Breslow, tipo histológico e presença de infiltrado linfocítico. A análise multivariada confirmou o valor preditivo da espessura de Breslow e do infiltrado linfocítico. A taxa de sobrevivência aos 5 anos correspondia ao valor de 53,1% no grupo biopsia de gânglio sentinela positiva e 88,2% no grupo biopsia de gânglio sentinela negativa. A espessura de Breslow e o status do gânglio sentinela são factores independentes do prognóstico destes doentes.Conclusões: Os factores de risco para biopsia de gânglio sentinela positiva são consistentes com os dados da literatura. O status do gânglio sentinela permanece o principal determinante da sobrevivência, facto que reforça a relevância da biopsia de gânglio sentinela no estadiamento de doentes com esta neoplasia cutânea.

Discordance in histopathologic evaluation of melanoma sentinel lymph node biopsy with clinical follow-up: results from a prospectively collected database.

Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. After internal review of the SLN material, 13 (8%) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.

Conditional survival in melanoma and thyroid cancer patients.

6599 Background: Melanoma and thyroid cancer are two increasingly common malignancies. Although likelihood of survival from both cancers can vary by disease severity, it isn't known how patients' life expectancy changes the further they are from time of diagnosis. Methods: Using Surveillance, Epidemiology, End Results (SEER) data we selected patients diagnosed with melanoma (N=95,041) or well-differentiated thyroid cancer (N=43,392) between 1998 - 2005. Patients were followed for up to 12 years. Cox regression provided estimates of disease-specific survival by SEER stage and age, which we then transformed to estimate conditional five year survival. Results: Patients with localized melanoma and thyroid cancer have an excellent five year survival at time of diagnosis and for subsequent years. For both regional melanoma and thyroid cancer there is an age gradient with improved conditional survival in melanoma patients over time. For distant melanoma, the initial five year survival is poor but improves rapidl...

Predicting Survival Time of Localized Melanoma Patients Using Discrete Survival Time Method

Melanoma is the most fatal type of skin cancer. It is ranked first in death of skin cancer diseases. This study establishes a statistical model that can predict the survival time of localized melanoma patients, as a function of age at diagnosis, tumor thickness, and extension of the tumor (tumor invasion). The discrete time survival method was used to build the statistical model. The patients involved in the current study were observed from the SEER database. Patients were divided into nine groups according to age at diagnosis. Variation in survival time was found to be significant among some of the age groups.

Sentinel lymph node biopsy in melanoma: final results of MSLT-I.

In 1994 an international randomized controlled clinical trial, MSLT-I, opened to study the utility of sentinel lymph node biopsy (SLNB) for patients with clinically localized melanoma. This trial compared outcomes of patients treated with wide local excision (WLE) and SLNB (followed by immediate completion lymph node dissection [CLND] for those with a positive sentinel node [SN]) with outcomes of patients treated with WLE alone and CLND upon the development of clinically apparent disease. In February 2014 the final analysis of long-term outcomes data was published. Importantly, these data showed that the rates of nodal positivity were the same between the two arms of the trial. Although no difference in 10-year melanoma-specific survival was noted between the two arms, this was not entirely surprising as the overall rate of nodal disease within the trial was 20.8%, meaning that 79.2% of patients could not derive a benefit from SLNB. Subset analysis was performed to determine the impact of early intervention for those patients most likely to have a benefit from early detection. This analysis showed that for patients with nodal disease and intermediate-thickness melanoma (defined as 1.2-3.5-mm Breslow depth), early treatment following positive SLNB was associated with improved 10-year distant disease-free survival and improved 10-year melanoma-specific survival.

Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans.

Endocannabinoids may modify cancer development, progression and associated pain. We determined whether cancer-evoked dysregulations in this system become manifest in altered tissue and plasma endocannabinoids. Endocannabinoid changes due to cancer were explored in a local and metastatic syngeneic mouse melanoma model. Endocannabinoid stratification in human cancer was cross-sectionally assessed in the plasma of 304 patients (147 men, 157 women, aged 32 - 87 years) suffering from several types of cancer at Roman Numeral Staging between I and IVc, mostly IV (n = 220), and compared with endocannabinoids of healthy controls. In mice with local tumor growth, ethanolamide endocannabinoids, i.e., anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were downregulated, whereas 2-arachidonoylglycerol (2-AG) was increased. Upon spreading of the cancer cells particularly 2-AG steadily increased in parallel to disease progression while OEA modulated cell migration. Results translated into humans, in whom cancer was associated with a decreased AEA, increased 2-AG and increased OEA correlating with the number of metastases. The endocannabinoid system was subject to cancer-associated regulations to an extent that led to measurable changes in circulating endocannabinoid levels, emphasizing the importance of the endocannabinoid system in the pathophysiology of cancer.

Melanoma: MSLT-1--putting sentinel lymph node biopsy into context.

The MSLT-1 study compared sentinel lymph node biopsy (SLNB) with nodal observation in patients with localized cutaneous melanoma. The final results of the trial—conducted from 1994 to 2002—strongly support using SLNB in staging patients with melanomas ≥1.0 mm in thickness, but the optimal staging approach for thinner melanomas is unanswered.

The association of host and genetic melanoma risk factors with Breslow thickness in the Western Australian Melanoma Health Study

Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness; however, the role of genetic loci has been little investigated to date. To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. Participants were 800 individuals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA sample. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding.

Perioperative nursing of local choroid melanoma excision combined with vitreous retinal surgery

Objective To study the perioperative nursing of local choroid melanoma excision combined with vitreous retinal surgery. Methods Analyzed 45 cases of choroid melanoma patients were partial resection combined with vitreous retinal surgery perioperative nursing experience. Results Among 45 patients, 1 case complicated with intraocular hemorrhage was improved after drug treatment, 1 case received ophthalmectomy for pathology report with the eye infiltration, and the postoperative intraocular pressure of other patients was stable without complications. The whole body transfer was not found during the follow - up period among patients. Conclusions Reasonable preoperative and postoperative nursing, and strengthen the observation of the postoperative complications, and discharge guidance are important factors for ensuring success. Key words: Choroid; Melanoma; Perioperative nursing

Predicting the development of brain metastases in patients with local/regional melanoma.

The brain is a common site of recurrence in melanoma patients. Brain recurrence may present as a seizure, hemorrhage, or death. We sought to determine predictors of brain metastases in patients with primary and regional melanoma in order to facilitate targeted screening. Prospectively maintained databases were used to identify patients treated for local or regional melanoma who developed stage IV melanoma with and without brain metastasis at initial recurrence. One hundred twenty patients were identified with brain relapse and compared to 487 patients without brain recurrence. On univariate analysis, patients with brain metastases were younger (55 vs. 59yrs, P = 0.04) but did not differ in primary site (head and neck 23% vs. 21%, P = 0.20). Brain metastasis patients had thinner primaries (mean 3.4 vs. 4.5 mm, P = 0.01). There were no other pathologic differences including ulceration (55% vs. 53%, P = 0.75), mitoses (7 vs.7.5, P = 0.61) or histologic subtype. Younger age and decreased Breslow thickness were independently associated with brain metastases at stage IV recurrence (OR = 1.10 P = 0.01 and OR = 1.02 P = 0.02, respectively). Our analysis, the largest to date, demonstrates that thinner Breslow depth and younger age were associated with brain recurrence at first presentation with Stage IV disease.

Sentinel Lymph Node Biopsy in Melanoma: Controversies and Current Guidelines

Melanoma is a global health problem and the incidence of this disease is rising. While localized melanoma has an excellent prognosis, regional and distant disease is associated with much poorer outcomes. Optimal treatment for clinically localized melanoma requires surgical control of the primary site and accurate staging of the regional nodal basin with sentinel lymph node biopsy (SLNB). While further data are required to determine if SLNB is associated with a survival advantage, currently available data supports the use of SLNB for staging of appropriate patients and the procedure may offer benefits beyond staging. This article reviews current data that shapes guidelines regarding patient selection for SLNB in melanoma and highlights areas where performing this procedure remains controversial.

Prognostic value of BRAF mutations in localized cutaneous melanoma

BRAF mutations are frequent in melanoma but their prognostic significance remains unclear. We sought to further evaluate the prognostic value of BRAF mutations in localized cutaneous melanoma. We undertook an observational retrospective study of 147 patients with localized invasive (stages I and II) cutaneous melanomas to determine the prognostic value of BRAF mutation status. After a median follow-up of 48 months, patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after adjustment for Breslow thickness, tumor ulceration, location, age, sex, and tumor mitotic rate. The retrospective design and the small number of events are limitations. Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring tumors with BRAF mutation might be warranted.

Recurrent acral lentiginous melanoma in situ suggesting the field cell theory.

Dear Editor: Acral lentiginous melanoma (ALM) is the most common type of cutaneous melanoma in Asians. Traditionally, ALM is believed to have a poor prognosis because of its aggressive behavior and a short radial growth phase, compared with that of lentigo maligna melanoma1. We describe a case of recurrent ALM in situ around the primary site during 8 years. A 56-year-old female patient presented with a black macule having an irregular border and color variegation on the left heel, which started 8 years ago (Fig. 1A). Dermoscopic examination showed a parallel ridge pattern and irregular pigmentation. She had undergone excisional biopsy (3-mm margin), which revealed only a few scattered melanocytes along the basal layer. She had returned after 2 years (Fig. 1B) and then after 4 years (Fig. 1C) because of newly appearing brown patches around the first location. Serial punch biopsies revealed mild melanocytic hyperplasia without marked cytologic atypia again. The results made a pathologist hesitant to diagnose ALM in situ instead of atypical melanocytic At that time, the patient didn't want additional surgery; we recommended regular follow-up considering the possibility of melanocytic proliferation. Most recently, she presented with further enlarged, multiple pigmented patches (Fig. 1D). She was treated with wide excision (1-cm margin) and split-thickness skin graft under the consideration of malignant melanoma. Bland lentiginous proliferation of melanocytes confined to the epidermis prompted the final diagnosis of ALM in situ (Fig. 1E). Immunohistochemically, melanocytes were stained positively for Melan-A, HMB-45, and anti-S-100 (Fig. 1F). Fig. 1 Acral lentiginous melanoma in situ. Clinical and histopathological feature. (A) Initial presentation 8 years ago. (B) Second presentation 6 years ago. (C) Third presentation 4 years ago. (D) Last presentation. Left, gross picture of the lesion; center, ... ALM was believed to have an aggressive biological behavior. However, in Asians, the specific population was reported inconsistent with the classical concept. After Nogita et al.2 described melanosis of the foot, acral melanocytic lesions have been described with histopathologically subtle melanocytic proliferation, despite clinically malignant melanoma3. These lesions did not show invasive behavior over a decade; though some of them reappeared around the primary site even after the surgical excision. There has been debate about the nature of these lesions; however, they are now considered as the precursor of ALM that fulfills both the clinical and dermoscopic criteria4. The most notable feature of our case was the recurrent melanocytic lesions appearing around the primary site in the absence of invasion during 8 years. Takata et al.5 suggested that acral and mucosal melanomas could originate from field melanocytes detected in normallooking skin extending over the obvious lesion. These field cells harbor mutations of the KIT gene and amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Although our case initially showed only bland melanocytic proliferation without marked atypia or invasion, local melanoma could reappear from the residual field cells. Therefore, we recommend that the clinician should consider these lesions as ALM in situ and treat with early complete excision. Also, it is better to perform an excisional biopsy for a review of the entire lesion in the suspicious acral melanocytic lesions. Finally, regular follow-up for several years is important for the detection of reappearing melanoma around the primary site, even after the surgical excision.

Evaluating biomarkers in melanoma.

The incidence of cutaneous melanoma has more than doubled over the last decades making it one of the fastest rising cancers worldwide. Improved awareness and early detection of malignant moles now permit earlier diagnosis aiming to decrease the likelihood of recurrence. However, it is difficult to identify those patients initially diagnosed with localized melanoma who subsequently develop metastatic disease. For this group, prognosis remains poor and clinical outcomes are variable and challenging to predict. Considerable efforts have focused on the search for novel prognostic tools, with numerous markers evaluated in the circulation and in tumor lesions. The most reliable predictors of patient outcome are the clinical and histological features of the primary tumor such as Breslow thickness, ulceration status, and mitotic rate. Elevated serum levels of the enzyme lactate dehydrogenase, likely to indicate active metastatic disease, are also routinely used to monitor patients. The emergence of novel immune and checkpoint antibody treatments for melanoma and increasing appreciation of key roles of the immune system in promoting or halting cancer progression have focused attention to immunological biomarkers. Validation of the most promising of these may have clinical applications in assisting prognosis, assessing endpoints in therapy, and monitoring responses during treatment.

Utility of diffusion-weighted imaging in the diagnosis of inguinal lymph node metastasis with malignant melanoma

Malignant melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin. Nodal metastases are an adverse prognostic factor compromising long term patient survival. Therefore, accurate detection of regional nodal metastases is required for optimization of treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) remain the primary imaging modalities for regional staging of malignant melanoma. However, both modalities rely on size-related and morphological criteria to differentiate between benign and malignant lymph nodes, decreasing the sensitivity for detection of small metastases. Surgery is the primary mode of therapy for localized cutaneous melanoma. Patients should be followed up for metastases after surgical removal. We report here a case of inguinal lymph node enlargement with a genital vesicular lesion with a history of surgery for malignant melanoma on her thigh two years ago. CT and diffusion weighted-MRI (DW-MRI) were applied for the lymph node identification. DW-MRI revealed malignant lymph nodes due to malignant melanoma metastases correlation with pathological findings.

Are we seeing the effects of public awareness campaigns? A 10-year analysis of Breslow thickness at presentation of malignant melanoma in the South West of England

The last 20 years has seen a marked improvement in skin cancer awareness campaigns. We sought to establish whether this has affected the presenting Breslow thickness of malignant melanoma in the South West. This is a retrospective study looking at the first presentation of melanomas from 2003 to 2011. Data was accessed using the local online melanoma database. A total of 2001 new melanomas presented from 2003 to 2012 (Male:Female = 1:1.062). The average yearly number of melanomas was 200.1 (range = 138-312). The mean age was 62.5 years (range 12-99). Data was analysed using a Chi² test. For 0-1 mm melanomas, there is a significant difference in the observed versus expected values over the 10 years (p = 0.0018). There is an increasing proportion of 0-1 mm (thin) melanomas presenting year on year, with a positive linear trend. This is very statistically significant (p < 0.0001). The 1-2 mm melanomas are decreasing in proportion with a negative linear trend (p = 0.0013). The 2-4 mm are also decreasing in proportion (p = 0.0253). There is no significant change in the thick >4 mm melanomas (p = 0.1456). The proportion of thin 0-1 mm melanomas presenting in South West England has significantly increased from 2003 to 2012. There is no significant change in the thick >4 mm melanomas. This may be a result of increased public awareness due to effective public health campaigns which has significant prognostic and financial implications.

Metabolomics and transcriptomics demonstrate severe oxidative stress in both localized chemotherapy-treated and bystander tumors

BackgroundLocalized radiotherapy is long known to cause damages to not only targeted but also non-targeted cells, the so-called bystander (BS) effect. Recently, BS effect was demonstrated in response to chemotherapy. To get further insight into the mechanism of chemotherapy-induced BS effect in vivo, we investigated the response of normal tissues and untreated BS melanomas, at distance from localized chemotherapy-treated melanomas. MethodsB16 melanoma cells were inoculated sc in one flank, in mice. Chemotherapy was administered intratumorally. After 3weeks, untreated melanomas were implanted into the other flank. Tumors were analyzed morphologically, and using metabolomics and transcriptomics. ResultsLocally-treated melanomas showed growth inhibition and pleiotropic metabolic and transcriptional alterations. Tumors recovered slow proliferation while exhibiting prominent oxidative stress response (decreased glutathione level, and increased expression of genes including Mt1, Gpx3, Sod3, and Hmox1). Plasma contained increased levels of oxidative stress products. However, liver and soleus muscle displayed unaltered morphological characteristics. In contrast, untreated BS melanomas induced from naive B16 cells showed reduced growth, marked oxidative stress response (decreased glutathione level, and increased expression of genes including Sod2, Gpx1 and Gsr), and ras oncogene expression alterations. Furthermore, metabolomics and transcriptomics enabled to estimate the proportion of cells undergoing the BS effect within treated tumors. ConclusionTreatment of tumors with chemotherapy induces BS effects, underpinned by oxidative stress, in abnormal proliferating tissues in vivo, not in normal tissue, that significantly contribute to overall tumor response. General significance BS effect significantly contributes to response to chemotherapy, and may be exploited to improve overall response to cancer treatment.

Can cancer registries show whether treatment is contributing to survival increases for melanoma of the skin at a population level?

It is uncertain whether survival increases from melanoma recorded by some population registries include a treatment effect. The US Surveillance, Epidemiology and End Results (SEER) programme has good data quality control, large numbers of cases enabling high statistical precision and summary stage plus thickness, which we consider to be a best-case population registry scenario to investigate potential for a treatment effect. We have investigated SEER data to indicate whether survivals increases are fully attributable to earlier diagnosis and other non-treatment factors. Through relative survival regression, the effects of diagnostic period on 5-year excess mortality were investigated, adjusting for socio-demographic factors, lesion sub-site, histology, thickness and stage at diagnosis in 1990-2009 (n = 99 690 cases). The reduction in excess mortality (95% confidence interval) between 1990-1999 and 2000-2009 was 31 (20-41)% for localised melanoma, 18 (12-22)% for regional melanoma and 3 (-5-10)% for melanomas with distant spread. Younger age was predictive of a greater percentage reduction. Treatment benefits are inferred from the higher survivals in 2000-2009 but uncertainty remains due to incomplete data to adjust for non-treatment factors and a lack of treatment data. Registries should use new information systems to collect more complete data on stage, other prognostic indicators, co-morbidities and treatment, to provide more definitive and detailed information on population effects of cancer control.